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Paraventricular nucleus mediates prolactin secretory responses to restraint stress, ether stress, and 5-hydroxy-L-tryptophan injection in the rat. The role of the paraventricular nucleus (PVN) in mediating acute stimulatory PRL responses was investigated in conscious male rats. Electrolytic lesions, verified histologically at autopsy, were stereotaxically made in the PVN region, and sham lesions were made in control rats. Blood was obtained through a chronically indwelling catheter in the right atrium. PVN-lesioned (PVL) rats showed significantly lower T3 levels 1 week after surgery (less than 34.4 ng/dl) compared with sham (mean +/- SEM, 91.2 +/- 5.0 ng/dl) and intact (86.8 +/- 2.0 ng/dl) animals, verifying a lesion in the PVN. T3 was restored to normal (95.6 +/- 1.8 ng/dl) by daily sc administration of T4 (10 micrograms/kg BW) for at least 4 days before the day of the experiments. Basal PRL levels in PVL rats did not differ significantly from those in control or sham-lesioned animals. In response to restraint stress, plasma PRL levels of PVL rats did not rise, in contrast to marked elevation in PRL in sham and intact rats [PRL levels (mean +/- SEM; nanograms per ml), basal to peak: PVL, 4.3 +/- 0.3 to 4.5 +/- 0.4; sham, 4.5 +/- 0.5 to 47.0 +/- 4.1; intact, 4.0 +/- 0.3 to 46.3 +/- 4.9]. PVL also resulted in the complete inhibition of PRL secretion induced by 30-min inhalation of ether (basal to peak: PVL, 3.3 +/- 0.3 to 4.5 +/- 0.2; sham, 5.7 +/- 0.8 to 19.9 +/- 0.9; intact, 3.3 +/- 0.4 to 27.9 +/- 4.0). The stimulatory effect on plasma PRL in sham and intact rats by one iv bolus injection of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP; 10 mg/kg BW) was completely abolished in PVL animals (basal to peak: PVL, 3.7 +/- 0.6 to 5.2 +/- 1.4; sham, 6.7 +/- 0.6 to 36.0 +/- 0.5; intact, 4.1 +/- 1.2 to 33.3 +/- 3.2). In contrast to the marked alteration in PRL regulation, PVL rats exhibited a typical ultradian rhythm of plasma GH secretion during a 6-h observation period and increased release of GH induced by iv injection of 5-HTP [GH (nanograms per ml), basal to peak; PVL, 4.5 +/- 0.6 to 21.0 +/- 4.9; sham, 3.7 +/- 0.3 to 18.4 +/- 4.4; intact, 2.9 +/- 0.1 to 17.8 +/- 3.5]. These findings indicate that PRL responses to stress and to serotonin act through the PVN, the site of origin of several putative PRL-releasing factors.(ABSTRACT TRUNCATED AT 400 WORDS)

[Evaluation of effect of community DOTS on treatment outcomes by TB surveillance data]. The purpose of this study is to evaluate effects of community DOTS on treatment outcome by cohort data derived from TB surveillance system and to find further problems. New sputum smear positive pulmonary TB patients registered in 2003 and 1998 under standard course regimens. In Japan, DOTS as a method of directly observed treatment by Short Course Chemotherapy is divided into hospital DOTS and community DOTS. Hospital DOTS is to observe hospitalized patients' drug taking directly by hospital staff such as nurses, pharmacists or other hospital staff. Community DOTS is to observe or confirm discharged patients' drug taking by several methods such as direct observation at facility or patient's home, confirmation through checking treatment notes and examining empty blister packages and so on. TB patients were categorized to following 3 groups by available methods of community DOTS. Treatment outcome of patients registered in 2003 was compared with outcome of patients registered in 1998 as the control group before the introduction of community DOTS. Group 1: TB patients under PHC where at least daily observation DOTS (daily observation of drug taking at clinic or PHC to TB patients with risk factors of defaulting such as homeless, alcohol abuse, past history of default and so on) is available. Group 2: TB patients under PHC where home-visit DOTS (home-visit for observation of drug taking to the elderly TB patients who have risk to forget to take TB medicines regularly) only is available or, PHC where home-visit DOTS and confirmation DOTS (periodical confirmation of drug taking to TB patients without risk of defaulting) is available. Group 3: TB patients under PHC where only confirmation DOTS is available. Group 4: TB patients under PHC where community DOTS is not available. In addition, high death rate of patients under public assistance is analyzed. In group 1 with daily observation DOTS, TB patients under social or national health insurance showed higher treatment success rate and lower defaulter rate. TB patients with insurance for aged showed lower defaulter rate but high death rate due to old age did not improve. Patients under public assistance showed relatively lower defaulter rate. In group 2 with home-visit DOTS, TB patients with national health insurance and insurance for aged showed rather lower defaulter rate. Cohort evaluation of TB patients under group 3 with confirmation DOTS and group 4 without community DOTS is difficult as high rate of unknown treatment result. TB patients receiving public assistance showed lower death rate than patients requiring but not receiving public assistance. Patients detected at clinic and hospitals showed higher death rate than other patients detected by screening for high risk groups and so on. Daily observation DOTS and home-visit DOTS were effective to improve success rate and defaulter rate but effect of confirmation DOTS was not proved due to lack of information. High death rate of patients with insurance for aged in all groups and lack of treatment results in group 3 and 4 were problems to be solved in the future. In order to avoid TB death among TB patients under public assistance, screening for homeless people as high risk groups, earlier detection and referral system of TB symptomatics and improvement of coverage in public assistance might be effective and be tried.

Clinical study of optical coherence tomography in the diagnosis of peripheral pulmonary artery thrombus. Peripheral pulmonary artery thrombus (PPT) is common in the clinic. However, due to the lack of an ideal diagnostic tool, PPT cannot be quickly diagnosed and effectively treated at present. Optical coherence tomography (OCT) is a new intravascular imaging technique that is characterized by high image resolution. This technique is suitable for small vessel imaging and has the ability to distinguish red and white thrombi. This study aimed to evaluate the value of OCT in the diagnosis of PPT and in identifying the nature of thrombi by comparing the difference in sensitivity between OCT and selective pulmonary angiography (SPA). Highly suspected PPT patients were enrolled in this study. Pulmonary ventilation/perfusion (V/Q) mismatch pulmonary segments or peripheral pulmonary arteries were chosen. SPA was performed first, followed by OCT imaging. The diagnostic standard of thrombus with SPA was an intraluminal filling defect. The procedure and criteria for OCT diagnosis of thrombus were previously introduced in intracoronary OCT thrombus images. The diameter of the imaging vessels was measured, and they were grouped according to diameter. The diameter was <2mm in the distal segment group, 2-3mm in the middle segment group, and >3mm in the proximal segment group. The recognition abilities of intravascular thrombus with the different diameters of these two techniques were compared. Patients with obvious clinical symptoms and more red thromboses revealed by OCT were given standardized anticoagulant therapy for half a year. The clinical symptoms, 6-minute walking test and changes in the thrombus in the OCT images of these patients before and after treatment were observed. A total of 22 patients with highly suspected PPT were suggested to undergo V/Q inspection. Finally, 12 patients were eligible for the study. SPA and OCT were performed in 61 peripheral pulmonary arteries in all 12 patients. The ideal SPA and OCT images obtained from a total of 76 blood vessel segments were suitable for comparative analysis. A total of 62 thrombi were found by SPA. Among these, eight thrombi were in the distal segment, 29 thrombi were in the middle segment, and 25 thrombi were in the proximal segment. A total of 81 thrombi were found by OCT, among which 22 thrombi were in the distal segment, 31 were in the middle segment, and 28 were in the proximal segment. There was a significant difference between two groups in the distal segment group (P=0.013), while there was no significant difference between two groups in the middle segment group or the proximal segment group (P>0.05). In addition to all the thrombi found by SPA, OCT found other thrombi that were missed by SPA. According to previous OCT images for determining the nature of thrombi, OCT revealed 81 thrombi, of which 48 (59%) were red thrombi and 33 (41%) were white thrombi. Then, seven patients who had obvious clinical symptoms and more red thrombi in the peripheral pulmonary artery were given anticoagulant therapy for six months. After treatment, these symptoms were improved, oxygenation indexes increased, and the six-minute walking test was extended in all these patients. After anticoagulation therapy, five patients underwent OCT review. These OCT images were matched and compared before and after anticoagulation therapy. The results revealed that most of the thrombi had disappeared, and a small amount of red thrombi turned white as the volume reduced. The mean lumen area before and after treatment was 2.05±1.03mm2 and 2.86±1.24mm2, respectively, and the difference was statistically significant (P=0.035). OCT can clearly show the structure of the lumen and the wall of the peripheral pulmonary artery tube. The sensitivity of the diagnosis of PPT with a diameter of <2mm was higher than that of SPA. Moreover, OCT has the ability to distinguish between red and white thrombi, which is of guiding significance in anticoagulant therapy.

Reduced paediatric hospitalizations for malaria and febrile illness patterns following implementation of a community-based malaria control programme in rural Rwanda. Malaria control is currently receiving significant international commitment. As part of this commitment, Rwanda has undertaken a two-pronged approach to combating malaria via mass distribution of long-lasting insecticidal-treated nets and distribution of antimalarial medications by community health workers. This study attempted to measure the impact of these interventions on paediatric hospitalizations for malaria and on laboratory markers of disease severity. A retrospective analysis of hospital records pre- and post-community-based malaria control interventions at a district hospital in rural Rwanda was performed. The interventions took place in August 2006 in the region served by the hospital and consisted of mass insecticide treated net distribution and community health workers antimalarial medication disbursement. The study periods consisted of the December-February high transmission seasons pre- and post-rollout. The record review examined a total of 551 paediatric admissions to identify 1) laboratory-confirmed malaria, defined by thick smear examination, 2) suspected malaria, defined as fever and symptoms consistent with malaria in the absence of an alternate cause, and 3) all-cause admissions. To define the impact of the intervention on clinical markers of malaria disease, trends in admission peripheral parasitaemia and haemoglobin were analyzed. To define accuracy of clinical diagnoses, trends in proportions of malaria admissions which were microscopy-confirmed before and after the intervention were examined. Finally, to assess overall management of febrile illnesses antibiotic use was described. Of the 551 total admissions, 268 (48.6%) and 437 (79.3%) were attributable to laboratory confirmed and suspected malaria, respectively. The absolute number of admissions due to suspected malaria was smaller during the post-intervention period (N = 150) relative to the pre-intervention period (N = 287), in spite of an increase in the absolute number of hospitalizations due to other causes during the post-intervention period. The percentage of suspected malaria admissions that were laboratory-confirmed was greater during the pre-intervention period (80.4%) relative to the post-intervention period (48.1%, prevalence ratio [PR]: 1.67; 95% CI: 1.39-2.02; chi-squared p-value < 0.0001). Among children admitted with laboratory-confirmed malaria, the risk of high parasitaemia was higher during the pre-intervention period relative to the post-intervention period (age-adjusted PR: 1.62; 95% CI: 1.11-2.38; chi-squared p-value = 0.004), and the risk of severe anaemia was more than twofold greater during the prei-ntervention period (age-adjusted PR: 2.47; 95% CI: 0.84-7.24; chi-squared p-value = 0.08). Antibiotic use was common, with 70.7% of all children with clinical malaria and 86.4% of children with slide-negative malaria receiving antibacterial therapy. This study suggests that both admissions for malaria and laboratory markers of clinical disease among children may be rapidly reduced following community-based malaria control efforts. Additionally, this study highlights the problem of over-diagnosis and over-treatment of malaria in malaria-endemic regions, especially as malaria prevalence falls. More accurate diagnosis and management of febrile illnesses is critically needed both now and as fever aetiologies change with further reductions in malaria.

Image Quality of a Novel Frequency Selective Nonlinear Blending Algorithm: An Ex Vivo Phantom Study in Comparison to Single-Energy Acquisitions and Dual-Energy Acquisitions With Monoenergetic Reconstructions. Aim of this ex vivo phantom study was to evaluate the contrast enhancement applying a new frequency split nonlinear blending algorithm (best contrast [BC]) and to compare it with standard 120-kV single-energy computed tomography (SECT) images, as well as with low-kiloelectron volt monoenergetic extrapolations (Mono+40-100keV) from dual-energy CT (DECT) and with low-kilovolt (70-100 kV) SECT acquisitions. A dilution series of iodinated contrast material-filled syringes was centered in an attenuation phantom and was scanned with SECT70-120kV and DECT80-100/Sn150. Monoenergetic images (40-100 keV) were reconstructed, and a new manual frequency split nonlinear blending algorithm (BC) was applied to SECT70kV and SECT120kV images. Manual BC settings were set to simulate a reading situation with fixed overall best values (FVBC120kV) as well as to achieve best possible values for each syringe (BVBC120kV) for maximum contrast enhancement. Contrast-to-noise ratios (CNRs) were used as an objective region of interest-based image analysis parameter. Two radiologists evaluated the detectability of hyperdense and hypodense syringes (Likert). Results were compared between SECT70-100kV, Mono+40-100keV, and DECT80-100/Sn150kV, as well as FVBC120kV, BVBC120kV, and BC70kV. Highest CNR without BC was detected at SECT70kV (5.04 ± 0.12) and Mono+40keV (4.40 ± 0.11). FVBC and BVBC images allow a significant increase of CNR compared with SECT120kV (CNRBVBC, 5.21 ± 0.15; CNRFVBC, 5.12 ± 0.16; CNRSECT120kV, 2.5 ± 0.08; all P ≤ 0.01). There was no significant difference in CNR between BVBC and FVBC. Averaged CNR in BVBC and FVBC was significantly higher compared with Mono+40-100keV (all P ≤ 0.01). Compared with SECT70kV, averaged CNR in BVBC and FVBC show no significant differences. BVBC70kV (7.67 ± 0.17) significantly increases CNR in SECT70kV up to 213%.Subjective image analysis showed an interobserver agreement of 0.63 to 0.83 (κ), confirming the superiority of BC in detecting hyperdense and hypodense syringes, when compared with SECT120kV. Compared with SECT120kV, BVBC70kV was scored highest, followed by SECT70kV. BVBC showed higher scores when comparing to Mono+40keV, however almost identical to those of SECT70kV. Scores of FVBC were slightly lower than SECT70kV, but in the range of Mono+40keV. The new frequency split nonlinear blending algorithm with fixed settings offers a superior differentiation of contrast levels from low- to high-contrast settings. Using the optimal settings, this algorithm shows an equivalent contrast enhancement when compared with SECT70kV. Because of the non-DECT-based algorithm of BC, the new method of contrast enhancement seems to be particularly valuable for implementation in CT systems not equipped for dual-energy or spectral CT imaging.

A comparative study of small field total scatter factors and dose profiles using plastic scintillation detectors and other stereotactic dosimeters: the case of the CyberKnife. Small-field dosimetry is challenging, and the main limitations of most dosimeters are insufficient spatial resolution, water nonequivalence, and energy dependence. The purpose of this study was to compare plastic scintillation detectors (PSDs) to several commercial stereotactic dosimeters by measuring total scatter factors and dose profiles on a CyberKnife system. Two PSDs were developed, having sensitive volumes of 0.196 and 0.785 mm(3), and compared with other detectors. The spectral discrimination method was applied to subtract Čerenkov light from the signal. Both PSDs were compared to four commercial stereotactic dosimeters by measuring total scatter factors, namely, an IBA dosimetry stereotactic field diode (SFD), a PTW 60008 silicon diode, a PTW 60012 silicon diode, and a microLion. The measured total scatter factors were further compared with those of two independent Monte Carlo studies. For the dose profiles, two commercial detectors were used for the comparison, i.e., a PTW 60012 silicon diode and Gafchromics EBT2. Total scatter factors for a CyberKnife system were measured in circular fields with diameters from 5 to 60 mm. Dose profiles were measured for the 5- and 60-mm cones. The measurements were performed in a water tank at a 1.5-cm depth and an 80-cm source-axis distance. The total scatter factors measured using all the detectors agreed within 1% with the Monte Carlo values for cones of 20 mm or greater in diameter. For cones of 10-20 mm in diameter, the PTW 60008 silicon diode was the only dosimeter whose measurements did not agree within 1% with the Monte Carlo values. For smaller fields (<10 mm), each dosimeter type showed different behaviors. The silicon diodes over-responded because of their water nonequivalence; the microLion and 1.0-mm PSD under-responded because of a volume-averaging effect; and the 0.5-mm PSD was the only detector within the uncertainties of the Monte Carlo simulations for all the cones. The PSDs, the PTW 60012 silicon diode, and the Gafchromics EBT2 agreed within 2% and 0.2 mm (gamma evaluation) for the measured dose profiles except in the tail of the 60-mm cone. Silicon diodes can be used to accurately measure small-field dose profiles but not to measure total scatter factors, whereas PSDs can be used to accurately measure both. The authors' measurements show that the use of a 1.0-mm PSD resulted in a negligible volume-averaging effect (under-response of ≈1%) down to a field size of 5 mm. Therefore, PSDs are strong candidates to become reference radiosurgery detectors for beam characterization and quality assurance measurements.

Decision-makers' preferences for approving new medicines in Wales: a discrete-choice experiment with assessment of external validity. Few studies to date have explored the stated preferences of national decision makers for health technology adoption criteria, and none of these have compared stated decision-making behaviours against actual behaviours. Assessment of the external validity of stated preference studies, such as discrete-choice experiments (DCEs), remains an under-researched area. The primary aim was to explore the preferences of All Wales Medicines Strategy Group (AWMSG) appraisal committee and appraisal sub-committee (the New Medicines Group) members ('appraisal committees') for specific new medicines adoption criteria. Secondary aims were to explore the external validity of respondents' stated preferences and the impact of question choice options upon preference structures in DCEs. A DCE was conducted to estimate appraisal committees members' preferences for incremental cost effectiveness, quality-adjusted life-years (QALYs) gained, annual number of patients expected to be treated, the impact of the disease on patients before treatment, and the assessment of uncertainty in the economic evidence submitted for new medicines compared with current UK NHS treatment. Respondents evaluated 28 pairs of hypothetical new medicines, making a primary forced choice between each pair and a more flexible secondary choice, which permitted either, neither or both new medicines to be chosen. The performance of the resultant models was compared against previous AWMSG decisions. Forty-one out of a total of 80 past and present members of AWMSG appraisal committees completed the DCE. The incremental cost effectiveness of new medicines, and the QALY gains they provide, significantly (p < 0.0001) influence recommendations. Committee members were willing to accept higher incremental cost-effectiveness ratios and lower QALY gains for medicines that treat disease impacting primarily upon survival rather than quality of life, and where uncertainty in the cost-effectiveness estimates has been thoroughly explored. The number of patients to be treated by the new medicine did not exert a significant influence upon recommendations. The use of a flexible-choice question format revealed a different preference structure to the forced-choice format, but the performance of the two models was similar. Aggregate decisions of the AWMSG were well predicted by both models, but their sensitivity (64 %, 68 %) and specificity (55 %, 64 %) were limited. A willingness to trade the cost effectiveness and QALY gains against other factors indicates that economic efficiency and QALY maximisation are not the only considerations of committee members when making recommendations on the use of medicines in Wales. On average, appraisal committee members' stated preferences appear consistent with their actual decision-making behaviours, providing support for the external validity of our DCEs. However, as health technology assessment involves complex decision-making processes, and each individual recommendation may be influenced to varying degrees by a multitude of different considerations, the ability of our models to predict individual medicine recommendations is more limited.

Meta-analytic review of the clinical effectiveness of oral deferiprone (L1). To summarize efficacy and effectiveness in iron overloaded patients treated with the orally active iron chelator deferiprone also known as L1 or, using meta-analysis of the literature. We reviewed the literature, searching Medline and Embase databases, as well as reviews and other literature on the topic. Inclusion criteria were: original clinical trials reporting results for serum ferritin concentration (SF), hepatic iron concentration or urinary iron excretion (UIE). Efficacy data had to have been reported after > or =3 months of treatment. Data were combined using a random effects model (Cochrane) modified for use with single groups to produce a point estimate and a 95% confidence interval. To summarize the clinical effectiveness, overall proportion of patients where deferiprone was able to reduce serum ferritin was calculated. We also examined average (mg x l(-1)) serum ferritin levels over the reported time (mean) and absolute decrease from the baseline after therapy. To summarize efficacy, success was defined as the proportion of patients who achieved UIE of 25 mg per day or 0.5 mg x kg(-1) x day(-1), which equals the average amount received from monthly blood transfusions. We also calculated the overall average level (mg per day) of UIE over the reported time of therapy (mean). As part of a sensitivity analysis, data were analyzed for two ranges of deferiprone dosage: < or = 50 mg x kg(-1) x day(-1) and > or =75 mg x kg(-1) x day(-1). Of 83 identified references, nine clinical trials met our inclusion criteria, providing data for 129 iron overloaded patients. After a mean of 16 months of therapy (range 6.4 36 months) with 66.4 mg x kg(-1) x day(-1) (mean) of deferiprone, 75.5% of highly iron overloaded patients had a decrease in serum ferritin from baseline. The average drop in serum ferritin of 0.8 mg x l(-1) was 23.5% from baseline. The overall average UIE for therapy was 28.8 mg per day in patients receiving > or = 75 mg x kg(-1) x day(-1) over 8.5 months of therapy. At the same dosage, more than half of the patients (51.8%) achieved negative iron balance. When studies with patients receiving lower dosage (< or = 50 mg x k(-1) x day(-1)) were included, the success rate was 45.1%. Overall, deferiprone has clinical efficacy in achieving negative iron balance and reducing body iron burden in highly iron overloaded patients. After an average of 16 months of deferiprone in doses > or = 75 mg x kg(-1) x day(-1), most patients had a decrease in ferritine concentration.

Studies on stercuia gum formulations in the form of osmotic core tablet for colon-specific drug delivery of azathioprine. The purpose of this research is to evaluate Sterculia urens gum as a carrier for a colon-targeted drug delivery system. Microflora degradation studies of Sterculia gum was conducted in phosphate-buffered saline pH 7.4 containing rat caecal medium under an anaerobic environment. Solubility, swelling index, viscosity, and pH of the polymer solution were determined. Different formulation aspects considered were gum concentration (10-40%) and concentration of citric acid (10-30%) on the swelling index and in-vitro dissolution release. The results of the isothermal stress testing showed that there is no degradation of samples of model drug, azathioprine, the drug polymer mixture, and the core tablet excipients. Differential scanning calorimetry and Fourier transform infrared spectroscopy study proved the compatibility of the drug with Sterculia gum and other tablet excipients. Microflora degradation study revealed that Sterculia gum can be used as tablet excipient for drug release in the colonic region by utilizing the action of enterobacteria. The swelling force of the Sterculia gum could concurrently drive the drug out of the polysaccharide core due to the rupture of the mixed film coating under colonic microflora-activated environment. Sterculia gum gives premature drug release in the upper gastrointestinal tract without enteric coating and may not reach the colonic region. Sterculia gum as a colon-targeting carrier is possible via double-layer coating with chitosan/Eudragit RLPO (ammonio-methacrylate copolymer) mixed blend as well as enteric polymers, which would provide acid as well as intestinal resistance but undergo enzymatic degradation once reaching the colon. The aim of the research is to evaluate wheather Sterculia urens, which is a polysaccharide, is suitable as a carrier for colonic delivery of drugs acting locally in the colon. Sterculia gum has been reported to have wide pharmaceutical applications such as tablet binder, disintegrant, gelling agent, and as a controlled release polymer. Sterculia gum falls under the category of a polysaccharide and is yet to be evaluated as a carrier for colonic delivery of drugs. First the susceptibility of the polysaccharide gum in rat caecal microflora was investigated because true polysaccharides are degraded by the action of normal colonic bacteria. Bacterial degradation of the gum in the colonic environment was confirmed by adding a small quantity of the gum in rat caecal content mixed with phosphate-buffered saline pH 7.4 under an anaerobic environment. Solubility, swelling index, viscosity, and pH of the polymer solution were determined. Different formulation aspects considered were gum concentration (10-40%), concentration of citric acid (10-30%) on swelling index, and in vitro dissolution behavior. Isothermal stress testing was done to determine that there was no degradation of the model drug, azathioprine, with Sterculia gum excipient mixtures under stressed conditions. Differential scanning calorimetry and Fourier transform infrared spectroscopy study proved the compatibility of the drug with Sterculia gum and other tablet excipients. Microflora degradation study revealed that Sterculia gum is digested by the colonic microflora and therefore can be used as a tablet excipient for drug release in the colonic region utilizing the microflora degradation mechanism. Sterculia gum gives premature drug release in the upper gastrointestinal tract without enteric coating and may not reach the colonic region. Sterculia gum as colon-targeting carrier is possible via double-layer coating with chitosan/Eudragit RLPO (ammonio-methacrylate copolymer) and Eudragit L100 polymers, which would provide acid as well as intestinal resistance but undergo enzymatic degradation once reaching the colon.

Differential regulation of rat peripheral 5-HT(2A) and 5-HT(2B) receptor systems: influence of drug treatment. Most studies of 5-HT(2) receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT(2A) and 5-HT(2C) receptors); very few in vitro studies have addressed the peripheral receptors 5-HT(2A) and 5-HT(2B). The aim of this investigation was to compare the possible short- and long-term processes regulating these peripheral receptors in the rat. The in vitro contractile response elicited by serotonin (5-HT, 10 micro M) in the rat gastric fundus (5-HT(2B) receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT(2A) receptor system), which was more stable, slower and sustained. To characterize drug-receptor interactions, cumulative concentration/response curves (CCRCs) for 5-HT were constructed ex vivo for rat tissues treated with drugs acting at these receptors. Rats were examined 4 or 24 h after a single, i.p. administration of (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)DOI, 1 or 2.5 mg/kg], clozapine, cyproheptadine or rauwolscine (10 mg/kg), 48 h after a single i.p. administration of (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine (10 mg/kg) or 24 h after the last of with 15 daily i.p. administrations of (+/-)DOI (1 or 2.5 mg/kg), clozapine, cyproheptadine or rauwolscine (10 mg/kg). In the aorta, E(max) (the maximum response elicited by 5-HT) was unchanged 4 h after a single dose of any of the drugs tested. However, 24 h after a single dose, E(max) was lower in animals treated with (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine than in controls, whilst 48 h after a single dose of (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine there was no difference in E(max) between experimental and control animals. After chronic treatment with (+/-)DOI (2.5 mg/kg), clozapine and cyproheptadine, E(max) was lower than in controls. In the gastric fundus, E(max) 4 h after a single dose of each drug was lower than in controls, and the response recovered by 24 or 48 h. Following chronic treatment, E(max) was significantly lower than in controls for each drug used. These findings suggest first, that regulation of peripheral 5-HT(2) receptors (5-HT(2A) and 5-HT(2B)) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT(2) receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT(2B) receptors in rat gastric fundus are more sensitive to drug-induced regulation than the 5-HT(2A) rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer.

A snapshot survey of perceptions of healthcare professionals on ageing surgeons. The aim of this research was to understand healthcare professionals' perception of the continued practice of ageing surgeons in Singapore. A quantitative method was chosen for this research to determine healthcare professionals' perception of the practice of ageing surgeons. Ethical approval was obtained from the local ethical review board. A cross-sectional method using a population survey was performed among healthcare professionals in two tertiary institutions and the study was confined to stakeholders in practices of ageing surgeons. The population sampled was limited to nurses in the theatre, anaesthetists, surgeons and geriatricians (physicians). An online questionnaire was designed for the survey that took into consideration the various conceptual frameworks of ageing surgeons' practice that was obtained from a literature review. There were 104 respondents of a population of 350 sampled (theatre nurses, anaesthetists, physicians and surgeons) giving a respondent rate of 30%. The mean age of the participants was 39.7; 72% were doctors (surgeons 34%, physicians 20% and anaesthetists 18%) and 28% nurses. Only 35% agreed with the statement that older surgeons face deterioration in cognitive faculties and 29% remained neutral. A similar trend was seen with the perception that older surgeons face a decline in memory. However, 44% agreed with the statement that older surgeons face a decline in visuospatial ability and another 40% agreed that they had a decline in psychomotor skills and reaction time. Fifty per cent agreed with the statement that they face deterioration in physical abilities. Sixty-three per cent did not think that older surgeons face a decline in reasoning and judgement. Forty-eight per cent believed that older surgeons' vast fund of knowledge and experience could compensate for physical and cognitive changes. Only 13% agreed with the statement that older surgeons have higher surgical mortality. Forty-five per cent agreed that the retirement age should be 65 while 22% believed it should be over 65. Forty-four per cent agreed that a regular multidisciplinary, objective and comprehensive evaluation of an older surgeon's physical and cognitive function would help to identify and treat reversible problems which when corrected would aid in restoring the surgeon's function. Seventy-four per cent felt that it was the responsibility of all stakeholders to decide or report on when an ageing surgeon is unsafe to continue practicing. Fifty-five per cent disagreed with a mandatory retirement age for surgeons. This study showed that, in Singapore, stakeholders agreed there are changes in physical and cognitive abilities of ageing surgeons but they thought that these can be overcome with selective strategies to optimise their role in the workforce. They also disagreed on a mandatory retirement age.

