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The endothelin receptor antagonist, bosentan, in combination with the cyclooxygenase inhibitor, diclofenac, counteracts pulmonary hypertension in porcine endotoxin shock. To prevent endotoxin-induced pulmonary hypertension in the pig with a combination of a nonpeptide mixed endothelin receptor antagonist, bosentan, and a cyclooxygenase inhibitor, diclofenac. Prospective, controlled trial. Animal laboratory at a large university medical center. Twelve domestic pigs, weighing 17.5 to 27 kg. Endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide endotoxin (15 micrograms/kg/hr). Six pigs receiving only endotoxin served as controls. Six pigs were pretreated with intravenous bolus injections of bosentan (5 mg/kg) and diclofenac (3 mg/kg) followed by a continuous bosentan infusion (2.5 mg/kg/hr). Systemic hemodynamics and regional circulation were measured using ultrasonic flow probes. Arterial and mixed venous blood samples were collected regularty for determination of Big endothelin-1-like immunoreactivity, endothelin-1-like immunoreactivity, norepinephrine, and blood gases. The bosentan/diclofenac pretreatment per se significantly decreased mean pulmonary arterial pressure (p < .001), pulmonary vascular resistance index (p < .001), and mean arterial blood pressure (p < .001), but cardiac index did not change. Splenic blood flow increased (p < .01) while renal blood flow decreased (p < .001). In addition, intestinal blood flow decreased slightly (p < .05). In the control group, only three animals survived the 3 hrs of endotoxin infusion, while all pretreated animals survived. The biphasic increase in mean pulmonary arterial pressure and pulmonary vascular resistance index seen in control animals during endotoxemia was markedly attenuated in animals pretreated with the bosentan/diclofenac combination. The pretreated group generally showed a favorable hemodynamic course, with a relatively higher cardiac index, stroke volume index, and splenic and renal blood flow. In control animals, a pronounced metabolic acidosis developed during endotoxin infusion. A relatively higher arterial plasma concentration of endothelin-1-like immunoreactivity was reached in pretreated animals, while the Big endothelin-1-like immunoreactivity plasma increase was similar in both groups. Arterial concentrations of norepinephrine were significantly (p < .01) higher in control animals when compared with diclofenac/bosentan-treated animals. The combination of bosentan and diclofenac induced systemic and pulmonary vasodilation in the intrinsic state. During endotoxin shock, this drug combination efficiently counteracts pulmonary hypertension and improves cardiac performance and splenic and renal blood flow. These favorable circulatory effects may have resulted in a reduction of both sympathetic nervous system activation and metabolic acidosis. Thus, we conclude that the endothelin receptors participate in intrinsic regulation of vascular tone in the anesthetized pig. During endotoxin shock, blockade of these receptors, as well as inhibition of the cyclooxygenase enzymes, contributes to a less adverse effect on the systemic and pulmonary circulation.

The energetic costs of trunk and distal-limb loading during walking and running in guinea fowl Numida meleagris: I. Organismal metabolism and biomechanics. We examined the energetic cost of loading the trunk or distal portion of the leg in walking and running guinea fowl (Numida meleagris). These different loading regimes were designed to separately influence the energy use by muscles used during the stance and swing phases of the stride. Metabolic rate, estimated from oxygen consumption, was measured while birds locomoted on a motorized treadmill at speeds from 0.5 to 2.0 m s-1, either unloaded, or with a mass equivalent to 23% of their body mass carried on their backs, or with masses equal to approximately 2.5% of their body mass attached to each tarsometatarsal segment. In separate experiments, we also measured the duration of stance and swing in unloaded, trunk-loaded, or limb-loaded birds. In the unloaded and limb-loaded birds, we also calculated the mechanical energy of the tarsometatarsal segment throughout the stride. Trunk and limb loads caused similar increases in metabolic rate. During trunk loading, the net metabolic rate (gross metabolic rate-resting metabolic rate) increased by 17% above the unloaded value across all speeds. This percentage increase is less than has been found in most studies of humans and other mammals. The economical load carriage of guinea fowl is consistent with predictions based on the relative cost of the stance and swing phases of the stride in this species. However, the available comparative data and considerations of the factors that determine the cost of carrying extra mass lead us to the conclusion that the cost of load carrying is unlikely to be a reliable indicator of the distribution of energy use in stance and swing. Both loading regimes caused small changes in the swing and/or stance durations, but these changes were less than 10%. Loading the tarsometatarsal segment increased its segmental energy by 4.1 times and the segmental mechanical power averaged over the stride by 3.8 times. The increases in metabolism associated with limb loading appear to be linked to the increases in mechanical power. The delta efficiency (change in mechanical power divided by the change in metabolic power) of producing this power increased from 11% in walking to approximately 25% in running. Although tarsometatarsal loading was designed to increase the mechanical energy during swing phase, 40% of the increase in segmental energy occurred during late stance. Thus, the increased energy demand of distal limb loading in guinea fowl is predicted to cause increases in energy use by both stance- and swing-phase muscles.

[Effects of 3-methyladenine on airway inflammation, airway hyperresponsiveness and mucus secretion in asthmatic mice]. Objective: To investigate the effects of 3-methyladenine on airway inflammation, airway hyperresponsiveness and mucus secretion in asthmatic mice, and to explore its mechanism. Methods: C57BL/6J female mice were randomly divided into normal control group (PBS), OVA group(OVA), OVA with 3-methyladenine group (OVA+3-MA), and OVA with 4-phenylbutyrate group (OVA+4-PBA). OVA group, OVA+3-MA group and OVA+4-PBA groups were all sensitized and challenged with OVA to establish asthmatic models, while PBS group was given PBS as a control. At 2 h before challenge, OVA+3-MA group was intraperitoneally injected with 3-methyladenine, and OVA+4-PBA group was intraperitoneally injected with 4-phenylbutyrate. Airway hyperresponsiveness, eosinophils, and pathological changes of pulmonary tissue (hematoxylin-eosin, HE staining) were measured to confirm the establishment of asthmatic models. Sections of pulmonary tissue were also stained with Masson and PAS. The expression level of LC3B was measured by immunofluorescence and Western blot. The Beclin1, Muc5ac, Atf6, Chop and Bip proteins in lung tissues were detected by Western blot. Results: The Penh value, and eosinophils in BALF in OVA group was significantly increased compared with PBS group (P<0.05). The Penh value in OVA+3-MA group and OVA+4-PBA group were significantly decreased compared with the OVA group at the concentration of 6.25 g/L, 12.50 g/L, 25.00 g/L, and 50.00 g/L of methacholine (all the P<0.05), and the eosinophils were also significantly decreased compared with the OVA group (P<0.05). Pulmonary histology revealed that OVA group showed high levels of inflammatory cell infiltration of bronchi and lung vessels, alveolar septal thickening, structural destruction, smooth muscle thickening, collagen deposition, and goblet cell hyperplasia. The levels of inflammatory cell infiltration of bronchi and lung vessels, alveolar septal thickening, structural destruction, smooth muscle thickening, collagen deposition, and goblet cell hyperplasia in OVA+3-MA group and OVA+4-PBA group were significantly lower than the OVA group, while the PBS group was normal. Compared with PBS group, the expression of LC3 Ⅱ/Ⅰ, Beclin1, Muc5ac, Atf6, Chop and Bip proteins in lung tissues in the OVA group were significantly increased (1.09±0.04 vs 0.34±0.09, P<0.05; 0.18±0.01 vs 0.06±0.01, P<0.05; 1.90±0.38 vs 0.46±0.11, P<0.05; 1.67±0.18 vs 0.41±0.08, P<0.05; 2.96±0.45 vs 1.11±0.10, P<0.05; 2.07±0.34 vs 0.49±0.17, P<0.05, respectively). Compared with the OVA group the expression of LC3 Ⅱ/Ⅰ, Beclin1, Muc5ac, Atf6, Chop and Bip proteins in lung tissues in the OVA+3-MA group and OVA+4-PBA group were significantly decreased (0.46±0.07 vs 1.09±0.04, 0.63±0.03 vs 1.09±0.04, both P<0.05; 0.11±0.02 vs 0.18±0.01, 0.12±0.02 vs 0.18±0.01, both P<0.05; 0.72±0.22 vs 1.90±0.38, 0.57±0.13 vs 1.90±0.38, both P<0.05; 1.06±0.12 vs 1.67±0.18, 1.02±0.12 vs 1.67±0.18, both P<0.05; 1.67±0.21 vs 2.96±0.45, 1.10±0.15 vs 2.96±0.45, both P<0.05; 1.03±0.11 vs 2.07±0.34, 0.97±0.10 vs 2.07±0.34, both P<0.05). Conclusion: 3-MA was shown to inhibit airway inflammation, airway hyperresponsiveness and mucus secretion in mice with bronchial asthma, and the mechanism may be related to inhibiting autophagy, and then inhibiting endoplasmic reticulum stress.

Curative radiotherapy for primary orbital lymphoma. To review our institutional experience with primary orbital lymphoma and determine the prognostic factors for survival, local control, and distant metastases. In addition, we also analyzed the risk factors for complications in the radiotherapeutic management of this tumor. Between 1973 and 1998, 47 patients (29 women [62%] and 18 men [38%], median age 69 years, range 32-89) with Stage IAE orbital lymphoma were treated with curative intent at one department. Five had bilateral orbital involvement. The tumor was located in the eyelid and extraocular muscles in 23 (44%), conjunctiva in 17 (33%), and lacrimal apparatus in 12 (23%). The histologic features according to the World Heath Organization classification of lymphoid neoplasms was follicular lymphoma in 25, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in 8, diffuse large B-cell lymphoma in 12, mantle cell lymphoma in 6, and peripheral T-cell lymphoma in 1. For the purposes of comparison with the existing literature on orbital lymphomas, the grading system according to the Working Formulation was also recorded. The histologic grade was low in 33 (63%), intermediate in 18 (35%), and high in 1 (2%). All patients were treated with primary radiotherapy alone. The median dose for low-grade tumors was 3000 cGy (range 2000-4020); the median dose for intermediate and high-grade tumors was 4000 cGy (range 3000-5100). A lens-sparing approach was used in 19 patients (37%). Late complications for the lens and cornea were scored according to the subjective, objective, management, and analytic (SOMA) scale of the Late Effects of Normal Tissue (LENT) scoring system. The median follow-up was 55 months (range 6-232). The local control rate was 100% in the 52 orbits treated. The 5-year overall survival and relapse-free survival rate was 73.6% and 65.5%, respectively. Tumor grade and location did not predict for overall survival or relapse-free survival. Seven patients (15%) developed distant recurrence (brain 2, extremity 2, mediastinum 1, liver 1, and retroperitoneum 1). One patient (2%) developed cervical node metastasis. The 5- and 10-year cataract-free survival rate was 56.7% and 32.9%, respectively. Of the 12 lens complications, 8 were LENT Grade 1 and 4 were Grade 3 toxicity. Only male gender predicted for an increased risk of cataract formation. Radiotherapy dose and technique did not predict for cataract formation; however, none of the patients who underwent the lens-sparing technique developed Grade 3 lens toxicity or required surgical correction. Of the nine corneal events, two were Grade 1, four Grade 2, and three were Grade 3 toxicity. Ten dry eyes were recorded; all were mild, and no patient had severe dry eye syndrome. Neovascular glaucoma was seen in 1 patient. No injury to the retina or optic nerve was reported. Radiotherapy alone is a highly effective modality in the curative management of primary orbital lymphoma. Most complications were minimal and did not require medical or surgical intervention. Although the use of the lens-sparing technique did not influence the incidence of cataractogenesis, we continue to recommend this approach whenever possible, because our experience indicates a higher grade of toxicity occurs and a higher incidence of corrective surgery is needed in patients treated without lens protection.

Opioids and cerebral physiology in the acute management of traumatic brain injury: a systematic review. Following traumatic brain injury (TBI), optimization of cerebral physiology is recommended to promote more favourable patient outcomes. Accompanying pain and agitation are commonly treated with sedative and analgesic agents, such as opioids. However, the impact of opioids on certain aspects of cerebral physiology is not well established. To conduct a systematic review of the evidence on the effect of opioids on cerebral physiology in TBI during acute care. A comprehensive literature search was conducted in five electronic databases for articles published in English up to November 2017. Studies were included if: (1) the study sample was human subjects with TBI; (2) the sample size was ≥3; (3) subjects were given an opioid during acute care; and (4) any measure of cerebral physiology was evaluated. Cerebral physiology measures were intracranial pressure (ICP), cerebral perfusion pressure (CPP), and mean arterial pressure (MAP). Subject and study characteristics, treatment protocol, and results were extracted from included studies. Randomized controlled trials were evaluated for methodological quality using the Physiotherapy Evidence Database tool. Levels of evidence were assigned using a modified Sackett scale. In total, 22 studies met inclusion criteria, from which six different opioids were identified: morphine, fentanyl, sufentanil, remifentanil, alfentanil, and phenoperidine. The evidence for individual opioids demonstrated equally either: (1) no effect on ICP, CPP, or MAP; or (2) an increase in ICP with associated decreases in CPP and MAP. In general, opioids administered by infusion resulted in the former outcome, whereas those given in bolus form resulted in the latter. There were no significant differences when comparing different opioids, with the exception of one study that found fentanyl was associated with lower ICP and CPP than morphine and sufentanil. There were no consistent results when comparing opioids to other non-opioid medications. Several studies have assessed the effect of opioids on cerebral physiology during the acute management of TBI, but there is considerable heterogeneity in terms of study methodology and findings. Opioids are beneficial in terms of analgesia and sedation, but bolus administration should be avoided to prevent additional or prolonged unfavourable alterations in cerebral physiology. Future studies should better elucidate the effects of different opioids as well as varying dosages in order to develop improved understanding as well as allow for tighter control of cerebral physiology. CPP: Cerebral Perfusion Pressure, GCS: Glasgow Coma Scale, ICP: Intracranial Pressure, MAP: Mean Arterial Pressure, PEDro: Physiotherapy Evidence Database, RCT: Randomized Controlled Trial, TBI: Traumatic Brain Injury.

Responses to post-ruminal infusions of casein and arginine, and to dietary protein supplements in lactating goats. 1. In Expt 1 a study was made in goats of responses in terms of milk production, nitrogen utilization and plasma amino acids to abomasas infusions of casein (45 g/d) in goats given 2.5 kg/d of a ration containing crude protein (N x 6.25) at 109 (L1) or 146 (H1) g/kg. 2. In Expt 2 a study was made in goats of responses in terms of milk production, nitrogen utilization, plasma amino acids and growth hormone levels to abomasal infusions of casein (45 g/d) or arginine (25 g/d) in goats given 2.3 kg/d of a ration containing crude protein (N x 6.25) at 104 g/kg (L2). These observations were made also in goats given a ration containing crude protein at 136 g/kg (H2). 3. Milk production in Expt 1 was 2.75, 2.45 and 2.76 kg/d on L1+casein, H1 and H1+casein treatments respectively, the response to casein infusion being significant (P less than 0.05). Milk production in Expt 2 was 1.90, 2.04, 1.96 and 1.96 kg/d on L1, L2+casein, L2+arginine and H2 treatments respectively, and the differences were not significant. 4. Total N intake in Expt 1 was 49, 58 and 64 g/d on L1+casein, H1 and H1+casein treatments respectively. Faecal N was similar on the three treatments (14 g/d), urinary N was 15, 23 and 30 g/d and milk N was 14, 12 and 14 g/d on the respective treatments. Total N intake in Expt 2 was 33, 40, 43 and 44 g/d on L2, L2+casein, L2+arginine and H2 treatments respectively. Faecal N was similar on the four treatments (12 g/d), urinary N was 7, 10, 13 and 14 g/d and milk N was 9, 9, 8 and 8 g/d on the respective treatments. 5. The concentration of indispensable amino acids in plasma was increased by casein infusion in both experiments. It was 1279, 825 and 1133 micrometers/l on L1+casein, H1 and H1+casein treatments respectively in Expt 1, and 1081, 1582, 1055 and 1163 micrometers/l on L2, L2+casein, L2+arginine and H2 treatments respectively in Expt 2. 6. The concentration of arginine in plasma was doubled 1 h after the onset of arginine infusion in Expt 2, Growth hormone levels in plasma were not increased when arginine levels rose following arginine infusion. and did not differ between treatments. 7. The results of the two experiments showed that the stimulatory effect on milk production of intra-abomasal infusion of casein was not reproduced by increasing the dietary intake of protein or by infusing arginine. The results of the second experiment showed that abomasal infusion of arginine did not stimulate production of growth hormone and that growth hormone apparently was not implicated in the effects of casein infusion on milk production.

Neural tuning to sound duration in the inferior colliculus of the big brown bat, Eptesicus fuscus. Neural tuning to different sound durations may be a useful filter for identification of certain sounds, especially those that are biologically important. The auditory midbrains of mammals and amphibians contain neurons that appear to be tuned to sound duration. In amphibians, neurons are tuned to durations of sound that are biologically important. The purpose of this study was to characterize responses of neurons in the inferior colliculus (IC) of the big brown bat, Eptesicus fuscus, to sounds of different durations. Our aims were to determine what percent of neurons are duration tuned and how best durations are correlated to durations of echolocation calls, and to examine response properties that may be relevant to the mechanism for duration tuning, such as latency and temporal firing pattern; we also examined frequency tuning and rate-level functions. We recorded from 136 single units in the central nucleus of the IC of unanesthetized bats. The stimuli were pure tones, frequency-modulated sweeps, and broadband noise. The criterion for duration tuning was an increase in spike count of > or = 50% at some durations compared with others. Of the total units sampled, 36% were tuned to stimulus duration. All of these units were located in the caudal half of the IC. Best duration for most units ranged from < 1 to 10 ms, but a few had best durations up to > or = 20 ms. This range is similar to the range of durations of echolocation calls used by Eptesicus. All duration-tuned neurons responded transiently. The minimum latency was always longer than the best duration. Duration-tuned units have best durations and best frequencies that match the temporal structure and frequency range of the echolocation calls. Thus the results raise the hypothesis that neurons in the IC of Eptesicus, and probably the auditory midbrain of other vertebrates, are tuned to biologically important sound durations. We suggest a model for duration tuning consisting of three components: 1) inhibitory input that is correlated with the onset of the stimulus and is sustained for the stimulus duration; 2) transient excitation that is correlated with the offset of the stimulus; and 3) transient excitation that is correlated with the onset of the stimulus but is delayed in time relative to the onset of inhibition. For the neuron to fire, the two excitatory events must coincide in time; noncoincident excitatory events are not sufficient.

Synaptic mediation from cutaneous mechanical nociceptors. 1. Responses of dorsal horn neurons to cutaneous mechanical stimulation were studied in an in vitro preparation of hamster spinal cord with partially intact innervation from an isolated patch of hairy skin. Stable extracellular and intracellular recordings were obtained from cells with different mechanoreceptive properties similar to those reported for other species in vivo. Analyses were made of the intracellular responses of 25 dorsal horn neurons activated selectively by mechanical stimulation to the skin patch. 2. Bath application of the broad spectrum, excitatory amino acid (EAA) receptor antagonist, kynurenic acid (1 mM) blocked excitation of 7 of 8 high-threshold mechanoreceptive units by either cutaneous nerve volleys or mechanical stimulation of the skin. This concentration of kynurenic acid suppressed peripherally evoked responses in 8 of 14 neurons responsive to innocuous mechanical stimuli. 3. High-threshold mechanoreceptive neurons of the superficial dorsal horn exhibited one of three distinctive patterns of postsynaptic potentials in response to electrical stimulation of cutaneous afferent fibers: 1) a simple fast excitatory postsynaptic potential (EPSP), 2) a fast EPSP with a prolonged decay phase lasting between 100 and 1,000 ms, and 3) a multiphasic response dissociable on the basis of stimulus strength consisting of a fast EPSP followed by a hyperpolarizing inhibitory postsynaptic potential (IPSP) (duration 80-100 ms). Gentle mechanical stimuli initiated inhibition from areas adjacent to the high-threshold mechanically excitatory field; this suggests that membrane hyperpolarization in these neurons was evoked by input from low-threshold mechanoreceptors. 4. Bath application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), a competitive EAA antagonist selective for non-N-methyl-D-aspartate (non-NMDA) receptor subtypes, substantially or completely (56-100%) suppressed EPSPs evoked from cutaneous afferent fibers in high-threshold mechanoreceptive neurons. CNQX also decreased the membrane depolarization, the frequency of EPSPs, and the frequency of action potentials evoked by mechanical stimulation of the receptive field. 5. CNQX (10 microM) or kynurenic acid (1 mM) had considerably weaker effects on IPSPs than on EPSPs evoked from the periphery in superficial dorsal horn neurons. IPSP amplitudes were unchanged by these agents in some neurons and decreased by only 20-25% in others. 6. We conclude that L-glutamate acting on non-NMDA receptors mediates fast synaptic excitation of superficial dorsal horn neurons from peripheral mechanical nociceptors with myelinated fibers. Furthermore, the observations imply either an agent other than L-glutamate or one acting at different membrane receptors is a synaptic mediator for other peripheral afferent units including some activated by innocuous mechanical stimuli.

Variations in low birth weight and preterm delivery among blacks in relation to ancestry and nativity: New York City, 1998-2002. Black women in the United States are more likely to give birth to preterm and low birth-weight infants than their white counterparts, but little is known about variation in birth outcomes within the black population. This study aimed to test the hypothesis that the risk of low birth weight and preterm birth within the black population varies by maternal ancestry and nativity. We conducted a retrospective cohort study using New York City birth records. All of the recorded live births to black women occurring in New York City between January 1, 1998, and December 31, 2002 (N = 168,039), were divided into the following self-reported ancestry groups: African, American, Asian, Cuban, European, Puerto Rican, South and Central American (excluding Brazilian), and West Indian and Brazilian. To estimate adjusted risk ratios for low birth weight (weight at birth <2500 g) and preterm birth (gestational age at delivery <37 weeks, based on clinical estimate), we ran 3 models for each outcome, using negative binomial regression and Poisson regression with robust SE estimation. All of the models used blacks reporting American ancestry as the reference group. The first model included ancestry as the primary exposure variable along with covariates that included maternal age, parity, smoking, and education, as well as paternal education and race. Nativity (US- or foreign-born) was included in the second model, and terms representing interaction effects between ancestry and nativity were included in the third model. There was substantial variation in risks of preterm birth and low birth weight among the black subgroups, with all of the groups having lower risks than the American black reference group, even after adjusting for maternal risk factors and other covariates. Risk ratios for low birth weight ranged from 0.55 among South/Central Americans to 0.91 among Cubans; risk ratios for preterm birth showed a similar pattern. Nativity was also associated with low birth weight and preterm birth; births to foreign-born women were less likely to be preterm or low birth weight than births to US-born women. Furthermore, nativity effects varied by ancestry group, with foreign-born status inversely associated with poor birth outcomes among South/Central Americans but not among West Indians/Brazilians. Important health differences may be masked in studies that treat black women in America as a homogeneous group and do not take ethnic variation and nativity into account.

[Effects of antidepressants on cognitive functions. Review of the literature]. In this review the authors propose to study the impact of antidepressants on attention, memory and motor functions in healthy volunteers and depressed patients on single and long-term administration. After reviewing the principal cognitive functions, we examine the actual investigation means to conclude that the Critical Flicker Fusion Test (CFFT) is one of the most drug-sensitive tests. It permits a categorization in: sedative antidepressants that in single administration lower CFFT; compounds with no effect on CFFT and no deleterious cognitive effect; and finally substances that raise CFFT and may have psychostimulating properties. On single administration amitriptyline is the most sedative antidepressant on attention or motor level. It seems to produce negative effects on memory level. However, experimental trials give contradictory results. Imipramine in single administration also has sedative effects on memory and car driving capacity. However divergent results of experimental trials do not allow any conclusions of a clearcut negative cognitive effect. Memory impairments with imipramine appear at administration levels of 150 mg. Mianserin has a sedative impact on attention and motor level at low doses (10 mg). Among the tricyclics, nortriptyline has a highly dose dependent sedative effect that has been shown on attention tests (Time Reaction:TR, Digit Symbol Substitution Test: DSST). Among non-tricyclic compounds, doxepine lowers attention and motor performances. Maprotiline (75 mg) lowers CFFT and has a dose dependent effect. Trazodone also has a negative impact on attention tests. Finally viloxazine lowers CFFT but does not impair other attention or motor tests on a 100 mg doses. Buspirone, lofepramine, midalcipran and zimelidine are antidepressants with no effect on CFFT and do not have any positive or negative cognitive effect. On the other hand nomifensine, paroxetine and fluoxetine raise CFFT in healthy volunteers on single administration. Improvement of CFFT performances was found in an isolated manner for nomifensine and paroxetine on 30 mg doses with no other memory or motor effects. MAO-Inhibitors do not impair attention or motor function; thus moclobemide has no negative impact on memory, attention or car driving tests. Cognitive impact of antidepressants in depressive patients seems the same with those of healthy volunteers on single administration. In long-term administration antidepressants have different effects in healthy and depressed subjects. In healthy volunteers cognitive effects of most compounds are normalized after the second week of treatment. However, attention and motor performances with amitriptyline are normalized after 3 weeks of treatment. Sedative motor or cognitive effects of imipramine do not exceed 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. Eli Lilly and Company.

Association between ambient temperature and humidity, vaginal temperature, and automatic activity monitoring on induced estrus in lactating cows. The objective of this study was to determine the association between ambient temperature and humidity, vaginal temperature, and automated activity monitoring in synchronized cows. Lactating Holstein cows (n = 641; 41.5 ± 9.4 kg of milk/d) were fitted with leg-mounted pedometers, resulting in 843 evaluated activity episodes of estrus. Vaginal temperature was monitored using thermometers attached to an intravaginal device as part of a timed artificial insemination (TAI) protocol; vaginal temperature was recorded every 10 min for 3 d. Ambient temperature and relative humidity were monitored using an external thermometer placed in the center of each pen. Milk production and body condition score (BCS) data were collected at the time of thermometer insertion. All statistical analysis was performed in R (https://www.r-project.org/) using Pearson correlation, analysis of variance, and logistic regression. Heat stress was calculated based on the percentage of time the cow spent with a vaginal temperature ≥39.1°C (PCT39) 9 to 11 d before TAI, and was classified as high (≥22.9%) or low (<22.9%). The mean vaginal temperature was 38.9 ± 0.2°C, and the mean maximum and minimum vaginal temperatures were 39.7 ± 0.5°C and 38.0 ± 0.8°C, respectively, with an average amplitude of 1.71 ± 0.9°C. Mean relative increase (RI) of estrus walking activity was 237.0 ± 160%. Animals with low BCS had a lower RI compared with cows with medium BCS (260.31 ± 17.45% vs. 296.42 ± 6.62%). Cows in early lactation showed lower RI compared with mid- and late-lactation animals (265.40 ± 9.90% vs. 288.36 ± 11.58% vs. 295.75 ± 11.29% for early, mid, and late lactation, respectively). Temperature-humidity index (THI) conditions categorized as low (THI ≤65) were associated with greater RI compared with medium (>65 to <70) and high THI (≥70). We detected no significant effect of PCT39 or milk production on RI, whereas parity exhibited a tendency. Cows that displayed greater RI at estrus had greater pregnancies per artificial insemination (P/AI) than cows with low RI (27 vs. 20%) or no RI (27 vs. 12%). Primiparous cows had greater P/AI than multiparous cows (27 vs. 20%), and cows in early and mid lactation had improved P/AI than those in late lactation (26 vs. 22 vs. 16% for early, mid, and late lactation, respectively). An interaction was observed between PCT39 and THI on P/AI, where a subpopulation of cows with high PCT39 had decreased P/AI under high THI conditions, but no differences in P/AI were observed for high PCT39 cows under medium or low THI conditions (13 vs. 24 vs. 26%). Future research should aim to refine variables related to hyperthermia and to understand the effects of body temperature on estrus expression and pregnancy rates.

Impaired beta-cell and alpha-cell function in African-American children with type 2 diabetes mellitus--"Flatbush diabetes". The incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has substantially increased over the past decade. This is attributed to obesity, insulin resistance and deficient beta-cell function. In children a pubertal increase in insulin resistance and an inability to mount an adequate beta-cell insulin response results in hyperglycemia. Adults with T2DM have a diminished first phase response to intravenous glucose and a delayed early insulin response to oral glucose. Long-term studies show progressive loss of beta-cell function in T2DM in adults; however, such long-term studies are not available in children. To characterize beta- and alpha-cell function in African-American adolescents with established T2DM, we used mixed meal, intravenous glucagon and oral glucose tolerance testing and compared them to obese non-diabetic controls. T2DM was defined as fasting C-peptide >0.232 nmol/l and absent autoimmune markers. BETA-CELL FUNCTION: Meal testing in 24 children and adolescents with T2DM, mean age 14 years, BMI 30 kg/m2, Tanner stage II-V, HbA1c 8.9%, were compared with BMI- and age-matched controls. Forty percent presented with DKA. Half were treated with insulin and half with diet/oral anti-diabetic agents. Although absolute C-peptide response in both groups was similar, the incremental rise in C-peptide relative to plasma glucose in the patients with T2DM compared to controls was 40% and 35% lower 30 and 60 min after the meal, p <0.007 and p <0.026. Glucagon testing in 20 pediatric patients with T2DM compared with 15 matched controls showed significantly lower 6 min stimulated C-peptide relative to the ambient plasma glucose in patients with T2DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p <0.05). The clinical utility is that 78% of patients with a 6 min C-peptide <1.4 nmol required insulin, while 81% of those >1.4 nmol required oral anti-diabetic agents, p <0.0001. Furthermore, the duration of T2DM up to 5 years after diagnosis was associated with lower fasting and glucagon-stimulated C-peptide levels, implying worsening beta-cell function over time, even in children and adolescents. ALPHA-CELL FUNCTION: During meal testing, children and adolescents with T2DM had less suppression of plasma glucagon than non-diabetic controls; this was more severe with longer duration of T2DM and poorer glycemic control. BETA-CELL RECOVERY: In African-American and Hispanic adults, intensive treatment of blood glucose may achieve beta-cell recovery with 35-40% of newly diagnosed patients going into remission after 6 months treatment. They remain off anti-diabetic pharmacological agents in remission for a median of over 3 years with normal HbA1c levels. We hypothesize this to be due to removal of a critical component of glucose or lipotoxicity at the level of the beta-cell and/or peripheral tissue. Four of 20 African-American children presenting with mean glucose 650 mg/dl maintained normal HbA1c levels on small doses of metformin after initial treatment with multiple insulin injections with or without metformin. This suggests a marked recovery of beta-cell function, similar to that in adults. T2DM in children, as in adults, is characterized by insulin deficiency relative to insulin resistance. Plasma C-peptide levels may be clinically useful in guiding therapeutic choices, since patients with lower levels required insulin treatment; beta-cell function is also diminished with longer duration of T2DM. The possibility exists that in children, as in adults, intensive glycemic regulation may allow for beta-cell recovery and preservation. Thus, optimum beta- and alpha-cell function are central to the prevention of DM and maintenance of good glycemic control in African-American and Hispanic children and adolescents with T2DM.

