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Interventions for improving the adoption of shared decision making by healthcare professionals. Shared decision making (SDM) can reduce overuse of options not associated with benefits for all and respects patient rights, but has not yet been widely adopted in practice. To determine the effectiveness of interventions to improve healthcare professionals' adoption of SDM. For this update we searched for primary studies in The Cochrane Library, MEDLINE, EMBASE, CINAHL, the Cochrane Effective Practice and Organisation of Care (EPOC) Specialsied Register and PsycINFO for the period March 2009 to August 2012. We searched the Clinical Trials.gov registry and the proceedings of the International Shared Decision Making Conference. We scanned the bibliographies of relevant papers and studies. We contacted experts in the field to identify papers published after August 2012. Randomised and non-randomised controlled trials, controlled before-and-after studies and interrupted time series studies evaluating interventions to improve healthcare professionals' adoption of SDM where the primary outcomes were evaluated using observer-based outcome measures (OBOM) or patient-reported outcome measures (PROM). The three overall categories of intervention were: interventions targeting patients, interventions targeting healthcare professionals, and interventions targeting both. Studies in each category were compared to studies in the same category, to studies in the other two categories, and to usual care, resulting in nine comparison groups. Statistical analysis considered categorical and continuous primary outcomes separately. We calculated the median of the standardized mean difference (SMD), or risk difference, and range of effect across studies and categories of intervention. We assessed risk of bias. Thirty-nine studies were included, 38 randomised and one non-randomised controlled trial. Categorical measures did not show any effect for any of the interventions. In OBOM studies, interventions targeting both patients and healthcare professionals had a positive effect compared to usual care (SMD of 2.83) and compared to interventions targeting patients alone (SMD of 1.42). Studies comparing interventions targeting patients with other interventions targeting patients had a positive effect, as did studies comparing interventions targeting healthcare professionals with usual care (SDM of 1.13 and 1.08 respectively). In PROM studies, only three comparisons showed any effect, patient compared to usual care (SMD of 0.21), patient compared to another patient (SDM of 0.29) and healthcare professional compared to another healthcare professional (SDM of 0.20). For all comparisons, interpretation of the results needs to consider the small number of studies, the heterogeneity, and some methodological issues. Overall quality of the evidence for the outcomes, assessed with the GRADE tool, ranged from low to very low. It is uncertain whether interventions to improve adoption of SDM are effective given the low quality of the evidence. However, any intervention that actively targets patients, healthcare professionals, or both, is better than none. Also, interventions targeting patients and healthcare professionals together show more promise than those targeting only one or the other.

Current techniques and protocols in the surgical management of scaphocephaly in young infants. Many techniques and protocols are currently used in the treatment of scaphocephaly worldwide, including total calvarial remodeling and minimally invasive strip craniectomies. This study reviews current techniques and protocols used in young infants (aged ≤ 6 months) as well as the outcomes in terms of reoperation rates. A short questionnaire was designed including questions about the preferred surgical techniques, transfusion protocols, and reoperation rates. Surgeons from the International Society of Craniofacial Surgery and the International Society for Pediatric Neurosurgery were requested to respond to this questionnaire online or by e-mail. Responses during a 2-week period were collated and analyzed using Fisher exact test. A total of 91 surgeons responded from the craniofacial centers around the world, of which 93.4% completed the questionnaire. Most respondents were from North America and Europe (35% and 20%, respectively). The operative volume was less than 15 cases per year in 56%, and the bicoronal skin incision was most commonly used (81%). Postoperative drainage was not performed by 55% but was statistically more common with use of the bicoronal incision (P = 0.029). Of the respondents, 66% used calvarial remodeling, and 34% strip craniectomy. Blood was most commonly transfused at a hemoglobin level under 8 g/dL (31%), with a mean transfusion rate of 66%. Of the respondents, 44% transfused in more than 90% of the cases, whereas only 18% transfused in 20% or less of the cases. The mean reoperation rate for secondary fusion was 1.7%, and 41% of the respondents claimed a 0% reoperation rate. A statistically higher frequency of reoperation was reported by centers with a case load of more than 15 cases per year (P = 0.035), and no statistical correlation was found with the type of surgical technique. Our survey of neurosurgeons and craniofacial plastic surgeons worldwide shows that for young infants treated for scaphocephaly, the bicoronal incision is most commonly used and a greater number of surgeons do not use drains. A great variability in the transfusion protocols used in the care of these patients as well as a low reoperation rate were also found. The latter however may suggest a lack of strict monitoring in most centers. Overall, this study presents a snapshot of the current surgical treatment of this subset of patients and should serve as a basis for quality improvement and outcome monitoring in their surgical management.

Phase I study of docetaxel and topotecan in patients with solid tumors. Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 micrograms was administered subcutaneously (s.c.) on days 5-14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9-18 weeks). Administration of TOPO on days 1-4 and DOC on day 4 resulted in increased neutropenia. DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 micrograms s.c. on days 5-14. The alternative schedule with DOC given on day 4 and TOPO on days 1-4 is not recommended.

Myeloid and lymphoid chimerism after T-cell-depleted bone marrow transplantation: evaluation of conditioning regimens using the polymerase chain reaction to amplify human minisatellite regions of genomic DNA. Determining both myeloid and lymphoid chimerism after T-cell-depleted allogeneic bone marrow transplantation (BMT) could be helpful in the understanding of the biology of engraftment and could provide a rational method of assessing the ability of different conditioning regimens to promote engraftment. We prospectively investigated the role of different pretransplant conditioning regimens in 29 leukemic patients post-BMT by assessing myeloid and T-cell chimerism using a rapid and sensitive polymerase chain reaction (PCR) method. Minisatellites are hypervariable regions of DNA consisting of tandem repeats of a core nucleotide sequence, and allelic polymorphism results from differences in the number of the repeats. We used this variation to distinguish between donor and recipient cells post-BMT. Seventeen patients (9 sibling and 8 unrelated donors) received conditioning with hyperfractionated total body irradiation (TBI), thiotepa, and cyclophosphamide (Cy). Of the other 12 patients (all sibling donors), 11 received TBI plus Cy plus another agent: VP16, carboplatinum, or AZQ. One patient received TBI plus thiotepa plus VP16. All but one of the patients studied received marrow from HLA-identical donors. PCR analysis confirmed donor lymphoid engraftment within 8 days of transplant in six of six patients studied. All granulocyte DNA was of donor origin within the first 4 weeks of transplant, regardless of the conditioning regimen. The day +28 T cells were exclusively of donor origin in 14 of 17 patients who received TBI plus thiotepa plus Cy, but were mixed chimeric in 10 of 12 patients who received other conditioning regimens (P < .001). Early graft rejection was seen in one unrelated transplant recipient conditioned with TBI plus thiotepa plus Cy. Late graft failure was observed in 3 of 12 patients with mixed T-cell chimerism and in none of 16 patients with full donor chimerism at day +28. However, 5 of 16 patients who had complete T-cell chimerism at day +28 developed acute graft-versus-host disease (GVHD), whereas no patient with mixed chimerism had acute GVHD. Our results indicate that minisatellite PCR is a rapid and sensitive method for assessing chimerism post-BMT, that the donor T cells are important for consistent durable engraftment, and that TBI plus thiotepa plus Cy may be superior to the other regimens studied in inducing full donor chimerism. Larger numbers and longer follow-up are necessary to confirm these data and also to assess the relationship between complete donor T-cell chimerism and leukemia-free survival.

Does the cost of care differ for patients with fee-for-service vs. capitation of payment? A case-control study in gastroenterology. There is growing evidence to demonstrate overuse of medical resources in fee for service (FFS) payment models (in which physicians are reimbursed according to volume of care provided) compared to capitation payment models (in which physicians receive a fixed salary regardless of level of care provided). In this medical centre, patients with and without insurance are admitted through the same access point (emergency room) and cared for by the same physicians. Therefore, apart from insurance status, all other variables influencing delivery of care are similar for both patient groups. However, physician reimbursement differs for both groups: FFS for patients with private insurance (i.e. the admitting physician's reimbursement escalates progressively with each day that the patient spends in hospital) and base salary irrespective of care provided for patients with universal insurance (capitation payment model). All admitting physicians are aware of the patient's insurance status and the duration of hospitalization is at the discretion of the admitting physician. This study aimed to compare cost of care of patients with and without insurance admitted to a teaching hospital with a primary gastroenterology or hepatology (GIH) diagnosis. All hospital inpatients admitted between January 2008 and December 2009 with a primary GI-related diagnosis related group (DRG) were identified. Patients were classified as uninsured (state-funded) or privately insured. Only DRGs with at least five patients in both the insured and uninsured patient groups were analyzed to ensure a precise estimate of inpatient costs. Patient level costing (PLC) was used to express the total cost of hospital care for each patient; PLC comprised a weighted daily bed cost plus cost of all medical services provided (e.g. radiology, pathology tests) calculated according to an activity-based costing approach, cost of medications were excluded. An overall mean cost of care per patient was calculated for both groups. All costs were discounted to 2009 values. In total, 630 patients were admitted with one of 11 GIH DRGs, 181 (29 %) with private insurance. Pooled mean cost of care was higher for uninsured (6,781 euros/patient) compared to insured patients (6,128 euros/patient). Apart from patients with 'non-cirrhotic non-alcoholic liver disease (non-complex)' in whom mean cost was higher for insured patients, there were no significant differences in mean cost of care nor mean patient age for insured and uninsured groups for any other diagnoses. Inpatient hospital costs were equivalent for patients with and without private health insurance when care was provided in a single hospital. Provision of care for all patients in a common hospital setting regardless of health insurance status may reduce disparities in healthcare utilization.

Interventions for preventing ankle ligament injuries. Some sports, for example basketball and soccer, have a very high incidence of ankle injuries, mainly sprains. This contributes to ankle sprains being one of the most commonly treated injuries. To assess the effects of interventions used for the prevention of ankle ligament injuries or sprains in physically active individuals from adolescence to middle age. We searched the Cochrane Musculoskeletal Injuries Group trials register, MEDLINE (1966 to July 1996), EMBASE (1980 to September 1996), CINAHL (1982 to June 1996), and bibliographies of study reports. We also contacted colleagues and some trialists. Date of the most recent search: March 1997. Randomised or quasi-randomised trials of interventions for the prevention of ankle sprains in physically active individuals from adolescence to middle age were included provided ankle sprains were recorded. Interventions include use of modified footwear and associated supports, adapted training programmes and health education. At least four reviewers independently assessed methodological quality and extracted data. Wherever possible, results of outcome measures were pooled and sub-grouped by history of previous sprain. Five randomised trials with data for 3954 participants were included. All trials involved young, active, mostly male adults participating in high-risk, usually sporting, activities. With the exception of ankle disc training, all prophylactic interventions entailed the application of an external ankle support in the form of a semi-rigid orthosis, air-cast brace or high top shoes. There was a significant reduction in the number of ankle sprains in people allocated external ankle support (Peto odds ratio 0.49; 95% confidence interval 0.37 to 0.66). This reduction was greater for those with a previous history of ankle sprain, but still possible for those without prior sprain. There was no apparent difference in the degree of severity of the ankle sprain prevented nor any change to the incidence of other leg injuries. The protective effect of 'high-top' shoes remains to be established. There was limited evidence for reduction in ankle sprain for those with previous ankle sprains who did ankle disc training exercises. This review provides good evidence for the beneficial effect of ankle supports in the form of semi-rigid orthoses or air-cast braces to prevent ankle sprain during high-risk sporting activities (e.g. soccer, basketball). Participants with a history of previous sprain can be advised that wearing such supports may reduce the risk of incurring a future sprain. However, any potential prophylactic effect should be balanced against the baseline risk of the activity, the supply and cost of the particular device, and for some, the possible or perceived loss of performance. Further research is indicated principally to investigate other prophylactic interventions and general applicability.

[Hyperdynamic hemodynamics following high-dose interleukin 2-interferon alpha therapy in patients with metastatic renal cell carcinoma. Immunotherapy as a clinical sepsis model?]. Human recombinant interleukin 2 (IL-2), alone or in combination with other cytokines, is currently under investigation for the immunotherapy of metastatic tumours. Objective responses of 20-35% have been reported in patients with disseminated melanoma and renal cell carcinoma who received high-dose intravenous IL-2 in combination with interferon-alpha (IFN alpha). However, treatment with IL-2 is complicated by a syndrome of life-threatening adverse reactions such as disseminated vascular leakage, fluid retention, severe hypotension, and (reversible) multiple organ dysfunction (MODS). A systemic inflammatory reaction (SIRS/sepsis sepsis-like haemodynamic pattern has been described in patients after IL-2 bolus application alone. Our purpose was to study the haemodynamic changes in patients treated with high-dose IL-2 administered as a constant infusion and in combination with IFN alpha. Haemodynamic variables were obtained during therapy courses of 11 patients (aged 48 to 71 years, median 61) with metastatic renal cell carcinoma receiving immunotherapy with IL-2/IFN alpha. Therapy consisted in IFN alpha 10 x 10(10) IU/m2 body surface area (BSA) once daily on days 1-5 i.m. on a regular ward, followed by IL-2 as a constant infusion of 18 x 10(6) IU/m2 BSA on days 6-11 in an intensive care unit (ICU). Haemodynamics were first measured after 5 days of IFN alpha application and transfer to the ICU on day 6, a further 24 h after the beginning of IL-2 infusion (day 7), and the end of the therapy course (days 10 and 11). Mean arterial pressure (MAP) was measured noninvasively using an oscillometric device (Dinamap, Critikon). Mixed-venous oxygen saturation (sv O2) was measured using an CO-oxymeter (OSM 3, Radiometer) and peripheral arterial oxygen saturation (psaO2) was recorded continuously with a pulse oximeter (Oxyshuttle, Critikon). In case of haemodynamic instability, stabilisation had priority over invasive haemodynamic measurements, so that nadir values of blood pressure (BP) did not influence mean MAP and are reported separately. Lactate values and criteria for SIRS were obtained before and during IL-2 infusion. Lactate measurements were performed using an enzymatic essay (Abbot FLx). The mean effect size of the haemodynamic values, SIRS criteria, and lactate concentrations during IL-2 infusion (days 6-11) were calculated, and 95% confidence intervals for the effect sizes are indicated. After their daily i.m. injections of IFN alpha, patients had short episodes of fever and tachycardia without significant drops in BP. A few hours after transfer to the ICU and continuous infusion of IL-2, they developed a syndrome of fever, tachycardia and tachypnoea. The haemodynamic values after 5 days of IFN alpha therapy remained in the normal range, whereas those during IL-2 infusion strongly resembled SIRS and sepsis, with a decrease in MAP (98 to 28 mm Hg) and systemic vascular resistance (SVR, 1477 to 805 dyn.s.cm-5) and an increase in cardiac output (cardiac index 2.8 to 4.3 l.min-1.m-2). MAP often had to be stablilized with colloids during the last 48 h of therapy; 5 patients had nadir values below 60 mm Hg, or 30% below basic values in hypertensive patients. Catecholamine therapy became mandatory in 1 patient and therapy had to be discontinued. Surprisingly, some patients already had elevated plasma lactate concentrations after IFN alpha therapy. During IL-2 infusion mean plasma lactate levels increased from 2.3 to 3.2 mmol.l-1 and all patients had lactate concentrations above 2.0 mmol.l-1 at the end of therapy. During the last 48 to 72 h of IL-2 infusion, patients suffered from MODS with altered mental state (7 patients), oliogoanuria (all patients), cardiac dysrhythmias (4 patients), congestive heart failure (1 patient, which led to a second case of therapy interruption), elevated bilirubin (4 patients), and pulmonary dysfunction. In 9 patients supplementary oxygen was necessary when psaO2 fell below 92

Biological mediators for periodontal regeneration. A review of the literature on the use of growth-regulatory molecules in the oral cavity permits a model in which to consider approaches to oral tissue engineering. These concepts apply to periodontal regeneration and to regeneration of alveolar bone. In either case, the formation of tissues is complex but proceeds in a deliberate and orderly sequence. In these sequence of events resulting in either bone or cementum formation, periodontal ligament and bone can be stimulated at various points. Different signals can apparently be used to stimulate tissue formation including mitogenic signals and differentiation factors. Additionally, both hard and soft tissue stimulatory molecules appear to be permissive. Classic receptor-mediated peptides or extracellular matrix molecules for soft and hard tissues appear to allow stimulation of tissue formation cascades. Importantly, it also appears that the stimulatory event is transitory (that is, short-lived) and leads itself to a sequence of cellular events. These cellular events in turn stimulate a number of subsequent events (such as chemotaxis, proliferation, differentiation or angiogenesis), which lead to further progression of tissue formation. While a solid scientific rationale exists for the use of a variety of growth and attachment factors in regeneration of oral tissues, only a small number are being pursued clinically. Many therapeutic regimens have failed in preclinical testing or have resulted in limited regenerative capacity. The mitogenic polypeptides that stimulate soft tissue growth (such as platelet-derived growth factor) and both hard and soft tissue growth (such as transforming growth factor-beta) appear to have not led to successful enough outcomes to facilitate further work towards regulatory approval. The demonstrated ability of bone morphogenetic proteins to generate substantial quantities of bone suggest many applications in the oral cavity where this is the only tissue desired. Another therapeutic candidate is enamel matrix derivative, a set of matrix proteins. Enamel matrix derivative appears to stimulate first acellular cementum formation, which may allow for functional periodontal ligament formation. It will be of interest in the future to determine whether the protein matrix contains classic mitogenic or differentiation factors as well as the amelogenins. It is also evident that the bone morphogenetic proteins permit periodontal ligament formation. The conditions for stimulating predictable periodontal ligament tissues with bone morphogenetic proteins however are not known. It is clear that the bone morphogenetic proteins are excellent molecules for stimulating oral bone formation. The results of all these studies will determine the future therapeutic potential for these growth molecules such that they may be used to optimally stimulate and direct specific points along tissue formation cascades.

Genetic determinants of cancer coagulopathy, angiogenesis and disease progression. Progression of human malignancies is accompanied by vascular events, such as formation and remodeling of blood vessels and systemic coagulopathy. Though long appreciated as comorbidity of cancer (Trousseau syndrome), vascular involvement is increasingly recognized as a central pathogenetic mechanism of tumor growth, invasion and metastasis. The major outstanding question in relation to this role has been, whether vascular perturbations are simply a reaction to the conditions of the tumor microenvironment, or are linked to the known genetic lesions causal for the onset and progression of malignancy. In this regard, we have previously hypothesized, and recently demonstrated experimentally that deregulation of certain hemostatic mechanisms, namely upregulation of tissue factor (TF) and possibly other changes (e.g. expression of thrombin receptor - PAR-1) are controlled by cancer-associated oncogenic events, such as activation of K-ras, epidermal growth factor receptor (EGFR), or inactivation of the p53 tumor suppressor gene in various human cancer cells. It appears that these respective transforming alterations exert their impact on both, cell-associated and soluble/circulating (microvesicle- associated) TF, i.e. may cause a systemic hypercoagulable state. Other genes, which more recently emerged as regulators of cancer coagulopathy include: PML-RARalpha, PTEN, and MET. While the spectrum of procoagulant targets of these genes may vary somewhat it includes: TF, PAI-1, COX-2 and possibly other hemostatic proteins. It is noteworthy that these prothrombotic changes may impact the malignant process directly (e.g. stimulate angiogenesis, tumor growth or metastasis) as a consequence of both coagulation-dependent and -independent effects. The latter are mostly related to cellular signaling events and changes in gene expression which are now known to be induced by the TF/FVIIa/Xa complex, thrombin and PARs, expressed on the surface of cancer cells, as well as tumor-associated endothelium. Interestingly, certain anticoagulants possess antimetastatic and anticancer properties (e.g. LMWH), an observation that further suggests that hypercoagulability may act as an effector mechanism of genetically driven tumor progression. Conversely, we suggest that oncogene-directed (targeted) anticancer agents could, at least in some cases, ameliorate not only cellular transformation itself, but also some of the chronic components of the cancer-related coagulopathy, something that may be relevant to therapeutic efficacy of these drugs. We also postulate that since TF is the oncogene target, circulating TF (microparticles) could serve as surrogate marker of the biological activity oncogene-directed agents exert in vivo. Thus, both genetic and epigenetic factors appear to conspire to activate various components of the hemostatic system in cancer patients, both locally and systemically. These activities act as mediators of cancer coagulopathy, angiogenesis, metastasis and other events involved in disease progression and should be recognized in designing better anticancer therapies.

[Mensurement of airflow resistance in neonatal prongs of nasal CPAP] OBJECTIVE: To measure airflow resistance in prongs of nasal CPAP, making use of different gas admission flow (GAF) in the ventilation circuit, in different internal diameters of the nasal prongs, besides verifying whether a GAF responding only to the demand of three times the minute-volume(MV) is enough to the circuit not to be cause of CO(2) retention. METHODOLOGY: Nasal prongs, assembled in the original circuits, were used, having their prongs kept open to the atmosphere. Pressure was read at a pressure monitor, in water centimeters, connected to the appropriate entrance of the circuit. A flowmeter balanced to the pressure was used, gauged at 50 psi, installed to the oxygen net of the Hospital, connected to the assessing set of the CPAP circuit. Initially, making use of the 8 l/min flow and keeping the exhaling set of the circuit closed, it was possible to eliminate the nasal prongs larger than two once the measured resistance was equal to zero. Having nasal parts number zero, 1 and 2 selected for this study, the system was then assembled as for the neonate: the inhaling set to the gas source and the exhaling set sunk into different depths in the water seal (2, 4, 6 and 8 centimeters). At the level of patient analysis, in order to assess the CO(2) retention, a mechanical pulmonary ventilation device was used as gas source and a nasal CPAP circuit was assembled to the device in adequate places. GAF values and FiO(2) were determined in the commands of the mechanical ventilation device. The assessment of gas concentration in the ventilation circuit was made while assisting two newborns. Gas samples were obtained within the ventilation circuit in the system assessing set (samples A), and right after the distal prong to the gas entrance (samples B). To determine MV the Tidal Volume (considered 10ml/kg) was multiplied by the respiratory frequency of the patient; GAF was three times MV. RESULTS: To a maximum GAF of 8 litres/min, only prongs sized zero, 1 and 2 showed resistance to the flow, measurable by the method used. There was an increase in resistance in proportion to the raise of GAF and proportionally opposite to the internal diameter of some prongs. Maximum difference in CO(2) partial pressure obtained from the gas given to the ventilation circuit and the one obtained from the nasal prongs was, in average, 0.43mmHg (p <0.5). CONCLUSIONS: Taking into account that during ventilation assistance through nasal CPAP there is the possibility of GAF incurring in the increase in resistance, what would involve a greater effort from the newborn to overcome such resistance during exhaling into the system (generating possibly an unexpected CPAP), and minimum GAF determined is that sufficient to meet no more than three times the MV, the conclusion is that prongs with the largest internal diameter possible and GAF only the necessary to meet, at least, the needs of the demand three times the MV should be used during this therapeutic procedure.

The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Results from the Transnational Study on Oral Contraceptives and the Health of Young Women. The objective of this study was to assess the risk of myocardial infarction (MI) associated with the use of new and old combination oral contraceptives (OC). A matched case-control study in 16 centers in Germany, the United Kingdom, France, Austria, and Switzerland explored the association of current use of combination OC with the occurrence of MI. Our subjects were 182 women aged 16-44 years with MI; the controls were 635 women without MI (at least one hospital control and one community control per case) matched for 5-year age group and region. The main outcome measures were odds ratios comparing current use of a specific group of OC against current use of other groups or against no current use. The adjusted overall odds ratio (OR; 95% confidence intervals) for MI for second generation OC versus no current use was 2.35 (1.42 to 3.89) and 0.82 (0.29 to 2.31) for third generation OC (low dose ethinyl estradiol, gestodene, and desogestrel). A direct comparison of third generation users with second generation users yielded an OR of 0.28 (0.09 to 0.86). In subgroup analyses, the odds ratio for the UK alone was 1.25 (0.36 to 4.29), while for continental Europe it was 0.10 (0.02 to 0.48). For hospital controls, the risk estimated was 0.98 (0.22 to 4.44), and 0.18 (0.04 to 0.65) for community controls. The independent risk of MI among current smokers adjusted for OC use was 7.21 (4.58 to 11.36). Among users of third generation OC, the OR for current smokers was 3.75 (0.65 to 21.74) and among users of second generation it was 9.50 (2.93 to 30.96). A comparison of OC use in the UK for the time before and after regulatory action was taken in October 1995 shows that the likelihood of a control (last control accrued June 1996) being treated with second generation OC is seven times higher after 1 November 1995 than it was before. Third generation OC are the first to be associated with no excess risk of MI. A significantly lower risk of MI is found when comparing use of third generation OC with use of second generation OC. There seems to be an impressive amelioration of risk among smokers using newer OC. An impact of regulatory action in the UK was found in the OC use spectrum of controls.

A Systematic Review of Instruments to Identify Mental Health and Substance Use Problems Among Children in the Emergency Department. Specialized instruments to screen and diagnose mental health problems in children and adolescents are not yet standard components of clinical assessments in emergency departments (EDs). We conducted a systematic review to investigate the psychometric properties, accuracy, and performance metrics of instruments used in the ED to identify pediatric mental health and substance use problems. We searched seven electronic databases and the gray literature for psychometric validation studies, diagnostic studies, and cohort studies that assessed any instrument to screen for or diagnose mental illness, emotional or behavioral problems, or substance use disorders. Studies had to include children and adolescents with mental health presentations or positive screens for substance use. Two reviewers independently screened studies for relevance and quality. Diagnostic study quality was assessed with the four QUADAS-2 domains. Psychometric study quality was assessed with published criteria for instrument reliability, validity, and usability. We present a descriptive analysis of the reported psychometric properties and diagnostic performance of instruments for each study. Of the 4,832 references screened, 14 met inclusion criteria. Included studies evaluate 18 instruments for identifying suicide risk (six studies), alcohol use disorders (six studies), mood disorders (one study), and ED decision making (need for assessment, admission; one study). Nine studies include a psychometric focus but quality varies, with no studies fully meeting criteria for reliability, validity, and usability. Seven studies examine diagnostic performance of an instrument, but no study has a low risk of bias for all QUADAS-2 domains. The HEADS-ED instrument has good inter-rater reliability (r = 0.785) for identifying general mental health problems and modest evidence for ruling in patients requiring hospital admission (positive likelihood ratio [LR+] = 6.30). Internal consistency (reliability) varies for instruments to screen for suicide risk (α = 0.46-0.97), and no instruments have both high sensitivity and high specificity. The Ask Suicide-Screening Questions (ASQ) is highly sensitive (98%) and has strong evidence for ruling out risk (negative likelihood ratio [LR-] = 0.04). Among screening instruments for alcohol use disorders, internal consistency is high for the consumption subscale of the Alcohol Use Disorders Identification Test (α = 0.83-0.88) and the Adolescent Drinking Index (α = 0.92). Both instruments also had sound internal validity. Diagnostically, a two-item instrument based on DSM-IV criteria is the most accurate in identifying patients with a disorder (area under the curve = 0.89) and has modest evidence for ruling in and out risk (LR+ = 8.80, LR- = 0.13). From available evidence, we recommend that ED clinicians use 1) the HEADS-ED to rule in ED admission among pediatric patients with visits for mental health care, 2) the ASQ to rule out suicide risk among pediatric patients with any visit type, and 3) the DSM-IV two-item instrument to rule in/rule out alcohol use disorders among pediatric patients currently using alcohol. These instruments require minimal to no training or time commitment. We also recommend that clinicians become familiar with each instrument's psychometric properties to understand the quality of the evidence base. In this review, however, we identify methodologic limitations in the evidence base. To develop a robust evidence base, additional research is necessary.

Organochlorine residues and elemental contaminants in U.S. freshwater fish, 1976-1986: National Contaminant Biomonitoring Program. As part of the National Contaminant Biomonitoring Program (NCBP, formerly a component of the National Pesticide Monitoring Program), the U.S. Fish and Wildlife Service periodically determined concentrations of organochlorine chemical residues and elemental contaminants in freshwater fish collected from a nationwide network of stations. In late 1986 and early 1987, the last time the network was sampled, a total of 319 composite fish samples were collected from 97 NCBP stations. The samples were analyzed for residues of organochlorine chemicals and the elements As, Cd, Cu, Hg, Pb, Se, and Zn. The mean concentration of total DDT and its homologs (p,p'-constituents) declined from 1984 to 1986, thus continuing a trend that began in 1970. The most persistent DDT homolog (p,p'-DDE) was detected at all stations sampled in 1986, and averaged 74% of total DDT residues, up from 70% in 1974-1979 but essentially unchanged from 1984. Collectively, these findings indicated a low rate of influx and continued weathering of DDT in the environment; nevertheless, DDT concentrations in fish from some stations in the South remained high enough to constitute a threat to piscivorous wildlife. Residues of polychlorinated biphenyls (PCBs) also remained widespread, but a significant downward trend in total PCB concentrations and incidence was evident, and PCB mixtures containing early eluting components were present at fewer stations than in the past. PCB concentrations were generally highest in fish from the industrialized rivers of the Northeast and Midwest and from the Great Lakes. Concentrations of toxaphene also declined, as did its incidence, from 88% of the stations sampled in 1980-1981 to 64% in 1986; however, analytical problems with the 1986 samples may have contributed to the latter. The risks represented by PCBs and toxaphene could not be evaluated on the basis of our data. Among cyclodiene insecticides, dieldrin and chlordane-related residues were the most widespread. Mean concentrations of dieldrin declined through 1986, but remained consistently highest in the Great Lakes. For chlordane-related residues, mean concentrations were lower that reported previously, and trans-nonachlor continued to replace cis-chlordane as the most abundant component. Collectively, these findings suggested a lower rate of chlordane influx to the aquatic environment; however, a point source of cyclodiene insecticides to the Mississippi R. near Memphis, TN, remained evident. Residues of mirex, PCA, BHC isomers, endrin, heptachlor, and HCB were either found at relatively few (< 25%) of the stations sampled in 1986 or were characterized by relatively low concentrations. Concentrations of the herbicide Dacthal (DCPA) were also low, but incidence increased from 46% of the stations sampled in 1984 to 61% in 1986. In general, organochlorine chemical concentrations were lower in 1986 than at any time reported previously. For elemental contaminants, the geometric mean, maximum, and 85th percentile concentrations (respectively, all in microgram/g wet weight) in 1986 samples were as follows: As, 0.083, 1.53, 0.24; Cd, 0.011, 0.32, 0.04; Cu, 0.794, 11.0, 1.7; Hg, 0.087, 0.44, 0.18; Pb, 0.058, 1.90, 0.21; Se, 0.417, 3.41, 0.66; and Zn, 21.191, 94.5, 31.7. Mean concentrations of Cu increased and concentrations of As decreased relative to the 1984 collection, but these changes may reflect subtle differences in the species composition of the 1986 collection relative to other collections; concentrations of both elements differ greatly among fishes. There were no other statistically significant changes from 1984 to 1986; however, mean concentrations of As, Cd, Pb, and Zn declined from 1976, when elemental contaminants in fish were first measured in the NCBP, and 1986. In contrast, mean concentrations of Hg and Se did not change appreciably. Moreover, and in contrast to the other elements measured in 1986, concentrations of Hg and Se were high enough to constitute a threat to pisc

Vaccines for the common cold. The common cold is a spontaneously remitting infection of the upper respiratory tract, characterised by a runny nose, nasal congestion, sneezing, cough, malaise, sore throat and fever (usually < 37.8˚C). The widespread morbidity it causes worldwide is related to its ubiquitousness rather than its severity. The development of vaccines for the common cold has been difficult because of antigenic variability of the common cold virus and the indistinguishable multiple other viruses and even bacteria acting as infective agents. There is uncertainty regarding the efficacy and safety of interventions for preventing the common cold in healthy people. To assess the clinical effectiveness and safety of vaccines for preventing the common cold in healthy people. We searched CENTRAL (2012, Issue 12), MEDLINE (1948 to January week 1, 2013), EMBASE (1974 to January 2013), CINAHL (1981 to January 2013) and LILACS (1982 to January 2013). Randomised controlled trials (RCTs) of any virus vaccines to prevent the common cold in healthy people. Two review authors independently evaluated methodological quality and extracted trial data. Disagreements were resolved by discussion or by consulting a third review author. This review included one RCT with 2307 healthy participants; all of them were analysed. This trial compared the effect of an adenovirus vaccine against a placebo. No statistically significant difference in common cold incidence was found: there were 13 events in 1139 participants in the vaccines group and 14 events in 1168 participants in the placebo group; risk ratio (RR) 0.95, 95% confidence interval (CI) 0.45 to 2.02, P = 0.90). No adverse events related to the live vaccine were reported. This Cochrane review has found a lack of evidence on the effects of vaccines for the common cold in healthy people. Only one RCT was found and this did not show differences between comparison groups; it also had a high risk of bias. There are no conclusive data to support the use of vaccines for preventing the common cold in healthy people. We identified the need for well-designed, adequately powered RCTs to investigate vaccines for the common cold in healthy people. Unless RCTs provide evidence of a treatment effect and the trade-off between potential benefits and harms is established, policy-makers, clinicians and academics should not recommend the use of vaccines for preventing the common cold in healthy people. Any future trials on medical treatments for preventing the common cold should assess a variety of virus vaccines for this condition. Outcome measures should include common cold incidence, vaccine safety and mortality related to the vaccine.