Combined radiation and hyperthermia: comparison of two treatment schedules based on data from a registry established by the Radiation Therapy Oncology Group (RTOG). A registry established by the Radiation Therapy Oncology Group provides data for assessing the impact of clinical heating in a set of non-randomized patients treated with hyperthermia in participating member institutions from 1/77 to 6/81. This analysis focuses on tumor response when localized hyperthermia is produced by microwave and applied pursuant to two distinctly different treatment schedules. Hyperthermia treatments were biweekly and combined with daily radiation treatments in one patient group, and combined with biweekly radiation treatment in another. Sample X consists of 65 patients who received a course of therapy using combined hyperthermia and radiation in consecutive treatment sessions each separated by at least 48 hours, but no more than 96 hours. Sample Y consists of 34 patients who received further radiation after the start of a course of combined therapy--either between or at the end of a series of combined treatment sessions. The average length of heat treatment was 72 minutes for Sample X and 32 minutes for Sample Y patients. None of the patients received concurrent chemotherapy; all received between 3 and 13 hyperthermia treatments; all had superficial, measurable tumors. On the average, Sample X patients received 704 total minutes of heat compared to Sample Y patients who received 233 total minutes of heat. Total tumor radiation doses ranged from 17.0 Gy to 44.0 Gy among Sample X patients with 92.3% receiving radiation at either 3 Gy or 4 Gy per fraction. In Sample Y the range for total tumor dose was 16.0 Gy to 70.2 Gy with 73.4% of the patients receiving radiation at 2.5 Gy or less per fraction. Generally, the two treatment schedules achieved similar levels of tumor response. Among treated tumors in Sample X and Sample Y, complete regression rates were 52.4 and 61.8%, respectively, and partial regression rates were 16.9 and 14.7%. Adenocarcinoma and squamous cell carcinoma in both samples responded well to these combined treatments. Only in Sample X was there a statistically significant trend of decreasing complete regression rate when the treated tumor sizes increased. Best responses to treatment generally occurred between 28 and 84 days after completion of the combined therapy course. There were no differences between the two samples with respect to median days to best response or response duration. Blister, ulcer or wet desquamation were reported in 47.7% of Sample X as the maximum skin reaction. In contrast, only 20.6% of Sample Y had these complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Retinoblastoma protein expression and radiation response in muscle-invasive bladder cancer. The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage. In this report we examine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4-6 weeks later by radical cystectomy. The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also described. Immunohistochemical staining of pRB and p53 in paraffin-embedded tumor sections using WL-1 anti-RB and DO1 anti-p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively. There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease. The median age was 62 years and follow-up for those living was 85 months. Staining for pRB was negative in 30% of the cases. Correlations were observed between pRB negativity and high pretreatment apoptosis level (p = 0.06), locally advanced clinical stage (p = 0.01), increased clinical-to-pathologic downstaging (p = 0.014), and more pathologic complete responses (Path-CRs; p = 0.019). Several other factors were tested and were not associated with pRB status, including p53 expression. RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p = 0.02). The overexpression of p53 also correlated with distant metastasis freedom and overall survival in Stage T3b patients. Patient outcome was best when RB negative and p53 negative staining were seen. Our results indicate that loss of RB function as measured by immunohistochemical staining is the strongest correlate of radiation response thus far recognized. Loss of RB expression also predicted for poor outcome in Stage T3b patients, which appeared to compliment the finding of normal p53 expression. While normal RB protein expression is usually associated with better patient outcome, other series have not examined patients treated with radiotherapy. The absence of pRB may be a useful marker for selecting patients for bladder preservation with radiotherapy, particularly when wild-type p53 is present.

A Clinical Significance of Intermittent Infusion Hemodiafiltration Using Backfiltration of Ultrapure Dialysis Fluid Compared to Hemodialysis: A Multicenter Randomized Controlled Crossover Trial. Intermittent infusion hemodiafiltration -(I-HDF) using repeated infusion of ultrapure dialysis fluid through a dialysis membrane or sterile nonpyrogenic substitution fluid was developed to prevent a rapid decrease in blood pressure by increasing the patient's circulating blood volume, to enhance the plasma refilling rate by improving peripheral circulation, and to enhance solute transfer from the extravascular space to the intravascular space by enhancing the plasma refilling rate. Furthermore, the effect of fouling caused by attachment of proteins to the membrane as a result of ultrafiltration can be reduced by backflushing of the membrane with the purified dialysate in I-HDF. Although there have been several clinical trials of I-HDF, there have been no comparisons of the clinical significance of and indications for -I-HDF with those of conventional hemodialysis (HD). The aim of this multicenter randomized controlled crossover trial was to compare the clinical significance of -I-HDF with that of HD in Japan. Patients were randomized to receive HD, I-HDF, and HD (group A) or I-HDF, HD, and I-HDF (group B) in that order for 14 weeks each. The sample size of 70 was determined based on the operability and patient availability. Treatment outcomes were evaluated 5 and 14 weeks after the start of each treatment period. The patients received 4-h treatment sessions with no changes in session duration or anticoagulant therapy during the study. I-HDF was performed using a GC-110N dialysis machine. Two hundred milliliters of ultrapure dialysis fluid were infused at a rate of 150 mL/min by backfiltration every 30 min during treatment. The first and last infusions were performed 30 min after the start and 30 min before the end of treatment, respectively. The total estimated infusion volume per session was 1.4 L (i.e., 200 mL × 7 infusions). I-HDF is a type of online HDF with a small fluid replacement volume. An ABH-P polysulfone membrane hemodiafilter was used for -I-HDF and a class 1 or 2 hemodialyzer with a polysulfone membrane not coated with vitamin E and approved by the Japanese reimbursement system was used for HD. The primary outcomes were the Short Form-36 version 2 summary scores for quality of life and the visual analog scale scores for clinical symptoms. Secondary outcomes were vital signs, number of interventions, and pre-treatment blood test results. These variables were evaluated 1 week before at the start of the study, and at 5 and 14 weeks after the start of each treatment period. The removal characteristics of the various solutes were evaluated when possible on the first day of each treatment period. All patients provided written informed consent to participate. Thirty-two patients in group A and 32 patients in group B completed the trial. There were no differences in the primary or secondary outcomes between I-HDF and HD. Serum α1-microglobulin (MG) levels at 14 weeks were significantly lower for I-HDF than for HD. During treatment, the removal rates for urea and creatinine, which are low molecular weight substances, were significantly lower during I-HDF than during HD. In contrast, the β2-MG and α1-MG removal rates were significantly higher during I-HDF than during HD. Furthermore, there was significantly less albumin leak during I-HDF than during HD. The solute removal results reflect the difference in pore size between the hemodiafilter used for I-HDF and the hemodialyzer used for HD and the difference in convective transport attributable to filtration between the 2 methods. These findings show that the removal rates of low molecular weight substances are significantly lower and those of medium to high molecular weight substances are significantly higher with I-HDF than with HD. They also indicate that there is significantly less albumin leak during I-HDF than during HD, meaning that I-HDF may be a particularly suitable dialysis modality for patients with malnutrition and the elderly in Japan.

[Personalized medicine and prostate cancer. The reality of change]. Prostate cancer (PCa) is a public health problem in western male populations on the basis of it's high incidence and prevalence. Nowadays we come to changes in the diagnostic technologies that deserve special attention and that once applied allow to show the way towards a personalized view of PCa being able to join this modern current trend of the oncologic pathology. In spite of the recognized heterogeneity of the disease; clinical, pathological and genetic variants in genes and the limitations of the PSA as a biomarker to determine the biological aggressiveness of PCa, the certain thing is that the therapeutic final decision is adopted on the basis of a distant information to the wished customization and it moves excessive uncertainty for patients.In this respect the search based on the identification of alterations on the genomic sequence and it's influence in the molecular characterization of the PCa is a constant in the investigation since nowadays. Actually, the progressive adjournment to the clinic of information tumour information that comes from the diagnostic tests related genetic material or their biochemical products, though still in initial phase, already allows to predict relevant changes in molecular characterization of the prostate cancer, in the eventual availability of predictive biomarkers from susceptibility to suffer the disease and of the personalized stratification of risk across the incorporation of newly and interesting molecular and immunohistochemistry biomarkers. Likewise the advances in the perspectives opened with the diagnosis, and the relevance in the decisions of biopsy indications that stem from it are based on the utilization, with the corresponding merger of images, of the multiparametric magnetic resonance (mpMRI) and the new prostate ecographic transrectal images with it's natural evolution towards focal treatments represent, in spite of the recognized complex interpretation of the images, another significant transformation towards the individualization and ideally customization of the clinical decisions opposite to a certain patient with PCa. Events all of them, even more, if they are considered to be combined turn out to be very promising and it's integration brings us over to personalized medicine in PCa since already it happens in others, though still small, neoplastic diseases. All this aspects are summarized and discussed in the present article in the light of the recent communicated information and the reflection and personal experience of the authors. Finally chasing how to improve the clinical managing and the treatment for patients with PCa.

Microshear bond strength and finite element analysis of resin composite adhesion to press-on-metal ceramic for repair actions after various conditioning methods. This study evaluated the repair bond strength of differently surface-conditioned press-on-metal ceramic to repair composites and determined the location of the accumulated stresses by finite element analysis. Press-on-metal ceramic disks (IPS InLine PoM, Ivoclar Vivadent) (N = 45, diameter: 3 mm, height: 2 mm) were randomly divided into 3 groups (n = 15 per group) and conditioned with one of the following methods: 9.5% hydrofluoric acid (HF) (Porcelain etch), tribochemical silica coating (TS) (CoJet), and an unconditioned group acted as the control (C). Each group was divided into three subgroups depending on the repair composite resins: a) Arabesk Top (V, a microhybrid; VOCO), b) Filtek Z250 (F, a hybrid;3M ESPE); c) Tetric EvoCeram (T, a nanohybrid; Ivoclar Vivadent) (n = 5 per subgroup). Repair composites disks (diameter: 1 mm, height: 1 mm) were photopolymerized on each ceramic block. Microshear bond strength (MSB) tests were performed (1 mm/min) and the obtained data were statistically analyzed using 2-way ANOVA and Tukey's post-hoc test (α = 0.05). Failure types were analyzed under SEM. Vickers indentation hardness, Young's modulus, and finite element analysis (FEA) were performed complementary to MSB tests to determine stress accumulation areas. MSB results were significantly affected by the surface conditioning methods (p = 0.0001), whereas the repair composite types did not show a significant effect (p = 0.108). The interaction terms between the repair composite and surface conditioning method were also statistically significant (p = 0.0001). The lowest MSB values (MPa ± SD) were obtained in the control group (V = 4 ± 0.8; F = 3.9 ± 0.7; T = 4.1 ± 0.7) (p < 0.05). While the group treated with T composite resulted in significantly lower MSB values for the HF group (T= 4.1 ± 0.8) compared to those of other composites (V = 8.1 ± 2.6; F = 7.6 ± 2.2) (p < 0.05), there were no significant differences when TS was used as a conditioning method (V = 5 ± 1.7; F = 4.7 ± 1; T = 6.2 ± 0.8) (p > 0.05). The control group presented exclusively adhesive failures. Cohesive failures in composite followed by mixed failure types were more common in HF and TS conditioned groups. Elasticity modulus of the composites were 22.9, 12.09, and 10.41 GPa for F, T, and V, respectively. Vickers hardness of the composites were 223, 232, and 375 HV for V, T, and F, respectively. Von Mises stresses in the FEA analysis for the V and T composites spread over a large area due to the low elastic modulus of the composite, whereas the F composite material accumulated more stresses at the bonded interface. Press-on-metal ceramic could best be repaired using tribochemical silica coating followed by silanization, regardless of the repair composite type in combination with their corresponding adhesive resins, providing that no cohesive ceramic failure was observed.

Inotropic response to hypothermia and the temperature-dependence of ryanodine action in isolated rabbit and rat ventricular muscle: implications for excitation-contraction coupling. We have used the sarcoplasmic reticulum (SR) inhibitor ryanodine to assess the contribution of the SR to the increase in twitch tension seen on cooling the mammalian myocardium. To select a suitable concentration of ryanodine, i.e., one that will exert a maximal effect at all temperatures studied, concentration-response curves for ryanodine action were constructed at 37 degrees, 29 degrees, and 23 degrees C in ventricular muscle from rabbit and rat. Using a concentration of ryanodine (1 microM) that exerted a maximal effect at all temperatures studied, the ability of ryanodine to inhibit SR function at 37 degrees, 29 degrees, and 23 degrees C was then confirmed by using rapid cooling contractures (RCCs) to provide an indirect assessment of the SR calcium content. To estimate the rest decay of the SR calcium content in the absence and presence of ryanodine (1 microM), RCCs were initiated after a range of rest intervals (0.3-300 seconds) in rabbit muscles maintained at 37 degrees, 29 degrees, or 23 degrees C. In the absence of ryanodine, low temperatures elevated RCCs at all rest intervals studied. In the presence of ryanodine, RCCs were only seen at rest intervals shorter than 2.0 seconds, even at 23 degrees C, the lowest temperature studied. Thus, even at 23 degrees C, ryanodine appears to be effective at inhibiting SR calcium release in muscles stimulated at 0.5 Hz (i.e., after 2 seconds rest). Therefore, using this concentration of ryanodine (1 microM) and a stimulation rate of 0.5 Hz, we have investigated the contribution of the SR to the positive inotropic response to hypothermia. Under these conditions, the positive inotropic response to cooling in rabbit ventricle was almost unaffected by the inhibition of the SR with ryanodine. In rat ventricle, a tissue in which SR calcium release may dominate excitation-contraction (EC) coupling, the inotropic response to hypothermia was still observed, although developed tension was strongly depressed at all temperatures. These results suggest that a change in SR function is not the principal mediator of the large (400-500%) increase in force associated with cooling mammalian ventricular muscle from 37 degrees to 25 degrees C. The ryanodine-sensitive fraction of tension development was greatest at 37 degrees C, suggesting that the relative contribution of the SR to tension development in rabbit ventricle is reduced at temperatures below 37 degrees C.(ABSTRACT TRUNCATED AT 400 WORDS)

Rapid changes in cytochrome P4502E1 (CYP2E1) activity and other P450 isozymes following ethanol withdrawal in rats. This study describes the effects of chronic ethanol (ETOH) treatment and withdrawal on the rat hepatic mixed-function mono-oxygenase system. Male Sprague-Dawley rats (150-200 g, 10 per group) were administered ETOH as part of the Lieber-deCarli liquid diet for 3 weeks. Ethanol was removed, and the animals were euthanized at 0, 24, 48, 72 and 168 hr post-withdrawal. Microsomes were prepared, and ethanol-inducible cytochrome P4502E1 (CYP2E1) activity was measured using the enzyme markers N-nitrosodimethylamine demethylase (NDMAd), p-nitrophenol hydroxylase (PNPH) and aniline hydroxylase (AH). Activities were found to be induced significantly after chronic ETOH feeding using all three assays (NDMAd, 5-fold; PNPH, 3.5-fold; AH, 9-fold). Upon ETOH withdrawal, all three activities dropped markedly, with NDMAd and PNPH at control values at 24 hr and all subsequent time points. AH activity remained 3-fold higher than controls at 24, 48 and 72 hr. Western blot analyses showed that immunoreactive CYP2E1 returned to control at 24 hr, consonant with NDMAd and PNPH activities. The prolonged induction of AH activity following ETOH withdrawal indicates that it is not a specific marker of CYP2E1-catalyzed reactions. Collectively, these data are suggestive of a rapid mechanism of CYP2E1 degradation in the rat liver. Of the other parameters investigated in this study, total cytochrome P450 content was increased 2.5-fold after ETOH feeding, with levels dropping markedly 24 hr post-withdrawal. NADPH-dependent cytochrome c reductase activity was unchanged throughout the course of the study. CYP1A1, CYP2B1 and CYP3A activities were assessed by the substrate probes ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD) and erythromycin N-demethylase (ERNd). EROD and PROD were induced significantly by ETOH administration (2-fold) at 0 hr, with EROD remaining elevated over controls 24 hr post-withdrawal. Quantitative western blot analysis of CYP1A1 and CYP2B1 revealed a pattern of immunostaining generally consistent with but less variable than levels predicted by the respective substrate markers. Both proteins were induced significantly by chronic ethanol administration (CYP1A1, 1.9-fold; CYP2B1, 4-fold). Induction of these P450 isoforms persisted for several days following withdrawal. In contrast, immunoreactive CYP1A2 was found to decrease significantly (by 30-40%) during ethanol withdrawal (24, 48, 72, 168 hr). ERNd activity was induced significantly by chronic ETOH feeding (2.5-fold) and remained so for 24 hr into the withdrawal period (2-fold). Immunoreactive CYP3A1 was also induced significantly following ETOH administration (0 hr) and 24 hr following withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)

Antiepileptic drugs for seizure control in people with neurocysticercosis. Neurocysticercosis is the most common parasitic infection of the brain. Epilepsy is the commonest clinical presentation, though it may also present with headache, symptoms of raised intracranial tension, hydrocephalus and ocular symptoms depending upon the localisation of the parasitic cysts. Anthelmintic drugs, anti-oedema drugs, such as steroids and antiepileptic drugs (AEDs) form the mainstay of treatment. To assess the effects (benefits and harms) of AEDs for the primary and secondary prevention of seizures in people with neurocysticercosis. We searched the Cochrane Epilepsy Group Specialized Register (5 May 2015), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library April 2015, Issue 4), MEDLINE (1946 to 5 May 2015), LILACS (Latin American and Caribbean Literature in Health Sciences, 5 May 2015), SCOPUS (1823 to 15 April 2014), ClinicalTrials.gov (7 May 2015), and the WHO International Clinical Trials Registry Platform ICTRP (7 May 2015). We also checked the references lists of identified studies, and contacted experts in the field and colleagues to search for additional studies and for information about ongoing studies. Randomised and quasi-randomised controlled trials.The studies may be single blind, double blind or unblinded. One review author screened all citations for eligibility.Two review authors independently extracted data and evaluated each study for risk of bias. We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures.We did not find any trials that evaluated evaluating individual AEDs in people with neurocysticercosis.We found one trial, comparing two AEDs in people with solitary neurocysticercosis with seizures. However, we excluded this study from the review as it was of poor quality.We found four trials that compared the efficacy of short term versus longer term AED treatment for people with solitary neurocysticercosis (identified on CT scan) presenting with seizures. In total, 466 people were enrolled. These studies compared various AED treatment durations, six, 12 and 24 months. The risk of seizure recurrence with six months treatment compared with 12 to 24 months treatment was not statistically significant (odds ratio (OR) 1.34, 95% confidence interval (CI) 0.73 to 2.47) (three studies n = 360, P 0.35). The risk of seizure recurrence with six to 12 months compared with 24 months treatment was not statistically significant (OR 1.36, 95% CI 0.72 to 2.57) (three studies, n = 385, P 0.34).Two studies co-related seizure recurrence with CT findings and suggested that persistent and calcified lesions had a higher recurrence risk and suggest longer duration of treatment with AEDs. One study reported no side effects, while the rest did not comment on side effects of drugs. None of the studies addressed the quality of life of the participants.These studies had certain methodological deficiencies such as a small sample size and a possibility of bias due to lack of blinding, which affect the results of this review. Despite neurocysticercosis being the most common cause of epilepsy worldwide, there is currently no evidence available regarding the use of AEDs as prophylaxis for preventing seizures among people presenting with symptoms other than seizures. For those presenting with seizures, there is no reliable evidence regarding the duration of treatment required. There is therefore a need for large scale randomised controlled trials to address these questions.

Robot-assisted laparoscopic transperitoneal infrarenal lymphadenectomy in patients with locally advanced cervical cancer by single docking: Do we need a backup procedure? To present our initial experience on the feasibility of robotic transperitoneal para-aortic lymphadenectomy up to left renal vein via single docking approach by high port insertion technique followed by left shoulder docking as a rescue backup procedure in surgically obstructed patients undergoing surgical staging because of locally advanced cervical cancer (LACC). Prospective observational preliminary study. Canadian Task Force classification II-3. Tertiary-care academic affiliated private hospital. Ten patients with LACC who underwent robotic transperitoneal infrarenal para-aortic lymphadenectomy between January 2012 and December 2014. All patients with pathologically proven cervical cancer underwent a PET/CT scanning in a similar fashion at the department of nuclear medicine. PET/CT scans were evaluated by the nuclear medicine specialist. Following pre-operative work-up, robot-assisted transperitoneal infrarenal para-aortic lymphadenectomy was performed up to left renal vein by the same experienced surgeon. Sections of 5 mm were performed and stained with routine hematoxylin and eosin (H&E), and node count was done separately by experienced gynecopathologist. During the study period, 12 consecutive patients with LACC were counseled for pre-therapeutic robot-assisted transperitoneal para-aortic lymphadenectomy. Two patients declined the procedure and underwent standardized chemo-radiation therapy whereas remaining ten patients constituted the study group. In the study group, the median age was 46 years (range 33-59 years), and the median body mass index 28.5 kg/m2 (range 18.5-35.1 kg/m2). Clinical staging was stage IIB in four patients, IIIB in four, and IVA in one. Histopathological diagnosis was squamous cell carcinoma in nine patients, and adenocarcinoma in one. On PET/CT scans, seven out of ten patients were positive for pelvic lymph node metastasis. With respect to para-aortic area, only one of the ten patients had suspected metastasis in PET/CT. For nine patients with LACC, the median docking time was 6.5 min (range 4-15 min), and the median operating time for para-aortic lymphadenectomy was 120 min (range 60-165 min). The median trocar time was 14.5 min (range 5-45 min). In two out of ten patients, the surgical removal of whole lymphatic tissue between inferior mesenteric artery and left renal vein was not completely possible by a single docking of robotic column. Therefore, a new optic trocar was placed in the umbilicus and the robotic column was relocated over the left shoulder of the patient and residual lymphatic tissue measuring approximately 2 cm in the long axis immediately below the left renal vein was removed and the surgery was completed up to the left renal vein. All para-aortic lymphadenectomies have been completed by robotic route. There were no intra-operative complications. No patient received a blood transfusion. Early post-operative grade 2 and 3a complications according to Dindo classification occurred in two patients: one symptomatic lymphocyst and one local infection on assistant port site in one patient. The patient with suspected para-aortic lymph node metastasis in PET/CT showed no metastatic disease on histopathologic exam of para-aortic lymph nodes. The patient with recurrent disease and negative para-aortic lymph nodes on frozen section examination underwent robot-assisted total pelvic exenteration. Five of the residual eight patients had histologically proven metastasis in the para-aortic lymph node(s). Treatment modification occurred in six patients related to pre-treatment staging surgery. According to pathological results, extended field radiation therapy has been added in five patients and it was omitted in one patient. The median time interval between surgery and initiation of radiotherapy was 12 days (range 6-23 days). Robotic transperitoneal infrarenal para-aortic lymphadenectomy up to left renal vein by high port insertion technique is a safe and feasible option for staging and treatment planning. However, technically, it is obstructed in a small group of patients and nodal staging surgery up to left renal vein can be completed by consecutive left shoulder docking approach as a backup rescue plan.

Protective effect of selenium on hemoglobin mediated lipid peroxidation in vivo. The toxicity of hemoglobin (Hb) solutions is related, at least in part, to the generation of oxygen free radicals with consequent induction of lipid peroxidation. The present study was designed to examine whether selenium (Se) may prevent the oxidative damage observed after Hb administration. Three groups of rats were compared; (I) the negative control group receiving autotransfusion; (II) the positive control group with replacement of 40% total blood volume (TBV) with modified bovine Hb solution; and (III) the experimental group which received dietary supplemented selenium (Na2SeO3) in daily doses of 5 micrograms.kg body wt-1 in drinking water, 4 days before and 3 days after administration of Hb solution in the same volume as in group II. Three days after Hb injection, all animals were sacrificed. Oxidative stress was determined by measuring conjugated dienes (CD) and thiobarbituric acid reactants (MDA) in homogenates of the perfused liver, heart, lungs, kidney, brain and plasma. Additionally, the 45k x g supernatants of the organs homogenates and plasma were assayed for the antioxidant enzymes activity: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and the intracellular level of reduced glutathione (GSH). Also, a measurement of nonprotein bound intracellular free iron (Fe) and tissue Se concentrations was performed. Simultaneously, injury dysfunction of vital organs was assessed by the measurement of plasma LDH, SGPT, creatinine, blood PaO2 and by histopathological studies. Results indicate that the exchange transfusion with Hb solution introduced significant increases in CD and MDA formation, particularly in the liver and heart tissues, and in plasma. While the values of the SOD and CAT in the liver and heart tissue were generally altered, the SOD/CAT ratio was also increased. After the Hb injection, activity of GSH-Px remained unchanged and was associated with significant depletion of GSH. The plasma levels of SGPT and LDH were increased, but the creatinine and PaO2 was similar to that of the control and corresponded with histopathological findings. The liver and heart intracellular free Fe was found to be higher than that of control. Treatment with Se was very effective in the prevention of oxidative damage introduced by Hb. Full protection from MDA formation was noted in liver tissue (p < 0.001). Also, plasma levels of MDA, SGPT and LDH were significantly decreased and appeared similar to that of the control group (I). Treatment with Se increased liver (p < 0.05) and plasma (p < 0.1) level of GSH-Px.(ABSTRACT TRUNCATED AT 400 WORDS)

Ca2+-assisted, direct hydride transfer, and rate-determining tautomerization of C5-reduced PQQ to PQQH2, in the oxidation of beta-D-glucose by soluble, quinoprotein glucose dehydrogenase. Spectral and kinetic studies were performed on enzyme forms of soluble glucose dehydrogenase of the bacterium Acinetobacter calcoaceticus (sGDH) in which the PQQ-activating Ca(2+) was absent (Holo X) or was replaced with Ba(2+) (Ba-E) or in which PQQ was replaced with an analogue or a derivative called "nitroPQQ" (E-NPQ). Although exhibiting diminished rates, just like sGDH, all enzyme forms were able to oxidize a broad spectrum of aldose sugars, and their reduced forms could be oxidized with the usual artificial electron acceptor. On inspection of the plots for the reductive half-reaction, it appeared that the enzyme forms exhibited a negative cooperativity effect similar to that of sGDH itself under turnover conditions, supporting the view that simultaneous binding of substrate to the two subunits of sGDH causes the effect. Stopped-flow spectroscopy of the reductive half-reaction of Ba-E with glucose showed a fluorescing transient previously observed in the reaction of sGDH with glucose-1-d, whereas no intermediate was detected at all in the reactions of E-NPQ and Holo X. Using hydrazine as a probe, the fluorescing C5 adduct of PQQ and hydrazine was formed in sGDH, Ba-E, and Holo X, but E-NPQ did not react with hydrazine. When this is combined with other properties of E-NPQ and the behavior of enzyme forms containing a PQQ analogue, we concluded that the catalytic potential of the cofactor in the enzyme is not determined by its adduct-forming ability but by whether it is or can be activated with Ca(2+), activation being reflected by the large red shift of the absorption maximum induced by this metal ion when binding to the reduced cofactor in the enzyme. This conclusion, together with the observed deuterium kinetic isotope effect of 7.8 on transient formation in Ba-E, and that already known on transient decay, indicate that the sequential steps in the mechanism of sGDH must be (1) reversible substrate binding, (2) direct transfer of a hydride ion (reversible or irreversible) from the C1 position of the beta-anomer of glucose to the C5 of PQQ, (3) irreversible, rate-determining tautomerization of the fluorescing, C5-reduced PQQ to PQQH(2) and release (or earlier) of the product, D-glucono-delta-lactone, and (4) oxidation of PQQH(2) by an electron acceptor. The PQQ-activating Ca(2+) greatly facilitates the reactions occurring in step 2. His144 may also play a role in this by acting as a general base catalyst, initiating hydride transfer by abstracting a proton from the anomeric OH group of glucose. The validity of the proposed mechanism is discussed for other PQQ-containing dehydrogenases.

Buprenorphine-Clinically useful but often misunderstood. Background There are a number of false myths about buprenorphine based on unconfirmed animal data, even from isolated animal organs, and early clinical research. These myths came into textbooks on pharmacology and pain about 30 years ago and have been difficult to eradicate. Animal models of pain and pain relief are notoriously unreliable as predictors of human clinical effects. The fact is that in clinical practice there is NO bell-shaped dose-response curve, there is NO plateau on the dose-response curve, and there is NO antagonist effect from buprenorphine on other mu-opioid agonists. Methods This narrative, topical review of relevant research publications evaluates new knowledge on the pharmacodynamics and pharmacokinetics of buprenorphine of importance in clinical practice. Results Buprenorphine is a potent opioid analgesic acting on all four opioid receptors: it is an agonist on the mu-, the delta, and the ORL-1 receptors. It is an antagonist at the kappa-receptor. Buprenorphine has a number of active metabolites with different effects on the four opioid receptors; all except the norbup-3-glu are analgesic. Buprenorphine itself is not a respiratory depressant or sedative, but some of its active metabolites are. Buprenorphine and its active metabolites are not excreted by the kidney. Therefore buprenorphine may be used in patients with advanced renal failure. Buprenorphine has a slow onset and a long offset. These properties are advantageous, except sometimes when treating severe acute pain. Its agonist effect on the ORL-1 receptor reduces reward-effects and slows the development of tolerance to the analgesic effects. Buprenorphine inhibits voltage-gated sodium-channels and enhances and prolongs peripheral nerve blocks. Its ORL-1 -effect at the spinal cord may do the same. Buprenorphine is well suited for treatment of chronic pain, especially chronic neuropathic pain and cancer pain. The beneficial effects as a co-medication during treatment of the opioid-abuse disease are due to its slow onset (less "kick-effect"). Its prolonged offset-time reduces the likelihood of acute withdrawal problems and reduces the "craving" of opioids. Adverse effects Buprenorphine, being a mu-agonist, may induce or maintain opioid addiction. Illegally obtained high-dose transmucosal buprenorphine, intended for treatment of addiction, is dissolved and injected by opioid abusers. This is an increasing problem in some countries. Conclusions Buprenorphine's unusual pharmacodynamics and pharmacokinetics make it an ideal opioid for treatment of most chronic pain conditions where opioid therapy is indicated. Implications Buprenorphine is a well studied and often misunderstood analgesic opioid drug. The evidence base predicts that it will be an increasingly important alternative for treatment of chronic pain conditions caused by cancer and non-cancer diseases. It will continue to be an attractive alternative to methadone for opioid abuse rehabilitation.

The stress system in the human brain in depression and neurodegeneration. Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer's disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels, but the individual variability is large. It is hypothesized that particularly a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder. On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression. Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN. Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported. Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men. This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients. Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure. Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations. In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure. In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress. Thus, the HPA-axis in AD is only moderately activated, possibly due to the initial (primary) hippocampal degeneration in this condition. There are no convincing arguments to presume a causal, primary role for cortisol in the pathogenesis of AD. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.