[Multiple primary malignancies in BRCA1 mutation carriers--two clinical cases]. Mutations of BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. So far; risk-reducing salpingo-oophorectomy has been the most effective strategy for gynecological cancer prevention in susceptibility gene mutation carriers. It does not prevent, however from the occurrence of primary peritoneal cancer We present two clinical cases of patients with the BRCA1 gene mutation. Both patients had a family history of cancer and both were presenting with metachronic malignances. The first patient, whose mother suffered from breast and ovarian cancer, was diagnosed with left breast cancer in 2004. The patient was 44 years old at diagnosis. Genetic testing revealed the BRCA1 gene mutation. A breast conserving therapy (BCT) was conducted, followed by chemotherapy, radiotherapy and immunotherapy with trastuzumab due to HER2 overexpression. Due to BRCA1 mutation, in November 2005, prophylactic hysterectomy with appendages was performed. Histological examination revealed bilateral ovarian cancer (adenocarcinoma G3) with metastasis to the paraaortal lymph node. The patient received six cycles of chemotherapy: paclitaxel and carboplatin. Ovarian cancer relapsed 3 years later After that the patient received 5 lines of chemotherapy and finally died due to disease progression in September 2011. The second patient, a 49-year-old woman, was diagnosed with breast cancer in July 2003 and subsequently treated with neoadjuvant chemotherapy breast conserving surgery and radiotherapy Genetic testing was also performed and revealed the BRCA1 gene mutation. A year earlier the patient had undergone hysterectomy with appendages due to uterine myomas. Three of her five sisters suffered from breast and ovarian cancer The patients father died of colorectal cancer The patient remained under surveillance. Because of the increasing level of Ca-125 (since October 2004), PET-CT was performed and revealed a tumor lesion of the peritoneum. Histological examination from the biopsy confirmed primary peritoneal cancer (papillary serous adenocarcinoma--primary peritoneal carcinoma). Reexamination of the tissues from hysterectomy with appendages was also performed and revealed an adenocarcinoma in the right ovary Pathologic examination excluded metastasis of a breast cancer Pathomorphology of the ovarian lesion was also different than in the lesions of the peritoneum. Thus, three different tumor types (breast, ovarian and peritoneal cancer) coexisted independently The patient received chemotherapy: paclitaxel and cisplatin. Later on, due to disease progression she was treated with five consecutive chemotherapy regimens and hormonal therapy The patient died in January 2008. These case illustrate that genetic diagnosis may be critical for the overall treatment plan.

Decomposition of the dose conversion factor based on fluence spectra of secondary charged particles: Application to lateral dose profiles in photon fields. The dose conversion factor plays an important role in the dosimetry by enabling the absorbed dose in the sensitive volume of a detector to be converted into the absorbed dose in the surrounding medium (in most cases water). The purpose of this paper is to demonstrate that a specific fluence-based approach for the decomposition of the dose conversion factor is in particular useful for the interpretation of the influences of detector properties on measurements under nonreference conditions. Data for the dose conversion factor and secondary fluence spectra were obtained by the Monte Carlo method. The calculation of the secondary charged particle fluence (electrons and positrons) in the sensitive detector volume was imbedded into the code for the calculation of absorbed dose in the detector. The decomposition method into subfactors is based on the use of these fluence data applied to a stepwise transition from the dose at the point of measurement next to a pure water detector and finally to the fully simulated detector geometry. Each subfactor is obtained as a ratio, at which the stopping power only is different in the numerator and the denominator or at which the fluence only is different in the numerator and the denominator. This method was applied at photon dose profiles obtained in water at different radiation qualities and with various detectors of cylindrical type. The resulting subfactors can be well identified as a stopping power ratio and as perturbation factors each reflecting particular detector properties. Two of them (f1 and f4 ) are equivalent with perturbation factors which have already been introduced by other authors previously. These are the volume perturbation factor and the extracameral perturbation factor. Subfactor f2 denoted as medium perturbation factor was found to resemble the density perturbation factor. Results obtained for the volume perturbation factor applied to dose profiles measured with cylindrical detectors confirm that the volume effect can be well described by a convolution of the true profile in water with a Gaussian kernel. It was found that the sigma parameter depends on the cylinder radius only and amounts almost exactly to half of its value. The medium perturbation factor strongly depends on the density of the detector medium. For an air-filled detector, the influence of the air again can be described by a Gauss convolution, however, with a less good agreement. For detectors with a density of the cavity medium larger than that of water, for instance, for a diamond detector, it was found that there is a tendency of compensation between the volume averaging effect and the medium effect. The fluence-based decomposition of the dose conversion factor leads to a fluence-based formulation of perturbation factors, referred to as volume, medium, and extracameral perturbation factor. These factors offer useful explanations for the behavior of detectors in nonreference conditions. An example was given for cylindrical detectors at dose profile measurements.

Different infusion durations for preventing platinum-induced hearing loss in children with cancer. Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is an update of a previously published Cochrane review. To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 4), MEDLINE (PubMed) (1945 to 18 May 2016) and EMBASE (Ovid) (1980 to 18 May 2016). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2015) and the American Society of Pediatric Hematology/Oncology (2014 and 2015). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 20 May 2016 and 24 May 2016 respectively). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.

Analgesic efficacy of celecoxib in postoperative oral surgery pain: a single-dose, two-center, randomized, double-blind, active- and placebo-controlled study. Celecoxib 200 mg has been reported to reduce pain following dental extraction but to offer poorer pain relief than active comparators. The aim of this study was to compare the efficacy and tolerability of celecoxib 400 mg, the recommended loading dose for treatment of acute pain, with that of ibuprofen 400 mg and placebo following oral surgery. This was a single-dose, 2-center, randomized, double-blind, active- and placebo-controlled study in which patients with moderate to severe pain following third molar extraction were randomized to receive a single dose of celecoxib 400 mg, ibuprofen 400 mg, or placebo. Pain assessments were completed using a 4-point pain intensity scale where 0=no pain and 3=severe pain and a 5-point pain relief scale where 0=no pain relief and 4= complete pain relief at baseline and 18 time points over 24 hours. Primary efficacy outcome measures were time to onset of analgesia (the median time to perceptible pain relief in those patients who achieved meaningful pain relief), time-specific pain intensity difference (PID), time-specific pain relief (PR), time-specific sum of PID and PR, and time to use of rescue medication. Times to perceptible and meaningful pain relief (secondary efficacy outcome measures) were recorded using 2 stopwatches. Tolerability was assessed through recording of adverse events, clinical laboratory tests, and physical examinations (including collection of vital signs). One hundred seventy-one patients were randomized to celecoxib 400 mg (30 women and 27 men; mean [SD] age, 21.4 [4.2] years); ibuprofen 400 mg (30 women and 27 men; mean [SD] age, 22.0 [4.7] years); or placebo (34 women and 23 men; mean [SD] age, 21.6 [5.0] years). Mean times to onset of analgesia with celecoxib 400 mg and ibuprofen 400 mg were rapid and comparable (median 28 minutes and 26 minutes, respectively) and were significantly shorter than with placebo (>24 hours) (both, P<0.05 vs placebo). Compared with placebo, mean time-specific PID scores were significantly greater with celecoxib from 0.5 to 24 hours and with ibuprofen from 0.5 to 16 hours (all, P<0.05 vs placebo). Time-specific PR scores with celecoxib and ibuprofen were significantly greater from 0.75 and 0.5 hour, respectively, compared with placebo (all, P<0.05 vs placebo). PID was significantly greater with celecoxib compared with ibuprofen beginning at 11 hours (all, P<0.05). PR scores were significantly higher with celecoxib versus ibuprofen beginning at 9 hours (all, P<0.05). Median (95% CI) time to use of rescue medication with celecoxib (>24 hours) was significantly longer than with ibuprofen (10 hours, 58 minutes [8 hours, 30 minutes- 14 hours, 34 minutes]) or placebo (1 hour, 51 minutes [1 hour, 40 minutes-2 hours, 22 minutes]) (both, P<0.05). The 3 most common adverse events experienced in the celecoxib group were headache (9 [15.8%] patients), nausea (9 [15.8%] patients), and dizziness (6 [10.5%] patients). In this postsurgical dental pain study, the onset and magnitude of pain relief with celecoxib 400 mg and ibuprofen 400 mg were found to be comparable. In addition, patients who received celecoxib 400 mg as a single dose had a significantly longer time to use of rescue medication and had higher pain relief scores later in the study than those who received ibuprofen 400 mg. Celecoxib was well tolerated compared with placebo.

Effects of natural and recombinant IL 2 on regulation of IFN gamma production and natural killer activity: lack of involvement of the Tac antigen for these immunoregulatory effects. Highly enriched populations of human large granular lymphocytes (LGL), natural killer (NK) cells, and T cells were obtained from low and high density fractions, respectively, of discontinuous Percoll gradients. The NK cells were composed of 75 to 90% LGL, with the majority of the contaminating cells being monocytes. The T cells were greater than 95% OKT3+. The proliferative and cytotoxic progenitors in both fractions were examined by using a limiting dilution assay with interleukin 2 (IL 2) from four sources: 1) crude supernatant of a gibbon lymphoma (MLA-144), 2) purified (150,000-fold) MLA-144 IL 2, 3) partially purified human IL 2, and 4) purified recombinant human IL 2. The proliferative capacity was measured at day 7 by [3H]thymidine incorporation, whereas the progenitors of cells with NK-like activity were evaluated by assessing cytotoxic activity against K562 cells at day 8 in a 4-hr 51Cr-release assay. The frequency of proliferative progenitors among T cells was approximately 1/5 and was approximately 1/60 with LGL. Titration of the highly purified IL 2 preparation demonstrated that LGL proliferated with as little as 2 U of IL 2. The frequency of detectable cytotoxic progenitors in the LGL population, however, fell sharply when less than 40 U of IL 2 were employed. The T cells failed to demonstrate cytotoxic activity against the NK-susceptible target cells at any concentration of IL 2 tested. The IL 2 preparations also were examined for their ability to directly and rapidly enhance the cytotoxic activity of highly purified NK cells. All four preparations of IL 2 enhanced the cytotoxic activity of LGL without any detectable accessory requirement after incubation for as little as 6 hr, even though the MLA-144 IL 2 preparations were devoid of detectable interferons (IFN). These data indicate that IL 2 has dual effects on NK cells, regulating their activity was well as promoting their proliferation. Collectively, these results demonstrate that highly purified IL 2, devoid of other detectable lymphokines, is capable of supporting the growth of human NK cells and augmenting their in vitro activity. In parallel experiments, these same IL 2 preparations were quite active in causing the proliferation of T lymphocytes, clearly demonstrating a role of IL 2 in promoting the proliferation of NK cells as well as T cells. The mechanism of IL 2 boosting appears to be a direct interaction with LGL, resulting in the production of IFN gamma.(ABSTRACT TRUNCATED AT 400 WORDS)

A novel bubble liposome and ultrasound-mediated gene transfer to ocular surface: RC-1 cells in vitro and conjunctiva in vivo. Gene therapy is a promising method; however, a potential risk of viral vector or low gene transfer efficacy of non-viral vector prevents it from clinical application for common diseases. The major obstacle in the clinical application of gene therapy is not due to the lack of an ideal gene, but rather the lack of a clinically safe and efficient gene transfer method. To complete a safe and effective gene transfer, we developed a novel bubble liposome (BL) with ultrasound (US) method. BL is composed of polyethylenglycol (PEG) modified liposome (PEGylated liposome) containing perfluoropropane gas, each of which independently has been used safely in human treatment and a PEGylated liposome is quite stable in vivo. Plasmids containing green fluorescent protein (GFP) cDNA were added to cultured rabbit corneal epithelial cells (RC-1, 2x10(5)cell/well and 5microl of a plasmid solution) followed by US exposure with BL (BL-US group). Similar experiments were conducted for US exposure-only (US-only group) and US exposure and conventional micro-bubble (MB-US group). Gene transfer efficacy was evaluated by immunofluorescent microscopy and the cell damage was analyzed by MTS assay. In an in vivo study, BL and plasmid were injected into rat subconjunctiva followed by US exposure (BLUS group, 1.2W/cm(2), 20s, duty cycle 50%) and GFP expression was evaluated by imaging (maximum +5 to minimum 0) for 8 days. Rats undergoing subconjunctival plasmid injection alone (injection group), plasmid injection and US exposure (US group), MB and plasmid injection and US exposure (MBUS group) were used as controls. Histological examination was conducted. BL and US exposure significantly increased gene transfer efficacy in cultured RC-1 cells (BL-US group, 27%; US-only group, 1%; MB-US group, 11%; P<0.05: ANOVA). Gene transfer was most prominent under the condition of US intensity of 1.2W/cm(2) with 21microg/well BL, duration 20s. No apparent cell damage was found in the BL-US group by MTS assay. In rat eyes, strong GFP staining was seen in conjunctiva of BLUS group (average: 3.6). It was significantly higher than in any of the following groups, injection group (average: 2.3), US group (average: 2.1), or MBUS group (average: 2.0; P=0.001, ANOVA). GFP-positive cells were mainly in the conjunctiva and no tissue damage was seen histologically. BL with US method effectively transfers genes to cultured corneal epithelial cells and rat subconjunctival tissue without causing any apparently adverse effect. This method would have a great advantage for gene therapy in ocular surface disease.

Effect of unilateral partial cochlear lesions in adult cats on the representation of lesioned and unlesioned cochleas in primary auditory cortex. We examined the effect of unilateral restricted cochlear lesions in adult cats on the topographic representations ("maps") of the lesioned and unlesioned cochleas in the primary auditory cortex (AI) contralateral to the lesioned cochlea. Frequency (tonotopic) maps were derived by conventional multineuron mapping procedures in anesthetized animals. In confirmation of a study in adult guinea pigs (Robertson and Irvine [1989] J. Comp. Neurol. 282:456-471), we found that 2-11 months after the unilateral cochlear lesion the map of the lesioned cochlea in the contralateral AI was altered so that the AI region in which frequencies with lesion-induced elevations in cochlear neural sensitivity would have been represented was occupied by an enlarged representation of lesion-edge frequencies (i.e., frequencies adjacent to those with elevated cochlear neural sensitivity). Along the tonotopic axis of AI the total representation of lesion-edge frequencies could extend up to approximately 2.6 mm rostal to the area of normal representation of these frequencies. There was no topographic order within this enlarged representation. Examination of threshold sensitivity at the characteristic frequency (CF, frequency to which the neurons were most sensitive) in the reorganized regions of the map of the lesioned cochlea established that the changes in the map reflected a plastic reorganization rather than simply reflecting the residue of prelesion input. In contrast to the change in the map of the lesioned contralateral cochlea, the map of the unlesioned ipsilateral cochlea did not differ from those in normal animals. Thus, in contrast to the normal very good congruency between ipsilateral and contralateral AI maps, in the lesioned animals ipsilateral and contralateral maps differed in the region of AI in which there had been a reorganization of the map of the lesioned cochlea. Outside the region of contralateral map reorganization, ipsilateral and contralateral AI maps remained congruent within normal limits. The difference between the two maps in the region of contralateral map reorganization suggested, in light of the physiology of binaural interactions in the auditory pathway, that the cortical reorganization reflected subcortical changes. Finally, response properties of neuronal clusters within the reorganized map of the lesioned cochlea were compared to normative data with respect to threshold sensitivity at CF, the size of frequency "response areas," and response latencies. In the majority of cases, CF thresholds were similar to normative data. The frequency "response areas" were slightly less sharply tuned than normal, but not significantly. Response latencies were significantly shorter than normal in three animals and significantly longer in one animal.

Analysis of the effects of several decalcifying agents alone and in combination with sodium hypochlorite on the chemical composition of dentine. To investigate the effects of several decalcifying agents alone and in combination with sodium hypochlorite (NaOCl) on the organic and inorganic components of dentine using attenuated total reflectance in Fourier transform infrared spectroscopy (ATR-FTIR). Dentine slices from bovine teeth were submitted to (n = 5) the following: 0.9% saline, 9% and 18% etidronic acid (HEDP), 5% and 10% tetrasodium EDTA (EDTANa4 ), 17% trisodium EDTA (EDTAHNa3 ), and 0.5% and 2.0% peracetic acid (PAA) for 0.5-10 min; and to the combinations: G1 - mixture 5% NaOCl + 18% HEDP (5 and 10 min); G2 - mixture 5% NaOCl + 10% EDTANa4 (5 and 10 min); G2 - 2.5% NaOCl (5 min) + 17% EDTAHNa3 (1 min); G3 - 2.5% NaOCl (5 min) + 0.5% PAA (1 min); G4 - 2.5% NaOCl (5 min) + 9% HEDP (5 min). Specimens of G2, G3 and G4 received final flushes with 2.5% NaOCl for 0.5-10 min. Amide III/phosphate and carbonate/phosphate ratios of the spectra collected from the dentine specimens before and after immersion in the solutions were determined. Data were submitted to one-way repeated measures and one-way anova. For the same decalcifying agent, the higher the concentration and immersion time the greater the removal of phosphate, exposure of collagen matrix and consequently the increases in amide III/phosphate ratio. However, significant differences were found only between the two concentrations of PAA (P < 0.05). PAA caused greater increases in this ratio, followed by EDTAHNa3 , EDTANa4 and HEDP, and this order was retained in the combinations with NaOCl. This ratio was significantly reduced in G1 (P < 0.05) and not altered in G2 (P > 0.05). Due to collagen degradation, the amide III/phosphate ratio reduced significantly after the use of NaOCl in G3, G4 and G5 (P < 0.05). NaOCl required approximately 0.5 s to deproteinate the collagen matrix exposed after phosphate removal by EDTAHNa3 and PAA. The carbonate of dentine was removed more rapidly than phosphate by all decalcifying agents alone and in G3, G4 and G5. In the combinations with NaOCl, the last irrigant used defined the dentine amide III/phosphate and carbonate/phosphate ratios. HEDP and EDTANa4 caused minor whilst EDTAHNa3 and PAA caused greater demineralization of dentine; both effects were time and concentration dependent. NaOCl degraded the dentine organic matrix more rapidly when it was exposed. Combinations of NaOCl and decalcifying agents can be used to create dentine surfaces with varying compositions for interaction with endodontic sealers.

Interneurons between giant axons and motoneurons in crayfish escape circuitry. 1. Crayfish giant fibers are generally believed to generate tailflip movements by means of direct connections to two classes of phasic flexor muscle motoneurons, the motor giants (MoGs) and the nongiant fast flexor motoneurons (FFs). It is shown here that the giants also stimulate a network of interneurons that make connections with the FFs. 2. This network includes an intraganglionic neuron, the segmental giant (SG), in each abdominal hemisegment and a number of intersegmental neurons, two of which (I2 and I3) were studied in detail. 3. The SGs are driven reliably by the giant fibers and they in turn drive the FFs of their hemisegment about as effectively as do the giant fibers themselves; it is possible that the giant fibers excite the FFs mainly by way of the SGs. The SGs also have an efferent first root axon whose peripheral targets we have been unable to determine. 4. I2 and I3 originate in the second and third abdominal ganglia, respectively, and descend to the last ganglion. In their ganglia of origin they are reliably driven by the giant fibers and by the SGs. In addition, I2 weakly excites I3 and both receive weak, apparently direct, excitatory input from FFs as well as less direct excitatory and inhibitory input from unidentified afferent sources. Both weakly excite most FFs in ganglia behind the one in which they originate. This excitation adds to that produced directly by giant fibers and SGs and, we believe, is sometimes decisive in causing FF firing. Their firing also causes inhibition involved in suppressing effects of reafference, as do the giant fibers themselves. 5. I3 strongly excites the motoneurons of certain tail fan muscles (the ventral and posterior telson flexors). However, the contraction of these muscles would be maladaptive during some giant fiber-mediated tailflips. Accordingly, when the giant fibers, which always recruit I3, fire, they cause an inhibition of the motoneurons that nullifies the excitatory input from I3. At a formal level this means that the giants, viewed as command neurons, not only drive but also alter or modulate the subordinate motor pattern-generating network that they control. 6. Tailflips that are less stereotyped than those mediated by giant fibers are known to occur without participation of the giants. It is suggested that the presence of complex circuitry mediating between giant fibers and FFs may be related to the use of portions of this circuitry as well as the FFs themselves in production of nongiant tailflips.

Preparation of Toxoplasma gondii RH strain antigen, antigen analysis and antigen detection in sera: a review. The prevalence of antibodies detected by serology against Toxoplasma gondii in Indonesia is quite high. Therefore further research concerning the antigen used is important to improve the quality of the assay being used with lower cost. An attempt to prepare T. gondii strain RH antigen followed by using it in the ELISA procedure for detecting IgG showed that there was no significant difference between the local ELISA and Toxonostika quantitatively and qualitatively. Analysis of the antigen was done by Western blot, using sera collected from 30 clinically suspected toxoplasmosis cases which contained IgG only (titer ranging from 1:1,600-> or = 1:3,200); from 9 asymptomatic healthy person, from 5 cases consisted of 1 case of lymphadenitis (IgM titer > or = 1:3200 and IgG titer 1:800) and 4 cases of visual disturbances which had IgM with titer ranging from 1:800 to > or = 1:3,200 and IgG with titer ranging from 1:800 to > or = 1:3,200. It was shown that antigen components of 90, 87, 82, 72, 41, 26 and < or = 6 kDa reacted to all sera containing IgG except sera containing both IgG and IgM. Especially bands of 41 and 26 kDa showed strong reaction with all sera containing IgG, except 2 sera which contained both IgG (titer 1:800) and IgM (titer 1:800 and 1:3,200). These sera collected from 2 left eye vision disturbance cases were not reactive to all antigen components. Strong reactions against bands of 41, 26 and < or = 6 kDa were also shown in sera which contained only IgG collected from 9 healthy persons without any toxoplasmosis symptoms whereas bands of 90, 87, 82 and 72 kDa all showed moderate strong reaction. Contrasting to sera containing only IgG, of 5 sera containing both IgG and IgM 3 of them showed only reactions against bands of 41, 26 and < or = 6 kDa which were strong. It seemed that almost all sera containing IgG gave reaction to 90, 87, 82, 72, 41, 26 and < or = 6 kDa, however different pattern of reaction might occur, probably depending on the nature of infection as more antigen components would be recognized by sera containing IgG alone rather than sera containing both IgM in large quantity and IgG. In another study, an attempt to detect T. gondii antigen in 60 samples was done by using ELISA, and it was shown that circulating antigen was found in 27 (90%) from 30 samples which contained both IgG and IgM, whereas only 2 (66%) from 30 samples which contained only IgG showed positive results. Therefore, antigen detection can be used to identify the acute phase of infection.

The health-related quality of life of people living with HIV/AIDS. The prevalence of people living with HIV/AIDS (PLWA) in South Africa is estimated to be approximately 14.2% of the total population. In the absence of anti-retroviral therapy, PLWA are likely to experience a steady decline in function, as their immune systems become increasingly compromised. However, there is limited information available to determine the potential role of rehabilitation interventions in the management of PLWA in a resource-poor community. Subjects were recruited from the population of beneficiaries of HIV/AIDS clinics run by Medecins Sans Frontières, which provides anti-retroviral therapy to PLWA within a resource poor community. The subjects, who were either in WHO Stage 3 or 4 of the disease and/or had a CD4 count of less than 200, were interviewed after enrolment on the anti-retroviral programme and before treatment was initiated. They were therefore not yet receiving anti-retroviral therapy. The control group consisted of a community sample randomly selected from the same area and who were in the same age range. As all participants were Xhosa speaking, the Xhosa version of the EQ-5D measure of HRQoL was utilized. The Mann-Whitney U-test was used to determine whether there was a difference in the rank ordering of responses to the five different domains of the EQ-5D and the Visual Analogue Scale of Health Status scores. There were 123 and 108 subjects in the experimental and control groups, respectively. In the domain of mobility 30.9% of the subjects reported some or severe problems, compared to 14.8% of the control group (p < 0.001). The corresponding figures for the other domains were: self-care 14.8% and 4.6% (p = 0.016), usual activity 31.7% and 10.2% (p < 0.001), pain/discomfort 69.1% and 33.3% (p < 0.001) and anxiety/depression 33.4% and 24.2% (p = 0.123) for the experimental and control groups respectively. PLWA reported a VAS score of 60.4 (SD 22.1), which was significantly lower than that of the community sample (80.13, SD 20.4, p < 0.001). Self-reporting indicates that Health Related Quality of Life is severely comprised in PLWA in Stages 3 and 4 and limitations in the four domains of mobility, usual activities, pain/discomfort and anxiety/depression constitute major problems for PLWA. There is an obvious need to provide a continuum of care, encompassing not only medical but also physical and mental rehabilitation services as well. In an area of high HIV prevalence, the provision of appropriate, multi-disciplinary health care services to PLWA presents a major challenge to the health services.

Biomechanics of brain edema and effects on local cerebral blood flow. Brain edema represents a disturbance of the volume equilibrium which, in the early stages of formation, must be compensated for by a reduction in other fluid and blood compartments. When this compensation is inadequate, tissue pressure and intracranial pressure increase, the magnitude of which depends on the compliance of the tissue. Tissue pressure gradients develop within the same hemisphere and between hemispheres, but these pressure gradients are transient and dissipate within a few hours after injury. The rate of dissipation is proportional to the product of hydraulic tissue resistance and compliance. These tissue pressure gradients are small in magnitude, less than 15 mm Hg; however, studies with an infusion model of edema in animals show that they are more than sufficient to propel fluid through the parenchyma by a process of bulk flow. The distention caused by the fluid increases the conductance and compliance of the tissue. This biomechanical response favors the dissipation of pressure gradients, and as a result hydrostatic gradients can be sustained only with a continued leakage of fluid from the site of injury. Without a continued extravasation of fluid, equilibration of the tissue pressure to the level of the ICP occurs rapidly. For this reason, the role of hydrostatic gradients in the resorption process may be limited. The development of an infusion model allows more rigid control and simulates the edematous process. Ultrastructural studies of the infusion model have shown that the tissue changes are similar to those reported for vasogenic edema, with the exception that in the infusion model the blood-brain barrier remains intact in the vicinity of the lesion and is not compromised by the mechanical distention of the ECS. The response of the cerebrovasculature to the infusion edema is in contrast to the usual reduction of flow seen after cryogenic injury. The CBF remains constant despite increased tissue water, as confirmed by gravimetric technique. The CO2 reactivity of the vessels in the area of edema is reduced, but the autoregulation to changes in perfusion pressure remains intact. When arterial pressure is raised beyond the limit of autoregulation, the pressure increase of CBF in the edematous area is less than the rise of CBF in normal tissue and suggests a "false autoregulation" caused by an increased tissue pressure. The differences in both the intracranial pressure and CBF response between these two models suggests that other factors must be operative. The cryogenic injury is indeed a traumatic injury to the brain and cannot be simply characterized by the increase in brain tissue water. In some animals a vasomotor paralysis disrupting the vascular compartmental volume and leading to a rapid rise in ICP with eventual reduction of CPP and CBF may explain these differences. Release of vasoactive substances into the ECS is an exciting hypothesis and is an area of investigation ideally suited to the infusion edema process where chemical composition of the fluid can be easily controlled.

A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much? While the ingestion of small amounts of an offending food can elicit adverse reactions in individuals with IgE-mediated food allergies, little information is known regarding these threshold doses for specific allergenic foods. While low-dose challenge trials have been conducted on an appreciable number of allergic individuals, a variety of different clinical protocols were used making the estimation of the threshold dose very difficult. A roundtable conference was convened to develop a consensus clinical protocol for low-dose challenge trials for the estimation of threshold doses for specific allergenic foods. In May 2002, 20 clinical allergists and other interested parties were invited to participate in a roundtable conference to develop consensus of the key elements of a clinical protocol for low-dose challenge trials. A consensus protocol was developed. Patients with convincing histories of food allergies and supporting diagnostic evidence including past challenge trials or high CAP-RAST scores can be enrolled in low-dose challenge trials. Care must be taken with younger patients to assure that they have not outgrown their food allergy. An approach was developed for the medication status of patients entering such trials. Challenge materials must be standardized, for example, partially defatted peanut flour composed of equal amounts of the three major varieties of peanuts (Florunner, Virginia, Spanish). Challenge materials must be appropriately blinded with sensory evaluation used to confirm the adequacy of blinding. A double-blind, placebo-controlled design should be used for low-dose challenge trials. Low-dose challenge trials would begin at doses of 10 microg of the allergenic food and would continue with doses of 100 microg and 1 mg followed by specific higher doses up to 100 mg depending upon the expert judgement of the physician; even higher doses might be applied to assure that the patient is indeed reactive to the particular food. A 30-min time interval would be used between doses, and reactive doses would be expressed as both discrete and cumulative doses. The goal of each challenge would be to develop objective symptoms; trials should not be discontinued on the basis of subjective symptoms only. Statistically, a minimum of 29 patients would be enrolled in low-dose challenge trials for each allergenic food because 0 reactors out of 29 patients at a particular dose allow the conclusion that there is 95% certainty that 90% of allergic individuals will not react to that dose. A consensus protocol was developed. Using this protocol, it will be possible to estimate threshold doses for allergenic foods, the lowest amount that elicits mild, objective symptoms in highly sensitive individuals.