Viral induced demyelination. Viral induced demyelination, in both humans and rodent models, has provided unique insights into the cell biology of oligodendroglia, their complex cell-cell interactions and mechanisms of myelin destruction. They illustrate mechanisms of viral persistence, including latent infections in which no infectious virus is readily evident, virus reactivation and viral-induced tissue damage. These studies have also provided excellent paradigms to study the interactions between the immune system and the central nervous system (CNS). Although of interest in their own right, an understanding of the diverse mechanisms used by viruses to induce demyelination may shed light into the etiology and pathogenesis of the common demyelinating disorder multiple sclerosis (MS). This notion is supported by the persistent view that a viral infection acquired during adolescence might initiate MS after a long period of quiescence. Demyelination in both humans and rodents can be initiated by infection with a diverse group of enveloped and non-enveloped RNA and DNA viruses (Table 1). The mechanisms that ultimately result in the loss of CNS myelin appear to be equally diverse as the etiological agents capable of causing diseases which result in demyelination. Although demyelination can be a secondary result of axonal loss, in many examples of viral induced demyelination, myelin loss is primary and associated with axonal sparing. This suggests that demyelination induced by viral infections can result from: 1) a direct viral infection of oligodendroglia resulting in cell death with degeneration of myelin and its subsequent removal; 2) a persistent viral infection, in the presence or absence of infectious virus, resulting in the loss of normal cellular homeostasis and subsequent oligodendroglial death; 3) a vigorous virus-specific inflammatory response wherein the virus replicates in a cell type other than oligodendroglia, but cytokines and other immune mediators directly damage the oligodendroglia or the myelin sheath; or 4) infection initiates activation of an immune response specific for either oligodendroglia or myelin components. Virus-induced inflammation may be associated with the processing of myelin or oligodendroglial components and their presentation to the host's own T cell compartment. Alternatively, antigenic epitopes derived from the viral proteins may exhibit sufficient homology to host components that the immune response to the virus activates autoreactive T cells, i.e. molecular mimicry. Although it is not clear that each of these potential mechanisms participates in the pathogenesis of human demyelinating disease, analysis of the diverse demyelinating viral infections of both humans and rodents provides examples of many of these potential mechanisms.

Outcome of untethering for symptomatic spina bifida occulta with lumbosacral spinal cord tethering in 31 patients: analysis of preoperative prognostic factors. The most important goal for treating symptomatic lumbosacral spinal cord tethering is early untethering. To investigate preoperative symptoms that may have affected the outcome. Patients with or without improvement and with or without favorable outcome after untethering were compared retrospectively by chart and image review. Thirty-one patients (age between 2 days to 25 years) with spina bifida occulta and symptomatic cord tethering were analyzed. Presenting symptoms (neurological deficits, urological dysfunction, and lower limb deformities) were assessed before and after untethering. Favorable outcome was defined as complete relief of symptoms or mild symptoms whereby patients are able to look after their own personal care without assistance. Unfavorable outcome was defined as moderate or severe disability whereby patients are unable to attend to their own bodily needs without assistance, are bedridden, or require constant nursing attention. Differences in patient characteristics and presenting symptoms were compared between those with and without clinical improvement and favorable outcome. Multivariate logistic regression was used to identify prognostic factors affecting the outcome. The average age at surgery was 7.2 years, with a male-to-female ratio of 1.2. The average follow-up time was 4 years. At least one of the following symptoms was present in all patients: neurological deficits (83.9%), urological dysfunction (77.4%), or limb deformities (38.7%). After untethering, all patients had either symptoms stabilized (14 patients, 45.2%) or improved (17 patients, 54.8%), and 14 patients (45.2%) achieved total resolving of symptoms. Logistic regression confirmed that younger age (< or =2 years, odds ratio [OR] 22.0, p=.026), lipomas of filum terminale (OR 25.6, p=.042), and a poor anal tone (OR 10.4, p=.061) were positive prognostic factors for the improvement in symptoms. The functional outcome was determined by the age at surgery (OR 0.9 per year since 1 year old, p=.04) and the presence of limb deformities (OR 0.06, p=.017). In conclusion, our study suggests that untethering should be performed immediately once the patient shows evidence of symptomatic lumbosacral cord tethering, irrespective of age. Untethering can interrupt progression of symptoms, but sphincter dysfunction and muscle weakness are more likely to improve or resolve. Benefits can be seen in all patients, but young children (before 2 years old) have a higher chance to gain favorable outcome. Retethering is a main concern during follow-up, particularly for the more complicated lipomyelomeningoceles. Investigations using electrophysiologic and urodynamic studies are helpful for early detection of subtle symptomatic cord tethering or retethering.

Evidence of Vowel Discrimination Provided by the Acoustic Change Complex. The objectives of this study were to measure the effects of level and vowel contrast on the latencies and amplitudes of acoustic change complex (ACC) in the mature auditory system. This was done to establish how the ACC in healthy young adults is affected by these stimulus parameters that could then be used to inform translation of the ACC into a clinical measure for the pediatric population. Another aim was to demonstrate that a normalized amplitude metric, calculated by dividing the ACC amplitude in the vowel contrast condition by the ACC amplitude obtained in a control condition (no vowel change) would demonstrate good sensitivity with respect to perceptual measures of vowel-contrast detection. The premises underlying this research were that: (1) ACC latencies and amplitudes would vary with level, in keeping with principles of an increase in neural synchrony and activity that takes place as a function of increasing stimulus level; (2) ACC latencies and amplitudes would vary with vowel contrast, because cortical auditory evoked potentials are known to be sensitive to the spectro-temporal characteristics of speech. Nineteen adults, 14 of them female, with a mean age of 24.2 years (range 20 to 38 years) participated in this study. All had normal-hearing thresholds. Cortical auditory evoked potentials were obtained from all participants in response to synthesized vowel tokens (/a/, /i/, /o/, /u/), presented in a quasi-steady state fashion at a rate of 2/sec in an oddball stimulus paradigm, with a 25% probability of the deviant stimulus. The ACC was obtained in response to the deviant stimulus. All combinations of vowel tokens were tested at 2 stimulus levels: 40 and 70 dBA. In addition, listeners were tested for their ability to detect the vowel contrasts using behavioral methods. ACC amplitude varied systematically with level, and test condition (control versus contrast) and vowel token, but ACC latency did not. ACC amplitudes were significantly larger when tested at 70 dBA compared with 40 dBA and for contrast trials compared with control trials at both levels. Amplitude ratios (normalized amplitudes) were largest for contrast pairs in which /a/ was the standard token. The amplitude ratio metric at the individual level demonstrated up to 97% sensitivity with respect to perceptual measures of discrimination. The present study establishes the effects of stimulus level and vowel type on the latency and amplitude of the ACC in the young adult auditory system and supports the amplitude ratio as a sensitive metric for cortical acoustic salience of vowel spectral features. Next steps are to evaluate these methods in infants and children with hearing loss with the long-term goal of its translation into a clinical method for estimating speech feature discrimination.

A pharmacogenetic approach to improve low ovarian response: The role of CAG repeats length in the androgen receptor gene. The AR (androgen receptor) polymorphism is associated with POR risk. Furthermore, the use of androgens in POR remains controversial. Our data could clarify the effectiveness of androgen pretreatment. AR genotyping could help us to identify patients at risk for POR and POR patients that will be benefited of androgen pretreatment. The aim of this project was to investigate if the AR (androgen receptor) polymorphism could be used to identify patients at risk for POR and that will benefit from androgens pretreatment. To evaluate the POR risk we performed a cohort study including 231 patients (54 POR and 177 control). Moreover, we included 88 IVF-cycles performed by 44 POR-patients to assess the effect on ovarian response. All patients performed two cycles: a standard ovarian stimulation and a second one with androgen preparation. We compare the results in pair from each. POR showed the highest frequency of CAG repeats at 24 vs 22 in controls. Only 33% of POR have alleles with a repeat number below 23, compared with 50% of controls (p < 0.05). According to AR polymorphism ovarian response differences were shown. Patients that carried CAG repeats in AR gene between 22 and 24 showed an increased in the number of oocytes (2.61 in cycles without androgens vs 5.11 when they were pretreated with androgens; p < 0.05). For the patients that carried repeats lower than 22 and higher than 24, no differences were reported in the number of oocytes obtained in the cycle with or without androgens (2.94 vs 2.56; p = 0.88). Similar results were obtained for mature oocytes in patients that carry a number of CAG repeats between 22 and 24 (1.86 MII in cycles without androgens vs 4.04 MII when they were pretreated with androgens; p < 0.05). No differences in the number of MII oocytes were found in patients that get out of 22 and 24 repeats between the two cycles (2.31 vs 2.13; p = 0.88). The AR polymorphism is associated with POR risk, patients with repeats greater than 22 show a higher risk. Our data suggest that AR genotype could play a role in natural ovarian aging. Furthermore, the use of androgens in POR remains controversial. Our data suggest that the AR genotype could clarify the effectiveness of the androgen pretreatment. AR genotyping could help us to identify patients at risk of POR and POR patients that could benefit from transdermal testosterone pretreatment.

Systematic review on the relationship between the nursing shortage and job satisfaction, stress and burnout levels among nurses in oncology/haematology settings. To establish the best available evidence regarding the relationship between the nursing shortage and nurses' job satisfaction, stress and burnout levels in oncology/haematology settings. Electronic databases (CINAHL, Medline, Scopus, ScienceDirect, PsycInfo, PsycArticles, Web of Science, The Cochrane Library, Proquest and Mednar) were searched using a three-step strategy in order to identify published and unpublished studies conducted between 1990 and 2010. Grey literature was excluded in the review. The identified studies were evaluated using standardised critical appraisal instruments from the Joanna Briggs Institute-Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). A total of seven descriptive and descriptive-correlational studies published in English were included and data were presented in a narrative summary. Findings revealed a positive bidirectional relationship between the nursing shortage and oncology registered nurses' (RNs') job dissatisfaction, stress and burnout. The extent of the job dissatisfaction, stress and burnout experienced by the oncology RNs and their perception of staffing inadequacy differed according to their demography and work settings. Particularly, nurses who had higher qualifications and positions, who worked full-time and who worked in inpatient settings and non-Magnet hospitals were more likely to attribute staffing inadequacy as one of the main contributing factors for their job dissatisfaction, stress and burnout. This led to a rise in the number of oncology RNs leaving the speciality. Within the constraints of the study and the few quality papers available, it appears that oncology RNs who worked in substandard staffing units often express job dissatisfaction, stress and burnout, which prompt them to seek new employment out of the oncology specialty. This entails a pressing need for organisations to ensure sufficient staffing in oncology/haematology settings, in order to ensure that quality patient care is provided. Limited studies that examine the relationship between the nursing shortage and oncology RNs' stress and burnout have been conducted. Also, no studies in the Asian context have previously been conducted. Organizations need to customize their strategies for the recruitment and retention of oncology nurses. The strategies should take into consideration the specific demographic characteristics of oncology nurses or those of work settings that are experiencing staffing inadequacy and negative nursing outcomes. The strategies should also aim to replicate features of other institutions that are attractive to oncology nurses, and also include training that help oncology nurses better manage their emotions. Future research needs to examine the relationship between the nursing shortage and oncology nurses' job satisfaction, stress and burnout in bone marrow transplant units, paediatric oncology settings and Asian oncology settings. The characteristics of oncology nurses or workplaces that are more likely to experience negative nursing outcomes due the nursing shortage should also be identified.

Extended-criteria donors in lung transplantation in Switzerland: an evaluation of two adapted lung donor scores. Various scoring systems aim to assess the quality of organs donated for transplantation on the basis of patient characteristics, clinical examination and laboratory results. How well such scoring systems reflect the practice in lung transplantation in Switzerland has never been studied. Therefore, we evaluated two scoring systems for their ability to predict whether or not donor lungs are accepted by the two Swiss lung transplant centres. We retrospectively analysed patient data of adult deceased organ donors in Switzerland between 1 July 2007 and 30 June 2014. Included were all donors from whom at least one organ was transplanted. We evaluated two lung donor quality scores, the multicentre-developed Eurotransplant donor score (EDS), and the single-centre-developed Zurich donor score (ZDS). Both scores were slightly adapted to be applicable to Swiss deceased organ donor data. We evaluated whether these scores can predict whether lungs were transplanted or refused by Swiss transplant centres, using univariate logistic regression. We further assessed their discriminative power by calculating the area under the receiver operating characteristic curve (AUC). Of the 635 donors included in our analysis, 295 (46%) were accepted as lung donors by one of the two lung transplant centres in Switzerland. Our analysis showed that both scores can predict whether or not a donor lung is likely to be accepted for transplantation in Switzerland. As the score value of a donor increases, the odds of the lung being transplanted significantly decreases (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.51-0.65 for the adapted EDS; OR 0.35, 95% CI 0.28-0.43 for the adapted ZDS). This effect is slightly more pronounced in the adapted ZDS than in the adapted EDS. The discriminatory power of the scores from the AUC was 0.719 (95% CI 0.680-0.758) for the adapted EDS, and 0.723 (95% CI 0.681-0.760) for the adapted ZDS, which for both was deemed fair discrimination. Both scoring systems are able to predict whether or not donor lungs are accepted by the two Swiss lung transplant centres. As an alternative to adapting an established scoring system, a national lung quality score could be derived de novo. This could be based on a logistic regression analysis including the most relevant donor characteristics. However, such a new score would need to be validated on an independent sample and ideally tested for its predictive value in terms of post-transplantation outcome.

In vitro and in vivo expression of alpha 7 integrin and desmin define the primary and secondary myogenic lineages. Skeletal muscle fibers form during two periods of development and differ biochemically, functionally and in their morphology. Primary fibers develop in the rat hindlimb during Days 14 to 16 of embryogenesis. These fibers are subsequently surrounded by secondary fibers that eventually constitute the bulk of muscle mass in the limbs. We have used the expression of the alpha 7 muscle laminin binding integrin (Song et al., J. Cell Biol. 117, 643-657, 1992) and the intermediate filament protein desmin to identify myogenic cells at distinct stages of development both in vitro and in vivo. The phenotypes of these cells, determined by immunofluorescence microscopy, discriminate two lineages and indicate that the development of primary and secondary muscle fibers is regulated by multiple mechanisms. The cells which compose the primary myogenic lineage are derived from a population of precursor cells that is in part present in the Day 12 embryo limb bud and which do not express either alpha 7 integrin or desmin. These precursor cells develop into cells that express desmin, but not alpha 7, and which subsequently mature into replicating myoblasts that are competent to undergo terminal differentiation. This maturation process requires the in vivo environment of the Day 13 embryo limb. The alpha 7 integrin and slow myosin heavy chain are first expressed in primary muscle cells well after the onset of terminal differentiation. Some cells that give rise to secondary muscle fibers also are present in the Day 12 embryo hindlimb. The precursors of secondary fibers will develop into cells which express either alpha 7 integrin or desmin and subsequently into replicating myoblasts that express both proteins. Upon terminal differentiation of secondary myoblasts there is an increase in the expression of both alpha 7 integrin and desmin. The temporal regulation of expression of these proteins indicates that the environment of the limb plays a role in the maturation of precursors of both lineages. At least two roles of alpha 7 integrin during myogenesis are related to its association with beta 1 integrin and its function as a laminin receptor. Laminin selectively maintains the proliferation of secondary myoblasts and modulates their shape and mobility in vitro. This responsiveness of secondary myoblasts to laminin corresponds to the time when laminin is a major component of the extracellular matrix, when there is an expansion of the population of secondary myoblasts, and when the alpha 7 integrin is expressed on secondary myoblasts in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Hip arthroscopy for labral tears in workers' compensation: a matched-pair controlled study. Workers' compensation (WC) status has been related to clinical outcomes; however, no comparative studies have been performed to assess 2-year outcomes between hip arthroscopy patients based on WC status. To evaluate 2-year outcomes of patients receiving WC who underwent hip arthroscopy for labral tears and to compare outcomes with those of a matched control group not receiving WC. Cohort study; Level of evidence, 3. During the study period between June 2008 and August 2010, data were collected on all patients treated with hip arthroscopy. Inclusion criteria for the study group were diagnosis of labral tear and WC status. All patients were assessed pre- and postoperatively with 4 patient-reported outcome (PRO) measures: the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Activities of Daily Living (HOS-ADL), and Hip Outcome Score-Sport-Specific Subscales (HOS-SSS). Pain was estimated on the visual analog scale (VAS), and satisfaction was measured on a scale from 0 to 10. A matched-pair group of patients not associated with WC was selected in a 1:1 ratio according to age within 3 years, sex, surgical procedures, and radiographic findings. Twenty-one hips were included in each group. Patients with WC status had significantly lower preoperative PRO scores for all measures (P < .001). However, there was no significant difference between VAS pain scores between the groups. Of the WC patients, 86% returned to work at a median 82 days postoperatively. For the WC group, the score improvement from preoperative to 2-year follow-up was 46 to 67.7 for mHHS, 39.3 to 66 for NAHS, 39.7 to 69.5 for HOS-ADL, and 15.3 to 49.8 for HOS-SSS. For the control group, the score improvement from preoperative to 2-year follow-up was 67.9 to 85.8 for mHHS, 62.6 to 84.4 for NAHS, 69.8 to 86.9 for HOS-ADL, and 41.9 to 73.8 for HOS-SSS. Both groups demonstrated statistically significant postoperative improvement in all scores, and the average amount of change of preoperative to postoperative scores between the 2 groups was only significantly different for the HOS-ADL in the control group (P = .043). However, the WC group demonstrated greater improvement in aggregate scores in the HOS-ADL. Pain scores decreased from 7 to 3.9 in the WC group and 5.8 to 3.2 in the control group and were not significantly different between the groups. Patient satisfaction was 6.8 for the WC group and 7.7 for the control group, with no significant difference between groups. Our study demonstrated that WC patients had significantly lower baseline PRO scores when compared with a matched-pair control group. However, both groups demonstrated statistically significant postoperative improvement in all scores. Patients with WC status started and ended with lower absolute scores but benefited from arthroscopic intervention for hip injuries. While patient and physician expectations may be adjusted accordingly, these results may reflect favorably on the use of hip arthroscopy for labral tears in the WC population.

[Somatic Conversion (Paramutation) at the sulfurea Locus of Lycopersicon esculentum Mill. : IV. The Genotypic Determination of the Frequency of Conversion]. 1. Several lines of Lycopersicon esculentum, which are heterozygous for a mutant sulfurea (sulf) allele vary greatly in the percentage of variegated plants among the heterozygotes. This variegation is caused by somatic conversion (paramutation). The different frequency of conversion is due to the presence of different sulf alleles. Within the sulfurea (pura) (sulf (pura) ) and sulfurea (variegata) (sulf (vag) ) groups there are different alleles, which - though indistinguishable in homozygous condition - can be distinguished by their different conversion activity (paramutagenicity) in heterozygotes with sulf (+). 2. The conversion activity (paramutagenicity) of an allele is expressed by the percentage of green-yellow variegated plants among the heterozygotes (e. g. sulf (pura-90%) means: 90 plants out of 100, which are heterozygous for this particular sulf (pura) allele, are variegated, and 10 are entirely green). 3. The conversion activity (paramutagenicity) of a particular sulf allele can be changed by mutations; it can be either increased or decreased. 4. Crosses have been made between sulf homozygotes (Lycopersicon esculentum, variety Lukullus) and different taxa of the subgenus Eulycopersicon (L. esculentum: marker stocks, German tomato varieties, distantly related varieties from South and Central America; L. pimpinellifolium). Within the subgenus Eulycopersicon the frequency of somatic conversion (paramutation) is - within the range of random and modificative fluctuations - determined only by the conversion activity (paramutagenicity) of the special sulf allele present. Effects of the genetic background could not be demonstrated. Conversion-stable (non-paramutable) sulf (+) isoalleles have not been found in this subgenus. 5. The sulf (pura) group consists of alleles with all possible degrees of conversion activity (paramutagenicity) between 0% and 100% for particular years and average conversion values between 3,6% and 92,9% for several years. The sulf (vag) alleles have a lower conversion activity; its maximum is about 12%. No sulf alleles have been found which have entirely lost their conversion activity. 6. After crossing sulf heterozygotes (L. esculentum) with the distantly related species Lycopersicon hirsutum (subgenus Eriopersicon) and Solanum pennellii significant deviations from the expected 3∶1 segregation for sulf have been found in F 1 and F 3; there is a distinct deficit of sulf sulf seedlings. In F 1 species hybrids somatic conversion (paramutation) occurred very seldom (less than 2%). However in F 2 of both crosses some progenies had frequencies of conversion up to 9,3% (L. esc. x L. hirs.) and 8,5% (L. esc. x Sol. pen.). In F 3 some progenies had frequencies which were slightly higher than those in F 2. In F 4 a progeny has had a frequency of conversion of 61,7%. 7. In F 1, F 2, F 3and F 4 of these species hybrids the sulf (+) allele is from L. hirsutum or S. pennellii and the sulf allele is from L. esculentum; i.e. the system sulf (+) - sulf is always the same. Therefore the differences in the conversion frequency between F 1 and F 2, F 3and F 4 respectively indicate an influence of the genetic background. The genetic background of the subgenus Eulycopersicon allows the full expression of the conversion system sulf (+) - sulf. Genes of L. hirsutum or S. pennellii, however, intensely inhibit the occurrence of somatic conversion in F 1. Genetic recombination in the species hybrids leads to the occurrence of genotypes in F 2, F 3and F 4 which allow conversion to take place more frequently. 8. In the discussion the results obtained with the sulf system of the tomato are compared with those of the analysis of the paramutation systems at the R and B locus in Zea mays, at the cruciata locus in Oenothera and in the rogue heterozygotes of Pisum sativum.

Teen Driving Education in a Pediatric Emergency Department: Effectiveness of a Toolkit. In the United States, the leading cause of death for adolescents aged 16 to 24 years is motor vehicle crashes, with Alabama ranked as the second-worst state in the nation for teen driving deaths. We sought to determine the efficacy of teenage driving education within the setting of the pediatric emergency department and to assess the driving habits of teenagers and their parents and their understanding of the Alabama Graduated Driver's License (GDL) law. Surveys were administered to noncritically ill teenagers aged 13 to 19 years and their parents who presented to the children's emergency department. Participation was voluntary and anonymous. Presurveys were administered to assess driving habits and knowledge. Intervention was then given in the form of a "safe driving toolkit," followed by postsurveys to measure educational outcomes. Pre- and postsurvey data were then analyzed and compared using Epistat. A total of 41 parents, 2 grandparents, and 45 teenagers were enrolled in this study. An additional 47 teenagers answered a single curfew question at a teen driving event. Of all of the participants, 63% had never heard of the Alabama GDL law, and of that 63%, 37% had been enrolled in a driver's education course. A χ2 analysis revealed no significant difference between parents and teenagers having taken a driver's education course. Of the participants, 22% responded that they knew the specifics of the Alabama GDL law, with only 1 correct on all 3 counts. The most common item missed was the curfew for teenagers, with 4 believing it to be 8 pm, 14 believing it to be 9 pm, 23 believing it to be 10 pm, and 7 believing it to be 11 pm. Sixty-nine percent of the respondents correctly answered that there was to be no cellular telephone use while driving for teenagers with a GDL. More than 97.2% of participants, both parents and teens, reported learning new information from this study. The majority of participants enrolled were not aware of the Alabama GDL law, which has been in place since 2002. More than 97% of those surveyed were given new information during the education session. There is a strong need for further public education regarding the law and safe driving habits. Sixty-one percent of respondents believe that the teen curfew is earlier than the present curfew. The authors believe that this shows support for revising the curfew in the present law to an earlier time. Nighttime driving restrictions starting at 10 pm or earlier have been shown to result in greater reductions in motor vehicle crashes involving teenagers. Our study affirmed that teen driving education within the pediatric emergency department setting is efficacious.

[Total parenteral nutrition in critical patients. The metabolic-nutritional aspects and effects on immune function of 2 different isocaloric-isonitrogenous regimens]. The aim of this investigation was to compare, in a randomized short-term study the effects on some parameters evaluating lipid metabolism, nutritional status and immune function of two different patients. Particularly, the influence of the intravenous (i.v.) infusion of a fat emulsion on above-mentioned parameters was evaluated. The two regimens (G and GL) were isocaloric (about 30 kcal.kg-1.d-1 non protein energy) and isonitrogenous (about 0.27 g.kg-1.d-1 nitrogen); the only difference was the source of non-protein calories administered. Regimen G consisted of glucose-based TPN (100% of non-protein energy as glucose) whereas, in regimen GL (glucose-lipid-based TPN), the 55% of non-protein caloric supply was given as glucose and 45% as lipids. 9 of the patients were randomly assigned to receive regimen GL (group GL) and 8 to receive regimen G (group G). TPN was delivered through a central vein catheter for 8 days; during this period no hepatic or metabolic complications have been observed. Clinical and laboratory tests were performed at day 0 (enrollment), at day 4 (after 4 days of TPN) and at day 8 (at the end of TPN). Both regimens of TPN were able to induce an improvement of the nutritional status and serum prealbumin (TBPA) significantly increased in all patients (p < 0.05). The results of the immune measurements showed that no significant change in immune function during the administration of either regimen occurred. However, in group GL, we observed a slight, non significant change in the percentage numbers of T-cells subpopulations that resulted in a decrease in the ratio of helper to suppressor T-cells (H:S). Serum lipids and lipoprotein profile didn't change significantly in group GL. On the contrary, in group G, we observed a significant decrease in serum concentrations of HDL cholesterol (p < 0.05), LDL cholesterol and apo A1 (p < 0.01) while total cholesterol remained unchanged; a non significant rise in serum triglyceride also occurred, These results show that the two regimens had a similar impact on nutritional status in both groups. The i.v. infusion of the fat emulsion didn't alter lipid profile and was not associated with an impairment of some aspects of the immune function. In conclusion, our results confirm that fat emulsions represent an important component of i.v. nutritional support regimens and should continue to be used when and where indicated in short-term TPN. However, long-term effects of i.v. infusion of fat emulsions on the immune systems should be further investigated, in a more substantial number of patients.

The effects of ventricular fibrillation duration and a preceding unsuccessful shock on the probability of defibrillation success using biphasic waveforms in pigs. While the defibrillation threshold has been reported to increase with ventricular fibrillation (VF) duration for monophasic waveforms, the effect of VF duration for biphasic waveforms is unknown. The ED 50 requirements (the 50% probability of defibrillation success) for an endocardial lead system, which included a subcutaneous array, were determined by logistic regression using a recursive up-down algorithm for a biphasic waveform (6/6 msec). The study was performed in two parts, each with eight pigs. In part 1, ED 50 was compared for shocks delivered after 10 seconds of VF and for shocks delivered after 20 seconds of VF following a failed first shock at 10 seconds. Energy at ED 50 decreased from 6.5 +/- 0.9 J for shocks delivered after 10 seconds of VF to 4.9 +/- 0.8 J (P < 0.01) for shocks delivered after 20 seconds. To determine if improved second shock efficacy was a result of preconditioning by the failed first shock or a function of VF duration, part 2 of the study compared defibrillation efficacy between shocks delivered after 10 seconds of VF with shocks delivered after 20 seconds of VF with and without a failed first shock at 10 seconds. Mean energy at ED 50 decreased from 10.1 +/- 2.4 J for shocks delivered after 10 seconds of VF to 7.9 +/- 2.4 J (P < 0.01) and 7.5 +/- 3.2 J (P < 0.01) for shocks delivered after 20 seconds of VF with and without a failed first shock, respectively. The mean energy at ED 50 for shocks delivered after 20 seconds of VF with and without a failed first shock was not significantly different (P = 0.53). A strong linear correlation for energy at ED 50 was found between shocks delivered after 10 seconds of VF and shocks delivered after 20 seconds of VF following a failed first shock (r = 0.95, P < 0.01). (1) As opposed to monophasic shocks, ED 50 is significantly lower for biphasic shocks delivered after 20 seconds of VF compared with shocks delivered after 10 seconds of VF in pigs. (2) An unsuccessful biphasic shock in pigs does not affect the defibrillation efficacy for a subsequent shock. (3) ED 50 for a biphasic shock delivered after 20 seconds of VF is linearly related to ED 50 for a shock delivered after 10 seconds of VF.