Applications of tissue heterogeneity corrections and biologically effective dose volume histograms in assessing the doses for accelerated partial breast irradiation using an electronic brachytherapy source. A low-energy electronic brachytherapy source (EBS), the model S700 Axxent x-ray device developed by Xoft Inc., has been used in high dose rate (HDR) intracavitary accelerated partial breast irradiation (APBI) as an alternative to an Ir-192 source. The prescription dose and delivery schema of the electronic brachytherapy APBI plan are the same as the Ir-192 plan. However, due to its lower mean energy than the Ir-192 source, an EBS plan has dosimetric and biological features different from an Ir-192 source plan. Current brachytherapy treatment planning methods may have large errors in treatment outcome prediction for an EBS plan. Two main factors contribute to the errors: the dosimetric influence of tissue heterogeneities and the enhancement of relative biological effectiveness (RBE) of electronic brachytherapy. This study quantified the effects of these two factors and revisited the plan quality of electronic brachytherapy APBI. The influence of tissue heterogeneities is studied by a Monte Carlo method and heterogeneous 'virtual patient' phantoms created from CT images and structure contours; the effect of RBE enhancement in the treatment outcome was estimated by biologically effective dose (BED) distribution. Ten electronic brachytherapy APBI cases were studied. The results showed that, for electronic brachytherapy cases, tissue heterogeneities and patient boundary effect decreased dose to the target and skin but increased dose to the bones. On average, the target dose coverage PTV V(100) reduced from 95.0% in water phantoms (planned) to only 66.7% in virtual patient phantoms (actual). The actual maximum dose to the ribs is 3.3 times higher than the planned dose; the actual mean dose to the ipsilateral breast and maximum dose to the skin were reduced by 22% and 17%, respectively. Combining the effect of tissue heterogeneities and RBE enhancement, BED coverage of the target was 89.9% in virtual patient phantoms with RBE enhancement (actual BED) as compared to 95.2% in water phantoms without RBE enhancement (planned BED). About 10% increase in the source output is required to raise BED PTV V(100) to 95%. As a conclusion, the composite effect of dose reduction in the target due to heterogeneities and RBE enhancement results in a net effect of 5.3% target BED coverage loss for electronic brachytherapy. Therefore, it is suggested that about 10% increase in the source output may be necessary to achieve sufficient target coverage higher than 95%.

Investigation of differences in the binding affinities of two analogous ligands for untagged and tagged p38 kinase using thermodynamic integration MD simulation. Thermodynamic integration (TI) molecular dynamics (MD) simulations for the binding of a pair of a reference ("ref") ligand and an analogous ("analog") ligand to either tagged (with six extra residues at the N-terminus) or untagged p38 kinase proteins were carried out in order to probe how the binding affinity is influenced by the presence or absence of the peptide tag in p38 kinase. This possible effect of protein length on the binding affinity of a ligand-which is seldom addressed in the literature-is important because, even when two labs claim to have performed experiments with the same protein, they may actually have studied variants of the same protein with different lengths because they applied different protein expression conditions/procedures. Thus, if we wanted to compare ligand binding affinities measured in the two labs, it would be necessary to account for any variation in ligand binding affinity with protein length. The pair of ligand-p38 kinase complexes examined in this work (pdb codes: 3d7z and 3lhj, respectively) were ideal for investigating this effect. The experimentally determined binding energy for the ref ligand with the untagged p38 kinase was -10.9 kcal mol(-1), while that for the analog ligand with the tagged p38 kinase was -11.9 kcal mol(-1). The present TI-MD simulation of the mutation of the ref ligand into the analog ligand while the ligand is bound to the untagged p38 kinase predicted that the binding affinity of the analog ligand is 2.0 kcal mol(-1) greater than that of the ref ligand. A similar simulation also indicated that the same was true for ligand binding to the tagged protein, but in this case the binding affinity for the analog ligand is 2.5 kcal mol(-1) larger than that for the ref ligand. These results therefore suggest that the presence of the peptide tag on p38 kinase increased the difference in the binding energies of the ligands by a small amount of 0.5 kcal mol(-1). This result supports the assumption that the presence of a peptide tag has only a minor effect on ΔG values. The error bars in the computed ΔG values were then estimated via confidence interval analysis and a time autocorrelation function for the quantity dV/dλ. The estimated correlation time was ~0.5 ps and the error bar in the ΔG values estimated using nanosecond-scale simulations was ±0.3 kcal mol(-1) at a confidence level of 95%. These predicted results can be verified in future experiments and should prove useful in subsequent similar studies. Graphical Abstract Thermodynamic cycles for binding of two analogous ligands with untagged and tagged p38 kinases and associated Gibbs free energy.

[Study about skin cancer screening in comparison with breast and cervix cancer screening in a female sample from Concordia, Argentina.] The aim of this study was to describe the knowledge, practices and attitudes regarding the screening of skin cancer, compared to the breast and cervix cancer. Methods. An observational, cross-sectional study using structured questionnaires was carried out among women in the city of Concordia, Entre Ríos. The sample consisted of 90 mothers or tutors from low (G1, n=32), middle (G2, n=29) and high (G3, n=29) socioeconomic status elementary schools students. Results. Mean age were 37,9±6,6, 38,0±6,9 and 43,1±5,6 years, respectively. The annual skin exam has been performed by dermatologist in 30.0% (G1), 30.8% (G2) and 51.7% (G3) of these women. The annual gynecological exam has been done by 46.4% (G1), 60.7% (G2) and 86.2% (G3). The existence of the skin cancer prevention campaign was known in 35,7%, 16% and 10,7% in G1, G2 and G3 respectively, but only 3,7% of G2, 3,7% of G3 and no women in G1 had ever participated in a campaign. Major conclusion. These data indicate the need to achieve effective strategies that allow improving the adherence of women to prevention campaigns, especially those for skin cancer prevention, where there is less participation when compared with breast and cervical cancer screening. An observational, cross-sectional study using structured questionnaires was carried out among women in the city of Concordia, Entre Ríos. The sample consisted of 90 mothers or tutors from low (G1, n=32), middle (G2, n=29) and high (G3, n=29) socioeconomic status elementary schools students. Results. Mean age were 37,9±6,6, 38,0±6,9 and 43,1±5,6 years, respectively. The annual skin exam has been performed by dermatologist in 30.0% (G1), 30.8% (G2) and 51.7% (G3) of these women. The annual gynecological exam has been done by 46.4% (G1), 60.7% (G2) and 86.2% (G3). The existence of the skin cancer prevention campaign was known in 35,7%, 16% and 10,7% in G1, G2 and G3 respectively, but only 3,7% of G2, 3,7% of G3 and no women in G1 had ever participated in a campaign. Major conclusion. These data indicate the need to achieve effective strategies that allow improving the adherence of women to prevention campaigns, especially those for skin cancer prevention, where there is less participation when compared with breast and cervical cancer screening. Mean age were 37,9±6,6, 38,0±6,9 and 43,1±5,6 years, respectively. The annual skin exam has been performed by dermatologist in 30.0% (G1), 30.8% (G2) and 51.7% (G3) of these women. The annual gynecological exam has been done by 46.4% (G1), 60.7% (G2) and 86.2% (G3). The existence of the skin cancer prevention campaign was known in 35,7%, 16% and 10,7% in G1, G2 and G3 respectively, but only 3,7% of G2, 3,7% of G3 and no women in G1 had ever participated in a campaign. Major conclusion. These data indicate the need to achieve effective strategies that allow improving the adherence of women to prevention campaigns, especially those for skin cancer prevention, where there is less participation when compared with breast and cervical cancer screening. These data indicate the need to achieve effective strategies that allow improving the adherence of women to prevention campaigns, especially those for skin cancer prevention, where there is less participation when compared with breast and cervical cancer screening.

'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Nanoparticles possessing poly(ethylene glycol) (PEG) chains on their surface have been described as blood persistent drug delivery system with potential applications for intravenous drug administration. Considering the importance of protein interactions with injected colloidal dug carriers with regard to their in vivo fate, we analysed plasma protein adsorption onto biodegradable PEG-coated poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(varepsilon-caprolactone) (PCL) nanoparticles employing two-dimensional gel electrophoresis (2-D PAGE). A series of corona/core nanoparticles of sizes 160-270 nm were prepared from diblock PEG-PLA, PEG-PLGA and PEG-PCL and from PEG-PLA:PLA blends. The PEG Mw was varied from 2000-20000 g/mole and the particles were prepared using different PEG contents. It was thus possible to study the influence of the PEG corona thickness and density, as well as the influence of the nature of the core (PLA, PLGA or PCL), on the competitive plasma protein adsorption, zeta potential and particle uptake by polymorphonuclear (PMN) cells. 2-D PAGE studies showed that plasma protein adsorption on PEG-coated PLA nanospheres strongly depends on the PEG molecular weight (Mw) (i.e. PEG chain length at the particle surface) as well as on the PEG content in the particles (i.e. PEG chain density at the surface of the particles). Whatever the thickness or the density of the corona, the qualitative composition of the plasma protein adsorption patterns was very similar, showing that adsorption was governed by interaction with a PLA surface protected more or less by PEG chains. The main spots on the gels were albumin, fibrinogen, IgG, Ig light chains, and the apolipoproteins apoA-I and apoE. For particles made of PEG-PLA45K with different PEG Mw, a maximal reduction in protein adsorption was found for a PEG Mw of 5000 g/mole. For nanospheres differing in their PEG content from 0.5 to 20 wt %, a PEG content between 2 and 5 wt % was determined as a threshold value for optimal protein resistance. When increasing the PEG content in the nanoparticles above 5 wt % no further reduction in protein adsorption was achieved. Phagocytosis by PMN studied using chemiluminescence and zeta potential data agreed well with these findings: the same PEG surface density threshold was found to ensure simultaneously efficient steric stabilization and to avoid the uptake by PMN cells. Supposing all the PEG chains migrate to the surface, this would correspond to a distance of about 1.5 nm between two terminally attached PEG chains in the covering 'brush'. Particles from PEG5K-PLA45K, PEG5K-PLGA45K and PEG5K-PCL45K copolymers enabled to study the influence of the core on plasma protein adsorption, all other parameters (corona thickness and density) being kept constant. Adsorption patterns were in good qualitative agreement with each other. Only a few protein species were exclusively present just on one type of nanoparticle. However, the extent of proteins adsorbed differed in a large extent from one particle to another. In vivo studies could help elucidating the role of the type and amount of proteins adsorbed on the fate of the nanoparticles after intraveinous administration, as a function of the nature of their core. These results could be useful in the design of long circulating intravenously injectable biodegradable drug carriers endowed with protein resistant properties and low phagocytic uptake.

A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Protein kinase C (PKC)-alpha and Raf-1 are important elements of proliferative signal transduction pathways in both normal and malignant cells. Abrogation of either Raf-1 or PKC-alpha function can both inhibit cellular proliferation and induce apoptosis in several experimental cancer models including prostate cancer cell lines. ISIS 3521 and ISIS 5132 are antisense phosphorothioate oligonucleotides that inhibit PKC-alpha and Raf-1 expression, respectively, and induce a broad spectrum of antiproliferative and antitumor effects in several human tumor cell lines. In Phase I evaluation both ISIS 3521 and ISIS 5132 could be safely administered on 21-day i.v. infusion schedules and demonstrated preliminary evidence of antitumor activity. On the basis of these findings, a randomized Phase II study of ISIS 3521 and ISIS 5132 was performed in two comparable cohorts of patients who had chemotherapy-naïve, hormone-refractory prostate cancer (HRPC). Patients with documented evidence of metastatic HRPC and a prostate-specific antigen (PSA) value > or =20 ng/ml were randomized to receive treatment with either ISIS 3521 or ISIS 5132 as a continuous i.v. infusion for 21 days repeated every 4 weeks. Patients were stratified according to the presence or absence of bidimensionally measurable disease at the time of randomization. The principal endpoints included PSA response, objective response in patients with bidimensionally measurable disease, and treatment failure defined as new or worsening symptoms; a fall in performance status of 2 levels; new or objective progression of disease; or a rise in PSA for 12 weeks without symptom improvement. Plasma samples were collected to assess individual steady-state concentrations and to relate this pharmacokinetic parameter to observed toxicities and responses. Thirty-one patients were randomized in this study; 15 patients received 43 courses of ISIS 3521 and 16 patients received 48 courses of ISIS 5132. The most common toxicities observed were mild to moderate (grade 1 or 2) fatigue and lethargy in 21% and 56% of patients treated with ISIS 3521 and ISIS 5132, respectively. Although no objective or PSA responses were observed in any patient treated with ISIS 3521 or ISIS 5132, persistent stable disease was observed in 3 patients for 5 or more months, and in 5 patients the PSA values did not rise >25% for 120 days or longer. The antisense oligonucleotides ISIS 3521 and ISIS 5132, at these doses and on this schedule, do not possess clinically significant single-agent antitumor activity in HRPC. Protracted stable disease in some patients may indicate a cytostatic effect. Additional work is required to define the optimal role of PKC-alpha or Raf-1 inhibition in the treatment of HRPC.

Hypoglycaemia induced by exogenous insulin--'human' and animal insulin compared. A systematic review of the literature was carried out to examine whether published evidence suggests a difference in the frequency and awareness of hypoglycaemia induced by 'human' and animal insulin. The review identified randomized controlled trials and studies of other designs including observational comparisons, case series and case reports in which the use of 'human' insulin was compared to animal insulin in people with diabetes. These were identified from bibliographic databases and hand-searches of key journals. The main outcome measures were frequency, severity, awareness and symptoms of insulin induced hypoglycaemia. Fifty-two randomized controlled trials, 37 of double-blind design, were identified which included one or more of the relevant outcome measures. Of these, 21 specifically investigated hypoglycaemic frequency and awareness as primary outcomes (six in people with previously reported reduced hypoglycaemic awareness). The remainder of the identified trials reported hypoglycaemic outcomes as a secondary or incidental outcome during comparative investigations of efficacy or immunogenicity. Seven of the double-blind studies reported differences in frequency of hypoglycaemia or awareness of symptoms, although none of the studies which selected subjects on the basis of previously reported impaired awareness demonstrated significant differences between insulin species. Four of the unblinded trials reported differences in hypoglycaemia. This reached statistical significance in two of the studies. A further 56 studies of other designs and case reports were considered. In addition to the 10 case reports describing individuals with impaired hypoglycaemic awareness, nine studies reported differences in the incidence and manifestation of hypoglycaemia during 'human' insulin treatment. Notably, none of the four population time trend studies found any relationship between the increasing use of 'human' insulin and hospital admission for hypoglycaemia or unexplained death among those with diabetes. The largest case series could find no support for the hypothesis that an influence of treatment with 'human' insulin on hypoglycaemia had contributed to any of the 50 deaths investigated. When all types of studies considered are ranked in order of rigour (according to the accepted 'hierarchy of evidence'), it is the least rigorous which lend most support to the notion that treatment with 'human' insulin has an effect on the frequency, severity or symptoms of hypoglycaemia. Evidence does not support the contention that treatment with 'human' insulin per se affects the frequency, severity or symptoms of hypoglycaemia. However, a number of studies, mainly those of less rigorous design, describe an effect when people are transferred from animal insulin to 'human' insulin. It is not possible to state how common this is or whether the phenomenon is specific to 'human' insulin or an effect resulting from stricter glycaemic control (perhaps compounded, in some cases, by neurological complications in long-standing diabetes). This remaining uncertainty makes it essential that insulin from animal sources continues to be available so that clinicians and patients may retain this choice of treatment.

Humoral and cell-mediated immune responses to influenza vaccination in equine metabolic syndrome (EMS) horses. Obesity is an increasing problem in the equine population with recent reports indicating that the percentage of overweight horses may range anywhere from 20.6-51%. Obesity in horses has been linked to more serious health concerns such as equine metabolic syndrome (EMS). EMS is a serious problem in the equine industry given its defining characteristics of insulin dysregualtion and obesity, as well as the involvement of laminitis. Little research however has been conducted to determine the effects of EMS on routine healthcare of these horses, in particular how they respond to vaccination. It has been shown that obese humans and mice have decreased immune responses to vaccination. EMS may have similar effects on vaccine responses in horses. If this is the case, these animals may be more susceptible to disease, acting as unknown disease reservoirs. Therefore, we investigated the effects of EMS on immune responses to routine influenza vaccination. Twenty-five adult horses of mixed-sex and mixed-breed (8-21 years old) horses; 13 EMS and 12 non-EMS were selected. Within each group, 4 horses served as non-vaccinate saline controls and the remaining horses were vaccinated with a commercially available equine influenza vaccine. Vaccination (influenza or saline) was administered on weeks 0 and 3, and peripheral blood samples taken on week 0 prior to vaccination and on weeks 1, 2, 3, 4, and 5 post vaccination. Blood samples were used to measure hemagglutination inhibition (HI) titers and equine influenza specific IgGa, IgGb, and IgGT levels. Blood samples were also used to isolate peripheral blood mononuclear cells (PBMCs) for analysis of cell mediated immune (CMI) responses via real-time polymerase chain reaction (RT-PCR). All horses receiving influenza vaccination responded with significant increases (P < 0.05) in HI titers, and IgGa and IgGb equine influenza specific antibodies following vaccination compared to saline controls. EMS did not significantly affect (P > 0.05) humoral immune responses as measured by HI titers or IgG antibody isotypes to influenza vaccination. There was an effect of metabolic status on CMI responses, with influenza vaccinated EMS horses having lower gene expression of IFN-γ (P = 0.02) and IL-2 (P = 0.01) compared to vaccinated non-EMS control horses. Given these results, it appears that while metabolic status does not influence humoral responses to an inactivated influenza vaccine in horses, horses with EMS appear to have a reduced CMI response to vaccination compared to metabolically normal, non-EMS control horses.

Myocardial revascularisation in elderly patients with refractory or unstable angina and advanced coronary disease. Elderly patients with ischaemic heart disease are often treated more conservatively and for longer than younger patients, but this strategy may result in subsequent invasive intervention of more advanced and higher risk coronary disease. We performed a retrospective analysis of 109 patients aged > or = 70 years (mean age 74 years, 66% men), who presented with angina refractory to maximal medical treatment or unstable angina over a 2-year period (1988-1990), to compare the relative risks and benefits of myocardial revascularisation [coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA)] in this higher-risk age group. Sixty patients underwent CABG and 49 patients PTCA. There were eight periprocedural deaths in total (six in the CABG group, and two in the PTCA group, P = 0.29). Six patients in the CABG group suffered a cerebrovascular accident (two fatal). Acute Q-wave myocardial infarction occurred in one patient in the CABG group and in two patients in the PTCA group. The length of hospital stay was longer for the CABG group (CABG group 11.4 +/- 5.4 days, range 7-30 days, PTCA group 7.4 +/- 7.6 days, range 1-39 days, P = 0.01). Outcome was assessed using the major cardiac event rate (MACE; i.e. the rate of death, myocardial infarction, repeat CABG or PTCA). The cumulative event-free survival in the CABG group in 1, 2 and 3 years was 87, 85 and 85%, respectively. In contrast, in the PTCA group it was 55, 48 and 48% (P = 0.0001). Age, sex, number of diseased vessels, degree of revascularisation and left ventricular function were not predictive of the recurrence of angina in both groups. Actuarial survival (total mortality, including perioperative mortality) was lower at 1 year in the CABG group due to the higher perioperative mortality, but similar in both groups after the second year (P = 0.62). Elderly patients with refractory or unstable angina who are revascularised surgically have a better long-term outcome (less frequent event rate of the composite end-point--myocardial infarction, revascularisation procedures and death) compared with those who are revascularised with PTCA. This benefit is been realised after the second year. Total mortality is similar in both groups after the second year. Therefore elderly patients who are fit for surgery should not be denied the benefits of CABG. PTCA may be regarded as a complementary and satisfactory treatment, especially for those whose life expectancy is limited to less than 2 years. The use of stents may improve outcome in the PTCA group and this needs to be evaluated.

Endometriosis induces gut microbiota alterations in mice. What happens to the gut microbiota during development of murine endometriosis? Mice with the persistence of endometrial lesions for 42 days develop a distinct composition of gut microbiota. Disorders in the immune system play fundamental roles in changing the intestinal microbiota. No study has used high-throughput DNA sequencing to show how endometriosis changes the gut microbiota, although endometriosis is accompanied by abnormal cytokine expression and immune cell dysfunction. This study includes a prospective and randomized experiment on an animal endometriosis model induced via the intraperitoneal injection of endometrial tissues. The mice were divided into endometriosis and mock groups and were sacrificed at four different time points for model confirmation and fecal sample collection. To detect gut microbiota, 16S ribosomal-RNA gene sequencing was performed. Alpha diversity was used to analyze the complexity and species diversity of the samples through six indices. Beta diversity analysis was utilized to evaluate the differences in species complexity. Principal coordinate analysis and unweighted pair-group method with arithmetic means clustering were performed to determine the clustering features. The microbial features differentiating the fecal microbiota were characterized by linear discriminant analysis effect size method. The endometriosis and mock mice shared similar diversity and richness of gut microbiota. However, different compositions of gut microbiota were detected 42 days after the modeling. Among the discriminative concrete features, the Firmicutes/Bacteroidetes ratio was elevated in mice with endometriosis, indicating that endometriosis may induce dysbiosis. Bifidobacterium, which is known as a commonly used probiotic, was also increased in mice with endometriosis. N/A. More control groups should be further studied to clarify the specificity of the dysbiosis induced by endometriosis. This study was performed only on mice. Thus, additional data acquired from patients with endometriosis are needed in future research. We only detected the changes of gut microbiota at 42 days after the modeling, while the long-term effect of endometriosis on gut microbiota remains poorly understood. Moreover, we only revealed a single effect of endometriosis on gut microbiota. This study provided the first comprehensive data on the association of endometriosis and gut microbiota from high-throughput sequencing technology. The gut microbiota changed with the development of endometriosis in a murine model. The communication between the host and the gut microbiota is bidirectional, and further studies should be performed to clarify their relationship. This research was supported by Grant (81571417) from the National Science Foundation of China and Grant (2015GSF118092) from the Technology Development Plan of Shandong Province. The authors report no conflict of interest.

Reduction in breast cancer mortality from organized service screening with mammography: 1. Further confirmation with extended data. In an earlier publication, our evaluation of data from breast cancer screening programs in seven Swedish counties suggested a 40% reduction in incidence-based breast cancer mortality among women actually screened. In the current study, we expand the previous analysis from seven counties to 13 large areas within nine counties, including six of the original counties and seven additional areas, examine a longer period of follow-up (20-44 years), apply new analytic methods for the evaluation of incidence-based breast cancer mortality, and estimate the number needed to screen to save one life. Data from six of the original counties (one being excluded as it does not yet have 10 years of follow-up after the initiation of screening), with increased follow-up, and seven additional large areas, within three counties, representing approximately 45% of Swedish women, provide information about age at diagnosis, age at death, and screening history for 542,187 women in the prescreening and 566,423 women in the screening epochs. Regardless of year of diagnosis, there were a total of 6,231 deaths due to breast cancer in the period of study as a whole. Of these, 4,778 were incidence-based deaths in the two epochs, i.e., death among cases diagnosed within either the prescreening or screening period. Data were analyzed using Poisson regression and adjusted, when necessary, for self-selection bias, contemporaneous changes in incidence, and changes in mortality independent of screening. Attendance was uniformly high, averaging 75% in the screening epochs. Recall rates for assessment varied from 4% to 5% at the first round of screening and approximately 3% at later rounds. Detection rates averaged five breast cancers per 1,000 women screened in the first round, and four breast cancers per 1,000 women screened in subsequent rounds. There was a significant 45% reduction in incidence-based breast cancer mortality among screened women in the screening epoch relative to incidence-based breast cancer mortality in the prescreening epoch (relative risk, 0.55; 95% confidence intervals, 0.51-0.59). After adjusting for self-selection bias, there still was a significant 43% reduction in incidence-based breast cancer mortality associated with screening (relative risk, 0.57; 95% confidence intervals, 0.53-0.62). These results indicate a reduction in breast cancer mortality of between 40% and 45% in association with screening, after adjustment for self-selection bias. These results were obtained with modest human costs: the number needed to screen to save one life was estimated as 472.

The 1993 epidemic of pertussis in Cincinnati. Resurgence of disease in a highly immunized population of children. In 1993 there was a resurgence of pertussis in the United States. Altogether, 6335 cases were reported, the most in 26 years. Using active microbiologic surveillance, we investigated the epidemic of pertussis in Greater Cincinnati in 1993. The population of 1.7 million in this area is served by a single children's hospital and pertussis laboratory. We prospectively followed patients given a new diagnosis of pertussis in July through September 1993 to determine the characteristics of the epidemic. From 1979 to 1992, there was a cumulative total of 542 cases of pertussis. In 1993, 352 cases were diagnosed, an increase of 259 percent over the 1992 total. Sixty-three percent of the cases had positive cultures for Bordetella pertussis, 18 percent were positive on direct fluorescent-antibody testing only, and 19 percent were diagnosed clinically. The outbreak began in the suburbs during the summer and spread through Greater Cincinnati. Of 255 total cases diagnosed in July through September (195 excess cases over the maximal base-line level of 20 per month in the previous 14 years), 75 percent were in white patients and 67 percent of the patients had private insurance or paid for care out of pocket. In 1993, as compared with 1979 through 1992, there was a shift in incidence from younger infants to older children; the percentages of cases according to age group were as follows: 0 to 6 months, 53 percent from 1979 through 1992 and 35 percent in 1993 (P < 0.001); 7 months to 5 years, 33 percent and 43 percent (P < 0.002); 6 to 12 years, 5 percent and 11 percent (P < 0.001); and more than 12 years, 5 percent and 11 percent (P < 0.003). Immunization records revealed that 74 percent (75 of 101) of the children with pertussis who were 19 months to 12 years old had received four or five doses of the combined diphtheria-pertussis-tetanus (DPT) vaccine, and that 82 percent (103 of 126) of those 7 to 71 months old had received at least three doses of DPT vaccine. The whole-cell vaccines used came from both of the major manufacturers (Connaught Laboratories and Lederle Laboratories). Disease was not severe, but 80 of the 255 children (31 percent) given diagnoses during the three epidemic months were hospitalized. There were no deaths. Since the 1993 pertussis epidemic in Cincinnati occurred primarily among children who had been appropriately immunized, it is clear that the whole-cell pertussis vaccine failed to give full protection against the disease.

The relationship between serum insulin-like growth factor-1 (IGF-1) concentration and reproductive performance, and genome-wide associations for serum IGF-1 in Holstein cows. The objectives of this study were to determine (1) factors associated with serum concentration of insulin-like growth factor-1 (IGF-1); (2) the relationship between serum IGF-1 concentration during the first week postpartum and ovarian cyclicity status by 35 d postpartum (DPP); (3) an optimum serum IGF-1 concentration threshold predictive of pregnancy to first artificial insemination (P/AI), including its diagnostic values; (4) the associations among categories of serum IGF-1 concentration and reproductive outcomes (P/AI and pregnancy risk up to 150 and 250 DPP); and (5) single nucleotide polymorphisms (SNP) associated with phenotypic variation in serum IGF-1 concentration in dairy cows. Serum IGF-1 concentration was determined at 7 (±2.4; ±standard error of the mean) DPP in 647 lactating Holstein cows (213 primiparous, 434 multiparous) from 7 herds in Alberta, Canada. The overall mean, median, minimum, and maximum serum IGF-1 concentrations during the first week postpartum were 37.8 (±1.23), 31.0, 20.0, and 225.0 ng/mL, respectively. Herd, age, parity, precalving body condition score, and season of blood sampling were all identified as factors associated with serum IGF-1 concentrations. Although serum IGF-1 concentration during the first week postpartum had no association with ovarian cyclicity status by 35 DPP in primiparous cows, it was greater in cyclic than in acyclic multiparous cows (32.2 vs. 27.4 ng/mL, respectively). The optimum serum IGF-1 thresholds predictive of P/AI were 85.0 ng/mL (sensitivity = 31.9%; specificity = 89.1%) and 31.0 ng/mL (sensitivity = 45.5%; specificity = 66.9%) for primiparous and multiparous cows, respectively. When cows were grouped into either high or low IGF-1 categories (greater or less than or equal to 85.0 ng/mL for primiparous cows and greater or less than or equal to 31.0 ng/mL for multiparous cows, respectively), primiparous cows with high IGF-1 had 4.43 times greater odds of P/AI and a tendency for higher pregnancy risk up to 150 DPP than those with low IGF-1, but not up to 250 DPP. Likewise, multiparous cows with high IGF-1 had 1.61 times greater odds of P/AI than those with low IGF-1. Pregnancy risk up to 150 and 250 DPP, however, did not differ between IGF-1 categories in multiparous cows. Moreover, 37 SNP across 10 Bos taurus autosomes were associated with variation in serum IGF-1 concentration, and 4 previously identified candidate genes related to fertility that were in linkage disequilibrium with some of these SNP were also identified.

Receipt of tetanus-containing vaccinations among adolescents aged 13 to 17 years in the United States: National Immunization Survey-Teen 2007. Tetanus-diphtheria-acellular pertussis (Tdap) was licensed in the United States in 2005 to be given in place of tetanus-diphtheria (Td) for single use in adolescents. This analysis was conducted to determine vaccination coverage with Td and Tdap among adolescents in the United States aged 13 to 17 years and to characterize adolescents who had not received a tetanus-containing booster vaccine. Data were analyzed from the National Immunization Survey-Teen (NIS-Teen) 2007, a random-digit-dialing telephone survey that is weighted to be nationally representative of adolescents aged 13 to 17 years. Parents gave verbal consent so that vaccination providers could be contacted to obtain the adolescents' immunization histories. Weighted coverage of Td and Tdap vaccines was estimated with bivariate analysis from returned vaccination data from the providers' records. A multivariable analysis was conducted to determine factors independently associated with nonreceipt of tetanus-containing vaccines. Missed opportunities for vaccination with Td or Tdap were determined from documented vaccination visits for other vaccines. Out of 69,289 households screened, 6572 had an eligible adolescent aged 13 to 17 years and 5486 (83.5%) completed the household interview. Among 5474 adolescents who met the age criterion and completed a household interview, consent to contact providers was obtained for 4114 (75.2%). A total of 2947 adolescents (53.7% of those with completed household interviews) had immunization histories returned from providers for verification. In 2007, a total of 2149 adolescents (weighted percentage, 72.3%) aged 13 to 17 years had received at least one tetanus booster since age 10 years; Tdap coverage was 30.4%. The mean (SE) age at Td or Tdap receipt was 13.04 (0.04) years (range, 10.00-17.84 years); the median age was 12.86 years. More than half (59.4%) of sampled adolescents had received their booster dose on or after January 1, 2005; among those vaccinated in 2007, 89.1% received Tdap as their booster dose. Factors associated with nonreceipt of Td or Tdap included geographic location and not having a provider-reported well-child visit at ages 11 to 12 years. Almost three quarters of adolescents aged 13 to 17 years included in the NIS-Teen 2007 received a tetanus-containing vaccine, and almost one third received Tdap. Among adolescents who received a tetanus-containing vaccine in 2007, a total of 89.1% received the new Tdap vaccine in place of Td, as recommended. Adolescents not receiving Td or Tdap may face barriers to accessing health care. Research is needed to identify evidence-based strategies to improve vaccination coverage among adolescents.

Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. NHS Blood and Transplant Research and Development.