Strategies to improve recruitment to randomised controlled trials. Recruiting participants to trials can be extremely difficult. Identifying strategies that improve trial recruitment would benefit both trialists and health research. To quantify the effects of strategies to improve recruitment of participants to randomised controlled trials. We searched the Cochrane Methodology Review Group Specialised Register - CMR (The Cochrane Library (online) Issue 1 2008) (searched 20 February 2008); MEDLINE, Ovid (1950 to date of search) (searched 06 May 2008); EMBASE, Ovid (1980 to date of search) (searched 16 May 2008); ERIC, CSA (1966 to date of search) (searched 19 March 2008); Science Citation Index Expanded, ISI Web of Science (1975 to date of search) (searched 19 March 2008); Social Sciences Citation Index, ISI Web of Science (1975 to date of search) (searched 19 March 2008); and National Research Register (online) (Issue 3 2007) (searched 03 September 2007); C2-SPECTR (searched 09 April 2008). We also searched PubMed (25 March 2008) to retrieve "related articles" for 15 studies included in a previous version of this review. Randomised and quasi-randomised controlled trials of methods to increase recruitment to randomised controlled trials. This includes non-healthcare studies and studies recruiting to hypothetical trials. Studies aiming to increase response rates to questionnaires or trial retention, or which evaluated incentives and disincentives for clinicians to recruit patients were excluded. Data were extracted on the method evaluated; country in which the study was carried out; nature of the population; nature of the study setting; nature of the study to be recruited into; randomisation or quasi-randomisation method; and numbers and proportions in each intervention group. We used risk ratios and their 95% confidence intervals to describe the effects in individual trials, and assessed heterogeneity of these ratios between trials. We identified 27 eligible trials with more than 26,604 participants. There were 24 studies involving interventions aimed directly at trial participants, while three evaluated interventions aimed at people recruiting participants. All studies were in health care. Some interventions were effective in increasing recruitment: telephone reminders to non-respondents (RR 2.66, 95% CI 1.37 to 5.18), use of opt-out, rather than opt-in, procedures for contacting potential trial participants (RR 1.39, 95% CI 1.06 to 1.84) and open designs where participants know which treatment they are receiving in the trial (RR 1.25, 95% CI 1.18 to 1.34). However, some of these strategies have disadvantages, which may limit their widespread use. For example, opt-out procedures are controversial and open designs are by definition unblinded. The effects of many other recruitment strategies are unclear; examples include the use of video to provide trial information to potential participants and modifying the training of recruiters. Many studies looked at recruitment to hypothetical trials and it is unclear how applicable these results are to real trials. Trialists can increase recruitment to their trials by using the strategies shown to be effective in this review: telephone reminders; use of opt-out, rather than opt-in; procedures for contacting potential trial participants and open designs. Some strategies (e.g. open trial designs) need to be considered carefully before use because they also have disadvantages. For example, opt-out procedures are controversial and open designs are by definition unblinded.

Chemistry in motion: tiny synthetic motors. CONSPECTUS: Diffusion is the principal transport mechanism that controls the motion of solute molecules and other species in solution; however, the random walk process that underlies diffusion is slow and often nonspecific. Although diffusion is an essential mechanism for transport in the biological realm, biological systems have devised more efficient transport mechanisms using molecular motors. Most biological motors utilize some form of chemical energy derived from their surroundings to induce conformational changes in order to carry out specific functions. These small molecular motors operate in the presence of strong thermal fluctuations and in the regime of low Reynolds numbers, where viscous forces dominate inertial forces. Thus, their dynamical behavior is fundamentally different from that of macroscopic motors, and different mechanisms are responsible for the production of useful mechanical motion. There is no reason why our interest should be confined to the small motors that occur naturally in biological systems. Recently, micron and nanoscale motors that use chemical energy to produce directed motion by a number of different mechanisms have been made in the laboratory. These small synthetic motors also experience strong thermal fluctuations and operate in regimes where viscous forces dominate. Potentially, these motors could be directed to perform different transport tasks, analogous to those of biological motors, for both in vivo and in vitro applications. Although some synthetic motors execute conformational changes to effect motion, the majority do not, and, instead, they use other mechanisms to convert chemical energy into directed motion. In this Account, we describe how synthetic motors that operate by self-diffusiophoresis make use of a self-generated concentration gradient to drive motor motion. A description of propulsion by self-diffusiophoresis is presented for Janus particle motors comprising catalytic and noncatalytic faces. The properties of the dynamics of chemically powered motors are illustrated by presenting the results of particle-based simulations of sphere-dimer motors constructed from linked catalytic and noncatalytic spheres. The geometries of both Janus and sphere-dimer motors with asymmetric catalytic activity support the formation of concentration gradients around the motors. Because directed motion can occur only when the system is not in equilibrium, the nature of the environment and the role it plays in motor dynamics are described. Rotational Brownian motion also acts to limit directed motion, and it has especially strong effects for very small motors. We address the following question: how small can motors be and still exhibit effects due to propulsion, even if only to enhance diffusion? Synthetic motors have the potential to transform the manner in which chemical dynamical processes are carried out for a wide range of applications.

Electrocardiographic Minnesota code findings predicting short-term mortality in asymptomatic subjects. The Italian RIFLE Pooling Project (Risk Factors and Life Expectancy). Aim of the study was to analyze the predictive power on short term mortality of electrocardiographic findings in asymptomatic subjects belonging to samples of the general population. In the Italian RIFLE Pooling Project (Risk Factors and Life Expectancy) 12 180 men and 10 373 women aged 30 to 69 years had a resting electrocardiogram (ECG) recorded at baseline examination. All of them were free from clinically symptomatic heart disease and represented 23 cohorts spread all over Italy. ECGs were read by the Minnesota Code using 5 large categories of abnormalities, i.e. Q-QS abnormalities, ST-T abnormalities, high R. waves, major arrhythmias, and blocks. Some clinically relevant ECG combination of abnormalities were also analyzed. Six-year mortality from coronary heart disease (CHD), cardiovascular diseases (CVD) and all-cause mortality (ALL) were the end-point. Those ECG findings were relatively common and covered the majority (80 to 90%) of all abnormalities found in the general population before excluding subjects with symptomatic heart disease. Most ECG findings on most occasions were associated with an excess mortality from the three end-points in both men and women and among relatively young (age 30-49) and mature (age 50-69) adults. The strongest predictor of fatal events were Q-QS items and blocks. The most consistent predictors were ST-T findings, although this was true for men and not for women. Relative risk against the absence of abnormalities (one by one and all together) were adjusted by multivariate analysis feeding in the models some possible confounders, i.e. age, systolic blood pressure, serum cholesterol, cigarette consumption and body mass index. Relative risks in cells with more than 20 events (cells being separately made by men, women, the 5 ECG findings categories and the 3 end-points) were ranging 1.00 to 9.88 for Q-QS abnormalities, 1.03 to 3.76 for ST-T abnormalities, 1.28 to 5.14 for high R waves, 0.81 to 2.28 for arrhythmias and 0.79 to 3.59 for blocks. Most of these relative risks were statistically significant. Combinations of clinically relevant ECG findings in the same individual (LVH, possible and definite myocardial infarction) were rare but carried a severe prognosis with high and statistically significant relative risks among men (ranging between 3.19 and 7.24) while they could not be properly tested in most cells for women due to the small numbers involved. It is concluded that in the general population high rates of prevalent ignored ECG abnormalities in asymptomatic subjects are associated with significant excess mortality from CHD, CVD and all-cause mortality, suggesting a high prevalence of silent heart disease.

Arsenic, cadmium, lead, copper and zinc in cattle from Galicia, NW Spain. Knowledge of trace and toxic metal concentrations in livestock is important for assessing the effects of pollutants on domestic animals and contaminant intakes by humans. Metal levels in cattle have been measured in various countries but not in Spain. In this study, the (wet wt.) concentrations of three toxic elements (arsenic, cadmium, lead) and two trace elements (copper, zinc) were quantified in the liver (Li), kidney (Ki), muscle (M) and blood (Bl) of calves (males and females between 6 and 10 months old) and cows (2-16 years old) from Galicia, NW Spain. For the toxic elements, geometric mean concentrations of arsenic in calves (sexes combined) and cows were 10.8 and 10.2 microg/kg (Li), 11.3 and 15.2 microg/kg (Ki), 3.75 and 4.25 microg/kg (M), 3.23 and 2.92 microg/l (Bl). The corresponding cadmium concentrations were 7.78 and 83.3 microg/kg (Li), 54.3 and 388 microg/kg (Ki), 0.839 and 0.944 microg/kg (M), 0.373 and 0.449 microg/l (Bl). Geometric mean concentrations of lead in calves and cows were similarly low and were 33.0 and 47.5 microg/kg (Li), 38.9 and 58.3 microg/kg (Ki), 6.37 and 12.5 microg/kg (M), 5.47 and 12.2 microg/l (Bl). Sex had almost no effect on the amount of toxic metal accumulated except that kidney cadmium concentrations were significantly higher in females than males. Age did influence accumulation; cadmium and lead (but not arsenic) concentrations in most tissues were significantly greater in cows than female calves. For the trace elements, geometric mean copper levels in calf and cow tissues were 49.9 and 36.6 mg/kg (Li), 4.27 and 3.63 mg/kg (Ki), 0.649 and 1.68 mg/kg (M) and 0.878 and 0.890 mg/l (Bl). The corresponding zinc concentrations were 46.3 and 52.5 mg/kg (Li), 14.2 and 20.7 mg/kg (Ki), 47.3 and 52.5 mg/kg (M) and 2.80 and 2.22 mg/l (Bl). Female calves had significantly higher levels than males of muscle zinc and blood copper and zinc. Female calves accumulated more copper but less zinc in the liver and kidneys compared with cows; this may have been associated with the chronic, low-level cadmium accumulation observed in cows. Overall, the levels of arsenic, cadmium, lead and zinc in cattle in Galicia do not constitute a risk for animal health. However, up to 20% of cattle in some regions in Galicia had levels of copper in the liver that exceeded 150 mg/kg wet wt. These animals may be at risk from copper poisoning.

Home style frying of steak and meat products: Survival of Escherichia coli related to dynamic temperature profiles. Microbial survival of heating and cross-contamination are the two transmission routes during food preparation in the consumers' kitchen that are relevant for QMRA (Quantitative Microbial Risk Assessment). The aim of the present study was to extend the limited amount of data on microbial survival during real-life preparation of meat and meat products and to obtain accessory temperature data that allow for a more general (product unspecific) approach. Therefore survival data were combined with extensive measurements of time- and location dependent temperature using an infrared camera for the surface and buttons for the inside of the product, supplemented with interpolation modelling. We investigated the survival of heating of Escherichia coli O111:H2 in beefsteak, hamburgers (beef and 50% beef 50% pork (HH)), meatballs (beef and HH) and crumbs (HH). For beefsteak, survival as a whole is dominated by the sides, giving a log reduction of 1-2 (rare), 3-4 (medium) and 6-7 (done). Limited measurements indicated that done preparation gave 5-6 log reduction for crumbs and at least 8-9 log for the other products. Medium preparation gave a higher reduction in hamburgers (2-4 log) than in meatballs (1-2 log) and in beef (3-4) than in HH (2-3) hamburgers. In general, our 'done' results give larger inactivation than found in literature, whereas 'rare' and 'medium' results are similar. The experiments resulted in two types of curves of D70/z-values, dependent on product, doneness and for beefsteaks sides vs. top/bottom. One type of curve agrees reasonably with literature D70/z estimates from isothermal temperature experiments, which supports using these estimates for home style cooking QMRA calculations. In case of the other type of curve, which is mainly found for (near) surface contamination in close contact with the pan, these literature estimates cannot be applied. We also applied a simplified approach, assuming thermal inactivation is dominated by the highest temperatures reached. The time duration of this highest temperature gives accessory D-values which prove to fit with isothermal temperature literature data, thus suggesting application of such data for QMRA is possible by this approach also, which is less labor intensive both in terms of measurements and modelling. In real life, variability in product properties and preparation styles is large. Further studies are needed to analyze the effect on survival, preferably focusing on determining the essential variables. More variation in heating time will allow for estimating D70/z point estimates rather than curves representing possible sets of D70/z-values.

Sexual dysfunction in women with human papilloma virus infection in the Turkish population. Human papilloma virus infection (HPV) is the most common sexually transmitted disease. It may increase the risk of several cancers, including those of the cervix, vulva, vagina, head and neck. HPV is usually transmitted during sexual intercourse; there are limited data about sexual dysfunction (SD) after infection with this virus. We aimed to measure the incidence of SD in women with HPV. In this study, we evaluated 67 HPV-infected female patients and 66 healthy controls. The Arizona Sexual Experience Scale (ASEX), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Socio Demographic Form were used for evaluation. Gynaecologists and psychiatrists evaluated the participants. Women with HPV were found to have significantly higher Arizona Sexual Experience Scale (ASEX) total scores and ASEX sub scores than the control group in the domains of sexual desire, arousal, genital response, orgasmic experience and their satisfaction from orgasm (p ≤ .05). The study group shows a statistically significant difference in the Beck Depression Inventory (BDI), but Beck Anxiety Inventory (BAI) scores show no significant differences between the experimental and control groups. Our study shows that HPV positivity in female patients is associated with a significant impairment in sexual function and that this impairment is not related to depression or anxiety. Impact statement What is already known on this subject? There are only a few studies concerned with sexual dysfunction in HPV patients. These studies have methodological problems, as they do not rule out the effect of depression on sexual dysfunction. It is very difficult to perform studies on sexual dysfunction and sexually transmitted diseases, because both physicians and patients are reluctant to talk about sexual problems. In the present study, only 6 out of 15 physicians accepted to contribute to the study. Although the physicians gave a questionnaire to more than 400 patients, only 133 of them completed that questionnaire. The most important difficulties in this study was to find enough patients. What do the results of this study add? Depression and sexual dysfunction are frequently seen in HPV patients. Although depression is one of the most common causes of sexual dysfunction, an HPV infection may lead to sexual dysfunction even in the patients without depression. What are the implications of these findings for clinical practice and/or further research? HPV infections may be associated with mental health problems and sexual dysfunction. The gynaecologists and other clinicians working with HPV patients should also evaluate patients psychologically and refer patients to psychiatry if required. The psychiatric problems associated with an HPV infection do not only impair sexual functions, but also may lead to difficulties in social life.

[Long-term therapeutic effects of whole lung lavage in the management of silicosis]. To investigate the long-term therapeutic effect of whole lung lavage (WLL) in the treatment of silicosis. A total of 70 patients with silicosis were randomly and equally divided into WLL group and control group based on chest X-ray, silicosis staging, age, and working age of dust exposure. Comparative analysis was performed to evaluate the long-term therapeutic effect of WLL. Moreover, 157 patients with silicosis treated by WLL were subject to long-term follow-up. Two years after treatment, the cough, expectoration, and asthma improvement rates of the WLL group were 62.5% , 75.0% , and 81.8%, respectively, significantly higher than those (24.0%, 23.8%, and 26.3%) of the control group (P < 0.05). Four years after treatment, the asthma improvement rate (59.1%) of the WLL group was significantly higher than that (21.1%) of the control group (P < 0.05). The WLL group showed slight decrease in forced vital capacity (FVC) and forced expiratory volume in one second (FEV(1)) after treatment (P > 0.05), while the control group showed significant decrease in FVC and FEV1 after treatment (P < 0.05 or P < 0.01). Two and four years after treatment, the WLL group had higher no change rate and lower progression rate and significant progression rate than the control group in terms of chest X-ray (P > 0.05). 22 cases of accelerated silicosis in the WLL group had significantly higher no change rate than the control group with respect to chest X-ray (75.0% vs. 30.0%; 58.3% vs. 20.0%). The WLL group had lower progression rate (2 years of treatment) and significant progression rate (4 years after treatment) than the control group (16.7% vs. 50.0%, P < 0.05; 8.3% vs. 30.0%, P < 0.05). Follow-up of 59 cases treated by WLL showed that the cough and asthma improvement rates were 74.4% and 76.3% 2 ∼ 3 years after treatment and remained 55.0% ∼ 57.1% 4 ∼ 5 years and 6 ∼ 7 years after treatment. Follow-up of 85 cases treated by WLL showed that FVC remained unchanged or slightly decreased 2 ∼ 3 years after treatment and decreased 4 ∼ 5 years and 6 ∼ 7 years after treatment and that the lower silicosis stage was, the less FVC decreased. Follow-up of 108 cases treated by WLL showed that the lower silicosis stage was, the higher no change rate was, according to the chest X-ray findings 2 ∼ 3, 4 ∼ 5, and 6 ∼ 7 years after treatment and that there were significant differences in no change rate between stages II and III silicosis groups and stages 0+ and I silicosis groups (P < 0.01). WLL is an effective therapy for silicosis, especially for early silicosis and accelerated silicosis. However, WLL should be used cautiously in the treatment of advanced silicosis.

Enhanced tumorigenesis and reduced transforming growth factor-beta type II receptor in lung tumors from mice with reduced gene dosage of transforming growth factor-beta1. To elucidate the role of transforming growth factor-beta1 (TGF-beta1) and the TGF-beta type II receptor (TGF-beta RII) as tumor-suppressor genes in lung carcinogenesis, we mated C57BL/6 mice heterozygous (HT) for deletion of the TGF-beta1 gene with A/J mice to produce AJBL6 TGF-beta1 HT progeny and their wild-type (WT) littermates. Immunohistochemical staining, in situ hybridization, and northern blot analyses showed lower staining and hybridization for TGF-beta1 protein and mRNA, respectively, in the lungs of normal HT mice versus WT mice. Competitive reverse transcription-polymerase chain reaction (CRT-PCR) amplification showed the level of TGF-beta1 mRNA in the lungs of HT mice to be fourfold lower than the level in WT lung. When challenged with ethyl carbamate, lung adenomas were detected in 55% of HT mice by 4 mo but only in 25% of WT littermates at this time. Whereas all HT mice had adenomas by 6 mo, it was not until 10 mo before all WT mice had adenomas. After 12 mo, the average number of adenomas was fivefold higher in HT lungs than in WT lungs. Most dramatic was the appearance of lung carcinomas in HT mice 8 mo before they were visible in WT mice. Thus, the AJBL6 TGF-beta1 HT mouse provides an excellent model system to examine carcinogen-induced lung tumorigenesis by increasing progressive lesion incidence and multiplicity relative to their WT littermates. Immunohistochemical staining showed expression of the TGF-beta type I receptor (TGF-beta RI) at moderate to strong levels in lung adenomas and carcinomas in HT and WT mice. In contrast, whereas weak immunostaining for TGF-beta RII was detected in 67% of HT carcinomas at 12 mo, only 22% of WT carcinomas showed weak staining for this protein. Individual lung carcinomas showing reduced TGF-beta RII expression and adjacent normal bronchioles were excised from HT lungs using laser capture microdissection, and CRT-PCR amplification of the extracted RNA showed 12-fold less TGF-beta RII mRNA in these carcinomas compared with bronchioles. Decreasing TGF-beta RII mRNA levels occurred with increasing tumorigenesis in lung hyperplasias, adenomas, and carcinomas, with carcinomas having fourfold and sevenfold lower levels of TGF-beta RII mRNA than adenomas and hyperplasias, respectively. These data show enhanced ethyl carbamate-induced lung tumorigenesis in AJBL6 HT mice compared with WT mice, suggesting that both TGF-beta1 alleles are necessary for tumor-suppressor activity. Reduction of TGF-beta RII mRNA expression in progressive stages of lung tumorigenesis in HT mice suggests that loss of TGF-beta RII may play an important role in the promotion of lung carcinogenesis in mice with reduced TGF-beta1 gene dosage when challenged with carcinogen.

Somatostatin analogs in oncology: a look to the future. In the past 15 years considerable advances have been made in our understanding of the molecular pharmacology of the mechanisms whereby somatostatin and its analogs mediate their direct and indirect antineoplastic effects. However, some important issues remain to be resolved, in particular the functional roles of the individual somatostatin receptors (SSTR-1-5) in tumor tissue and up- or downregulation of the hSSTRs with prolonged administration of somatostatin analogs. Answers to these questions are essential before we can maximize the therapeutic efficacy of somatostatin analogs in cancer. For example, is continuous administration more or less effective than intermittent therapy? The role of somatostatin analogs in the management of acromegaly and to a lesser extent neuroendocrine tumors is firmly established. The development of depot preparations of all 3 somatostatin analogs currently available for clinical use will undoubtedly improve both patient compliance and quality of life in patients with these conditions. There are only likely to be minor differences in the therapeutic efficacy of octreotide, lanreotide and vapreotide since all three analogs exert the majority of their antineoplastic effects via hSSTR-2 and hSSTR-5 and at the end of the day, price may well dictate which of these drugs oncologists use to provide symptomatic palliation of acromegaly and neuroendocrine tumors. Apart from some notable exceptions, somatostatin analog therapy has proven to be very disappointing in the management of advanced malignancy. Improvements in the management of solid tumors are likely to come only from combination therapy of somatostatin analogs with cytotoxic agents or other hormones in both advanced malignancy and in the adjuvant setting. Clinical trials with clear-cut objective outcome measures and health-related quality of life assessment are needed to evaluate the therapeutic efficacy of combination treatment in advanced malignancy and as an adjuvant to surgery. Particular attention needs to be paid to possible adverse effects of somatostatin analog therapy on the immune response to cancer. Further studies are required to establish whether the adverse effects of somatostatin analog therapy alone or in combination with cytotoxics or other hormones can be reversed with appropriate immunomodulatory treatment. Targeted somatostatin analog radiotherapy and chemotherapy are currently being investigated and the results of these studies are awaited with interest. Novel approaches using combinations of somatostatin analogs with antiangiogenic drugs or gene therapy are of particular interest and may provide important advances in the management of cancer in the not too distant future.

[Effect of Achyranthes bidentata polysaccharides stimulated dendritic cells co-cultured with cytokine induced killer cells against SW480 cells]. Achyranthes bidentata polysaccharides (ABPS) was extracted from the root of A. bidentata. Dendritic cells (DC), which were stimulated with ABPS and/or tumor antigen SW480, were co-cultured with cytokine induced killer cells (CIK) to test the cytotoxic effect on colon cancer cell line SW480. Peripheral blood mononuclear cells (PBMNCs) which were separated from human peripheral blood were cultured to DC and CIK separately. (1) DC were divided into four groups: pure DC served as control group; ABPS (50 mg x L(-1)) stimulated DC served as experimental group; SW480 tumor antigen stimulated DC served as the second experimental group; ABPS (50 mg x L(-1)) and SW480 tumor antigen co-stimulated DC served as the third experimental group. Flow cytometry was used to detect the difference of the positive rate of molecules in the cell surface of DC, include CD80, CD86, CD1c, CD40, HLA-DR (6 samples for each group). (2) The four DC groups were mixed with CIK at the ratio 1:5 and acted as effect cells (DC + CIK groups), and the colon cancer cell line SW480 acted as target cells. The effect cells and the target cells were mixed together at the ratio 30: 1, 20:1 and 10:1 separately, and the CCK-8 kit was used to test the cytotoxic effect on colon cancer cell line SW480. (3) At the mixing ratio 30:1 of effect cells and target cells, ELISA was used to test the level of cytokines secretion, including IL-2, IL-12p70, IL-17 and TNF-alpha, in the liquid supernatant of every test group (3 duplication per sample). The results showed as following: (1) The positive rates of CD80, CD11c, HLA-DR, in the cell surface of DC which was co-stimulated by ABPS (50 mg x L(-1)) and SW480 tumor antigen, were obviously higher than the other DC groups (P < 0.05), and the positive rates of CD86, CD40 were obviously higher than the pure DC group (P < 0.05), and there was no remarkable difference with the other two DC groups. (2) At the mixing ratio 30:1, 20:1 and 10:1 of the effect cells and the target cells, the cytotoxic effect of ABPS stimulated DC + CIK group and SW480 tumor antigen stimulated DC + CIK group was obviously higher than DC + CIK group (P < 0.05), the cytotoxic effect of ABPS and SW480 tumor antigen co-stimulated DC + CIK group was obviously higher than all the other groups. (3) At the mixing ratio 30:1 of the effect cells and the target cells, the secretion levels of IL-12p70 and TNF-alpha in the liquid supernatant of the ABPS and SW480 tumor antigen co-stimulated DC + CIK group were obviously higher than all the other groups (P < 0.05), the secretion levels of IL-2 and IL-17 in the liquid supernatant of every test group have no remarkable difference. The cytotoxic effect of ABPS stimulated DC + CIK on SW480 was obviously increased. The cytotoxic effect of ABPS and SW480 tumor antigen co-stimulated DC + CIK group was obviously higher than all the other.

Contribution behavior of 401(k) plan participants. This Issue Brief examines the 1999 contribution behavior of 1.7 million 401(k) plan participants drawn from the EBRI/ICI Participant-Directed Retirement Plan Data Collection Project. The findings in this paper build on previous academic research examining the contribution activity of 401(k) participants, by using a large sample of participants in a wide range of plan sizes and by examining in detail the factors that influence contribution activity. Eighty-five percent of participants in the sample only made before-tax contributions to their plans, and 97 percent of all dollars contributed by employees were contributed on a before-tax basis. On average, participants contributed 6.8 percent of their salaries on a before-tax basis. Before-tax contribution activity varied among participants. About 61 percent of participants contributed more than 5 percent of their salaries on a before-tax basis and about 21 percent set aside more than 10 percent of their salaries on a before-tax basis. Eleven percent of participants analyzed in this study earning more than $40,000 a year contributed at the $10,000 before-tax IRC limit in 1999. Thirteen percent of participants with salaries between $70,000 and $80,000 contributed at the cap, and 18 percent of those with salaries between $80,000 and $90,000 were at the limit. However, it appears that among participants not contributing at the IRC limit, 52 percent could not have done so because of formal plan-imposed contribution limits below the IRC limit. Older participants tended to contribute a higher percentage of their salaries to plans than did younger participants, even after factoring out differences in salary and job tenure. Participants tended to increase the share of their salary (and amounts) contributed to their 401(k) plan as their salaries rose until salaries reached $80,000. For individuals with salaries above $80,000, before-tax contribution rates (though not the amounts contributed) tended to fall as salaries rose because IRC, and possibly plan sponsor, contribution limits became binding for some participants. Giving employees the option of borrowing from their 401(k) accounts increased participant contribution rates. On average, a participant in a plan offering loans appeared to contribute 0.6 percentage point more of his or her salary to the plan than a participant in a plan with no loan provision. Total contributions--the sum of employee and employer contributions--were higher for participants who received an employer contribution as part of their 401(k) plan than for those who did not. The average total contribution rate was 10 percent of salary for employees in plans offering an employer contribution, compared with 7.4 percent for those in plans not offering an employer contribution.

Magnesium-enriched coronary sinus retroperfusion during acute coronary artery occlusion. The protective effect of coronary sinus retroperfusion in cases of ischaemic myocardium is clearly known. It restores the blood flow to the ischaemic tissue, reduces the infarct size, and improves the left ventricular pump function. In this study, we investigated the effects of coronary sinus retroperfusion with the addition of magnesium sulphate on myocardial haemodynamics. A total of sixteen animals were entered into the study and divided equally into four groups: group I, control group, left anterior descending (LAD) coronary artery occlusion only; group II, LAD artery occlusion and Mg SO infusion; group III, LAD occlusion and retrograde coronary sinus perfusion; and group IV, LAD occlusion, retrograde coronary sinus perfusion and Mg SO infusion.(4) (4) Haemodynamic measurements were obtained throughout the study, at baseline, during the first and third hour of occlusion, and in the second, fourth and sixth hour of reperfusion. Although, the cardiac index was decreased in all groups, in the second hour of reperfusion it was significantly higher in groups III and IV compared to the control group. In the second hour of reperfusion cardiac index values were 56 +/- 5 and 63 +/- 6 ml/kg per min in groups III and IV respectively (P < 0.05) and as time passed this incremental change in groups III and IV became more apparent. In the fourth hour of reperfusion, group II showed significantly higher values than the control group. Group IV had higher values compared to group III at the fourth and sixth hours post-reperfusion. In general there were significant differences between groups II, III and IV at four and six hours post-reperfusion. The first derivative of pressure measured over time-the dP/dt value-was higher in groups III and IV compared to the control group in the first hour of occlusion (being 1650 +/- 55 and 1700 +/- 35 in groups III and IV respectively, and 1420 +/- 45 in the control group) and these differences continued throughout the occlusion and the reperfusion periods (P < 0.05). Group IV had the highest left ventricular stroke work index (LVSWI) values compared to the other groups in various pulmonary capillary wedge pressure (PCWP) measurements (P < 0.05). It was 0.78 g.m/kg at the 20 mmHg PCWP. Magnesium, if administered in an antegrade direction had only a limited effect, whereas magnesium-enriched retrograde coronary sinus perfusions appeared to significantly protect the ischaemic myocardium against the hazardous effects of ischaemic reperfusion injury.

Final report on the safety assessment of Arnica montana extract and Arnica montana. Arnica Montana Extract is an extract of dried flowerheads of the plant, Arnica montana. Arnica Montana is a generic term used to describe a plant material derived from the dried flowers, roots, or rhizomes of A. montana. Common names for A. montana include leopard's bane, mountain tobacco, mountain snuff, and wolf's bane. Two techniques for preparing Arnica Montana Extract are hydroalcoholic maceration and gentle disintegration in soybean oil. Propylene glycol and butylene glycol extractions were also reported. The composition of these extracts can include fatty acids, especially palmitic, linoleic, myristic, and linolenic acids, essential oil, triterpenic alcohols, sesquiterpene lactones, sugars, phytosterols, phenol acids, tannins, choline, inulin, phulin, arnicin, flavonoids, carotenoids, coumarins, and heavy metals. The components present in these extracts are dependent on where the plant is grown. Arnica Montana Extract was reported to be used in almost 100 cosmetic formulations across a wide range of product types, whereas Arnica Montana was reported only once. Extractions of Arnica Montana were tested and found not toxic in acute toxicity tests in rabbits, mice, and rats; they were not irritating, sensitizing, or phototoxic to mouse or guinea pig skin; and they did not produce significant ocular irritation. In an Ames test, an extract of A. montana was mutagenic, possibly related to the flavenoid content of the extract. No carcinogenicity or reproductive/developmental toxicity data were available. Clinical tests of extractions failed to elicit irritation or sensitization, yet Arnica dermatitis, a delayed type IV allergy, is reported in individuals who handle arnica flowers and may be caused by sesquiterpene lactones found in the flowers. Ingestion of A. montana-containing products has induced severe gastroenteritis, nervousness, accelerated heart rate, muscular weakness, and death. Absent any basis for concluding that data on one member of a botanical ingredient group can be extrapolated to another in the group, or to the same ingredient extracted differently, these data were not considered sufficient to assess the safety of these ingredients. Additional data needs include current concentration of use data; function in cosmetics; ultraviolet (UV) absorption data-if absorption occurs in the UVA or UVB range, photosensitization data are needed; gross pathology and histopathology in skin and other major organ systems associated with repeated dermal exposures; dermal reproductive/developmental toxicity data; inhalation toxicity data, especially addressing the concentration, amount delivered, and particle size; and genotoxicity testing in a mammalian system; if positive, a 2-year dermal carcinogenicity assay performed using National Toxicology Program (NTP) methods is needed. Until these data are available, it is concluded that the available data are insufficient to support the safety of these ingredients in cosmetic formulations.