Failed back surgery syndrome. The failed back or postlaminectomy syndrome is obviously multidimensional. Failure of therapy may result from structural abnormalities in the back, psychosocial influences, or a combination of both. The causes of back pain are largely unknown. Correlations with diagnostic studies are uncertain. The lack of precise diagnoses is reflected in a multiplicity of nonspecific treatments, mostly of unproven value. Our current disability-litigation system adds greatly to the problem. Patients are rewarded for nonfunction. Some physicians become advocates for patients, others for insurance carriers and employers. Decisions concerning appropriate treatment are often made by patients, attorneys, the disability determination system, employers, and judges for extraneous reasons, which include financial gain or personal bias and often reflect lack of current information. Even when correct decisions are made, there is a lack of adequate programs for diagnosis and comprehensive treatment of these individuals. The failed back syndrome is not likely to disappear quickly. Large numbers of these patients require care. The best available evaluation includes thorough, but not overly minute investigation using the best current imaging techniques. These studies combined with the history and physical examination should provide a reasonably accurate assessment of the patient's condition. Concomitant evaluation of psychosocial issues is mandatory, and those who treat these patients without understanding the importance of the various comorbidities discussed are likely to be detrimental. Reparative surgery has real, but limited use. Nerve root compression and instability are the only two conditions demonstrated to be correctable at the present time. However, even when a potentially remediable lesion is found, these patients should undergo a reasonable attempt at physical rehabilitation with attention to both local factors and general function. The best data available today suggest that most of the patients suffering from failed back syndrome are incapacitated by psychiatric, psychologic, and social/vocational factors, which relate to the back complaint only indirectly. Those currently suffering from this problem can be best treated by comprehensive programs that address these complex psychosocial issues. New additions to this category can be reduced by rigorous attention to physical abnormalities, so that surgery is undertaken only for clear indications, and appreciation of the importance of the psychologic aspects of disability from low back pain. The smaller group suffering principally from physical abnormalities can be improved by reparative surgery or pain-relieving procedures if intensive conservative rehabilitation efforts fail. All surgical procedures fail occasionally, and as long as there is a need for reparative surgery, some patients will fail to benefit or be worsened by the procedures.(ABSTRACT TRUNCATED AT 400 WORDS)

[Effect of electroacupuncture stimulation of "Ganshu" (BL 18) on locomotor, gastric mucosal and hypothalamic SP immunoactivity and hippocampal 5-HT content in rats with depression and gastric ulcer]. To observe the effect of electroacupuncture (EA) stimulation of "Ganshu" (BL18) on expression of substance P (SP) in the gastric mucosa and hypothalamus tissues and hippocampal 5-hydroxytryptamine (5-HT) content in rats with depression + gastric ulcer, so as to explore its mechanism underlying improvement of depressive gastric ulcer. A total of 60 SD rats were equally randomized into normal, model, EA-BL18 and non-acupoint groups. The depression + gastric ulcer model was established by chronic unpredictable mild stress (CUMS) paradigm for 21 days in accordance with Willner and colleagues' methods (1987), and injection of 90% glacial acetic acid (0.01 mL) into the sub-serous layer near the gastric antrum under anesthesia on day 10 after starting CUMS. Following modeling, EA (4 Hz/15 Hz, 2 V) was applied to bilateral "Ganshu" (BL 18) for 20 min, once daily for 2 weeks, with one day's interval between two weeks. The non-acupoint was located about 2.5 cm lateral to the umbilicus and stimulated by EA similar to EA-BL18. The rats' locomotor ability was assessed by open field tests (crossing and rearing numbers). The gastric ulcer index was calculated according to Guth's method, and hypothalamic and gastric antrum SP immunoactivity was determined by immunohistochemistry and hippocampal 5-HT content was detected by ELISA. After modeling, compared to the normal group, both crossing number and rearing number of open field tests on day 21 and 34 were significantly decreased in the model group (P < 0.01), while compared to the model group, both crossing and rearing numbers on day 34 were considerably increased in the EA-BL18 group (P < 0.01) rather than in the non-acupoint group (P > 0.05). Following modeling, the gastric ulcer index, SP expression levels in the gastric antrum and hypothalamus tissue were obviously increased in the model group (P < 0.01), and notably decreased in the EA-BL18 group (P < 0.01) but not in the non-acupoint group (P > 0.05). The hippocampal 5-HT content was remarkably lower in the model group than in the normal group, but obviously higher in the EA-BL18 group than in the model group (P < 0.01). No significant difference was found between the model and non-acupoint groups in the hippocampal 5-HT content (P > 0.05). EA of "Ganshu" (BL18) can promote locomotor and reduce gastric ulcer index in depression + gastric ulcer rats, which may be related to its effects in lowering gastric and hypothalamic SP immunoactivity and in raising hippocampal 5-HT content.

[Analysis of the discrepancy of crown-root morphology of central incisors among different skeletal malocclusion using cone-beam CT]. Objective: To investigate the discrepancy of crown-root morphology of upper and lower central incisors in adult patients with different skeletal malocclusions using cone-beam CT (CBCT). Methods: Patients visiting the Department of Orthodontics, College of Stomatology, Xi'an Jiaotong University from January 2015 to December 2017 were selected, including 108 cases (52 males, 56 females, aged from 18 to 30 years, mean age 25.8 years). According to CBCT data and cephalometric analysis, 66 patients with average angle were selected as the sagittal skeletal group, including 24 Class Ⅰ patients, 20 Class Ⅱ and 22 Class Ⅲ patients. In the other selected 66 skeletal Class Ⅰ patients including 21 low angle patients, 24 average angle patients (from the sagittal skeletal Class Ⅰ subgroup) and 21 high angle patients. Invivo 5 software was used to locate the CBCT image three dimensionally and then obtain the middle labio-lingual section of right central incisor. Auto CAD 2007 software was applied to measure the angle formed by the long axis of root and the extension line of the long axis of crown (Collum angle), and the angle between the long axis of crown and the lip tangent line passing through the center of the labial surface of crown (labial surface angle). One-way ANOVA and Scheff were used to analyze the discrepancies among classifications and Pearson correlation analysis was used to determine the correlation between the Collum angles and labial surface angles. Results: Significant differences were found in Collum angles and labial surface angles among different sagittal skeletal patterns (P<0.05). The Collum angle of maxillary central incisors in Class Ⅱ patients was 5.18°±4.97° and the average labial surface angle was 17.78°±3.74°, which were both significantly higher than that of maxillary central incisors in Class Ⅰ and Ⅲ subgroups (P<0.05). Similarly, the above two angles of mandibular central incisors in Class Ⅲ were 5.59°±5.64° and 15.32°±3.05°, which were significantly higher than that of mandibular central incisors in Class Ⅰ and Ⅱ subgroups (P<0.05). There was no significant difference among different vertical skeletal patterns (P>0.05). Notably, the Collum angles of maxillary or mandibular central incisors presented significantly positive correlation with labial surface angles (maxillary: r=0.723, P<0.001; mandibular: r=0.752, P<0.001). Conclusions: The long axis of the crown of the maxillary central incisor in skeletal Class Ⅱ patients and the mandibular central incisor in skeletal Class Ⅲ patients are obviously deviated toward the lingual side relative to the long axis of the root, and correspondingly there is a greater labial surface angle of the crown, which indicates that equivalent positioning deviation during bracket bonding can cause greater torque expression error.

[The search for "od." Karl Ludwig Freiheer von Reichenbach (1788-1869) and Karl Wilhelm Mayrhofer (1806-1853), two joined against Justus von Liebig]. The author describes the controversy between Justus von Liebig on one side and Reichenbach and Mayrhofer on the other side. It is a controversy about problems of science and medicine which are characteristic for the late 18th and the first half of the 19th century, when Mesmerism and similar ideas of occultic and comparative phenomenona were discussed and often refused as being "not scientific". Justus von Liebig and Karl Ludwig Freiherr von Reichenbach were both chemists, both interested in scientific progress and working in this field. They were friends in the years 1830 to 1848. But later on this friendship ended when Reichenbach--who in the mean time moved to Vienna--became more and more interested in phenomenons seen by sensitive persons concerning effects of light. Although Reichenbach himself was not able to recognize the phenomenons he was sure that other persons had this ability. He had the impression that there is a special force floating through the universe, and this force he called "od". Liebig, who was not able to follow this theory and rejected it has speculation, turned against Reichenbach in 1852-3. So the controversy began and their old friendship came to an end. Reichenbach's theory of the "od", characteristic for the time of the romanticism and leading back to Mesmerism was accepted and supported by the Austrian physician Dr. Karl Wilhelm Mayrhofer who had aroused his interest by describing similar phenomenos some of this patients had. The letters of both men, the chemist and the doctor, which are well preserved (Technical Museum of Vienna) and discussed here, give a good impression of Reichenbach's ideas concerning his theory of the "od" and his philosophical ideas. As Reichenbach tried to find a philosophy corresponding to his theory and as he meant to have found this in the philosophy of Friedrich Eduard Beneke his remarks in those letters give a good information about Beneke's discussion of Reichenbach's theory. Mayrhofer, on the other hand, following Reichenbach's theory of the "od", rejected Beneke's philosophy because he himself joined another philisophy on the basis of the christian religion. However, when Reichenbach's latest book on these problems appeared in 1854, Beneke and Mayrhofer had died shortly before and no further discussion was possible. But Reichenbach's theory, based on the ideas of Mesmerism, and the controversial discussion about new explanations of the phenomenona seen by sensitive persons are characteristic for this time and also for our time as such perceptions are not entirely denied but thought over in a new way.

First Report of Cucumber mosaic virus Associated with Capsicum chinense var. Scotch Bonnet in Florida. Scotch bonnet (Capsicum chinense) is a tropical hot pepper variety that is grown in South America, the Caribbean Islands, and in Florida, and is an important cash crop. In Florida, scotch bonnet is grown on ~100 acres annually. Virus-like leaf symptoms including mosaic and yellow mottling were observed on scotch bonnet plants in a field at Quincy, FL, with a disease incidence of ~5%. Two symptomatic and one non-symptomatic plant sample were collected from this field for identification of the causal agent associated with the symptoms. Viral inclusion assays (2) of the epidermal tissues of the symptomatic scotch bonnet samples using Azure A stain indicated the presence of spherical aggregates of crystalline inclusion bodies. Testing of the symptomatic samples using lateral flow immunoassays (Immunostrips, Agdia, Elkhart, IN) specific to Cucumber mosaic virus (CMV), Potato virus Y (PVY), Pepper mild mottle virus (PMMoV), Tobacco mosaic virus (TMV), Zucchini yellow mosaic virus (ZYMV), and Papaya ringspot virus (PRSV), showed a positive reaction only to CMV. The sap from an infected leaf sample ground in 0.01 M Sorensons phosphate buffer (pH 7.0) was used to mechanically inoculate one healthy scotch bonnet plant (tested negative for CMV with Immunostrip) at the 2- to 3-leaf stage. The inoculated plant developed mild mosaic and mottling symptoms 12 to 14 days post inoculation. The presence of CMV in the mechanically inoculated plant was further verified using CMV Immunostrips. Total RNA was extracted (RNeasy Plant Mini Kit, Qiagen, Valencia, CA) from the previously collected two symptomatic and one non-symptomatic scotch bonnet samples. The samples were subjected to reverse-transcription (RT)-PCR assays using SuperScript III One-Step RT-PCR System (Invitrogen, Life Technologies, Grand Island, NY), and using multiplex RT-PCR primer sets (1). The primers were designed to differentiate the CMV subgroup I and II, targeting the partial coat protein gene and the 3'UTR. The RT-PCR assays using the multiplex primers produced an amplicon of 590 bp, with the CMV subgroup I primers. The RT-PCR product was only amplified from the symptomatic leaf samples. The obtained amplicons were gel eluted, and directly sequenced bi-directionally (GenBank Accession Nos. KF805389 and KF805390). BLAST analysis of these sequences showed 97 to 98% nucleotide identities with the CMV isolates in the NCBI database. The isolates collected in Florida exhibited highest identity (98%) with the CMV isolate from tomato (DQ302718). These results revealed the association of CMV subgroup I with symptomatic scotch bonnet leaf samples. Although CMV has been reported from scotch bonnet, this is the first report of its occurrence in Florida. References: (1) S. Chen et al. Acta Biochim Biophys Sin. 43:465, 2011. (2) R. G. Christie and J. R. Edwardson. Plant Dis. 70:273, 1986.

Effect of diet fermentability and unsaturated fatty acid concentration on recovery from diet-induced milk fat depression. Diet-induced milk fat depression is caused by highly fermentable and high-unsaturated fatty acid (FA) diets, and results in reduced milk fat concentration and yield, reduced de novo FA, and increased trans isomers of the alternate biohydrogenation pathways. The hypothesis of the current experiment was that a diet higher in fermentability and lower in unsaturated FA (UFA) would accelerate recovery compared with a high-UFA and lower-fermentability diet. Eight ruminally cannulated and 9 noncannulated multiparous Holstein cows were randomly assigned to treatment sequences in a replicated Latin square design. During each period milk fat depression was induced for 10 d by feeding a low-fiber, high-UFA diet [25.9% neutral detergent fiber (NDF) and 3.3% C18:2]. Following the induction phase, cows were switched to recovery treatments for 18 d designed to correct dietary fermentability, UFA, or both fermentability and UFA concentration. Treatments during recovery were (1) correction of fiber and UFA diet [control; 31.8% NDF and 1.65% C18:2], (2) a diet predominantly correcting fiber, but not UFA [high oil (HO); 31.3% NDF and 2.99% C18:2], and (3) a diet predominantly correcting UFA, but not fiber concentration [low fiber (LF); 28.4% NDF and 1.71% C18:2]. Milk and milk component yield, milk FA profile, ruminal pH, and 11 rumen microbial taxa were measured every third day during recovery. Milk yield decreased progressively in HO and control, whereas it was maintained in the LF diet. Milk fat concentration increased progressively during recovery in all treatments, but was on average 9% lower in LF than control from d 12 to 18. Milk fat yield increased progressively in all treatments and was not different between control and LF at any time point, but was lower in HO than control on d 15. Milk trans-10 C18:1 and trans-10,cis-12 conjugated linoleic acid decreased progressively in all treatments, but was higher in HO than control from d 3 to 18 [136 ± 50 and 188 ± 57% (mean ± SD)], whereas LF caused a smaller increase in these FA compared with control (67 ± 25 and 90 ± 22%). Additionally, milk trans-11 C18:1 and cis-9,trans-11 conjugated linoleic acid was decreased in control and LF and increased in HO during recovery. Selected microbial species observed changed during recovery, but major treatment differences were only observed for Streptococcus bovis. The LF diet that was similar in UFA but 3.4% units lower in NDF compared with to the control had a similar decrease in alternate trans biohydrogenation intermediates in milk. The HO diet that was similar in NDF but 2.0% units higher in UFA compared with the control had higher alternate trans biohydrogenation intermediates in milk compared with control. However, recovery of milk fat yield was similar between treatments at most time points.

Phosphatidylinositol 4,5-bisphosphate binding to the pleckstrin homology domain of phospholipase C-delta1 enhances enzyme activity. The pleckstrin homology (PH) domain is a newly recognized protein module believed to play an important role in signal transduction. While the tertiary structures of several PH domains have been determined, some co-complexed with ligands, the function of this domain remains elusive. In this report, the PH domain located in the N terminus of human phospholipase C-delta1 (PLCdelta1) was found to regulate enzyme activity. The hydrolysis of phosphatidylinositol (PI) was stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) in a dose-dependent manner with an EC50 = 1 microM (0.3 mol%), up to 9-fold higher when 5 microM (1.5 mol%) of PIP2 was incorporated into the PI/phosphatidylserine (PS)/phosphatidylcholine (PC) vesicles (30 microM of PI with a molar ratio of PI:PS:PC = 1:5:5). Stimulation was specific for PIP2, since other anionic phospholipids including phosphatidylinositol 4-phosphate had no stimulatory effect. PIP2-mediated stimulation was, however, inhibited by inositol 1,4, 5-triphosphate (IP3) in a dose-dependent manner, suggesting a modulatory role for this inositol. When a nested set of PH domain deletions up to 70 amino acids from the N terminus of PLCdelta1 were constructed, the deletion mutant enzymes all catalyzed the hydrolysis of the micelle forms of PI and PIP2 with specific activities comparable with those of the wild type enzyme. However, the stimulatory effect of PIP2 was greatly diminished when more than 20 amino acid residues were deleted from the N terminus. To identify the specific residues involved in PIP2-mediated enzyme activation, amino acids with functional side chains between residues 20 and 40 were individually changed to glycine. While all these mutations had little effect on the ability of the enzyme to catalyze the hydrolysis of PI or PIP2 micelles, the catalytic activity of mutants K24G, K30G, K32G, R38G, or W36G was markedly unresponsive to PIP2. Analysis of PIP2-stimulated PI hydrolysis by a dual substrate binding model of catalysis revealed that the micellar dissociation constant (Ks) of PLCdelta1 for the PI/PS/PC vesicles was reduced from 558 microM to 53 microM, and the interfacial Michaelis constant (Km) was reduced from 0.21 to 0.06 by PIP2. The maximum rate of PI hydrolysis (Vmax) was not affected by PIP2. These results demonstrate that a major function of the PH domain of PLCdelta1 is to modulate enzyme activity. Further, our results identify PIP2 as a functional ligand for a PH domain and suggest a general mechanism for the regulation of other proteins by PIP2.

Analyses of 24-hour growth hormone profiles in children: relation to growth. The relationship between height and amount of GH measured during a 24-h period was studied in 127 children who were growing at different rates. Of the children, 88 were prepubertal (3-16 yr old) and 39 were pubertal (10-16 yr old). The height of each child was expressed as the SD score, i.e. height in relation to the sex- and age-matched Swedish reference groups, and spontaneous GH secretion was estimated by taking integrated 20-min blood samples for a 24-h period, i.e. 72 samples/child. In a few children, discrete samples were taken in parallel with the integrated 20-min samples with virtually the same results. Plasma GH was estimated in each sample using a polyclonal RIA method. To compare different 24-h GH profiles, the profiles were analyzed using a computer program (Pulsar). One objective of the study was to determine if less frequent sampling and/or shorter sampling periods yielded the same information as that obtained by 20-min sampling for the whole 24-h period. To determine if less frequent sampling provided the same information as that obtained by the 20-min period, we simulated 40- and 60-min periods by pooling two or three consecutive samples. No difference was found between 20- and 40-min sampling, but with 60-min sampling the mean calculated baseline plasma GH concentrations increased, and the GH concentration within peaks [the area under the curve above the baseline (AUCb)] decreased markedly. A 30-min sampling interval thus seems to be a valid practical compromise. To determine if sampling periods shorter than 24 h provided the same information, we divided the profiles, which started at 0900 h, into two 12-h, three 8-h and four 6-h periods. A graded decrease in AUCb and a corresponding increase in the baseline was found with the shorter periods, indicating that the whole 24-h period is necessary for GH sampling. Another objective of the study was to determine whether there was a correlation between 24-h GH secretion and the height, age, and sex of the children. In the prepubertal children, the height (in SD scores) was highly correlated (r = 0.69; P less than 0.001) with GH AUCb during the 24-h period. Height also correlated with AUCb estimated over shorter time periods; the correlation diminished with decreasing time. In the pubertal children, a nonlinear correlation (r = 0.36; P less than 0.05) was found between height and 24-h GH (AUCb).(ABSTRACT TRUNCATED AT 400 WORDS)

Needle aspiration versus intercostal tube drainage for pneumothorax in the newborn. Pneumothorax occurs more frequently in the neonatal period than at any other time of life and is associated with increased mortality and morbidity. It may be treated with either needle aspiration or insertion of a chest tube. The former consists of aspiration of air with a syringe through a needle or an angiocatheter, usually through the second or third intercostal space in the midclavicular line. The chest tube is usually placed in the anterior pleural space passing through the sixth intercostal space into the pleural opening, turned anteriorly and directed to the location of the pneumothorax, and then connected to a Heimlich valve or an underwater seal with continuous suction. To compare the efficacy and safety of needle aspiration and intercostal tube drainage in the management of neonatal pneumothorax. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 11), MEDLINE via PubMed (1966 to 30 November 2015), EMBASE (1980 to 30 November 2015), and CINAHL (1982 to 30 November 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing needle aspiration (either with the needle or angiocatheter left in situ or removed immediately after aspiration) to intercostal tube drainage in newborn infants with pneumothorax. For each of the included trial, two authors independently extracted data (e.g. number of participants, birth weight, gestational age, kind of needle and chest tube, choice of intercostal space, pressure and device for drainage) and assessed the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are mortality during the neonatal period and during hospitalisation. One randomised controlled trial (72 infants) met the inclusion criteria of this review. We found no differences in the rates of mortality (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.27 to 8.45) or complications related to the procedure. After needle aspiration, the angiocatheter was left in situ (mean 27.1 hours) and not removed immediately after the aspiration. The angiocatheter was in place for a shorter duration than the intercostal tube (mean difference (MD) -11.20 hours, 95% CI -15.51 to -6.89). None of the 36 newborns treated with needle aspiration with the angiocatheter left in situ required the placement of an intercostal tube drainage. Overall, the quality of the evidence supporting this finding is low. At present there is insufficient evidence to determine the efficacy and safety of needle aspiration versus intercostal tube drainage in the management of neonatal pneumothorax. Randomised controlled trials comparing the two techniques are warranted.

New oxaliplatin-based combinations in the treatment of colorectal cancer. The synergism between oxaliplatin and 5-fluorouracil (5FU)/leucovorin in the treatment of colorectal cancer raises the prospect of further clinically effective combinations. Phase I/II trials of capecitabine, an oral fluoropyrimidine, plus oxaliplatin have established this combination (XELOX) as an effective treatment for advanced disease, with response rates of over 50% in first line therapy. Phase III studies of XELOX are now in progress, while further studies are investigating the combined use of oxaliplatin and a second oral fluoropyrimidine, UFT, after positive phase I/II results. Studies of combined oxaliplatin and irinotecan treatment have reported response rates varying from 25% to 60% in second-line therapy of treatment resistant metastatic disease, and 42% in first line therapy. The optimum dosing combination of these two agents has yet to be determined however, and in many patients it is likely that greater overall survival will be achieved by using them in successive lines rather than in combination. Clinical studies have also demonstrated clinically significant response rates when oxaliplatin is combined with other agents including raltitrexed and mitomycin C. Alongside these novel chemotherapeutic combinations, a range of biological therapies is now being investigated in combination with oxaliplatin in advanced colorectal cancer. Cetuximab (C225) is a monoclonal antibody that inhibits signalling through the epidermal growth factor receptor (EGFR), a pathway that has been associated with a variety of pathological process in cancer including dysregulated growth, differentiation, angiogenesis, cell motility and cell adhesion. Studies of second-line therapy combining oxaliplatin and cetuximab in advanced disease and in patients with unresectable liver-only metastases are in progress in the United States. A phase I/II study is also investigating the combined use of oxaliplatin and ZD1839 ('Iressa'), a small molecule inhibitor of the EGFR specific tyrosine kinase activating the same pathways. Anti-angiogenesis agents are also being studied intensely. A key angiogenic pathway in the stimulation of tumour growth is the vascular endothelial growth factor (VEGF) pathway, inhibited by the monoclonal antibody bevacizumab. Phase II first line and phase III second line studies of oxaliplatin in combination with bevacizumab are now in progress. Oxaliplatin is being investigated in combination with a number of other classes of biological agent, including the proteasome inhibitor PS-341. The sudden appearance of a wide range of chemotherapeutic and biological agents with activity against colorectal cancer presents many challenges to the current system of clinical trials, given the large number of permutations requiring prospective testing. However, by building upon the encouraging results achieved using oxaliplatin plus 5FU/leucovorin, the introduction of new agents will eventually translate into significantly improved clinical outcomes.

Influence of aluminum on the regulation of PTH- and 1,25(OH)2D3-dependent pathways in the rat osteosarcoma cell line ROS 17/2.8. The role of hormonal status in the development of aluminum (Al)-dependent renal osteodystrophy, which is characterized by reduced bone matrix deposition, still remains largely unknown. To address this question, we used the osteoblast-like osteosarcoma cell line ROS 17/2.8 to evaluate the role of Al on parathyroid hormone (PTH)- and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-dependent activities in these cells. Al (1 microM) caused an inhibition of basal and 1,25(OH)2D3-induced alkaline phosphatase, but only at low doses (< 1 nM) of the steroid. Al partly inhibited basal osteocalcin (OC) secretion in ROS cells (p < 0.001), and the dose-dependent increase in 1,25(OH)2D3-induced OC release by these cells was also reduced by 1 microM Al at low concentrations of the steroid (< or = 1 nM), whereas high doses of 1,25(OH)2D3 (> or = 5 nM) totally prevented the inhibiting effects of Al. Al also had strong inhibitory actions on PTH-dependent cAMP production by ROS cells over the concentration range tested (0.5-50 nM). This inhibitory action of Al was also observed for PTH-related peptide- (PTHrp, 50 nM) but not for Isoproterenol-dependent (100 nM) cAMP formation. To evaluate more fully the mechanism of this inhibition of cAMP formation, we investigated the effect of Al on toxin-modulated, G protein-dependent regulation of cAMP formation and on the activation of adenylate cyclase by Forskolin. Cholera toxin (CT, 10 micrograms/ml), applied to cells for 4 h prior to PTH challenge, enhanced cAMP production about 2-fold above PTH alone (p < 0.001), a process that was further stimulated by Al. Pertussis toxin (PT, 1 microgram/ml, 4 h) did not modify basal PTH-dependent cAMP formation by ROS cells. However, PT treatment prevented the inhibitory effect of Al on cAMP formation by these cells (p < 0.025). The stimulation of adenylate cyclase by Forskolin (0.1 and 1 microM), which bypasses G protein regulation, was not modified by Al, indicating that Al does not affect adenylate cyclase directly. Northern blot analysis of PTH receptor mRNA levels showed that Al did not modify PTH receptor message in ROS cells. Likewise, Western blot analyses of G protein subunits showed that Al did not significantly alter Gs alpha subunit levels, in accordance with the results obtained for cAMP-dependent formation in response to CT. In contrast, Gi alpha-1 and Gi alpha-2 subunits were decreased by Al treatment, consistent with PT-restricted increases in cAMP formation in Al-treated ROS cells. Taken together, these results suggest that Al has multiple actions in osteoblast-like ROS cells. The effects of Al are modulated by hormonal control of the pathways investigated. Al affects 1,25(OH)2D3-regulated functions only when this steroid is low. Al has large inhibitory effects on PTH- and PTHrp-dependent cAMP formation. This last feature is related to the ability of Al to alter the G protein transducing pathway for PTH/PTHrp-dependent formation of cAMP since it does not affect adenylate cyclase activity directly and does not affect the PTH receptor message level. Thus, Al has stronger deleterious effects in osteoblast-like cells with an already compromised 1,25(OH)2D3 status and can modulate specifically PTH/PTHrp-mediated cAMP formation at the postreceptor level.

Microscopic polyangiitis: clinical aspects and treatment. Recently individualized from polyarteritis nodosa (PAN), microscopic polyangiitis (MPA) is defined as a systemic necrotizing vasculitis that clinically and histologically affects small-sized vessels (ie, capillaries, venules or arterioles) without granulomata and is associated with focal segmental necrotizing glomerulonephritis. Males are more frequently affected than females and the average age of onset is about 50 years old. Most patients experience some systemic symptoms before diagnosis of vasculitis. Clinically, renal involvement is the major feature of MPA and is characterized by rapidly progressive glomerulonephritis (RPGN). Most of the patient have renal impairment at admission and renal function deteriorates rapidly without treatment. Lung involvement is also common. Lung hemorrhage is observed in 12 to 29% of the patients with MPA and is an important contributory factor to morbidity and mortality. Some patients with small-vessel lung vasculitis may present clinical, radiologic and functional findings consistent with an interstitial process mimicking idiopathic pulmonary fibrosis. Others clinical features are similar to those observed in PAN. Musculoskeletal involvement (myalgias, arthralgias and arthritis) are present in 65 to 72% of the patients. Cutaneous lesions (purpura, splinter hemorrhages) are found in 44 to 58% of the patients. Gastrointestinal symptoms are characterized by abdominal pain (32 to 58%) and digestive tract bleeding (29%). Peripheral neuropathy is found in only 14 to 36% of the cases, thus occurring less frequently than in PAN. Ocular manifestations and ear, nose and throat lesions are commonly seen, more frequently than in PAN. Non-specific laboratory tests reflect the systemic inflammatory nature. Almost all patients are negative for hepatitis B virus (HBV) surface antigen. Renal insufficiency with creatininemia > 120 microns/l is present in the majority of patients. Antineutrophil cytoplasm antibodies (ANCA) are found in 75% of MPA patients and the majority of these ANCA detected are perinuclear-staining anti-myeloperoxidase ANCA, although anti-proteinase 3 has also be detected. Microaneurysms, commonly present in PAN, are rarely seen on at visceral angiograms. MPA is part of a spectrum of systemic vasculitides. Differentiation between PAN and MPA should be based on clinical manifestations (especially lung and kidney involvement), biologic signs (ANCA, HBV or HCV infection) and angiographic data. The therapeutic strategies for treatment of PAN and MPA do not differ extensively. Prognosis of systemic vasculitides have been transformed by corticosteroids that are the basis of the treatment. Immunosuppressive drugs, especially cyclophosphamide, also contribute to a better prognosis. Considering the high frequency of renal involvement in MPA, most of the patients should considered as having factors or poor prognosis and the high number of relapses that can occur in patients with MPA could justify prolonged steroid administration or immunosuppressive treatment.

Effects of extreme pH on the physiology of the Australian 'yabby' Cherax destructor: acute and chronic changes in haemolymph carbon dioxide, acid-base and ionic status Freshwater habitats throughout the world are becoming increasingly threatened by the likelihood of acidification, but little consideration has been given to the importance of severe alkalization. Acute and chronic fluctuations in haemolymph acid&shy;base status (PCO2, CCO2 and pH), [Na+] and [Ca2+] were monitored for up to 504 h (21 days) in the Australian freshwater crayfish Cherax destructor exposed to low- and high-pH water. The importance of carapace [Ca2+] during acid exposure was assessed. Crayfish were exposed to pH 7.1, pH 4.5 and pH 8.0 water containing calcium at 500 &micro;mol l-1 while the effect of a lower calcium concentration (50 &micro;mol l-1) was assessed in pH 4.5 water. Cherax in acid water containing 50 &micro;mol l-1 Ca2+ exhibited a significant decrease in CO2 content after 2 h (mean decrease 1.13 mmol l-1, venous; 1.57 mmol l-1, arterial) and large ranges in PCO2 throughout the treatment (2.4&shy;7.3 mmHg). The overall acid&shy;base response was a metabolic acidosis compensated by a respiratory alkalosis. The haemolymph Na+ concentration in both control (pH 7.1, 50 &micro;mol l-1) and acid-exposed animals in lower-Ca2+ water was up to 50 % reduced compared with that in animals in pH 7.1, 500 &micro;mol l-1 Ca2+ water. Ion regulatory mechanisms, causing a subsequent increase in haemolymph [Na+] after 288 h, were implicated as an important component in acid&shy;base homeostasis. Crayfish in acid, low-Ca2+ water also exhibited a 3.2 mmol l-1 increase in haemolymph [Ca2+] and showed a haemolymph alkalosis compared with animals in acid water with higher [Ca2+]. At higher water [Ca2+] in pH 4.5 water (500 &micro;mol l-1 Ca2+), the haemolymph pH of Cherax was only 0.1 unit lower than that of animals in 50 &micro;mol l-1 Ca2+ acid water after 96 h, and both CaCO2 and CvCO2 were unchanged compared with the initial condition. As with low-Ca2+ acid-exposure, the potential haemolymph acidosis appeared largely to be compensated by respiratory alkalosis. There was a transient 31 % reduction in haemolymph [Na+], although osmolality was unchanged (control 411&plusmn;7.29 mosmol kg-1). Acid&shy;base equilibrium recovered rapidly, probably in association with changes in ion flux and the re-establishment of normal haemolymph Na+ concentration. Alkaline-exposed Cherax destructor exhibited a mixed respiratory alkalosis and metabolic acidosis. Whereas haemolymph [Ca2+] increased by 1.8 mmol l-1 after only 1 h, haemolymph Na+ levels increased by 36 % after 2 h, possibly as part of a net H+ loss from the haemolymph. Increased HCO3-/Cl- exchange could contribute to the 4.3 mmol l-1 decrease in haemolymph CO2 level after 0.5 h of alkaline exposure. The responses of Cherax to extreme pH are different from those of the European and North American crayfish species studied to date.