Transmembrane topography of nicotinic acetylcholine receptor: immunochemical tests contradict theoretical predictions based on hydrophobicity profiles. In our preceding paper [Ratnam, M., Sargent, P. B., Sarin, V., Fox, J. L., Le Nguyen, D., Rivier, J., Criado, M., & Lindstrom, J. (1986) Biochemistry (preceding paper in this issue)], we presented results from peptide mapping studies of purified subunits of the Torpedo acetylcholine receptor which suggested that the sequence beta 429-441 is on the cytoplasmic surface of the receptor. Since this finding contradicts earlier theoretical models of the transmembrane structure of the receptor, which placed this sequence of the beta subunit on the extracellular surface, we investigated the location of the corresponding sequence (389-408) and adjacent sequences of the alpha subunit by a more direct approach. We synthesized peptides including the sequences alpha 330-346, alpha 349-364, alpha 360-378, alpha 379-385, and alpha 389-408 and shorter parts of these peptides. These peptides corresponded to a highly immunogenic region, and by using 125I-labeled peptides as antigens, we were able to detect in our library of monoclonal antibodies to alpha subunits between two and six which bound specifically to each of these peptides, except alpha 389-408. We obtained antibodies specific for alpha 389-408 both from antisera against the denatured alpha subunit and from antisera made against the peptide. These antibodies were specific to alpha 389-396. In binding assays, antibodies specific for all of these five peptides bound to receptor-rich membrane vesicles only after permeabilization of the vesicles to permit access of the antibodies to the cytoplasmic surface of the receptors, suggesting that the receptor sequences which bound these antibodies were located on the intracellular side of the membrane. Electron microscopy using colloidal gold to visualize the bound antibodies was used to conclusively demonstrate that all of these sequences are exposed on the cytoplasmic surface of the receptor. These results, along with our previous demonstration that the C-terminal 10 amino acids of each subunit are exposed on the cytoplasmic surface, show that the hydrophobic domain M4 (alpha 409-426), previously predicted from hydropathy profiles to be transmembranous, does not, in fact, cross the membrane. Further, these results show that the putative amphipathic transmembrane domain M5 (alpha 364-399) also does not cross the membrane. Our results thus indicate that the transmembrane topology of a membrane protein cannot be deduced strictly from the hydropathy profile of its primary amino acid sequence. We present a model for the transmembrane orientation of receptor subunit polypeptide chains which is consistent with current data.

The GH, prolactin, ACTH and cortisol responses to Hexarelin, a synthetic hexapeptide, undergo different age-related variations. Hexarelin (HEX) is a synthetic growth hormone-releasing peptide (GHRP) which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in an age-dependent manner. Like other GHRPs, HEX possesses also prolactin (PRL) and ACTH/cortisol-releasing activity. similar to that of human corticotropin-releasing hormone (hCRH). The mechanisms underlying the stimulatory effect of GHRPs on lactotrope and corticotrope secretion are even less clear and the influence of age on these endocrine activities of GHRPs is unknown. To clarify this point we studied the GH, PRL, ACTH and cortisol responses to the maximal effective dose of HEX (2.0 micrograms/kg i.v.) in: 12 prepubertal children (Pre-C, 8 male, 4 female, age 5.8-12.1 years); 12 pubertal normal short children (Pub-C, 5 male, 7 female, age 9.7-15.5 years, pubertal stage II-IV); 20 normal young adults (Young, 6 males, 14 females, age 23-32 years); and in 16 normal elderly people (Elderly, 5 male, 11 female, age 66-81 years). The GH response to HEX was clear in Pre-C (0-120 min area under curve, mean +/- S.E.M. 769.5 +/- 122.2 micrograms*min/l) but strikingly increased (P < 0.001) in Pub-C (1960.2 +/- 283.5 micrograms*min/l). The HEX-induced GH rise in Young (1829.7 +/- 243.1 micrograms*min/l) persisted similar to that in Pub-C, but decreased in Elderly (951.1 +/- 232.9 micrograms*min/I, P < 0.005); the latter was, in turn, similar to that in Pre-C. HEX induced a significant PRL increase which, however, showed no age-related variations, being similar in Pre-C (512.1 +/- 88.0 micrograms*min/l), Pub-C (584.0 +/- 106.0 micrograms*min/l), Young (554.9 +/- 56.0 micrograms*min/l) and Elderly (523.9 +/- 59.6 micrograms*min/l). The ACTH-releasing activity of HEX was present in Pre-C (1356.6 +/- 204.9 pg*min/ml) and was clearly enhanced (P < 0.02) in Pub-C (2253.5 +/- 242.8 pg*min/ml). The ACTH rise after HEX in Young (1258.1 +/- 141.2pg*min/ml) was lower (P < 0.02) than that in Pub-C and similar to that in Pre-C, while the ACTH response to HEX in Elderly (1786.5 +/- 340.1 pg*min/ml) showed a further trend toward increase, being similar to that in Pub-C. On the other hand, the cortisol response to HEX showed no significant age-related variations, being not different in Pre-C (7747.2 +/- 1031.6 micrograms*min/l), Pub-C (6106.0 +/- 862.9 micrograms*min/l), Young (6827.5 +/- 509.6 micrograms*min/I) and Elderly (7950.6 +/- 658.3 micrograms*min/l). In conclusion, our present data demonstrate that in humans the GH- and ACTH-releasing activities of HEX undergo different age-related variations, while its PRL-releasing activity is not dependent on age. These finding suggest that actions at different levels and/or on different receptor subtypes mediate the different age-related hormonal effects of GHRPs.

Activated carbon does not prevent the toxicity of culture material containing fumonisin B1 when fed to weanling piglets. Fumonisins are mycotoxins found primarily in corn and corn products that are produced by Fusarium verticillioides, F. proliferatum, and several other Fusarium species. The toxicity of fumonisin B1 (FB) from culture material with and without activated carbon was evaluated using weanling piglets. Fifty-six weanling pigs were assigned to one of four treatments diets based on BW. The treatment diets were 1) control = corn-soybean basal diet with < 2 ppm FB; 2) AC = control + activated carbon at 1% of the diet, as fed; 3) FB = control + culture material (formulated to contain 30 ppm FB, as-fed basis); and 4) AC + FB = control + activated carbon at 1% of the diet as fed + culture material (formulated to contain 30 ppm FB). A total of four replicates of four pigs per pen for the control and AC treatments and three piglets per pen for the FB and AC + FB treatments were used. Feed and water were offered ad libitum for the duration of the 42-d experiment. Compared with pigs fed the control or AC diets, pigs receiving the two FB-contaminated diets (FB or AC + FB) had lower G:F (P < 0.01), higher serum enzyme activities of gamma-glutamyltransferase and glutamic oxaloacetic transaminase (P < 0.05), and higher concentrations of cholesterol, free sphinganine, sphingosine-1-phosphate, and sphinganine 1-phosphate (P < 0.05). Although animals consuming FB diets showed no signs of respiratory distress, all pigs consuming either the FB or the AC + FB diets had marked pulmonary edema. Lesions were observed in the lungs, heart, and liver of pigs fed the FB or AC + FB diets, and treatment-associated changes also were seen in the pancreas, intestines, spleen, and lymph nodes. No lesions were observed in the brain. In liver, lung, heart, pancreas, spleen, intestines, and lymph nodes, the histopathological effects observed were more severe in the AC + FB group, suggesting that the AC treatment worsened the toxic effects of FB. Additionally, immunological measurements of macrophage function (CD14) were affected (P < 0.05) by the consumption of the FB diets. The consumption of FB diets containing 30 ppm fumonisin B1 from cultured material significantly affected performance, biochemical measurements, and organ pathology in weanling pigs. The addition of activated carbon at the rate of 1% to the diet was not effective in protecting against the detrimental effects of fumonisin consumption.

Important abnormalities of bone mineral metabolism are present in patients with coronary artery disease with a mild decrease of the estimated glomerular filtration rate. Chronic kidney disease (CKD)-mineral and bone disorder (MBD) is characterized by increased circulating levels of parathormone (PTH) and fibroblast growth factor 23 (FGF23), bone disease, and vascular calcification, and is associated with adverse outcomes. We studied the prevalence of mineral metabolism disorders, and the potential relationship between decreased estimated glomerular filtration rate (eGFR) and CKD-MBD in coronary artery disease patients in a cross-sectional study of 704 outpatients 7.5 ± 3.0 months after an acute coronary syndrome. The mean eGFR (CKD Epidemiology Collaboration formula) was 75.8 ± 19.1 ml/min/1.73 m(2). Our patients showed lower calcidiol plasma levels than a healthy cohort from the same geographical area. In the case of men, this finding was present despite similar creatinine levels in both groups and older age of the healthy subjects. Most patients (75.6 %) had an eGFR below 90 ml/min/1.73 m(2) (eGFR categories G2-G5), with 55.3 % of patients exhibiting values of 60-89 ml/min/1.73 m(2) (G2). PTH (r = -0.3329, p < 0.0001) and FGF23 (r = -0.3641, p < 0.0001) levels inversely correlated with eGFR, whereas calcidiol levels and serum phosphate levels did not. Overall, PTH levels were above normal in 34.9 % of patients. This proportion increased from 19.4 % in G1 category patients, to 33.7 % in G2 category patients and 56.6 % in G3-G5 category patients (p < 0.001). In multivariate analysis, eGFR and calcidiol levels were the main independent determinants of serum PTH. The mean FGF23 levels were 69.9 (54.6-96.2) relative units (RU)/ml, and 33.2 % of patients had FGF23 levels above 85.5 RU/ml (18.4 % in G1 category patients, 30.0 % in G2 category patients, and 59.2 % in G3-G5 category patients; p < 0.001). In multivariate analysis, eGFR was the main predictor of FGF23 levels. Increased phosphate levels were present in 0.7 % of the whole sample: 0 % in G1 category patients, 0.3 % in G2 category patients, and 2.8 % in G3-G5 category patients (p = 0.011). Almost 90 % of patients had calcidiol insufficiency without significant differences among the different degrees of eGFR. In conclusion, in patients with coronary artery disease there is a large prevalence of increased FGF23 and PTH levels. These findings have an independent relationship with decreased eGFR, and are evident at an eGFR of 60-89 ml/min/1.73 m(2). Then, mild decreases in eGFR must be taken in consideration by the clinician because they are associated with progressive abnormalities of mineral metabolism.

Reduction of interlaboratory variability in flow cytometric immunophenotyping by standardization of instrument set-up and calibration, and standard list mode data analysis. Two workshops addressed the question to which degree standardization of instrument set-up and calibration, and standard list mode data analysis would reduce interlaboratory variability of flow cytometric results on prestained peripheral blood mononuclear cells (PBMC). Standard instrument set-up included uniform positioning of the "windows of analysis" for the forward and sideward light scatter and fluorescence (FL) 1 (i.e., fluorescein isothiocyanate [FITC]) and 2 (i.e., phycoerythrin [PE]) parameters. Reference standards and PBMC, double-stained with FITC- and PE-conjugated monoclonal antibodies covering a wide range of FL intensities and coexpression patterns, were sent out to 25 laboratories in Workshop 1 and to 35 laboratories in Workshop 2 with the following requests: a) to set up instruments according to local and standard protocols, b) to acquire list mode data on the PBMC with both instrument settings, and c) to analyze both datasets according to local protocols. Standard analysis of the list mode data acquired with uniform instrument settings was performed centrally using so-called "latent class model" software (Van Putten et al., Cytometry 14:86-96, 1993). This software provides an automated, "no-gating" analytical method of lymphocyte immunophenotypes and employs fixed FL marker settings as defined prior to each analytical run. In Workshop 1, these markers were set in identical histogram channels for all instruments based on results obtained with a reference instrument. Standard analysis of list mode data acquired after uniform instrument set-up led only to a 13% reduction of interlaboratory variability of results as compared to data analysis using local protocols. The standard protocol for instrument set-up led to uniform positioning of relatively strong FL signals but variable positioning of unstained cells on the FL histogram scales. Hence, standard FL marker settings were inappropriate for some instruments. Therefore, instrument responses to FITC and PE signals in Workshop 2 were calibrated using microbeads labeled with FITC or PE in a range of predefined FL intensities expressed in MESF units (molecules of equivalent soluble fluorochrome). That approach allowed the positioning of the FL markers for the standard analysis on the basis of identical FL1 and FL2 intensities, expressed in MESF units, for all instruments. Standard analysis of list mode data acquired after uniform instrument set-up and calibrated FL marker settings led to a 43% reduction of interlaboratory variability as compared to data analysis to local protocols. We conclude that standard list mode data analysis using fixed FL marker settings reduces the interlaboratory variability of flow cytometric results on prestained PBMC, provided that the instruments have been set up in a uniform way and that FL markers have been standardized on the basis of calibration of each instrument's response to the corresponding FL signals.

[HYBRID MONOVISION]. To evaluate our own results of the use of hybrid monovision technique, in patients after bilateral cataract surgery, where in the dominant eye the monofocal intraocular lens is implanted and in the non-dominant eye the multifocal intraocular lens (IOL) is implanted. Prospective follow-up of group of 33 patients with bilateral cataract surgery and induced hybrid monovision. In the dominant eye, the hydrophilic monofocal aspheric intraocular lens Auroflex (Aurolab) was implanted, and in the non-dominant eye the hydrophilic multifocal aspheric intraocular lens Seelens (Hanita) was implanted. During the post-operative period, the uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (CDVA), uncorrected near visual acuity (UNVA), best-corrected near visual acuity (CNVA), and distance-corrected near visual acuity (DCNVA) were established. Further, the monocular contrast sensitivity, subjective satisfaction, and dysfotopsias appearance were examined. The examinations were held 3 and 6 months after the surgery. In dominant eyes with implanted monofocal lens, UDVA improved from 0.61 ± 0.39 logMAR preoperatively to 0.03 ± 0.14 logMAR at 6 months after the surgery. In non-dominant eyes, with implanted multifocal intraocular lens, UDVA improved from 0.30 ± 0.23 logMAR preoperatively to -0.04 ± 0.06 logMAR. The average binocular UDVA (bUDVA) was -0.07 ± 0.08 logMAR and binocular CDVA (bCDVA) -0.12 ± 0.06. The average UNVA in dominant eyes 6 months after the surgery was 0.62 ± 0.18 logMAR, in non-dominant eyes 0.18 ± 0,15 logMAR, binocularly 0.15 ± 0.11 logMAR. The contrast sensitivity was in the eyes with implanted multifocal IOL slightly worse comparing to the eyes with implanted monofocal lens, albeit only in the space frequency of 6 cycles per degree (CPD) this difference was statistically significant. Subjectively, the presence of dysfotopsia and other problems were very low, the average values of single answers were from 1.3 to 2.1 (on the scale 1 - 5, 1 - no problems and 5 - severe problems). Also, we noticed high percentage of subjective satisfaction with the surgery results (94 %). Six percent of patients wear glasses for near distance as a standard, 42 % of patients wear them occasionally, and 45 % of patients dont use glasses for near distance at all. The technique of hybrid monovision is effective, safe, and relatively cheap method solving the loss of accommodation in patients after the cataract surgery. This method extends the spectrum of our possibilities how to solve the loss of accommodation in these patients.Key words: hybrid monovision, multifocal intraocular lens, contrast sensitivity.

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Atrial fibrillation is associated with an increased risk of ischemic stroke. Data on individual patients were pooled from five recently completed randomized trials comparing warfarin (all studies) or aspirin (the Atrial Fibrillation, Aspirin, Anticoagulation Study and the Stroke Prevention in Atrial Fibrillation Study) with control in patients with atrial fibrillation. The purpose of the analysis was to (1) identify patient features predictive of a high or low risk of stroke, (2) assess the efficacy of antithrombotic therapy in major patient subgroups (eg, women), and (3) obtain the most precise estimate of the efficacy and risks of antithrombotic therapy in atrial fibrillation. For the warfarin-control comparison there were 1889 patient-years receiving warfarin and 1802 in the control group. For the aspirin-placebo comparison there were 1132 patient-years receiving aspirin and 1133 receiving placebo. The daily dose of aspirin was 75 mg in the Atrial Fibrillation, Aspirin, Anticoagulation Study and 325 mg in the Stroke Prevention in Atrial Fibrillation Study. To monitor warfarin dosage, three studies used prothrombin time ratios and two used international normalized ratios. The lowest target intensity was a prothrombin time ratio of 1.2 to 1.5 and the highest target intensity was an international normalized ratio of 2.8 to 4.2. The primary end points were ischemic stroke and major hemorrhage, as assessed by each study. At the time of randomization the mean age was 69 years and the mean blood pressure was 142/82 mm Hg. Forty-six percent of the patients had a history of hypertension, 6% had a previous transient ischemic attack or stroke, and 14% had diabetes. Risk factors that predicted stroke on multivariate analyses in control patients were increasing age, history of hypertension, previous transient ischemic attack or stroke, and diabetes. Patients younger than 65 years who had none of the other predictive factors (15% of all patients) had an annual rate of stroke of 1.0%, 95% confidence interval (CI) 0.3% to 3.0%. The annual rate of stroke was 4.5% for the control group and 1.4% for the warfarin group (risk reduction, 68%; 95% CI, 50% to 79%). The efficacy of warfarin was consistent across all studies and subgroups of patients. In women, warfarin decreased the risk of stroke by 84% (95% CI, 55% to 95%) compared with 60% (95% CI, 35% to 76%) in men. The efficacy of aspirin was not as consistent. The risk reduction with 75 mg of aspirin in the Atrial Fibrillation, Aspirin, Anticoagulation Study was 18% (95% CI, 60% to 58%), and with 325 mg of aspirin in the Stroke Prevention in Atrial Fibrillation Study the risk reduction was 44% (95% CI, 7% to 66%). When both studies were combined the risk reduction was 36% (95% CI, 4% to 57%). The annual rate of major hemorrhage (intracranial bleeding or a bleed requiring hospitalization or 2 units of blood) was 1.0% for the control group, 1.0% for the aspirin group, and 1.3% for the warfarin group. In these five randomized trials warfarin consistently decreased the risk of stroke in patients with atrial fibrillation (a 68% reduction in risk) with virtually no increase in the frequency of major bleeding. Patients with atrial fibrillation younger than 65 years without a history of hypertension, previous stroke or transient ischemic attack, or diabetes were at very low risk of stroke even when not treated. The efficacy of aspirin was less consistent. Further studies are needed to clarify the role of aspirin in atrial fibrillation.

Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study. Birth asphyxia represents a serious problem worldwide, resulting in approximately 1 million deaths and an equal number of serious sequelae annually. It is therefore important to develop new and better ways to treat asphyxia. Resuscitation after birth asphyxia traditionally has been carried out with 100% oxygen, and most guidelines and textbooks recommend this; however, the scientific background for this has never been established. On the contrary, theoretic considerations indicate that resuscitation with high oxygen concentrations could have detrimental effects. We have performed a series of animal studies as well as one pilot study indicating that resuscitation can be performed with room air just as efficiently as with 100% oxygen. To test this more thoroughly, we organized a multicenter study and hypothesized that room air is superior to 100% oxygen when asphyxiated newborn infants are resuscitated. In a prospective, international, controlled multicenter study including 11 centers from six countries, asphyxiated newborn infants with birth weight >999 g were allocated to resuscitation with either room air or 100% oxygen. The study was not blinded, and the patients were allocated to one of the two treatment groups according to date of birth. Those born on even dates were resuscitated with room air and those born on odd dates with 100% oxygen. Informed consent was not obtained until after the initial resuscitation, an arrangement in agreement with the new proposal of the US Food and Drug Administration's rules governing investigational drugs and medical devices to permit clinical research on emergency care without the consent of subjects. The protocol was approved by the ethical committees at each participating center. Entry criterion was apnea or gasping with heart rate <80 beats per minute at birth necessitating resuscitation. Exclusion criteria were birth weight <1000 g, lethal anomalies, hydrops, cyanotic congenital heart defects, and stillbirths. Primary outcome measures were death within 1 week and/or presence of hypoxic-ischemic encephalopathy, grade II or III, according to a modification of Sarnat and Sarnat. Secondary outcome measures were Apgar score at 5 minutes, heart rate at 90 seconds, time to first breath, time to first cry, duration of resuscitation, arterial blood gases and acid base status at 10 and 30 minutes of age, and abnormal neurologic examination at 4 weeks. The existing routines for resuscitation in each participating unit were followed, and the ventilation techniques described by the American Heart Association were used as guidelines aiming at a frequency of manual ventilation of 40 to 60 breaths per minute. Forms for 703 enrolled infants from 11 centers were received by the steering committee. All 94 patients from one of the centers were excluded because of violation of the inclusion criteria in 86 of these. Therefore, the final number of infants enrolled in the study was 609 (from 10 centers), with 288 in the room air group and 321 in the oxygen group. Median (5 to 95 percentile) gestational ages were 38 (32.0 to 42.0) and 38 (31.1 to 41.5) weeks (NS), and birth weights were 2600 (1320 to 4078) g and 2560 (1303 to 3900) g (NS) in the room air and oxygen groups, respectively. There were 46% girls in the room air and 41% in the oxygen group (NS). Mortality in the first 7 days of life was 12.2% and 15.0% in the room air and oxygen groups, respectively; adjusted odds ratio (OR) = 0.82 with 95% confidence intervals (CI) = 0.50-1.35. Neonatal mortality was 13.9% and 19.0%; adjusted OR = 0. 72 with 95% CI = 0.45-1.15. Death within 7 days of life and/or moderate or severe hypoxic-ischemic encephalopathy (primary outcome measure) was seen in 21.2% in the room air group and in 23.7% in the oxygen group; OR = 0.94 with 95% CI = 0.63-1.40. (ABSTRACT TRUNCATED)

Low-profile titanium mesh in the use of orbital reconstruction: A pilot study. The purpose of this study was to share our clinical experience in the use and accuracy of a newly designed, low-profile titanium mesh (Modus OPS 1.5; Medartis, Basel, Switzerland) for primary internal orbital reconstruction. Observational study. This study was conducted at the Department of Cranio-Maxillofacial Surgery at the University Hospital of Bern, Switzerland, starting November 2008. Patients were included who had a defect size of ≥2 cm(2) or fractures of more than one wall. The operations were performed within 14 days after trauma. To repair the orbital fracture, a newly designed titanium mesh was applied. The technical innovation in regard to these plates is the low-profile height of 0.25 mm along the border and 0.2 mm in the mesh area. Two different sizes of two different types of mesh are available for reconstruction. Preoperative computed tomography (CT) scans were obtained to assess the fracture size and location. A maxillofacial surgeon performed pre- and postoperative assessments (at 2 weeks, 12 weeks, and 6 months). Ophthalmologic assessments were performed preoperatively and 6 months after the operation. Postoperative CT scans were obtained within 12 weeks after the operation and the orbital volumes analyzed by a radiologist. Twenty-seven patients underwent surgery (11 female; average age, 55.2 years). Final postoperative ophthalmologic follow-up was obtained at a mean of 8.8 months (range, 4.0-20.1 months). Twenty-five patients (93%) had a successful treatment outcome without complications. In two patients, the plate was buckled in the posterior edge region and had to be replaced. Surgical revision was performed within 3 weeks after the first procedure. These patients showed good clinical and radiologic outcome after the second procedure. At the final assessment, none of the patients had experienced diplopia. Three patients showed slight enophthalmos (2-mm side difference), however, without any subjective functional or aesthetic concerns. According to the literature, an average orbital volume difference of up to 1.95 cm(3) is normal. In our study, radiologic volume assessment showed a side difference of ≥2 cm(3) in four patients, of which one patient presented with a clinically detectable enophthalmos. The newly designed, thin titanium mesh is a reliable and safe implant for the repair of orbital defects. Owing to insufficient intraoperative control, two plates showed buckling at the posterior border, which made a repair necessary. Awareness of this problem may avoid such complications in the future. However, it would seem reasonable to improve the stability of the mesh by increasing the profile height, to minimize potential complications.

Exploration of earth-abundant transition metals (Fe, Co, and Ni) as catalysts in unreactive chemical bond activations. Activation of inert chemical bonds, such as C-H, C-O, C-C, and so on, is a very important area, to which has been drawn much attention by chemists for a long time and which is viewed as one of the most ideal ways to produce valuable chemicals. Under modern chemical bond activation logic, many conventionally viewed "inert" chemical bonds that were intact under traditional conditions can be reconsidered as novel functionalities, which not only avoids the tedious synthetic procedures for prefunctionalizations and the emission of undesirable wastes but also inspires chemists to create novel synthetic strategies in completely different manners. Although activation of "inert" chemical bonds using stoichiometric amounts of transition metals has been reported in the past, much more attractive and challenging catalytic transformations began to blossom decades ago. Compared with the broad application of late and noble transition metals in this field, the earth-abundant first-row transition-metals, such as Fe, Co, and Ni, have become much more attractive, due to their obvious advantages, including high abundance on earth, low price, low or no toxicity, and unique catalytic characteristics. In this Account, we summarize our recent efforts toward Fe, Co, and Ni catalyzed "inert" chemical bond activation. Our research first unveiled the unique catalytic ability of iron catalysts in C-O bond activation of both carboxylates and benzyl alcohols in the presence of Grignard reagents. The benzylic C-H functionalization was also developed via Fe catalysis with different nucleophiles, including both electron-rich arenes and 1-aryl-vinyl acetates. Cobalt catalysts also showed their uniqueness in both aromatic C-H activation and C-O activation in the presence of Grignard reagents. We reported the first cobalt-catalyzed sp(2) C-H activation/arylation and alkylation of benzo[h]quinoline and phenylpyridine, in which a new catalytic pathway via an oxidative addition process was demonstrated to be much preferable. Another interesting discovery was the Co-catalyzed magnesiation of benzylic alcohols in the presence of different Grignard reagents, which proceeded via Co-mediated selective C-O bond activation. In C-O activation, Ni catalysts were found to be most powerful, showing the high efficacy in different kinds of couplings starting form "inert" O-based electrophiles. In addition, Ni catalysts exhibited their power in C-H and C-C activation, which have been proven by us and pioneers in this field. Notably, our developments indicated that the catalytic efficacy in cross coupling between aryl bromides and arenes under mild conditions was not the privilege of several noble metals; most of the transition metals exhibited credible catalytic ability, including Fe, Co, and Ni. We hope our studies inspire more interest in the development of first row transition metal-catalyzed inert chemical bond functionalization.

Displacement of mammillary bodies by craniopharyngiomas involving the third ventricle: surgical-MRI correlation and use in topographical diagnosis. Accurate diagnosis of the topographical relationships of craniopharyngiomas (CPs) involving the third ventricle and/or hypothalamus remains a challenging issue that critically influences the prediction of risks associated with their radical surgical removal. This study evaluates the diagnostic accuracy of MRI to define the precise topographical relationships between intraventricular CPs, the third ventricle, and the hypothalamus. An extensive retrospective review of well-described CPs reported in the MRI era between 1990 and 2009 yielded 875 lesions largely or wholly involving the third ventricle. Craniopharyngiomas with midsagittal and coronal preoperative and postoperative MRI studies, in addition to detailed descriptions of clinical and surgical findings, were selected from this database (n = 130). The position of the CP and the morphological distortions caused by the tumor on the sella turcica, suprasellar cistern, optic chiasm, pituitary stalk, and third ventricle floor, including the infundibulum, tuber cinereum, and mammillary bodies (MBs), were analyzed on both preoperative and postoperative MRI studies. These changes were correlated with the definitive CP topography and type of third ventricle involvement by the lesion, as confirmed surgically. The mammillary body angle (MBA) is the angle formed by the intersection of a plane tangential to the base of the MBs and a plane parallel to the floor of the fourth ventricle in midsagittal MRI studies. Measurement of the MBA represented a reliable neuroradiological sign that could be used to discriminate the type of intraventricular involvement by the CP in 83% of cases in this series (n = 109). An acute MBA (< 60°) was indicative of a primary tuberal-intraventricular topography, whereas an obtuse MBA (> 90°) denoted a primary suprasellar CP position, causing either an invagination of the third ventricle (pseudointraventricular lesion) or its invasion (secondarily intraventricular lesion; p < 0.01). A multivariate model including a combination of 5 variables (the MBA, position of the hypothalamus, presence of hydrocephalus, psychiatric symptoms, and patient age) allowed an accurate definition of the CP topography preoperatively in 74%-90% of lesions, depending on the specific type of relationship between the tumor and third ventricle. The type of mammillary body displacement caused by CPs represents a valuable clue for ascertaining the topographical relationships between these lesions and the third ventricle on preoperative MRI studies. The MBA provides a useful sign to preoperatively differentiate a primary intraventricular CP originating at the infundibulotuberal area from a primary suprasellar CP, which either invaginated or secondarily invaded the third ventricle.

Spontaneous and induced chromosomal damage and mutations in Bloom Syndrome mice. Bloom Syndrome (BS) is characterized by both cancer and genomic instability, including chromosomal aberrations, sister chromosome exchanges, and mutations. Since BS heterozygotes are much more frequent than homozygotes, the issue of the sensitivity of heterozygotes to cancer is an important one. This and many other questions concerning the effects of BLM (the gene responsible for the BS) are more easily studied in mice than in humans. To gain insight into genomic instability associated with loss of function of BLM, which codes for a DNA helicase, we compared frequencies of micronuclei, somatic mutations, and loss of heterozygosity (LOH) in Blmtm3Brd homozygous, heterozygous, and wild-type mice carrying a cII transgenic reporter gene. It should be noted that the Blmtm3Brd is inserted into the endogenous locus with a partial duplication of the gene, so some function of the locus may be retained. The cII reporter gene was introduced from the Big Blue mouse by crossing them with Blmtm3Brd mice. All measurements were made on F2 mice from this cross. The reticulocytes of Blmtm3Brd homozygous mice had more micronuclei than heterozygous or wild-type mice (4.5, 2.7, and 2.5 per thousand, respectively; P < 0.01) but heterozygotes did not differ significantly from wild-type. Unlike spontaneous chromosome damage, spontaneous mutant frequencies did not differ significantly among homozygous, heterozygous, and wild-type mice (3.2 x 10(-5), 3.1 x 10(-5), and 3.1 x 10(-5), respectively; P > 0.05). Mutation measurements were also made on mice that had been treated with ethyl-nitrosourea (ENU) because Bloom Syndrome cells are sensitive to ethylating agents. The ENU-induced mutation frequency in Blmtm3Brd homozygous, heterozygous, and wild mice were 54 x 10(-5), 35 x 10(-5), and 25 x 10(-5) mutants/plaques, respectively. ENU induced more mutations in Blmtm3Brd homozygous mice than in wild-type mice (P < 0.01), but not significantly more in heterozygous mice (P = 0.06). Spontaneous LOH did not differ significantly among the genotypes, but ENU treatment induced much more LOH in Blmtm3Brd homozygous mice, as measured by means of the Dlb-1 test of Vomiero-Highton and Heddle. Hence, these Blmtm3Brd mice resemble Bloom Syndrome except that they have normal frequencies of spontaneous mutation. The fact that these mice have elevated rates of both cancer and chromosomal aberrations (as shown by more micronuclei and LOH) but normal rates of spontaneous mutation, shows the greater importance of chromosomal events than mutations in the origin of their cancers.