Shunt survival after failed endoscopic treatment of hydrocephalus. It is not known whether previous endoscopic third ventriculostomy (ETV) affects the risk of shunt failure. Different epochs of hydrocephalus treatment at the CURE Children's Hospital of Uganda (CCHU)-initially placing CSF shunts in all patients, then attempting ETV in all patients, and finally attempting ETV combined with choroid plexus cauterization (CPC) in all patients-provided the opportunity to assess whether prior endoscopic surgery affected shunt survival. With appropriate institutional approvals, the authors reviewed the CCHU clinical database to identify 2329 patients treated for hydrocephalus from December 2000 to May 2007. Initial ventriculoperitoneal (VP) shunt placement was performed in 900 patients under one of three circumstances: 1) primary nonselective VP shunt placement with no endoscopy (255 patients); 2) VP shunt placement at the time of abandoned ETV attempt (with or without CPC) (370 patients); 3) VP shunt placement subsequent to a completed but failed ETV (with or without CPC) (275 patients). We analyzed time to shunt failure using the Kaplan-Meier method to construct survival curves, Cox proportional hazards regression modeling, and risk-adjusted analyses to account for possible confounding differences among these groups. Shunt failure occurred in 299 patients, and the mean duration of follow-up for the remaining 601 was 28.7 months (median 18.8, interquartile range 4.1-46.3). There was no significant difference in operative mortality (p = 0.07 by log-rank and p = 0.14 by Cox regression adjusted for age and hydrocephalus etiology) or shunt infection (p = 0.94, log-rank) among the 3 groups. There was no difference in shunt survival between patients treated with primary shunt placement and those who underwent shunt placement at the time of an abandoned ETV attempt (adjusted hazard ratio [HR] 1.14, 95% CI 0.86-1.51, p = 0.35). Those who underwent shunt placement after a completed but failed ETV (with or without CPC) had a lower risk of shunt failure (p = 0.008, log-rank), with a hazard ratio (adjusted for age at shunting and etiology) of 0.72 (95% CI 0.53-0.98), p = 0.03, compared with those who underwent primary shunt placement without endoscopy; but this was observed only in patients with postinfectious hydrocephalus (PIH) (adjusted HR 0.55, 95% CI 0.36-0.85, p = 0.007), and no effect was apparent for hydrocephalus of noninfectious etiologies (adjusted HR 0.98, 95% CI 0.64-1.50, p = 0.92). Improved shunt survival after failed ETV in the PIH group may be an artifact of selection arising from the inherent heterogeneity of ventricular damage within that group, or a consequence of the timing of shunt placement. The anticipated benefit of CPC in preventing future ventricular catheter obstruction was not observed. A paradigm for infant hydrocephalus involving intention to treat by ETV with or without CPC had no adverse effect on mortality or on subsequent shunt survival or infection risk. This study failed to demonstrate a positive effect of prior ETV or CPC on shunt survival.

Long-acting FSH versus daily FSH for women undergoing assisted reproduction. Assisted reproduction techniques (ART) such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) can help subfertile couples to create a family. It is necessary to induce multiple follicles; this is achieved by follicle stimulating hormone (FSH) injections. Current treatment regimens prescribe daily injections of FSH (urinary FSH with or without luteinizing hormone (LH) injections or recombinant FSH (rFSH)).Recombinant DNA technologies have produced a new recombinant molecule which is a long-acting FSH, named corifollitropin alfa (Elonva) or FSH-CTP. A single dose of long-acting FSH is able to keep the circulating FSH level above the threshold necessary to support multi-follicular growth for an entire week. The optimal dose of long-acting FSH is still being determined. A single injection of long-acting FSH can replace seven daily FSH injections during the first week of controlled ovarian stimulation (COS) and can make assisted reproduction more patient friendly. To compare the effectiveness of long-acting FSH versus daily FSH in terms of pregnancy and safety outcomes in women undergoing IVF or ICSI treatment cycles. We searched the following electronic databases, trial registers and websites: the Cochrane Central Register of Controlled Trials (CENTRAL), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the ISI Web of Knowledge, LILACS, Clinical Study Results (for clinical trial results of marketed pharmaceuticals), PubMed and OpenSIGLE (10 October 2011). We also carried out handsearches. All randomised controlled trials (RCTs) comparing long-acting FSH versus daily FSH in women who were part of a couple with subfertility and undertaking IVF or ICSI treatment cycles with a GnRH antagonist or agonist protocol were included. Data extraction and assessment of risk of bias was independently done by two review authors. Original trial authors were contacted in the case of missing data. We calculated Peto odds ratios for each outcome; our primary outcomes were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate. We included four RCTs with a total of 2335 participants. A comparison of long-acting FSH versus daily FSH did not show evidence of difference in effect on overall live birth rate (Peto OR 0.92; 95% CI 0.76 to 1.10, 4 RCTs, 2335 women) or OHSS (Peto OR 1.12; 95% CI 0.79 to 1.60, 4 RCTs, 2335 women). We compared subgroups by dose of long-acting FSH. There was evidence of reduced live birth rate in women who received lower doses (60 to 120 μg) of long-acting FSH compared to daily FSH (Peto OR 0.60; 95% CI 0.40 to 0.91, 3 RCTs, 645 women). There was no evidence of effect on live births in the medium dose subgroup (Peto OR 1.03; 95% CI 0.84 to 1.27) and no evidence of effect on clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate, miscarriage rate or ectopic pregnancy rate. The use of a medium dose of long-acting FSH is a safe treatment option and equally effective compared to daily FSH. Further research is needed to determine if long-acting FSH is safe and effective for use in hyper- or poor responders and in women with all causes of subfertility.

Incidence, prevalence, diagnostic delay, morbidity, mortality and socioeconomic status in males with 46,XX disorders of sex development: a nationwide study. What is the epidemiology and trajectory of health and socioeconomic status in males with 46,XX disorders of sex development (DSD)? 46,XX DSD males had an increased overall morbidity compared to male background population controls, and the socioeconomic status was inferior on outcome parameters such as education and long-term income. 46,XX DSD males are rare and estimates of prevalence and incidence are limited. An increased morbidity and mortality as well as a negatively affected socioeconomic status are described in males with Klinefelter Syndrome. However, this has never been systematically studied in 46,XX DSD males. In this nationwide registry study including 44 males with a verified diagnosis of 46,XX DSD we aimed to estimate incidence, prevalence and diagnostic delay. Further, we aimed to study morbidity, mortality and socioeconomic outcome parameters using the Danish registries. The socioeconomic outcome parameters were education, income, retirement, parenthood and cohabitation. 46,XX DSD males were born during 1908-2012 and follow-up started at birth or at start of registration and ended in 2014. Potential cases (n = 69) were identified in the Danish Cytogenetic Central Registry and the diagnosis was verified by medical record evaluation (n = 44). A randomly selected age-matched control group of 100 males and 100 females per case was identified by Statistics Denmark. Among newborn males the prevalence of diagnosed 46,XX DSD males was 3.5-4.7 per 100 000. Median age at diagnosis was 17.0 years (range: 0.0-62.8). Overall morbidity was increased compared to male controls (hazard ratio [HR] = 2.4, 95% CI: 1.8-3.3) but not when excluding endocrine and urogenital diseases as well as congenital malformations (HR = 1.2, 95% CI: 0.8-1.6). Mortality was not increased (HR = 0.6, 95% CI: 0.2-2.5) compared to male controls. 46,XX DSD males had poorer education (HR = 0.1, 95% CI: 0.0-0.9) and fewer fatherhoods (HR = 0.4, 95% CI: 0.2-0.7) than male controls, and their income was reduced for the following age groups; 45-49 years: odds ratio [OR] = 0.4 (95% CI: 0.2-0.7); 50-54 years: OR = 0.1 (95% CI: 0.0-0.6). The study cohort is rather small, although it is large in comparison to other studies on 46,XX DSD males. Some 46,XX DSD males may have been excluded from the study owing to lack of data in medical records, making the diagnosis impossible to verify. As in all epidemiologic studies a risk of misclassification must be considered when interpreting the study results, and as the study included diagnosed 46,XX DSD males only, conclusions cannot be extended to non-diagnosed 46,XX DSD males. This study provides a new insight into trajectory of health and socioeconomic status of 46,XX DSD males. This study was funded by research grants from the Health Research Fund of Central Denmark Region, the A.P. Møller Foundation 'Fonden til Laegevidenskabens Fremme', the Lundbeck Foundation and the Novo Nordisk Foundation (NNF13OC0003234 and NNF15OC0016474). The authors have nothing to declare. N/A.

Using experimental manipulation to assess the roles of leaf litter in the functioning of forest ecosystems. The widespread use of forest litter as animal bedding in central Europe for many centuries gave rise to the first litter manipulation studies, and their results demonstrated that litter and its decomposition are a vital part of ecosystem function. Litter plays two major roles in forest ecosystems: firstly, litterfall is an inherent part of nutrient and carbon cycling, and secondly, litter forms a protective layer on the soil surface that also regulates microclimatic conditions. By reviewing 152 years of litter manipulation experiments, I show that the effects of manipulating litter stem from changes in one, or both, of these two functions, and interactions between the variables influenced by the accumulation of litter can result in feedback mechanisms that may intensify treatment effects or mask responses, making the interpretation of results difficult.Long-term litter removal increased soil bulk density, overland flow, erosion, and temperature fluctuations and upset the soil water balance, causing lower soil water content during dry periods. Soil pH increased or decreased in response to manipulation treatments depending on forest type and initial soil pH, but it is unclear why there was no uniform response. Long-term litter harvesting severely depleted the forests of nutrients. Decreases in the concentrations of available P, Ca, Mg, and K in the soil occurred after only three to five years. The decline in soil N occurred over longer periods of time, and the relative loss was greater in soils with high initial nitrogen concentration. Tree growth declined with long-term litter removal, probably due to lower nutrient availability. Litter manipulation also added or removed large amounts of carbon thereby affecting microbial communities and altering soil respiration rates. Litter manipulation experiments have shown that litter cover acts as a physical barrier to the shoot emergence of small-seeded species; further, the microclimate maintained by the litter layer may be favourable to herbivores and pathogens and is important in determining later seedling survival and performance. Litter manipulation altered the competitive outcomes between tree seedlings and forbs, thereby influencing species composition and diversity; changes in the species composition of understorey vegetation following treatments occurred fairly rapidly. By decreasing substrate availability and altering the microclimate, litter removal changed fungal species composition and diversity and led to a decline in populations of soil fauna. However, litter addition did not provoke a corresponding increase in the abundance or diversity of fungi or soil fauna.Large-scale long-term studies are still needed in order to investigate the interactions between the many variables affected by litter, especially in tropical and boreal forests, which have received little attention. Litter manipulation treatments present an opportunity to assess the effects of increasing primary production in forest ecosystems; specific research aims include assessing the effects of changes in litter inputs on the carbon and nutrient cycles, decomposition processes, and the turnover of organic matter.

First Report of Fruit Rot and Associated Branch Dieback of Almond in California Caused by a Phomopsis Species Tentatively Identified as P. amygdali. A fruit rot of almond (Prunus dulcis (Mill.) D. Webb.) was observed in an orchard in Durham, CA (Butte County), in June of 1998 after an unusually wet spring with a total precipitation of 17.2 cm for April and May. Disease incidence on fully developed fruit of almond cv. Sonora was nearly 90% in the lower tree canopy by July. Almond cv. Nonpareil grown in alternate rows in the same orchard was much less affected. Fruit symptoms included extensive grayish brown discolored and shriveled hulls, often associated with a clear gum secretion and shriveled kernels. Affected fruit frequently abscised. Leaf symptoms and branch dieback were not associated with the disease in 1998. In May of 1999, however, extensive twig dieback was observed on almond cv. Sonora in the same orchard. Isolations from more than 100 symptomatic fruit were conducted from 9 sampling sites in the 9-ha orchard. Based on morphological characteristics, the same fungus was isolated from 93% of the fruit. The fungus also was isolated consistently from samples exhibiting twig dieback. During a major disease survey conducted in 1998, the fungus was only incidentally isolated from almond fruit from other California orchards. Ascomata were not observed in vivo or in vitro. The fungus produced alpha and beta spores in pycnidia when cultured on potato dextrose agar. Spore measurements were obtained from 10 spores for each of 3 isolates obtained from fruit or twig dieback of almond cv. Sonora. Conidial dimensions of fruit and twig isolates were very similar. Based on spore sizes, with alpha spores measuring 5.3 to 7.5 (to 8) × 1.7 to 2.5 μm and beta spores measuring12.8 to 29.8 × 0.6 to 0.7 μm, the fungus was tentatively identified as Phomopsis amygdali (Del.) Tuset & Portilla (2). Previous reports on this fungus (2), however, indicated that beta spores are not produced in culture, and disease symptoms have not been observed on fruit. The fungus was morphologically different from other species of Phomopsis reported from almond and other Prunus species, including P. mali Roberts, P. padina (Sacc. & Roum.) Died., P. parabolica Petrak, P. perniciosa Grove, P. pruni (Ellis & Dearn.) Wehm., P. prunorum (Cooke) Grove, P. ribetejana Camara, and P. stipata (Lib.) Sutton (3). Field inoculation studies were performed in May of 1999 on almond cvs. Carmel and Mission. Almond fruit were wounded (2 × 2 × 2 mm) or left unwounded and were sprayed with water (control) or a suspension of alpha spores (105 spores per ml). Branches were bagged for 4 days to maintain high humidity. Fruit symptoms on cv. Carmel were observed after 4 weeks on wounded and nonwounded inoculated fruit, and P. amygdali was successfully reisolated from diseased tissue. No symptoms were observed in the control treatment for almond cv. Carmel or in any treatment for cv. Mission. This is the first report of P. amygdali causing a late spring and summer fruit rot and associated branch dieback of almond in North America (1). References: (1) D. F. Farr et al. 1989. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, St. Paul, MN. (2) J. J. Tuset and M. T. Portilla. Taxonomic status of Fusicoccum amygdali and Phomopsis amygdalina. Can. J. Bot. 67:1275, 1989. (3) F. A. Uecker. 1988. A World List of Phomopsis Names with Notes on Nomenclature, Morphology, and Biology. Mycologia Memoir No. 13. J. Cramer, Berlin.

Subcellular tension fields and mechanical resistance of the lamella front related to the direction of locomotion. Keratocytes derived from the epidermis of aquatic vertebrates are now widely used for investigation of the mechanism of cell locomotion. One of the main topics under discussion is the question of driving force development and concomitantly subcellular force distribution. Do cells move by actin polymerization-driven extension of the lamella, or is the lamella edge extended at regions of weakness by a flow of cytoplasm generated by hydrostatic pressure? Thus, elasticity changes were followed and the stiffness of the leading front of the lamella was manipulated by local application of phalloidin and cytochalasin D (CD). In scanning acoustic microscopy (SAM), elasticity is revealed from the propagation velocity of longitudinal sound waves (1 GHz). The lateral resolution of SAM is in the micrometer range. Using this method, subcellular tension fields with different stiffnesses (elasticity) can be determined. A typical pattern of subcellular stiffness distribution is related to the direction of migration. Cells forced to change their direction of movement by exposure to DC electric fields of varying polarity alter their pattern of subcellular stiffness in relationship to the new direction. The cells spread into the direction of low stiffness and retract at zones of high stiffness. The pattern of subcellular stiffness distribution reveals force distribution in migrating cells; i.e., if a cell moves exactly in a direction perpendicular to its long axis, then the contractile forces are largest along the long axis and decrease toward the short axis. Locomotion in any angle oblique to this axis requires an asymmetric stiffness distribution. Inhibition of actomyosin contractions by La3+ (2 mM), which inhibits Ca2+ influx, reduces cytoplasmic stiffness accompanied by an immediate cessation of locomotion and a change of cell shape. Local release of CD in front of a progressing lamella activates a cell to follow the CD gradient: The lamella thickens locally and is extended toward the tip of the microcapillary. Release of phalloidin stops extension of the lamella, and the cell turns away from the releasing microcapillary. The response to CD is assumed to be the result of local weakening of the cytoplasm due to severing of the actin fibrils. Phalloidin is supposed to stabilize the leading front by inhibition of F-actin depolymerization. These observations are in favor of the assumption that migration is due to an extension of the cell into the direction of minimum stiffness, and they are consistent with the hypothesis that local release of hydrostatic pressure provides the driving force for the flux of cytoplasm.

NMR structural and dynamic characterization of the acid-unfolded state of apomyoglobin provides insights into the early events in protein folding. Apomyoglobin forms a denatured state under low-salt conditions at pH 2.3. The conformational propensities and polypeptide backbone dynamics of this state have been characterized by NMR. Nearly complete backbone and some side chain resonance assignments have been obtained, using a triple-resonance assignment strategy tailored to low protein concentration (0.2 mM) and poor chemical shift dispersion. An estimate of the population and location of residual secondary structure has been made by examining deviations of (13)C(alpha), (13)CO, and (1)H(alpha) chemical shifts from random coil values, scalar (3)J(HN,H)(alpha) coupling constants and (1)H-(1)H NOEs. Chemical shifts constitute a highly reliable indicator of secondary structural preferences, provided the appropriate random coil chemical shift references are used, but in the case of acid-unfolded apomyoglobin, (3)J(HN,H)(alpha) coupling constants are poor diagnostics of secondary structure formation. Substantial populations of helical structure, in dynamic equilibrium with unfolded states, are formed in regions corresponding to the A and H helices of the folded protein. In addition, the deviation of the chemical shifts from random coil values indicates the presence of helical structure encompassing the D helix and extending into the first turn of the E helix. The polypeptide backbone dynamics of acid-unfolded apomyoglobin have been investigated using reduced spectral density function analysis of (15)N relaxation data. The spectral density J(omega(N)) is particularly sensitive to variations in backbone fluctuations on the picosecond to nanosecond time scale. The central region of the polypeptide spanning the C-terminal half of the E helix, the EF turn, and the F helix behaves as a free-flight random coil chain, but there is evidence from J(omega(N)) of restricted motions on the picosecond to nanosecond time scale in the A and H helix regions where there is a propensity to populate helical secondary structure in the acid-unfolded state. Backbone fluctuations are also restricted in parts of the B and G helices due to formation of local hydrophobic clusters. Regions of restricted backbone flexibility are generally associated with large buried surface area. A significant increase in J(0) is observed for the NH resonances of some residues located in the A and G helices of the folded protein and is associated with fluctuations on a microsecond to millisecond time scale that probably arise from transient contacts between these distant regions of the polypeptide chain. Our results indicate that the equilibrium unfolded state of apomyoglobin formed at pH 2.3 is an excellent model for the events that are expected to occur in the earliest stages of protein folding, providing insights into the regions of the polypeptide that spontaneously undergo local hydrophobic collapse and sample nativelike secondary structure.

The ACTIVE Trial: comparison of the effects on renal function of iomeprol-400 and iodixanol-320 in patients with chronic kidney disease undergoing abdominal computed tomography. We performed a multicenter, double-blind, randomized, parallel-group study to compare the renal effects of iomeprol-400 and iodixanol-320 in patients with preexisting chronic kidney disease undergoing contrast-enhanced multidetector computed tomography of the liver. One hundred forty-eight patients with moderate-to-severe chronic kidney disease, ie, serum creatinine (SCr) > or =1.5 mg/dL (132.6 micromol/L) and/or calculated creatinine clearance (CrCl) <60 mL/min, undergoing contrast-enhanced multidetector computed tomography of the liver were randomized to equi-iodine doses (40 gI) of either the low-osmolar agent iomeprol-400 (400 mgI/mL, 726 mOsm/kg, N = 76) or the isotonic agent iodixanol-320 (320 mgI/mL, 290 mOsm/kg, N = 72), injected intravenously at 4 mL/S, followed by a bolus of 20 mL normal saline solution at the same rate. SCr was obtained at screening, baseline and at 48 to 72 hours postdose. SCr measurements and CrCl calculations were performed by a central laboratory. Contrast-induced nephropathy (CIN) was defined as an absolute SCr increase of > or =0.5 mg/dL (44.2 micromol/L) from baseline to 48 to 72 hours postdose. Mean SCr changes from baseline were also assessed. A Renal Safety Review Board comprised 3 medical experts reviewed the renal safety data, demographics, medical history, CIN risk factors, concomitant medications, and hydration status of each subject in a blinded manner. The 2 study groups were comparable with regard to age, gender distribution, concomitant nephrotoxins, hydration status, and total iodine dose; however, the iomeprol-400 group showed a significantly higher proportion of patients with diabetes mellitus (P = 0.02). Baseline SCr was 1.7 +/- 0.6 mg/dL (150.3 +/- 53.0 micromol/L) in the iomeprol-400 group and 1.7 +/- 0.7 mg/dL (150.3 +/- 61.9 micromol/L) in the iodixanol-320 group (P = 0.87). Predose CrCl was 41.5 +/- 13.1 mL/Min in the iomeprol-400 group and 43.0 +/- 13.3 mL/Min in the iodixanol-320 group (P = 0.49). Five of 72 patient receiving iodixanol-320 (6.9%) and none of the patients receiving iomeprol-400 showed an increase of > or =0.5 mg/dL (44.2 micromol/L) from baseline [P = 0.025, 95% CI (-12.8%, -1.1%)]. The mean SCr change from baseline was significantly higher (P = 0.017 ANCOVA) after iodixanol-320 (0.06 +/- 0.27) than after iomeprol-400 (-0.04 +/- 0.19). The incidence of CIN was significantly higher after IV administration of iodixanol-320 than iomeprol-400. The mean rise in SCr from baseline was also higher in patients receiving iodixanol.

Pyoderma gangrenosum: clinical and laboratory findings in 15 patients with special reference to polyarthritis. Fifteen consecutive patients with PG have been studied during the period 1971-78. Systemic disease was found in 13 of the patients and preceded the skin disease in 10 patients by 1-25 years. Only two patients had ulcerative colitis. One patient had paroxysmal nocturnal hemoglobinuria and three patients had an IgA myeloma. Eight patients had polyarthritis; this was classical seropositive rheumatoid arthritis in two patients, and a seronegative inflammatory polyarthritis in six patients. Four patients had an unusual progressive erosive seronegative polyarthritis without evidence of granulomatous bowel disease, psoriasis, genital, urinary tract or eye disease. In three of these four patients the arthritis preceded the PG. Synovial fluid analysis showed depressed complement levels and in one patient deposits of immunoglobulins and complement were demonstrated in the synovial membrane. The course of the arthritis was progressive with development of disabling joint deformities and erosive destruction of joints, despite treatment with penicillamine, corticosteroids and nonsteroidal anti-inflammatory drugs. One other patient had severe degenerative joint disease and chondrocalcinosis in association with a seronegative inflammatory polyarthritis, and another patient had ulcerative proctitis and severe degenerative joint disease secondary to chronic seronegative inflammatory polyarthritis. None of the patients had colitic arthritis, but in view of the association between PG and ulcerative colitis, some patients previously reported with PG and joint disease may have been suffering from the arthritis of ulcerative colitis. PG developed at the site of skin trauma in six patients. The natural history of the skin disease ran one of two courses: an acute, progressive course in which the ulcers rapidly enlarged until arrested by treatment; and a chronic course in which the lesions extended slowly and which after a period of weeks began to show signs of spontaneous healing. In only the patients with ulcerative colitis was there any correlation between the activity of the associated disease and the onset and progression of the skin disease. Serum complement levels were normal and no circulating cryoprecipitable immune complexes were found. Skin histology showed no evidence of vasculitis and direct immunofluorescence examination of involved skin was negative for IgG, IgM, IgA and C3. No consistent abnormality of cell-mediated immunity or neutrophil function was found and no significantly increased prevalence of any HLA antigen type was noted. Twelve patients have been treated with systemic corticosteroids. Six of these patients developed serious steroid complications and four patients have died, all from complications of steroid therapy.

Prenatal screening for and diagnosis of aneuploidy in twin pregnancies. To provide a Canadian consensus document with recommendations on prenatal screening for and diagnosis of fetal aneuploidy (e.g., Down syndrome and trisomy 18) in twin pregnancies. The process of prenatal screening and diagnosis in twin pregnancies is complex. This document reviews the options available to pregnant women and the challenges specific to screening and diagnosis in a twin pregnancy. Clinicians will be better informed about the accuracy of different screening options in twin pregnancies and about techniques of invasive prenatal diagnosis in twins. PubMed and Cochrane Database were searched for relevant English and French language articles published between 1985 and 2010, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis, twin gestation). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. Searches were updated on a regular basis and incorporated in the guideline to August 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline. The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). There is a need for specific guidelines for prenatal screening and diagnosis in twins. These guidelines should assist health care providers in the approach to this aspect of prenatal care of women with twin pregnancies. SUMMARY STATEMENTS 1. Fetal nuchal translucency combined with maternal age is an acceptable first trimester screening test for aneuploidies in twin pregnancies. (II-2) 2. First trimester serum screening combined with nuchal translucency may be considered in twin pregnancies. It provides some improvement over the performance of screening by nuchal translucency and maternal age by decreasing the false-positive rate. (II-3) 3. Integrated screening with nuchal translucency plus first and second trimester serum screening is an option in twin pregnancies. Further prospective studies are required in this area, since it has not been validated in prospective studies in twins. (III) 4. Non-directive counselling is essential when invasive testing is offered. (III) 5. When chorionic villus sampling is performed in non-monochorionic multiple pregnancies, a combination of transabdominal and transcervical approaches or a transabdominal only approach appears to provide the best results to minimize the likelihood of sampling errors. (II-2) Recommendations 1. All pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies. In addition, they should be offered a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (I-A) 2. Counselling must be non-directive and must respect a woman's right to accept or decline any or all of the testing or options offered at any point in the process. (III-A) 3. When non-invasive prenatal screening for aneuploidy is available, maternal age alone should not be an indication for invasive prenatal diagnosis in a twin pregnancy. (II-2A) If non-invasive prenatal screening is not available, invasive prenatal diagnosis in twins should be offered to women aged 35 and over. (II-2B) 4. Chorionicity has a major impact on the prenatal screening process and should be determined by ultrasound in the first trimester of all twin pregnancies. (II-2A) 5. When screening is done by nuchal translucency and maternal age, a pregnancy-specific risk should be calculated in monochorionic twins. In dichorionic twins, a fetus-specific risk should be calculated. (II-3C) 6. During amniocentesis, both amniotic sacs should be sampled in monochorionic twin pregnancies, unless monochorionicity is confirmed before 14 weeks and the fetuses appear concordant for growth and anatomy. (II-2B) 7. Prior to invasive testing or in the context of twins discordant for an abnormality, selective reduction should be discussed and made available to those requesting the procedure after appropriate counselling. (III-B) 8. Monitoring for disseminated intravascular coagulopathy is not indicated in dichorionic twin pregnancies undergoing selective reduction. (II-2B).

Effects of supplemental rumen-protected conjugated linoleic acid or corn oil on fatty acid composition of adipose tissues in beef cattle. Thirty-six Angus x Hereford heifers (365 +/- 60 kg) were used to determine the effects of supplemental dietary lipid sources on fatty acid composition of i.m., perianal (p.a.), and s.c. lipid depots. Lipid was supplied to diets as either corn oil or a rumen-protected conjugated linoleic acid (CLA) salt for two specific treatment periods of either the final 32 or 60 d on feed. Following an initial 56-d feeding period, heifers were fed one of three dietary treatments (DM basis): 1) basal diet containing 88% concentrate and 12% grass hay (CON), 2) basal diet plus 4% corn oil (OIL), or 3) basal diet plus 2% rumen-protected CLA salt (RPCLA) containing 31% CLA. The trans-10, cis-12 CLA concentration was greatest (P < 0.05) for heifers fed RPCLA and OIL diets and least (P < 0.05) for CON, regardless of time on dietary treatment. Heifers fed supplemental RPCLA had greater (P < 0.05) total CLA content than either CON- or OIL-fed heifers. Adipose tissue concentration of trans-11 vaccenic acid (TVA) was less (P < 0.05) for CON than OIL or RPCLA, which did not differ (P > 0.05). Percentages of C18:1 trans-10 were least (P < 0.05) in i.m. lipid compared with p.a. and s.c., which did not differ (P > 0.05). Following 60 d of lipid supplementation, heifers fed OIL and RPCLA had lower (P < 0.05) concentrations of oleic acid and total monounsaturated fatty acids (MUFA) compared with CON. The ratio of cis-9, trans-11 CLA:TVA was higher (P < 0.05) for heifers fed 60 vs. 32 d, but did not differ (P > 0.05) between adipose depots. Feeding OIL increased (P < 0.05) adipose concentration of C18:2 fatty acid, whereas feeding RPCLA increased (P < 0.05) total CLA isomers by 22%. Intramuscular lipid contained the lowest (P < 0.05) percentage of cis-9, trans-11 CLA, total CLA, C18:1 cis-9, C18:1 trans-10, and TVA. Total CLA and cis-9, trans-11 CLA isomers were increased (P < 0.05) in p.a. and s.c. adipose depots, whereas i.m. adipose tissue contained increased (P < 0.05) amounts of total PUFA. Results from this study indicate that short-term lipid supplementation to feedlot cattle can increase adipose tissue CLA concentrations, but only marginally (8.3 to 17.5%). Moreover, observed decreases in oleic acid and total MUFA concentrations of adipose tissues from heifers fed rumen-protected CLA or corn oil suggest that lipid supplementation may decrease delta9 desaturase activity in adipose tissues, which in turn would lower the conversion of TVA to cis-9, trans-11 CLA isomer.

Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs. The aim of the present study was to develop and evaluate a novel drug solubilization platform (so-called solid nanodispersion) prepared by a simple co-grinding and solvent-free process. Using structurally diverse model compounds from the Pfizer drug library, including ingliforib, furosemide and celecoxib, we successfully prepared stable solid nanodispersions (SNDs) without the use of solvent or heat. Stable colloidal particles (<350 nm) containing drug, polyvinylpyrrolidone (PVP) K12 and sodium dodecyl sulfate (SDS) in 1:2.75:0.25 ratio were produced after 2 h of co-grinding. The composition and particle size of SNDs were optimized by varying the grinding media size, powder-to-grinding media ratio, milling speed and milling time. The resulting formulations contained crystalline drug and were stable at room temperature for over one month. Greater than 80% of the drug was released from the SND in less than 30 min, with sustained supersaturation over 4 h. Using furosemide (BCS class IV compound) as a model compound, we conducted transport studies with Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK/MDR1), followed by pharmacokinetics studies in rats. Results showed that the SND formulation enhanced the absorptive flux of furosemide by more than 3-fold. In the pharmacokinetics studies, the SND formulation increased C(max) and AUC of furosemide by 36.6 and 43.2 fold respectively, relative to Methocel formulation. Interestingly, physical mixture containing furosemide, PVP K12 and SDS produced a similar level of oral exposure as the SNDs, albeit with a longer T(max) than the SND formulation. The results suggest that PVP K12 and SDS were able to increase the furosemide free fraction available for oral absorption. Low solubility, poor permeability, and high first-pass effect of furosemide may also have produced the effect that small improvements in solubilization resulted in significant potentiation of the oral exposure of the physical mixture. However the use of a physical mixture of drug, polymer and surfactant, to increase drug bioavailability cannot be generalized to all drugs. There are only a few reported cases of such phenomenon. While SNDs may not be the only option to solubilize compounds in every case, SNDs are expected to be applicable to a broader chemical space of pharmaceutical compounds compared to a physical mixture. Ultimately, the formulation scientist will have to exercise judgment in choosing the appropriate formulation strategy for the compound of interest. SNDs represent a significant improvement over current enabling technologies such as nanocrystal and spray-dried dispersion technologies, in that SNDs are simple, do not require solvent or heat, are applicable to a structurally diverse chemical space, and are readily amenable to the development of solid dosage forms.