Treatment of cerebral arteriovenous malformations with a combination of preoperative embolization and surgery. Forty-nine patients with cerebral arteriovenous malformations (AVMs) were treated with preoperative embolization followed by resection using a microsurgical approach. In 27 patients, the AVM was located in an eloquent area; in 32 patients, the volume of the AVM was over 20 cm3. Preoperatively, flow-directed embolization was performed in 10 patients (28 procedures), selective embolization with threads was performed in 35 patients (46 procedures), and a combination of flow-directed and selective embolization was performed in 4 patients (12 procedures). The percentage of reduction of the AVM volume averaged 36% after embolization. Five minor complications (transient neurological deficits, in 2 cases associated with ischemic areas on the CT scan) were observed after embolization. The interval between the last embolization and surgery was as follows: within 10 days in 7 patients; between 11 and 20 days in 3 patients; between 21 and 30 days in 10 patients; between 31 and 60 days in 11 patients; and 2 months later in 18 patients. The efficacy of this combined treatment (embolization plus surgery) was evaluated by the incidence of hyperemic complications and the clinical outcome. Hyperemic complications occurred more frequently in patients with an AVM volume greater than 20 cm3. When compared with flow-directed embolization, selective embolization was linked with decreased bleeding during surgery; postoperatively, the incidence of cerebral edema was also lower. Clinical outcome was better after selective embolization, with no occurrence of major deficits and no mortality. When the percentage of reduction of the AVM volume after embolization was 40% or more, the incidence of intraoperative hyperemic complications was lower; moreover, new permanent deficits were never observed in patients with this volume reduction. A retrospective clinical comparison of two groups of patients with similar AVM volumes (greater than 20 cm3)--those given combined treatment (n = 32) versus those treated by direct surgery alone (n = 27)--showed that intraoperative bleeding appeared to decrease in patients treated by embolization; the incidence of postoperative hyperemic complications was not different in the two groups. New major deficits and deaths were less frequent in patients treated by embolization (P = 0.05 for the incidence of major deficits); postoperative epilepsy was also less common in these patients. In conclusion, combined treatment with selective preoperative embolization and direct surgery may help the neurosurgeon in the treatment of large, high-flow AVMs, reducing the risks connected with their surgical removal.

Culture, universals, and the personal. This chapter summarizes a part of the case that can be made that the individual construction of a personal domain of choice and privacy generalizes across cultures and is not restricted to persons who live within Western or so-called modern societies. The research findings reported here are consistent with the view that persons seek to establish such areas of control in order to maintain a differentiated personal identity and a sense of personal agency. Children, adolescents, and adults from the United States and traditional cultures have been found to identify a class of behaviors and issues as being outside the legitimate sphere of social or moral regulation. Mothers from Western and traditional cultural settings recognize and foster their children's claims to areas of personal choice and privacy. Across cultures, as children mature and move toward adulthood, they lay claim to a broader range of issues and actions as personal matters. Research on adolescent-parent conflict with U.S. and Chinese samples has indicated that these shifts associated with adolescent claims to freedom are the source of most family conflicts. Anthropological accounts of adolescent-parent conflicts in 160 cultures have provided evidence that such conflicts are widespread (Schlegel and Barry, 1991). Finally, we are beginning to obtain evidence that parental overcontrol of personal issues is associated with symptoms of psychological problems in their adolescent children. These research findings are consistent with the proposal (Nucci, 1996) that establishment of a personal domain is an intrinsic feature of normal human development, resulting from the inevitable attempt by individuals to account for and differentiate between their own motives, values, and experiences and those of others. The evidence also points to the fact that such personal issues are coexistent with concerns for interpersonal harmony and social integration. Thus, it is not surprising that the work summarized here also suggests considerable social-class and cultural variation in how the personal is expressed. Such variation is consistent with the assumption that the personal is constructed out of social interactions (Nucci, 1996) that entail reciprocal interchange between individual and societal structures (Turiel, 1996). In Spiro's analysis (1984), the results of such reciprocal structural interaction cannot be accounted for by reducing the analysis of psychological structures in terms of cultural structures and vice versa. Thus, any accurate interpretation of the impact of culture on psychological development must be constrained by features that are peculiar to psychological systems. Extending this to the cross-cultural study of the personal domain, a case can be made for the need to explore such issues at the level of the individual, rather than at the level of the cultural shared-symbol system. On the other hand, this nonreductionist approach and the available evidence rule out the reification of the personal as a culturally empty set of psychological issues. As illustrated in studies of the distribution of rights in relation to gender and social hierarchy among Druze Arabs (Wainryb and Turiel, 1994), the interplay between the personal and the cultural system of roles and obligations provides a rich and contradictory portrait that can be understood only by shifting perspective from the social to the individual and back again without favor.

Choroid plexus tumors in adult and pediatric populations: the Cleveland Clinic and University Hospitals experience. Choroid plexus tumors (CPT) are rare neoplasms accounting for 1-4% of all pediatric brain tumors. They are divided into choroid plexus papilloma (CPP), atypical choroid plexus papilloma (APP) and choroid plexus carcinoma (CPC). CPTs are known to primarily affect children less than 2 years of age. Gross total resection is the most important predictor of survival especially in CPC. Although small case series have been published, limited clinical data are available to describe treatment and outcome of CPTs. More clinical data would be necessary to complete the picture, particularly in populations that are not age limited. Here we share data from the two major hospitals in Cleveland to describe treatment and outcome of adult and pediatric patients. We performed a retrospective analysis of patients with CPT seen in Cleveland Clinic from 1990 to 2015 and at University Hospitals from 1994 to 2015. Results were compared to previously published historical controls. We identified 30 cases with CPT, including 22 pediatric and eight adult cases; 11 females and 19 males. The mean age at presentation was 12.4 years with a median age of 4.5 years (range 2 months-51 years). Gross total surgical resection was achieved in 22, subtotal resection in four, partial resection in two and unknown in two. The histology was CPP in 23 patients, two of whom developed recurrence requiring repeat resection and adjuvant therapy. Median event free survival (EFS) for CPP patients was 7.6 years. The histology was CPC in seven patients. All CPC patients were treated with adjuvant therapy. Median EFS of CPC patients was 4.4 years. Overall survival of all CPT patients was 100% with a median follow up of 7 years. A systematic literature review identified 1012 CPT patients treated from 1989 to 2013. The mean and median age of CPT patients was 13 and 3 years respectively. The median survival of 541 CPP patients was undefined vs. 2.7 years for the 452 CPC patients. The difference between the two populations was highly significant (p < 0.001). Kaplan-Meier survival curves comparing CPTs at Cleveland Clinic and University Hospitals versus a systematic literature review showed a statistically significant advancement in overall survival among the patients treated at Cleveland Clinic and University Hospitals. Our data are consistent with the literature review regarding epidemiology, clinical presentation, and treatment modalities but differed in regards to survival. Differences in survival may be related to different methods of data collection or details in patient care.

[Effects of bond strength evaluation on different durations of adult permanent teeth and youth permanent teeth by using universal adhesives to dentin]. To compare the dentin bonding strength evaluation between adult permanent teeth and youth permanent teeth after treatment for different durations by universal adhesives. Ten adult permanent teeth and ten youth permanent teeth were selected for this study. The occlusal enamel layer was removed, and each tooth was cut into three pieces along the long axis. In total, 30 pieces of adult and youth teeth were prepared. The adult and youth teeth pieces were randomly divided into three groups and treated by universal adhesives for 10, 20, and 30 s. In this study, Scotchbond Universal (SBU) was selected as the universal adhesive. Slabs were treated by dual-cure resin cements. The specimens were tested by microshear strength test through a universal testing machine. Fracture modes were observed by a stereomicroscope. Other adult teeth and youth teeth were selected, two for each type, and treated and grouped in the same manner. Fluorescein (0.1% Rhodamine B) was dissolved in SBU adhesive, and the specimens were treated by the adhesives for 10, 20, and 30 s. Micromorphology of the resin protrusions on the adhesive surface was observed by laser confocal microscopy (CLSM). For the adult teeth, the highest micro-shear bonding strength was observed in the 20 and 30 s groups, and the values were higher than that of the 10 s group (P<0.05). For the youth teeth, the highest micro-shear bonding strength was observed in the 10 and 20 s groups, and the values were higher than that of the 30 s group (P<0.05). The micro-shear bonding strength in the 10 s youth teeth group was higher than that of the 10 s adult teeth (P<0.05) and was same as the adult teeth treated for 20 s (recommendation time of material instructions) (P>0.05). The main break patterns in different groups comprised adhesive failure fractures and several mixed failure fractures. No resin fracture mode was observed. CLSM revealed very few short resin protrusions in 10 s adult teeth group, whereas the number and length of resin protrusions significantly increased in the 20 s adult teeth group. The resin protrusions of the 30 s group were shorter than those of the 20 s adult teeth group. In different durations, the bonding interface in different youth teeth groups presented the same trend of change as the adult teeth. However, the number and length of resin protrusions in the 10 s group of youth teeth were all higher than those of the 10 s adult teeth group. In clinical practice, the bonding agent treatment duration shall be shortened appropriately for youth permanent teeth, and that for adult permanent teeth shall not be shortened to less than 20 s. On the whole, the bond strength of youth permanent teeth can achieve no significant difference with the adult permanent teeth.

Basal, pulsatile, entropic, and 24-hour rhythmic features of secondary hyperprolactinemia due to functional pituitary stalk disconnection mimic tumoral (primary) hyperprolactinemia. Under physiological conditions, PRL secretion is regulated precisely by various stimulating and inhibiting factors. Hyperprolactinemia may arise as a primary consequence of a PRL-secreting pituitary adenoma. Secondary hyperprolactinemia (SH) may emerge in patients with hypothalamic disease, hypophyseal stalk compression, or suprasellar extension of a (nonlactotrope) pituitary adenoma. The latter may reflect diminished delivery of dopamine or other inhibitory factors to normal lactotropes. We hypothesized that diurnal and ultradian rhythms of PRL secretion would differ in secondary (e.g. hypothalamic) and primary (e.g. tumoral states) hyperprolactinemia (PH), assuming that the underlying pathophysiologies differ. To test this clinical postulate, we investigated the patterns of 24-h PRL release in eight patients with SH associated with functional hypothalamo-pituitary disconnection and in eight patients with PH attributable to microprolactinoma. Data in each group were compared with values in healthy gender-matched controls. PRL time series were obtained by repetitive 10-min blood sampling, followed by high- precision immunofluorometric assay. PRL concentration profiles were analyzed by the complementary tools of model-free discrete peak detection, waveform-independent deconvolution analysis, cosinor regression, and the approximate entropy metric to quantitate pulsatile, basal, 24-h rhythmic, and pattern-dependent (entropic) PRL secretion. Patients with tumoral hyperprolactinemia (PH) showed a 2-fold higher 24-h mean serum PRL concentration than patients with SH (62 +/- 13 microg /L vs. 30 +/- 6.9 microg/L, respectively, P = 0.029). Estimated PRL pulse frequency (events/24 h) was similar in the two patient groups (18.5 +/- 0.7 vs. 17.6 +/- 0.8; P = 0.395) but elevated over that in euprolactinemic controls (P < 0.0001 for both). Deconvolution analysis disclosed a mean daily PRL secretion rate of 790 +/- 170 microg in PH patients vs. 380 +/- 85 microg in SH patients (P = 0.030). Nonpulsatile PRL secretion comprised nearly 70% of total secretion in both patient groups and 50% in controls (P < 0.0001). Cosinor analysis revealed similar acrophases in all three study cohorts. The mean skewness of the statistical distribution of the individual PRL sample secretory rates was reduced, compared with controls (P < 10 (-5) for each), but equivalent in SH and PH patients (0.83 +/- 0.12 vs. 0.78 +/- 0.08, respectively), denoting a loss of the normal spectrum of low- and higher-amplitude secretion rates. Approximate entropy, a regularity statistic, was markedly elevated in both patient groups over controls (P < 10 (-6) for each) and was slightly higher in PH patients than in SH patients (1.639 +/- 0.029 vs. 1.482 +/- 0.067, P = 0.048). In summary, patterns of PRL secretion in PH and SH states exhibit an equivalently increased frequency of PRL pulses, a comparably marked rise in nonpulsatile (basal) PRL secretion. Despite overlap, the regularity of PRL release patterns is disrupted even more profoundly in PH (tumoral), compared with SH. Assuming that the orderliness of serial PRL output monitors normal integration within a feedback-controlled neurohormone axis, then the more disorderly patterns of tumoral PRL secretion point to greater regulatory disruption in PH. The latter may reflect abnormal secretory behavior associated with lactotrope neoplastic transformation and/or isolation of the tumor cell mass from normal hypothalamic controls.

Control of vasogenic edema in a brain tumor model: comparison between dexamethasone and superoxide dismutase. The production of prostaglandin (PG) within brain tumors probably generates excessive amounts of oxygen free radicals that may disrupt microvessel permeability within the tumor and in the adjacent brain. We evaluated the effect of systemic therapy with recombinant human manganese-superoxide dismutase (r-hMnSOD) and with dexamethasone on the vascular permeability (VP) of a brain tumor and the adjacent brain. Treatment effect was also evaluated in control animals subjected to mild penetration injury. Fischer rats were injected stereotactically with either 10(5) cells of malignant sarcoma or with vehicle into the right parietal hemisphere. Nine days later, the animals were treated with r-hMnSOD (50 mg/kg of body weight every 12 h [one intravenous, then two intraperitoneal injections]; serum levels, 1100-1800 micrograms/ml), dexamethasone (2 mg/kg every 12 h [one intravenous, then two intraperitoneal injections]), or vehicle and were killed after 30 hours for evaluation of VP and PG production. The VP was markedly increased within the tumor (P < 0.001), in the brain adjacent to it, and in the vehicle injection site. The VP of the normal brain was unaffected by r-hMnSOD or dexamethasone treatment, unlike the VP in the tumor, the adjacent brain, and the injection sites of control animals, where it was reduced by 50, 54, and 23%, respectively (P < 0.04), for r-hMnSOD and 50, 41, and 71%, respectively (P < 0.05), for dexamethasone. A one- to threefold increase in synthesis of thromboxane and PGE2 was measured within the tumor, the adjacent brain, and the injection sites of control animals (P < 0.0001). Treatment with r-hMnSOD had no effect on tumor PG production, but it reduced the synthesis in the brain tissue adjacent to the tumor and in traumatized control animals (P < 0.04). Immunohistochemical evaluation revealed vascular proliferation with abnormal basal membrane, atypical astrocytes, and large numbers of reactive macrophages present in the adjacent brain and at the injection sites of control animals but not within the tumor mass. Oxygen free radicals probably enhance vasogenic brain edema resulting from tumor and penetration injury. The edema can be attenuated by systemic r-hMnSOD therapy, which has been proven to be as effective as steroid treatment. An inflammatory response may account for oxygen free radical production in brain tissue adjacent to the tumor and at the injection site of vehicle solution, but other mechanisms probably generate oxygen free radicals within the tumor mass.

[Revision and optimization of processes: a fundamental timing for adequate use of the resources and technological innovation. An example of intervention in the cardiology field and considerations on "total quality" in medicine]. The Cardiology Unit of the Este General Hospital began its activity in 1988. We soon identified a mismatch between a good, up-to-date diagnostic instrumentation with growing customers' demand and an inadequate utilization of the instruments. Waiting lists were getting longer, customers were not satisfied, no-shows at the appointments increased and we had a progressive loss in image. We therefore decided to intervene on our processes, starting the project "TOTAL QUALITY IN CARDIOLOGY". We focused our attention on two main fields, namely (1) electrocardiography, (2) other diagnostic techniques, separately analyzed because of important differences. Point (1) is basically worked out by paramedical personnel, in high numbers and with stable demand, while point (2) is determinantly linked to medical activity, although with concomitant need for paramedical support. The figures are lower for point (2) but are steadily growing. In the two operating fields we further identified two separate adverse effects: 1). ELECTROCARDIOGRAPHIC EXAMINATIONS (ECG) ARE TOO TIME CONSUMING, 2) THE NUMBER OF DIAGNOSTIC PROCEDURES IS TOO LOW FOR THE INSTRUMENTS AVAILABLE. We used preliminary analysis with process flow diagrams and our interventional methods were policy deployment and daily routine work. ELECTROCARDIOGRAPHIC EXAMINATIONS ARE TOO TIME CONSUMING. From cause-effect diagram for cause classification and subsequent Pareto analysis we identified two groups of main causes: 1. the paramedical-patient team is not able to optimise usage of the instrument; in particular, total time for undressing of the patient, lead attachment, dressing of the patient, change in ECG conductivity cream and, if necessary, repetition of ECG for mistakes in procedure is much longer than operative time of the instrument; 2. the necessary copy of the ECG done by the instrument was too time consuming (2') as compared to total procedure time. Implementation plans have been as follows: activity was concentrated in one single room at constant temperature (20 degrees); we augmented the number of dressing rooms and nurses (from 1 to 2 unit); we substituted the ECG conductivity cream with a water-alcoholic solution and the copy with a photocopy. decrease in mean time for ECG from 6'52" to 3'25" (for example: total ECGs 1992: 14,827, total spared time: 852 working hours); reductions in dead times; capability to cope rapidly with high demand; consequent possibility to utilise paramedical personnel for other activities; reduction in copy costs from 156 to 50 Lit each (total reduction 1,571,662 Lit). EXPECTATIONS. further revision of the procedures to keep pace with new electrocardiographic instruments and to achieve shorter operative times.

An improved method of electrode placement in configuration Lead II for the reliable ECG recording by telemetry in the conscious rat. Telemetry represents the gold standard technique for the acquisition of animal haemodynamic signals in the pharmaceutical preclinical development of new chemical entities. In terms of electrocardiographic signal recording, the quality is well established in large animals, mainly dog, non human primates and minipig, whereas it is still lacking in terms of satisfactory results in rodents (mouse and rat in particular). In very recent times, an increasing interest in early safety prediction for the reduction of cardiovascular attrition has been raised in all the major pharmaceutical companies, focusing in particular, on in vivo models. Crl:CD(SD) and Wistar Han rats (Crl:WI[Han], Charles River) underwent surgery for the implantation of telemetry devices (Data Science International, USA) for the acquisition of blood pressure and electrocardiogram (ECG). A group of male CD rats (N=6) was implanted using the standard procedure as described by DSI technical documentation; another male CD group (N=3) was implanted using the technique described by Sgoifo et al. (1996); a third group (total of N=46, N=26 male CD rats, and N=10 male WI and N=10 female WI) was implanted using an alternative approach developed in our laboratory. The new surgical procedure was analysed based on technical difficulties, time to complete the surgery, time to recover, animal care, survival time after surgery and quality of telemetry signal recordings. Although a quantitative and qualitative comparison with other techniques described in literature was beyond the scope of the present work, based on our laboratory experience, Sgoifo's methodology showed better results compared to DSI standard approach, but surgical procedure was not easy to perform and more invasive. The novel approach described in the present paper was characterised by simplicity, repeatability, high rate of survival and improved quality of ECG signals for all the implanted rats. Telemetry in small rodents became of particular interest in the early safety assessment of cardiovascular liability during the development of new chemical entities. Although several surgical procedures are well described in literature, none seem to offer high standard electrocardiography signals in order to reliably detect intervals or arrhythmias. In the Safety Pharmacology Laboratory at GlaxoSmithKline, Verona (Italy), a novel and alternative surgical placement of the electrocardiographic electrodes in Lead II configuration was developed, in the rat. The scope of the present paper is to illustrate that this alternative surgical procedure is easily reproducible, minimally invasive and gives high standard quality ECG signals.

Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients. The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38% of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14% of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12% of SUCLA2 and in 10% of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69% of SUCLA2 and 80% of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.

Comparative effects of three 1,4-dihydropyridine derivatives [OSI-1210, OSI-1211 (etaftoron), and OSI-3802] on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers: relevance to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. The 1,4-dihydropyridines OSI-1210, OSI-1211 (etaftoron), and OSI-3802 are compounds with similar chemical structure. They differ by the length of the alkoxyl chain in positions 3 and 5 of the dihydropyridine (DHP) ring and by their pharmacological action characteristics. However, as far as we know, a clear relationship between the effects of these compounds and the length of the alkoxyl chain in positions 3 and 5 of the DHP has not been established. The goal of this study was to compare the influence of OSI-1210, OSI-1211 (etaftoron), and OSI-3802 on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers, correlating their actions with the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. Using either glutamate/malate or succinate as respiratory substrates, all the compounds, in concentrations of up to 500 microM, depressed state 3 and uncoupled respiration, respiratory control (RCR) and ADP/O ratios, and phosphorylation rate, whereas state 4 respiration was stimulated. However, the stimulatory effect on state 4 induced by OSI-3802, the compound with the longest chain in positions 3 and 5 of the DHP ring, as well as its inhibitory effects on RCR and ADP/O ratios and phosphorylation rate were more pronounced than that induced by OSI-1210 and OSI-1211 (etaftoron), the compounds with the shortest and intermediate chains, respectively. Moreover, OSI-3802 maximized state 4 stimulation and minimized RCR and ADP/O ratios, and phosphorylation rate at a concentration of 100 microM, whereas low graduate effects were detected with OSI-1210 and OSI-1211 (etaftoron) for concentrations of up to 500 microM. At low concentrations (< or =30 microM), OSI-3802, like its analogue OSI-1212 (cerebrocrast), reduced the phase transition temperature, the cooperative unit size, and the enthalpy associated with the phase transition temperature of dimyristoylphosphatidylcholine (DMPC) membrane bilayers. A good correlation was established between the effects of 200 microM OSI-1210, OSI-1211 (etaftoron), and OSI-3802 on glutamate/malate- and succinate-dependent RCR of rat liver mitochondria and on the enthalpy change (Delta H) for the thermotropic profile of DMPC membrane bilayers at a 0.2 drug/DMPC molar ratio, indicating that the changes induced by these compounds on both mitochondrial membrane integrity and physical properties of DMPC membrane bilayers are strongly related to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. A putative relationship between membrane physical perturbation, bioenergetics impairment and the molecular characteristics of the compounds will be established as an approach to better understand their differentiated toxicological and pharmacological actions.

Competing irradiation techniques for para-aortic lymph nodes: dose distribution and NTCP for the kidney. Partial coirradiation of both kidneys is an unavoidable consequence of adequate dose delivery in radiation therapy of para-aortic lymph nodes (PLN). Depending on total dose anteroposterior/posteroanterior (AP/PA), opposed-fields or multifield techniques are used. To optimize the treatment of potentially tumor-affected PLN with minimal kidney involvement, we calculated normal tissue complication probabilities (NTCPs) of coirradiated kidneys for four common irradiation techniques used in the PLN area. Planning target volume (PTV) delineation was performed in computed tomography scans of 21 patients with a lateral safety margin of 3 cm from the aorta and 2 cm aside the vena cava. Ventral and dorsal margins of the PTV were delineated 2 cm from the vessels. As previously shown (Nevinny-Stickel M, et al. Int J Radiat Oncol Biol Phys 2000;48:147-151), PTVs optimized by these altered delineations permit inclusion of at least 97% of potentially involved PLN in contrast to standard delineations based on bony structures that are more likely to miss affected lymph nodes. The present study compared NTCPs for individual PTV-based treatment planning with NTCPs for standard planning based on bony structures. For each patient, four hypothetical treatment plans were created: (A) standard AP/PA opposed fields technique with lateral field margins along the tips of the transverse processes of the vertebral bodies; (B) individually planned AP/PA opposed fields with lateral field margins according to the optimized PTV; (C) standard four-field box technique with lateral width as described for (A), with dorsal borders at the center of the vertebral bodies and ventral margins 3 cm in front of the vertebrae; and (D) individually planned four-field box with lateral field margins according to the optimized PTV. Calculation of irradiation-induced complication probability values for nonuniform kidney irradiation was performed for model doses 19.8 Gy, 30.6 Gy, and 50.4 Gy according to the Lyman-Wolbarst model. No dose showed a statistically significant difference (p < 0.00833, corrected for six multiple interrelated comparisons) in the median of total organ kidney NTCPs between techniques A, C, and D, with technique D intermediately ranging between technique A and C (e.g., for 50.4 Gy: A: median, 0.39; range, 0.01-0.83; C: median, 0.27 range; 0.05-0.68; D: 0.36; range, 0.03-0.72). In comparison to techniques A, C, and D, the individually planned AP/PA opposed-fields technique (B) was accompanied by significantly higher and intolerable overall kidney NTCP rates (e.g., for 50.4 Gy: median, 0.68; range, 0.01-0.99). Conformal four-field planning with individually optimized PTVs (D) resulted in only moderate tissue complication probabilities in both kidneys with the advantage of providing significantly greater inclusion of potentially involved PLNs in comparison to accepted standard procedures (A and C).

TB questions, East Kwaio answers: community-based participatory research in a remote area of Solomon Islands. East Kwaio is a remote region on the island of Malaita, Solomon Islands. Atoifi Adventist Hospital (the Hospital) is the only hospital and tuberculosis (TB) services provider in the region. If people come to the Hospital with TB, they are usually admitted for the two-month intensive phase of treatment as there are no community-based TB services. Most people walk or travel by canoe to the Hospital as there are no roads. East Kwaio is known to have high rates of TB; however, it has a low case detection rate and low treatment completion. The aims of this study were to explore why people with TB, especially from the mountain areas, present to the Hospital so late in their illness or do not present at all. The study was part of a larger project to strengthen the research capacity of local health workers and community leaders, supported by visiting researchers from Australia. Semi-structured interviews with TB patients, a focus group of key informants and direct interaction with a community with a history of TB were used to explore reasons why people present to the Hospital late in their TB illness. Four interviews and a focus group of 12 key informants were conducted and a mountain hamlet with a history of TB was visited. The results represent the data from the interviews and the focus group. The time delay in presenting to the Hospital from when participants first became unwell ranged between two and three years. In the mountain hamlet, two additional people with probable TB were seen who had not presented to the Hospital during illnesses of five and nine months. Reasons for delays included: seeking care from traditional healers; the challenge of accessing health services due to distance, cost and cultural issues different from the Hospital's worldview; social isolation when in hospital; and being old so not having long to live. Delays in diagnosis of people with TB will increase the risk of transmission to family and through hamlets and villages. This study has led to plans being developed to build a more culturally appropriate TB ward and community treatment program. The study has identified TB questions that need East Kwaio answers. It has shown that a small project can inform the development of important changes to TB services, such as the redevelopment and relocation of the TB ward. To enable TB control, the local health services need to develop an understanding of, and appropriately engage with, traditional beliefs that influence how people interact with Hospital TB treatment and management. This is the case even if the beliefs are based on a worldview different than that of the health service providers. Ongoing operational research is required into TB diagnosis and treatment services and the many factors that contribute to the high TB burden in this remote area.

Broad-band ultraviolet B phototherapy in zoster patients may reduce the incidence and severity of postherpetic neuralgia. Postherpetic neuralgia (PHN) is one of the common complications of herpes zoster infection, particularly in the elderly. Current therapeutic measures are only partially effective in the affected patients. As inflammatory mediators released by different cells play an important role in the pathogenesis of this neuropathic pain and with regard to the immunomodulatory effects of ultraviolet B (UVB) spectrum, we presumed that UVB phototherapy might be effective in the prevention of PHN. This study was performed in two phases. Phase I was a prospective open controlled trial. Twenty-five patients with severe pain in the first 7 days of zoster rash were divided into two groups: the prevention group (n=12) received oral acyclovir (800 mg five times a day for 10 days) plus broad-band UVB to the affected dermatomes, starting with 20 mJ/cm(2) and gradually increasing the dose by 10 mJ/cm(2) each session to a maximum dose of 100 mJ/cm(2). Treatment sessions were repeated three times a week until pain relief or to a maximum of 15 sessions. The control group (n=13), who had disease characteristics similar to the prevention group, received only oral acyclovir with the same dose. All patients reported their severity of pain on a verbal rating scale (VRS, score 0-4) before treatment and at 1 and 3 months' follow-up. In phase II of the study, five patients with established PHN (more than 3 months after rash onset) received UVB with the above-mentioned protocol. A total of 17 patients older than 40 (10 females, seven males; mean age, 65.5 years; range: 47-82 years) who had intractable pain due to zoster infection received UVB in two phases of the study. In patients who received phototherapy in the first 7 days of rash, 58.33% and 83.33% were completely pain free at 1-and 3-month follow-up, respectively. The corresponding figure in the control group was significantly lower (38.46% at 1 month and 53.85% at 3 months). The severity of pain was also lower in the phototherapy group than the control group (mean VRS 2.50 vs. 3.28 at 3 months). None of the patients who were treated more than 3 months after rash onset (established PHN) experienced significant (more than 50%) pain relief. UVB phototherapy in the acute stage of zoster rash might reduce the incidence and severity of PHN. Treatment after 3 months does not seem to have a significant beneficial effect.

Protective effects of vitamin E forms (alpha-tocopherol, gamma-tocopherol and d-alpha-tocopherol polyethylene glycol 1000 succinate) on retinal edema during ischemia-reperfusion injury in the guinea pig retina. The purpose of this study is to provide evidence that free radical damage is a component of retinal ischemia-reperfusion (I/R) injury, and to determine whether alpha-tocopherol, gamma-tocopherol and d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) can protect the retina from this injury. The right eyes of 40 male guinea pigs weighing 500-600 g were used. The animals were randomly assigned to group 1 (control), group 2 (I/R), group 3 (I/R plus alpha-tocopherol), group 4 (I/R plus gamma-tocopherol) and group 5 (I/R plus TPGS). Groups 3, 4 and 5 received four subcutaneous injections at six-hour intervals for total dosage of 800 IU/kg alpha-tocopherol, 1000 IU/kg gamma-tocopherol and 750 IU/kg TPGS, respectively. The first dose of each substance was administered 5 minutes before retinal ischemia. Retinal ischemia was induced for 90 minutes, then followed by reperfusion for 24 hours. Injections of three substances were repeated at 6, 12 and 18 hours during reperfusion. The animals were killed at 24 hours of reperfusion. Sagittal sections of 4 microm were cut and stained with hematoxylin and eosin for light microscopic evaluation. The average thickness (edema) of the inner plexiform layer for each eye was measured in sagittal sections near the optic nerve and expressed in microns. All the three substances showed statistically significant protection against the formation of retinal edema during ischemia-reperfusion injury. The mean thickness of the inner plexiform layer were 15.0, 25.44, 19.81, 21.38 and 20.88 microm in control, I/R, I/R plus alpha-tocopherol, I/R plus gamma-tocopherol and I/R plus TPGS groups, respectively. The results showed that the thickness of the inner plexiform layer in group 1 (control) was significantly lower than the other groups (p<0.001). The inner plexiform layer was thicker in the I/R group than with I/R plus alpha-tocopherol (p<0.001), I/R plus gamma-tocopherol (p<0.001) and I/R plus TPGS (p<0.01). The inner plexiform layer was not thicker in the I/R plus TPGS group than in the I/R plus alpha-tocopherol and I/R plus gamma-tocopherol groups. Compared to the I/R plus alpha-tocopherol group, the inner plexiform layer was significantly thicker in the I/R plus gamma-tocopherol group (p<0.01). The results from these experiments indicate that vitamin E forms have protective effects on the retina during retinal ischemia-reperfusion injury, but, the effects of alpha-tocopherol and TPGS appear to be much greater than that of gamma-tocopherol.

[Meta-analysis on efficacy and safety of external use of tradition Chinese medicines and western medicines in treating knee osteoarthritis]. To assess the efficacy and safety of the external use of tradition Chinese medicine (TCM) in treating knee osteoarthritis. By computer retrieval of MEDLINE, CNKI and VIP database on data from the establishment of database to May 2011,all of the randomized controlled trials on the external use of TCMs in treating knee osteoarthritis with western medicines as the control drugs were collected to screen out literatures in line with the inclusion standards. The quality of the included literatures was strictly assessed, and a meta-analysis was conducted by RevMan 5.1 software. Totally 25 RCTs involving 2 159 patients were included [1152 patients in the TCM group (TCMG), 1007 patients in the western medicine group (WMG)], in which 21 articles were brought into the analysis on efficacy. The results of meta-analyses showed that the efficient rates of the TCMG and the WMG were 92.35% (941/ 1019) and 81.19% (712/877), respectively, OR = 2.88 [2.16-3.83], with a hypothesis testing on total effect of Z = 7.20 (P < 0.00001)], suggesting that the external use of TCMs had a better efficacy than the WMG. A total of 25 literatures were brought into the analysis on adverse effect. The adverse effects rate of the TCMG and the WMG were 1.30% (15/1 152) and 5.36% (54/1007), respectively, OR = 0.40 [0.11-1.38], Z = 1.46 (P = 0.15)], indicating no significant difference between them. The sub group analysis shows that compared with the external use of western medicines,the adverse effect rate of the two groups are similar [(1.87% (11/589): 1.60% (9/564)], OR = l.12 [0.48-2.58], Z = 0.26 (P = 0.80). But as for inhibitors NSAIDS and COX-2 for oral,the adverse effect rate of the TCMG was lower than that of the WMG [(1.07% (4/375): 15.46% (45/291)], OR = 0.11 [0.01-0.87], Z = 2.09 (P = 0.04). The efficacy of the external use of TCMs in treating OA is better than that of western medicines. The adverse effect rates of the external use of TCMs is equivalent to that of western medicines, and significantly lower than that of oral western medicines. But because of the poor quality of the included literatures, the final conclusion for the efficacy of TCMs in treating knee osteoarthritis could not be reached only based on this Meta-analysis and remain to be proved with the results of high-quality clinical studies.