A comparison of the prevalence of autoantibodies in individuals with chronic hepatitis C and those with autoimmune hepatitis: the role of interferon in the development of autoimmune diseases. Viral hepatitis due to hepatitis C virus results in chronic liver disease in more than 70% of individuals infected with the virus. Hepatitis C virus is also thought to be the cause of autoimmune chronic hepatitis, type II. The only treatment for chronic hepatitis C is interferon (IFN). IFN is both an antiviral agent and an up regulator of the cellular immune system. The latter effect is non-specific. Thus, IFN diffusely activates the cellular immune system and can initiate new autoimmune diseases in patients treated with it. To determine the prevalence of autoantibodies in patients with chronic hepatitis C and in patients with autoimmune hepatitis and to determine the incidence of new onset autoimmune disease in IFN-treated subjects with chronic hepatitis C, the records of 323 unselected patients with chronic hepatitis were reviewed. A total of 203 patients with a mean age of 45.7 +/- 0.8, ranging 18-81 with either HCV disease or autoimmune hepatitis, were identified and studied. One hundred sixty-two patients with chronic hepatitis C defined by elevations of serum alanine aminotransferase (ALT) for at least 6 months, the presence of detectable anti-HCV (HCV; second generation enzyme immunoassay [EIA2], a positive recombinant immunoblot assay [RIBA], the presence of HCV-RNA by PCR in serum and an abnormal biopsy consistent with chronic hepatitis C) were identified. Each was also negative for HbsAg, HbeAg and anti-Delta. Forty-one patients with a putative autoimmune chronic hepatitis (AIH) diagnosed on the basis of serologic positivity for classical autoantibodies (ANA and anti-smooth muscle antibodies), tissue typing (B8, Dr3 positive), characteristic liver biopsy findings and the absence of anti-HCV and HCV-RNA in serum were identified. The records of both of these groups of patients were reviewed for the following antibodies: anti-nuclear antibodies (ANA), antimitochondrial antibodies (AMA), anti-liver-kidney microsomal antibody (LKM), anti-smooth muscle antibodies (SMA), anti-microsomal antibodies (MSA). The rate of ANA positivity was 63% in both groups; the rate of SMA positivity was 65% in patients with HCV infection (group I) and 63% in patients with AIH (group II). AMA was positive in 4% of the subjects in group I and 50% of the subjects in group II; anti-LKM antibodies were absent in all 91 HCV cases and were present in 4% of the cases in group II; MSA positivity was present in 17% of group I and 10% of group II. Eighty-one of the one hundred sixty-two patients (50%) with chronic hepatitis C received IFN treatment at a dose of 5 MU SQ daily for 6 months. Thirty-two of these eighty-one patients (42 females and 39 males with a mean age of 45.0 +/- 1.3, ranging from 18 to 81 yr.) had at least two autoantibodies detectable prior to the IFN therapy (subgroup 1) and 49 had one or no identifiable autoantibodies (subgroup 2) present prior to IFN therapy. No significant differences in the interferon response rate defined by HCV-RNA negativity and normalization of serum ALT levels at the end of therapy was noted between those with autoantibodies and those without autoantibodies. Fifteen of the interferon-treated patients developed a clinical manifestation of a new onset autoimmune disease during the course of their interferon treatment. Six of the fifteen patients belonged to subgroup 1 (n = 32) and the remaining 9 patients to subgroup 2 (n = 49) (p > 0.05). None were managed by discontinuing the interferon. Most required some form of specific treatment.(ABSTRACT TRUNCATED)

[The calmodulin inhibitor R24571 induces a short-term Ca2+ entry and a pulse-like secretion of ATP in Ehrlich ascites tumor cells]. The properties of the Ca2+ channel induced by a calmodulin inhibitor in Ehrlich ascites tumor cells were investigated using fluorescent indicators Indo-1 and chlortetracycline. The inhibitor of calmodulin calmidazolium (R24571) in concentrations of 1-2 microM induces a short-term Ca2+ entry and a pulse-like ATP secretion. Repeated addition of R24571 also causes a transient Ca2+ signal. Ca2+ channels induced by R24571 are permeable for Mn2+. Ca2+ entry does not depend on endoplasmic reticulum depletion by thapsigargin, ATP, or ionomycin and is suppressed by nordihydroguaretic acid (EC50 = 6.7 microM), quercetin (EC50 = 1.5 microM), dihydroquercetin (EC50 = 17 microM), arachidonic acid (AA) (EC50 = 8.6 microM), and suramin (EC50 = 0.25 +/- 0.05 MM), and weakly depends on temperature in the range of 18 - 37 degrees C. The apparent activation constant for R24571 and the Hill coefficient are 2.5 +/- 0.2 and 4 +/- 0.3 microM, respectively. The products of arachidonic acid oxidation are neither activators nor inhibitors of these channels. The inhibitory effect of nordihydroguaretic acid is indirect and is conceivably caused by the accumulation of arachidonic acid due to suppression of its lipoxygenase-catalyzed oxidation at phospholipase A2 activation. The maximal level of about 1.3 microM in the dependence of Ca2+ signal amplitude on R24571 concentration points to possible inhibition of the channel by increased Ca2+ concentration in the cytosol. The weak dependence on temperature implies that the channel is highly permeable, the chain of enzymic processes is not involved in Ca2+ entry activation, and the mutual compensation of processes with opposite contributions is possible. Using chlortetracycline fluorescence, we have shown in model experiments on calmodulin solution that Ca2+ induces cooperatively a conformational transition of calmodulin with the exposure of a hydrophobic chlortetracycline-Ca(2+)-binding site. The interaction of R24571 with the CaM-Ca2+ complex results in quenching of fluorescence to its level in water, which is interpreted as the elimination of the availability of calmodulin hydrophobic site for chlortetracycline-Ca+. Nordihydroguaretic acid, quercetin, and dihydroquercetin, but not suramin, also interact with calmodulin, but this does not result in the complete closing of its hydrophobic site. It is supposed that the activation of the Ca2+ channel occurs owing to the activation of calmodulin-dependent phospholipase A2 by R24571, which leads to the formation of a low-molecular short-lived secondary messenger, or because of the interaction of R24571 with calmodulin, which directly inhibits the channel. The termination of Ca2+ entry is probably due to the inhibition of phospholipase A2 and/or of the channel at increased concentrations of arachidonic acid and Ca2+.

Half-dose thrombolysis to begin with, when immediate coronary angioplasty in acute myocardial infarction is not possible. Low-dose lytic drugs are sometimes administered to patients with ST-elevation acute myocardial infarction (AMI) as a bridge to coronary angioplasty (facilitated PTCA). Reports are scarce. The characteristics and outcomes of a recent series of consecutive patients treated in our Center are presented. In August 2000 facilitated PTCA with half-dose reteplase was started in our Center in all cases when the cath lab was not immediately (< 30 min) available, or the patient had to be transferred to us. Since August 2000, 153 patients were admitted to our cath lab to undergo facilitated (n = 80) or primary (n = 73) PTCA. The data of all patients were prospectively collected, and were analyzed on an "intention-to-treat" basis. No significant differences were found between facilitated and primary PTCA patients with regard to: gender, diabetes, hypertension, previous PTCA/bypass surgery, heart rate at admission, systolic blood pressure, anterior AMI, number of leads with ST-segment elevation, total ST-segment deviation, collateral flow to the infarct-related artery, and three-vessel disease. In our series, facilitated vs primary PTCA patients had a better risk profile: they were younger (61 +/- 13 vs 66 +/- 11 years, p = 0.016), less frequently had a previous AMI (7 vs 24%, p = 0.01), had a shorter time from pain onset to first emergency room admission (122 +/- 104 vs 168 +/- 162 min, p = 0.045), and a trend to a shorter total time to the cath lab (209 +/- 121 vs 255 +/- 183 min, p = 0.073) despite a similar emergency room-to-cath lab component (89 +/- 50 vs 98 +/- 92 min, median 74 vs 65 min, p = NS). Moreover, they presented with a lower Killip class on admission (1.1 +/- 0.4 vs 1.5 +/- 0.98, p = 0.01), with more patients in Killip class 1 (95 vs 74%, p = 0.001). One vs 8% of patients were in shock. Facilitated vs primary PTCA patients had an initial TIMI 2-3 flow in 42 vs 25% of cases (p = 0.031), a final TIMI 3 flow in 82 vs 71% (p = NS), > or = 50% ST-segment resolution in 73 vs 58% (p = NS), and both of the latter in 62 vs 45% (p = 0.099); distal coronary embolization occurred in 9 vs 14% of cases (p = NS); intra-aortic balloon counterpulsation was used in 5 vs 12% and glycoprotein IIb/IIIa inhibitors in 10% of the whole population. The overall in-hospital mortality was 3.7 vs 9.6% (p = NS), and 2.5 vs 4.5% (p = NS) when patients in shock at admission were not considered. Reinfarction occurred in 2 patients submitted to facilitated PTCA (who had had no immediate PTCA, due to full reperfusion) and in none of the patients submitted to primary PTCA; no patient presented with stroke or major bleeding. Pre-treatment with thrombolysis often provides a patent vessel before PTCA, appears to be safe, and may improve reperfusion after PTCA. In this setting, the additional use of glycoprotein IIb/IIIa inhibitors before PTCA only in non-reperfused patients may be significantly risk- and cost-effective.

Repeated sinomenine administration alleviates chronic neuropathic pain-like behaviours in rodents without producing tolerance. Background and aims We have previously reported that systemic administration of sinomenine produced antinociception in various experimental pain conditions in rodents, particularly in models of neuropathic pain. In the present study we assessed the effects of repeated administration of sinomenine in two rodent models of neuropathic pain in order to study the development of tolerance. Methods The analgesic effect of sinomenine was tested in female Sprague-Dawley rats that exhibited mechanical and cold hypersensitivity following ischaemic injury to the spinal cord and in male C57/BL6 mice that developed mechanical hypersensitivity after ischaemic injury to the sciatic nerve. Briefly, the animals were anaesthetized and injected i.v. with the photosensitizing dye erythrosine B. Vertebral segments T12 to T13 in rats or the sciatic nerve in mice were exposed and irradiated under an argon ion laser for 10min or 45s, respectively. In rats, mechanical hypersensitivity to pressure with von Frey hairs, the response to brushing and decreasing cold temperature were tested in the flanks or upper back areas. In mice, mechanical hypersensitivity on the hind paw to von Frey hairs and response to cold following a drop of acetone were measured. Sinomenine was administered i.p. in rats and p.o. in mice at 10:00 and 16:00, twice a day for 5 days. Response threshold before and 2h after drug administration at 10.00h was recorded. Results Repeated administration of sinomenine at 10 or 20mg/kg twice a day, doses that have no analgesic effect as single injection, alleviated mechanical, but not cold allodynia in spinally injured rats and the effect was maintained during the 5 day treatment period with no signs of tolerance. Furthermore, the pre-drug response threshold was significantly elevated during repeated treatment with 20mg/kg sinomenine. Sinomenine administered at 40mg/kg twice a day for 5 days significantly reduced mechanical and cold alldoynia, elevated pre-drug response threshold without tolerance development in spinally injured rats. Similarly, sinomenine at 80mg/kg twice a day for 5 days significantly reduced mechanical allodynia in mice with sciatic nerve injury and increased pre-drug response threshold with no sign of tolerance. The effect of sinomenine on response threshold persisted for days after termination of the 5 day drug administration. Conclusions The results suggest that repeated administration of simomenine produced an enhanced anti-allodynic effect without tolerance in rodent models of neuropathic pain. Implications Sinomenine may be tested as a novel analgesic in treating some forms of chronic neuropathic pain in patients.

Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea. A dose of 30 mg/kg of azithromycin is recommended for treatment of yaws, a disease targeted for global eradication. Treatment with 20 mg/kg of azithromycin is recommended for the elimination of trachoma as a public health problem. In some settings, these diseases are co-endemic. We aimed to determine the efficacy of 20 mg/kg of azithromycin compared with 30 mg/kg azithromycin for the treatment of active and latent yaws. We did a non-inferiority, open-label, randomised controlled trial in children aged 6-15 years who were recruited from schools in Ghana and schools and the community in Papua New Guinea. Participants were enrolled based on the presence of a clinical lesion that was consistent with infectious primary or secondary yaws and a positive rapid diagnostic test for treponemal and non-treponemal antibodies. Participants were randomly assigned (1:1) to receive either standard-dose (30 mg/kg) or low-dose (20 mg/kg) azithromycin by a computer-generated random number sequence. Health-care workers assessing clinical outcomes in the field were not blinded to the patient's treatment, but investigators involved in statistical or laboratory analyses and the participants were blinded to treatment group. We followed up participants at 4 weeks and 6 months. The primary outcome was cure at 6 months, defined as lesion healing at 4 weeks in patients with active yaws and at least a four-fold decrease in rapid plasma reagin titre from baseline to 6 months in patients with active and latent yaws. Active yaws was defined as a skin lesion that was positive for Treponema pallidum ssp pertenue in PCR testing. We used a non-inferiority margin of 10%. This trial was registered with ClinicalTrials.gov, number NCT02344628. Between June 12, 2015, and July 2, 2016, 583 (65·1%) of 895 children screened were enrolled; 292 patients were assigned a low dose of azithromycin and 291 patients were assigned a standard dose of azithromycin. 191 participants had active yaws and 392 had presumed latent yaws. Complete follow-up to 6 months was available for 157 (82·2%) of 191 patients with active yaws. In cases of active yaws, cure was achieved in 61 (80·3%) of 76 patients in the low-dose group and in 68 (84·0%) of 81 patients in the standard-dose group (difference 3·7%; 95% CI -8·4 to 15·7%; this result did not meet the non-inferiority criterion). There were no serious adverse events reported in response to treatment in either group. The most commonly reported adverse event at 4 weeks was gastrointestinal upset, with eight (2·7%) participants in each group reporting this symptom. In this study, low-dose azithromycin did not meet the prespecified non-inferiority margin compared with standard-dose azithromycin in achieving clinical and serological cure in PCR-confirmed active yaws. Only a single participant (with presumed latent yaws) had definitive serological failure. This work suggests that 20 mg/kg of azithromycin is probably effective against yaws, but further data are needed. Coalition for Operational Research on Neglected Tropical Diseases.

The role of RNA pseudoknot stem 1 length in the promotion of efficient -1 ribosomal frameshifting. The ribosomal frameshifting signal present in the genomic RNA of the coronavirus infectious bronchitis virus (IBV) contains a classic hairpin-type RNA pseudoknot that is believed to possess coaxially stacked stems of 11 bp (stem 1) and 6 bp (stem 2). We investigated the influence of stem 1 length on the frameshift process by measuring the frameshift efficiency in vitro of a series of IBV-based pseudoknots whose stem 1 length was varied from 4 to 13 bp in single base-pair increments. Efficient frameshifting depended upon the presence of a minimum of 11 bp; pseudoknots with a shorter stem 1 were either non-functional or had reduced frameshift efficiency, despite the fact that a number of them had a stem 1 with a predicted stability equal to or greater than that of the wild-type IBV pseudoknot. An upper limit for stem 1 length was not determined, but pseudoknots containing a 12 or 13 bp stem 1 were fully functional. Structure probing analysis was carried out on RNAs containing either a ten or 11 bp stem 1; these experiments confirmed that both RNAs formed pseudoknots and appeared to be indistinguishable in conformation. Thus the difference in frameshifting efficiency seen with the two structures was not simply due to an inability of the 10 bp stem 1 construct to fold into a pseudoknot. In an attempt to identify other parameters which could account for the poor functionality of the shorter stem 1-containing pseudoknots, we investigated, in the context of the 10 bp stem 1 construct, the influence on frameshifting of altering the slippery sequence-pseudoknot spacing distance, loop 2 length, and the number of G residues at the bottom of the 5'-arm of stem 1. For each parameter, it was possible to find a condition where a modest stimulation of frameshifting was observable (about twofold, from seven to a maximal 17 %), but we were unable to find a situation where frameshifting approached the levels seen with 11 bp stem 1 constructs (48-57 %). Furthermore, in the next smaller construct (9 bp stem 1), changing the bottom four base-pairs to G.C (the optimal base composition) only stimulated frameshifting from 3 to 6 %, an efficiency about tenfold lower than seen with the 11 bp construct. Thus stem 1 length is a major factor in determining the functionality of this class of pseudoknot and this has implications for models of the frameshift process.

Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report. The objectives of this study were: 1) to compare the time to hematologic recovery (absolute neutrophil count [ANC] > or = 1,000/mm3 and platelet count > or = 100,000/mm3) in a randomized prospective study of two doses of granulocyte colony-stimulating factor (G-CSF) (5.0 vs. 10.0 microg/kg per day) after ifosfamide, carboplatin, and etoposide (ICE) chemotherapy; and 2) to determine the response rate (complete response [CR] + partial response [PR]) of ICE in children with refractory or recurrent solid tumors. From June 1992 until November 1994, 123 patients with recurrent or refractory pediatric solid tumors were treated with ifosfamide (1,800 mg/m2 per day x 5), carboplatin (400 mg/m2 per day x 2), and etoposide (100 mg/m2 per day x 5) and randomized to receive either 5.0 microg/kg per day or 10.0 microg/kg per day of G-CSF subcutaneously until recovery of ANC to > or = 1,000/mm3. The incidence of grade 4 neutropenia during the first course was 88%. Median time from the start of chemotherapy to ANC > or = 1,000/mm(-3) for all patients during courses 1 and 2 was 21 and 19 days, respectively. The incidence of developing platelet count < or = 20,000/mm3 during course 1 was 82%. The median time from the start of the course of chemotherapy to platelet recovery > or =100,000/mm3 for all patients during courses 1 and 2 was 27 days. There was no significant difference in the median time of ANC recovery, platelet recovery, or incidence of grade 4 neutropenia; and in the median days of fever and the incidence of infections requiring hospitalization and intravenous antibiotics during courses 1 and 2, there was no significant difference between the two doses of G-CSF. One hundred eighteen patients were evaluated for response to ICE. The overall response rate (CR + PR) in this study was 51% (90% confidence interval, 43%-59%). The CR rate for all diagnostic categories was 27%. The Kaplan-Meier estimates of 1-year and 2-year survival probabilities for all patients were 52% and 30%, respectively. In summary, this combination of chemotherapy (ICE) was associated with a high CR rate (27%) in children with recurrent or refractory solid tumors, but also with a high incidence of grade 4 neutropenia and thrombocytopenia. Doubling the dose of G-CSF from 5.0 to 10.0 microg/kg per day after ICE chemotherapy did not result in an enhancement of neutrophil or platelet recovery or the incidence of grade 4 neutropenia developing.

Sacral nerve stimulation for voiding dysfunction: One institution's 11-year experience. The purpose of this study was to review our institution's 11-year experience with SNS for the treatment of refractory voiding dysfunction. Dating back to 1993, it covers a span of time which describes the evolution of SNS as it includes PNE trials, non-tined (bone-anchored or fascial-anchored) leads, percutaneous tined leads with two-staged procedures, and even percutaneous pudendal trials. A retrospective review was performed on SNS patients who received an implantable pulse generator (IPG) in our practice from 12/1993 to 12/2004. After Institutional Review Board approval, consents for chart review were obtained from 104 patients, representing 44% of this neuromodulatory patient population. Of our population, 87% were female and 13% were male. Average age at implant was 50 years +/- 13.4 years. Duration of symptoms before implantation was 116 months (range 9-600 months). Eighty percent were implanted for a predominant complaint of urinary urgency and frequency (U/F). Overall, 22% had U/F only, 38% had concomitant urge incontinence (UI), and 20% had concomitant mixed incontinence (MI). Twenty percent were treated for non-obstructive urinary retention (UR), with half of these associated with a neurogenic etiology. Additionally, 46.2% had pelvic pain, 58.6% had bowel complaints, and 51% reported sexual dysfunction. In patients with U/F, mean voiding parameters as described by pre-implant voiding diaries revealed the following: 12.4 (+/-5.1) voids per 24 hr; 2.3 (+/-1.8) voids per night; 5.0 (+/-4.7) leaks per 24 hr; and 2.3 (+/-2.6) pads per 24 hr. Statistically significant improvements post-implantation were noted with mean decreases in the following: 4.3 voids per 24 hr; 1.0 void per night; 4.4 leaks per 24 hr; and 2.3 pads per 24 hr (all P < 0.05). In the UR group a statistically significant improvement post-implantation was noted only in voids per night, with a mean decrease of 0.8 (P < 0.05). With a mean follow up of 22 months (range 3-162 months), sustained subjective improvement was >50%, >80%, and >90% in 69%, 50%, and 35% of patients, respectively. By quality of life survey, 60.5% of patients were satisfied and 16.1% were dissatisfied with current urinary symptoms. Only 13% (14 patients) abandoned therapy, making up a significant portion of those dissatisfied with current urinary symptoms. Good overall lead durability was seen (mean 22 months, range 1-121 months), with the first successful lead proving to be the most durable (mean 28 months, range 1.4-120 months). Lead durability decreased progressively with subsequent trials. Overall, 53% of patients experienced at least one reportable event (RE) attributable to either lead or IPG. A total of 126 REs were noted, with 97% mild-to-moderate in severity. REs included lack of efficacy, loss of efficacy, infection, hematoma/seroma, migration, pain, undesirable change in sensation, and device malfunction. In this population, 47.1% of leads were tined while 52.9% were non-tined. Tined leads had an overall lower RE rate as compared to non-tined leads: 28% and 73%, respectively. SNS is an effective method for treating certain types of voiding dysfunction. Although 53% of patients experienced at least one RE, 97% were mild-to-moderate and did not appear to affect the continued use of this therapy. With improved technology, such as percutaneous tined leads, the RE rate is decreasing. Further analyses of subsets of this population are currently underway.

A New Begomovirus Species in Association with Betasatellite Causing Tomato Leaf Curl Disease in Gandhinagar, India. In December 2012, tomato leaf curl disease (ToLCD) (2) was observed in tomato-growing areas of Gandhinagar District of Gujarat, a state in northwestern India. Incidence of ToLCD was estimated to be between 40 and 70% depending on the cultivars used. Infected plants exhibited symptoms consisting of leaf rolling, leaf curling, and yellowing typical of begomoviruses. Total DNA was isolated from a single affected tomato plant (2). Begomovirus infection in this sample was established by amplification of the expected-size 550-bp DNA fragment from this extract by PCR with degenerate DNA-A primers (3). Rolling circle amplification (RCA) using ϕ29 DNA polymerase was carried out on the total DNA, followed by digestion with Bam HI. An amplicon of ~2.8 kb was gel-eluted and cloned into Bam HI linearized pBluescript II KS(+). Restriction enzyme digestion of plasmid DNA from the resulting clones indicated the presence of one type of molecule. Using PCR and universal betasatellite primers, the expected 1.3-kb fragment was amplified from the DNA extract (1). An amplicon of ~1.3 kb was gel-eluted and cloned into pTZ57RT vector. Sequence analysis revealed that DNA-A (GenBank Accession No. KC952005) is composed of 2,753 nt and showed the highest identity (87.8%) with Tomato leaf curl Kerala virus[India:Kerala:2008] (GenBank Accession No. EU910141). An analysis for recombination showed this begomovirus DNA likely to have originated by recombination between Tomato leaf curl Kerala virus and Tomato leaf curl Karnataka virus. The satellite DNA-β (GenBank Accession No. KC952006) is composed of 1,365 nt and showed the highest identity (75.6%) with Tomato leaf curl betasatellite[India:Ludhiana:2004] (ToLCB-[IN:Lud:04]) (GenBank Accession No. AY765255). On the basis of DNA-A sequence analysis, the ICTV species demarcation criteria of 89% DNA-A sequence identity, and genome organization, the present isolate was considered as a new begomovirus species and named Tomato leaf curl Gandhinagar virus (ToLCGNV). The betasatellite shares less than 78% identity with (ToLCB-[IN:Lud:04]), it is considered a new species of betasatellite and the name, Tomato leaf curl Gandhinagar betasatellite (ToLCGNB) is proposed. Multimeric clones of the begomovirus and betasatellite DNAs were generated in a binary vector and these plasmids transformed into Agrobacterium tumefaciens. Nicotiana benthamiana and tomato plants agroinoculated with the cloned begomovirus DNA developed leaf curl symptoms, whereas plants co-agroinoculated with the cloned begomovirus and betasatellites developed more severe symptoms, including leaf rolling, leaf curling, and yellowing. The symptoms induced by the begomovirus and betasatellite DNAs were indistinguishable from those observed in the field. Thus, ToLCGNV is a new monopartite begomovirus which, in association with a new species of betasatellite, causes ToLCD in Gandhinagar, India. The presence of ToLCGNV needs to be considered, along with the already reported begomoviruses infecting tomatoes in this state, e.g., Tomato leaf curl Gujarat virus (2), in studies aimed to developing tomato cultivars with stable resistance to these tomato-infecting begomoviruses in India. References: (1) R. W. Briddon et al. Mol. Biotechnol. 20:315, 2002. (2) C. Reddy et al. Arch Virol. 150:845, 2005. (3) S. D. Wyatt and J. K. Brown. Phytopathology 86:1288, 1996.

Trend-Based Progression Analysis for Examination of the Topography of Rates of Retinal Nerve Fiber Layer Thinning in Glaucoma. Measurement of the rates of retinal nerve fiber layer (RNFL) thinning has consisted primarily of the circumpapillary RNFL profile. This study reports the rates of RNFL thinning over the 6 × 6 mm2 RNFL thickness map and their application for indication of visual field (VF) worsening in patients with glaucoma. To investigate the association between the rates of RNFL thinning and the risk of VF worsening in patients with glaucoma. This prospective study included 117 eyes of 89 Chinese patients with primary open-angle glaucoma followed up at approximate 4-month intervals for 5 or more years between July 1, 2007, and October 30, 2015, with progressive RNFL thinning detected by optical coherence tomography trend-based progression analysis (TPA). The mean and the peak rates of RNFL thinning and the area of progressive RNFL thinning were measured by the rates of change of RNFL thickness map. Visual field worsening was determined by the Early Manifest Glaucoma Trial and pointwise linear regression criteria. Hazard ratios (HRs) for indication of VF worsening determined by time-varying Weibull survival models. Of 89 patients (117 eyes) included in the study, 53 (59.6%) were men; mean (SD) age was 54.0 (13.8) years. At the time that progressive RNFL thinning was confirmed by TPA, the mean and the peak rates of RNFL thinning were 9.06 (8.05) µm/y and 4.52 (3.19) µm/y, respectively, and the area of progressive RNFL thinning was 1.54 (1.83) mm2. The inferotemporal meridians at 268° to 288° and the superotemporal meridians at 40° to 60° were the most frequent locations where progressive RNFL thinning was observed; 41.9% of the eyes had progressive RNFL thinning at these locations. After controlling for baseline covariates, the peak and the mean rates of RNFL thinning, but not the area of progressive RNFL thinning, were indicative of VF worsening. For each micrometer-per-year increase in the peak and the mean rates of RNFL thinning, the hazard ratios were 1.12 (95% CI, 1.04-1.19) for the peak rate and 1.39 (95% CI, 1.19-1.62) for the mean rate by the Early Manifest Glaucoma Trial criteria, and 1.07 (95% CI, 1.03-1.10) for the peak rate and 1.18 (95% CI, 1.09-1.28) for the mean rate by the pointwise linear regression criteria. Topographic measurement of the rates of RNFL thinning by optical coherence tomography TPA is informative for risk assessment of VF loss in glaucoma. Although progressive RNFL thinning may not necessarily be associated with VF worsening, faster rates of RNFL thinning were associated with a higher risk of subsequent decline in VF.

Clinician attitudes, skills, motivations and experience following the implementation of clinical decision support tools in a large dental practice. This study assesses dental clinicians' pre- and post-implementation attitudes, skills, and experiences with three clinical decision support (CDS) tools built into the electronic health record (EHR) of a multi-specialty group dental practice. Electronic surveys designed to examine factors for acceptance of EHR-based CDS tools including caries management by risk assessment (CAMBRA), periodontal disease management by risk assessment (PEMBRA) and a risk assessment-based Proactive Dental Care Plan (PDCP) were distributed to all Willamette Dental Group employees at 2 time points; 3 months pre-implementation (Fall 2013) and 15 months after implementation (winter 2015). The surveys collected demographics, measures of job experience and satisfaction, and attitudes toward each CDS tool. The baseline survey response rate among clinicians was 83.1% (n = 567) and follow-up survey response rate was 63.2% (n = 508). Among the 344 clinicians who responded to both before and after surveys, 27% were general and specialist dentists, 32% were dental hygienists, and 41% were dental assistants. Adherence to the CDS tools has been sustained at 98%+ since roll-out. Between baseline and follow-up, the change in mean attitude scores regarding CAMBRA reflect statistically significant improvement in formal training, knowing how to use the tools, belief in the science supporting the tools, and the usefulness of the tool to motivate patients. For PEMBRA, statistically significant improvement was found in formal training, knowing how to use the tools, belief in the science supporting the tools, with improvement also found in belief that the format and process worked well. Finally, for the PDCP, significant and positive changes were seen for every attitude and skill item scored. A strong and positive correlation with post-implementation attitudes was found with positive experiences in the work environment, whereas a negative correlation was found with workload and stress. Clinicians highly ranked a commitment to evidence-based care and sense that the tools were helping to improve patient care, health, and experience as motivations to use the tools. Peer pressure, fears about malpractice, and incentive pay were rated the lowest among the motivation factors. This study shows that CDS tools built into the EHR can be successfully implemented in a dental practice and widely accepted by the entire clinical team. Achieving a high level of adherence to use of CDS can be done through adequate training, alignment with the mission and purpose of the organization, and is compatible with an improved work environment and clinician satisfaction.