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. To assess the effectiveness and safety of late initiation of EPO (initiated at eight days after birth or later) in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants. For this update MEDLINE, EMBASE, CINAHL, and The Cochrane Library were searched in March 2012. Additional searches included the Pediatric Academic Societies Annual Meetings from 2000 to 2012 (Abstracts2 View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp). Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. Data collection and analyses were performed in accordance with the methods of the Cochrane Neonatal Review Group. In this 2012 update one new study for inclusion was identified. Twenty-eight studies enrolling 1361 preterm infants in 21 countries were included. Most trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions [typical risk ratio (RR); 0.66 (95% confidence interval (CI); 0.59 to 0.74); typical risk difference (RD) -0.21 (95% CI; -0.26 to -0.16); typical number needed to benefit (NNTB) of 5 (95% CI 4 to 6) 19 studies, 912 infants]. There was moderate heterogeneity for this outcome [for RR (P < 0.00001; I(2) = 74.0%); for RD (P = 0.0006; I(2) = 58.9%)]. Similar results were obtained in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. In this update there was no significant reduction in the total volume (mL/kg) of blood transfused per infant [typical MD -1.61mL/kg (95% CI -5.78 to 2.57); 5 studies, 197 infants] There was high heterogeneity for this outcome (P = 0.00001, I(2) = 92%). There was a significant reduction in the number of transfusions per infant (nine studies enrolling 567 infants); [typical MD -0.78 (-0.97 to -0.59)]. Three studies including 331 patients reported on retinopathy of prematurity (ROP) (all stages), with a typical RR 0.79 (95% CI 0.57 to 1.10) and a typical RD of -0.05 (95% CI -0.13 to 0.02). This outcome was not statistically significantly different between the groups. There was no heterogeneity for this outcome for either RR (P = 0.41; I(2) = 0%) or RD (P = 0.43; I(2) = 0%). Two trials enrolling 212 patients reported on severe ROP (stage 3 or greater). The typical RR was 0.83 (95% CI 0.23 to 2.98) and the typical RD was -0.01 (95% CI -0.06 to 0.05); neither were statistically significant. There was no heterogeneity for this outcome for either RR (P = 0.29; I(2) = 9.3%) or RD (P = 0.36; I(2) = 0%).There were no significant differences in other clinical outcomes. Long-term neurodevelopmental outcomes were not reported. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant but not the total volume of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment.

Body composition in dialysis patients: a functional assessment of bioimpedance using different prediction models. The assessment of body composition (BC) in dialysis patients is of clinical importance given its role in the diagnosis of malnutrition and sarcopenia. Bioimpedance techniques routinely express BC as a 2-compartment (2-C) model distinguishing fat mass (FM) and fat-free mass (FFM), which may be influenced by the hydration of adipose tissue and fluid overload (OH). Recently, the BC monitor was introduced which applies a 3-compartment (3-C) model, distinguishing OH, adipose tissue mass, and lean tissue mass. The aim of this study was to compare BC between the 2-C and 3-C models and assess their relation with markers of functional performance (handgrip strength [HGS] and 4-m walking test), as well as with biochemical markers of nutrition. Forty-seven dialysis patients (30 males and 17 females) (35 hemodialysis, 12 peritoneal dialysis) with a mean age of 64.8 ± 16.5 years were studied. 3-C BC was assessed by BC monitor, whereas the obtained resistivity values were used to calculate FM and FFM according to the Xitron Hydra 4200 formulas, which are based on a 2-C model. FFM (3-C) was 0.99 kg (95% confidence interval [CI], 0.27 to 1.71, P = .008) higher than FFM (2-C). FM (3-C) was 2.43 kg (95% CI, 1.70-3.15, P < .001) lower than FM (2-C). OH was 1.4 ± 1.8 L. OH correlated significantly with ΔFFM (FFM 3-C - FFM 2-C) (r = 0.361; P < .05) and ΔFM (FM 3-C - FM 2-C) (r = 0.387; P = .009). HGS correlated significantly with FFM (2-C) (r = 0.713; P < .001), FFM (3-C) (r = 0.711; P < .001), body cell mass (2-C) (r = 0.733; P < .001), and body cell mass (3-C) (r = 0.767; P < .001). Both physical activity (r = 0.456; P = .004) and HGS (r = 0.488; P = .002), but not BC, were significantly related to walking speed. Significant differences between 2-C and 3-C models were observed, which are partly explained by the presence of OH. OH, which was related to ΔFFM and ΔFM of the 2-C and 3-C models, is therefore an important parameter for the differences in estimation of BC parameters of the 2-C and 3-C models. Both FFM (3-C) and FFM (2-C) were significantly related to HGS. Bioimpedance, HGS, and the 4-m walking test may all be valuable tools in the multidimensional nutritional assessment of both hemodialysis and peritoneal dialysis patients.

The impact of general practice nursing care on patient satisfaction and enablement in Australia: A mixed methods study. The numbers of nurses in general practice in Australia tripled between 2004 and 2012. However, evidence on whether nursing care in general practice improves patient outcomes is scarce. Although patient satisfaction and enablement have been examined extensively as outcomes of general practitioner care, there is little research into these outcomes from nursing care in general practice. The aim of this study was to examine the relationships between specific general practice characteristics and nurse consultation characteristics, and patient satisfaction and enablement METHODS: A mixed methods study examined a cross-section of patients from 21 general practices in the Australian Capital Territory. The Patient Enablement and Satisfaction Survey was distributed to 1665 patients who received nursing care between September 2013 and March 2014. Grounded theory methods were used to analyse interviews with staff and patients from these same practices. An integrated analysis of data from both components was conducted using multilevel mixed effect models. Data from 678 completed patient surveys (response rate=42%) and 48 interviews with 16 nurses, 23 patients and 9 practice managers were analysed. Patients who had longer nurse consultations were more satisfied (OR=2.50, 95% CI: 1.43-4.35) and more enabled (OR=2.55, 95% CI: 1.45-4.50) than those who had shorter consultations. Patients who had continuity of care with the same general practice nurse were more satisfied (OR=2.31, 95% CI: 1.33-4.00) than those who consulted with a nurse they had never met before. Patients who attended practices where nurses worked with broad scopes of practice and high levels of autonomy were more satisfied (OR=1.76, 95% CI: 1.09-2.82) and more enabled (OR=2.56, 95% CI: 1.40-4.68) than patients who attended practices where nurses worked with narrow scopes of practice and low levels of autonomy. Patients who received nursing care for the management of chronic conditions (OR=2.64, 95% CI: 1.32-5.30) were more enabled than those receiving preventive health care. This study provides the first evidence of the importance of continuity of general practice nurse care, adequate time in general practice nurse consultations, and broad scopes of nursing practice and autonomy for patient satisfaction and enablement. The findings of this study provide evidence of the true value of enhanced nursing roles in general practice. They demonstrate that when the vision for improved coordination and multidisciplinary primary health care, including expanded roles of nurses, is implemented, high quality patient outcomes can be achieved.

[Growth modulation in operative treatment of juvenile scoliosis by USS paediatric]. Growth modulation in operative treatment of juvenile scoliosis can be done by USS paediatric instrumentation to control spinal growth in patients of small stature with juvenile scoliosis. The double-rod system has to be distracted every 4-6 months. The system is used in young patients too tall for VEPTR (vertical expandable prosthetic titanium rib) instrumentation. The system with a very low profile allows reduced soft-tissue pressure saving soft tissue from atrophy or the development of pseudocysts above the screws. With this procedure controlled growth with growth modulation of the spine is possible and final spondylodesis can be done later. Congenital, idiopathic and neuromuscular scolioses. Children, who are too tall and big for a VEPTR instrumentation. Cobb angle > 40 degrees or progression > 10 degrees during brace therapy. Adults. Dysplastic pedicles with vertebral anomalies. Arthrogryposis. The patient should be positioned prone, lying flat on the table. Median skin incision with subperiosteal preparation of the paraspinal muscles is done to expose the vertebrae. Next, the pedicle is prepared with a tap, and the USS paediatric pedicle screw system with its very low profile is inserted under fluoroscopic control in anterior-posterior and lateral view. In the upper thoracic spine the authors use screws 4.2 mm in diameter, in the lower thoracic spine 5-mm screws, and in the lumbar spine 6-mm screws. Measurement of the rod length and insertion of the rod are performed. When spinal growth for > 4 years is expected, distraction of the double-rod system by the use of two dominos is done on the concave and convex side of the curve to modulate spinal growth. When spinal growth for 2-4 years is expected, distraction is done just at the concave side of the curve. For correction of the curve, either segmental correction or classic derotation by the Cotrel-Dubousset technique can be performed. Postoperative on block rotation. Mobilization of the patient on day 2 after surgery with a rigid brace. Individual rigid custom-made plaster brace for 3-8 months. During postoperative recovery, muscular efforts should be reduced for 6 months after first implantation. Distraction of the system is necessary every 4-6 months to modulate spinal growth. From 2004 to 2008, 26 patients (15 girls, eleven boys) with a mean age of 9 years (6-13 years) were treated using this technique. Follow-up examinations were performed 3, 6, 12, and 24 months after surgery. The mean follow-up was 26 months (6-40 months). At first implantation of the scoliosis instrumentation, just little scoliosis correction was done depending on the quality of bone. At every distraction, an average correction of the Cobb angle of 5 degrees was reached. The Cobb angle could be reduced from 71 degrees to 34 degrees on average. Fusion rate in the cranial and caudal part was evaluated by X-ray. 5-mm rods have a reduced stiffness of 50% compared to USS 6-mm rods. Average spinal growth was about 5.6 cm (4.0-8.1 cm) over a period of 3.2 +/- 1.2 years. During 2-year follow-up, rod or pedicle screw breakage, dislocation, or loosening of the Cobb angle did not occur.

Genetics and imaging to assess oocyte and preimplantation embryo health. Two major criteria are currently used in human assisted reproductive technologies (ART) to evaluate oocyte and preimplantation embryo health: (1) rate of preimplantation embryonic development; and (2) overall morphology. A major gene that regulates the rate of preimplantation development is the preimplantation embryo development (Ped) gene, discovered in our laboratory. In mice, presence of the Ped gene product, Qa-2 protein, results in a fast rate of preimplantation embryonic development, compared with a slow rate of preimplantation embryonic development for embryos that are lacking Qa-2 protein. Moreover, mice that express Qa-2 protein have an overall reproductive advantage that extends beyond the preimplantation period, including higher survival to birth, higher birthweight, and higher survival to weaning. Data are presented that suggest that Qa-2 increases the rate of development of early embryos by acting as a cell-signalling molecule and that phosphatidylinositol-32 kinase is involved in the cell-signalling pathway. The most likely human homologue of Qa-2 has recently been identified as human leukocyte antigen (HLA)-G. Data are presented which show that HLA-G, like Qa-2, is located in lipid rafts, implying that HLA-G also acts as a signalling molecule. In order to better evaluate the second criterion used in ART (i.e. overall morphology), a unique and innovative imaging microscope has been constructed, the Keck 3-D fusion microscope (Keck 3DFM). The Keck 3DFM combines five different microscopic modes into a single platform, allowing multi-modal imaging of the specimen. One of the modes, the quadrature tomographic microscope (QTM), creates digital images of non-stained transparent cells by measuring changes in the index of refraction. Quadrature tomographic microscope images of oocytes and preimplantation mouse embryos are presented for the first time. The digital information from the QTM images should allow the number of cells in a preimplantation embryo to be counted non-invasively. The Keck 3DFM is also being used to assess mitochondrial distribution in mouse oocytes and embryos by using the k-means clustering algorithm. Both the number of cells in preimplantation embryos and mitochondrial distribution are related to oocyte and embryo health. New imaging data obtained from the Keck 3DFM, combined with genetic and biochemical approaches, have the promise of being able to distinguish healthy from unhealthy oocytes and embryos in a non-invasive manner. The goal is to apply the information from our mouse model system to the clinic in order to identify one and only one healthy embryo for transfer back to the mother undergoing an ART procedure. This approach has the potential to increase the success rate of ART and to decrease the high, and undesirable, multiple birth rate presently associated with ART.

Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.

Influence of topiramate in the regulation of energy balance. Topiramate (TPM) is a novel neurotherapeutic agent currently indicated for the treatment of epilepsy and undergoing development for other central nervous system indications including neuropathic pain, bipolar disorder, and migraine prophylaxis. TPM is synthesized from D-fructose and contains a sulfamate moiety that is essential for its pharmacologic activity. TPM has been observed to significantly reduce body weight in patients treated for seizure, which has prompted the realization of preclinical studies to characterize the effects of TPM in the regulation of energy balance. Studies carried out in various strains of rats have provided good evidence for the ability of TPM to blunt energy deposition. Body composition analyses from rat trials have demonstrated that TPM inhibits fat deposition while reducing the activity of lipoprotein lipase (LPL) in various white adipose tissue depots. High doses of TPM (likely above the therapeutic dose range) have also been observed to reduce protein gain without catabolic effects. Although TPM cannot be described as a potent anorectic agent, it seems to have the ability to reduce food intake; significant reductions in food intake have been observed in female obese (fa/fa) Zucker rats and in female Wistar rats. TPM can also reduce energy deposition in the absence of alterations in food intake. This effect has been clearly emphasized in female lean (Fa/?) Zucker rats. In female Sprague-Dawley rats, TPM also increased energy expenditure and it has been observed to increase LPL activity in brown adipose tissue, which could indicate that TPM has the ability to enhance regulatory thermogenesis. In addition, TPM stimulates LPL activity in skeletal muscles, further emphasizing its potential to promote substrate oxidation. The mechanisms whereby TPM affects the regulation of energy balance have yet to be understood. TPM represents an antiepileptic drug (AED) with complex biochemical/pharmacologic actions. Its negative effects on energy deposition cannot be readily predicted from these actions, as AEDs are generally expected to stimulate body weight gain. Recent data, obtained from investigations aimed at assessing the effects of TPM on neuropeptidergic systems involved in the regulation of energy balance, have failed to demonstrate any significant effects of TPM on the neuropeptide Y and proopiomelanocortin systems. In conclusion, it is clear that TPM can reduce fat deposition by either reducing food intake or stimulating energy expenditure. The mechanisms whereby an AED such as TPM controls food intake and energy expenditure remains to be delineated. Copyright1999 ASCRS and ESCRS

Novel approaches in melanoma prevention and therapy. The incidence of cutaneous melanoma has risen at a rate significantly higher than that for other malignancies. This increase persists despite efforts to educate the public about the dangers of excess exposure to UV radiation from both the sun and tanning beds. Melanoma affects a relatively younger population and is notorious for its propensity to metastasize and for its poor response to current therapeutic regimens. These factors make prevention an integral component to the goal of decreasing melanoma-related mortality. Transformation of melanocytes into malignant melanoma involves the interplay between genetic factors, UV exposure, and the tumor microenvironment. The roles of UV radiation in the etiology of melanoma are mediated by both direct damage of DNA through formation of photoproducts and production of reactive oxygen species (ROS). Many of the promising antioxidant agents under development for the prevention of melanoma are derived from foodstuffs. B-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases that plays a role in regulating the MAP kinase/ERKs signaling pathway. About 50 % of melanomas harbor activating BRAF mutations. BRAF mutations are found in 59 % of the melanomas arising in skin with intermittent sun exposure, such as trunk and arms, as compared with only 23 % of the acral melanomas, 11 % of mucosal melanomas, and 0 % of uveal melanomas. Two new agents, ipilimumab and vemurafenib, have been shown to improve outcome of advanced melanoma as presented at the plenary session of the 2011 annual meeting of the American Society of Clinical Oncology. Vemurafenib is the first personalized compound which demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in metastatic melanoma harboring the BRAFV600 mutation and represents the first drug of a class that exerts its anti-proliferative activity through inhibition of a highly specific molecular target. GSK2118436 (dabrafenib), the second BRAF inhibitor, in phase I and II trial obtained similar results to vemurafenib. A phase III trial is now ongoing. Taken together, the early clinical development of vemurafenib and dabrafenib clearly confirms that BRAF inhibitors can halt or reverse disease in patients with melanomas carrying this mutation, improving survival times compared with historically standard treatments (chemotherapy and interleukin-2). The clinical development of other new BRAF inhibitors such as RAF265 and LGX818 is now ongoing. Combination strategies of BRAF inhibitors with ipilimumab, an anti-CTLA-4 antibody, and/or MEK inhibitors or metformin are now under investigation in clinical trials.

Cost-Effectiveness Data Regarding Spinal Cord Stimulation for Low Back Pain. Review of published literature pertaining to spinal cord stimulation (SCS) cost data analysis. To acquire, organize, and succinctly summarize the available literature regarding the costs associated with, and the cost-effectiveness of, SCS. Chronic back and limb pain is a pervasive complaint in modern society, with estimated annual costs of medical care greater than $100 billion. The traditional standard medical management with or without intermittent surgical decompression/fusion has been plagued by high costs and inconsistent results, leading to poor patient satisfaction and functional outcome, and questions from policy makers regarding use of limited healthcare resources. Neuromodulation techniques, including SCS have recently become more common in the treatment of chronic back/leg pain, with clinical studies showing a high degree of efficacy in alleviating otherwise intractable pain. Given the relatively high upfront costs associated with the hardware and implantation, policy makers have, however, questioned their use in the framework of cost-containment and resource utilization. We reviewed the available literature summarizing cost data of SCS in chronic back and limb pain, as an understanding of these data will be vital to justify continued payment for this expensive, but often very effective, treatment modality. We performed a PubMed literature search utilizing the following terms: "spinal cord stimulation," "SCS," "financial," "cost," "cost-effectiveness," and "cost-utility." All studies published in English and containing complete or partial cost evaluations of SCS for chronic back and limb pain were included. The search revealed 21 studies that evaluated cost data, with or without outcomes analysis and cost-utility analysis, for patients with chronic back and limb pain. The overwhelming majority of data presented shows that SCS is not only an effective treatment option for these patients, but also represents cost savings and efficient use of healthcare resources relative to current standards of care. Although not all studies performed cost-utility analyses, those that did tended to show SCS falling well within accepted thresholds of "willingness-to-pay" on the part of third-party payers. That being said, the articles included in this review were almost all small, retrospective, single-institution studies. In addition, many of them relied on modeling for their analyses, and published literature values for cost and/or outcomes data rather than prospectively collected patient data. Although the data presented in this review are encouraging, it should serve as a foundation for a thorough, prospective, cost-utility analysis of SCS in chronic back and limb pain so that the role of this important treatment modality may be cemented in the treatment paradigm for these patients without questions from third-party payers. The large majority of data covering costs of SCS argue in favor of the cost-effectiveness of this treatment modality for chronic neuropathic pain, especially in comparison to reoperation and medical management. Although most of the higher-quality evidence is relatively short-term, clinical experience with the durability of treatment benefit of SCS in these patients is promising. Given the pushback regarding high upfront costs of implantation, longer-term, prospective, randomized studies evaluating this topic will be important to help maintain third-party payer reimbursements for SCS. 5.

Changes in thyroid hormone metabolism in exertional heat stroke with or without acute renal failure. The effects of exertional heat stroke (ExHS), with or without acute renal failure (ARF), on thyroid hormone metabolism were investigated. Eighteen ExHS patients were recruited and divided into two groups based on the presence or absence of ARF. Eleven age-matched healthy subjects served as a control group. Serum values of T3, T4, TSH, free T4 (FT4), rT3, and sulfated T3 (T3S) were measured in these groups during the acute and recovery stages of ExHS. Serum T3, T4, and FT4 levels were reduced, with reciprocal increases in rT3 and T3S levels as the severity of ExHS increased. The following mean levels of thyroid hormones were found (controls vs. ExHS without ARF vs. with ARF): T3, 1514 vs. 1164 vs. 393 pmol/L (P < 0.05 each); T4, 97 vs. 79 vs. 49 nmol/L (P = NS and P < 0.05, respectively); FT4, 20.5 vs. 19.5 vs. 19.0 pmol/L (P = NS each); rT3, 371 vs. 617 vs. 805 pmol/L (P < 0.05 and P = NS, respectively); and T3S, 30.1 vs. 34.2 vs. 71.1 pmol/L (P = NS and P < 0.05, respectively). The serum TSH levels were not significantly different among the three groups. Significantly negative correlations were found between serum creatinine and T3 (r = -0.75; P < 0.001) and T4 levels (r = -0.65; P < 0.001), whereas no relationship was noted between serum creatinine and rT3 values (r = 0.11; P < 0.05). In contrast, a correlation was observed between serum glutamic pyruvic transaminase and rT3 (r = 0.45; P < 0.01). Thyroid function tests returned to normal after patients recovered. In conclusion, our results show that patients suffering from ExHS, with or without ARF, displayed altered serum thyroid function in proportion to the severity of their condition. No significant changes in serum levels of rT3 were observed between the two groups, whereas a positive relationship was observed between serum rT3 and serum glutamic pyruvic transaminase values, suggesting that the changes in serum rT3 levels were more dependent on extrarenal illness than on renal disease per se. The moderate increase in serum T3S levels found in patients suffering from both ExHS and ARF may represent a decrease in tissue 5'-monodeiodinase activity as found in other nonthyroidal illnesses. A return of serum thyroid function tests to normal values after recovery from ExHS suggests that the low T3 state may play a protective role to prevent undesirable catabolic effects. Replacement therapy is thus not recommended.

Violence in mental disorders and community sample: an evolutionary model related with dominance in social relationships. The major risk determinants of violence are to be young and male, to have low socioeconomic status and suffering substance abuse. This is true whether it occurs in the context of a concurrent mental illness or not; i.e., mental disorders are neither necessary, nor sufficient causes for violence. Intense motivation is a facilitating factor for violence in clinical and non clinical samples. This explains why 'normal' people, are implicated in planned violence at higher rates than mentally ill (e.g. in criminal acts against property). However mentally ill patients are more easily implicated in impulsive violence or in violence without obvious cause due to veiled motivation fuelled by unidentified symptoms. Subjective or real awareness of competitive disadvantage increases motivation for violence (e.g. paranoid, narcissistic symptoms, etc.). Many psychiatric disorders as antisocial disorder, borderline, schizophrenia, have most of the factors that facilitate the appearance of violence. Antisocial disorder is a good model to study determinants of violence in normal samples as it is present in young males that do not have any psychotic symptom, have stable symptomatology, self control under scrutiny, and their motivations are similar to normal samples. Our evolutionary model suggests that there is a non random association of genetic factors (genes, pseudogenes, promoting areas, etc.), that is, a genetic cluster (cluster DO), whose phylogenetic function is to motivate to be the dominant in social relationships. To be the dominant is a major psychological feature present in many social groups of animals, included primates. DO cluster have sense from an evolutionary viewpoint: when expressed in no pathological way it increases inclusive fitness (transmission of the genes of a person genotype whether by oneself or by relatives reproduction). Features of cluster DO in humans are expressed differently according to sex, age, moral education, level of intelligence, etc. Cluster DO has higher phenotypical expression in males and young people. Primary antisocial personality disorder and other related disorders (cluster B personality disorders, disocial, defiant disorder, etc.), are a pathological manifestation of this cluster DO. Some other genetic clusters that causes the genetic liability to some disorders (e.g. attention deficit disorder) are non random associated with cluster DO, thus explaining clinical comorbidity. According to our model, motivation for dominance usually prevails over motivation for material benefit or antinormative behaviour, this explains some incongruent behaviour in antisocial patients not elucidated by other models. Along with the primary expressed feature of dominance of cluster DO there are other secondary features that have been identified by psychobiological studies: novelty seeking, intolerance for frustration, impulsiveness, fearless, aggressiveness, higher threshold for activation of the sympathetic system, lack of empathy, egoism, non acceptance of rules, defiant and rebellious behaviour, manipulation in social interactions, selfishness and deficits in altruism or in social co-operation.

Three Rs potential in the development and quality control of pharmaceuticals. The intention of a pharmaceutical company is to develop new, efficient products quick and with a minimum of costs. Compared to in vitro methods, animal experiments in general consume much more time and resources (costs as well as time to the market) than in vitro methods. Therefore, the use of whole animal models depends primarily on the judgement of their efficacy in the screening process, but the willingness to incorporate in vitro methods in general is high and is furthered by new developments such as high-throughput screening. Nevertheless, in vitro tests might be politically promoted by increasing their costs (quality controls, requested housing conditions) and duration (time to start of an experiment, sequential performance). Which models are favoured by industry to include them in a screening process: They have to be based on our most recent understanding of the respective disease, well characterised to allow interpretation of results and require only limited development time. All these aspects argue in favour of collaboration between industry and academia, where our understanding of pathophysiology is generated and mechanism based models are developed and characterised. However, technology transfer towards industry represents a bottle-neck for industrial use of these new in vitro models. New platforms to promote this transfer should be developed in order to bring together developer and user of novel in vitro systems and promote demonstration projects. Financing of such collaborations is not the key problem (the development of a single drug makes up to 500 million $) but the dilemma of publication of results: The development advantage compared to competitors depends on the exclusive use of novel models. The protection of intellectual property rights and the public interest in spreading alternatives to animal experiments must be balanced, e.g. by delayed but indispensable publication or advantages for companies employing alternatives in the regulatory approval process for a new drug. Quality control of therapeutic drugs (except hormones and blood products) represents a minor field of animal consumption with the exception of pyrogenicity testing. Despite considerable progress due to the introduction of the Limulus assay which represents the most successful in vitro alternative in use so far. However, some limitations of this in vitro test might be overcome in the near future by the currently validated human whole blood assay. During the last few years considerable progress has been made in the replacement (and deletion) of animal tests required for the potency and safety testing of hormones. This has been made possible by biotechnical production methods, by better-defined products, and because physico-chemical methods can be used for the potency testing of these products. In general, the better defined a drug is, the easier chemical, physical or in vitro techniques can be used for batch control. Control authorities should therefore urge the use of highly standardised components.

Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. Whether concomitant therapy is superior to bismuth quadruple therapy or 14-day triple therapy for the first-line treatment of Helicobacter pylori infection remains poorly understood. We aimed to compare the efficacy and safety of 10-day concomitant therapy, 10-day bismuth quadruple therapy, and 14-day triple therapy in the first-line treatment of H pylori. In this multicentre, open-label, randomised trial, we recruited adult patients (aged >20 years) with H pylori infection from nine medical centres in Taiwan. Patients who had at least two positive tests from the rapid urease test, histology, culture, or serology or who had a single positive 13C-urea breath test for gastric cancer screening were eligible for enrolment. Patients were randomly assigned (1:1:1) to either concomitant therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily) for 10 days; bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days; or triple therapy (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily) for 14 days. A computer-generated permuted block randomisation sequence with a block size of 6 was used for randomisation, and the sequence was concealed in an opaque envelope until the intervention was assigned. Investigators were masked to treatment allocation. The primary outcome was the eradication frequency of H pylori with first-line therapy assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01906879. Between July 17, 2013, and April 20, 2016, 5454 patients were screened for eligibility. Of these, 1620 patients were randomly assigned in this study. The eradication frequencies were 90·4% (488/540 [95% CI 87·6-92·6]) for 10-day bismuth quadruple therapy, 85·9% (464/540 [82·7-88·6]) for 10-day concomitant therapy, and 83·7% (452/540 [80·4-86·6]) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14-day triple therapy (difference 6·7% [95% CI 2·7-10·7, p=0·001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy. The frequency of adverse events was 67% (358/533) in patients treated with 10-day bismuth quadruple therapy, 58% (309/535) in patients treated with 10-day concomitant therapy, and 47% (252/535) in patients treated with 14-day triple therapy. Bismuth quadruple therapy is preferable to 14-day triple therapy in the first-line treatment in the face of rising prevalence of clarithromycin resistance. Concomitant therapy given for 10 days might not be optimum and a longer treatment length should be considered. National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.

Effects of some 7-arylidene and 7-heteroarylidene morphinan-6-ones on the antinociceptive activity of [D-Pen2, D-Pen5]enkephalin and [D-Ala2, Glu4]deltorphin II and on multiple opioid receptors. The in vivo and functional effects of several 7-arylidene and 7-heteroarylidene morphinan-6-ones were determined at the mu-, delta-, and kappa-opioid receptors using the guinea pig brain membranes, guinea pig ileum (GPI), and mouse vas deferens (MVD). In vivo effects included the antagonism by these compounds given subcutaneously on the antinociceptive actions of intracerebroventricularly injected [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2, Glu4]deltorphin II (deltorphin II), the highly selective putative delta 1- and delta 2-opioid receptor agonists. Finally, the partition coefficients of these compounds were estimated (CLOGP) and determined experimentally at pH 7.4 in the 1-octanol/water system. Compared with E-7-benzylidenenaltrexone (BNTX), most compounds except for E-7-(4-chlorobenzylidene)naltrexone, were more potent at delta-opioid receptors than at the mu-opioid receptor, whereas, in comparison to the kappa-opioid receptor, the activities of the E-7-arylidene or E-7-heteroarylidene naltrexone derivatives at the delta-receptor were in the following order, where the 7-substituents were: 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- > 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene > 4-chlorobenzylidene. In the MVD preparation, the potencies at the delta-opioid receptor, in comparison to BNTX, were in the following order, where the 7-substituents were: benzylidene = 1-methyl-2-imidazolylmethylene- > 4-fluorobenzylidene- = 3-pyridylmethylene- = 4-pyridylmethylene-. All compounds antagonized delta 1, and delta 2-opioid receptor agonist-induced analgesia. The antagonist potencies at the delta 1-opioid receptor were in the following order, where the 7-substituents were: benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- approximately 4-pyridylmethylene-, whereas at the delta 2-opioid receptor, the order was benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- > 4-pyridylmethylene. In general, all compounds exhibited greater potency at the delta 2- than delta 1-opioid receptor. The computed partition coefficients were, as expected, greater than the apparent log P values, which were determined experimentally. Generally, the lipophilicity values in decreasing order were: 4-chlorobenzylidene- > 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- = 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene-. In general, the benzylidene and 4-pyridylmethylene derivatives, which have medium lipophilicities, were equally effective at the delta 1- and delta 2-receptors; the 3-pyridylmethylene and 1-methyl-2-imidazolylmethylene derivatives had lower lipophilicities and were more selective for the delta 2- than delta 1-receptor; the 4-chlorobenzylidene and 4-fluorobenzylidene derivatives were more lipophilic and had intermediate activity. The plot of pED50 values for the in vivo tests for the delta 1- and delta 2-receptors showed that the two receptors are not independent with respect to this series of compounds.