Guidetomeasure-OT: A mobile 3D application to improve the accuracy, consistency, and efficiency of clinician-led home-based falls-risk assessments. A key falls prevention intervention delivered within occupational therapy is the home environment falls-risk assessment process. This involves the clinician visiting the patient's home and using a 2D paper-based measurement guidance booklet to ensure that all measurements are taken and recorded accurately. However, 30% of all assistive devices installed within the home are abandoned by patients, in part as a result of the inaccurate measurements being recorded as part of the home environment falls-risk assessment process. In the absence of more appropriate and effective guidance, high levels of device abandonment are likely to persist. This study presents guidetomeasure-OT, a mobile 3D measurement guidance application designed to support occupational therapists in carrying out home environment falls-risk assessments. Furthermore, this study aims to empirically evaluate the performance of guidetomeasure-OT compared with an equivalent paper-based measurement guidance booklet. Thirty-five occupational therapists took part in this within-subjects repeated measures study, delivered within a living lab setting. Participants carried out the home environment falls-risk assessment process under two counterbalanced treatment conditions; using 3D guidetomeasure-OT; and using a 2D paper-based guide. Systems Usability Scale questionnaires and semi-structured interviews were completed at the end of both task. A comparative statistical analysis explored performance relating to measurement accuracy, measurement accuracy consistency, task completion time, and overall system usability, learnability, and effectiveness of guidance. Interview transcripts were analysed using inductive and deductive thematic analysis, the latter was informed by the Unified Theory of Acceptance and Use of Technology model. The guidetomeasure-OT application significantly outperformed the 2D paper-based guidance in terms task efficiency (p < 0.001), learnability (p < 0.001), system usability (p < 0.001), effectiveness of guidance (p = 0.001). Regarding accuracy, in absolute terms, guidetomeasure-OT produced lower mean error differences for 11 out of 12 items and performed significantly better for six out of 12 items (p = < 0.05). In terms of SUS, guidetomeasure-OT scored 83.7 compared with 70.4 achieved by the booklet. Five high-level themes emerged from interviews: Performance Expectancy, Effort Expectancy, Social Influence, Clinical Benefits, and Augmentation of Clinical Practice. Participants reported that guidetomeasure-OT delivered clearer measurement guidance that was more realistic, intuitive, precise and usable than the paper-based equivalent. Audio instructions and animated prompts were seen as being helpful in reducing the learning overhead required to comprehend measurement guidance and maintain awareness of task progression. This study reveals that guidetomeasure-OT enables occupational therapists to carry out significantly more accurate and efficient home environment falls-risk assessments, whilst also providing a measurement guide tool that is considered more usable compared with the paper-based measurement guide that is currently used by clinicians in practice. These results are significant as they indicate that mobile 3D visualisation technologies can be effectively deployed to improve clinical practice, particularly within the home environment falls-risk assessment context. Furthermore, the empirical findings constitute overcoming the challenges associated with the digitisation of health care and delivery of new innovative and enabling technological solutions that health providers and policy makers so urgently need to ease the ever-increasing burden on existing public resources. Future work will focus on the development and empirical evaluation of a mobile 3D application for patient self-assessment and automated assistive equipment prescription. Furthermore, broader User Experience aspects of the application design and the interaction mechanisms that are made available to the user could be considered so as to minimize the effect of cognitive overloading and optimise user performance.

Molecular electrocatalysts for oxidation of hydrogen using earth-abundant metals: shoving protons around with proton relays. Sustainable, carbon-neutral energy is needed to supplant the worldwide reliance on fossil fuels in order to address the persistent problem of increasing emissions of CO2. Solar and wind energy are intermittent, highlighting the need to develop energy storage on a huge scale. Electrocatalysts provide a way to convert between electrical energy generated by renewable energy sources and chemical energy in the form of chemical bonds. Oxidation of hydrogen to give two electrons and two protons is carried out in fuel cells, but the typical catalyst is platinum, a precious metal of low earth abundance and high cost. In nature, hydrogenases based on iron or iron/nickel reversibly oxidize hydrogen with remarkable efficiencies and rates. Functional models of these enzymes have been synthesized with the goal of achieving electrocatalytic H2 oxidation using inexpensive, earth-abundant metals along with a key feature identified in the [FeFe]-hydrogenase: an amine base positioned near the metal. The diphosphine ligands P(R)2N(R')2 (1,5-diaza-3,7-diphosphacyclooctane with alkyl or aryl groups on the P and N atoms) are used as ligands in Ni, Fe, and Mn complexes. The pendant amines facilitate binding and heterolytic cleavage of H2, placing the hydride on the metal and the proton on the amine. The pendant amines also serve as proton relays, accelerating intramolecular and intermolecular proton transfers. Electrochemical oxidations and deprotonations by an exogeneous amine base lead to catalytic cycles for oxidation of H2 (1 atm) at room temperature for catalysts derived from [Ni(P(Cy)2N(R')2)2](2+), Cp(C6F5)Fe(P(tBu)2N(Bn)2)H, and MnH(P(Ph)2N(Bn)2)(bppm)(CO) [bppm = (PAr(F)2)2CH2]. In the oxidation of H2 catalyzed by [Ni(P(Cy)2N(R')2)2](2+), the initial product observed experimentally is a Ni(0) complex in which two of the pendant amines are protonated. Two different pathways can occur from this intermediate; deprotonation followed by oxidation occurs with a lower overpotential than the alternate pathway involving oxidation followed by deprotonation. The Mn cation [Mn(P(Ph)2N(Bn)2)(bppm)(CO)](+) mediates the rapid (>10(4) s(-1) at -95 °C), reversible heterolytic cleavage of H2. Obtaining the optimal benefit of pendant amines incorporated into the ligand requires that the pendant amine be properly positioned to interact with a M-H or M(H2) bond. In addition, ligands are ideally selected such that the hydride-acceptor ability of the metal and the basicity of a pendant are tuned to give low barriers for heterolytic cleavage of the H-H bond and subsequent proton transfer reactions. Using these principles allows the rational design of electrocatalysts for H2 oxidation using earth-abundant metals.

Deregulation of cyclooxygenase and nitric oxide synthase gene expression in the inflammatory cascade triggered by experimental group B streptococcal meningitis in the newborn brain and cerebral microvessels. Group B Streptococcus (GBS) is the most common cause of neonatal sepsis and meningitis. Despite antibiotics, GBS in the newborn initiates a cascade of molecular and biological events leading to altered cerebral perfusion, blood-brain barrier disruption, cerebral edema, intracranial hypertension, neurological damage, and even death. Having previously shown that GBS infection impairs cerebral blood flow autoregulation and increases prostaglandin (PG) levels, we examined the regulation of some crucial inflammatory mediators (PGs, nitric oxide (NO), tumor necrosis factor-a) in the brain and cerebral microvessels (MVs) from newborn piglets. Cyclooxygenase (COX), the key enzyme in PG biosynthesis, exists in two isoforms, COX-1 and COX-2. Both may be directly induced by NO in a model of renal inflammation. Besides its neurotransmitter role, NO is a potent vasorelaxant whose production is catalyzed by at least three distinct nitric oxide synthases (NOS) (bNOS, ecNOS, iNOS). Western blot analyses showed that the newborn (4 day old) brain expressed lower levels of COX-1 (8-fold), COX-2 (20-fold), bNOS (12-fold), and ecNOS (5-fold) than in the 1 day old. MV showed approximately equal levels of COX-2, lower levels of COX-1 (4-fold), bNOS (5-fold), and higher levels of ecNOS (20-fold) in comparison to 4-day-old cerebral MV. A 4-day-old brain expressed lower levels of bNOS (5-fold), ecNOS (10-fold), and COX-1 (2-fold) than the 6-week-old pig. COX-2 protein was undetected in a 4-day-old pig brain, but present in great excess in MV. Purified MV showed lower ecNOS (14-fold), COX-1 (2-fold), and about equal levels of bNOS and COX-2 in comparison with MV from 6-week-old pigs. Reverse transcription polymerase chain reaction analyses confirmed these results. Treatment with noo-nitro-L-arginine (LNA), a NOS inhibitor, downregulated COX-1 expression in the newborn brain and both COX-1 and COX-2 cerebral MV expression. GBS infection (10(9) colony-forming units, 0.5 mL intracerebroventricular) of sedated newborn piglets induced the expression of tumor necrosis factor-alpha in the cerebrospinal fluid after 2 hours, upregulated bNOS expression in both brain and MVs, upregulated ecNOS in MVs, and downregulated COX-1, COX-2, and ecNOS in the brain. GBS did not trigger the expression of iNOS. Our data suggest that there is a net deficiency of NOS isoforms in the immature brain and microvasculature of the 4-day-old piglet and that the differences in expression lead to the immature control of NO and PG production, rendering newborns particularly susceptible to neurological damage because of the undeveloped nature of their response mechanisms. Moreover, the GBS-induced cascade deregulates the gene expression of interacting inflammatory mediators and may cause a net vasoconstrictor/vasodilator imbalance, leading to cerebral hypertension and edema in the early stages of infection. Pharmacological manipulations of the inflammatory cascade could lead to novel therapeutic approaches for the treatment of GBS meningitis.

Release kinetics of cardiac troponin I and cardiac troponin T in effluents from isolated perfused rabbit hearts after graded experimental myocardial contusion. Few experimental studies report effects of direct contusion on cardiac enzyme release. Cardiac troponins I (cTnI) and T (cTnT) have been shown to be highly sensitive and specific markers of myocardial cell injury. This investigation was designed to determine and compare the acute effects of quantified magnitudes of blunt cardiac trauma upon release of cTnI and cTnT in comparison with creatine kinase (CK) and lactate dehydrogenase (LD). In 24 rabbit hearts prepared on a standard Langendorff apparatus, myocardial contusion (MC) was produced by a single blow with a ball falling from a predefined height, delivered directly to the surface of the heart. Hearts were divided into control (n = 6) and various quantified impacts: 75 mJoules (mJ) (n = 6), 100 mJ (n = 6), 200 mJ (n = 6). Coronary effluent samples for cTnI, cTnT, CK, and LD were collected at baseline, immediately after MC and 5, 15, 30, 45, and 60 minutes after MC. At the end of experiment, histologic condition was evaluated. The anti-cTnI and cTnT MAbs used in the cTnI (Access) and cTnT (Elecsys) assays cross-react with cTnI and cTnT of the rabbit. The time-courses of cTnI, cTnT, CK, and LD were monophasic in form. After MC, all parameters rose significantly compared with baseline and with control group. The maximal release occurred immediately after MC. The area under the cTnI curve and the maximal cTnI concentration were linked to the contusion energy when increased at 200 mJ. Maximal concentrations and areas under cTnT, CK, LD time activity curve were not linked to the contusion energy level and showed no between-energy group differences. The correlation found between maximal cTnI and maximal cTnT concentrations was 0.70 (p = 0.0001). Histologic examination showed cellular disruption and after the more severe impact, the extent of pathologic changes was more extensive. After graded experimental MC, maximal cTnI concentration and area under cTnI curve increase with the power of impact kinetic energy. Levels of cTnI allow a much higher accuracy in detecting the extent of myocardial injury postMC in comparison with cTnT, CK, and LD in this experimental study. These results should be consistent with the more extensive cTnI release with more severe impact in patients with blunt chest trauma. Furthermore, because specificity and time-course of release, both cTnI and cTnT should have a role in the diagnosis and evaluation of such patients.

[Anti-Ma2-associated encephalitis and paraneoplastic limbic encephalitis]. Anti-Ma2-associated encephalitis (or anti-Ma2 encephalitis) is a paraneoplastic neurological syndrome (PNS) characterized by isolated or combined limbic, diencephalic, or brainstem dysfunction. Anti-Ma2 antibodies detected in the serum or cerebrospinal fluid of patients are highly specific for this disease entity and belong to a group of well-characterized onconeuronal antibodies (or classical antibodies). The corresponding antigen, Ma2 is selectively expressed intracellularly in neurons and tumors as is the case with other onconeuronal antigens targeted by classical antibodies. However, in most cases the clinical pictures are different from those of classical PNS and this creates a potential risk of underdiagnosis. Although limbic dysfunction is the most common manifestation in patients with anti-Ma2 encephalitis which is one of the major causes of paraneoplastic limbic encephalitis (LE), it has been reported that less than 30% of the patients with anti-Ma2 LE exhibit clinical presentations typical of the classical description of LE. Of the remaining, many exhibit excessive daytime sleepiness, vertical ophthalmoparesis, or both associated with LE, because of frequent involvement of the diencephalon and/or upper brainstem. Anti-Ma2 LE can also be manifested as a pure psychiatric disturbance such as obsessive-compulsive disorder in a few cases. Some patients develop mesodiencephalic encephalitis with minor involvement of the limbic system, and some may manifest severe hypokinesis. About 40% of the patients with anti-Ma2 antibodies also have antibodies against different epitopes on Ma1, a homologue of Ma2. These patients may have predominant cerebellar and/or brainstem dysfunctions due to more extensive involvement of subtentorial structures. Anti-Ma2 encephalitis is outstanding among other PNS associated with classical antibodies in that the response rate to treatment is relatively high. While it can cause severe neurological deficits or death in a substantial proportion of the patients, approximately one-third show neurological improvement and another 20 - 40% stabilize in response to treatment, including immunotherapy and/or tumor treatment. Patients who have limited CNS involvement and testicular tumors with complete response to therapy are more likely to show neurological improvement. This fact emphasizes the importance of early diagnosis and prompt initiation of therapy. However, it should be noted that even carcinoma in situ, which is difficult to detect can cause severe neurological disorders. In this respect, it is useful to highlight that anti-Ma2 encephalitis is almost always associated with testicular germ cell tumors in men younger than 50 years. We experienced a 40-year-old patient with severe hypokinesis caused by anti-Ma2 encephalitis associated with bilateral intratubular germ-cell neoplasm of the testes. In older men and women, non-small-cell lung cancer is most common but various types of cancers are reported to be associated. In this study,in addition to reviewing the above case we have reviewed the significance of anti-Ma2 antibodies in the diagnosis of anti-Ma2 encephalitis and the clinical features of this disease.

Expression of the alpha 6A integrin splice variant in developing mouse embryonic stem cell aggregates and correlation with cardiac muscle differentiation. Mouse embryonic stem (ES) cells grown in aggregates give rise to several different cell types, including cardiac muscle. Given the lack of cardiac muscle cell lines, ES cells can be a useful tool in the study of cardiac muscle differentiation. The laminin-binding integrin alpha 6 beta 1 exists in two different splice variant forms of the alpha chain (alpha 6A and alpha 6B), the alpha 6A form having been implicated as possibly playing a role in cardiac muscle development, based on its distribution pattern [4, 53]. In this study we characterise the ES cell model system in terms of the expression of the two different alpha 6 splice variants. We correlate their expression with that of muscle markers and the transcription factor GATA-4, using the reverse transcription-polymerase chain reaction (RT-PCR). We confirm that alpha 6B is constitutively expressed by ES cells. In contrast, alpha 6A expression appears later and overlaps in time with a period when the muscle marker myosin light chain-2V (MLC-2V) is expressed, but no MyoD is present, which indicates the presence of cardiac muscle cells in the aggregates. We further show that GATA-4 is present at the same time. Culturing the aggregates under conditions that stimulate (transforming growth factor beta 1 supplement) or inhibit (TGF beta 1 plus 10(-9) M retinoic acid supplement) cardiac muscle differentiation does not lead to any qualitative differences in the timing of expression of these genes, but quantitative changes cannot be excluded. The TGF beta 1 supplement does, however, lead to a relatively greater expression of alpha 6A compared to alpha 6B than the TGF beta 1 plus 10(-9) M RA supplement after 6 days in culture, suggesting that alpha 6A expression is favoured under conditions that stimulate cardiac muscle differentiation. The switch towards alpha 6A expression in ES cell aggregates is paralleled by expression of the binding receptor for TGF beta (T beta RII). Stable expression of a mutated (dominant negative) T beta RII in ES cells, however, still resulted in (TGF beta-independent) upregulation of alpha 6A, demonstrating that these events were not causally related and that parallel or alternative regulatory pathways exist. The initial characterisation of differentiating ES cell aggregates in terms of alpha 6A integrin subunit expression suggests that this model system could be a valuable tool in the study of the role of the alpha 6A beta 1 integrin in cardiac muscle differentiation.

[Maternal pre-pregnancy body mass index and gestational weight gain with preschool children's overweight and obesity]. To examine the effect of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with childhood overweight and adiposity, and to explore possible early life risk factors for obesity in preschool children. Basic information of pregnant women and gestation period came from the Ma'anshan Birth Cohort Study, a part of the China-Anhui Birth Cohort Study (C-ABCS). Pregnant women in routine health care from four municipal medical and health institutions were enrolled voluntarily during October 2008 and October 2010 in Ma'anshan City. A total of 5 084 pregnant women and 4 669 singleton live births were included in this study. Between April 2014 and April 2015, 3 797 children were followed up. Children whose BMI were >85th percentiles for age and genders of World Health Organization (WHO) reference were considered as overweight, and >95th percentiles for age and genders cut-off values were considered as obesity (pathological and secondary causes of obesity were excluded). Gestational weight gain was defined according to the Institute of Medicine (IOM) guidelines. Univariate and binary regression model analysis was used to examine the effect of pre-pregnancy BMI and GWG with childhood overweight and adiposity. Of the 3 797 pregnant women, the prevalence of underweight, normal weight, overweight and obesity were respectively 22.6% (n=858), 70.3% (n=2 671), 6.2% (n=234) and 0.9% (n=34). There were 3 563 pregnant women who were obtained gestational weight gain data, the prevalence of inadequate GWG, appropriate GWG, excessive GWG were respectively 12.4% (n=443), 25.9% (n=922) and 61.7% (n=2 198). The prevalence of overweight and obesity were 11.5% (n=437) and 10.8% (n= 411) in preschool children, respectively. After adjusting confounding factors including age at delivery, genders of children, children age, birth weight, breastfeeding and household economic status, binary logistic regression analysis showed that pre-pregnancy overweight and obesity(OR=2.01, 95% CI: 1.53-2.65), excessive GWG(OR=1.65, 95% CI: 1.35-2.03) were risk factors for overweight and obesity, and pre-pregnancy underweight was protective factor for childhood overweight and obesity (OR=0.49, 95% CI: 0.39-0.62). Joint associations of pre-pregnancy BMI and inappropriate GWG were also noticed in the study: compared to only pre-pregnancy higher BMI or excessive GWG or indequate GWG, combination of high pre-pregnancy BMI and excessive GWG or high pre-pregnancy BMI and inadequate GWG, adverse effects on childhood overweight and obesity were much higher,OR (95%CI) values were 2.90(1.97-4.28), 3.17(1.44-6.97) respectively. Both high pre-pregnancy BMI and inappropriate GWG are associated with greater offspring BMI. Pregnant women should achieve appropriate weight gain and help prevent obesity in their children.

The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor. SPH3127 is a novel direct renin inhibitor designed as an oral drug for the regulation of blood pressure and body fluid homeostasis via the renin-angiotensin-aldosterone system (RAAS). This candidate is now being evaluated in a phase I clinical trial in China. The purpose of this study is to investigate detailed nonclinical pharmacokinetic data, and to predict human pharmacokinetic parameters. In vivo pharmacokinetic studies of SPH3127 were performed to investigate the exposure, absorption, clearance, distribution and metabolism after intravenous and oral administration in rats, beagle dogs and cynomolgus monkeys. The cynomolgus monkey pharmacokinetics/pharmacodynamics study was conducted to investigate the effect-concentration relationship of SPH3127. Its human pharmacokinetic properties were predicted employing an allometric scaling approach based on non-clinical species data. In vitro studies were also employed in a cytochrome P450 (CYP) enzyme phenotyping study, an inhibition and induction study, and a Caco-2 cell permeation and metabolites profile analysis. After a single intravenous administration of SPH3127 in rats and monkeys, high clearance and volume of distribution and a short terminal elimination half-life were seen for both species. The oral bioavailability of SPH3127 to rats and monkeys was about 11.5-24.5% and 3.3-11.3%, respectively, with the short peak time, Tmax, ranging from 0.25 to 1.3 h. SPH3127 shows low permeability across Caco-2 cell membranes, and as the substrate of p-gp with apparent efflux characteristics. SPH3127 is mainly distributed in the gastrointestine, liver, kidney, pancreas and lung after oral dose in rats, and which decreased quickly to a 1% peak concentration during 12 h. The plasma protein binding ratio of SPH3127 is low as 11.7-14.8% for all species. Excretion studies in rats suggested that fecal, urine and bile excretion represented about 15% of the intake dose, indicating that SPH3127 undergoes extensive metabolism after oral dosing. Phenotyping data revealed that CYP3A4 was the most active enzyme catalyzing the metabolism of SPH3127. The key metabolites were likely N-hydroxylation (M8-7), mono-oxidation-dehydrogenation (M7-4) and mono-oxidation (M8-1, M8-2), both for in vitro liver microsome incubation of all species and in vivo results in rats. The in vitro CYP inhibition study only found very weak action for CYP3A4 (midazolam 1'-hydroxylation) and CYP3A4 (midazolam 6β-hydroxylation) with IC50 of 56.8 µM and 41.1 µM, respectively. Monkey pharmacokinetic/pharmacodynamic data showed favorable safety margins when compared with the exposure of the effect dose and that of the monkey NOAEL level. Simple four-species allometric scaling led to predicted human plasma clearance and volume of distribution, and then simulated the oral human plasma concentration-time profile, which are both in good consistency with phase I clinical trial pharmacokinetic data. SPH 3127 has appropriate pharmacokinetic properties for further clinical exploration.

Days-lost to training and competition in relation to workload in 263 elite show-jumping horses in four European countries. Orthopaedic, or other, injuries in sports medicine can be quantified using the 'days-lost to training' concept. Both the training regimen and the surface used in training and racing can affect the health of racehorses. Our aim was to associate 'days-lost to training' in elite-level show-jumpers to horse characteristics, training and management strategies, and the time spent working on various training and competition surfaces. We designed a longitudinal study of professional riders in four European countries. Data were recorded using training diaries. Reasons for days-lost were classified into non-acute and acute orthopaedic, medical, hoof-related, and undefined. We produced descriptive statistics of training durations, relative to type of training, surfaces used, and days-lost. We created zero-inflated negative-binomial random-effects models using the overall days-lost as outcome. In the whole dataset, duration variables related to training surfaces were analysed as independent. The Swedish data only were also used to test whether duration variables were related to competition surfaces. Thirty-one riders with 263 horses provided data on 39,028 days at risk. Of these, 2357 (6.0%) were days-lost (55% and 22% of these were due to non-acute and acute orthopaedic injuries, respectively) in 126 horses. In the all-country model, controlling for season, a significant variable was country. Switzerland and the UK had lower incidence-rate ratios (IR) compared to Sweden (IRs 0.2 and 0.03, respectively). Horses with previous orthopaedic problems had almost a doubled IR (1.8) of days-lost due to orthopaedic injury, compared to baseline. If the horse had jumping training more than 1 min per day at risk the IRs were 6.9-7 (compared to less than this amount of time); this was, however, likely an effect of a small baseline. Variation in training was a protective factor with a dose-response relationship; the category with the highest variation had an IR of 0.1. In the Swedish model, controlling for season, there was an association of year (IR 2.8 year 2010). Further, if the horse rested >17-25% of the days at risk, or >33% of the DAR2, had IRs 3.5 and 3.0, compared to less time. Horses ≥ 6 years had IRs of 1.8-2.0, compared to younger horses. Limited training use of sand surface was a risk-factor (IR 2.2; >4 ≤ 12 min/day at risk), compared to not training on sand. Training/competing on sand-wood was a protective factor (IRs 0.4-0.5) compared to not using this surface.

[Effect of melatonin on the activation and proliferation of neonatal cord blood mononuclear cell]. A growing body of evidence suggests that the pineal hormone, melatonin (MLT), has immunomodulatory properties; MLT can induce an increment of cell proliferation and an increase or a decrease of a number of cytokines in adults' peripheral blood mononuclear cells (PBMC). However, the influence of MLT on the modulation of neonatal cord blood mononuclear cells (CBMC) proliferation has not been reported. The present study aimed to investigate the possible regulatory effects of MLT on the proliferation of CBMC in vitro. Ten cord blood preparations from placenta vena umbilicalis of 10 healthy full-term normally delivered newborns and 10 healthy adult volunteers' peripheral blood preparations as controls were obtained. Cord/peripheral blood mononuclear cells suspension were prepared, 2 x 10(5) cells were added to 96-well plate and co-cultured with different stimulants (in cell cultures containing 5 microg phytohemagglutinin (PHA)/ml, 50 ng MLT/ml, 5 ng MLT/ml, 500 pg MLT/ml, 50 pg MLT/ml, 50 ng IL-2/ml, 5 ng MLT/ml + 5 microg PHA/ml or 5 ng MLT/ml + 50 ng IL-2/ml) for 72 h, while the cell suspension (with no stimulant) was used as controls, also cultured for 72 h. With the methods of microscopic examination and (3)H-TdR incorporation test, the influence of melatonin on CBMC morphology and proliferation were investigated, and the effects of MLT on the proliferation of CBMC and PBMC were compared with LSD-t T test and independent samples T test. In CBMC, MLT (50 pg/ml - 50 ng/ml) increased the (3)H-TdR incorporation rates in a dose-dependent manner, the rate was the highest in the concentration of 5 ng/ml. After 72 h of cell culture, the number of cells in the MLT (5 ng/ml)-exposed group was higher than that recorded before incubation when observed under the high power microscope, including many big mononuclear cells. After adding different stimulants MLT (5 ng/ml), IL-2 (50 ng/ml), MLT plus PHA (5 microg/ml) or MLT plus IL-2 into mediums, the (3)H-TdR incorporation rates of CBMC (cpm) was 114 327 +/- 52 863, 16 087 +/- 9006, 118 360 +/- 59 207 and 17 682 +/- 7391 respectively. In comparison with the controls (14 133 +/- 8688), the incorporation rates of both MLT-exposed group and MLT + PHA-exposed group increased significantly (t = 5.9143, P < 0.001; t = 5.5078, P < 0.001); the rate of IL-2-treated group or MLT + IL-2-treated group demonstrated no significant changes (t = 0.4938, P > 0.05; t = 0.9839, P > 0.05); while the incorporation rates of MLT-exposed group or MLT + PHA-exposed group had no significant difference compared with that of PHA-exposed group (t = 0.1730, P > 0.05; t = 0.3286, P > 0.05). After adding different stimulants into the medium, the incorporation rates of CBMC were all higher than those of PBMC. MLT can promote not only the proliferation of PBMC, but also the proliferation of CBMC, and the effects of MLT on CBMC were stronger than those on PBMC. This suggests that MLT could be involved in the regulation of the newborn immune system and suggests a new immunotherapeutic strategy in the treatment of certain diseases of neonates.

A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children. To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenolate mofetil (MMF), mycophenolate sodium (MPS) and sirolimus as possible immunosuppressive therapies for renal transplantation in children. Electronic databases were searched up to November 2004. Data from selected studies were extracted and quality assessed. An economic model [Birmingham Sensitivity Analysis paediatrics (BSAp)] was produced based on an adaptation of a model previously developed for the assessment of the cost-effectiveness of immunosuppressants in adults following renal transplant. For the addition of basiliximab, one unpublished paediatric randomised control trial (RCT), reported that the addition of basiliximab to tacrolimus-based triple therapy (BTAS) failed to significantly improve 6-month biopsy-proven acute rejection (BPAR), graft function, graft loss and all-cause mortality. No significant difference between groups was seen in 6-month or 1-year or longer graft loss, all-cause mortality and side-effects. In a meta-analysis of adult RCTs, the addition of basiliximab to a ciclosporin, azathioprine and steroid regimen (CAS) significantly reduced short-term BPAR. There was no significant difference in short- or long-term graft loss, all-cause mortality or side-effects. One adult RCT was included for the addition of daclizumab to CAS, which reported reduced 1-year BPAR, although no difference between groups was seen in either 1- or 3-year graft loss, all-cause mortality and side-effects. For tacrolimus versus ciclosporin, one unpublished paediatric RCT found that a regimen of tacrolimus, azathioprine and a steroid (TAS) reduced 6-month BPAR and improved graft function [glomerular filtration rate (GFR)] compared with CAS. This improvement in BPAR with tacrolimus was as shown in the meta-analysis of adult RCTs. There was evidence, particularly in children, that in comparison with ciclosporin, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. The total level of withdrawal in children was reduced in children receiving tacrolimus. Adult RCTs showed an increase in post-transplant diabetes mellitus with tacrolimus. For MMF versus azathioprine, a meta-analysis of adult RCTs showed MMF [regimen of ciclosporin, MMF and a steroid (CMS)] to reduce 1-year BPAR compared with azathioprine (CAS). There was evidence, particularly in children, that in comparison with azathioprine, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. There was an increase in the level of cytomegalovirus infection with MMF, although the overall level of withdrawal due to adverse events was not different to that of azathioprine-treated adults. No study comparing MPS with azathioprine (CAS) was identified. In an adult RCT comparing MMF with MPS, there was no significant difference between groups in 1-year efficacy or side-effects. One unpublished paediatric RCT assessed the addition of sirolimus to CAS. BPAR, graft loss and all-cause mortality were not reported. In two adult RCTs, compared with azathioprine, sirolimus reduced 1-year BPAR, reduced graft function (as assessed by an increased serum creatinine) and increased the level of hyperlipidaemia. No significant differences were seen in other efficacy and side-effect outcomes. On an adult RCT comparing sirolimus with ciclosporin, there were no significant differences between groups in 1-year efficacy or side-effects with the exception of an increased level of hyperlipidaemia with sirolimus substitution. Both the assessment group and drug companies assessed the cost-effectiveness of the newer renal immunosuppressants currently licensed in children using an adaptation (BSAp) of the Birmingham Sensitivity Analysis (BSA) model. This model is based on a 10-year extrapolation of 1-year BPAR results sourced from paediatric RCTs or adult RCTs (where paediatric RCTs were not available). The addition of basiliximab and that of daclizumab to CAS was found to increase quality-adjusted life-years (QALYs) and decreased overall costs, a finding that was robust to sensitivity analyses. The incremental cost-effectiveness ratio (ICER) of replacing ciclosporin with tacrolimus was highly sensitive to the selection of the hazard ratio for graft loss from acute rejection, dialysis costs and the incorporation (or not) of side-effects. The ICERs for tacrolimus versus ciclosporin ranged from about 46,000 pounds/QALY to about 146,000 pounds/QALY. Although sensitive to varying the hazard ratio for graft loss with acute rejection, the ICER for replacing azathioprine with MMF remained in excess of 55,000 pounds/QALY. In general, compared with a regimen of ciclosporin, azathioprine and steroid, the newer immunosuppressive agents consistently reduced the incidence of short-term biopsy-proven acute rejection. However, evidence of the impact on side-effects, long-term graft loss, compliance and overall health-related quality of life is limited. Cost-effectiveness was estimated based on the relationship between short-term acute rejection levels from RCTs and long-term graft loss. Both the addition of daclizumab and that of basiliximab were found to be dominant strategies, that is, regarding cost savings and increased QALYs. The incremental cost-effectiveness of tacrolimus relative to ciclosporin was highly sensitive to key model parameter values and therefore may well be a cost-effective strategy. The incremental cost-effectiveness of MMF compared with azathioprine, although also sensitive to model parameter, was unattractive. There is a particular need for RCTs to assess the use of MMF, MPS and daclizumab for renal transplantation in children where no such evidence currently exists. Future comparative studies need to report not only on the impact of the newer immunosuppressants on short- and long-term clinical outcomes but also on side-effects, compliance, healthcare resource, costs and health-related quality of life.