Hypnosis as adjunct therapy in conscious sedation for plastic surgery. Sedation is often requested during local and regional anesthesia. However, some surgical procedures, such as plastic surgery, require conscious sedation, which may be difficult to achieve. Hypnosis, used routinely to provide conscious sedation in the authors' Department of Plastic Surgery, results in high patient and surgeon satisfaction. The authors conducted a retrospective study to investigate the benefits of hypnosis in supplementing local anesthesia. The study included 337 patients undergoing minor and major plastic surgical procedures under local anesthesia and conscious intravenous sedation. Patients were divided into three groups depending on the sedation technique: intravenous sedation (n = 137) using only midazolam and alfentanil; hypnosis (n = 172), during which patients achieved a hypnotic trance level with age regression; and relaxation (n = 28), comprising patients in whom hypnosis was induced without attaining a trance level. In all three groups, midazolam and alfentanil were titrated to achieve patient immobility, in response to patient complaints, and to maintain hemodynamic stability. Midazolam and alfentanil requirements; intra- and postoperative pain scores; as well as pre-, intra-, and postoperative anxiety score, reported on a 10-cm visual analog scale, were recorded and compared in the three groups. Intraoperative anxiety reported by patients in the hypnosis group (0.7 +/- 0.11) and in the relaxation group (2.08 +/- 0.4) was significantly (P < .001) less than in the intravenous sedation group (5.6 +/- 1.6). Pain scores during surgery were significantly greater in the intravenous sedation group (4.9 +/- 0.6) than in the hypnosis group (1.36 +/- 0.12; P < .001) and the relaxation group (1.82 +/- 0.6; P < .01). Furthermore, midazolam requirements were significantly lower in the hypnosis group (P < .001) and in the relaxation group (P < .01) as compared with the intravenous sedation group: respectively, 0.04 +/- 0.002, 0.07 +/- 0.005, and 0.11 +/- 0.01 mg/kg/h. Alfentanil requirements were significantly decreased in the hypnosis group, as compared with the intravenous sedation group: 10.2 +/- 0.6 microgram/kg/h versus 15.5 +/- 2.07 micrograms/kg/h; P < .002. In the relaxation group, alfentanil requirements were 14.3 +/- 1.5 micrograms/kg/h (ns). Postoperative nausea and vomiting were reported by 1.2% of patients in the hypnosis group, 12.8% in the relaxation group and 26.7% in the intravenous sedation group. Greater patient satisfaction with the anesthetic procedure and greater surgical comfort were also reported in the hypnosis group. Successful hypnosis as an adjunct sedation procedure to conscious intravenous sedation provided better pain and anxiety relief than conventional intravenous sedation and allowed for a significant reduction in midazolam and alfentanil requirements. Patient satisfaction was significantly improved.

Mass spectrometry in emergency toxicology: Current state and future applications. This manuscript offers a broad overview of the state of emergency toxicology testing in clinical laboratories. We summarize the specific challenges of performing emergency toxicology testing, introduce a variety of currently used methods including mass spectrometry, and compare and contrast the utility of different types of mass spectrometers for this purpose. Finally, we examine evidence on the utility of toxicological testing in the treatment of poisoned patients, with special emphasis on the demonstrated utility of mass spectrometry-based tests. This review included primary literature indexed in the NCBI PubMed Database. Search terms included "emergency toxicology", "emergency mass spectrometry", "mass spectrometry toxicology", "utility of toxicology testing", and "toxicology surveillance". There are relatively few clinical trials on the utility of toxicology testing in overdosed or poisoned patients, and those studies that exist have a number of limitations. One of the most significant is that nearly all were conducted with immunoassay-based tests, which can only detect a limited number of compounds and are known to have a high false-positive rate. In addition, few are prospective. The overwhelming majority of studies of immunoassay-based tests concluded that results rarely changed patient management, regardless of the patient's clinical presentation. Many of these studies suggest that results could still be useful in other contexts, including identification of opportunities to refer a patient to substance abuse treatment or avoidance of drug-drug interactions. Mass spectrometry-based testing has several advantages over immunoassays, including the breadth of compounds that can be detected and substantially higher specificity, yet many questions remain about utility in emergency toxicology. The utility of mass spectrometry-based testing has not been assessed in a prospective clinical trial, rather the literature is overwhelmingly case-based, and a small number of laboratories are responsible for the majority of the case reports. The limited evidence that exists suggests that mass spectrometry can be useful in emergency situations, provided that results are available rapidly, interpreted by a knowledgeable physician, and that the scope of the method includes the compound implicated in the poisoning. Like results from immunoassays, many authors report using mass spectrometry-based testing for purposes other than direct patient care, namely surveillance of emerging drugs and trends in local drug use. A number of case reports and larger case series present evidence in support of this use. Despite the potential advantages of mass spectrometry, the quantity and quality of published evidence are not sufficient to adequately assess the utility of mass spectrometry-based emergency toxicology results. This is a field that is ripe for investigation, particularly as mass spectrometers become less expensive and the technology is adopted by an increasing number of clinical laboratories. There is a strong need for prospective studies on implementation of STAT mass spectrometry-based tests in emergency toxicology and larger scale assessments of impact on acute patient care as well as public health.

Lagopsis supina exerts its diuretic effect via inhibition of aquaporin-1, 2 and 3 expression in a rat model of traumatic blood stasis. Lagopsis supina has been used as a traditional medicinal herb for centuries in China. In folk medicine, it is used for promoting blood circulation and removing blood stasis (PBCRBS), anti-inflammatory and diuretic activities. Modern pharmacological investigation have shown that L. supina have an improvement in blood and lymphatic microcirculation, myocardioprotective, and antioxidative activities. Although the pharmacological research of L. supina was more, there was no report on the diuretic activity. This study was to evaluate the diuretic activity and the underlying mechanism of an ethanol extract of L. supina (LS) in a rat model of traumatic blood stasis (TBS). There were 30 male Sprague-Dawley rats that were randomly assigned to the control group, TBS group, and LS group (10 animals in each group). LS was administered orally (460 mg/kg) once daily for 7 successive days. The control group and TBS group were given an equal amount of 0.3% sodium carboxymethyl cellulose (CMC-Na). For the efficacy evaluation, the urine output volume, the urinary electrolyte concentrations (Na+, K+, Cl- and Ca2+) and pH value, the levels of angiotensin II (Ang II), atriopeptin (ANP), anti-diuretic hormone (ADH) and aldosterone (ALD), as well as aquaporin (AQP)-1, 2 and 3 protein expressions were detected in a rat model of TBS. The protein expressions of AQP-1, 2 and 3 were detected by quantitative immunohistochemistry (IHC) and Western blot analysis. In the efficacy evaluation, rat models treated with LS showed a significant increase in the total urine output (p < 0.01). The urinary electrolyte and the acid-base disturbances, including the decrease of Na+ and Ca2+ levels and the Na+/K+ value together with the increase in the Cl- level and the pH value, in the urine of the LS group were compared with the TBS group. Moreover, the levels of Ang II, ADH and ALD of rat model were decreased after being treated with LS (p < 0.05 or p < 0.01), while the ANP level was increased (p < 0.05). In addition, the results of the quantitative IHC and the Western blot analysis showed that the expression levels of AQP-1, 2 and 3 proteins decreased significantly compared with those of the TBS group. This is the first reported notable diuretic effect by LS, which probably was through the suppression of the renin-angiotensin-aldosterone system (RAAS) and the regulation of the signaling pathways of AQP-1, 2 and 3 protein expressions. Based on our results, we conclude that L. supina carries out its diuretic effect mainly by down-regulating the levels of AQP-1, 2 and 3 expressions in TBS rat model. These data also embody the traditional Chinese medicine (TCM) application principle of Huo xue li shui. These findings suggest that LS may warrant further evaluation as a possible agent for the diuretic drug in clinical applications. Further research is underway to elucidate the active compounds responsible for the diuretic activity of LS.

Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: four cases of rare tumors and a review of the literature. Neurofibromatosis type 1 (NF1) is a genetic syndrome that predisposes patients to benign and malignant tumor development. Patients with NF1 develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors. In contrast, malignant tumors unrelated to the nervous system rarely coexist with neurofibromatosis. The aim of this article was to present four cases of adult NF1 patients with malignant tumors unrelated to the nervous system as well as a bibliographic search for papers describing these tumors in NF1, focusing on osteosarcomas, gastrointestinal stromal tumors (GISTs), leiomyosarcomas and somatostatinomas and their genetic alterations in NF1. Search engines such as PubMed and MEDLINE were browsed for English-language articles since 1989 using a list of keywords, as well as references from review articles. Search terms were NF1, osteosarcoma, leiomyosarcoma, somatostatinoma and GIST. Data were summarized in a table at the end of the Results section. In our four NF1 cases, there were one osteosarcoma, one leiomyosarcoma, one somatostatinoma and GIST and one GIST. NF1 was diagnosed at an adult age when these patients were admitted to our oncology department. The results generated by the literature search yielded 75 articles about NF and GIST. We summarized the clinical characteristics of 43 patients with NF1 and somatostatinoma. Forty-five articles involving NF and osteosarcoma were found, and of these, 26 involved NF1; from these articles, we identified the clinical features of 8 patients. Twenty-five articles were found concerning NF1 and leiomyosarcoma, and of those, we summarized the clinical features of 15 patients. Here we reviewed somatostatinomas, GISTs, osteosarcomas and leiomyosarcomas occurring in NF1 patients. Patients with NF1 who present with gastrointestinal symptoms, should be carefully evaluated carefully with a high index of suspicion of potential GISTs, periampullary and duodenal tumors. Patients with pathological fractures or bone pain along with NF1 should be carefully screened for malignant bone tumors. Patients with NF1 can develop leiomyosarcoma less frequently than other malignancies, but the association of uterine leiomyoma and NF1 may not be fortuitous. Somatic mutations were defined for frequent tumors, including neurogenic tumors and GISTs but not for sarcomas due to the complexity of underlying mechanisms of the disease and tumorigenesis. Based on the findings; all NF patients can develop malignant tumors, including the less frequently observed ones. Therefore, we recommend that new genetic studies should be performed for rare malignancies in cases of NF1.

Early knee motion after open and arthroscopic anterior cruciate ligament reconstruction. The hypothesis proposed in this study was that the initiation of active and passive knee motion within 48 hours of major intraarticular knee ligament surgery would not have the deleterious effects of increasing knee effusion, hemarthrosis, periarticular soft tissue edema, and swelling. We conducted a prospective study with randomized assignment of 18 patients into two groups: 9 patients in the "motion" group began 10 hours of daily continuous passive motion (CPM) on the 2nd postoperative day, while the remaining 9 in the "delayed motion" group used a soft hinged knee brace with knee hinges locked at 10 degrees of flexion and entered into the motion program on the 7th postoperative day. All knees were allowed full 0 degrees to 90 degrees of motion except for a total of seven knees with concomitant mensicus repairs and extraarticular reconstructions where 20 degrees to 90 degrees of motion was allowed, limiting the last 20 degrees of knee extension for the first 4 postoperative weeks to protect the repair. In all other respects, the rehabilitation program after surgery was the same for the two groups, including postoperative compression dressings, exercises, and weight-bearing status. Ten of the eighteen patients had acute ACL disruptions and 8 had chronic ACL insufficiencies. There was an even distribution of acute and chronic knee cases and of open and arthroscopic ligament procedures in the early and delayed motion groups. Associated surgery included four meniscus repairs, three medial collateral ligament repairs, and one lateral collateral ligament repair. Special suturing and fixation techniques were used at surgery to maintain the integrity of ligament and meniscus structures, allowing the surgeon to feel safe in subjecting the joint to early postoperative motion. The objective parameters measured were KT-1000 arthrometer measurements, Cybex isokinetic testing, girth measurements at four lower limb locations, range of motion goniometer measurements, postoperative pain medications, and days of hospitalization. Starting intermittent passive motion on the 2nd postoperative day did not increase joint effusion, hemarthrosis, or soft tissue swelling. In both motion groups, postoperative joint effusions were absent after the 14th postoperative day. There was no statistically significant difference in knee extension or flexion limits, pain medication used, or hospital stay in comparing the two knee motion programs. An important finding of this study was the significant decreases in thigh circumference that occurred within the first few weeks of surgery, which progressed despite a closely supervised inpatient and outpatient rehabilitation program.(ABSTRACT TRUNCATED AT 400 WORDS)

[Preoperative changes in fluid filtration capacity in patients undergoing vascular surgery]. Patients undergoing major vascular surgery frequently require a substantial intraoperative fluid replacement to assure hemodynamic stability, which is in excess of the expected fluid requirements due to starving, blood and insensible losses. This leads to a positive fluid balance which can not be readily explained. We have used venous congestion plethysmography (VCP) a non-invasive method for measurement of microvascular parameters in limbs to investigate the changes in microvascular permeability (FFK) and the balance of Starling forces of patients undergoing surgery for unilateral femoral artery reconstruction (FEM) under epidural anaesthesia or abdominal aortic aneurysm repair (AAA) under general anaesthesia. The control group consisted of patients scheduled for inguinal hernia repair or hand surgery under general anaesthesia. All patients were measured 24 hours pre-operatively, immediately after the induction of anaesthesia or completion of epidural anaesthesia and on the 1st, 5th and 10th postoperative day. The perioperative patient management followed a standard protocol and all patients with vascular disease were invasively monitored using indwelling arterial lines and central venous catheters. Continuous infusion of Ringers lactate and 6% Dextran 60 was sustained during the induction period. Each patient gave informed consent. Preoperatively we found no significant difference in the mean FFK-values of controls (4.1 +/- 0.4, ml.min-1 100 ml tissue-1 mmHg-1 x 10(-3) = FFKU), the AAA (3.6 +/- 0.3 FFKU) and FEM (4.2 +/- 0.3 FFKU). After induction of anaesthesia the mean FFK value in the controls fell to 3.5 +/- 0.5 FFKU (p = 0.07), whereas in the AAA patients we observed a significant increase to 4.7 +/- 0.2 FFKU (p < 0.005) and after epidural anaesthesia in FEM to 5.5 +/- 0.4 FFKU (p < 0.001) respectively. Those post anaesthetic FFK values where significantly higher in FEM and AAA than in the controls (p < 0.02). In AAA we found a significant positive correlation between the increase in FFK and the intraoperative fluid balance (r2 = 0.69, p < 0.01). No such correlation was found in controls and FEM. The postoperative values of FFK where unchanged in the control group, whereas a further increase was seen in both patient groups with vascular disease, with a maximum in AAA on the 1st postoperative day (to 5.4 +/- 0.4 FFKU mean both legs) and the 5th postoperative day in FEM (to 7.3 +/- 1.7 non-ischemic leg, 7.1 +/- 1.2 ischemic leg FFKU). In both groups normal FFK values where found on the 10th day after the operation. The data presented suggests an increase in extravascular fluid loss in patients undergoing vascular surgery, which becomes evident after the induction of general anaesthesia or completion of epidural anaesthesia. The positive correlation with the intraoperative fluid requirements may partially explain the often reported large intraoperative fluid requirements of patients undergoing AAA repair. The fact that the maximum change in fluid filtration capacity is found postoperatively may be explained by the additional effect of an ischemia/reperfusion injury in response to both the clamping an declamping of the artery and the increase in arterial blood flow to the limb due to the successful reconstruction of the blood vessel.

Long-term outcome of high-dose γ knife surgery in treatment of trigeminal neuralgia. Despite the widespread use of Gamma Knife surgery (GKS) for trigeminal neuralgia (TN), controversy remains regarding the optimal treatment dose and target site. Among the published studies, only a few have focused on long-term outcomes (beyond 2 years) using 90 Gy, which is in the higher range of treatment doses used (70-90 Gy). The authors followed up on 315 consecutive patients treated with the Leksell Gamma Knife unit using a 4-mm isocenter without blocks. The isocenter was placed on the trigeminal nerve with the 20% isodose line tangential to the pontine surface (18 Gy). At follow-up, 33 patients were deceased; 282 were mailed an extensive questionnaire regarding their outcomes, but 32 could not be reached. The authors report their analysis of the remaining 250 cases. The patients' mean age at the time of survey response and the mean duration of follow-up were 70.8 ± 13.1 years and 68.9 ± 41.8 months, respectively. One hundred eighty-five patients (85.6%) had decreased pain intensity after GKS. Modified Marseille Scale (MMS) pain classifications after GKS at follow-up were: Class I (pain free without medication[s]) in 104 (43.7%), Class II (pain free with medication[s]) in 66 (27.7%), Class III (> 90% decrease in pain intensity) in 23 (9.7%), Class IV (50%-90% decrease in pain intensity) in 20 (8.4%), Class V (< 50% decrease in pain intensity) in 11 (4.6%), and Class VI (pain becoming worse) in 14 (5.9%). Therefore, 170 patients (71.4%) were pain free (Classes I and II) and 213 (89.5%) had at least 50% pain relief. All patients had pain that was refractory to medical management prior to GKS, but only 111 (44.4%) were being treated with medication at follow-up (p < 0.0001). Eighty patients (32.9%) developed numbness after GKS, and 74.5% of patients with numbness had complete pain relief. Quality of life and patient satisfaction on a 10-point scale were reported at mean values (± SD) of 7.8 ± 3.1 and 7.7 ± 3.4, respectively. Most of the patients (87.7%) would recommend GKS to another patient. Patients with prior surgical treatments had increased latency to pain relief and were more likely to continue medicines (p < 0.05). Moreover, presence of altered facial sensations prior to radiosurgery was associated with higher pain intensity, longer pain episodes, more frequent pain attacks, worse MMS pain classification, and more medication use after GKS (p < 0.05). Conversely, increase in numbness intensity after GKS was associated with a decrease in pain intensity and pain length (p < 0.05). Gamma Knife surgery using a maximum dose of 90 Gy to the trigeminal nerve provides satisfactory long-term pain control, reduces the use of medication, and improves quality of life. Physicians must be aware that higher doses may be associated with an increase in bothersome sensory complications. The benefits and risks of higher dose selection must be carefully discussed with patients, since facial numbness, even if bothersome, may be an acceptable trade-off for patients with severe pain.

The effect of high-frequency electrical pulses on organic tissue in root canals. To evaluate debris and smear layer scores after application of high-frequency electrical pulses produced by the Endox Endodontic System (Lysis Srl, Nova Milanese, Italy) on intact pulp tissue and organic and inorganic residues after endodontic instrumentation. The study comprised 75 teeth planned for extraction. The teeth were randomly divided into two groups (60 teeth) and a control group (15 teeth): group 1 (30 teeth) was not subjected to instrumentation; group 2 (30 teeth) was instrumented by Hero Shaper instruments and apical stops were prepared to size 40. Each group was subdivided into subgroups A and B (15 teeth); two electrical pulses were applied to subgroups 1A and 2A (one in the apical third and one in the middle third, respectively, at 3 and 6 mm from the root apices); four electrical pulses were applied to subgroups 1B and 2B (two in the apical third, two in the middle third). The control group (15 teeth) was prepared with Hero Shapers and irrigated with 5 mL of EDTA (10%) and 5 mL of 5% NaOCl at 50 degrees C but not subjected to the electrical pulse treatment. Roots were split longitudinally and canal walls were examined at 80x, 200x, 750x, 1500x and 15,000x magnifications, using a scanning electron microscope. Smear layer and debris scores were recorded at the 3 and 6 mm levels using a five-step scoring scale and a 200-microm grid. Means were tested for significance using the one-way anova model and the Bonferroni post-hoc test. The differences between groups were considered to be statistically significant when P < 0.05. The mean value for debris scores for the three groups varied from 1.80 (+/-0.77) to 4.50 (+/-0.68). The smear layer scores for group 2 and the control specimens varied from 2.00 (+/-0.91) to 2.33 (+/-0.99). A significant difference was found in mean debris scores at the 3 and 6 mm levels between the three groups (P < 0.001). The Bonferroni post-hoc test confirmed that the difference was due to group 1. In the two subgroups treated with four high-frequency pulses (1B and 2B) a substantial reduction in mean debris scores was found at the 3 and 6 mm level; subgroup 2B was practically free of organic residue. No significant differences for mean smear layer and debris scores were recorded between group 2 and the control group at the two levels; a significant difference was found only for mean smear layer scores at the 3 mm level between subgroup 2B and the control group (P < 0.05). The Endox device used with four electrical pulses had optimal efficacy when used after mechanical instrumentation. Traditional canal shaping and cleaning was essential to ensure an effective use of high-frequency electrical pulses in eliminating residues of pulp tissue and inorganic debris.

Association between use of β-blockers and outcomes in patients with heart failure and preserved ejection fraction. Heart failure with preserved ejection fraction (HFPEF) may be as common and may have similar mortality as heart failure with reduced ejection fraction (HFREF). β-Blockers reduce mortality in HFREF but are inadequately studied in HFPEF. To test the hypothesis that β-blockers are associated with reduced all-cause mortality in HFPEF. Propensity score-matched cohort study using the Swedish Heart Failure Registry. Propensity scores for β-blocker use were derived from 52 baseline clinical and socioeconomic variables. Nationwide registry of 67 hospitals with inpatient and outpatient units and 95 outpatient primary care clinics in Sweden with patients entered into the registry between July 1, 2005, and December 30, 2012, and followed up until December 31, 2012. From a consecutive sample of 41,976 patients, 19,083 patients with HFPEF (mean [SD] age, 76 [12] years; 46% women). Of these, 8244 were matched 2:1 based on age and propensity score for β-blocker use, yielding 5496 treated and 2748 untreated patients with HFPEF. Also we conducted a positive-control consistency analysis involving 22,893 patients with HFREF, of whom 6081 were matched yielding 4054 treated and 2027 untreated patients. β-Blockers prescribed at discharge from the hospital or during an outpatient visit, analyzed 2 ways: without consideration of crossover and per-protocol analysis with censoring at crossover, if applicable. The prespecified primary outcome was all-cause mortality and the secondary outcome was combined all-cause mortality or heart failure hospitalization. Median follow-up in HFPEF was 755 days, overall; 709 days in the matched cohort; no patients were lost to follow-up. In the matched HFPEF cohort, 1-year survival was 80% vs 79% for treated vs untreated patients, and 5-year survival was 45% vs 42%, with 2279 (41%) vs 1244 (45%) total deaths and 177 vs 191 deaths per 1000 patient-years (hazard ratio [HR], 0.93; 95% CI, 0.86-0.996; P = .04). β-Blockers were not associated with reduced combined mortality or heart failure hospitalizations: 3368 (61%) vs 1753 (64%) total for first events, with 371 vs 378 first events per 1000 patient-years (HR, 0.98; 95% CI, 0.92-1.04; P = .46). In the matched HFREF cohort, β-blockers were associated with reduced mortality (HR, 0.89; 95% CI, 0.82-0.97, P=.005) and also with reduced combined mortality or heart failure hospitalization (HR, 0.89; 95% CI, 0.84-0.95; P = .001). In patients with HFPEF, use of β-blockers was associated with lower all-cause mortality but not with combined all-cause mortality or heart failure hospitalization. β-Blockers in HFPEF should be examined in a large randomized clinical trial.

[Varicella complications: is it time to consider a routine varicella vaccination?]. Varicella is a common and benign disease of childhood. Complications are rare, but in some patients, even without risk factors, severe, life treathening complications could be seen. The aim of this study was to establish the type and frequency of varicella complications among hospitalised patients over an 8-year period. This retrospective analysis included medical charts of the patients hospitalised in the Infectious Disease Clinic, Belgrade, Serbia, from 2001-2008 (4.85% of all registered patients with varicella in Belgrade, 2001-2008). Among hospitalised patients dermografic characteristics were analysed: hospitalisation lenght, presence and type of complications, presence of immunocompromising conditions and outcome of the disease. The diagnosis of varicella was made on clinical grounds, and in persons >40 years, with negative epidemiological data of contacts, serological confirmation (ELISA VZV IgM/IgG BioRad) and avidity of IgG antibodies were done to exclude the possibility of disseminated herpes zoster. A total of 474 patient were hospitalised over an 8-year period. The age of patients was from 5 months to 75 years (mean 22.4 +/- 16.1, median 23.5 years). The majority of patients were adults (n=279; 58.9%) and 195 (41.1%) patients were < or =15 years old. Complications were found in 321/474 (67.7%) patients. The registered complications were: varicella pneumonia (n=198; 41.38%), bacterial skin infections (n=40; 8.4%), cerebelitis (n=28; 5.9%), bacterial respiratory infection (n=21; 4.4%), viral meningitis (n=10; 2.31%), encephalitis (n=9; 1.9%), thrombocytopenia (n=2; 0.4%); 11 (2.3%) patients had more than one complication, among them were sepsis, myopericarditis and retinal hemorrhages. When complications were analysed according to the age, there were no statistical significance, but when type of complication was analysed statistical significance was found (p < 0.05). In adults, pneumonia was the most common complication: 173/279 (62%), followed by skin infections (2.9%), bacterial respiratory infections (2.2%), and more than one complication (2.3%). Pneumonia was more common in adults than in children (7:1). In children skin infections were the most common complications (16.4%), followed by cerebelitis (13.3%), viral pneumonia (12.8%), bacterial respiratory infections (7.7%), encephalitis (3.6%), and more than one complication (4.1%). Neuroinfections were more common in children than in adults (6:1), as well as bacterial skin infections (4:1). Two patients died (0.4%). There was no difference in the incidence of varicella complication in children and adults, but the type of complication differed. In children the most common complications were skin and neurological infections, while in adults it was varicella pneumonia. These data provide a baseline for estimating the burden of varicella in Belgrade and support the inclusion of varicella vaccine in childhood immunisation program in Serbia.

Upper airway dysfunction associated with collapse of the apex of the corniculate process of the left arytenoid cartilage during exercise in 15 horses. To report dynamic collapse of the apex of the left corniculate process under the right corniculate process into the airway at the dorsal apposition of the paired arytenoid cartilages during exercise as a cause of upper airway dysfunction in horses. Retrospective study. Fifteen horses with a history of poor performance and/or upper respiratory tract noise during exercise. Video recordings of all horses referred for upper airway evaluation using high-speed treadmill videoendoscopy (HSTV) between January 1998 and December 2003 were reviewed. Records of horses that developed dynamic collapse of the apex of the left corniculate process into the airway were included. Clinical history, age, gender, breed, and use of the horse were retrieved. Of 309 horses referred for examination for poor performance and/or upper respiratory tract noise during exercise, 15 (4.9%) had collapse of the apex of the left corniculate process under the right and into the airway at the dorsal apposition between the paired arytenoid cartilages during HSTV. There were 3 females and 13 males, aged from 2 to 5 years. Five horses had previous surgery for left recurrent laryngeal neuropathy (RLN): 2 had nerve muscle pedicle graft and 3 had laryngeal prosthesis. During HSTV, all 15 horses had progressive collapse of the apex of the left corniculate process under the right at the dorsal apposition of the 2 arytenoid cartilages, and into the dorsal aspect of the rima glottidis. Review of video recordings revealed that collapse of the apex of the corniculate process was followed by progressive collapse of the left aryepiglottic fold and left vocal fold. The ventral aspect of the left corniculate cartilage maintained abduction in all horses. Two horses also had progressive collapse of the right vocal fold, 1 had rostral displacement of the palatopharyngeal arch, and another had dorsal displacement of the soft palate. Dynamic collapse of the apex of the left corniculate process of the arytenoid cartilage under the right is an uncommon cause of upper airway dysfunction in horses and the pathogenesis is unclear. We speculate that the left arytenoideus transversus muscle is unable to support the dorsal apposition between the arytenoid cartilages. This loss of support allows the elastic cartilage of the left corniculate process to collapse under the right and into the airway, as inspiratory pressure increases during exercise. This condition may be associated with an unusually advanced neuropathy of the adductor components of the left recurrent laryngeal nerve and may be an unusual manifestation of RLN; however, this is speculative and further investigation is required to determine its cause. Dynamic collapse of the apex of the left corniculate process and into the airway at the dorsal apposition between the paired arytenoid cartilages can only be diagnosed during HSTV. It is an uncommon cause of upper airway dysfunction but may affect the athletic potential of racing Thoroughbreds and Standardbreds.

The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. The metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, is associated with subsequent development of type 2 diabetes mellitus and cardiovascular disease (CVD). Despite its high prevalence, little is known of the prospective association of the metabolic syndrome with cardiovascular and overall mortality. To assess the association of the metabolic syndrome with cardiovascular and overall mortality using recently proposed definitions and factor analysis. The Kuopio Ischaemic Heart Disease Risk Factor Study, a population-based, prospective cohort study of 1209 Finnish men aged 42 to 60 years at baseline (1984-1989) who were initially without CVD, cancer, or diabetes. Follow-up continued through December 1998. Death due to coronary heart disease (CHD), CVD, and any cause among men with vs without the metabolic syndrome, using 4 definitions based on the National Cholesterol Education Program (NCEP) and the World Health Organization (WHO). The prevalence of the metabolic syndrome ranged from 8.8% to 14.3%, depending on the definition. There were 109 deaths during the approximately 11.4-year follow-up, of which 46 and 27 were due to CVD and CHD, respectively. Men with the metabolic syndrome as defined by the NCEP were 2.9 (95% confidence interval [CI], 1.2-7.2) to 4.2 (95% CI, 1.6-10.8) times more likely and, as defined by the WHO, 2.9 (95% CI, 1.2-6.8) to 3.3 (95% CI, 1.4-7.7) times more likely to die of CHD after adjustment for conventional cardiovascular risk factors. The metabolic syndrome as defined by the WHO was associated with 2.6 (95% CI, 1.4-5.1) to 3.0 (95% CI, 1.5-5.7) times higher CVD mortality and 1.9 (95% CI, 1.2-3.0) to 2.1 (95% CI, 1.3-3.3) times higher all-cause mortality. The NCEP definition less consistently predicted CVD and all-cause mortality. Factor analysis using 13 variables associated with metabolic or cardiovascular risk yielded a metabolic syndrome factor that explained 18% of total variance. Men with loadings on the metabolic factor in the highest quarter were 3.6 (95% CI, 1.7-7.9), 3.2 (95% CI, 1.7-5.8), and 2.3 (95% CI, 1.5-3.4) times more likely to die of CHD, CVD, and any cause, respectively. Cardiovascular disease and all-cause mortality are increased in men with the metabolic syndrome, even in the absence of baseline CVD and diabetes. Early identification, treatment, and prevention of the metabolic syndrome present a major challenge for health care professionals facing an epidemic of overweight and sedentary lifestyle.