Immediate 1-month efficacy of desmopressin and anticholinergic combination therapy versus desmopressin monotherapy in the treatment of pediatric enuresis: A meta-analysis. Several studies have proposed the combination of desmopressin and anticholinergic as a treatment regimen to address the pathophysiology of polyuria and bladder dysfunction in pediatric enuresis. However, the available literature is inconsistent with regards to the immediate 1-month efficiency of the combination therapy in the treatment for pediatric enuresis. The aim was to assess the immediate 1-month efficacy and safety of desmopressin and anticholinergic agent combination therapy versus desmopressin monotherapy in the treatment of pediatric enuresis using meta-analysis of randomized controlled trials (RCTs). Systematic literature acquisition was carried out on electronic medical databases up to April 2015. RCTs relevant to the topic were critically appraised. Dichotomous data of the 1-month post-treatment response rate (defined as ≥90% reduction of wet nights) were extracted for calculation of the risk ratio (RR) and 95% confidence interval (CI). The Mantel-Haenszel method with the random effects model was used to pool effect estimates. Inter-study heterogeneity and publication bias were assessed. Subgroup analysis was done for the desmopressin treatment-naive versus treatment-resistant groups: PROSPERO (CRD42015017922). Four RCTs of good methodological quality without heterogeneity were included for meta-analysis. The pooled effect estimates showed that combination therapy was associated with a significantly better immediate 1-month response rate than desmopressin monotherapy. Subgroup analysis showed a greater immediate 1-month response rate among desmopressin-resistant patients than treatment-naive patients. No severe adverse events were noted among combination therapy treated groups. The limitation of the current meta-analyses is the small sample size, albeit with high-quality studies pooled for effect estimation. Despite the limitation, the study results were able to consistently illustrate a large treatment effect of combination therapy among desmopressin treatment-resistant patients. It was consistent with the literature review of retrospective and non-comparative studies by Alloussi et al. (2011), who summarized a similar impressive treatment outcome. However, due to the low level of evidence available at the time of their study, only a grade B-C recommendation was given to combination therapy as an approach for second-line treatment. This study also summarized that combination therapy was well tolerated and similar to desmopressin monotherapy. This study was able to summarize the immediate 1-month efficacy of combination therapy compared with desmopressin monotherapy in the treatment of pediatric enuresis. For both treatment-naive and desmopressin-resistant pediatric enuresis, combination therapy of desmopressin with an anticholinergic agent is well tolerated and resulted in a significantly better immediate 1-month response rate than desmopressin monotherapy.

Thermal-induced residual stresses affect the lifetime of zirconia-veneer crowns. The purposes of this study were to investigate the effects of thermal residual stresses on the reliability and lifetime of zirconia-veneer crowns. One hundred and twenty eight second upper premolar zirconia-veneer crowns were manufactured for testing the initial strength (n=64) and under cyclic fatigue (n=64). Zirconia copings (YZ Cubes, VITA Zahnfabrik, CTE: alphac=10.5 ppm/°C) were milled using a Cerec3 InLab (Sirona) machine and sintered to a final thickness of 0.7 mm. Sixty-four copings were sandblasted with 105 μm alumina particles (15 s, 3 cm distance, 45° angle, 0.4 MPa pressure) in order to trigger a tetragonalmonoclinic transformation and to produce a rough surface. The copings were veneered using two different porcelains (VM9, VITA Zahnfabrik, CTE: alphaVM9=9.1 ppm/°C, Lava Ceram, 3M ESPE, CTE: alphaLava=10.2 ppm/°C) so to result in crowns with either high thermal mismatch (+1.4 ppm/°C with VM9) and low thermal mismatch (+0.3 ppm/°C with Lava Ceram). The porcelains were applied by the same operator and fired (VITA Vacumat 4000) according to the firing schedules defined by the manufacturers to a final thickness of 1.4mm (total crown thickness=2.1mm, core/veneer ratio=0.5). After the last glaze firing the crowns were cooled following a fast (600°C/min) or a slow (30°C/min) cooling protocol. The glazed crowns were submitted to a sliding-motion (0.7 mm lateral movement) cyclic fatigue in a chewing simulator (SD Mechatronik) under 20 kg (~200 N load) weight until failure (chipping) (n=16). The other half of the crowns were subjected to a compressive loading test in an universal testing machine (Instron model 4240) until failure at a cross-head speed of 0.75 mm/min (n=16). The failure probability for initial strength and cyclic fatigue was performed using a Weibull distribution approach at a scale factor of n=16. The compressive strength test showed a low sensitivity to detect reliability variations regarding thermal stresses created within the veneer layer of tested crowns. For cyclic fatigue, slow cooling resulted in statistically higher cycles to failure only for the crowns that presented a high thermal mismatch between core and veneer (VM9 group). Comparisons between veneers with high or low thermal mismatches showed statistically higher sigma0 for Lava Ceram-veneered crowns only when the groups were fast-cooled. Minimizing the thermal residual stresses within the veneer through the use of a veneer with a closer CTE to the zirconia delays the failure of zirconia-veneer crowns. Slow-cooling increases the lifetime of crowns presenting large differences in CTE between the zirconia core and the veneering porcelain.

Costs and effects of long-acting risperidone compared with oral atypical and conventional depot formulations in Germany. Schizophrenia is one of the most expensive psychiatric conditions because of high direct and indirect costs associated with the nature of the illness, its resistance to treatment and the consequences of relapse. Long-acting risperidone is a new formulation of an atypical antipsychotic drug that also offers the improvements in compliance associated with haloperidol depot. The aim of this simulation study was to compare the benefits and costs of three pharmacological treatment strategies comprising first-line treatment with long-acting risperidone injection, a haloperidol depot or an oral atypical antipsychotic agent, over a 5-year period in Germany. A discrete event simulation model was developed to compare three treatment scenarios from the perspective of major third-party payers (sickness funds and social security 'Sozialversicherung'). The scenarios comprised first-line treatment with haloperidol depot (scenario 1), long-acting risperidone (scenario 2) and oral olanzapine (scenario 3). Switches to second or third-line options were allowed when side-effects occurred or a patient suffered more than a fixed number of relapses. The model accounted for fixed patient characteristics, and on the basis of these, simulated patient histories according to several time-dependent variables. The time horizon for this model was limited to 5 years, and in accordance with German guidelines, costs and effects were discounted by between 3 and 10%. Direct costs included medication, type of physician visits and treatment location. Indirect costs were not included. Information on treatment alternatives, transition probabilities, model structure and healthcare utilization were derived from the literature and an expert panel. Outcomes were expressed in terms of the number and duration of psychotic episodes, cumulative symptom scores, costs, and quality-adjusted life-years (QALY). Univariate sensitivity analyses were carried out, as were subgroup analyses based on disease severity and for patients at high risk of being non-compliant. The long-acting risperidone strategy was calculated to avoid 0.23 and 0.33 relapses per patient, decrease the cumulative symptom score by 25 and 33 points, and decrease the costs by 2017 Euro and 6096 Euro per patient (1608 Euro and 5422 Euro discounted), compared with the haloperidol depot and olanzapine strategies, respectively, over a 5-year period (year of costing 2004). Among high-risk non-compliant patients, long-acting risperidone was estimated to avoid 0.23 and 0.47 relapses and save 4822 Euro and 10,646 Euro per patient (4107 Euro and 9490 Euro discounted), compared with the haloperidol depot and olanzapine strategies, respectively. Sensitivity analyses showed that the results were robust and mainly sensitive to changes in the reported relative effectiveness of atypical and conventional formulations for preventing symptom recurrence, and in the relative compliance with oral and long-acting formulations. In this model, long-acting risperidone is a dominant strategy compared with a haloperidol depot or oral atypical antipsychotic agent, being both more effective and less costly over a 5-year period. Results for long-acting risperidone are even more favourable among patients at high risk of being noncompliant or with more severe disease.

[Budd-Chiari syndrome in children and adolescents: therapeutic radiological intervention]. Due to its minimal-invasive approach, endovascular procedure had replaced surgery in treating Budd-Chiari syndrome (BCS). The interventional therapy was a safe and effective treatment in adults with BCS and the cure rate was high. However Budd-Chiari syndrome in children and adolescents is rare. Published literature on interventional procedure for Budd-Chiari syndrome in children and adolescents is scarce. The aim of the study was to present results of percutaneous transluminal angioplasty (PTA) and stents placement in children and adolescents with BCS and to evaluate the efficacy and safety in these patients of this approach. Twenty-five patients [16 boys and 9 girls; average age of (14.5 ± 3.4) years old; age ranged from 5 to 17 years] with Budd-Chiari syndrome who were hospitalized from December 1990 to August 2012 were presented. All of them were diagnosed by color Doppler ultrasound scan while 12 of them had magnetic resonance venography (MRV) scan. All of the patients had undergone angiographic examination. Four cases with membranous obstruction of the inferior vena cava (IVC) were treated with PTA. One case with segmental block of IVC was treated with PTA and stent placement. Five cases with membranous obstruction of IVC and hepatic vein (/and accessory hepatic vein) were treated with PTA. Among 8 cases with membranous obstruction of hepatic veins, 6 cases were treated with PTA and the others with PTA and stent placement. Among 4 cases with blocks of 3 hepatic veins (HVs), one was treated with PTA, one with PTA plus catheter thrombolysis plus PTA, one with PTA and stent placement and the other one was unsuccessful. Three cases with obstruction of HV and accessory HV (AHV) were treated with PTA. Totally, 24 patients were treated with interventional approach and followed up. The procedure was successful in 24 patients. The involved veins (hepatic veins or IVC) were patented after interventional procedure. The pressure of hepatic vein was (42.1 ± 4.2) cm H2O (37-50 cm H2O) (1 cm H2O = 0.098 kPa) before the interventional therapy, while it was (17.3 ± 3.3) cm H2O (14-26 cm H2O) after it. The pressure of IVC was (30.6 ± 2.9) cm H2O (26-36 cm H2O) before the interventional therapy, while it was (18.8 ± 4.2) cm H2O (15-26 cm H2O) after it. The symptoms and signs vanished instantly after interventional procedure. There were no procedure-related complications. The rate of overall initial cure was 96%. The patients were followed up for a mean of 25.8 months (range 6 months to 8 years). Seven cases developed restenosis after first procedure. Five of them were treated with PTA, one with PTA plus catheter thrombolysis plus PTA, one with PTA and stent placement. All of the involved veins were patented again. Clinical symptoms were relieved. There were no procedure-related complications as well. The interventional procedure in children and adolescents with BCS is the same as in adults. Radiological therapeutic intervention is efficacious and safe in children and adolescents with BCS.

[Applicative aspects of liquid-based cytology in cervical cancer screening]. The quality of cytological services is the very heart of the prevention of cervical pathologies. Indeed, various studies have demonstrated that inadequate sampling, mistakes made in the organisational and management methods of the screening programme, and incorrect diagnoses result in unnecessarily high incidence and mortality rates. The aim of this work is to compare the effectiveness of two different methods, i.e. a conventional smear test and a liquid based ThinPrep (TP) test. Said methods were tested on a sample 453 cases diagnosed as being "Atypical Squamous Cells of Undetermined Significance"/"Atypical Glandular Cells of Undetermined Significance" according to the 1991 Bethesda System. All the women with an "Atypical Squamous Cells of Undetermined Significance "/"Atypical Glandular Cells of Undetermined Significance" cytological diagnosis were called back within 3 months for a ThinPrep test, as part of the Level 2 diagnostic controls of a cervical cancer screening programme. Of the initial diagnoses of "Atypical Squamous Cells of Undetermined Significance"/"Atypical Glandular Cells of Undetermined Significance" with a conventional smear test, 124 cases (27.4%) were classified as being adequate, while 329 (72.6%) were satisfactory, although they did have limited indicators of quality. Upon repetition of the cytology with a ThinPrep test, 322 cases (71.1%) were found to be adequate, 129 (28.4%) "suboptimal" and 2 inadequate (p < 0.0001). The main reasons for insufficient results in conventional smear tests are: bad preservation (40.2%), the presence of granulocytes (36.4%), intense phlogosis (12.1%) and erythrocytes (5.5%). In liquid based smear tests, the main indicator of quality is the absence of endocervical glandular cells (56.7%). As for the cytological diagnosis, the use of ThinPrep supplied the following results: of the 453 cases diagnosed initially as being "Atypical Squamous Cells of Undetermined Significance"/"Atypical Glandular Cells of Undetermined Significance", 371 (84.1%) were negative, 54 (11.9%) "Atypical Squamous Cells of Undetermined Significance "/"Atypical Glandular Cells of Undetermined Significance" and 18 (4%) L-SIL (p < 0.0001). Histological follow-up of the 18 cases with L-SIL confirmed the presence of a dysplastic lesion in 8 out of 12 cases (66.7%); in 4 cases there was no consistency between the cytological and histological diagnoses, and in 6 patients no biopsy had been taken. The preliminary experience of this study, although indeed carried out on a limited number of cases, appears to show that suitable training for the collection of samples in a liquid solution could improve the adequacy of the sample and thus the precision of the cytological diagnosis.

A comparison of 60, 70, and 90 kDa stress protein expression in normal rat NRK-52 and human HK-2 kidney cell lines following in vitro exposure to arsenite and cadmium alone or in combination. Arsenite and cadmium are two potent nephrotoxicants and common Superfund site elements. These elements are included among the stress protein inducers, but information regarding relationships between toxicity produced by combinations of these agents to the stress protein response is lacking. In this study, the immortalized cell lines normal rat kidney NRK-52E and human kidney HK-2 were exposed in vitro to arsenite (As(3+)), cadmium (Cd(2+)), or to equimolar As(3+) plus Cd(2+) mixture combinations for 3 and 5 h over a concentration range of 0.1-100 microM. After a 12-h recovery period, cultured cells were then evaluated for expression of the 60, 70, and 90 kDa major stress protein families. Results indicated that expression of stress proteins varied depending on the species of kidney cells exposed, the exposure concentrations, and the length of exposure to each element on an individual basis and for combined mixtures. For the HK-2 kidney cell line, increased levels of the 70 kDa stress protein was observed for single and combined element exposures whereas there was no change or a decrease of stress proteins 60 and 90 kDa. Increased 70 kDa expression was observed for 10-microM doses of single elements and for a lower dose of 1 microM of the As plus Cd mixture at 3- and 5-h exposures. NRK-52 kidney cells exposed to equivalent doses of As(3+) and Cd(2+) alone or in combination showed increased levels of all stress proteins 60, 70, and 90 kDa. This increase was seen for 10 microM of the As plus Cd mixture at 3 h whereas for single element exposures, increased stress protein levels were generally observed for the 100-microM doses. At 5 h- exposure, 60 and 90 kDa levels increased for 10 microM of Cd(2+) and 60 kDa levels increased for 1 microM of As(3+). However, exposures to 10 microM of the As plus Cd mixture decreased 60 kDa protein expression to control levels at 5 h. For both kidney cell lines, there was a decrease in the stress protein expression levels for all three stress protein families for 100-microM doses of the mixture combination for 3- and 5-h exposures. These data indicate a dose- and combination-related correlation between depression of the stress protein response and the onset of overt cellular toxicity and/or cell death. The threshold for these changes was cell line specific.

Stocking density, milking duration, and lying times of lactating cows on Canadian freestall dairy farms. Lying time is an important measure of cow comfort, and the lying behavior of dairy cattle can now be recorded automatically with the use of accelerometers. To assess the effect that stall stocking density and the time that cows spend away from the home pen being milked has on the lying behavior of Holstein cattle, a total of 111 commercial freestall dairy farms were visited in Canada. Accelerometers were used to automatically record the lying behavior of 40 focal cows per farm. Total duration of lying, lying bout frequency, and the mean duration of lying bouts were calculated. Pen population was the total number of cows in the pen. To calculate stall stocking density (%) the number of cows in the pen and the number of useable stalls were counted and multiplied by 100, and the length × width of the pen was divided by the number of cows in the pen to calculate area/cow (m(2)). Time away from the pen per day was recorded from when the first cow in each pen was taken out of the home pen for milking until the last cow returned to the home pen after milking, and this time was multiplied by daily milking frequency. The median value for lying duration at the farm level was 10.6h/d, with 10.5 lying bouts/d, and a median lying bout duration of 1.2h. Stall stocking density ranged from 52.2 to 160.0%, with very few farms (7%) stocking at greater than 120%. Although stall stocking density was not significantly correlated with lying behavior, the results showed that no farm with stocking density greater that 100% achieved an average herd lying duration of 12h/d or higher, whereas 21.6% of farms with a stocking density of 100% or less did achieve the target lying time of ≥ 12 h/d, as recommended by the Canadian Code of Practice (χ(2)=4.86, degrees of freedom = 1). Area/cow (m(2)) was not correlated with any aspect of lying behavior, but regardless of space per cow, pen population was correlated with daily frequency and duration of lying bouts. As the number of cows in the pen increased, lying daily bout frequency increased (correlation coefficient = 0.24) and lying bout duration decreased (correlation coefficient = -0.30). Lying behavior was affected by the time the cows were away from the pen being milked. When cows were away from the pen for longer than 3.7h/d, no farm achieved the recommended herd median lying time of 12h/d or longer. These results suggest that providing 1 stall for each cow in the pen and minimizing time away from the pen are important factors if cattle are to achieve the recommended daily lying duration of 12h/d.

Chronic granulomatous disease: two members of a single family with different dermatologic manifestations. Case 1: A 33-year-old man with a 14-year history of localized skin disease on the face and scalp was evaluated at the department of dermatology. The physical examination revealed plaques with papules, pustules, and a golden yellow crusting on the forehead, cheeks, upper lip, and chin (Figure 1). The scalp presented fine, whitish scales. At the beginning of his disease, the patient presented large red and painful purulent boils. The 14-year clinical course of these lesions was characterized by partial remissions and recurrences, but he did not specify any treatment related to improvement. The clinical diagnosis given for the scalp lesions was seborrheic dermatitis. For the facial lesions, many differential diagnoses were considered, among them: seborrheic dermatitis, acneiform dermatitis, impetigo, folliculitis, seborrheic pemphigus, and demodicidosis. The histopathologic study of a biopsy taken from the cheek (Figure 2) showed superficial spongiform dermatitis with neutrophils and folliculitis that are compatible with the diagnosis of seborrheic dermatitis. Both Gram and periodic acid-Schiff stains were negative. Follow-up of the patient was not possible since he did not come back. The disease in this patient initially manifested at age five by the presence of recurrent ganglionic abscesses. At age 15, he presented a pulmonary abscess of a left lobule that was surgically removed; at this point the diagnosis of chronic granulomatous disease was established. At age 28, an exploratory laparotomy was performed due to peritonitis and multiple hepatic abscesses. At that time, he was treated with antibiotics (mainly trimethoprim-sulfamethoxazole) and interferon-g. The patient had two brothers who died due to complications of chronic granulomatous disease. In addition, both his mother and sister presented a history of discoid lupus-like lesions. Case 2: Coincidentally, his 27-year-old sister was seen in our department of dermatology 5 years before, presenting infiltrated and erythematous plaques with fine scales (Figure 3) on the right side of the nose and the left annular finger. No other cutaneous or mucous lesions were seen. She referred onset in childhood with similar lesions on sun-exposed areas that disappeared without scarring. A biopsy was performed and the results were compatible with the diagnosis of discoid lupus erythematosus (Figure 4). Direct immunofluorescence was not available. At that time, she did not mention the family history of chronic granulomatous disease. Clinical follow-up was not possible, but his brother referred that she afforded complete remission only with sun protection.

Neuroborreliosis in patients hospitalised for Lyme borreliosis in the Czech Republic in 2003 - 2013. The objective was to analyse and evaluate a cohort of Lyme borreliosis (LB) patients with neuroborreliosis (LNB) hospitalised in the Czech Republic in 2003-2013. Data analysed in this study were obtained from the National Register of Hospitalised Patients, which is a nationwide population register maintained at the Institute of Health Information and Statistics of the Czech Republic. Data collection from all departments of bed care establishments are regularly processed every year. Registration of basic hospitalisation diagnoses is performed in accordance with the 10th revision of the International Classification of Diseases (ICD-10). The study cohort consisted of 23,631 patients with clinically and laboratory confirmed LB hospitalised between 2003 and 2013. Nervous system involvement, i. e. LNB (ICD-10 codes G00-G99) was recorded in 27.1% (6,392) of LB patients. Hospital admissions for LB exhibited a slight downward trend with year-on-year fluctuations over the study period. In contrast, LNB showed an upward trend with slight year-on-year fluctuations (345-779 cases) (p = 0.003). Overall, 6,392 persons, 3,220 males and 3,172 females, were diagnosed with LNB over the 11-year study period. Some patients presented with multiple concomitant neurological symptoms. Overall, 6,392 hospitalised patients were diagnosed with 8,168 diseases of the nervous system. The most common diagnoses were facial nerve disorders (21.1%), meningitis (18.3%), polyneuropathies (13.6%), encephalitis, myelitis, and encephalomyelitis (11.3%), and nerve root and plexus disorders (4.9%). The average age of male and female patients hospitalised with LNB was 44.4 and 44.7 years, respectively. It varied significantly between the ICD-10 code groups (p < 0.001) from 38.0 to 63.0 years. The relative incidence of LB by five-year age group showed the first peak at the age of 5-9, followed by a considerable drop at the age of 20-24 and then by another higher peak at the age of 55-59 (the hospitalisation rate ratio comparing the peaks in the adults and children was 1.78). For LNB, the second peak shifted to the age of 65 to 74 years and was similar to the peak in children age groups (hospitalisation rate ratio of 0.95). The distribution of hospital admissions for LNB by month of admission showed the highest numbers of admissions in July and September and the lowest numbers of admissions in December and April. The length of hospital stay was significantly higher (mean of 12.4 days and median of 13 days) in LNB patients (p < 0.001) than in other LB patients (mean of 10.3 days and median of 10 days). The basic prerequisite for reliable diagnosis of LNB is a multidisciplinary collaboration of highly experienced neurologists, infection disease specialists, and microbiologists. The cohort of 6,392 patients hospitalised for LNB was analysed by gender, length of hospital stay, and month of hospital admission. The study found LNB cases to occur in all age groups. LNB diagnosis performed in accordance with the ICD-10 enables valid comparison between neurological outcomes of LB patients at both the national and international levels.

Assessing concordance between patient preferences in advance care plans and in-hospital care. Objective The aims of this study were to assess: (1) concordance between patient preferences stated in advance care plans (ACPs) and hospital care over the subsequent 12 months; (2) change in preferences over time; (3) justifications for discordant care; and (4) effects of ACP completion on hospital utilisation.Methods A retrospective study was conducted of 198 patients with an ACP form registered with an ACP registry and tagged with a hospital unique record number. Data collected from ACP forms and hospital records comprised ACP completion and revisions, care preferences, patient characteristics and hospital care. Instances of care discordant with preferences were analysed as Type A (no ascertainable justification) and Type B (direct patient request or appropriate clinical indications). In a survivor subset, hospital utilisation was compared before and after ACP completion.Results Mean (± s.d.) patient age was 79.5±11.8 years. Patients had a mean (± s.d.) of 5.5±2.5 comorbidities and 90 (46.4%) died within the 12 months after ACP completion. Most ACPs (130; 65.5%) were completed during index hospitalisation and 13 (6.5%) underwent revision, on average, 6.8 months later, all related to rescinding request for cardiopulmonary resuscitation. Hospital care was fully concordant for 154 (77.8%) patients, with 39 (22.2%) receiving 60 instances of discordant care (15 (25%) Type A, 45 (75%) Type B), mostly related to surgical procedures (20; 33%) and intravenous fluids or antibiotics (26; 43%). Patients receiving discordant care had higher mortality (77% vs 45%; P<0.001) and more rapid response team activations (34% vs 13%; P=0.001) at 12 months than patients with concordant care. Among the 108 confirmed survivors at 12 months after ACP completion, emergency department presentations and hospital admissions per patient had decreased by ≥50% (P<0.001) and hospital days had decreased by 25% (P=0.042) compared with the 12 months before ACP completion.Conclusion Most patients completing an ACP received hospital care fully concordant with their stated preferences, with few revising their preferences over time. Discordant care mostly related to justified supportive treatments or surgical procedures. Among survivors, ACP completion was associated with decreased use of hospital care.What is known about the topic? ACPs that list patient preferences and care goals relieve family and patient distress and uncertainty regarding future care decisions as death approaches, decrease unwanted medical interventions and hospitalisations, and are associated with more patients dying at home. However, uncertainty surrounds the extent to which in-patient care provided to patients' concords with preferences stated in ACPs, which preferences are most adhered to, and whether preferences change over time, warranting revision of ACPs.What does this paper add? This retrospective study of 198 patients completing an ACP, of whom almost half died within the following 12 months, showed that more than 75% received hospital care fully concordant with their stated preferences and, for decedents, most died at their preferred place of death. Relatively few patients changed their documented preferences over time, and all changes were for less use of cardiopulmonary resuscitation (CPR). Instances of discordant care mostly related to the administration of supportive treatments or surgical procedures and most were justified on the basis of patient request or appropriate clinical indications. Among 108 survivors, the number of emergency department presentations and hospital admissions per patient at 12 months after ACP completion was half those seen in the 12 months before ACP completion, whereas hospital days per patient decreased by 25%.What are the implications for practitioners? Encouraging patients with progressive chronic disease to complete an ACP reduces their risk of receiving care they do not want, reflected in decreased use of hospital care. Preferences stated in ACPs are mostly stable over time and, if changed, tend to become more conservative in terms of CPR. Conversely, preferences stated in the ACP do not, as circumstances change, bind patients or clinicians to withholding care that relieves symptoms or prevents major morbidity in the short term.

Scar Quality of Skin Graft Borders: A Prospective, Randomized, Double-Blinded Evaluation. Prominent scars may remain around the border of a mature skin graft (SG) at the interface of the SG with normal skin. The border of a SG may be constructed by either exactly approximating (A) or slightly overlapping (O) the edge of the SG on the wound margin. The purpose of this study was to evaluate whether A or O affects the quality of the border scar of SGs applied to burn patients. This prospective study was a within-border design in which adult burn patients requiring SGs served as their own control. Half of each study border was fashioned using O and the immediately adjacent other half was made using A. We randomly assigned O or A to the proximal or distal halves of vertical borders and the medial and lateral halves of horizontal borders. Both halves of the study border were identically fixated with staples or sutures and were managed in the same fashion postoperatively. Blinded evaluations at 3, 6, and 12 months of O and A borders were performed using the Vancouver Scar Scale (VSS), the observer component of the Patient and Observer Scar Assessment Scale (POSAS), and a global binary assessment of which half of the study border "looked better." Blinded patients also rated each half of the study border with a 10-point Likert scale. Values are reported as the mean ± SD or median (interquartile range), as appropriate. There were 34 borders studied in 15 subjects (46.7% female, age 29 [22,57], % TBSA burn 9.7 ± 5.3, and no inhalation injuries). Study borders were constructed at 7 (5,11) days postburn, had a total length of 12 (9.3,14.5) cm, and all involved split thickness SGs of thickness 13 (12,14)/1000th of an inch. Sheet grafts were applied in 27% and meshed grafts in 73%. SGs were applied immediately after excision in 75% or after allografting in 25%. Border scars matured between 3 and 12 months with reductions in total VSS from 8 (7,8) to 4 (3,6) for O borders (P < .001) and from 8 (7,9) to 4 (1,6) for A borders (P < .001). However, there were no significant differences between O and A borders in total VSS at 3 months (P = .165), 6 months (P = .602), and 12 months (P = .358) or in total OSAS at 3 months (P = .681), 6 months (P = .890), or 12 months (P = .601). At 12 months, 60% of O borders and 40% of A borders were globally rated as "better" (P = .258). There were no significant differences in the patients' subjective ratings of the O and A borders at 3 months (P = .920), 6 months (P = .960), and 12 months (P = .66). The scar quality at the border of a skin graft does not appear to be affected by the surgical technique used to construct the border at the time of grafting.

Bioassay of 2-methyl-1-nitroanthraquinone for possible carcinogenicity. A bioassay of 2-methyl-1-nitroanthraquinone for possible carcinogenicity was conducted using Fischer 344 rats. 2-Methyl-1-nitroanthraquinone was administered in the feed at either of two concentrations to groups of 50 male and 50 female animals. The high and low dietary concentrations used were 0.12 and 0.06 percent, respectively, for the male and female rats. After a 78-week treatment period, observation of the rats continued for an additional 31 weeks. Fifty rats of each sex were placed on test as controls. No 2-methyl-1-nitroanthraquinone was added to their diet. Survival in both the male and female rats was adequate for a meaningful statistical analysis of late-developing tumors; however, there was a significant positive association between increased dosage and elevated mortality in female rats. Hepatocellular carcinomas and neoplastic nodules of the liver occurred in both the male and female treated rats. A statistically significant association between increased dosage and an elevated incidence of hepatocellular carcinomas was indicated by the Cochran-Armitage test for the males (1/48, 5/48, and 9/49 in control, low dose, and high dose, respectively); however, the Fisher exact tests supported these results only for the high dose males. The incidence of neoplastic nodules was statistically significant in the male rats (0/48, 2/48, and 6/49 in control, low dose, and high dose, respectively), as indicated by the Cochran-Armitage test and supported by the Fisher exact test for the high dose group. When those rats having either hepatocellular carcinomas or neoplastic nodules of the liver were combined and evaluated simultaneously, the Cochran-Armitage tests indicated statistically significant associations between increased dosages and elevated tumor incidences in both the males and females. This was supported by the Fisher exact tests for males but not for females. The incidences of one tumor type, subcutaneous fibroma, were found to be statistically significant in both male and female rats. No other tumors occurred in treated animals in statistical]y significant incidences when compared to controls. Squamous-cell papillomas and squamous cell carcinomas of the forestomach were observed only in high dose rats. Although the incidences of these gastric tumors were not statistically significant, historical data indicate that these tumors are rare in Fischer 344 rats. The occurrence of these tumors in high dose rats, together with the frequent occurrence of nonneoplastic proliferative lesions of the forestomach in treated rats, indicates that the occurrence of these tumors was related to administration of 2-methyl-1-nitroanthraquinone. An increased incidence of bladder tumors (papillomas, transitional-cell papillomas, and sarcomas) was observed among female rats. Under the conditions of this bioassay, the results indicate that orally administered 2-methyl-1-nitroanthraquinone is carcinogenic in male Fischer 344 rats, producing hepatocellular carcinomas. Increased incidences of subcutaneous fibromas in both male and female Fischer 344 rats were also associated with the administration of the compound. Tumors of the forestomach and bladder in these animals may also have been related to the administration of the test chemical.