[Single-stage repair of penile urethral stricture using combined dorsal onlay oral mucosa grafting with ventral onlay penile skin flap]. To evaluate the clinical effect of single-stage repair of penile urethral stricture using combined dorsal onlay oral mucosa grafting with ventral onlay penile skin flap. We retrospectively reviewed the clinical database of 22 male patients with penile urethral stricture who received single-stage repair using combined dorsal onlay oral mucosa grafting with ventral onlay penile skin flap from November 2015 to October 2018. All the cases had no complications, such as skin fistula. The causes of stricture included iatrogenic (14/22, 63.6%), inflammation (2/22, 9.1%) and idiopathic (6/22, 27.3%). A ventral urethrotomy was made in the segment of stricture and extended proximally and distally until the normal calibre urethra was encountered. The oral mucosa graft was secured to the corpus spongiosum in dorsal onlay fashion or underlying corpora cavernosum after resection of the severe scarred urethra. Then the prepared Orandi fasciocutaneous penile skin flap was secured to edges of corpus spongiosum or oral mucosa graft. A 16 F or 14 F Foley catheter was left in situ for a minimum of 3 weeks, at which time a urethrogram was performed to look for extravasation, and the urethroscopy was performed if necessary. Success was defined as an open urethra with Qmax≥15 mL/s and no need for further surgical intervention. all the 22 patients with a mean age of 52.6 (18-73) years underwent the combined tissue-transfer technique. The mean length of the penile urethral stricture was 5.3 (2.5-10.0) cm and the mean preoperative Qmax was 6.7 mL/s. the mean length of oral mucosa grafts and fasciocutaneous skin flaps were 5.5 (3.2-10.5) cm and 6.0 (3.5-11.0) cm, respectively. The mean operation time was 225 (150-420) minutes and the mean evaluated blood loss was 53 (20.0-110.0) mL. The grafts included buccal mucosa (19/22, 86.4%) and lingual mucosa (3/22, 13.6%). The mean postoperative Q max was 21.2 (15-32) mL/s. A case of skin fistula and 2 cases of recurrent stricture were found, so the technique success rate was 81.8% (18/22) at a mean follow-up of 20.5 (5-51) months. The perioperative complications included 2 cases of infection and skin necrosis, which healed well after conservative treatment. Single-stage repair of penile urethral stricture using combined dorsal onlay oral mucosa grafting with ventral onlay penile skin flap appears to be an excellent option to repair penile urethral stricture with unsalvageable urethral plate and the penile skin is available. The present clinical series showed a successful rate of 81.8% (18/22).

Changes in L-selectin expression on CD34-positive cells upon cryopreservation of peripheral blood stem cell transplants. Several studies have pointed out that L-selectin on CD34-positive cells plays a role in haematopoietic reconstitution after peripheral blood stem cell (PBSC) transplantation. Since it is known that a decrease in L-selectin expression in lymphocytes and granulocytes can be induced by a variety of stress situations, we have investigated in this study whether the freeze-thawing procedure, used in PBSC transplantation, would affect L-selectin expression on CD34+ stem cells. Flow cytometry was performed by labelling the cells with anti-CD34 (HPCA2 PE) and anti-CD62L (FMC46 FITC). The leucapheresis procedure itself caused a slight decrease of L-selectin expression on CD34 cells in 11 out of 12 cases (mean decrease of the percentage of positive cells 11.9; range 6-23). A much larger decrease was found upon freeze-thawing: a mean of 39% (range 4-78% in 27 cases) compared to fresh material. To determine if L-selectin expression might be up-regulated after cryopreservation, thawed transplant samples (n = 11) were incubated at 37 degrees C in RPMI with 10% FCS at 5% CO2. Already early in the course of incubation two CD34-positive populations appeared in the blast region, characterized by either a low or high forward scatter. Simultaneous viability staining with the DNA dye 7-Amino Actinomycin D and the DNA/RNA dye Syto16 revealed that the population with low forward scatter was apoptotic while the population with the high forward scatter was non-apoptotic. The latter population is considered to be most relevant for transplantation. In this population an increase of L-selectin expression after overnight incubation was observed in 8/11 samples up to values of 46-120% of the values of the fresh nonfrozen samples. In addition, the mean fluorescence intensity was significantly increased in 10/11 cases. Kinetic experiments with shorter incubation times revealed that only part of the leucapheresis samples (two out of 8) showed an increase of L-selectin expression within 4 h. In addition, a decrease of L-selectin expression was found upon CD34 purification from fresh leucapheresis material by magnetic isolation (decrease ranging from 59 to 92%, n = 5). In contrast to frozen samples, L-selectin reappearance was seen already within 4 h of incubation in all samples. Both the loss of L-selectin expression on CD34 cells occurring upon freeze-thawing, the emergence of apoptosis, as well as the recovery of L-selectin expression on non-apoptotic cells varies largely between individual leucapheresis samples, and therefore it is concluded that such processes should be considered when correlations with clinical outcome after transplantation are made.

A retrospective study on outcome of microscopic polyangiitis in chronic renal replacement therapy. Pauci-immune vasculitis is a heterogeneous disorder with an unfavourable prognosis. Renal involvement is frequently observed in antineutrophil cytoplasm autoantibody (ANCA)-associated small-vessel vasculitis and is an important cause of end-stage renal disease (ESRD). Renal replacement therapy (RRT) is frequently required. Although better prognosis under dialysis is well known, the long-term follow-up of pauci-immune renal vasculitis with RRT is rarely reported. We described 24 patients with pauci-immune vasculitis and requirement of dialysis who were admitted in our institutions from January 1989 to December 2008. Mean age was 65 ± 12 years at the beginning of dialysis. There were 12 males and 12 females. Patients with Wegener's granulomatosis, Churg-Strauss syndrome or evidence of anti-glomerular basement membrane were excluded. The study group was formed by patients with a diagnosis of necrotizing extracapillary glomerulonephritis and microscopic polyangiitis. The distribution according to ANCAs was 14 p-ANCA (58%), 5 c-ANCA (21%) and 5 ANCA-negative (21%) pauci-immune renal vasculitis. Pulmonary renal syndrome (PRS) was observed in 10 patients at the onset of vasculitis. Corticosteroids and daily cyclophosphamide were administered to 18 patients, and one patient had intravenous cyclophosphamide. Five patients received isolated corticosteroid therapy. Early reduction in cyclophosphamide dosage was required in five patients due to leucopaenia. Mean follow-up after first dialysis was 89 ± 66 months (range 2-208). Twenty patients were included in haemodialysis (HD), and four patients were included in peritoneal dialysis (PD). At the end of the study, nine patients had received a cadaveric kidney transplant (KT). Relapses rate after the onset of dialysis was 0.03 episode/patient/year. PRS-associated relapses after beginning dialysis were observed in four patients. Main therapy in relapses was also corticosteroids and cyclophosphamide. Survival rates for year 1, 2 and 5 was 91%, 91% and 85%, respectively. Overall mortality at the end of the study was 31.8%. Five patients died in the PRS group, but only one death was associated with progressive pulmonary fibrosis. Higher mortality was observed in PRS vasculitis present at the onset of RRT (50% vs 16.7%, P = NS). Better outcome in patients who received a renal transplantation was observed (88.8% vs 53.8%, P = NS). Conclusions. Despite a low number of patients in this series, pauci-immune vasculitis prognosis under dialysis seems equal to other causes of chronic kidney disease. This study observed a low rate of relapses after beginning dialysis. Poor prognosis is related to severe complications at the beginning of RRT. Today, kidney transplantation is an important therapeutic option for these patients.

[Rationale of inpatient care--towards a new payment system]. German statutory health insurance is introducing a system of lump sum payments for hospital care in the framework of a sectorial budget. All hospital cases covered by a major regional health insurance fund (AOK Magdeburg) and completed in 1995 to 1997 (590,000 cases and 7.6 million hospital days, resp.) were analysed to find out changes in the main parameters of inpatient care. The number of hospital cases per 10,000 insured persons continues to increase even after age-adjustment. The increase was 3.1% from 1996 to 1997. Hence the objective "outpatient treatment ranks before inpatient treatment" has not been achieved. The number of hospital days per 10,000 insured patients also increased. Hence the concept of "controlled touch down" (i.e. reaching the prospectively negotiated number of hospital days exactly) has not succeeded. After taking age into account, the number of hospital days slightly and for the first time decreased in 1997 compared to 1996. The average level of hospital stay (LOS) is decreasing, but still high. The proportion of cases with hospital stays exceeding the "Length of Stay Guidelines" was more than 30% in 1997. The pattern of the three parameters (number of cases, hospital days, and LOS) indicate that hospitals manage bed occupancy rates in the first place and that the indications for inpatient treatment are getting softer. Between 1996 and 1997 there has been a 17.5% increase in the total number of cases reimbursed by lump sums. In some categories of the fee schedule the increase is considerably greater. Such changes in performance make it difficult for both contracting parties to assess the "necessary" amount of cases and procedures to be covered by lump sum payments. In a considerable proportion of cases covered by lump sum renumeration, the LOS is longer than the calculated average on which costing is based. In spite of this, however, most hospitals gain more income from lump sum payment than they would if their per diem rates were applied. The proportion of cases with the LOS exceeding the upper compensation limit is low. Between hospitals, the average LOS in the same categories of the fee schedule differs by a factor of 1.5 to 2. There is no consistent indication of adverse risk selection. If the present payment system is maintained until the end of 1999 (or even 2001 as preferred by some), German hospitals will have an opportunity to continue with their development of organisation and costing, to improve their structure of services as well as their negotiating power and- the full compensation scheme having been abandoned in favour of prospective budgets- to net rationalization profits.

Improving patient knowledge and safe use of opioids: a randomized controlled trial. The use of opioid analgesics in the United States has significantly increased in recent years. However, there is minimal consensus on what discharge counseling should accompany these high-risk prescriptions and large variations in what is done in practice. The objective of this study was to evaluate the effect of a dual-modality (written and spoken) literacy-appropriate educational strategy on patients' knowledge of and safe use of opioid analgesics. This was a prospective, randomized controlled trial. Consecutive discharged patients at an urban academic ED (>88,000 visits) with new prescriptions for hydrocodone-acetaminophen were enrolled. Patients were randomized to receive either usual care or the educational intervention. The educational intervention was a one-page information sheet about hydrocodone-acetaminophen, which was both given to the patients and read aloud by the research assistant (nonblinded). Follow-up phone calls were conducted 4 to 7 days after the visit to assess patient knowledge about the medication and self-report of activities associated with safety of use (e.g., double-dipping with acetaminophen, storage, use with alcohol or while driving). A total of 274 patients were enrolled; 210 completed follow-up (110 usual care and 100 intervention). No significant differences in baseline characteristics emerged between the study arms; 42% were male, and 51% were white, with a median age of 43 years. Half of patients had non-back pain orthopedic injuries (49.5%). On follow-up, overall knowledge was poor, with only 28% able to name both active ingredients in the medication. The intervention group had better knowledge of precautions related to taking additional acetaminophen (usual care 18.2%, 95% confidence interval [CI] = 10.9% to 25.5% vs. intervention 38%, 95% CI = 28.3% to 47.7%; difference = 27.6, 95% CI of difference = 21.5 to 33.7) and knowledge of side effects (usual care median = 1, interquartile range [IQR] 0 to 2 vs. intervention median = 2, IQR = 1 to 2; p < 0.0001). Additionally, those who received the intervention were less likely to have reported driving within 6 hours after taking hydrocodone (usual care 13.6%, 95% CI = 7.2% to 20% vs. intervention 3%, 95% CI = -0.3% to 6.3%; difference = 10.6, 95% CI of difference = 3.4 to 17.9). There was no difference between groups related to knowledge about drinking alcohol while taking hydrocodone (overall 18.1%) or knowledge that the opioid could be addictive (overall 72.4%). This simple strategy improved several, but not all, aspects of patient knowledge and resulted in fewer patients in the intervention arm driving while taking hydrocodone. Integration of a patient education document into conversations about opioids holds promise for improving patient knowledge about these high-risk medications.

Demyelination, and remyelination by Schwann cells and oligodendrocytes after kainate-induced neuronal depletion in the central nervous system. Excitotoxins are thought to kill neurons while sparing afferent fibers and axons of passage. The validity of this classical conclusion has recently been questioned by the demonstration of axonal demyelination. In addition, axons are submitted to a profound alteration of their glial environment. This work was, therefore, undertaken to reassess axonoglial interactions over time after an excitotoxic lesion in the rat. Ultrastructural studies were carried out in the ventrobasal thalamus two days to 18 months after neuronal depletion by in situ injections of kainic acid. In some cases, lemniscal afferents were identified by using anterograde transport of wheatgerm agglutinin conjugated to horseradish peroxidase from the dorsal column nuclei. Two and four days after kainate injection, numerous dying axons displaying typical signs of Wallerian degeneration were observed in a neuropile characterized by the loss of neuronal somata and dendrites, an increase in number of microglia/macrophages and the disappearance of astrocytes. Ten and 12 days after kainate injection, degenerating axons were no longer observed although myelin degeneration of otherwise unaltered axons was ongoing with an accumulation of myelin remnants in the neuropile. At 16 and 20 days, the demyelination process was apparently complete and axons of different diameters were sometimes packed together. One and two months after kainate injection, the axonal environment changed again: remyelination of large-caliber axons occurred at the same time as reactive astrocytes, oligodendrocytes and numerous Schwann cells appeared in the tissue. Schwann cell processes surrounded aggregates of axons of diverse calibers, ensheathed small ones and myelinated larger ones. Axons were also remyelinated by oligodendrocytes. Horseradish peroxidase-labeled lemniscal afferents could be myelinated by either of the two cell types. After three months, the neuropile exhibited an increase in number of hypertrophied astrocytes and the progressive loss of any other cellular or axonal element. At this stage, remaining Schwann cells were surrounded by a glia limitans formed by astrocytic processes. These data indicate that although excitotoxins are sparing the axons, they are having a profound and complex effect on the axonal environment. Demyelination occurs over the first weeks, accompanying the loss of astrocytes and oligodendrocytes. Axonal ensheathment and remyelination takes place in a second period, associated with the reappearance of oligodendrocytes and recruitment of numerous Schwann cells, while reactive astrocytes appear in the tissue at a slightly later time. Over the following months, astrocytes occupy a greater proportion of the neuron-depleted territory and other elements decrease in number.(ABSTRACT TRUNCATED AT 400 WORDS)

Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis. Acute psychotic illness, especially when associated with agitated or violent behaviour, can require urgent pharmacological tranquillisation or sedation. In several countries, clinicians often use benzodiazepines (either alone or in combination with antipsychotics) for this outcome. To estimate the effects of benzodiazepines, alone or in combination with antipsychotics, when compared to placebo or antipsychotics, to control disturbed behaviour and reduce psychotic symptoms. We searched the Cochrane Schizophrenia Group's register (October 2002 and April 2005), inspected reference lists of included and excluded studies and contacted authors of relevant studies. We included all randomised clinical trials comparing benzodiazepines, alone or in combination with antipsychotics, with placebo or sole use of antipsychotics, for people with acute psychotic illnesses. We reliably selected studies, quality assessed them and extracted data. For binary outcomes we calculated standard estimates of relative risk (RR) and their 95% confidence intervals (CI), and weighted number needed to treat or harm (NNT/NNH) statistics. For continuous outcomes we estimated a weighted mean difference between groups. If heterogeneity was found, we used a random effects model. We included eleven studies with a total of 648 participants. When comparing benzodiazepines with placebo, sedation was equally prevalent (n=102, 1 RCT, RR 1.67 CI 0.4 to 6.6), however, fewer people allocated lorazepam remained excited at 24 hours (n=102, RR 0.62 CI 0.4 to 1.0, NNT 5 CI 3 to 59). The lorazepam and placebo group experienced similar non-significant, low levels of adverse effects. In the comparison of benzodiazepines versus use of antipsychotics without use of anticholinergics/antihistamines, people allocated benzodiazepines did not clearly need additional medication compared with those given antipsychotics (n=216, 2 RCTs, RR 1.28 CI 0.5 to 3.2). Numbers sedated were also equivocal between groups (n=324, 6 RCTs, RR 0.76 CI 0.5 to 1.2) as were mental state ratings. Extrapyramidal symptoms were significantly higher in the antipsychotic treatment group (n=391, 7 RCTs, RR 0.17 CI 0.1 to 0.4, NNT 6 CI 2 to 17). Two trials (total n=83) comparing lorazepam plus haloperidol with lorazepam alone found no clear difference for the need of additional medication (n=83, 2 RCTs, RR 1.02 CI 0.8 to 1.3) or 'not improved' at one hour (n=20, 1 RCT, RR 1.47 CI 0.66 to 3.25). There was no difference in the incidence of extrapyramidal symptoms (n=83, 2 RCTs, RR 1.94 CI 0.2 to 20.3). Finally when the benzodiazepine plus antipsychotic combination was compared with antipsychotics alone (2 RCTs, n=95) there was no difference between groups in the need for additional medications (n=67, 1 RCT, RR 0.95 CI 0.8 to 1.2) or for mental state measures. Extrapyramidal symptoms were significantly lower for people receiving both benzodiazepines and antipsychotics compared with those receiving antipsychotics alone (n=95, 2 RCTs, RR 0.45 CI 0.2 to 0.9, NNH 2 CI 1 to 5). There was no significant difference in the number of participants unfit for early discharge (n=28, 1 RCT, RR 0.90 CI 0.54 to 1.5). There is insufficient data from these studies to support or refute the use of benzodiazepines with or without antipsychotics where emergency drugs are needed. The sole use of older antipsychotics unaccompanied by anticholinergic drugs may be problematic, but studies in this review are not large enough to identify any serious adverse effects of benzodiazepines such as respiratory depression. Larger, more informative studies are needed before definite conclusions can be drawn as to the efficacy of benzodiazapines.

Interventions for necrotising pancreatitis. Acute necrotising pancreatitis carries significant mortality, morbidity, and resource use. There is considerable uncertainty as to how people with necrotising pancreatitis should be treated. To assess the benefits and harms of different interventions in people with acute necrotising pancreatitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 4), MEDLINE, EMBASE, Science Citation Index Expanded, and trials registers to April 2015 to identify randomised controlled trials (RCT). We also searched the references of included trials to identify further trials. We considered only RCTs performed in people with necrotising pancreatitis, irrespective of aetiology, presence of infection, language, blinding, or publication status for inclusion in the review. Two review authors independently identified trials and extracted data. We calculated the odds ratio (OR) and mean difference with 95% confidence intervals (CI) using Review Manager 5 based on an available-case analysis using fixed-effect and random-effects models. We planned a network meta-analysis using Bayesian methods, but due to sparse data and uncertainty about the transitivity assumption, performed only indirect comparisons and used Frequentist methods. We included eight RCTs with 311 participants in this review. After exclusion of five participants, we included 306 participants in one or more outcomes. Five trials (240 participants) investigated the three main treatments: open necrosectomy (121 participants), minimally invasive step-up approach (80 participants), and peritoneal lavage (39 participants) and were included in the network meta-analysis. Three trials (66 participants) investigated the variations in the main treatments: early open necrosectomy (25 participants), delayed open necrosectomy (11 participants), video-assisted minimally invasive step-up approach (12 participants), endoscopic minimally invasive step-up approach (10 participants), minimally invasive step-up approach (planned surgery) (four participants), and minimally invasive step-up approach (continued percutaneous drainage) (four participants). The trials included infected or sterile necrotising pancreatitis of varied aetiology.All the trials were at unclear or high risk of bias and the overall quality of evidence was low or very low for all the outcomes. Overall, short-term mortality was 30% and serious adverse events rate was 139 serious adverse events per 100 participants. The differences in short-term mortality and proportion of people with serious adverse events were imprecise in all the comparisons. The number of serious adverse events and adverse events were fewer in the minimally invasive step-up approach compared to open necrosectomy (serious adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study; adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study). The proportion of people with organ failure and the mean costs were lower in the minimally invasive step-up approach compared to open necrosectomy (organ failure: OR 0.20, 95% CI 0.07 to 0.60; 88 participants; 1 study; mean difference in costs: USD -11,922; P value < 0.05; 88 participants; 1 studies). There were more adverse events with video-assisted minimally invasive step-up approach group compared to endoscopic-assisted minimally invasive step-up approach group (rate ratio 11.70, 95% CI 1.52 to 89.87; 22 participants; 1 study), but the number of interventions per participant was less with video-assisted minimally invasive step-up approach group compared to endoscopic minimally invasive step-up approach group (difference in medians: 2 procedures; P value < 0.05; 20 participants; 1 study). The differences in any of the other comparisons for number of serious adverse events, proportion of people with organ failure, number of adverse events, length of hospital stay, and intensive therapy unit stay were either imprecise or were not consistent. None of the trials reported long-term mortality, infected pancreatic necrosis (trials that included participants with sterile necrosis), health-related quality of life at any time frame, proportion of people with adverse events, requirement for additional invasive intervention, time to return to normal activity, and time to return to work. Low to very low quality evidence suggested that the minimally invasive step-up approach resulted in fewer adverse events, serious adverse events, less organ failure, and lower costs compared to open necrosectomy. Very low quality evidence suggested that the endoscopic minimally invasive step-up approach resulted in fewer adverse events than the video-assisted minimally invasive step-up approach but increased the number of procedures required for treatment. There is currently no evidence to suggest that early open necrosectomy is superior or inferior to peritoneal lavage or delayed open necrosectomy. However, the CIs were wide and significant benefits or harms of different treatments cannot be ruled out. The TENSION trial currently underway in Netherlands is assessing the optimal way to perform the minimally invasive step-up approach (endoscopic drainage followed by endoscopic necrosectomy if necessary versus percutaneous drainage followed by video-assisted necrosectomy if necessary) and is assessing important clinical outcomes of interest for this review. Implications for further research on this topic will be determined after the results of this RCT are available.

[Effects of insulin receptor substrate-1 and its serine phosphorylation and tyrosine phosphorylation on insulin resistance in skeletal muscle cells in the state of sepsis: experiment with rats]. To investigate the effects of insulin receptor substrate (IRS)-1 and its serine (Ser)(307) phosphorylation and tyrosine (Tyr) phosphorylation on insulin resistance in skeletal muscle cells in the state of sepsis. 120 SD rats were randomly divided into 3 groups: 10% group, with 10% of the total cecal length ligated and punctured without use of antibiotic so as to make sepsis model; 30% group, with 30% of the total cecal length ligated and punctured; and control group, undergoing sham operation. Fasting venous blood samples were collected before the operation to detect the fasting plasma glucose (FPG). 0, 8, 16, 24, and 48 hours after the operation 8 rats in each group underwent fasting of food and without fasting of water for 8 hours, i.e., until the 8 th, 16 th, 24 th, 48 th, and 72 nd hours after the operation. Then the rats underwent anesthesia, with blood sample from the vena cava and specimen of gastrocnemius of the hind leg collected, and then killed. The levels of FPG, fasting plasma insulin (FINS), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were measured. HOMA method was used to calculate the insulin resistance index (Ig-IRI). Immunohistochemistry was used to quantitatively examine the IRS-1 protein and its Ser(307) phosphorylation and Tyr phosphorylation in the gastrocnemius. Western blotting and immunoprecipitation were used to semi-quantitatively examine the changes in contents of IRS-1 and its Ser(307) phosphorylation and Tyr phosphorylation in the gastrocnemius respectively. The survival rates at different time points of the control group were all 100%, all significantly higher than those of the other 2 groups (all P < 0.01), and those of the 10% group were all significantly higher than those of the 30% group (all P < 0.01). The levels of TNF-alpha and IL-6 of the 10% and 30% groups at different time points were all significantly higher than those of the control group (all P < 0.01), and those of the 30% group were all significantly higher than those of the 10% group (all P < 0.01). The FPG, FINS, and IgIRI were not significantly different among the 3 groups before the operation, and those of the 10% and 30% groups at different time points after operation were all significantly higher than those of the control group (all P < 0.01) and peaked 8 h after the operation, with those of the 30% group all significantly higher than those of the 10% group (all P < 0.01). The degree of increase of FINS was remarkably higher than that of FPG. IRS-1 was positive and located in the cytoplasm of the gastrocnemius cells in both the control and 30% groups; IRS-1 Tyr phosphorylation was positive in the control group and sporadic positive in the 30% group. IRS-1 Ser(307) was negative in the control group and strong positive in the 30% group. Semi-quantitative examination showed that the IRS-1 level at different time points after operation of the 30% group were not significantly different from those of the control group (all P > 0.05), and IRS-1 Tyr phosphorylation degrees at different time points of the 30% group were all significantly lower than those of the control group (all P < 0.01), and the IRS-1 Ser(307) phosphorylation at different time points of the 30% group were all significantly higher than those of the control group (all P < 0.01). Spearman correlation analysis showed that IgIRI was significantly negatively correlated with IRS-1 Tyr phosphorylation (r = -0.957, P < 0.01), and significantly positively correlated with IRS-1 Ser(307) phosphorylation (r = -0.955, P < 0.01). Under the status of sepsis the IRS-1 content in the skeletal muscle cells is unchanged, the level of IRS-1 Tyr phosphorylation level is decreased, and the IRS-1 Ser phosphorylation is increased. The degrees of such changes are closely related with the degree of insulin resistance.

Carotid endarterectomy saphenous vein patch rupture revisited: selective use on the basis of vein diameter. The single major disadvantage of carotid endarterectomy (CEA) patch reconstruction with greater saphenous vein (GSV) is central patch rupture, which has a reported incidence of 0.5% to 4%. This is a prospective evaluation of the selective use of GSV for a CEA patch based on previously established vein diameter criteria. Between 1988 and mid-1995, 534 of 671 CEAs (80%) were reconstructed with GSVs that had a distended diameter > or = 3.5 mm. Thigh veins were used in all 252 women who underwent CEA. Of the 282 men who underwent CEA, 265 GSVs (94%) were harvested from below the knee and 17 from the thigh. During this period four thigh and 13 below-knee veins (3.2%) were rejected because the diameter was < 3.5 mm, and a synthetic patch was used instead. In 408 of the CEAs with GSV (76%) the vein rupture pressures and diameters were measured, the CEA geometry was measured, and the predicted CEA vein patch rupture pressures were calculated. No GSV patches ruptured in this series. This compares favorably with three patch ruptures in 239 previous CEAs when no vein diameter criteria was used (p = 0.03). This also compares favorably with a multicenter series of 13 GSV patch ruptures (0.73%) in 1773 CEAs (p = 0.03) and with a single-center series of eight ruptures (0.47%) in 1699 CEAs (p = 0.05). GSV diameters were 4.9 +/- 0.9 mm (mean +/- 1 SD); vein rupture pressures, 3.9 +/- 1.5 atmospheres; carotid bulb major axis diameters, 12.5 +/- 1.6 mm; carotid bulb maximum diameters of curvature, 14.2 +/- 2.2 mm; and CEA patch rupture pressures, 1.3 +/- 0.6 atmospheres (range, 280 mm Hg to 4 atmospheres). CEA vein patch rupture pressure correlates positively with vein diameter (p < 0.001, slope), but there is wide variability (correlation coefficient = 0.39). The 14 CEAs (3.4%) with predicted rupture pressures < 400 mm Hg were performed with veins 3.5 to 5.5 mm in diameter (mean, 4.2 mm), and all had carotid bulb major axis diameters > 12 mm (mean, 15.3 mm). Eight of these CEAs were reconstructed with thigh veins. Use of GSVs with a distended diameter > or = 3.5 mm for CEA patch reconstruction significantly reduces the probability of central patch rupture; however, a few CEAs reconstructed with veins > 3.5 mm in diameter and large carotid bulbs have predicted patch rupture pressures < 400 mm Hg. Because at times some veins will have rupture pressures lower than desirable, CEA reconstruction should be tailored to keep the carotid bulb major axis diameter < 13 mm.

Molecular phylogeny of the carnivora (mammalia): assessing the impact of increased sampling on resolving enigmatic relationships. This study analyzed 76 species of Carnivora using a concatenated sequence of 6243 bp from six genes (nuclear TR-i-I, TBG, and IRBP; mitochondrial ND2, CYTB, and 12S rRNA), representing the most comprehensive sampling yet undertaken for reconstructing the phylogeny of this clade. Maximum parsimony and Bayesian methods were remarkably congruent in topologies observed and in nodal support measures. We recovered all of the higher level carnivoran clades that had been robustly supported in previous analyses (by analyses of morphological and molecular data), including the monophyly of Caniformia, Feliformia, Arctoidea, Pinnipedia, Musteloidea, Procyonidae + Mustelidae sensu stricto, and a clade of (Hyaenidae + (Herpestidae + Malagasy carnivorans)). All of the traditional "families," with the exception of Viverridae and Mustelidae, were robustly supported as monophyletic groups. We further have determined the relative positions of the major lineages within the Caniformia, which previous studies could not resolve, including the first robust support for the phylogenetic position of marine carnivorans (Pinnipedia) within the Arctoidea (as the sister-group to musteloids [sensu lato], with ursids as their sister group). Within the pinnipeds, Odobenidae (walrus) was more closely allied with otariids (sea lions/fur seals) than with phocids ("true" seals). In addition, we recovered a monophyletic clade of skunks and stink badgers (Mephitidae) and resolved the topology of musteloid interrelationships as: Ailurus (Mephitidae (Procyonidae, Mustelidae [sensu stricto])). This pattern of interrelationships of living caniforms suggests a novel inference that large body size may have been the primitive condition for Arctoidea, with secondary size reduction evolving later in some musteloids. Within Mustelidae, Bayesian analyses are unambiguous in supporting otter monophyly (Lutrinae), and in both MP and Bayesian analyses Martes is paraphyletic with respect to Gulo and Eira, as has been observed in some previous molecular studies. Within Feliformia, we have confirmed that Nandinia is the outgroup to all other extant feliforms, and that the Malagasy Carnivora are a monophyletic clade closely allied with the mongooses (Herpestidae [sensu stricto]). Although the monophyly of each of the three major feliform clades (Viverridae sensu stricto, Felidae, and the clade of Hyaenidae + (Herpestidae + Malagasy carnivorans)) is robust in all of our analyses, the relative phylogenetic positions of these three lineages is not resolvable at present. Our analyses document the monophyly of the "social mongooses," strengthening evidence for a single origin of eusociality within the Herpestidae. For a single caniform node, the position of pinnipeds relative to Ursidae and Musteloidea, parsimony analyses of data for the entire Carnivora did not replicate the robust support observed for both parsimony and Bayesian analyses of the caniform ingroup alone. More detailed analyses and these results demonstrate that outgroup choice can have a considerable effect on the strength of support for a particular topology. Therefore, the use of exemplar taxa as proxies for entire clades with diverse evolutionary histories should be approached with caution. The Bayesian analysis likelihood functions generally were better able to reconstruct phylogenetic relationships (increased resolution and more robust support for various nodes) than parsimony analyses when incompletely sampled taxa were included. Bayesian analyses were not immune, however, to the effects of missing data; lower resolution and support in those analyses likely arise from non-overlap of gene sequence data among less well-sampled taxa. These issues are a concern for similar studies, in which different gene sequences are concatenated in an effort to increase resolving power.