Effect of early intervention with almotriptan vs placebo on migraine-associated functional disability: results from the AEGIS Trial. To investigate the effect of early acute migraine intervention with almotriptan vs placebo on functional disability and health-related quality of life (HRQoL) indicators. In this multicenter, double-blind, parallel-group trial, adults with international classification of headache disorders-defined migraine, with or without aura, were randomized 1:1 to treat 3 consecutive headaches with either almotriptan 12.5 mg or placebo. Patients were instructed to take their study medication at the first sign of migraine headache pain of any intensity, within 1 hour of onset. Patients recorded level of functional disability (normal, disturbed, bed rest required, emergency room [ER]/hospitalization required) at baseline (pretreatment), 0.5, 1, 2, 4, and 24 hours posttreatment and at time of pain-free. Patients completed the Migraine Disability Assessment Scale (MIDAS) at randomization and completed the Migraine Quality-of-Life Questionnaire (MQoL) at 24 hours after each attack. Results are presented for 315 patients (160 almotriptan, 155 placebo) in the evaluable for efficacy population. At 2 hours posttreatment of Attack 1, 54.4%, 32.5%, 13.1%, and 0%, respectively, of almotriptan-treated patients reported normal function, disturbed function, bed rest required, and ER/hospitalization required compared with 38.1%, 45.2%, 16.1%, and 0.6%, respectively, of placebo-treated patients. The differences in level of functional disability between the 2 treatment groups were statistically significant at 2 hours (P = .007; Cochran-Mantel-Haenszel, stratified by center) and at 4 hours (P < .001). Resolution of pain was associated with a normal level of function; at 2 hours posttreatment, 91.7% of patients in the total population who achieved pain-free reported normal function compared with 44.8%, 8.0%, and 0% of patients with mild, moderate, and severe pain, respectively. The absence compared with the presence of photophobia, phonophobia, and nausea at 2 hours also was associated with less disability (P < .0001 for each symptom). Treatment with almotriptan compared with placebo resulted in consistently better 24-hour MQoL scores with significant results for all 3 migraine headache attacks in the social function and feelings/concern domains. A logistic regression model determined that pretreatment functional level (P = .0117), pretreatment pain intensity (P = .0089), and pretreatment MIDAS score (P = .0152) were significant covariates of the proportion of patients who achieved normal function at 2 hours posttreatment. Early treatment with almotriptan within 1 hour of migraine pain onset significantly reduced levels of functional disability at 2 and 4 hours posttreatment compared with placebo. Consistency in improvement of HRQoL indicators was observed across 3 headaches treated.

Clinical and psychological correlates of lumbar motion abnormalities in low back disorders. Low back pain (LBP) and low back disorders (LBDs) identify a complex constellation of conditions that frustrate both diagnosis and therapy. Dynamic quantitative assessment and questionnaire instruments directed toward psychosocial and situational variables provide potentially powerful tools for determining functional pathology and potentially outcome. Our goal was to independently assess clinical correlates of a trunk motion measurement device, the lumbar motion monitor (LMM). The reliability of the LMM as a clinical test was assessed by comparison with an independent medical examination and biobehavioral questionnaires. There were three study components. A multispecialty physician panel that administered a structured physical examination contributed to a clinical correlation case series study. Standardized outcomes and risk identification questionnaires were administered to the case population. Finally, the LMM was administered in a customary fashion to the same population. Nineteen subjects were recruited on the basis of criteria that included symptoms of chronic recurrent low back pain. This was an employed and active, although impaired, population. Eighteen of the subjects were currently employed with limited lost work time, but chronic and recurrent pain was a common feature. Questionnaire outcome measures were both characterologic and situation based. In addition to providing diagnoses, the physician panel was also asked to offer certain qualitative assessments, such as rehabilitative potential and functional level pertinent to activities of daily living. The impact of LMM measures on physician decision making was also assessed. Trunk angular measurements were used to assess function of patients with chronic low back disorders. Kinematic performance on the LMM was expressed as three probability scores. These were the likelihood of abnormality, the "sincerity of effort" (exacerbation or aggravation of impairment), and the likelihood of structural anatomic disease. These variables were examined against established self-report measures of pain and disability. The LMM and physician panels were in agreement on the presence or absence of abnormality. LMM findings tended to be more consistent with clinical history than the clinical examination. The LMM results were also generally consistent with the self-reported measures of pain and disability: a high likelihood of structural disease was associated with depression, somatization, poor health perception and diminished vitality. The LMM appears to be a useful assessment tool for gauging the presence of LBP and LBD. It was accurate in detecting abnormality when abnormality was determined by clinical history and physician diagnosis. The LMM's differentiation of mechanical low back disease (nonanatomically specific disorders) from structurally specific low back disease was not consistent with a parallel clinical differentiation. Larger trials in a prospective format and studies on a chronically disabled population seem warranted. In an impaired but less disabled population, elevated pain and somatization did not appear to weaken the effort during testing.

Neurological deterioration after foramen magnum decompression for Chiari malformation type I: old or new pathology? Decompression of the foramen magnum is widely accepted as the procedure of choice for patients with Chiari malformation Type I (CM-I). This study was undertaken to determine the mechanisms responsible for neurological deterioration after foramen magnum decompression and the results of secondary interventions. Between 1987 and 2010, 559 patients with CM-I presented, 107 of whom had already undergone a foramen magnum decompression, which included a syrinx shunt in 27 patients. Forty patients who were neurologically stable did not undergo another operation. Sixty-seven patients with progressive symptoms received a recommendation for surgery, which was refused by 16 patients, while 51 patients underwent a total of 61 secondary operations. Hospital and outpatient records, radiographic studies, and intraoperative images were analyzed. Additional follow-up information was obtained by telephone calls and questionnaires. Short-term results were determined after 3 and 12 months, and long-term outcomes were evaluated using Kaplan-Meier statistics. Sixty-one secondary operations were performed after a foramen magnum decompression. Of these 61 operations, 15 involved spinal pathologies not related to the foramen magnum (spinal group), while 46 operations were required for a foramen magnum issue (foramen magnum group). Except for occipital pain and swallowing disturbances, the clinical course was comparable in both groups. In the spinal group, 5 syrinx shunt catheters were removed because of nerve root irritations or spinal cord tethering. Eight patients underwent a total of 10 operations on their cervical spine for radiculopathies or a myelopathy. No permanent surgical morbidity occurred in this group. In the foramen magnum group, 1 patient required a ventriculoperitoneal shunt for hydrocephalus 7 months after decompression. The remaining 45 secondary interventions were foramen magnum revisions, of which 10 were combined with craniocervical fusion. Intraoperatively, arachnoid scarring with obstruction of the foramen of Magendie was the most common finding. Complication rates for foramen magnum revisions were similar to first decompressions, whereas permanent surgical morbidity was higher at 8.9%. Postoperative clinical improvements were marginal in both surgical groups. With the exception of 1 patient who underwent syrinx catheter removal and had a history of postoperative meningitis, all patients in the spinal group were able to be stabilized neurologically. Long-term results in the foramen magnum group revealed clinical stabilizations in 66% for at least 5 years. Neurological deterioration in patients after a foramen magnum decompression for CM-I may be related to new spinal pathologies, craniocervical instability, or recurrent CSF flow obstruction at the foramen magnum. Whereas surgery for spinal pathologies is regularly followed by clinical stabilization, the rate of long-term success for foramen magnum revisions was limited to 66% for 5 years due to severe arachnoid scarring in a significant proportion of these patients. Therefore, foramen magnum revisions should be restricted to patients with progressive symptoms.

Danaparoid: a review of its use in thromboembolic and coagulation disorders. Danaparoid (danaparoid sodium) is a low molecular weight heparinoid which has undergone clinical study for use as continued anticoagulant therapy in patients with heparin-induced thrombocytopenia (HIT), for the prophylaxis and treatment of deep vein thrombosis (DVT), and for the treatment of disseminated intravascular coagulation (DIC). A nonblind study in patients with HIT has reported that complete clinical resolution is significantly more likely in patients receiving danaparoid than in patients receiving dextran 70. In addition, retrospective analyses and noncomparative data support the use of danaparoid for continued anticoagulant therapy in patients with HIT. Studies in patients undergoing hip surgery have shown that danaparoid significantly reduces the incidence of postoperative DVT compared with aspirin, warfarin, dextran 70 and heparin-dihydroergotamine, while additional data suggest no difference between danaparoid, enoxaparin and dalteparin. In patients undergoing abdominal or thoracic surgery for removal of a malignancy, danaparoid reduced the incidence of postoperative DVT compared with placebo, but showed no significant difference when compared with unfractionated heparin (UFH). Two studies have compared danaparoid with UFH in the prophylaxis of DVT following acute ischaemic stroke; twice daily danaparoid was significantly superior to UFH whereas there was no significant difference between a once-daily dosage and UFH. Danaparoid did not differ from UFH in terms of efficacy in the treatment of existing DVT. In all comparative studies examining the efficacy of danaparoid in the prophylaxis or treatment of DVT (versus warfarin, dextran 70, enoxaparin, dalteparin, aspirin, heparin-dihydroergotamine, UFH and placebo), the incidence of haemorrhagic complications did not differ between treatment groups. In patients with DIC, 61.9% of those patients receiving danaparoid experienced either disappearance or reduction of symptoms of DIC whereas 62% of those receiving UFH showed either no change or aggravation of their symptoms. There was no significant difference between treatment groups in tolerability or overall improvement of DIC. Danaparoid is an effective anticoagulant agent which has undergone clinical evaluation in a wide range of disease indications. Current guidelines support the use of danaparoid in prophylaxis of DVT following ischaemic stroke, and in patients who develop HIT. Danaparoid has shown efficacy in DIC, and for DVT prophylaxis in patients undergoing hip surgery although further data are required to establish the role of danaparoid in these indications. In particular, double-blind trials comparing danaparoid with such recommended therapies as the low molecular weight heparins will provide more definitive data on the place of danaparoid in the clinical management of these conditions and ultimately lead to improved patient outcomes.

Expectations of recovery and functional outcomes following thoracolumbar trauma: an evidence-based medicine process to determine what surgeons should be telling their patients. The aim of this study was to define the expected functional and health-related quality of life outcomes following common thoracolumbar injuries on the basis of consensus expert opinion and the best available literature. Patient expectations are primarily determined by the information provided by health care professionals, and these expectations have been shown to influence outcome in various medical and surgical conditions. This paper presents Part 2 of a multiphase study designed to investigate the impact of patient expectations on outcomes following spinal injury. Part 1 demonstrated substantial variability in the information surgeons are communicating to patients. Defining the expected outcomes following thoracolumbar injury would allow further analysis of this relationship and enable surgeons to more accurately and consistently inform patients. Expert opinion was assembled by distributing questionnaires comprising 4 cases representative of common thoracolumbar injuries to members of the Spine Trauma Study Group (STSG). The 4 cases included a thoracolumbar junction burst fracture treated nonoperatively or with posterior transpedicular instrumentation, a low lumbar (L-4) burst fracture treated nonoperatively, and a thoracolumbar junction flexion-distraction injury managed with posterior fusion. For each case, 5 questions about expected outcomes were posed. The questions related to the proportion of patients who are pain free, the proportion who have regained full range of motion, and the patients' recreational activity restrictions and personal care and social life limitations, all at 1 year following injury, as well as the timing of return to work and length of hospital stay. Responses were analyzed and combined with the results of a systematic literature review on the same injuries to define the expected outcomes. The literature review identified 38 appropriate studies that met the preset inclusion criteria. Published data were available for all injuries, but not all outcomes were available for each type of injury. The survey was completed by 31 (57%) of 53 surgeons representing 24 trauma centers across North America (15), Europe (5), India (1), Mexico (1), Japan (1) and Israel (1). Consensus expert opinion supplemented the available literature and was used exclusively when published data were lacking. For example, 1 year following cast or brace treatment of a thoracolumbar burst fracture, the expected outcomes include a 40% chance of being pain free, a 70% chance of regaining pre-injury range of motion, and an expected ability to participate in high-impact exercise and contact sport with no or minimal limitation. Consensus expert opinion predicts reemployment within 4-6 months. The length of inpatient stay averages 4-5 days. This synthesis of the best available literature and consensus opinion of surgeons with extensive clinical experience in spine trauma reflects the optimal methodology for determining functional prognosis after thoracolumbar trauma. By providing consistent, accurate information surgeons will help patients develop realistic expectations and potentially optimize outcomes.

Pre-steady-state kinetic study of the mechanism of inhibition of the plasma membrane Ca(2+)-ATPase by lanthanum. Lanthanides are known to be effective inhibitors of the PMCa(2+)-ATPase. The effects of LaCl3 on the partial reactions that take place during ATP hydrolysis by the calcium-dependent ATPase from plasma membrane (PMCa(2+)-ATPase) were studied at 37 degrees C on fragmented intact membranes from pig red cells by means of a rapid chemical quenching technique. LaCl3 added before phosphorylation (K0.5 = 2.8 +/- 0.2 microM) raised the kapp of the E2-->E1 transition from 14 +/- 2 to 23 +/- 4 s-1. The effect was independent of Ca2+ and Mg2+, as if La3+ substituted for Mg2+ and/or Ca2+ in accelerating the formation of E1 with higher efficiency. At non-limiting conditions, LaCl3 doubled the apparent concentration of E1 in the enzyme at rest with Ca2+ and Mg2+. LaCl3 during phosphorylation (K0.5 near 20 microM) lowered the vo of the reaction from 300 +/- 20 to 60 +/- 7 pmol/mg of protein/s, a close rate to that in the absence of Mg2+. This effect was reversed by Mg2+ (and not by Ca2+), and the K0.5 for Mg2+ as activator of the phosphorylation reaction increased linearly with the concentration of LaCl3, suggesting that La3+ slowed phosphorylation by displacing Mg2+ from the activation site(s). If added before phosphorylation, LaCl3 lowered the kapp for decomposition of EP to 0.8 +/- 0.1 s-1, a value which is characteristic of phosphoenzyme without Mg2+. The K0.5 for this effect was 0.9 +/- 0.5 microM LaCl3 and increased linearly with the concentration of Mg2+. If added after phosphorylation, LaCl3 did not change the kapp of 90 +/- 7 s-1 of decomposition of EP, suggesting that La3+ displaced Mg2+ from the site whose occupation accelerates the shifting of E1P to E2P. In medium with 0.5 mM MgCl2, 2 microM LaCl3 lowered rapidly the rate of steady-state hydrolysis of ATP by the PMCa(2+)-ATPase to a value close to the rate of decomposition of EP made in medium with LaCl3. Increasing MgCl2 to 10 mM protected the PMCa(2+)-ATPase against inhibition during the first 10 min of incubation. Results show that combination of La3+ to the Mg2+ (and Ca2+) site(s) in the unphosphorylated PMCa(2+)-ATPase accelerates the E2-->E1 transition and inhibits the shifting E1P--> E2P. Since with less apparent affinity La3+ slowed but did not impede phosphorylation, it seems that the sharp slowing of the rate of transformation of E1P into E2P by displacement of Mg2+ was the cause of the high-affinity inhibition of the PMCa(2+)-ATPase by La3+.

Comparative analysis of efficacy and cleaning ability of hand and rotary devices for gutta-percha removal in root canal retreatment: an in vitro study. To evaluate the efficacy and cleaning ability of Hedstrom files, and ProTaper retreatment instruments in removing gutta-percha from root canals with and without xylene as solvent. Sixty extracted single rooted human teeth were selected and decoronated, straight access established working length determined 1 mm short of canal, chemomechanical preparation done and obturated with guttapercha and AH plus sealer. Samples were stored for 1 week in humidifier divided into four groups of 15 teeth each. • Group I: Hedstrom files without xylene. • Group II: Hedstrom files with xylene. • Group III: ProTaper retreatment instruments without xylene. • Group IV: ProTaper retreatment instruments with xylene. and the following criteria were assessed - Time taken for initial plunge of instrument into guttapercha. - Time taken for complete removal of gutta-percha to reach working length - Ability of H files and ProTaper retreatment files with/ without xylene to remove gutta-percha in coronal, middle and apical 1/3 of canal. The teeth were grooved in labiolingual cross section, observed under a steromicroscope and scored according to gutta-percha debris left in the canal. Results were evaluated using ANOVA test and multiple comparisons done using Scheffe test. The least time to reach working length was found with group IV followed by groups III, II and group I respectively. Also the fastest way to remove maximum gutta-percha was group IV followed by groups III, II, and I respectively with a statistically significant difference among all groups. Apical 1/3 has more amount of remaining gutta-percha debris than middle and coronal 1/3 in all groups. The amount of gutta-percha debris in apical 1/3 was least in group IV followed by groups III, II and I respectively. The better performance of ProTaper rotary instruments has been attributed to their special flute design which tends to pull gutta-percha coronally directing it toward orifice. Also the movements of engine driven instruments produce frictional heat which plasticises gutta-percha and aids in easy removal. Apical third of root canals showed more guttapercha debris compared to coronal and middle 1/3 and has been attributed to the greater anatomic variability and difficulty of instrumentation in the apical area. The existence of deep groves and depressions on dentine walls in this apical 1/3 make them less instrumented areas as it did be difficult to direct the file against the extreme root canal wall. The fastest technique to remove gutta-percha and the shortest time to reach working length was observed with ProTaper retreatment instruments with xylene followed by ProTaper retreatment files without xylene and Hedstrom files without xylene. After instrumentation for removal of gutta-percha, apical third was found to have more debris compared to coronal and middle 1/3 of the root canal.

Association of SNPs in interferon receptor genes in chronic hepatitis C with response to combined therapy of interferon and ribavirin. Hepatitis C Virus is one of the main reasons for chronic liver disease and hepatocellular carcinoma. Combination therapy with Interferon (peg-IFN-α) and Ribavirin (RBV) clear the virus more likely than the others. Different factors like virus and host characteristics influence on response to treatment. The most important viral factors include virus genotype and viral load; host factors like genetic, gender, race, age, weight and liver enzymes are also important. Previous studies have shown that single nucleotide polymorphisms (SNPs) in IFNR genes can regulate and influence on treatment with IFN. The purpose of this study is to investigate the association between SNPs in IFN-α receptor (IFNAR1 & IFNAR2) genes among subjects affected with chronic hepatitis C, who have treated with IFN and RBV, and also relationship between HCV genotypes and response to combination antiviral therapy. Peripheral blood mononuclear cells (PBMCs) were taken from whole blood of 61 patients affected with chronic hepatitis C who were treated with IFN and Ribavirin. Then, DNA was extracted from PBMCs and quality of DNA was assessed with Nanodrop finally two SNPs [Ex4-30G>C] and [Ivs1-4640 G>A] of IFN receptor genes (IFNAR1 and IFNAR2) were measured by TaqMan Real-Time PCR in ABi Prism 7900 system. Also to confirm the response rate to therapy, RNA was extracted then RT PCR was performed and final product was studied with gel electrophoresis and UV spectroscopy. Statistical analysis was performed using SPSS version 18.0 for Windows. The analysis of results from TaqMan SNP Genotyping has been shown that two SNPs (Ex4-30G>C and Ivs1-4640 G>A) of IFNAR1 and IFNAR2 didn't show any relationship with response to combined therapy in subjects affected with chronic hepatitis C who have treated with peg-IFN-α and Ribavirin. 61 patients complete the treatment period. 54 patients (%88/5) of them responded to treatment and 7 patients (%11/5) did not. Research and data analysis have shown that there is no significant relationship between sex (P=0 /7) and age (P=0 /2). But there is a relationship between genotype-3a and response to combined therapy of IFN-α and RBV (0/02). Studies have shown that gene polymorphisms in IVSS1-22G location of IFNAR1 gene had a relationship with IFN treatment response. But current study has shown that there is no significant relationship between two SNPs Ex4-30G>C and Ivs1-4640 G>A and response to IFN therapy. In continue we suggest that it would be better to use this technique to evaluate other SNPs in IFN genes.

The fate of organs refused locally and transplanted elsewhere. The number of kidney allografts procured from deceased donors has been fairly constant in the past few years, while organs from living donors steadily increase. In our program, existing protocols refused some kidneys which were subsequently accepted and transplanted at other hospitals. Thus, a review of our criteria to accept kidneys became necessary. We studied the outcome of all kidneys refused by us but transplanted in other programs between 2002 and 2004. The data analyzed included ID no. donor, transplant center, procurement date, donor age, ischemic times, recipient alive or dead, creatinine level (when it was offered), initial function, hypertension, diabetes mellitus, biopsy, reason why the kidney was not accepted in our program, kidney functioning or lost, and cause of graft failure. The chi-square, Fisher, and t tests were used to analyze our data; P values of <.05 were regarded as significant. Originally 137, we excluded kidneys exported due to mandatory sharing (26 of 137 = 18.97%) and multiorgan placement (10 of 137 = 7.3%). Thus, 101 kidneys were not accepted by us because they did not meet the existing criteria of our program, but were accepted elsewhere. Reasons for nonacceptance were divided into donor quality, donor social history, donor age, donor size/weight, positive serological test, as well as organ preservation time, organ anatomical damage, elevated creatinine, abnormal urinalysis, abnormal biopsy, and decreased urine output. Donor issues were 66 of 101 (65.3%) with a graft loss of 13.6%, and organ issues were 35 of 101 (34.7%) with a graft loss of 66.6%. Donor quality totaled 24 of 66 (36.4%) and donor social history totaled 20 of 66 (30.3%); these were the most common causes for kidney nonacceptance related to donor issues. Reasons related to organ quality included elevated creatinine (15 of 35 = 42.9%; graft loss, 46.6%), and abnormal biopsy (9 of 35 = 25.7%; graft loss, 11.1%) and organ anatomical damage (4 of 35 = 11.4%; graft loss, 75%) (P = .42). Graft loss was more frequent with creatinine levels above 2.4 mg/dL (P < .001, RR gf = 1.5). Long-term fate of these 101 kidneys transplanted elsewhere: 82 (81.2%) were still working while 19 (18.8%) were lost. The causes of graft loss were renal artery thrombosis (42.1%), renal venous thrombosis (26.3%), death for other reasons (15.8%), graft never worked (10.5%), and ESRD (5.7%). The results suggest that the criteria for refusal related to donor issues, including hypertension, diabetes mellitus, donor age and donor size, should be revised owing to the low percentage of graft loss. Other donor issues such as positive serological test and donor social history (drug use, alcoholism) represent a serious potential risk for the health of recipients; for this reason, considering these persons as possible donors is very difficult irrespective of the graft outcome. Kidney refusals related to organ issues (especially elevated creatinine and anatomical damage) due to the very high percentage of graft loss should be considered high risk and probably be excluded. The increase in the demand of kidneys to be transplanted is a very important reason for a continuous and systematic review of donor exclusion criteria in every transplant program. The results presented here have helped us to improve both our outcomes and utilizations based on scientific evidence.

Comparative biology of chronic and aggressive periodontitis vs. peri-implantitis. This review was undertaken to address the similarities and dissimilarities between the two disease entities of periodontitis and peri-implantitis. The overall analysis of the literature on the etiology and pathogenesis of periodontitis and peri-implantitis provided an impression that these two diseases have more similarities than differences. First, the initiation of the two diseases is dependent on the presence of a biofilm containing pathogens. While the microbiota associated with periodontitis is rich in gram-negative bacteria, a similar composition has been identified in peri-implant diseases. However, increasing evidence suggests that S. aureus may be an important pathogen in the initiation of some cases of peri-implantitis. Further research into the role of this gram-positive facultative coccus, and other putative pathogens, in the development of peri-implantitis is indicated. While the initial host response to the bacterial challenge in peri-implant mucositis appears to be identical to that encountered in gingivitis, persistent biofilm accumulation may elicit a more pronounced inflammatory response in peri-implant mucosal tissues than in the dentogingival unit. This may be a result of structural differences (such as vascularity and fibroblast-to-collagen ratios). When periodontitis and peri-implantitis were produced experimentally by applying plaque-retaining ligatures, the progression of mucositis to peri-implantitis followed a very similar sequence of events as the development of gingivitis to periodontitis. However, some of the peri-implantitis lesions appeared to have periods of rapid progression, in which the infective lesion reached the alveolar bone marrow. It is therefore reasonable to assume that peri-implantitis in humans may also display periods of accelerated destruction that are more pronounced than that observed in cases of chronic periodontitis. From a clinical point of view the identified and confirmed risk factors for periodontitis may be considered as identical to those for peri-implantitis. In addition, patients susceptible to periodontitis appear to be more susceptible to peri-implantitis than patients without a history of periodontitis. As both periodontitis and peri-implantitis are opportunistic infections, their therapy must be antiinfective in nature. The same clinical principles apply to debridement of the lesions and the maintenance of an infection-free oral cavity. However, in daily practice, such principles may occasionally be difficult to apply in peri-implantitis treatment. Owing to implant surface characteristics and limited access to the microbial habitats, surgical access may be required more frequently, and at an earlier stage, in periimplantitis treatment than in periodontal therapy. In conclusion, it is evident that periodontitis and peri-implantitis are not fundamentally different from the perspectives of etiology, pathogenesis, risk assessment, diagnosis and therapy. Nevertheless, some difference in the host response to these two infections may explain the occasional rapid progression of peri-implantitis lesions. Consequently, a diagnosed peri-implantitis should be treated without delay.

Reperfusion therapy for acute myocardial infarction. Which strategy for which patient? Several modes of reperfusion therapy for evolving myocardial infarction (MI) have been developed, which differ in terms of effectiveness, complexity and costs. Reperfusion resources are often restricted by budgetary or logistical circumstances. To arrive at an equitable distribution of treatment options, physicians should therefore consider which treatment to apply in which patient. Two major questions which arise in this respect are discussed here: what is the treatment effect in an individual patients, and what is an equitable resource allocation? Currently, the most relevant treatment options are: streptokinase (1.5MU over 1h), reteplase (2 boluses of 10MU), alteplase (tissue plasminogen activator; t-PA) [100mg over 1.5 hours] and immediate angioplasty. In combination with aspirin, streptokinase leads to an almost 40% mortality reduction at 1 month compared with placebo [from 13.2 to 8.0%; Second International Study of Infarct Survival (ISIS-2) trial]. The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-1) study demonstrated a further mortality reduction by early combination therapy of aspirin, intravenous heparin and alteplase vs aspirin, heparin (either intravenous or subcutaneous) plus streptokinase (from 7.3 to 6.3%). The clinical effects of reteplase fall somewhere between those of streptokinase and alteplase. Combined analysis of the angioplasty trials suggests that angioplasty is superior to thrombolysis, especially in patients with a high cerebral bleeding risk. The noticed gradient of efficacy runs parallel to a gradient of costs and complexity: streptokinase is the least costly treatment option while direct angioplasty is the most expensive and complex. Subgroup analyses indicate that there are neither apparent deviations in the relative effect of reperfusion therapy as compared to control treatment, nor in the additional effect of more intensive therapy (alteplase) upon 'standard' therapy (streptokinase). Consequently, the absolute number of deaths avoided by reperfusion therapy appears to be greatest in those groups with a high mortality risk without therapy. There is one major exception: in patients treated early after symptom onset a much greater relative mortality reduction is observed than in those treated later. Owing to the higher mortality risk, the life expectancy of a patient with MI is shorter than that of an 'average' person of the same community and the same age. Since mortality reduction of reperfusion therapy is maintained at long term follow-up, part of this potential loss can be regained. This 're-gain of lost years' is judged to be the ultimate treatment effect in an individual patient. An equitable treatment allocation should be such that patients who will benefit most will receive the most effective therapy, while patients with similar expected benefit will be offered the same mode of therapy. The conclusion is that treatment guidelines or protocols can be very useful in clinical practice, especially if rapid decision making is of vital importance.

[Effects of scar excision combined with negative-pressure on repair of hypertrophic scar in burn children]. Objective: To explore the effects of scar excision combined with negative-pressure on repair of hypertrophic scar in burn children. Methods: From October 2010 to August 2016, 25 children with hypertrophic scar after deep burn were hospitalized, with scar course ranging from 3 months to 11 years and scar area ranging from 35 to 427 [83(51, 98)]cm(2). A total of 35 scars of 25 children were located in trunk (11 scars), upper limb (11 scars), and lower limb (13 scars). All children received scar excision operation and negative-pressure treatment (negative-pressure value ranged from -40 to -20 kPa), among which 6 cases received scar excision operation and negative-pressure treatment for two times for further removal of scars. After scar excision, electronic spring scale was used to measure the tension of the incision. The tension value of children ranged from 3.43 to 23.84 [7.16 (5.59, 9.12)] N, and then the incision was closed with appropriate suture according to the value of the tension. The incision with smaller tension was firstly opened on post operation day (POD) 8. After removing the suture, negative-pressure was conducted to POD 14. The incision with larger tension was firstly opened on POD 12. After removing the suture, biological semi-membrane was used to reduce tension to POD 16. All healed incisions were performed with anti-scar treatment for 1 year and relaxation and fixation for 3 months. General condition of the incision was observed after operation. The reduction percentage of scar area was calculated half-year after operation. The Patient and Observer Scar Assessment Scale was used to record the overall score of scar and scar score of trunk, upper limb, and lower limb before operation and half-year after operation. Data were processed with paired t test and Wilcoxon rank sum test. Results: After removing the suture, all incisions of children healed well without redness, effusion, and rupture. Half-year after operation, the appearance and deformity of incision were obviously improved, and the symptoms including pruritus and pain were basically relieved. Half-year after operation, the scar area of children ranged from 0 to 174 [21(9, 47)]cm(2,) which was significantly decreased as compared with that before operation (Z=-5.16, P<0.05). The reduction percentage of scar area ranged from 36% to 100% [(73±19)%]. Half-year after operation, the overall score of scar and scar score of trunk, upper limb, and lower limb of children were obviously decreased as compared with those before operation (with t values from 6.42 to 17.37, P values below 0.05). Conclusions: Scar excision combined with negative-pressure treatment has a good clinical effect on repair of hypertrophic scar in burn children, which is suitable for clinical application.

Effects of flavonoids on the release of reactive oxygen species by stimulated human neutrophils. Multivariate analysis of structure-activity relationships (SAR). In the present study we measured the inhibition by 34 compounds, either flavonoids or related substances, of the release of reactive oxygen species by human neutrophils after stimulation by three agents: the bacterial peptide N-fMetLeuPhe (FMLP), the protein kinase C activator phorbol myristate acetate (PMA) or opsonized zymosan (OZ), using two chemiluminescent probes, lucigenin or luminol in the presence or absence of horseradish peroxidase (HRP). The data matrix (34 x 7) was submitted to multivariate analysis: first, a correspondence factorial analysis to uncover levels of correlation among the biochemical parameters and the specificity of action of the test-compounds and second, a minimum spanning tree analysis that classified the chemical structures into a network describing both specificity and amplitude of the inhibition of the chemiluminescence response. The major conclusions of the analyses were: (a) opposition between inhibition of poly-morphonuclear leukocytes (PMNs) stimulated by FMLP and of PMNs stimulated by PMA or OZ implying that, for the molecules under study, there was a fundamental difference in the manner in which this inhibition occurred and, conversely, a difference in the nature of the stimulatory action of these activators. Molecules lacking hydroxyl groups on ring B, i.e. chrysin, chalcone, flavone and galangin, molecules glycosylated in position 7, i.e. hesperidin and naringin and ring B mono-hydroxylated molecules were, for the most part, at the origin of this dichotomy and might interfere with the membrane FMLP receptor; (b) a marked difference in chemiluminescence inhibition in the presence or absence of HRP that can be explained by the differential action of catechins compared to flavone and flavonol derivatives; (c) a similarity in biological profile between non-flavonoids such as chalcone and phloretin and low mean-activity flavonoids such as chrysin and galangin and between the non-flavonoid curcumin and the highly active flavonoid isorhamnetin; (d) a reaffirmation of the importance of ring A (C5,7) and ring B (C3',4') dihydroxylation, ring C (C3) hydroxylation, but also of the presence of a methoxy group on ring B in engendering high potency. This potency is generally decreased by C2-C3 saturation and by glycosylation. The most active molecules identified in this study provide valuable information for the selection of simpler molecules (e.g. metabolites accounting for the potency of orally administered flavonoids) for further structure-activity relationship (SAR) studies that could lead to the design of novel drugs or prodrugs.