The effects of Carmeda Bioactive Surface on human blood components during simulated extracorporeal circulation. Postoperative morbidity after cardiopulmonary bypass most commonly manifests as bleeding diatheses or pulmonary dysfunction. The pathophysiology has been attributed to the activation of cellular and humoral components of blood after contact with an artificial surface. Development of a surface that would be nonthrombogenic and also would constitute a less potent inflammatory stimulus would therefore be beneficial. In the following experiments, we evaluated the heparin-bonded Carmeda Bioactive Surface (Medtronics Cardiopulmonary, Anaheim, Calif.) in an in vitro model of extracorporeal circulation at standard-dose heparin (5 U/ml), to examine the effects of the surface treatment on activation of blood elements, and at reduced-dose heparin (1 U/ml), to determine whether surface-bound heparin would serve as an effective anticoagulant. During the initial recirculation period, platelet counts in the Carmeda (n = 12) circuits were preserved at both doses of heparin and compared with control values (n = 12): At 5 U/ml, control 36% +/- 4% (mean +/- standard error of the mean) versus Carmeda 81% +/- 5%; at 1 U/ml, 43% +/- 3% versus 61% +/- 10%, expressed as a percent of baseline at 30 minutes, p < 0.05. Furthermore, plasma levels of platelet factor 4 and beta-thromboglobulin were significantly reduced in the Carmeda circuits throughout the experiment: At heparin 5 U/ml, 2500 +/- 340 ng/ml versus 604 +/- 191 ng/ml; at 1 U/ml, 2933 +/- 275 ng/ml versus 577 +/- 164 ng/ml of platelet factor 4 at 2 hours (p < 0.05). The pattern of beta-thromboglobulin release was similar, with effects more pronounced at the lower dose of heparin. Surface modification also reduced leukocyte depletion (p < 0.05) and release of elastase at both concentrations of heparin (5 U/ml, 0.72 +/- 0.29 ng/ml versus 0.33 +/- 0.23 ng/ml; 1 U/ml, 0.85 +/- 0.08 ng/ml versus 0.20 +/- 0.05 ng/ml, at 2 hours, p < 0.05). Moreover, as heparin concentration was reduced, Carmeda surface treatment significantly decreased generation of C3a des Arg (1 U/ml, 14,410 +/- 3558 ng/ml versus 3053 +/- 1039 ng/ml at 2 hours, p < 0.05). Although heparin bonding was originally intended to obviate the need for systemic heparinization, Carmeda treatment did not reduce fibrinopeptide A generation at the lower dose of heparin. In summary, Carmeda treatment failed to exhibit anticoagulant efficacy in this model; however, the data suggest that surface modification may have a role in ameliorating the typical inflammatory response initiated by blood contact with an artificial surface.

Effects of long-term theophylline exposure on recovery of respiratory function and expression of adenosine A1 mRNA in cervical spinal cord hemisected adult rats. Our lab has previously shown that when administered acutely, the methylxanthine theophylline can activate a latent respiratory motor pathway to restore function to the hemidiaphragm paralyzed by an ipsilateral C2 spinal cord hemisection. The recovery is mediated by the antagonism of CNS adenosine A1 receptors. The objective of the present study was to assess quantitatively recovery after chronic theophylline administration, the effects of weaning from the drug, and the effects of the drug on adenosine A1 receptor mRNA expression in adult rats subjected to a C2 hemisection. Rats subjected to a left C2 hemisection received theophylline orally for 3, 7, 12, or 30 days and were classified as 3D, 7D, 12D, or 30D respectively. Separate groups of 3D animals were weaned from drug administration for 7, 12, and 30 days before assessment of respiratory recovery. Additional groups of 7D and 12D animals were also weaned from drug administration for 7 and 12 days prior to assessment. Sham-operated controls received theophylline vehicle for similar periods. Quantitative assessment of recovered respiratory activity was conducted under standardized electrophysiologic recording conditions approximately 18 h after each drug application period. Serum theophylline analysis was conducted at the end of electrophysiologic recordings. Adenosine A1 receptor mRNA expression in the phrenic nucleus was assessed with in situ hybridization and immunohistochemistry. Chronic theophylline induced a dose-dependent effect on respiratory recovery over a serum theophylline range of 1.2-1.9 microg/ml. Recovery was characterized as respiratory-related activity in the left phrenic nerve and expressed as a percentage of activity in the homolateral nerve in noninjured animals under similar recording conditions. Recovered activity was 34.13 +/- 2.07, 55.89 +/- 2.96, 74.78 +/- 1.93, and 79.12 +/- 1.75% respectively in the 3D, 7D, 12D, and 30D groups. Theophylline-induced recovered activity persisted for as long as 30 days when drug administration was stopped and serum levels of the drug were virtually undetected. Furthermore, recovered activity in 3D and 7D animals increased significantly as a function of duration of weaning. Adenosine A1 receptor mRNA expression was not significantly changed by theophylline administration. It is concluded that recovery of respiratory function in C2-hemisected rats induced by chronic theophylline is unrelated to adenosine A1 receptor mRNA expression. Recovered activity persists even when drug administration has been stopped. The significance of our results is that in the clinical application of theophylline to improve respiratory impairment, intermittent drug administration may be sufficient to engender and maintain the therapeutic benefits of the drug.

[The Russian consensus on the diagnosis and treatment of chronic pancreatitis: Enzyme replacement therapy]. Pancreatology Club Professional Medical Community, 1A.S. Loginov Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow; 2A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow; 3Kazan State Medical University, Ministry of Health of Russia, Kazan; 4Kazan (Volga) Federal University, Kazan; 5Far Eastern State Medical University, Ministry of Health of Russia, Khabarovsk; 6Morozov City Children's Clinical Hospital, Moscow Healthcare Department, Moscow; 7I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, Saint Petersburg; 8Siberian State Medical University, Ministry of Health of Russia, Tomsk; 9M.F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow; 10Maimonides State Classical Academy, Moscow; 11V.I. Razumovsky State Medical University, Ministry of Health of Russia, Saratov; 12I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; 13S.M. Kirov Military Medical Academy, Ministry of Defense of Russia, Saint Petersburg; 14Surgut State Medical University, Ministry of Health of Russia, Surgut; 15City Clinical Hospital Five, Moscow Healthcare Department, Moscow; 16Nizhny Novgorod Medical Academy, Ministry of Health of Russia, Nizhny Novgorod; 17Territorial Clinical Hospital Two, Ministry of Health of the Krasnodar Territory, Krasnodar; 18Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, Saint Petersburg; 19Rostov State Medical University, Ministry of Health of Russia, Rostov-on-Don; 20Omsk Medical University, Ministry of Health of Russia, Omsk; 21Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Moscow; 22Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk; 23Stavropol State Medical University, Ministry of Health of Russia, Stavropol; 24Kemerovo State Medical University, Ministry of Health of Russia, Kemerovo; 25N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow; 26A.M. Nikiforov All-Russian Center of Emergency and Radiation Medicine, Russian Ministry for Civil Defense, Emergencies and Elimination of Consequences of Natural Disasters, Saint Petersburg; 27Research Institute for Medical Problems of the North, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk; 28S.P. Botkin City Clinical Hospital, Moscow Healthcare Department, Moscow; 29Tver State Medical University, Ministry of Health of Russia, Tver The Russian consensus on the diagnosis and treatment of chronic pancreatitis has been prepared on the initiative of the Russian Pancreatology Club to clarify and consolidate the opinions of Russian specialists (gastroenterologists, surgeons, and pediatricians) on the most significant problems of diagnosis and treatment of chronic pancreatitis. This article continues a series of publications explaining the most significant interdisciplinary consensus statements and deals with enzyme replacement therapy.

Internet based multicenter study for thoracolumbar injuries: a new concept and preliminary results. This article reports about the internet based, second multicenter study (MCS II) of the spine study group (AG WS) of the German trauma association (DGU). It represents a continuation of the first study conducted between the years 1994 and 1996 (MCS I). For the purpose of one common, centralised data capture methodology, a newly developed internet-based data collection system ( http://www.memdoc.org ) of the Institute for Evaluative Research in Orthopaedic Surgery of the University of Bern was used. The aim of this first publication on the MCS II was to describe in detail the new method of data collection and the structure of the developed data base system, via internet. The goal of the study was the assessment of the current state of treatment for fresh traumatic injuries of the thoracolumbar spine in the German speaking part of Europe. For that reason, we intended to collect large number of cases and representative, valid information about the radiographic, clinical and subjective treatment outcomes. Thanks to the new study design of MCS II, not only the common surgical treatment concepts, but also the new and constantly broadening spectrum of spine surgery, i.e. vertebro-/kyphoplasty, computer assisted surgery and navigation, minimal-invasive, and endoscopic techniques, documented and evaluated. We present a first statistical overview and preliminary analysis of 18 centers from Germany and Austria that participated in MCS II. A real time data capture at source was made possible by the constant availability of the data collection system via internet access. Following the principle of an application service provider, software, questionnaires and validation routines are located on a central server, which is accessed from the periphery (hospitals) by means of standard Internet browsers. By that, costly and time consuming software installation and maintenance of local data repositories are avoided and, more importantly, cumbersome migration of data into one integrated database becomes obsolete. Finally, this set-up also replaces traditional systems wherein paper questionnaires were mailed to the central study office and entered by hand whereby incomplete or incorrect forms always represent a resource consuming problem and source of error. With the new study concept and the expanded inclusion criteria of MCS II 1, 251 case histories with admission and surgical data were collected. This remarkable number of interventions documented during 24 months represents an increase of 183% compared to the previously conducted MCS I. The concept and technical feasibility of the MEMdoc data collection system was proven, as the participants of the MCS II succeeded in collecting data ever published on the largest series of patients with spinal injuries treated within a 2 year period.

Vitamin K to prevent fractures in older women: systematic review and economic evaluation. To determine the clinical and cost-effectiveness of vitamin K in preventing osteoporotic fractures in postmenopausal women. Searches were conducted in May 2007 in MEDLINE, MEDLINE In-Process, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, BIOSIS, CINAHL, DARE, NHS EED and HTA databases, AMED, NRR, Science Citation Index and Current Controlled Trials. The MEDLINE search was updated in March 2009. Selected studies were assessed and subjected to data extraction and quality assessment using standard methods. Where appropriate, meta-analysis was carried out. A mathematical model was constructed to estimate the cost-effectiveness of vitamin K1. The electronic literature searches identified 1078 potentially relevant articles. Of these, 14 articles relating to five trials that compared vitamin K with a relevant comparator in postmenopausal women with osteoporosis or osteopenia met the review inclusion criteria. The double-blind ECKO trial compared 5 mg of phylloquinone (vitamin K1) with placebo in Canadian women with osteopenia but without osteoporosis. Four open-label trials used 45 mg of menatetrenone (vitamin K2) in Japanese women with osteoporosis; the comparators were no treatment, etidronate or calcium. The methodological quality of the ECKO trial was good; however, all four menatetrenone trials were poorly reported and three were very small (n < 100 in each group). Phylloquinone was associated with a statistically significant reduction in the risk of clinical fractures relative to placebo [relative risk 0.46, 95% confidence interval (CI) 0.22 to 0.99]; morphometric vertebral fractures were not reported. The smaller menatetrenone trials found that menatetrenone was associated with a reduced risk of morphometric vertebral fractures relative to no treatment or calcium; however, the larger Osteoporosis Fracture (OF) study found no evidence of a reduction in vertebral fracture risk. The three smaller trials found no significant difference between treatment groups in non-vertebral fracture incidence. In the ECKO trial, phylloquinone was not associated with an increase in adverse events. In the menatetrenone trials, adverse event reporting was generally poor; however, in the OF study, menatetrenone was associated with a significantly higher incidence of skin and skin appendage lesions. No published economic evaluations of vitamin K were found and a mathematical model was thus constructed to estimate the cost-effectiveness of vitamin K1. Comparators were alendronate, risedronate and strontium ranelate. Vitamin K1 and alendronate were markedly more cost-effective than either risedronate or strontium ranelate. The base-case results favoured vitamin K1, but this relied on many assumptions, particularly on the efficacy of preventing hip and vertebral fractures. Calculation of the expected value of sampled information was conducted assuming a randomised controlled trial of 5 years' duration comparing alendronate with vitamin K1. The costs incurred in obtaining updated efficacy data from a trial with 2000 women per arm were estimated to be a cost-effective use of resources. There is currently large uncertainty over whether vitamin K1 is more cost-effective than alendronate; further research is required. It is unlikely that the present prescribing policy (i.e. alendronate as first-line treatment) would be altered.

[The study assessed the prevalence of TPS and its associations with psychopathy in a population of forensic violent patients in a Belgian security hospital]. The population was composed of 76 male patients (mean age=36.14). All of them having committed a violent offence indexed in their institutional file: (1) sexual offences on children; (2) rapes of adult women; (3) homicide offence; and (4) assaults and batteries. TPS was defined by the following 8 diagnostic criteria as described in DSM III-R: 1) has used physical cruelty or violence for the purpose of establishing dominance in a relationship; 2) humiliates or demeans people in the presence of others; 3) has treated or disciplined someone under his or her control unusually harshly; 4) is amused by, or takes pleasure in, the psychological or physical suffering of others; 5) has lied for the purpose of harming or inflicting pain on others 6) gets other people to do what he or she wants by frightening them 7) restricts the autonomy of people with whom he or she has a close relationship; 8) is fascinated by violence, weapons, martial arts, injury, or torture. These criteria were assessed from (a) clinical and institutional files and (b) clinical collateral informations. TPS assessment was conducted by two -trainees in clinical psychology (kappa=0.87; n=20). The assessment of psychopathy was conducted according to the guidelines of the Hare psychopathy checklist manual (PCL-R, 1991, 2003): coding of clinical and institutional files and semi-structural clinical interviews. The PCL-R is mainly composed by 2 factors: factor 1 "Emotional detachment" describing the core psychological component of psychopathy, and factor 2 "Chronically antisocial factor" reflecting behavioral instability and antisocial life style. The total cut-off score for the inclusion of the diagnosis was 25. The prevalence of TPS in the population was 25% (n=19) and is congruent with the large range described in the literature (0.5 to 33%). The most frequent criteria were 6 (gets other people to do what he or she wants by frightening them), 1 (has used using physical cruelty or violence for the purpose of establishing dominance in a relationship) and 3 (has treated or disciplined someone under his or her control unusually harshly). The most sensible criteria were: 7 (restricts the autonomy of people with whom he or she has a close relationship), 8 (major interest for violence) and 4 (pleasure in the psychological or physical suffering of others). The most specific criteria were: 3 (has treated or disciplined someone under his or her control unusually harshly), 6 (gets other people to do what her or she wants by frightening them), 4 (takes pleasure in the psychological or physical suffering of others) and 1 (has used physical -cruelty or violence for the purpose of establishing dominance in a relationship). As concerns psychopathy, the mean of factor 1, factor 2 and the PCL-R total scores were 7.40, 9.08 and 18.67. Thus, 38% of patients were considered as "low psychopaths", 36% were considered as "moderate psychopaths" and 26% were considered as "high psychopaths". In spite of few significant positive correlations between some TPS and PCL-R criteria, TPS diagnosis was not significantly correlated with factors 1, factor 2, nor with total score of the PCL-R. The mean psychopathy total score did not differ between sadistic and non-sadistic patients. Moreover, a two ways ANOVA comparing PCL-R factors 1 and 2 did not reveal any differences between sadism and non-sadism. Again, these comparisons did not support hypothesis of a strong association between TPS and psychopathy.

Enhancing the health of medical students: outcomes of an integrated mindfulness and lifestyle program. Medical students experience various stresses and many poor health behaviours. Previous studies consistently show that student wellbeing is at its lowest pre-exam. Little core-curriculum is traditionally dedicated to providing self-care skills for medical students. This paper describes the development, implementation and outcomes of the Health Enhancement Program (HEP) at Monash University. It comprises mindfulness and ESSENCE lifestyle programs, is experientially-based, and integrates with biomedical sciences, clinical skills and assessment. This study measured the program's impact on medical student psychological distress and quality of life. A cohort study performed on the 2006 first-year intake measured effects of the HEP on various markers of wellbeing. Instruments used were the depression, anxiety and hostility subscales of the Symptom Checklist-90-R incorporating the Global Severity Index (GSI) and the WHO Quality of Life (WHOQOL) questionnaire. Pre-course data (T1) was gathered mid-semester and post-course data (T2) corresponded with pre-exam week. To examine differences between T1 and T2 repeated measures ANOVA was used for the GSI and two separate repeated measures MANOVAs were used to examine changes in the subscales of the SCL-90-R and the WHOQOL-BREF. Follow-up t-tests were conducted to examine differences between individual subscales. A total of 148 of an eligible 270 students returned data at T1 and T2 giving a response rate of 55%. 90.5% of students reported personally applying the mindfulness practices. Improved student wellbeing was noted on all measures and reached statistical significance for the depression (mean T1 = 0.91, T2 = 0.78; p = 0.01) and hostility (0.62, 0.49; 0.03) subscales and the GSI (0.73, 0.64; 0.02) of the SCL-90, but not the anxiety subscale (0.62, 0.54; 0.11). Statistically significant results were also found for the psychological domain (62.42, 65.62; p < 0.001) but not the physical domain (69.11, 70.90; p = 0.07) of the WHOQOL. This study is the first to demonstrate an overall improvement in medical student wellbeing during the pre-exam period suggesting that the common decline in wellbeing is avoidable. Although the findings of this study indicate the potential for improving student wellbeing at the same time as meeting important learning objectives, the limitations in study design due to the current duration of follow-up and lack of a control group means that the data should be interpreted with caution. Future research should be directed at determining the contribution of individual program components, long-term outcomes, and impacts on future attitudes and clinical practice.

Correlation of the partitioning of dissolved organic matter fractions with the desorption of Cd, Cu, Ni, Pb and Zn from 18 Dutch soils. Eighteen Dutch soils were extracted in aqueous solutions at varying pH. Extracts were analyzed for Cd, Cu, Ni, Pb and Zn by ICP-AES. Extract dissolved organic carbon (DOC) was also concentrated onto a macroreticular resin and fractionation into three operationally defined fractions: hydrophilic acids (Hyd), humic acids (HA) and fulvic acids (FA). In this manner, change in absolute solution concentration and relative percentage for each fraction could be calculated as a function of extraction equilibrium pH. The soils were also analyzed for solid phase total organic carbon and total recoverable metals (EPA Method 3051). Partitioning coefficients were calculated for the metals and organic carbon (OC) based on solid phase concentrations (less the metal or OC removed by the extraction) divided by solution concentrations. Cu and Pb concentrations in solution as a function of extract equilibrium pH are greatest at low and high pH resulting in parabolic desorption/dissolution curves. While processes such as proton competition and proton promoted dissolution can account for high solution metal concentrations at low pH, these processes cannot account for higher Cu and Pb concentrations at high pH. DOC increases with increasing pH, concurrently with the increase in Cu and Pb solution concentrations. While the absolute concentrations of FA and HA generally increase with increasing pH, the relative proportional increase is greatest for HA . Variation in HA concentrations spans three orders of magnitude while FA concentrations vary an order of magnitude over the pH range examined. Correlation analysis strongly suggests that HA plays a major role in increasing the concentration of solution Cu and Pb with increasing pH in the 18 soils studied. The percentage of the OC that was due to FA was nearly constant over a wide pH range although the FA concentration increased with increasing pH and its concentration was greater than that of the HA fraction at lower pH values (pH = 3-5). Thus, in more acidic environments, FA may play a larger role than HA in governing organo-metallic interactions. For Cd, Ni, and Zn, the desorption/dissolution pattern shows high metal solution concentrations at low pH with slight increases in solution concentrations at extremely high pH values (pH>10). The results presented here suggest that the effects of dissolved organic carbon on the mobilization of Cd, Ni, and Zn may only occur in systems governed by very high pH. At high pH, it is difficult to distinguish in this study whether the slightly increased solution-phase concentrations of these cations is due to DOC or hydrolysis reactions. These high pH environments would rarely occur in natural settings.

Laparoscopic Partial Bladder Cystectomy for Bladder Endometriosis: A Combined Cystoscopic and Laparoscopic approach. Urinary tract endometriosis involves the bladder and/or the ureters and is present in approximately 1% of women with endometriosis [1]. Bladder endometriosis is the most frequent type of urinary tract endometriosis, occurring in about 70% to 85% of cases [2,3]. Bladder endometriosis is defined as the presence of endometrial glands and stroma in the detrusor muscle. Surgically, there are 2 ways of excising this disease. The first is by transurethral bladder resection of the tumor, and the second is laparoscopic/robotic/open partial cystectomy of the bladder endometriosis. Because the nodule develops from the outer layer of the bladder wall toward the inner layer, complete excision of the endometriotic lesion is virtually unachievable with transurethral resection surgery. There is also a high risk of bladder perforation [4-8]. Partial cystectomy of the bladder runs a risk of excising normal bladder tissues because it is difficult to ascertain the margins of the bladder nodule. However, we found the best method to deal with bladder endometriosis is a combined approach whereby the margins of the bladder nodule are cut via a cystoscopy and then excision of the bladder nodule is done laparoscopically. This particular technique is presented here with an accompanying video. Excision of bladder endometriosis by first delineating the tumor via cystoscopy and simultaneously excising the nodule laparoscopically SETTING: Mahkota Medical Centre, Melaka, Malaysia. Here we describe a simultaneous cystoscopic and laparoscopic excision of bladder endometriosis. The patient was first seen in 2005 at age 19 years with an endometrioma. She was single (virgo intacta) at that time. She underwent a laparoscopic cystectomy. Postoperatively, she received 3 doses of monthly gonadotropin-releasing hormone (GnRH) analogue injection. She was last seen in 2006 and was well. She conceived spontaneously after that and delivered 2 babies spontaneously in 2007 and 2010 in another city. She consulted me again in April 2016 complaining of dysuria, dysmenorrhea, and inability to hold her urine. She had consulted a urologist 6 months earlier. Cystoscopy performed by the urologist showed bladder endometriosis. No further surgery was performed, and she was given GnRH analogues for 6 months. However, her symptoms persisted after completion of the GnRH analogue. Examination and ultrasound showed a large bladder nodule measuring 4.17 × 2.80 cm. Intravenous urogram showed stricture in the upper right ureter. She underwent a combined urology and gynecology surgery to excise the bladder nodule. Informed consent was obtained from the patient, and the local institutional board provided the approval. The surgery was performed with the patient in the dorsosacral position. A Verres needle was inserted into the abdomen at the umbilicus, and carbon dioxide insufflation was performed. A 10-mm trocar was inserted in the umbilicus, and a 3-dimensional laparoscope (Aesculup-BBraun Einstein Vision; BBraun, Melsungen AG, Germany) was inserted to view the pelvis. Three 5-mm trocars were inserted, 1 on the right side and 2 on the left side of the abdomen. A RUMI (CooperSurgical, Trumbull, CT) uterine manipulator was placed into the uterine cavity. Laparoscopy showed no adhesions in the upper and mid-abdomen. The appendix and the intestines looked normal. Both the ovaries and fallopian tubes were normal. Uterine insufflation with methylene blue showed that both tubes were patent. There was dense endometriosis between the bladder and fundus of the uterus. The omentum was also adherent to the site of the endometriosis. There were endometriotic nodules on the left uterosacral ligaments and the peritoneum in the wall in the pouch of Douglas. The omentum was released, and laparoscopic adhesiolysis was performed. Both the paravesical spaces lateral to the nodule were dissected out. The bladder was released from the uterus with some difficulty. The peritoneal endometriosis in the Pouch of Douglas and the nodules in the left uterosacral ligament were excised. Cystoscopy was performed and stents were first placed in both ureters. The nodule was found to be in the central position, and the margins were about 2 cm from both the ureteral orifices. The nodule was seen protruding into the bladder containing bluish lesions. Demarcation of the bladder endometriosis was done using a resectoscope. Using a needle electrode, a deep circular incision was made around the bladder nodule and into the detrusor muscle. Cystoscopic perforation of the bladder was done and was seen laparoscopically. The bladder endometriotic nodule was completely excised laparoscopically after the demarcation line created via the cystoscopy. Stay sutures were first placed at the superior and inferior edges of the defect. The bladder was repaired continuously in 1 layer using polyglactin 3-0 sutures. The nodule was placed in a bag cut into smaller pieces and removed through the umbilical incision. At the end of the surgery a cystoscopy was perform to check the integrity of the suture. The pelvis was then washed. A bladder catheter was placed. The trocars were then removed under vision, and the rectus sheath was closed using polyglactin 1 suture. The skin incisions were closed. The operation time was 2 hours. The patient received antibiotics for 10 days. She was discharged with a catheter in place on day 3. She underwent a cystogram on day 10 of the surgery, and the bladder was found to be intact. The catheter was then removed. She was seen 6 weeks after the surgery and was well without any symptoms. The ureteric catheters were removed. Histopathology confirmed bladder endometriosis. Five months later she conceived spontaneously and delivered her third child naturally in June 2017. She was seen after her delivery and was advised to take oral contraceptive pills continuously or an intrauterine contraceptive device to prevent recurrence of the endometriosis. She took the oral contraceptive pills for 3 months and then refused any further treatment. She was last seen in February 2019 and was well without any symptoms. In bladder endometriosis a combined approach with the urologist can assist in safely excising deep bladder endometriosis without removal of normal bladder tissue. Stents placed in the ureter assist in avoiding injury to the ureters. Demarcating the endometriotic nodule by the urologist through the bladder and excising the bladder nodule laparoscopically is both safe and effective.

Formoterol as dry powder oral inhalation compared with salbutamol metered-dose inhaler in acute exacerbations of chronic obstructive pulmonary disease. Acute exacerbations of chronic obstructive pulmonary disease (COPD) are managed with increased doses or frequency of the patient's existing bronchodilator therapy. The use of formoterol in the treatment of mild acute exacerbations of COPD has been suggested; however, a comparison of cumulative doses of formoterol with salbutamol, the gold standard bronchodilator agent for this pathologic condition, is still lacking. The aim of the study was to compare the inhaled beta2-agonists salbutamol (rapid onset, short duration of action) and formoterol (rapid onset, long duration of action), both used as needed in patients attending outpatient clinics because of mild acute exacerbations of COPD (Anthonisen exacerbation type I or II). A dose-response curve to formoterol via Turbuhaler or salbutamol via pressurized metered-dose inhaler (pMDI) was constructed. On 2 consecutive days, the patients received, in randomized order, both of the following active dose regimens: A = 12 + 12 + 24 microg formoterol via Turbuhaler (48-microg cumulative metered dose); B = 200 + 200 + 400 microg salbutamol via pMDI (800-microg cumulative metered dose). Dose increments were given at 30-minute intervals, with measurements made 25 minutes after each dose. The maximum forced expiratory volume in 1 second (FEV1) value during the dose-response curve to formoterol or salbutamol was chosen as the primary outcome variable to compare the 2 treatments. Oxygen saturation by pulse oximetry (SpO2) and pulse rate were also measured at each assessment period. Every adverse event, either reported spontaneously by the patients or observed by the investigators, was recorded. Sixteen patients (2 women, 14 men) aged 51 to 77 years (most older than 65 years) participated in the study. Both formoterol and salbutamol induced a large, significant, dose-dependent increase in FEV1, inspiratory capacity (IC), and forced vital ca- pacity (FVC). There was no significant difference between FEV1, IC, and FVC values after 48 microg formoterol and 800 microg salbutamol. There was no significant difference in FEV1 after 24 microg formoterol and 800 microg salbutamol; however, the difference in FEV1 after 24 and 48 microg formoterol was significant. Neither heart rate (mean differences from baseline after 48 microg formoterol, 1.9 beats/min [95% CI, -3.4, 7.2] and 800 microg salbutamol, 3.7 beats/min [95% CI, -1.1, 8.5]) nor SpO2 (mean percentage differences from baseline after 48 microg formoterol, -0.37% [95% CI, -1.22, 0.47] and 800 microg salbutamol, -0.75% [95% CI, -1.73, 0.23]) changed significantly. However, SpO2 decreased below 90% in 2 patients after the highest dose of formoterol and in 1 patient after the highest dose of salbutamol. In this small, selected group of patients with mild acute exacerbations of COPD, formoterol via Turbuhaler induced a fast bronchodilation that was dose dependent and not significantly different from that caused by salbutamol. Furthermore, formoterol appeared to be as well tolerated as salbutamol.

Is normobaric hypoxia an effective treatment for sustaining previously acquired altitude acclimatization? This study examined whether normobaric hypoxia (NH) treatment is more efficacious for sustaining high-altitude (HA) acclimatization-induced improvements in ventilatory and hematologic responses, acute mountain sickness (AMS), and cognitive function during reintroduction to altitude (RA) than no treatment at all. Seventeen sea-level (SL) residents (age = 23 ± 6 yr; means ± SE) completed in the following order: 1) 4 days of SL testing; 2) 12 days of HA acclimatization at 4,300 m; 3) 12 days at SL post-HA acclimatization (Post) where each received either NH (n = 9, [Formula: see text] = 0.122) or Sham (n = 8; [Formula: see text] = 0.207) treatment; and 4) 24-h reintroduction to 4,300-m altitude (RA) in a hypobaric chamber (460 Torr). End-tidal carbon dioxide pressure ([Formula: see text]), hematocrit (Hct), and AMS cerebral factor score were assessed at SL, on HA2 and HA11, and after 20 h of RA. Cognitive function was assessed using the SynWin multitask performance test at SL, on HA1 and HA11, and after 4 h of RA. There was no difference between NH and Sham treatment, so data were combined. [Formula: see text] (mmHg) decreased from SL (37.2 ± 0.5) to HA2 (32.2 ± 0.6), decreased further by HA11 (27.1 ± 0.4), and then increased from HA11 during RA (29.3 ± 0.6). Hct (%) increased from SL (42.3 ± 1.1) to HA2 (45.9 ± 1.0), increased again from HA2 to HA11 (48.5 ± 0.8), and then decreased from HA11 during RA (46.4 ± 1.2). AMS prevalence (%) increased from SL (0 ± 0) to HA2 (76 ± 11) and then decreased at HA11 (0 ± 0) and remained depressed during RA (17 ± 10). SynWin scores decreased from SL (1,615 ± 62) to HA1 (1,306 ± 94), improved from HA1 to HA11 (1,770 ± 82), and remained increased during RA (1,707 ± 75). These results demonstrate that HA acclimatization-induced improvements in ventilatory and hematologic responses, AMS, and cognitive function are partially retained during RA after 12 days at SL whether or not NH treatment is utilized.NEW & NOTEWORTHY This study demonstrates that normobaric hypoxia treatment over a 12-day period at sea level was not more effective for sustaining high-altitude (HA) acclimatization during reintroduction to HA than no treatment at all. The noteworthy aspect is that athletes, mountaineers, and military personnel do not have to go to extraordinary means to retain HA acclimatization to an easily accessible and relevant altitude if reexposure occurs within a 2-wk time period.