Malignant tumor of the distal part of the femur or the proximal part of the tibia: endoprosthetic replacement or rotationplasty. Functional outcome and quality-of-life measurements. The present study was performed to determine whether there is a difference, with regard to functional outcome and quality of life, between endoprosthetic replacement and rotationplasty for the treatment of malignant tumors of the distal part of the femur or the proximal part of the tibia. Sixty-seven patients, between the ages of eleven and twenty-four years at the time of the diagnosis, had a malignant tumor of the distal part of the femur or the proximal part of the tibia. A rotationplasty was performed in thirty-three patients, and an endoprosthetic replacement was done in thirty-four patients. The median duration of follow-up was six years and one month (range, two years to sixteen years and two months). The scale developed by the Musculoskeletal Tumor Society was used to evaluate the functional results. Quality-of-life issues were assessed with the questionnaire developed by the European Organization for Research and Treatment of Cancer. The patients who had had a rotationplasty had a mean functional score, according to the system of the Musculoskeletal Tumor Society, of 24 points, and the patients who had had an endoprosthetic replacement had a mean score of 25 points. This difference was not found to be significant, with the numbers available (p = 0.47). Only one patient who had had a rotationplasty used an assistive device when walking long distances, whereas six patients who had had an endoprosthetic replacement used an assistive device. This difference was significant (p<0.001). The quality-of-life questionnaire revealed that the patients who had had a rotationplasty could participate in hobbies such as carpentry and sports as well as in other daily activities to a significantly greater degree than those who had had an endoprosthetic replacement (p = 0.001). Restriction in daily activities due to pain was significantly less common in the group that had had a rotationplasty than it was in the group that had had an endoprosthetic replacement (p = 0.047). Rotationplasty was not associated with any disadvantages with regard to function or quality of life in comparison with endoprosthetic replacement. It is possible that the psychosocial outcome is influenced by the fact that patients who have a rotationplasty know that additional operative intervention is not usually necessary. Despite good functional and quality-of-life results, the cosmetic appearance may be the most serious disadvantage of rotationplasty. The decision to perform this procedure must be made on a case-by-case basis.

Clinical predictors of mortality and cause of death in lymphangioleiomyomatosis: a population-based registry. Lymphangioleiomyomatosis (LAM) is a rare, progressive, frequently lethal cystic lung disease that almost exclusively affects women. Prognostic information in LAM has been limited by small numbers and heterogeneous study methodology. Early retrospective cohorts cited 5- and 10-year mortality of 40 and 80 %, respectively. More recently, mortality at 10 years has been estimated to be approximately 10-20 % from the onset of symptoms and 30 % at 10 years from the time of lung biopsy but varies widely in individual patients. Given the heterogeneous disease course, it would be useful to establish which clinical characteristics are associated with survival to develop prediction models for disease outcome. The LAM Foundation maintains a population-based registry of 1,149 registered self-identified LAM patients. Of these, 590 have completed a "General Information/Clinical History Questionnaire" with limited demographic and clinical data, 410 of whom were identified as U.S. residents and provided date of birth. Vital status was obtained on all 410 participants through December 31, 2007 by linking patient identifiers and the National Death Index. Survival time was calculated as the time since first lung-related symptom or physician diagnosis until censoring (still alive, received lung transplant, or died). Cox proportional hazard analysis evaluated the association of demographic and clinical features with survival. Among the 410 subjects, there were 50 deaths and 55 lung transplantations during a median of 10.4 years of observation time. The estimated median transplant-free survival time for LAM patients in the United States is 29 years from symptom onset and 23 years from diagnosis. The estimated 10-year survival transplant-free was 86 %. Age at disease onset, smoking status, race, presence of tuberous sclerosis, occurrence of pneumothorax, and pregnancy did not demonstrate an association with survival or transplant. Greater age at presentation and presence of angiomyolipoma were associated with less risk of mortality. Treatment with hormonal therapy was associated with an increased risk of death/transplant (hazard ratio (HR) 2.93; 95 % confidence interval (CI), 1.54-5.58; p = 0.001), particularly progesterone therapy (HR 2.17; 95 % CI 1.26-3.75, p = 0.005), and may represent confounding by indication. Patients who required oxygen therapy had a worse outcome (HR 4.53; 95 % CI 2.76-7.42; p < 0.001). Our population-based study showed that the median survival in patients with LAM from the onset of symptoms or diagnosis is much longer than previously described. This has important implications for life choices and treatment decisions regarding medication use and lung transplantation for patients with LAM.

Linseed oil and DGAT1 K232A polymorphism: Effects on methane emission, energy and nitrogen metabolism, lactation performance, ruminal fermentation, and rumen microbial composition of Holstein-Friesian cows. Complex interactions between rumen microbiota, cow genetics, and diet composition may exist. Therefore, the effect of linseed oil, DGAT1 K232A polymorphism (DGAT1), and the interaction between linseed oil and DGAT1 on CH4 and H2 emission, energy and N metabolism, lactation performance, ruminal fermentation, and rumen bacterial and archaeal composition was investigated. Twenty-four lactating Holstein-Friesian cows (i.e., 12 with DGAT1 KK genotype and 12 with DGAT1 AA genotype) were fed 2 diets in a crossover design: a control diet and a linseed oil diet (LSO) with a difference of 22 g/kg of dry matter (DM) in fat content between the 2 diets. Both diets consisted of 40% corn silage, 30% grass silage, and 30% concentrates (DM basis). Apparent digestibility, lactation performance, N and energy balance, and CH4 emission were measured in climate respiration chambers, and rumen fluid samples were collected using the oral stomach tube technique. No linseed oil by DGAT1 interactions were observed for digestibility, milk production and composition, energy and N balance, CH4 and H2 emissions, and rumen volatile fatty acid concentrations. The DGAT1 KK genotype was associated with a lower proportion of polyunsaturated fatty acids in milk fat, and with a higher milk fat and protein content, and proportion of saturated fatty acids in milk fat compared with the DGAT1 AA genotype, whereas the fat- and protein-corrected milk yield was unaffected by DGAT1. Also, DGAT1 did not affect nutrient digestibility, CH4 or H2 emission, ruminal fermentation or ruminal archaeal and bacterial concentrations. Rumen bacterial and archaeal composition was also unaffected in terms of the whole community, whereas at the genus level the relative abundances of some bacterial genera were found to be affected by DGAT1. The DGAT1 KK genotype was associated with a lower metabolizability (i.e., ratio of metabolizable to gross energy intake), and with a tendency for a lower milk N efficiency compared with the DGAT1 AA genotype. The LSO diet tended to decrease CH4 production (g/d) by 8%, and significantly decreased CH4 yield (g/kg of DM intake) by 6% and CH4 intensity (g/kg of fat- and protein-corrected milk) by 11%, but did not affect H2 emission. The LSO diet also decreased ruminal acetate molar proportion, the acetate to propionate ratio, and the archaea to bacteria ratio, whereas ruminal propionate molar proportion and milk N efficiency increased. Ruminal bacterial and archaeal composition tended to be affected by diet in terms of the whole community, with several bacterial genera found to be significantly affected by diet. These results indicate that DGAT1 does not affect enteric CH4 emission and production pathways, but that it does affect traits other than lactation characteristics, including metabolizability, N efficiency, and the relative abundance of Bifidobacterium. Additionally, linseed oil reduces CH4 emission independent of DGAT1 and affects the rumen microbiota and its fermentative activity.

Posterior musculofascial reconstruction after radical prostatectomy: a systematic review of the literature. In 2001, Rocco et al. described a surgical technique whose aim was the reconstruction of the posterior musculofascial plate after radical prostatectomy (RP) to improve early return to urinary continence. Since then, many surgeons have applied this technique-either as it was described or with some modification-to open, laparoscopic, and robot-assisted RP. To review the outcomes reported in comparative studies analysing the influence of reconstruction of the posterior aspect of the rhabdosphincter after RP. The main outcome evaluated was urinary continence at 3-7 d, 30-45 d, 90 d, 180 d, and 1 yr after catheter removal. A systematic review of the literature was performed in November 2011, searching the Medline, Embase, Scopus, and Web of Science databases. A "free-text" protocol using the terms posterior reconstruction of the rhabdosphincter, posterior rhabdosphincter, and early continence was applied. Studies published only as abstracts and reports from meetings were not included in this review. One thousand seven records were retrieved from the Medline database, 1541 from the Embase database, 1357 from the Scopus database, and 1041 from the Web of Science database. The authors reviewed the records to identify studies comparing cohorts of patients who underwent RP with or without restoration of the posterior aspect of the rhabdosphincter. Only papers evaluating use of this technique as the only technical modification among the groups were included. A cumulative analysis was conducted using Review Manager v.5.1 software (Cochrane Collaboration, Oxford, UK). Eleven studies were identified in the literature search, including two randomised controlled trials (RCTs), which were negative studies. The cumulative analysis of comparative studies showed that reconstruction of the posterior musculofascial plate improves early return of continence within the first 30 d after RP (p=0.004), while continence rates 90 d after surgery are not affected by use of the reconstruction technique. The statistical significance of the reconstruction seems to decrease when higher continence rates are reported. Use of posterior rhabdosphincter reconstruction does not seem to be related to positive surgical margin (PSM) rates or with complications like acute urinary retention (AUR) and bladder neck stricture (BNS). Some studies suggested lower anastomotic leakage rates with the posterior musculofascial plate reconstruction technique. The role of reconstruction of the posterior musculofascial plate in terms of earlier continence recovery is encouraging but still controversial. Methodological flaws and poor surgical standardisation seem to be the major causes. In two RCTs and one parallel (not randomised) group trial, posterior rhabdosphincter reconstruction offered no significant advantage for return of early continence after RP. No significant complications related to the posterior musculofascial plate reconstruction technique have been reported so far. A multicentre RCT is necessary to clarify the possible role of the technique in terms of earlier continence recovery.

Prevention of bone loss by clodronate in early postmenopausal women with vertebral osteopenia: a dose-finding study. This double-masked, placebo-controlled study was undertaken to determine the efficacy and safety of oral clodronate in the prevention of bone loss in early postmenopausal women with vertebral osteopenia. Altogether 610 women with a mean age of 53 years were recruited for the study. They were 1-5 years postmenopausal and their lumbar spine bone mineral density (BMD) was at least 1 standard deviation below the mean of premenopausal women ( T-score < or =-1). The subjects were randomized into five study groups to receive either placebo, clodronate 65 mg, 400 mg or 800 mg daily, or intermittent clodronate in 3 month cycles with 400 mg daily for 15 days followed with no treatment for 75 days for 3 years. One hundred and eighty-seven of 509 women who completed the primary study continued in the extension study of 2 years in which previous placebo users were switched to clodronate 800 mg daily, while previous users of 400 mg or 800 mg of clodronate used either placebo or 800 mg of clodronate daily. In the primary study clodronate was administered in the evening, and in the extension 1 h before breakfast on an empty stomach. In the primary study mean changes in lumbar spine BMD were -3.4% in the placebo group and +0.4% in 800 mg clodronate group [difference between groups at 3 years 3.8% (95% CI 2.7% to 4.9%, p<0.0001)], and in the trochanter area BMD -1.1% in the placebo group, and + 0.4% in the 800 mg clodronate group [difference between groups at 3 years 1.5% (95% CI 0.05% to 2.9%)]. During the extension study mean changes in lumbar spine BMD were +1.5% in the clodronate group and -0.2 % in the placebo group [difference between groups 1.7% (CI 0.4% to 3.0%, p = 0.010)] and in trochanter BMD were +2.5% in the clodronate group and no change in the placebo group [difference between groups 2.1% (CI 0.3% to 3.9%, p = 0.007)]. No statistically significant differences between the placebo and 800 mg clodronate groups were found in the femoral neck BMD. In the primary study the urinary excretion of type I collagen aminoterminal telopeptide (NTX) decreased by 44% ( p<0.0001 compared with placebo) and that of deoxypyridinoline by 18% ( p<0.0001) in the clodronate 800 mg group. In the extension study urinary NTX decreased by 51% ( p<0.0001) in those who were switched to 800 mg of clodronate and increased by 67% ( p<0.0001) in those who stopped using that dose. There was no difference in the frequency of gastrointestinal complaints between clodronate- and placebo-treated patients in the primary study, but they were more common among women who received clodronate in the extension phase. Clodronate in daily doses of 400-800 mg caused a slight elevation of aminotransferase levels, usually within the reference range. In bone biopsies no defect in mineralization was found. In conclusion, clodronate in a daily dose of 800 mg prevents early postmenopausal bone loss at the sites of the skeleton in which cancellous bone predominates. It effectively reduces bone resorption and bone turnover rate. Antifracture efficacy of clodronate remains to be established by prospective, placebo-controlled trials.

Continuous infusion of opioid and bupivacaine by externalized intrathecal catheters in long-term treatment of "refractory" nonmalignant pain. To explore the possibility of obtaining pain relief by continuous intrathecal infusion of bupivacaine and opioid in patients with intractable nonmalignant pain. Prospective, cohort, nonrandomized, consecutive trial. Tertiary care center, institutional practice, hospitalized, and ambulatory care. A total of 90 patients, 40 men and 50 women, 20 to 96 years old (median, 70 years), with various nonmalignant "refractory" pain conditions lasting for 0.3 to 50 years (median, 3 years) with nociceptive (n = 9), neurogenic/neuropathic (n = 17), and mixed pain (n = 64) were consecutively included in the study when (a) the pain dominated their lives totally, (b) other methods failed to provide acceptable pain relief, and (c) unacceptable side effects from opioids had occurred. Moribund patients and those with overt psychoses at the time of the assessment were excluded from the study. (a) Insertion of externalized, tunnelled intrathecal catheters (101 in 90 patients). (b) Intrathecal infusion of opioid (morphine 0.5 mg/ml, or buprenorphine 0.015 mg/ml, and/or bupivacaine 4.75-5.0 mg/ml) from external electronic pumps was started in the operating room at a basic rate of 0.2 ml/hour, with optional bolus doses (0.1 ml 1-4 times/hour) by patient-controlled analgesia (PCA). Thereafter, the daily volumes were tailored to give the patients satisfactory to excellent (60-100%) pain relief, with acceptable side effects from the infused drugs, by increase or decrease of the basic rates and/or of the bolus doses, and their timing. (c) Supervision of the patients for 24 hours after catheterization in the postoperative ward. (d) Daily phone contact with the patients, their families, or the nurses in charge. (e) The patients had ad libitum access to nonopioid analgesics/sedatives and to opioids administered by various routes, until they obtained satisfactory pain and anxiolytic relief. (a) Pain intensity (visual analog scores 0-10) and pain relief (0-100%). (b) Daily dosages (opioid administered by intrathecal and other routes, and intrathecal bupivacaine). (c) Scores (0-5) of nonopioid analgesics, gait and ambulation, duration of nocturnal sleep, and (d) rates of adverse effects. During the intrathecal period [range, 3-1,706 days; median, 60 days; totaling 14,686 days, 7,460 (50% of which were spent at home)], 86 patients (approximately 95%) obtained acceptable (60-100%) pain relief. The nocturnal sleep duration increased from <4 to 7 hours (median values), nonopioid analgesic and sedative daily consumption became approximately two times lower, whereas the gait ability and ambulation patterns remained practically unchanged. Five patients still had ongoing treatment after durations of 30 to 1,707 (median, 206) days at the close of the study. In the remaining 85 patients, the intrathecal treatment was terminated because of patients' death (n = 23), replacement of the intrathecal treatment by dorsal column stimulation (n = 1), pain resolution (n = 32), refusal to continue the intrathecal treatment (n = 19), lack of cooperation due to delirium or to manipulation of the pump (n = 8), and loss of efficacy of the intrathecal treatment (n = 2). Thus, in the long run, the intrathecal treatment failed in 29 of the 85 patients with terminated treatment (34%). The principal side-effects and complications, except those attributed to the dural puncture, the equipment, and the long-term catheterization of the subarachnoid space, which are presented separately, were severe bradypnea (n = 1), transient paresthesiae (n = 26), short-lasting pareses (n = 16), temporary urine retention (n = 34), episodic orthostatic arterial hypotension (n = 11), and attempted suicide (n = 5, 3 of which were successful). No neurologic sequelae or death could be attributed to the intrathecal procedure. (ABSTRACT TRUNCATED)

[The dose-response relationship and time course of the neuromuscular blockade by alcuronium]. Although alcuronium has been in clinical use for almost 40 years, there is still considerable controversy in the literature regarding its neuromuscular blocking potency, the time course of the drug action and the side effects. The aim of this study was to investigate the dose-response relationship of alcuronium and to compare the time course of its neuromuscular effects with vecuronium following intubation doses of both compounds. METHODS. The study was carried out in two parts. In the first part 60 patients and in the second part 30 consenting ASA class I or II patients 20-60 years of age were included. The patients were undergoing elective gynecological or intra-abdominal operations. In the first part the patients received six different doses of alcuronium (60, 90, 120, 150, 180 or 210 micrograms/kg) in order to establish its dose-response relationship. Each dose was administered to ten patients. In the second part patients received either 300 micrograms/kg alcuronium (n = 15) or 100 micrograms/kg vecuronium (n = 15), and the time course of these two compounds (onset time, duration 25%, duration 75% and the recovery index) were compared. To test the reversibility, ten patients in each group received 30 micrograms/kg neostigmine at 25% recovery of T1. The neuromuscular effects of alcuronium and vecuronium were quantitated by EMG using the DATEX relaxograph. RESULTS. The log-logit analysis of the dose response data revealed an ED50 of 111 micrograms/kg and an ED95 of 250 micrograms/kg, which is in reasonable agreement with the measured effects following 120 micrograms/kg and 210 micrograms/kg alcuronium, resulting in 52 +/- 21% and 96 +/- 4% T1 depression, respectively. The onset time, duration 25%, duration 75% and spontaneous recovery index following 300 micrograms/kg alcuronium (5.0 +/- 3.4 min, 62 +/- 25 min, 119 +/- 38 min and 58 +/- 34 min) appeared to be significantly longer (P less than 0.05) than those observed after 100 micrograms/kg vecuronium (3.2 +/- 1.2 min, 33 +/- 7 min, 49 +/- 9 min and 18 +/- 7 min), respectively. The most striking finding of this study is the enormous individual variations observed in both neuromuscular potency and the time course of action of alcuronium. Following 150 micrograms/kg (routinely employed in daily clinical practice), the magnitude of T1 depression ranged between 19% and 100%. The same vast individual variations were observed in the time course of action following 300 micrograms/kg of alcuronium. The onset time, duration 25%, duration 75% and spontaneous recovery index ranged between 1.3 and 14 min, 22 and 110 min, 93 and 186 min and 32 and 116 min, respectively. CONCLUSIONS. The ED50 and ED95 values for alcuronium found in this study are in the same order of magnitude as 106.8 micrograms/kg and 135 micrograms/kg for ED50 and with 280 micrograms/kg for ED95, respectively, as reported by others. The long duration with slow recovery and the wide individual variation in the neuromuscular effects observed in our study have been reported earlier. Based on the above observations and because of the availability of better alternatives with fewer side effects, we conclude that alcuronium should be added to the list of obsolete neuromuscular blocking agents, together with gallamine and d-tubocurarine.

Milk production of crossbred daughters of high- and low-milk EPD Angus and Hereford bulls. Milk yield from 273 Angus- and Hereford-sired cows and preweaning performance of their calves were used to determine how accurately milk EPD of Angus and Hereford sires predicted milk production of crossbred daughters and subsequent calf performance. Mean milk EPD (kg) for high Angus (HA), low Angus (LA), high Hereford (HH), and low Hereford (LH) bulls (n = 41) selected as sires were +8.7, -6.2, +7.6, and -4.8, respectively. Cows calved in spring or fall from 1992 to 1997 and yielded a total of 660 records. Twenty-four-hour milk production of the cows was estimated by two weigh-suckle-weigh measurements at monthly intervals. The statistical model included breed, milk EPD level, sire of cow within breed and milk EPD level, year, season, cow age, calf sire, sex, and all two- and three-way interactions. Means were obtained for monthly milk production, total milk production, time and yield of peak production, monthly calf weights, monthly cow weights and body condition scores (1 through 9), and calf birth and weaning data. The least squares means for 24-h milk production (kg) of HA, LA, HH, and LH with P-values for high vs low, across breeds, were, respectively, as follows: mo 1: 6.9, 5.9, 7.1, and 5.7 (P < 0.01); mo 2: 7.2, 6.1, 6.9, and 5.7 (P < 0.01); mo 3: 6.1, 5.1, 5.1, and 4.3 (P = 0.01); mo 4: 6.1, 4.9, 4.9, and 4.8 (P = 0.01); mo 5: 4.8, 4.0, 4.2, and 3.8 (P = 0.01); mo 6: 4.7, 3.4, 3.2, and 3.0 (P < 0.01); and mo 7: 3.7, 2.5, 3.0, and 3.0 (P = 0.05). Least squares means for total milk (kg) were 911.4, 729.6, 758.0, and 664.2 (P < 0.01); for yield at peak (kg/d) were 7.0, 5.7, 6.1, and 5.2 (P < 0.01); for birth weight (kg) were 37.1, 37.9, 38.3, and 38.8 (P = 0.31); for 205-d weight (kg) were 237.3, 218.2, 222.2, and 214.1 (P < 0.01); for final cow weight (kg) were 482.4, 505.4, 509.5, and 511.7 (P = 0.11); and for final cow BCS were 4.9, 5.3, 5.1, and 5.2 (P < 0.01). The correlations of total production with the monthly productions were 0.52, 0.56, 0.52, 0.54, 0.35, 0.37, and 0.31 (P < 0.01) and were 0.12 with birth weight, 0.45 with 205-d weight, -0.12 with final cow weight, and -0.26 with final cow body condition score (all P < 0.01). Daughters of high-milk EPD sires produced more milk and weaned heavier calves than those of low-milk EPD sires at the expense of body condition. These results suggest that sire milk EPD are sufficiently associated with milk yield and calf performance to be useful tools in genetic improvement of preweaning performance.

Carbohydrate ingestion during team games exercise: current knowledge and areas for future investigation. There is a growing body of research on the influence of ingesting carbohydrate-electrolyte solutions immediately prior to and during prolonged intermittent, high-intensity exercise (team games exercise) designed to replicate field-based team games. This review presents the current body of knowledge in this area, and identifies avenues of further research. Almost all early work supported the ingestion of carbohydrate-electrolyte solutions during prolonged intermittent exercise, but was subject to methodological limitations. A key concern was the use of exercise protocols characterized by prolonged periods at the same exercise intensity, the lack of maximal- or high-intensity work components and long periods of seated recovery, which failed to replicate the activity pattern or physiological demand of team games exercise. The advent of protocols specifically designed to replicate the demands of field-based team games enabled a more externally valid assessment of the influence of carbohydrate ingestion during this form of exercise. Once again, the research overwhelmingly supports carbohydrate ingestion immediately prior to and during team games exercise for improving time to exhaustion during intermittent running. While the external validity of exhaustive exercise at fixed prescribed intensities as an assessment of exercise capacity during team games may appear questionable, these assessments should perhaps not be viewed as exhaustive exercise tests per se, but as indicators of the ability to maintain high-intensity exercise, which is a recognized marker of performance and fatigue during field-based team games. Possible mechanisms of exercise capacity enhancement include sparing of muscle glycogen, glycogen resynthesis during low-intensity exercise periods and attenuated effort perception during exercise. Most research fails to show improvements in sprint performance during team games exercise with carbohydrate ingestion, perhaps due to the lack of influence of carbohydrate on sprint performance when endogenous muscle glycogen concentration remains above a critical threshold of ∼200 mmol/kg dry weight. Despite the increasing number of publications in this area, few studies have attempted to drive the research base forward by investigating potential modulators of carbohydrate efficacy during team games exercise, preventing the formulation of optimal carbohydrate intake guidelines. Potential modulators may be different from those during prolonged steady-state exercise due to the constantly changing exercise intensity and frequency, duration and intensity of rest intervals, potential for team games exercise to slow the rate of gastric emptying and the restricted access to carbohydrate-electrolyte solutions during many team games. This review highlights fluid volume, carbohydrate concentration, carbohydrate composition and solution osmolality; the glycaemic index of pre-exercise meals; fluid and carbohydrate ingestion patterns; fluid temperature; carbohydrate mouthwashes; carbohydrate supplementation in different ambient temperatures; and investigation of all of these areas in different subject populations as important avenues for future research to enable a more comprehensive understanding of carbohydrate ingestion during team games exercise.

Stapled versus handsewn methods for colorectal anastomosis surgery. Randomized controlled trials comparing stapled with handsewn colorectal anastomosis have not shown either technique to be superior, perhaps because individual studies lacked statistical power. A systematic review, with pooled analysis of results, might provide a more definitive answer. To compare the safety and effectiveness of stapled and handsewn colorectal anastomosis. The following primary hypothesis was tested: the stapled technique is more effective because it decreases the level of complications. The RCT register of the Cochrane Review Group was searched for any trial or reference to a relevant trial (published, in-press, or in progress). All publications were sought through computerised searches of EMBASE, LILACS, MEDLINE, the Cochrane Controlled Clinical Trials Database, and through letters to industrial companies and authors. There were no limits upon language, date, or other criteria. All randomized clinical trials (RCTs) in which stapled and handsewn colorectal anastomosis were compared. Adult patients submitted electively to colorectal anastomosis. Endoluminal circular stapler and handsewn colorectal anastomosis. a) Mortality b) Overall Anastomotic Dehiscence c) Clinical Anastomotic Dehiscence d) Radiological Anastomotic Dehiscence e) Stricture f) Anastomotic Haemorrhage g) Reoperation h) Wound Infection i) Anastomosis Duration j) Hospital Stay. Data were independently extracted by the two reviewers (SASL, DM) and cross-checked. The methodological quality of each trial was assessed by the same two reviewers. Details of the randomization (generation and concealment), blinding, whether an intention-to-treat analysis was done, and the number of patients lost to follow-up were recorded. The results of each RCT were summarised on an intention-to-treat basis in 2 x 2 tables for each outcome. External validity was defined by characteristics of the participants, the interventions and the outcomes. The RCTs were stratified according to the level of colorectal anastomosis. The Risk Difference method (random effects model) and NNT for dichotomous outcomes measures and weighted mean difference for continuous outcomes measures, with the corresponding 95% confidence interval, were presented in this review. Statistical heterogeneity was evaluated by using funnel plot and chi-square testing. Of the 1233 patients enrolled ( in 9 trials), 622 were treated with stapled, and 611 with manual, suture. The following main results were obtained: a) Mortality: result based on 901 patients; Risk Difference - 0.6% Confidence Interval -2.8% to +1.6%. b) Overall Dehiscence: result based on 1233 patients; Risk Difference 0.2%, 95% Confidence Interval -5.0% to +5.3%. c) Clinical Anastomotic Dehiscence : result based on 1233 patients; Risk Difference -1.4%, 95% Confidence Interval -5.2 to +2.3%. d) Radiological Anastomotic Dehiscence : result based on 825 patients; Risk Difference 1.2%, 95% Confidence Interval -4.8% to +7.3%. e) Stricture: result based on 1042 patients; Risk Difference 4.6%, 95% Confidence Interval 1.2% to 8.1%. Number needed to treat 17, 95% confidence interval 12 to 31. f) Anastomotic Hemorrhage: result based on 662 patients; Risk Difference 2.7%, 95% Confidence Interval - 0.1% to +5.5%. g) Reoperation: result based on 544 patients; Risk Difference 3.9%, 95% Confidence Interval 0.3% to 7.4%. h) Wound Infection: result based on 567 patients; Risk Difference 1.0%, 95% Confidence Interval -2.2% to +4.3%. i) Anastomosis duration: result based on one study (159 patients); Weighted Mean Difference -7.6 minutes, 95% Confidence Interval -12.9 to -2.2 minutes. j) Hospital Stay: result based on one study (159 patients), Weighted Mean Difference 2.0 days, 95% Confidence Interval -3.27 to +7.2 days. The evidence found was insufficient to demonstrate any superiority of stapled over handsewn techniques in colorectal anastomosis, regardless of the level of anastomosis.

Reconstitution of core light-harvesting complexes of photosynthetic bacteria using chemically synthesized polypeptides. 2. Determination of structural features that stabilize complex formation and their implications for the structure of the subunit complex. Chemically synthesized polypeptides have been utilized with a reconstitution assay to determine the role of specific amino acid side chains in stabilizing the core light-harvesting complex (LH1) of photosynthetic bacteria and its subunit complex. In the preceding paper [Meadows, K. A., Parkes-Loach, P. S., Kehoe, J. W., and Loach, P. A. (1998) Biochemistry 37, 3411-3417], it was demonstrated that 31-residue polypeptides (compared to 48 and 54 amino acids in the native polypeptides) having the same sequence as the core region of the beta-polypeptide of Rhodobacter sphaeroides (sph beta 31) or Rhodospirillum rubrum (rr beta 31) could form subunit-type complexes. However, neither polypeptide interacted with the native alpha-polypeptides to form a native LH1 complex. In this paper, it is demonstrated that larger segments of the native Rb. sphaeroides beta-polypeptide possess native behavior in LH1 formation. Polypeptides were synthesized that were six (sph beta 37) and ten amino acids (sph beta 41) longer than sph beta 31. Although sph beta 37 exhibited behavior nearly identical to that of sph beta 31, sph beta 41 behaved more like the native polypeptide. In the case of rr beta 31, a polypeptide with four additional amino acids toward the C terminus was synthesized (rr beta 35). Because LH1-forming behavior was not recovered with this longer polypeptide, one or more of the three remaining amino acids at the C-terminal end of the native beta-polypeptide seem to play an important role in LH1 stabilization in Rs. rubrum. Three analogues of the core region of the Rb. sphaeroides beta-polypeptide were synthesized, in each of which one highly conserved amino acid was changed. Evidence was obtained that the penultimate amino acid, a Trp residue, is especially important for subunit formation. When it was changed to Phe, the lambda Max of the subunit shifted from 823 to 811 nm and the association constant decreased about 500-fold. Changing each of two other amino acids had smaller effects on subunit formation. Changing Trp to Phe at the location six amino acid residues toward the C terminus from the His coordinated to Bchl resulted in an approximately 10-fold decrease in the association constant for subunit formation but did not affect the formation of a LH1-type complex compared to sph beta 31. Finally, changing Arg to Leu at the location seven amino acid residues toward the C terminus from the His coordinated to Bchl decreased the association constant for subunit formation by about 30-fold. In this case, no LH1-type complex could be formed. On the basis of these results, in comparison with the crystal structure of the LH2 beta-polypeptide of Rhodospirillum molischianum, two possible structures for the subunit complex are suggested.