[Biomechanical effects of iliac screw plates on stability of lumbo-iliac fixation construct]. To evaluate the biomechanical effect of a self-made iliac screw plate on the stability of lumbo-iliac fixation construct before and after fatigue loading. Twelve fresh lumbo-pelvic specimens from donated adult cadavers with formalin embalm were used in the study. According to whether use the iliac screw plate or not, the specimens were randomly assigned into group A (with iliac screw plate, n=6) and group B (without iliac screw plate, n=6). The bone mineral density (BMD) of L(t-4) was measured using dual-energy radiograph absorptiometry. The pedicle screw and iliac screw fixation were given at L3-5, and bilateral facetectomy and diskectomy at L5, S1 level were performed to prepare the model of the intervertebral destabilization. The biomechanical testing was conducted on a material testing machine under 0-600 N compression and -7-7 N.m torsion loading modes for the initial compressive stiffness and torsional stiffness evaluation. And then 20 000 cyclic compressive loading of 40-400 N was given to the specimen, the stiffness evaluation was repeated. Then the maximum pull-out strength of screws at every level was measured and compared. Gross observation and radiological observation were performed during experiment. The BMD values of groups A and B were (1.15 +/-0.13) g/cm(2) and (1.12 +/-0.11) g/cm(2) respectively, showing no significant difference between 2 groups (t=0.428, P=0.678). All pedicle screws and iliac screws were inserted in good position; no loosening or breaking of screw was observed during loading. After fatigue loading, the incidence of halo ring around the iliac screws of groups A and B was 16.7% (1/6) and 50.0% (3/6), respectively. The compressive stiffness and torsional stiffness after fatigue loading were significantly lower than those in initial state in groups A and B (P < 0.05); there was no significant difference in compressive stiffness and torsional stiffness between groups A and B before fatigue loading (P > 0.05). However, group A had higher compressive stiffness than group B (t=2.664, P=0.024) after fatigue loading, and there was no significant difference in torsional stiffness between 2 groups (t=0.410, P=0.690). No significant difference was found in screw pull-out strength of pedicle screws at L3, L4, and L5 levels between groups A and B (P > 0.05); however, the pull-out strength of the iliac screws in group A was significantly higher than that in group B (t=3.398, P=0.007). In groups A and B, the pull-out strength of L3 screw was significantly lower than that of L4 and L5 screws (P < 0.05). In group A, pull-out strength of the iliac screws was significantly higher than that of L3, L4, and L5 screws (P < 0.05); in group B, the pull-out strength of iliac screws was significantly lower than that of L4 and L5 screws (P < 0.05). In the lumbo-iliac reconstruction, the use of iliac screw plate could resist iliac screw loosening, therefore, it has the potential to increase the stability oflumbo-iliac fixation construct.

Different impact of carvedilol and transdermal scopolamine on cardiovascular performance of mild-moderate chronic heart failure patients: evidence of useful effects of scopolamine on tolerance to work load. To verify and compare the effects respectively exercised in chronic heart failure patients by transdermal, slow release scopolamine patch and by the beta and alfa adrenoreceptor blocker carvedilol upon the main indexes derived from maximal cardiopulmonary stress test, as well as from analysis of heart rate variability. In each of 14 patients suffering from NYHA class II chronic heart failure, admitted to study, the maximal cardiopulmonary test and heart period power spectrum assessment were performed, firstly during usual therapy, then after 7 days of continuous adjunctive treatment with scopolamine patch, and, finally after 3 months of regular administration of oral carvedilol, added to the basal therapy. The need of time enough to the adaptation of the cardiovascular system against the carvedilol pharmacodynamics, together with the need of slow, progressive dose titration, caused that the onset of therapy with carvedilol was separated from assessment of its effects on ergometric and spectral parameters by an interval period of 3 months. During administration of low doses of scopolamine, the values of VO2max, exercise time and double product were respectively 24 +/- 5.3 ml/kg/min, 12 +/- 3 min and 23630 +/- 3760, and resulted significantly higher than basal (p < 0.05 in all cases) and carvedilol-related readings (p < 0.01 by comparisons with VO2max and double product; p < 0.05 by comparison with exercise time). Again during scopolamine, the total variance, LF and HF powers exhibited the values reported as follows: 1255 msec2 and, respectively, 430 and 250 msec2, thus exceeding significantly the basal levels (p < 0.05 from comparison with total power, p < 0.01 from comparisons with LF and HF bands) as well as the levels reached during adrenergic blockade with carvedilol (LF scopolamine vs LF carvedilol: p < 0.01; total power and HF scopolamine vs corrispective carvedilol values p < 0.05). Compared to the basal findings, the carvedilol induced a significant reduction in VO2max (p < 0.05), double product (p < 0.01), peack of heart rate (p < 0.05) and LF power (p < 0.05), and elicited no significant decreases in exercise time; similarly a weak, not significant surge was product by carvedilol in total and HF powers. Therefore, in patients with left ventricle asymptomatic dysfunction, the low doses of scopolamine potentiate simultaneously the spontaneous heart rare variability and cardiopulmonary maximal testing; whereas, the carvedilol acts upon LF oscillatory component only, the effects upon total variance and HF band being negligible; moreover, this drug depress the myocardial functional capability; in fact, the carvedilol has been demonstrated to produce a remarkable fall in VO2max, this significant reduction in O2 maximal uptake involving the poor rise in cardiac output during the effort or less effective O2 removal from capillary beds or both.

[Accessibility of doctors' surgeries in Essen, Germany]. Constructional barriers often prevent persons who are only partially able, for example those requiring a wheel chair for pre-ambulation, from entering buildings where doctors practise. Even though many international and national resolutions have long been demanding free access to the environment for the partially able, this has not been specially prescribed in Germany. Hence, no one knows anything about outpatient health care facilities in this regard. The present study aimed at analysing accessibility to orthopaedic and neurological practices and surgeries for wheelchair patients. We chose Essen, the sixth largest town in Germany, as an example of an urban area, where orthopaedists and neurologists are frequently accessed by wheelchair patients. We performed on-site investigations of the exterior and interior zones of all orthopaedic and neurological surgery buildings in Essen (each n = 29). Criteria for our descriptive analysis were parking lots for the handicapped, shunting areas, entrances at-grade, steps/stories, banisters, ramps, bells and openers of front, elevator and surgery doors, their opening and width. Following the criteria of the DIN 18 024 standard part 2 ("accessibility") the surgeries were divided into four groups 1) fully accessible; 2) slight barriers; 3) considerable barriers; 4) massive barriers. None of the 58 investigated surgeries was fully accessible, 21 of the 29 surgeries of each medical specialty had massive barriers, so that wheelchair patients could access these surgeries only with the help of at least two (strong) persons. Six of the 29 orthopaedic and three of the 29 neurological surgeries had slight barriers, whereas two orthopaedic and five neurological surgeries had distinct barriers. Main barriers were steps in the entrance area; front, elevator or surgery doors too narrow (width less than 80 cm), and elevators too small. For wheelchair patients in Germany, free choice of doctors seems to be massively reduced. Since 80 % of orthopaedic and 90 % of neurological surgeries in Essen do not fulfil the quality feature "constructional accessibility", measures that have been taken in the past to help partially able persons to participate in this respective aspect of social life have not been effective. New measures to improve the present situation should be agreed upon by all the institutions involved (politics, local authorities/construction supervision, sickness funds, doctors and associations of sickness fund physicians, and concerned persons). If voluntary measures do not lead to free choice of doctors for wheelchair patients, further legal regulations appear to be mandatory.

Differential modulation of CYP2E1 activity by cAMP-dependent protein kinase upon Ser129 replacement. Many toxic compounds are activated by cytochrome P450 (CYP) 2E1 to reactive metabolites, which represents a potential hazard for cellular homeostasis. Therefore knowledge about CYP2E1 regulation could be of great biological importance. It has been shown that CYP2E1 is controlled transcriptionally and post-translationally by phosphorylation. In the present study we investigated the role of serine-129 (Ser129) in the protein kinase A (PKA) recognition sequence motif Arg-Arg-Phe-Ser129. To gain further insights into the possible relevance of Ser129 for CYP2E1 function, Ser129 was replaced by alanine (Ala) or glycine (Gly) by site-directed mutations of the cDNA coding for CYP2E1. The mutant cDNAs were transfected into Chinese hamster lung fibroblast V79 cells. Despite the mutation in the PKA phosphorylation motif, all strains produced catalytically active CYP2E1. However, there was a marked change in the substrate preference: The Gly129-containing strains hydroxylated p-nitrophenol (PNP) to a markedly higher extent than the wild-type cDNA-containing cells, while they demethylated N-nitrosodimethylamine (NDMA) to a markedly lower extent than the wild-type cells. All the strains activated NDMA to mutagenic products. Treatment with the membrane-permeating cAMP derivative db-cAMP reduced markedly both the PNP hydroxylase and the NDMA demethylase activities as well as the mutation frequency induced by NDMA in the Ser129-containing strain. This decrease in activity was not accompanied by a decrease in CYP2E1 content. In addition, the catalytic activities of CYP2E1 were decreased in microsomes from rat hepatocytes treated with db-cAMP. Also in this case, the decrease in activities was not accompanied by a decrease in enzyme protein. These findings argue that involvement of Ser129 and its phosphorylation is not in determining CYP2E1 protein level, but rather in controlling its catalytic activity. In contrast, in the strains containing Ala129 or Gly129, treatment with db-cAMP caused a marked increase in both PNP hydroxylase and NDMA demethylase. In these strains a similar db-cAMP-mediated increase was also observed in the mutation frequency, resulting from the treatment with the promutagen NDMA, which is activated by CYP2E1. Our results show that CYP2E1 in V79 cells responds in two separate ways to db-cAMP exposure depending on the amino acid residue present in the PKA recognition sequence. The enzyme is committed to a negative regulation by db-cAMP if Ser129 is the target amino acid for PKA, leading to a decrease in the metabolic activation to mutagenic and carcinogenic species. On the other hand, Ala129 or Gly129 substitution directed CYP2E1 toward a positive regulation by increasing its catalytic activities and metabolic activation to mutagenic intermediates in the presence of db-cAMP. We also obtained evidence that cAMP-mediated downregulation of wild-type (Ser129) CYP2E1 was not accompanied by its destruction but instead by its stabilization, which shows that Ser129 is not involved in CYP2E1 degradation but dictates requirements for its specific activities.

Toxic effects of orimulsion on rainbow trout Oncorhynchus mykiss. Orimulsion (stable emulsion of natural bitumen and water) is a new imported industrial fuel in Lithuania. No data on its toxicity to fish is freely available. The aim of this study was to investigate sensitivity of rainbow trout (Oncorhynchus mykiss) to acute and chronic toxicity of orimulsion and to estimate the Maximum Acceptable Toxicant Concentration (MATC) of orimulsion to fish. Laboratory tests were conducted on rainbow trout in all stages of development (embryos, larvae, adults). Acute toxicity (96-hour duration) and long-term (28 or 60-day duration) tests evaluating the wide range spectrum of biological indices were performed under semi-static conditions. Median lethal concentration (96-hour LC50) values and their 95% confidence intervals derived from the tests were: 0.1 (0.09-0.12) to embryos, 0.06 (0.05-0.07) to larvae and 2.22 (2.02-2.43) to adult fish, and 28-day LC50 to adult fish was found to be 0.26 (0.21-0.32) g/l of total orimulsion respectively. The acute toxicity of orimulsion to rainbow trout can be characterised by a narrow zone of toxic effect and a sharp boundary between lethal and sublethal concentrations. The lowest 'safe' or 'no-effect' concentration values of total orimulsion obtained in long-term tests were equal to 0.09 g/l to adult fish, 0.019 g/l to embryos, and 0.0017 g/l to larvae. Proposed value of 'application factor' for orimulsion was found to be equal to 0.03. Since orimulsion has the property to disperse in all water volume, its toxic effect on fish can be characterised by the combined effects of dispersion and water-soluble-fraction. Maximum Acceptable Toxicant Concentration (MATC) of 0.0017 g/l of total orimulsion to fish was derived from long-term tests based on the most sensitive parameter of rainbow trout larvae (relative mass increase at the end of the test). According to substance toxicity classification accepted for Lithuanian inland waters, orimulsion can be referred to substances of 'moderate' toxicity to fish. For prediction and evaluation of toxic impact of orimulsion accident spills on fish, some recommendations should be given. Since orimulsion has the property to disperse in all water volume during short time periods, the amounts of both spilled orimulsion and polluted water should be ascertained. Once both parameters are known, the real concentration of orimulsion in the water body must be determined. Then this concentration must be compared with 'safe' concentration to fish. By use of 'application factor' 0.03, approximate MATC for other fish species can be estimated when only acute toxicity data (96-hour LC50 value) is available.

Evaluation of the effect on heart rate variability of some agents acting at the beta-adrenoceptor using nonlinear scatterplot and sequence methods. There is evidence that the processes regulating heart rate variability (HRV) reflect nonlinear complexity and show "chaotic" determinism. Data analyses using nonlinear methods may therefore reveal patterns not apparent with the standard methods for HRV analysis. We have consequently used two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, in addition to the standard time-domain summary statistics, during a normal volunteer investigation of the effects on HRV of some agents acting at the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 25 normal volunteers received placebo, salbutamol 8 mg (beta 2-adrenoceptor partial agonist), pindolol 10 mg (beta 2-adrenoceptor partial agonist), or atenolol 50 mg (beta 1-adrenoceptor antagonist). Single oral doses of medication (at weekly intervals) were administered at 22:30 hours, with sleeping heart rates recorded overnight. The long-term (SDNN, SDANN) and short-term (rMSSD) time-domain summary statistics were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo. The reductions in both SDNN and SDANN were greater after salbutamol 8 mg compared with pindolol 10 mg. The reduced HRV after pindolol 10 mg differed from the increased HRV following atenolol 50 mg. The Poincaré plot, constructed by plotting each RR interval against the preceding RR interval, was measured using a reproducible computerized method. Scatterplot length and area were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo; scatterplot length and area were lower after pindolol 10 mg compared with atenolol 50 mg. Geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At the higher percentiles (i.e., 90% of scatterplot length: low HR), salbutamol 8 mg reduced and atenolol 50 mg increased dispersion; at lower percentiles (i.e., 10%, 25%, and 50% length), atenolol 50 mg and pindolol 10 mg increased dispersion compared with placebo and salbutamol 8 mg. Cardiac sequence analysis (differences between three adjacent beats; delta RR vs. delta RRn + 1) was used to assess the short-term patterns of cardiac acceleration and deceleration. Four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration episodes (i.e., number of times delta RR and delta RRn + 1 were both changed) were increased in quadrants -/- and +/+ following pindolol 10 mg and salbutamol 8 mg; the beat-to-beat difference (delta RRn + 1) was reduced after salbutamol 8 mg compared with the three other groups. These results demonstrated a shift towards sympathetic dominance (beta-adrenoceptor partial agonist salbutamol 8 mg) or parasympathetic dominance (beta 1-adrenoceptor antagonist atenolol 50 mg); pindolol 10 mg exhibited HR-dependent effects, reducing HRV at low but increasing variability at high prevailing heart rates. These nonlinear methods appear to be valuable tools to investigate HRV in health and to study the implications of perturbation of HRV with drug therapy in disease states.

[The reproductive function following a hydatidiform mole]. This paper starts with a short description of the history of the discovery of the hydatidiform mole ( Tulp in 1641) and of the treatment (before 1956, hysterectomy in most cases). After 1961 chemotherapy started to be used even in patients who had cerebral metastases. 72 patients who had attended Professor Hubinont 's department in the University Hospital of Saint-Pierre in Brussels between January 1971 and December 1981 were followed up. Questionnaires were sent to the patients and to their doctors who were treating them in order to try and find out what had happened in subsequent pregnancies and what the maternal and fetal consequences and complications were. The social class and the marital status of the patients was also considered as well as their wish to become pregnant again. Of the 72 cases that were followed up after evacuation 63 (87.5%) recovered while 9(12.5%) had clinical, biological or radiological signs of persistent non-metastatic (3) and metastatic (6 cases) active disease. The department asked patients not to become pregnant in the year following evacuation of the mole. 10% were sterilised, 4 by hysterectomy and 4 by tubal ligation. 42% used the oral contraceptive pill and 34% (24 cases) condoms. Control follow-up of patients who became pregnant was compared with a group of 2 529 pregnancies in Saint-Pierre Hospital during the year 1981. 44 out of the 72 patients who were followed up after hydatidiform mole became pregnant with a total of 52 pregnancies. Ten became pregnant in the first 6 months after attempting it, 11 between 6 and 12 months and 23 after a delay of 12 months. Out of the 52 pregnancies, 34 5%) had a live baby at term. 6 were premature and 31 out of 34 babies delivered at term were delivered vaginally and 3 by Caesarean. There were 9 spontaneous abortions (17%) and 2 terminations of pregnancy (4%). Three patients had repeated non-intentional abortions and one had a still-birth for which the cause could not be found. Only one other had a second mole. When these results are compared with the histories of these patients before they had the hydatidiform mole there did not seem to be any increase in the number of spontaneous abortions or premature labours, nor was there when this group was compared with a control group. Only one of the 38 live-born children showed a major congenital abnormality which was varus equinus. There was no possibility of picking out statistically anything of value as far as congenital malformations was concerned.

Interdialytic weight gain as a marker of blood pressure, nutrition, and survival in hemodialysis patients. Excessive interdialytic weight gain (IDWG) is usually related to an overload of sodium and water, and is the most important factor for arterial hypertension in dialysis. On the other hand, food intake also contributes to IDWG, and is the basic factor for nutrition. The objective of this study is to assess the long-term prognostic effect of IDWG and its relationship with the nutritional status and blood pressure in patients in hemodialysis (HD). We describe the results of a 5-year prospective observation study in which 134 HD patients were included (70 males and 64 females), with ages between 18 and 81. Initially, the average data were collected during 4 weeks, including total IDWG and percentages according to dry weight (IDWG%), nutritional parameters, and blood pressure. Patients were divided into 3 cohorts according to IDWG% (<2.9, 2.9-3.9, and >3.9%, respectively). Student t test, ANOVA, linear regression analysis, and Kaplan-Meier survival curves compared with log-rank test were used as statistical tools. The mean IDWG% for the whole studied population was 3.5 +/- 1.1% (1.5-8.0%). It was not related to gender, but had an inverse correlation with age (P < 0.000) and serum bicarbonate level (P= 0.009). It was directly correlated with predialysis systolic and diastolic blood pressure, nPCR, urea and creatinine levels (P < 0.01 for all of them), and the body mass index (P < 0.000). Serum levels of albumin (44.7 +/- 4.0 g/dL) and prealbumin (31.9 +/- 7.4 mg/dL) had a direct correlation with total IDWG (P < 0.01). We found no significant relationship between or IDWG% and ferritin and transferrin levels. Five-year actuarial survival was 0.38, 0.52, and 0.63, respectively, in the 3 cohorts for IDWG% (P < 0.01). Our results show that a greater IDWG is directly associated with a better nutritional status, although it is also associated with higher predialysis blood pressure. The greater the IDWG%, the better the long-term prognosis of the patients. The beneficial effects of IDWG on the nutritional status and prognosis are greater than the negative aspects that depend on its effects on blood pressure. One must distinguish clearly between some isolated instances of not complying with a diet from those situations where a higher IDWG is merely a reflection of a good nutritional status, and one must be careful so that dietary recommendations will not have a negative influence on nutritional aspects. One must watch and correct the trend towards higher acidosis in patients with a greater IDWG.

[Association of angiotensin converting enzyme polymorphism and echocardiographic measures in young siblings of hypertensive parents]. To evaluate angiotensin converting enzyme gene (ACE) polymorphism with transthoracic bidimensional echocardiogram of normotensive young medical students, siblings of hypertensive parents comparing them with those with normotensive parents. We had studied 80 normotensive youngs divided in two groups. Hypertensive parents' normotensive young medical students 40 x Normotensive parents' and normotensive medical students. Exclusion criteria were hypertension, obesity, smoke, use of oral contraceptives, as well as those who use chronically drugs or the presence of any disease. The group has been enrolled between 1994 to 1996. 50 students made transthoracic bidimensional echocardiogram. The statistical analysis was done by "T-student" test. The evaluation of polymorphism ACE gene was studied in 80 people in each step: 1) 5 mL of blood in EDTA tube, 2) extraction of DNA, 3) evaluation of DNA concentration by electrophoresis analyses; 4) Polymerase chain reaction with primer of ACE gene, 5) Analysis of polymorphism ACE gene by electrophoresis 6) Statistical analysis by Chi-square test. The group of students with hypertensive parents presented thicker interventricular septum (7.82 mm +/- 0.69 against 7.38 mm +/- 0.8, p<0.05). On the other hand, we didn't find differences between the groups concerning ACE gene genotype: students with hypertensive parents DD: 42.5%, DI: 37.5%, II: 20% against Students with normotensive parents: DD: 37.5%, DI: 32.5%, II: 30%, (p=0.58), in addition we also did not find differences concerning the alleles Group of hypertensive parents: D: 61.25%, I: 38.75% versus normotensive parents: D: 53.75%, I: 46.25%, p=0.33. We divided these groups into two in relation to the mean thickness of interventricular septum and left ventricular mass and we did not find any difference: in students with hypertensive parents group septum > 7.82 mm: DD: 32%, DI: 24%, II: 20% x septum < 7.82 mm: DD: 8%, DI: 12%, II: 4%, p=0.7) in normotensive parents group septum septum > 7.38 mm: DD: 28%, DI: 12%, II: 12% x septum < 7.38 mm: DD: 16%, DI: 16%, II: 16%, p=0.59). The study of the left ventricular mass in hypertensive parents group mass > 131.52 g: DD: 20.69%, DI: 13.79%, II: 6.9% x mass < 131.52 g DD: 24.24%, DI: 17.24%, II: 17.24%, (p=0.72) in normotensive parents group mass > 117.11 g: DD: 30.43%, DI: 8.7%, II: 8.7% x mass < 117.11 g: DD: 13.04%, DI: 21.74%, II: 17.39%, (p=0.17). We found differences between the thickness of the interventricular septum of normotensive students sibling of hypertensive parents and normotensive parents. On the other hand we didn't find any difference between the two groups concerning the ACE gene polymorphism as well as any relation of ACE gene and thickness of interventricular septum and interventricular left ventricular mass.

Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial. In patients with type 2 diabetes, intensive glucose control can be renoprotective and albuminuria-lowering treatments can slow the deterioration of kidney function. We assessed the albuminuria-lowering effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin with and without the dipeptidyl peptidase-4 inhibitor saxagliptin, and the effect of dapagliflozin-saxagliptin on glycaemic control in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. In this double-blind, placebo-controlled trial (DELIGHT), we enrolled patients at 116 research centres in Australia, Canada, Japan, South Korea, Mexico, South Africa, Spain, Taiwan, and the USA. We included patients with a known history of type 2 diabetes, increased albuminuria (urine albumin-to-creatinine ratio [UACR] 30-3500 mg/g), an estimated glomerular filtration rate of 25-75 mL/min per 1·73 m2, and an HbA1c of 7·0-11·0% (53-97 mmol/mol), who had been receiving stable doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy and glucose-lowering treatment for at least 12 weeks. After a 4-week, single-blind placebo run-in period, participants were randomly assigned (1:1:1; via an interactive voice-web response system) to receive dapagliflozin (10 mg) only, dapagliflozin (10 mg) and saxagliptin (2·5 mg), or placebo once-daily for 24 weeks. Primary endpoints were change from baseline in UACR (dapagliflozin and dapagliflozin-saxagliptin groups) and HbA1c (dapagliflozin-saxagliptin group) at week 24 in all randomly allocated patients with available data (full analysis set). This study is registered with ClinicalTrials.gov, number NCT02547935 and is completed. The study took place between July 14, 2015, and May 18, 2018. 1187 patients were screened, of whom 461 were randomly assigned: 145 to the dapagliflozin group, 155 to the dapagliflozin-saxagliptin group, and 148 to the placebo group (13 patients were excluded because of data integrity issues). Dapagliflozin and dapagliflozin-saxagliptin reduced UACR versus placebo throughout the study period. At week 24, the difference (vs placebo; n=134 patients with available data) in mean UACR change from baseline was -21·0% (95% CI -34·1 to -5·2; p=0·011) for dapagliflozin (n=132) and -38·0% (-48·2 to -25·8; p<0·0001) for dapagliflozin-saxagliptin (n=139). HbA1c was reduced in the dapagliflozin-saxagliptin group (n=137) compared with the placebo group (n=118) at week 24 (-0·58% [-0·80 to -0·37; p<0·0001]). The numbers of patients with adverse events (79 [54%] in the dapagliflozin group, 104 [68%] in the dapagliflozin-saxagliptin group, and 81 [55%] in the placebo group) or serious adverse events (12 [8%], 12 [8%], and 16 [11%], respectively) were similar across groups. There were no new drug-related safety signals. Dapagliflozin with or without saxagliptin, given in addition to angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, is a potentially attractive option to slow the progression of kidney disease in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. AstraZeneca.

[Surgical palliation for pancreatic cancer. The 25-year experience of a single reference centre]. In spite of dynamic development of modern diagnostic and therapeutic methods, the long-term results of surgical therapy in pancreatic cancer are still unsatisfying. The aim of this study was to analyse long-term results of surgical palliation for pancreatic cancer in a pancreatic surgery centre. We performed a retrospective analysis of 418 patients who underwent non-resective, palliative procedures for pancreatic cancer between 1975 and 1999. In order to compare two consecutive periods of time, the patients were divided in 2 groups; group I treated from 1975 to 1990 (n = 204), and group II from 1991 to 1999 (n = 214). Of all patients qualified for surgery, 281 (67.2 %) underwent surgical bypass, 107 (25.6 %) laparotomy, and in 30 cases surgical intervention was limited to implantation of endoprosthesis. A significant tendency towards double (i. e. biliary and gastric) anastomosis was observed (32.3 % vs. 74.8 %; p < 0.01) in patients who underwent bypass procedures. The postoperative morbidity was 16.3 %. The postoperative mortality rate was 5.7 % and significantly (p < 0.01) decreased from 10.3 % (group I) to 1.4 % (group II). No differences neither in mortality nor morbidity related to the type of performed surgery were found. The mean time of hospital stay was 15.5 +/- 6.9 days and showed no differences related to the type of intervention. Jaundice or symptoms of gastric outlet obstruction were observed in 16 % of patients in the follow-up period and concomitantly performed biliary and gastric bypasses were associated with the lowest rate of the late gastrointestinal obstruction (4 %). The median survival time was 169 days and only 4 % of patients survived 12 months. The univariate analysis of prognostic factors showed that location and stage of the tumour, the type of surgical intervention and bypass procedure influenced 1-year survival. The multivariate analysis using Cox proportional hazard model proved that only stage and location of the tumour had independent prognostic value. Surgical palliation for pancreatic cancer can be performed with acceptable morbidity and mortality rates. For tumours located in the head and body of the pancreas combined biliary and gastric bypass should be preferred. For cancers located in the tail of the pancreas gastric bypass should be performed routinely. Because surgical palliation can prevent gastric outlet obstruction by gastroenterostomy, endoscopic biliary stenting should be only performed in patients with pancreatic head cancers and simultaneous evidence of distal metastases as well as in older patients with high comorbidity.

Dental Patient Safety in the Military Health System: Joining Medicine in the Journey to High Reliability. Delivering consistent high quality care in a safe environment is the goal of the modern dental delivery system. Preventable adverse events, however, are still commonplace in dentistry. As has been demonstrated in the medical field, a concerted and persistent effort will be required to objectively understand and begin to eliminate the sources of dental error. In civilian dental practice this effort is hampered by the underreporting of patient safety events in comparison to the medical field. Patient safety reporting in the Military Health System (MHS) is robust and includes dentistry. This provides an important opportunity to analyze these data as the foundation for improvements in dental care and the elimination of preventable harm. The purpose of this article is to review MHS dental patient safety data, identify the primary sources of dental error and describe current initiatives based on the adoption of the High Reliability Organization (HRO) model of care that has been profitably embraced by the medical community. Dental patient safety report data from the Defense Health Agency Patient Safety Analysis Center (PSAC) for the period 2013-2016 were analyzed to determine the type, incidence, contributing factors, setting and trends for dental errors occurring within the MHS. Comparison to medical data was also performed. From 2013 to 2016, there was a 32.1% increase in dental patient safety reports in the MHS. For this period, dentistry accounted for the highest number of Sentinel Events (SEs) compared to other clinical specialties and accounted for 32.7% of all SEs for the period. From 2013 to 2016, there was a five-fold increase in reported dental SEs. Wrong-Site Surgeries (WSS) comprised the highest proportion of SEs followed by intraoperative or immediate post-operative/post-procedure or surgery issues (63% and 14%, respectively). Within the WSS category, wrong-site anesthesia and wrong-tooth treated were the two largest sub-categories (40% and 32%, respectively). The data reviewed are not rates and do not take into account the total number of procedures performed by dentistry in comparison to medicine. Root cause analysis identified communication failures and inconsistent adoption of the Universal Protocol as the leading contributing factors for WSSs. Safety initiatives in the dental profession remain immature in comparison to the medical field and the use of an HRO framework is just beginning to emerge in dentistry. The MHS benefits from a robust dental patient safety reporting system when compared to civilian practice in the United States. Review of these data demonstrates that a high priority focus should be the elimination of WSS. Initiatives based on high reliability strategies to address this issue will be discussed. A commitment to reporting and analyzing its performance and adopting the principles and behaviors of HROs will accelerate the MHS goal of providing ever increasing safety and quality in the dental care it provides.