Conserved domains of glycosyltransferases. Glycosyltransferases catalyze the synthesis of glycoconjugates by transferring a properly activated sugar residue to an appropriate acceptor molecule or aglycone for chain initiation and elongation. The acceptor can be a lipid, a protein, a heterocyclic compound, or another carbohydrate residue. A catalytic reaction is believed to involve the recognition of both the donor and acceptor by suitable domains, as well as the catalytic site of the enzyme. To elucidate the structural requirements for substrate recognition and catalytic reactions of glycosyltransferases, we have searched the databases for homologous sequences, identified conserved amino acid residues, and proposed potential domain motifs for these enzymes. Depending on the configuration of the anomeric functional group of the glycosyl donor molecule and of the resulting glycoconjugate, all known glycosyltransferases can be divided into two major types: retaining glycosyltransferases, which transfer sugar residue with the retention of anomeric configuration, and inverting glycosyltransferases, which transfer sugar residue with the inversion of anomeric configuration. One conserved domain of the inverting glycosyltransferases identified in the database is responsible for the recognition of a pyrimidine nucleotide, which is either the UDP or the TDP portion of a donor sugar-nucleotide molecule. This domain is termed "Nucleotide Recognition Domain 1 beta," or NRD1 beta, since the type of nucleotide is the only common structure among the sugar donors and acceptors. NRD1 beta is present in 140 glycosyltransferases. The central portion of the NRD1 beta domain is very similar to the domain that is present in one family of retaining glycosyltransferases. This family is termed NRD1 alpha to designate the similarity and stereochemistry of sugar transfer, and it consists of 77 glycosyltransferases identified thus far. In the central portion there is a homologous region for these two families and this region probably has a catalytic function. A third conserved domain is found exclusively in membrane-bound glycosyltransferases and is termed NRD2; this domain is present in 98 glycosyltransferases. All three identified NRDs are present in archaebacterial, eubacterial, viral, and eukaryotic glycosyltransferases. The present article presents the alignment of conserved NRD domains and also presents a brief overview of the analyzed glycosyltransferases which comprise about 65% of all known sugar-nucleotide dependent (Leloir-type) and putative glycosyltransferases in different databases. A potential mechanism for the catalytic reaction is also proposed. This proposed mechanism should facilitate the design of experiments to elucidate the regulatory mechanisms of glycosylation reactions. Amino acid sequence information within the conserved domain may be utilized to design degenerate primers for identifying DNA encoding new glycosyltransferases.

Survival of short implants is improved with greater implant length, placement in the mandible compared with the maxilla, and in nonsmokers. The authors conducted a search of MEDLINE and EMBASE databases for the period January 1980 to October 2009. This was supplemented by searching reference lists of literature obtained. There was no language restriction applied. Two authors reviewed the search yield for relevance, disagreement was resolved by consensus discussion, and the selected articles deemed relevant for full-text review were read by one reviewer. The relevant articles selected were judged against inclusion/exclusion criteria. Included studies were restricted to randomized controlled trials (RCTs) or prospective cohort studies. Only studies with partially edentulous applications of at least 5 implants shorter than 10 mm followed for more than 1 year were included. No (alumina)-zirconium implants or mini-implants for orthodontic anchorage or short implants used for cantilevered prostheses were included. A validity assessment using methodological criteria for cohort and RCTs was accomplished by 2 reviewers. The focus of the review was to determine the prognosis of short (<10 mm) implants in the partially edentulous patient. The authors sought to identify important influences on survival rate by conducting subgroup analyses where the subgroups included individual implant lengths shorter than 10 mm, smoking, implants in the mandible versus maxilla, and bone augmentation procedures. The 2-year estimated survival rate was selected based on evidence suggesting that after 1 year the implant survival rate is considered to be constant, an important aspect for survival function estimation. To allow a pooled estimate of prognosis from multiple studies, the estimated failure rate per year and estimated implant survival rate after 2 years was determined for each study. The estimated failure rate per study was determined as a function of number of implant failures and total implant "exposure" time. Exposure in this context means the time an implant is in vivo and, hence, exposed to failure risk. Consequently, exposure time includes implants followed the entire study, those up to the time of failure, and those followed to a premature study end (eg, patient death, moving, refusal to continue). When study data were not provided separately for the short implants in a publication, a proportional exposure (short implants/total implants χ overall exposure time) was determined. The 2-year survival calculation made from the estimated failure rate assumed a constant rate of implant failure (considered to follow a Poisson distribution). Additional analyses sought to identify independent effects on failure based on implant surface topography (rough vs machined), maxilla versus mandible, smoking status, and augmentation. Twenty-nine studies were identified that met both the inclusion criteria and methodological requirements of the 1353 articles identified in the literature search. Of these 29 studies, 28 were prospective cohort studies and 1 was an RCT. The mean follow-up for the studies was 3.7 years, with a range from 1.6 to 8.1 years. There were 2611 short implants in the identified studies ranging in length from 5.0 mm to 9.5 mm. Table 1 provides the outcome data by implant length, including the number of implants in each group, the estimated annual failure rate (expressed as a percentage), and the 2-year estimated failure rate (expressed as a percentage). Overall, 5-mm implants were calculated to have a 2-year survival rate of 93%, whereas 9-mm implants had a 2-year survival rate of 98%. Additional analyses revealed that for all implant lengths, both rough and machined (smooth) implants had similar failure rates (0.008 and 0.010, respectively). Implants placed in the maxilla had a significantly greater failure rate than those placed in the mandible (0.010 and 0.003, respectively). Estimated failure rates in studies that excluded smokers were twice as low as those seen in studies that included heavy smokers (0.004 and 0.080, respectively). No significant difference in estimated failure rate was seen for implants placed with simultaneous augmentation compared with no augmentation (0.007 and 0.010, respectively). The findings from this systematic review are important in that collectively they support consideration of placement of short implants in partially edentulous patients. The estimated data showed a tendency for improved survival rate with increasing implant length, implant placement in the mandible compared with the maxilla, and for implants placed in nonsmokers.

35-year-old woman with progressive bilateral leg weakness. A 35-year-old woman presented with one month's history of progressive bilateral leg weakness and altered sensation. There had been no pain. She had noted urinary frequency and constipation in the previous two weeks. On examination, the patient had diffuse lower extremity weakness (2-3/5), with a T6 sensory level to pain and temperature sensation. MRI demonstrated a T4-5 intradural mass ventral to the spinal cord, with an enhancing dural tail, consistent with meningioma. At surgery an intradural, extramedullary, firm, black neoplasm was encountered, which invaded the ventral dura and elevated and distorted the spinal cord. The mass was removed, leaving only microscopic invasion of the ventral dura. There was no bone invasion. Serial sections revealed a homogeneous black tumor without necrosis. H&E stained sections showed an occasionally fascicular tumor of melanocytes and small round blue tumor spindle cells with melanin pigmentation and 1-2 mitotic figures per 10 high-powered fields. The nuclei are generally oval-shaped and elongated, with prominent nucleoli. Necrosis, hemorrhage, and nuclear and cellular pleomorphism are not present and mitotic figures are rare. Immunohistochemical staining was positive for S-100 and HMB-45. MIB-1 labeling averaged 1-2%. A diagnosis of primary meningeal melanocytic tumor was made. Primary meningeal melanocytic tumors (PMMTs) are rare; fewer than 100 cases have been described. PMMTs of the CNS consist of a spectrum of tumors ranging from well-differentiated melanocytoma to its overtly malignant counterpart, melanoma. Intermediate grade melanocytomas (IMGs) are the least common variant, comprising about 10% of PMMTs reported. IGMS occur in the spinal leptomeninges and intracranially in approximately equal proportions. IGMs are more cellular than the well-differentiated variant, with 1-3 mitotic figures per 10 HPFs and MIB-1 labeling of <6%. By contrast, melanomas contain more mitotic figures (3-15 per 10 HPF) and MIB-1 labeling rates up to 15%. Once metastasis, including drop metastasis from pigmented medulloblastomas, have been excluded, the differential includes pigmented meningiomas and schwannomas (solitary or as part of Carney complex), as well as other pigmented CNS tumors such as ependymoma and pineoblastoma and systemic diseases such as lymphoma . . . For primary CNS melanocytic neoplasms, complete tumor resection is preferred, as it leads to cure of well-differentiated and intermediate-grade melanocytomas and most melanomas. Radiotherapy is recommended for incomplete resection of IMGs and melanomas; the recurrence potential of low-grade melanocytomas is less clear and watchful waiting may be employed, since recurrent tumors may be treated surgically prior to radiation. Two months after surgery, the patient had normal sensation and strength. She was given focused radiotherapy to the region of the ventral thecal sac to 40 cGy. At one year following surgery, the patient's neurological examination is normal and she remains free of residual disease by MR examination.

The effects of heat stress on protein metabolism in lactating Holstein cows. Heat stress (HS) decreases milk protein synthesis beyond what would be expected based on the concomitant reduction in feed intake. The aim of the present study was to evaluate the direct effects of HS on milk protein production. Four multiparous, lactating Holstein cows (101 ± 10 d in milk, 574 ± 36 kg of body weight, 38 ± 2 kg of milk/d) were individually housed in environmental chambers and randomly allocated to 1 of 2 groups in a crossover design. The study was divided into 2 periods with 2 identical experimental phases (control phase and trial phase) within each period. During phase 1 or control phase (9 d), all cows were housed in thermal neutral conditions (TN; 20°C, 55% humidity) and fed ad libitum. During phase 2 or treatment phase (9 d), group 1 was exposed to cyclical HS conditions (32 to 36°C, 40% humidity) and fed ad libitum, whereas group 2 remained in TN conditions but was pair-fed (PFTN) to their HS counterparts to eliminate the confounding effects of dissimilar feed intake. After a 30-d washout period in TN conditions, the study was repeated (period 2), inverting the environmental treatments of the groups relative to period 1: group 2 was exposed to HS and group 1 to PFTN conditions. Compared with PFTN conditions, HS decreased milk yield (17.0%), milk protein (4.1%), milk protein yield (19%), 4% fat-corrected milk (23%), and fat yield (19%). Apparent digestibility of dry matter, organic matter, neutral detergent fiber, acid detergent fiber, crude protein, and ether extract was increased (11.1-42.9%) in HS cows, as well as rumen liquor ammonia (before feeding 33.2%; after feeding 29.5%) and volatile fatty acid concentration (45.3%) before feeding. In addition, ruminal pH was reduced (9.5 and 6% before and after feeding, respectively) during HS. Heat stress decreased plasma free amino acids (AA; 17.1%) and tended to increase and increased blood, urine, and milk urea nitrogen (17.2, 243, and 24.5%, respectively). Further, HS cows had reduced plasma glucose (8%) and nonesterified fatty acid (39.8%) concentrations compared with PFTN controls. These data suggest that HS increases systemic AA utilization (e.g., decreased plasma AA and increased nitrogen excretion), a scenario that limits the AA supply to the mammary gland for milk protein synthesis. Furthermore, the increase in AA requirements during HS might represent the increased need for gluconeogenic precursors, as HS is thought to prioritize glucose utilization as a fuel at the expense of nonesterified fatty acids.

Further characterization of a novel triacylglycerol hydrolase activity (pH 6.0 optimum) from microvillous membranes from human term placenta. We recently identified the presence of two distinct triacylglycerol hydrolases with pH optima of 6.0 and 8.0 in human placental microvillous membranes (MVM). The TAG hydrolase with a pH optimum of 8.0 has properties similar to lipoprotein lipase, whereas TAG hydrolase with a pH optimum of 6.0 still to be fully characterized. In order to understand the functional and structural relationships between these two TAG hydrolases of MVM we have further investigated their biochemical and molecular properties. The presence of oleic acid inhibited TAG hydrolase activity with a pH optimum of 8.0 by 60 per cent whilst it had very little effect on the pH 6.0 TAG hydrolase activity. K(m)values for TAG hydrolases at pH 6.0 and pH 8. 0 optima were 170.6 and 9.83 nmol triolein, respectively, whereas the corresponding V(max)values were 0.32 and 0.037 nmol oleic acid/min mg/protein. Treatment of MVM with phenylmethylsulphonofluoride or protamine had no effect on TAG hydrolase at pH 6.0 whereas both decreased activity at pH 8.0, by 70 per cent and 52 per cent, respectively (P< 0.05), compared with control. p-Chloromercuribenzoate inhibited both TAG hydrolase activities by 25-30 per cent whereas iodoacetate inhibited TAG hydrolase activity with optimum pH 8.0 by 74 per cent and the activity at pH 6.0 by 28 per cent. Unlike the TAG hydrolase activity at pH 8.0, the activity at pH 6.0 was not affected by heparin. TAG hydrolase activity at pH 6.0 was significantly decreased compared with that of pH 8.0 optimum TAG hydrolase activity in smokers placenta. A threefold increase in pH 6.0 TAG hydrolase activity was observed following differentiation, whereas membrane associated TAG hydrolase activity with optimum pH 8.0 did not change. The TAG hydrolase with optimum pH 6.0 was subsequently purified from MVM to almost 1000-fold enrichment of the activity over the starting material. The final preparation however, still contained three distinct protein bands (90, 70 and 45 kDa). When extracted from non-denaturing polyacrylamide gels, the 70 kDa protein was the only protein to have TAG hydrolysing activity and had a pH optimum of 6.0. Labelling of samples with [(14)C]tetrahydrolipstatin also confirmed that the TAG hydrolase active protein was a 70 kDa protein. In conclusion, we report that there is a 70 kDa TAG hydrolase with optimum pH 6.0 in human placental MVM which is quite distinct from placental lipoprotein lipase.

[Neuroleptic-induced movement disorders: historical perspectives]. Soon after the discovery of neuroleptics, neurological side effects of the extrapyramidal type were reported. The first description of neuroleptic-induced parkinsonism dates back to the "Swiss Symposium on Chloropromazine" held in 1953. Steck in 1954 vividly described the symptoms in a convincing manner. In 1955, Delay and Denicker, observing the therapeutic efficacy and extrapyramidal activity of two seemingly different compounds as chloropromazine and reserpine, used the term "neuroleptic" to characterize this common property. Two years later they proposed a definition of neuroleptics taking into account therapeutic efficacy as well as side effects. Such a definition was not accepted by American authors who preferred term like "major tranquilizers" and finally "antipsychotics". The meaning of neuroleptic parkinsonism (whether it was a side effect or part of the therapeutic action) had been discussed for a long time. The analogy with the clinical manifestations of Von Economo's encephalitis lethargica was also mentioned. Tardive dyskinesia appeared in the literature in the late 1950's. The first report was made by Schoenecker in 1957 who described bucco-oral movements persisting after the neuroleptics were diminished or discontinued. He concluded that these manifestations were different from the acute extrapyramidal side effects. Two years later Sigwald et al. reported involuntary movements of the tongue, lips and facial muscles which appeared after several years of phenothiazine treatment. In 1960 Uhrbrand and Faurbye described bucco-linguo-masticatory movements sometimes associated with trunk and foot movements. Half of these cases persisted (and a few aggravated) after neuroleptic withdrawal. In others the condition was unmasked by the neuroleptic discontinuation. In 1964 Faurbye et al. proposed the term "tardive dyskinesia" for this extrapyramidal side effect. After an initial description by Druckman et al. in 1962, the term of "tardive dystonia" was first used in 1973 by Keegan and Rajput. The patients described in the early literature were mainly of an advanced age with organic involvement. The first serious epidemiological studies were undertaken in the late 1960's, showing prevalences varying between 0.5 to 65%! Most of the predisposing factors suspected in early studies (cerebral lesions, lobotomy, ECT) were not confirmed in more recent studies that emphasized the role of an older age and a female gender. The interest in tardive dyskinesia varies from one country to another. Perhaps, dyskinesia was more severe and problematic in the USA because of more liberal indications for neuroleptic use, higher doses and smaller choice of neuroleptic medications. Medicolegal aspects have also increased the apprehension of american physicians. Tardive dyskinesia remains an enigmatic phenomenon and a therapeutic challenge. In the future, the possible discovery of antipsychotic molecules devoid of extrapyramidal side effects may discourage the research on these unresolved issues.

[Inhibition of angiogenesis in the cornea with amiloride]. For its transparency, avascularity and possibility of measurement of the new vessels ingrowth, cornea is a frequent model for angiogenesis research. New vessels are made in several phases: after the action of the stimulus, there is a localised fragmentation of the basal membrane and the extracellular matrix around the involved capillary. Then, endothelial cells migrate through the openings in the capillary wall and the lysis of the extracellular matrix continues as a new vessel is being formed. Enzymes, plasminogen-activators, convert plasminogen from the blood and tissues to plasmin which starts proteolytic cascade of the lysis of the extracellular matrix. Amilorid, previously known as a diuretic, is found to be a competitive inhibitor of plasminogen activator-urokinase (u-PA). Its effect was shown in the prostaglandin-induced model of corneal vascularization [6]. The purpose of this work is to show that amilorid acts as an angiostatic in the traumatic model of corneal vascularization. There were two groups of experimental animals (rabbits, weight 1.5-3 kg). Deepitelisation and trephination were performed on all corneas (traumatic model of vascularisation). The first group of animals (17 eyes) was given 15 mg of amilorid (Sigma) intraperitoneally for five days, while the control group consisted of 7 eyes. Neovascularization was measured after 5 and 15 days. Animals were sacrificed on day 15. Three eyes from each group were tested for corneal wound tensile strength. In the experimental group there was a 0.5 mm ingrowth of the new vessels after the first five days and no further ingrowth till the end of the experiment. In the control group there was a 2 mm ingrowth after five days, and a further 1 mm after the next ten days. No statistical difference was found with regard to tensile strengths of the corneal wounds between the two groups. Although the traumatic model is closer to the clinical situation than the prostaglandin-induced vascularization model, more potential angiogenic factors are involved. Trephination damages basal membrane which may liberate angiogenic substances (heparan-sulphate, for example) [9]. Products of damaged cells attract leucocytes by haemotaxis. Also, hyopxia in the depth of the wound may be the site of macrophage induced angiogenesis [10]. It is difficult to say at which point amilorid acts but, considering the new vessel ingrowth for only 0.5 mm, it might be at the beginning of the process (lysis of extracellular matrix). Amilorid acts as angiogenesis inhibitor in the traumatic corneal vascularization model without changing the tensile strength of the wound.

Radiation therapy for Bowen's disease of the skin. To assess the clinical outcome in the radiation therapy (RT) of squamous carcinoma in situ of the skin (Bowen's disease). We focused on the local control rate and the toxicity according to the biologically effective dose (BED). A retrospective review was performed on 44 patients with Bowen's disease treated at Princess Margaret Hospital from April 1985 to November 2000. RT was the primary treatment for 32 patients, whereas 12 received RT for residual disease after local ablative therapy. Lesions were located as follows: scalp, 9 patients (20%); face, 12 (27%); trunk, 6 (14%), extremity, 12 (27%), perianal, 3 (7%), and penis, 2 (5%). Orthovoltage X-rays were used in the majority (39 of 44, 89%). There was no standard fractionation regimen: some physicians prescribed high doses, as for invasive skin cancer, whereas others prescribed lower doses because of the noninvasive nature of the disease, a sensitive anatomic location (e.g., extremity), or large treatment area. Because of the variations in fractionation regimens, BED was used as a common metric for biologic effect in the comparison of different regimens and analyzed for correlation with recurrence and toxicity. Local control was defined as the lack of persistent or recurrent disease at the treated site for the follow-up period. Grade 4 toxicity was defined as necrosis (cartilage/bone damage) and/or ulceration for a duration of >3 months. The mean patient age was 67.7 years, and the male/female ratio was 29:15. The median pretreatment lesion size was 2.65 cm(2) (range, 0.07-34.56 cm(2)). Complete remission was achieved in 42 patients, with follow-up unavailable for the remaining 2 patients. Subsequently, 3 patients experienced recurrences at 0.2, 1.1, and 1-1.5 years after complete remission. One recurrence was Bowen's disease (local); the others were squamous cell carcinoma (one local, one marginal). Four patients experienced a new squamous lesion at a distant cutaneous site. As of last follow-up, 32 patients (73%) were known to be alive. Median follow-up was 2.6 years (range, 0-11.8 years). All but 3 patients were disease-free at last follow-up, 1 of whom died with distant, but not local disease. The 5-year overall survival rate was 68%. Biologically effective dose was not associated with recurrence. The crude local control rate was 93%. There was a trend toward higher radiation doses for smaller pretreatment tumor and field sizes. The BED did not correlate with Grade 4 toxicity; however, the three cases of Grade 4 toxicity occurred in patients treated with hypofractionated regimens (dose per fraction >4 Gy) for extremity lesions. Radiation therapy is an effective treatment option for Bowen's disease of the skin. Local recurrences seem to be equally low in patients treated with high- and low-dose regimens. Avoiding hypofractionated regimens (dose per fraction >4 Gy) in extremity locations might reduce the risk of Grade 4 toxicity.

Effect of age, exercise and growth rate on bone mineral density (BMD) in third carpal bone and distal radius of Dutch Warmblood foals with osteochondrosis. This study aimed a the determining bone mineral density (BMD) in the 3rd carpal bone and distal radius of foals age 5 and 11 months that had been subjected to different exercise regimens from birth until age 5 months. It was hypothesised that BMD would be greater in older animals, and that differences in exercise regimens before age 5 months would be associated with differences in BMD at both age 5 and 11 months. Epiphyseal bone tissue was available from 5 and 11 month old Warmblood foals bred from sires known to have radiographic evidence of osteochondrosis (OC). The foals were in a clinical trial which assessed the effect of exercise up to age 5 months on osteochondrosis (OC). Until age 5 months, foals were either box confined, box confined and sprint trained daily, or kept at pasture. Half the horses in each group were then confined together in a large stall, with access to pasture for 2 h daily, from age 6 to 11 months. BMD was assessed by dual x-ray absorptiometry in 4 areas of interest (AOIs) of excised third carpal bone (C3) and 5 in the distal radius. Volumetric BMD was determined in C3, only surface BMD was analysed in the radius. Across age groups, exercise had an effect on BMD in the mediodorsal and mediopalmar areas of C3. In the 5-month-old animals, the training exercise had similar effect to constant pasture exercise. In all AOIs, BMD was significantly greater in 11-month than in 5-month-old animals. Between age groups there was a difference in effect of exercise regimen before 5 months, in mediodorsal C3 and medial aspect of the radius, and the difference observed between exercise groups at age 5 months was no longer present in horses age 11 months, indicating no residual effect of early exercise. BMD was lower in the group with high OC scores. In the group of horses with the most severe OC, monthly growth rate did not fall uniformly with age over the first 5 months, as it did in groups with lower OC scores. It was concluded that exercise influenced significantly BMD at 5 months, suggesting that carefully designed training programmes to increase bone mineral could be employed in young animals. There was no residual effect at 11 months.

Manual Therapy for Hip Osteoarthritis: A Systematic Review and Meta-analysis. Hip osteoarthritis (HOA) is one of the major causes of disability in seniors and is costly to society. Manual therapy is one therapeutic approach to treating HOA. To assess the effect of manual therapy compared to the placebo or wait-list/no treatment or a minimal intervention control for HOA at post-treatment and short-, intermediate- and long-term follow-ups. A systematic review and meta-analysis of randomized controlled trials (RCTs). Hospital outpatient clinic in China. We searched PubMed, EMBASE, the Cochrane Library, CINAHL, ISI web of knowledge, and Chinese databases from the inception to October 2014 without language restrictions. References of systematic reviews and other related reviews, files in our department, and conference proceedings as grey literature were also screened by hand. RCTs compared manual therapy to the placebo, wait-list/no treatment or a minimal intervention control with an appropriate and precise description of randomization. Two reviewers independently conducted the search results identification, data extraction, and methodological quality assessment. We calculated the risk difference (RD) for dichotomous data and the mean difference (MD) or standardized mean difference (SMD) for continuous data in a fixed or random effect model. The primary outcomes were self-reported pain in the past week and physical function. The secondary outcomes were the quality of life, global perceived effect, patients' satisfaction, cost, and adverse events. Six studies involving 515 HOA patients were included. Five of the 6 studies ranked as high quality in the methodological assessment. Immediately post-treatment, there was low-quality evidence that manual therapy could not statistically significantly relieve pain (SMD: -0.07 [95%CI -0.38 to 0.24]); for physical function, a moderate quality of evidence showed that manual therapy could not improve the physical function significantly (SMD: 0.14 [95%CI -0.08 to 0.37]). We still found low-quality evidence that manual therapy did not benefit the patients in the global perceived effect (RD: 0.12 [95%CI -0.12 to 0.36]), and in terms of quality of life. In addition, the risks of patients in the manual therapy group was 0.13 times higher than that in the controls (RD: 0.13 [95%CI -0.05 to 0.31]) in the low-quality evidence studies. We could not find any evidence that manual therapy benefits the patients at short-, intermediate- or long-term follow-up. There were no studies reporting patients' satisfaction or cost. The limitations of this systematic review include the paucity of literature and inevitable heterogeneity between included studies. This review did not suggest there was enough evidence for manual therapy for the management of HOA. However, we are not confident in making such a conclusion due to the limitations listed above.

Arachidonic acid metabolism in the marine fish Stenotomus chrysops (Scup) and the effects of cytochrome P450 1A inducers. Cytochrome P450-mediated arachidonic acid (AA) metabolism was investigated in the marine fish scup, Stenotomus chrysops. Liver microsomes incubated with AA and NADPH produced epoxyeicosatrienoic acids (EETs) and their hydration products (dihydroxyeicosatrienoic acids, DHETs), midchain conjugated dienols (midchain HETEs), and C16-through C20-alcohols of AA (omega-terminal HETEs), all identified by HPLC and GC/MS. Gravid females had 4-fold lower AA metabolism rates than males but identical metabolite profiles. The 5,6-EET (inferred from stable metabolites) was most abundant (47% of total EETs) followed by 14,15-, 11,12-, and 8,9-EET (27, 13, and 13%, respectively). The 12-HETE represented 25% of total HETEs followed in abundance by 16-, 15-, 11-, 19-, 20-, 8-, and 9-HETE. Antibodies against scup CYP1A and a scup CYP2B-like protein inhibited liver microsomal AA metabolism by 30 and 46%, respectively. GC/MS analysis revealed EETs and DHETs as endogenous constituents in scup liver; the predominant EETs were 8,9- and 14,15-EET, followed by a lesser amount of 11,12-EET. Chiral analysis showed a preference for the S,R-enantiomers of endogenous 8,9-, 11,12-, and 14,15-EET (optical purities 80, 64, and 64%, respectively). Treatment of scup with the CYP1A inducer benzo(a)pyrene (BP) increased liver microsomal formation of EETs and HETEs by 2.7-fold in spring and 1.7-fold in summer. BP treatment did not affect microsomal EET regioselectivity, but shifted hydroxylation in favor of 19-HETE and induced 17-HETE formation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) treatment in summer did not induce liver microsomal AA metabolism rates, yet BP and TCDD both increased endogenous EET content of liver (5- and 3-fold, respectively), with a shift to 14,15-EET. BP treatment increased the selectivity for the S,R-enantiomers of endogenous 8,9-, 11,12-, and 14,15-EET (optical purities 91, 84, and 83%, respectively). Kidney, gill, and heart microsomes all metabolized AA, at rates 10- to 30-fold less than liver microsomes. Similar amounts of endogenous 8,9- and 14,15-EET and less 11,12-EET were detected in heart and kidney, and there was a strong enantioselectivity for 8(R),9(S)-EET in heart (optical purity 78%) but not in kidney. BP treatment did not alter the total EET content in these organs but did shift the regiochemical profile in heart to favor 14,15-EET. Thus, scup liver and extrahepatic organs metabolize AA via multiple cytochrome P450 (CYP) forms to eicosanoids in vitro and in vivo. BP or TCDD induced endogenous AA metabolism in liver, altering EET regioselectivity and, with BP, stereoselectivity. While AhR agonists alter metabolism of AA in early diverging vertebrates expressing both CYP1A and AhR, the magnitude of effects may depend upon the type of inducer.

Immunohistochemical characterization of 22 monoclonal antibodies against the CA125 antigen: 2nd report from the ISOBM TD-1 Workshop. We evaluated the immunohistological (IH) characteristics of 22 different antibodies that were submitted for study in the frame of the TD-1 ISOBM Workshop on monoclonal antibodies against CA125. Information on relative affinities and epitope similarities was obtained from a parallel immunochemical study. Antibodies were tested at concentrations of 10 and 1 micrograms/ml on frozen and paraffin sections. Paraffin sections were stained according to the streptavidin-biotin complex protocol, and frozen sections according to a two-step immunoperoxidase technique. Aminoethylcarbazole served as the chromogen. The tissues were from normal proliferative endometrium (formalin-fixed paraffin-embedded) material and clear-cell adenocarcinoma of the ovary (formalin-fixed paraffin-embedded and frozen material). Sections were scored for staining in epithelial cells, basal, apical and diffuse cytoplasmic and in stromal components. Intensity was graded as 1, 2 or 3 for epithelial cells and as -1, -2 or -3 for stroma. The cumulative scores for each antibody expressed the discriminative properties of specific epithelial staining against background. M11 and M11-like antibodies, as well as OC125 and OC125-like antibodies, in general showed good staining results. Although there was a trend for high-affinity antibodies to show higher scores, there was no clear relationship between affinity and staining result. For nine antibodies (ZR45, MA602-1, K102, K94, K90, OV185, K97, K96, OV198), the reactions in paraffin and frozen sections were of similar intensity. Most of these were of low affinity with one exception: antibody ZR45, a rat monoclonal antibody (MAb) which had a high relative affinity. For eight antibodies (M11, K101, MA602-6, ZS33, B27.1, B43.13, K93, OC125), a loss of specific staining was observed in frozen sections. All but two of these antibodies (MA602-6 and OC125) were of high relative affinity. With four antibodies (K91, ZR38, K95, K100), the reverse situation was observed. One (K100) was of low affinity, two (K95 and K91) of high affinity and the fourth (ZR38) was a rat MAb of high affinity. Mainly due to the increased cytoplasmic staining in carcinoma, the reactivity in paraffin sections was less extensive in normal endometrium compared to ovarian carcinoma for the majority of antibodies, irrespective of their affinity or epitope group. The IH characterization of these antibodies may be of help in selecting antibodies with specific properties for further comparative studies. The reactivity of normal endometrium with all useful antibodies makes it a good candidate for standard external IH tissue control.

C-reactive protein polymorphism rs3091244 is associated with abdominal aortic aneurysm. Abdominal aortic aneurysm (AAA) formation involves an inflammatory process with a strong genetic background. C-reactive protein (CRP) regulates inflammation and is elevated in patients with AAA. The aim of this study was to investigate the association of the triallelic (C, A, and T alleles) rs3091244 functional CRP single nucleotide polymorphism (SNP) with AAA. This was a case-control study involving two independent populations: 351 AAA patients (mean aortic diameter, 6.25 ± 1.47 cm) and 391 controls (mean diameter, 2.4 ± 0.2 cm) were recruited from Greece (the main cohort); and 371 patients (mean diameter, 5.4 ± 1.0 cm) and 362 controls (mean diameter, 2.4 ± 0.6 cm) were recruited from the United Kingdom (replication cohort). The frequency of the functional triallelic (C, T, and A alleles) rs3091244 polymorphism was analyzed in univariate and adjusted (for cardiovascular risk factors) analyses, assuming that the rare T and A alleles have similar functional properties (pooled analysis for T and A). Three groups were constructed: group A included those with the rare T and A alleles (genotypes TT, AA, and TA), group B included heterozygotes for the C allele (CT, CA), and group C included C allele homozygotes (CC, reference genotype). Finally, meta-analysis of the two populations was performed together with previously reported results. Genotype distributions differed significantly between cases and controls in both cohorts (P < .001 and P = .001). Adjusted analysis (for all aneurysm-related risk-factors) showed an estimated odds ratio of 4.88 (95% confidence interval [CI], 2.96-8.04) for SNP group A and 2.38 (95% CI, 1.69-3.36) for SNP group B (P < .001 in both cases) in the initial cohort and 2.07 (95% CI, 1.33-3.21) for SNP group A and 1.70 (95% CI, 1.21-2.39) for SNP group B (P = .001 and .002) in the replication cohort. The SNP group A patients among the main cohort also had higher CRP levels (median, 26; interquartile range, 17-52 mg/L vs median, 4; interquartile range, 4-12 mg/L; P < .001). Aneurysms >5.5 cm were significantly more frequent among the SNP groups A and B compared with C allele homozygotes both in the main and the replication cohorts (P < .001 and P = .001, respectively). Meta-analysis of the two populations with previously reported results showed a positive association between minor-allele and aneurysm presence with an odds ratio of 1.47 (95% CI, 1.01-2.14; I(2) = 83.1%; P = .04). The rare T and A alleles were significantly related with AAA presence in both populations and correlated with higher CRP levels and AAA diameter.