Morphological and physiological changes during growth: an update. Skeletal growth and changes in body composition during growth present important variations; body mass index and lean body mass related to age show important gender differences. The process of ossification is developed in two different ways, endochondral and intramembraneous. The former is characterised by the formation of bone from growth cartilage. Intramembraneous ossification is characterised by the formation of bone from a mesenchymal structure, as occurs with the flat bones of the skull. During childhood and adolescence and up to the acquisition of adult stature, two phenomenons are produced simultaneously: the synthesis of new bone from growth cartilage due to the process of endochondral ossification, and modeling-remodeling of previously synthesized bone. Bone growth and mineralisation of its extracellular matrix are simultaneous phenomenons, the final result being the acquisition and maintenance of body bone mass. A positive calcium balance is necessary during adolescence in order to achieve the maximum peak of bone mass and even with the termination of longitudinal growth of bone, the process of mineralisation can last a further 4 years. Childhood and adolescence are the period of life in which the peak of bone mass must be achieved, and if during this time this does not happen there will be a greater risk for the later development of osteoporosis. Regulation of bone mass is a polygenic process and during recent years studies have been centred on the receptor genes of vitamin D and estrogens. A maximum calcium retention during adolescence may influence the achievement of a high peak of bone mass but at a certain level of calcium intake the calcium retention reaches a plateau. The expression of grams of hydroxyapatite per square centimetre has been used clinically, or expressed in volume as g/cm3. From birth until 3 years, the increase represents approximately 30% of the total increase, from 3 years until the beginning of pubertal development the increase is 20%. During pubertal development there is an increase of 30-40% and from the end of growth until the age of 21 years there is an increase of 15-20%. Both prepubertal boys and girls show a progressive increase of leptin levels during the years prior to the onset of puberty and until Tanner's stage 11 and higher levels are observed in girls in this period, possibly in relation to their earlier onset of puberty. This increase of leptin in girls during pubertal development suggests that leptin may be a link between adipose tissue and puberty.

Comparative study of permanent interstitial prostate brachytherapy post-implant evaluation among seven Italian institutes. The purposes of this multicentric study are (a) the evaluation of four different commercially available treatment planning systems (TPSs) and (b) to verify whether the dosimetric results are comparable, also when considering the inter-observer variabilities and the different scanning protocols used. This work is to be considered a first step to test the value of multicentric studies based on dosimetric evaluation of the quality of the implants. Four different TPSs were used and the following tests were performed:Comparison of the parameters and mathematical algorithms used; comparison of the dose distributions generated by three different geometries of sources based on 32 dose-points on each source geometry. An octagonal geometric phantom was used to compare volume algorithms and dose-volume histogram (DVH) calculations (V150(Gy), V100(Gy), V50(Gy) and V25(Gy)). Comparison of the post-plan source distribution performed on a prostate-phantom implanted with (125)I seeds. A CT scan of the phantom was obtained at each participating center. Both the geometrical coordinates (with respect to the most caudal one), and the spread of the geometrical distribution, were calculated. The volumes included within different isodoses were also collected. Comparison of the post-plan source distribution performed on an actual patient. Post-plan V100% and D90(Gy) derived from seed distributions obtained by different operators were calculated, using the same target delineation. All the considered TPSs satisfied the AAPM dosimetric parameter recommendations. Point-dose examinations revealed differences smaller than 5%, except for one of the systems. Although the volume algorithm was not the same for all systems, no statistically significant difference was found in the volume measurements. The DVHs also presented differences smaller than 5%, except for one TPS. The distances between the seeds, based on the same CT images, showed a mean SD of 0.13 mm. The mean maximum difference of the position of each seed was 0.36 mm. The most significant errors were made in the cranio-caudal direction (mean maximal difference: 0.44 mm); here the size of the step between slices played an important role. The algorithm of source positioning of the different TPSs may also help explain this difference. The compiled DVHs showed differences smaller than 5%. Post-plans derived from different seed distributions showed a mild dependence upon operators. We obtained a mean value of 97.8 and 152.7 with a percentage of SD of 0.43 and 1.7, respectively, for V100% and D90(Gy). Three-dimensional (3D) geometric reconstructions of seed distributions are slightly dependent upon the operators and the scanning protocols have little effect on the dosimetric evaluation. Some relevant discrepancies were found between one of the TPSs and the other three if few sources were used; increasing the number of seeds those differences became less pronounced. Multicentric studies on the quality of prostate implants based on post-implant dosimetry are feasible, provided an accurate step-wise evaluation of the procedure be performed.

Subjective referral of the timing for a conscious sensory experience: a functional role for the somatosensory specific projection system in man. Subjective experience of a peripherally-induced sensation is found to appear without the substantial delay found for the experience of a cortically-induced sensation. To explain this finding, in relation to the putative delay of up to about 500 ms for achieving the "neuronal adequacy" required to elicit the peripherally-induced experience, a modified hypothesis is proposed: for a peripheral sensory input, (a) the primary evoked response of sensory cortex to the specific projection (lemniscal) input is associated with a process that can serve as a 'time-marker'; and (b), after delayed neuronal adequacy is achieved, there is a subjective referral of the sensory experience backwards in time so as to coincide with this initial 'time-marker'. A crucial prediction of the hypothesis was experimentally tested in human subjects using suitably implanted electrodes, and the results provide specific support for the proposal. In this, the test stimuli to medial lemniscus (LM) and to surface of somatosensory cortex (C) were arranged so that a minimum train duration of 200 ms or more was required to produce any conscious sensory experience in each case. Each such cerebral stimulus could be temporally coupled with a peripheral one (usually skin, S) that required relatively negligible stimulus duration to produce a sensation. The sensory experiences induced by LM stimuli were found to be subjectively timed as if there were no delay relative to those for S, that is, as if the subjective experience for LM was referred to the onset rather than to the end of the required stimulus duration of 200 ms or more. On the other hand, sensory experiences induced by the C stimuli, which did not excite specific projection afferents, appeared to be subjectively timed with a substantial delay relative to those for S, that is, as if the time of the subjective experience coincided roughly with the end of the minimum duration required by the C stimuli. The newly proposed functional role for the specific projection system in temporal referral would be additional to its known role in spatial referral and discrimination. A temporal discrepancy between corresponding mental and physical events, i.e., between the timing of a subjective sensory experience and the time at which the state of 'neuronal adequacy' for giving rise to this experience is achieved, would introduce a novel experimentally-based feature into the concept of psychophysiological parallelism in the mind-brain relationship.

Colour and pulsed Doppler US and tumour marker CA 125 in differentiation between benign and malignant ovarian masses. Colour and pulsed Doppler flow imaging have been proposed as methods that may be useful in differentiating benign from malignant ovarian masses. It was hypothesised that the detection of neovascularisation with abnormal, low-resistance blood flow peculiar to malignant tumours is possible, which is characterised with angle-independent Doppler indices Pl and Rl (pulsatility and resistance index, respectively). Tumour marker CA 125 SC (serum concentration) was found to be elevated in 80-85% of patients with serous epithelial ovarian cancer and in a lower percentage in other ovarian cancers, with levels over 35U/ml suggestive of malignancy. In our study we wanted to determine whether colour and pulsed Doppler US and CA 125 SC can be used to differentiate benign from malignant ovarian masses and whether, by combining the methods, the results can be even improved. Ovarian masses identified by sonography in 71 patients aged 35 years or more were confirmed at surgery (n = 61) or endoscopy (n = 4) or followed up to resolution with US (n = 6). Colour and pulsed Doppler US were used to identify intratumoral areas of vascularisation and to calculate the lowest Pl and Rl for each ovarian mass. CA 125 SC were measured. In 16 of 18 ovarian malignancies and 28 of 53 benign masses, areas of intratumoral vascularisation were detected with colour Doppler US (p = 0.002). Pl and Rl values displayed considerable overlap between malignant and benign lesions and the differences were not significant. Mean CA 125 SC was higher in malignant than in benign masses (p = < 0.0001). For cut-off at 35U/ml, sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) for ovarian cancer were 83%, 74%, 79% and 75% respectively. Either CA 125 SC > 35U/ml or intratumoral colour Doppler signal was detected in all 18 patients with ovarian cancer, but neither of them was detected in 25 patients all of whom had benign tumours. Thus, combining the two methods, SE, SP, PPV and NPV for ovarian cancer were: 100%, 47%, 32% and 100% respectively. RI and PI values thus cannot be used to differentiate between benign and malignant ovarian tumours. The determination of CA 125 serum level is useful in identifying ovarian cancer. CA 125 SC under 35U/ml, together with the lack of detectable colour flow in the tumour, can reliably exclude ovarian malignancy (NPV = 100%).

Human error in hospitals and industrial accidents: current concepts. Most data concerning errors and accidents are from industrial accidents and airline injuries. General Electric, Alcoa, and Motorola, among others, all have reported complex programs that resulted in a marked reduction in frequency of worker injuries. In the field of medicine, however, with the outstanding exception of anesthesiology, there is a paucity of information, most reports referring to the 1984 Harvard-New York State Study, more than 16 years ago. This scarcity of information indicates the complexity of the problem. It seems very unlikely that simple exhortation or additional regulations will help because the problem lies principally in the multiple human-machine interfaces that constitute modern medical care. The absence of success stories also indicates that the best methods have to be learned by experience. A liaison with industry should be helpful, although the varieties of human illness are far different from a standardized manufacturing process. Concurrent with the studies of industrial and nuclear accidents, cognitive psychologists have intensively studied how the brain stores and retrieves information. Several concepts have emerged. First, errors are not character defects to be treated by the classic approach of discipline and education, but are byproducts of normal thinking that occur frequently. Second, major accidents are rarely causedby a single error; instead, they are often a combination of chronic system errors, termed latent errors. Identifying and correcting these latent errors should be the principal focus for corrective planning rather than searching for an individual culprit. This nonpunitive concept of errors is a key basis for an effective reporting system, brilliantly demonstrated in aviation with the ASRS system developed more than 25 years ago. The ASRS currently receives more than 30,000 reports annually and is credited with the remarkable increase in safety of airplane travel. Adverse drug events constitute about 25% of hospital errors. In the future, the combination of new drugs and a vast amount of new information will additionally increase the possibilities for error. Two major advances in recent years have been computerization and active participation of the pharmacist with dispensing medications. Further investigation of hospital errors should concentrate primarily on latent system errors. Significant system changes will require broad staff participation throughout the hospital. This, in turn, should foster development of an institutional safety culture, rather than the popular attitude that patient safety responsibility is concentrated in the Quality Assurance-Risk Management division. Quality of service and patient safety are closely intertwined.

[Isoflurane produces delayed preconditioning against renal ischemia/reperfusion injury via hypoxia inducible factor 1 alpha activation]. Isoflurane has an acute preconditioning effectiveness against ischemia in kidney, but this beneficial effectiveness can only last for 2-3 hours. To investigate whether isoflurane produces delayed preconditioning against renal ischemia/reperfusion (I/R) injury, and whether this process is mediated by hypoxia inducible factor 1 alpha (HIF-1 alpha). A total of 52 male C57BL/6 mice were randomly assigned to 4 groups (n=13 in each group): the control group (group A), PBS/isoflurane treated group (group B), scrambled small interference RNA (siRNA)/isoflurane treated group (group C), and HIF-1 alpha siRNA/isoflurane treated group (group D). In groups C and D, 1 mL RNase-free PBS containing 50 microg scrambled siRNA or HIF-1 alpha siRNA was administered via tail vein 24 hours before gas exposure, respectively. Equivalent RNase-free PBS was given in groups A and B. Then the mice in groups B, C, and D were exposed to 1.5% isoflurane and 25% O2 for 2 hours; while the mice in group A received 25% O2 for 2 hours. After 24 hours, 5 mice in each group were sacrificed to assess the expressions of HIF- 1 alpha and erythropoietin (EPO) in renal cortex by Western blot. Renal I/R injury was induced with bilateral renal pedicle occlusion for 25 minutes followed by 24 hours reperfusion on the other 8 mice. At the end of reperfusion, the serum creatinine (SCr), the blood urea nitrogen (BUN), and the histological grading were measured. The expressions of HIF-1 alpha and EPO in groups B and C were significantly higher than those in group A (P < 0.01). The concentrations of SCr and BUN in groups B and C were significantly lower than those in group A, as well as the scores of tubules (P < 0.01), and the injury of kidney was ameliorated noticeably in groups B and C. The expressions of HIF-1 alpha and the concentrations of SCr and BUN in group D were significantly lower than those in group A (P < 0.01). Compared with groups B and C, the expression of HIF-1 alpha and EPO in group D decreased markedly (P < 0.01), the concentrations of SCr and BUN were increased obviously, as well as the scores of tubules (P < 0.01), and the renal injury was aggravated significantly. Isoflurane produces delayed preconditioning against renal I/R injury, and this beneficial effectiveness may be mediated by HIF-1 alpha.

Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the treatment of Crohn disease (CD). The immunosuppressive properties of AZA/6-MP are mediated by the intracellular metabolism of 6-MP into its active metabolites, 6-thioguanine nucleotides (6TGN) and 6methylmercaptopurine (6-MMP). Preliminary studies have suggested that the red blood cell concentration of 6TGN (RBC 6TGN) is a potential guide to therapy. The aims of the study were to evaluate the RBC 6TGN concentrations in adult patients with CD under long-term AZA/6-MP therapy and to correlate it with response to treatment and haematological parameters. Twenty-eight CD patients treated for at least 3 months with AZA/6-MP were prospectively studied. Patients were separated into three main groups: group 1 (n = 19), corresponding to quiescent CD receiving AZA (dose: 2.05 +/- 0.4 mg/kg/day for a mean of 28.6 +/- 25 months) or 6-MP (dose: 1.4 +/- 01 mg/kg/day for a mean of 7.5 +/- 3.5 months) alone; group 2 (n = 6), corresponding to quiescent CD treated by AZA (dose: 2.14 +/- 0.5 mg/kg/day for a mean of 29.5 +/- 22 months) with oral steroids; and group 3 (n = 3), corresponding to active CD on AZA (dose: 1.94 +/- 0.6 mg/kg/day for a mean of 31.3 +/- 35 months) as the only treatment. An assessment was also made by merging groups 1 and 2 forming a larger group of patients (n = 25) defined by clinical remission and groups 2 and 3 forming a larger group of patients (n = 9), non-complete responders with AZA/6-MP alone. Crohn disease index activity (CDAI), blood samples for full blood count and differential white cell count and measurement of RBC 6TGN and 6-MMP concentrations were evaluated at inclusion and at 6 months (n = 17). RBC 6TGN were measured using high performance liquid chromatography (HPLC) on heparinized blood. The baseline characteristics of the three groups of patients were similar. There was no significant difference among the three groups of patients regarding the dose and the duration of immunosuppressive treatment. There was no significant difference between groups according to various parameters tested. Particularly, the median RBC 6TGN concentration at inclusion was similar in the three groups of patients (166 (105-688), 183 (90-261) and 160 (52-194) pmol/8 x 10(8) RBC, respectively). The majority of patients had no detectable level of 6-MMP metabolite, except for 3 patients. There was also no difference between merging groups. Furthermore, there was no significant correlation between RBC 6TGN concentrations and the various biological parameters tested except for the mean erythrocyte volume. At 6 months, all patients of group 1 remained in remission and median RBC 6TGN concentration remained stable. No side effects were observed. There is, contrary to preliminary studies, a broad overlap in RBC 6TGN levels as well as for haematological parameters in patients in remission or not and responders or not to AZA/6-MP therapy. This suggests, beside a variability in the metabolism of these drugs, the existence of complex mechanisms of action. Nevertheless, beside the use of RBC 6TGN determination to confirm compliance to therapy, this dosage could be useful in non-responding patients, allowing, in absence of leukopenia, to increase the dose of AZA/6-MP safely.

[Comparative morphometric assessment between eyes with acute primary angle-closure glaucoma and contralateral eyes]. To establish the profile of patients with acute primary angle-closure glaucoma (APACG) and to assess comparatively clinical and morphometric parameters between eyes with APACG and contralateral eyes (CLEs). Prospective study including patients attended from September 2005 to March 2007. diagnosis of APACG. presence of cataract (except for "glaukomflecken") that may cause low visual acuity or myopization, secondary glaucoma, previous APAGC or surgical procedure in the (CLE), no possibility to control the acute crisis of glaucoma clinically, plateau iris. The following were evaluated: incidence of APACG, age, gender, race, family history of glaucoma, corrected visual acuity (CVA) and uncorrected visual acuity (UVA), spherical equivalent (SE), cup/disc ratio (C/D), gonioscopy, keratometry (K), central corneal thickness (CCT), and echobiometric data [anterior central chamber depth (ACCD), axial length (AL), lens thickness (LT)] and relation between lens thickness and axial length (LT/AL). One thousand and three hundred and forty-three patients were examined from September 2005 to March 2006; 28 (2.1%) had the diagnosis of APACG. The incidence of the APACG was 20.8 cases per 1000 patients. The patients with APACG were manly white women with a negative familial history of glaucoma and with an average age of 59.6 years. When clinical aspects were compared between eyes with APACG and CLEs, statistical significance was observed: UVA (APACG: 0.27 +/- 0.32; CLE: 0.57 +/- 0.33, p=0.000); CVA (APACG: 0.53 +/- 0.44; CLE: 0.88 +/- 0.23, p=0.000); SE (APACG: +0.49 +/- 1.98; CLE: +1.21 +/- 2.03, p=0.007); C/D (APACG: 0.51 +/- 0.28; CLE: 0.42 +/- 0.20; p=0.031). Also, by gonioscopy, eyes with APACG demonstrated more frequently angle closure than CLEs. The eye of the crisis showed the following characteristics: average K of 45.21 +/- 1.96 D, average CCT of 534.46 +/- 34.15 mm, average ACCD of 2.43 +/- 0.28 mm, average AL of 21.68 +/- 0.96 mm, average LT 4.85 +/- 0.32 mm and average LT/AL of 2.24 +/- 0.16. The CLE presented average K of 44.92 +/- 1.86 D, average CCT of 533.18 +/- 31.41 microm, average ACCD of 2.51 +/- 0.29 mm, average AL of 21.82 +/- 0.92 mm, average LT 4.85 +/- 0.36 mm and average LT/AL of 2.23 +/- 0.18. There were statistically significant differences only in two parameters (K and ACCD) when affected and the CLE were compared. The incidence of the APACG was 20.8/1000. It was more frequent in white women, leu kodermics, without family history of glaucoma and with an age average of 59.6 years. The eyes with APACG showed, with statistical significance, worse visual acuity, higher C/D, lower hypermetropic SE, higher average K, and lower ACCD than CLEs.

Pyramidal excitation in long propriospinal neurones in the cervical segments of the cat. 1. The effect of stimulating the contralateral pyramid has been investigated with intracellular recording from 128 long propriospinal neurones (long PNs) in the C3-Th1 segments of the cat. Long PNs were identified by the antidromic activation from the Th13 segment. They were located in laminae VII-VIII of Rexed. Single pyramidal stimulation evoked monosynaptic EPSPs in 15/40 of the long PNs in cats with intact pyramid. In 15 other long PNs, a train of three to four pyramidal stimuli evoked EPSPs with latencies indicating a minimal disynaptic linkage. The remaining 25% of the long PNs lacked mono- or disynaptic pyramidal EPSPs. In a few cases longer latency excitation was observed. 2. The location of the intercalated neurones which mediate the disynaptic pyramidal EPSPs was investigated by making four different lesions of the corticofugal fibres: 1) at the border of the C5 and C6 segments, 2) at the border of the C2 and C3 segments, 3) at the caudal part of the pyramid; three mm rostral to the decussation and 4) at the level of the trapezoid body. Stimulation of the corticofugal fibres was made either rostral to lesion 3 (rPyr) in order to activate neurones in a cortico-bulbospinal pathway or caudal to lesion 3 (cPyr) to activate neurones in a corticospinal pathway. In the former case, in one experiment, stimulation was made in the pyramid between lesions 3 and 4 (double pyramidal lesion). In case of cPyr stimulation, lesions 1 and 2 were added sequentially in order to investigate if the corticospinal excitation was mediated via C3-C4 PNs. All lesions were made mechanically, except lesion 2 which in some of the experiments was performed by reversible cooling. 3. Stimulation in the pyramid rostral to lesion 3 and in between lesions 3 and 4 evoked disynaptic EPSPs in the long PNs, which shows that they were mediated via reticulospinal neurones. Stimulation in cPyr after lesion 3 elicited disynaptic EPSPs, which remained after lesion 1 but were abolished after adding lesion 2. It is concluded that the disynaptic cPyr EPSPs were mediated via intercalated neurones in the C3-C4 segments. 4. When the disynaptic cPyr EPSP was conditioned with a single volley in nucleus ruber and/or in tectum, it was markedly facilitated, especially when the conditioned volley was applied simultaneously with the effective cPyr volley. The results show that the intercalated neurones in the C3-C4 segments receive monosynaptic convergence from cortico-, rubro- and tectospinal fibres. Stimulation in the lateral reticular nucleus (LRN) evoked monosynaptic EPSPs.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential helper and effector responses of Lyt-2+ T cells to H-2Kb mutant (Kbm) determinants and the appearance of thymic influence on anti-Kbm CTL responsiveness. The goal of this study was to assess and compare the allorecognition requirements for eliciting Lyt-2+ helper and effector functions from primary T cell populations. By using interleukin 2 (IL 2) secretion as a measure of T helper (Th) function, and cytolytic T lymphocyte (CTL) generation as a measure of effector function, this study compared the responses of Lyt-2+ T cells from wild-type B6 mice against a series of H-2Kb mutant determinants. Although all Kbm determinants stimulated B6 Lyt-2+ T cells to become cytolytic effector cells, the various Kbm determinants differed dramatically in their ability to stimulate Lyt-2+ T cells to function as IL 2-secreting helper cells. For example, in contrast to Kbm1 determinants that stimulated both helper and effector functions, Kbm6 determinants only stimulated B6 Lyt-2+ T cells to become cytolytic and failed to stimulate them to secrete IL 2. The distinct functional responses of Lyt-2+ T cells to Kbm6 determinants was documented by precursor frequency determinations, and was not due to an inability of the Kbm6 molecule to stimulate Lyt-2+ Th cells to secrete IL 2. Rather, it was the specific recognition and response of Lyt-2+ T cells to novel mutant epitopes on the Kbm6 molecule that was defective, such that anti-Kbm6 Lyt-2+ T cells only functioned as CTL effectors and did not function as IL 2-secreting Th cells. The failure of Lyt-2+ anti-Kbm6 T cells to function as IL 2-secreting Th cells was a characteristic of all Lyt-2+ T cell populations examined in which the response to novel mutant epitopes could be distinguished from the response to other epitopes expressed on the Kbm6 molecule. The absence of significant numbers of anti-Kbm6 Th cells in Lyt-2+ T cell populations was examined for its functional consequences on anti-Kbm6 CTL responsiveness. It was found that primary anti-Kbm6 CTL responses could be readily generated in vitro, but unlike responses to most class I alloantigens that can be mediated by Lyt-2+ Th cells, anti-Kbm6 CTL responses were strictly dependent upon self-Ia-restricted L3T4+ Th cells. Because the restriction specificity of L3T4+ Th cells is determined by the thymus, in which their precursors had differentiated, anti-Kbm6 CTL responsiveness, unlike responsiveness to most class I alloantigens, was significantly influenced by the Ia phenotype of the thymus in which the responder cells had differentiated.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of circulating progesterone and insulin on early embryo development in beef heifers. The aims of this study were to determine the effect on early embryo development of feeding a diet formulated to enhance circulating insulin concentrations and secondly to investigate the association between early embryo development and maternal progesterone concentrations in beef heifers. The study was carried out in 32 Simmental x Holstein Friesian heifers 22-25 months of age weighing 506+/-7kg and in condition score 3.1+/-0.1. Animals were fed two diets that were isoenergetic and isonitrogenous, but that would encourage either propionate (diet A) or acetate (diet B) production in the rumen. The rationale was that propionate would induce a greater insulin release in response to feeding. Animals were fed a 50:50 mix of the two diets for 14 days at 0.8x maintenance, with straw provided ad libitum. Animals were then fed one of the experimental diets for 3 weeks prior to synchronisation of oestrus and insemination and for a further 16 days following mating. All heifers were blood sampled daily from oestrus synchronisation and eight animals on each diet underwent daily transrectal real-time ultrasonography to determine the day of ovulation. All heifers were slaughtered at Day 16 after mating. While feeding of diet A (propionic) caused a significant (P<0.05) increase in the plasma insulin to glucagons ratio differences in insulin were not significantly different. This is probably due to the fact that insulin concentrations were quite high as the heifers used in the present study were in good body condition making further increases in insulin difficult to achieve. Diet did not affect size of ovulatory follicle (DIET A: 15.1+/-0.7mm; diet B: 14.6+/-0.7mm), day of ovulation (diet A: 3.5+/-0.2 days; diet B: 3.4+/-0.2 days), mean plasma progesterone concentration (diet A: 4.7+/-0.4ng/ml; diet B: 5.2+/-0.3ng/ml), corpus luteum weight (diet A: 6.0+/-0.2g; diet B: 6.0+/-0.2g) or pregnancy rate (diet A: 81.3%; diet B: 81.3%). However, the proportion of well-elongated (>10cm) embryos on Day 16 was higher in animals fed diet A than in those fed diet B (84.6% versus 38.5%; P<0.05). While progesterone concentration did not differ between pregnant and non-pregnant heifers, progesterone did show an earlier post-ovulatory rise in heifers with well-elongated (>10cm) embryos with levels in these animals significantly higher on Days 4 and 5 than in heifers with small (<10cm) embryos at slaughter. This study demonstrated an enhancement in early embryo development in animals fed a diet generating an increased insulin:glucagon ratio that was not related to circulating maternal progesterone concentrations. However, across diets, enhanced embryo development was associated with elevated plasma progesterone on Days 4 and 5 following mating.

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials. To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258). Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries. Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5-2 mg/day or placebo (1:1) for 12 weeks. Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29-203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression - Severity of illness (CGI-S) as related to agitation. Safety was also assessed. In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, -3.77; confidence limits, -7.38, -0.17; t(316) = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5-2 mg/day did not achieve statistical superiority over placebo (-2.34; -5.49, 0.82; t(230) = -1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (-5.06; -8.99, -1.13; t(144) = -2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (-0.16; -0.39, 0.06; t(337) = -1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5-2 mg/day in Study 2 (-0.31; -0.55, -0.06; t(222) = -2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5-2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity. Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

The concept of fillet flaps: classification, indications, and analysis of their clinical value. Tissue of amputated or nonsalvageable limbs may be used for reconstruction of complex defects resulting from tumor and trauma. This is the "spare parts" concept. By definition, fillet flaps are axial-pattern flaps that can function as composite-tissue transfers. They can be used as pedicled or free flaps and are a beneficial reconstruction strategy for major defects, provided there is tissue available adjacent to these defects.From 1988 to 1999, 104 fillet flap procedures were performed on 94 patients (50 pedicled finger and toe fillets, 36 pedicled limb fillets, and 18 free microsurgical fillet flaps). Nineteen pedicled finger fillets were used for defects of the dorsum or volar aspect of the hand, and 14 digital defects and 11 defects of the forefoot were covered with pedicled fillets from adjacent toes and fingers. The average size of the defects was 23 cm2. Fourteen fingers were salvaged. Eleven ray amputations, two extended procedures for coverage of the hand, and nine forefoot amputations were prevented. In four cases, a partial or total necrosis of a fillet flap occurred (one patient with diabetic vascular disease, one with Dupuytren's contracture, and two with high-voltage electrical injuries).Thirty-six pedicled limb fillet flaps were used in 35 cases. In 12 cases, salvage of above-knee or below-knee amputated stumps was achieved with a plantar neurovascular island pedicled flap. In seven other cases, sacral, pelvic, groin, hip, abdominal wall, or lumbar defects were reconstructed with fillet-of-thigh or entire-limb fillet flaps. In five cases, defects of shoulder, head, neck, and thoracic wall were covered with upper-arm fillet flaps. In nine cases, defects of the forefoot were covered by adjacent dorsal or plantar fillet flaps. In two other cases, defects of the upper arm or the proximal forearm were reconstructed with a forearm fillet. The average size of these defects was 512 cm2. Thirteen major joints were salvaged, three stumps were lengthened, and nine foot or forefoot amputations were prevented. One partial flap necrosis occurred in a patient with a fillet-of-sole flap. In another case, wound infection required revision and above-knee amputation with removal of the flap.Nine free plantar fillet flaps were performed-five for coverage of amputation stumps and four for sacral pressure sores. Seven free forearm fillet flaps, one free flap of forearm and hand, and one forearm and distal upper-arm fillet flap were performed for defect coverage of the shoulder and neck area. The average size of these defects was 432 cm2. Four knee joints were salvaged and one above-knee stump was lengthened. No flap necrosis was observed. One patient died of acute respiratory distress syndrome 6 days after surgery. Major complications were predominantly encountered in small finger and toe fillet flaps. Overall complication rate, including wound dehiscence and secondary grafting, was 18 percent. This complication rate seems acceptable. Major complications such as flap loss, flap revision, or severe infection occurred in only 7.5 percent of cases. The majority of our cases resulted from severe trauma with infected and necrotic soft tissues, disseminated tumor disease, or ulcers in elderly, multimorbid patients. On the basis of these data, a classification was developed that facilitates multicenter comparison of procedures and their clinical success. Fillet flaps facilitate reconstruction in difficult and complex cases. The spare part concept should be integrated into each trauma algorithm to avoid additional donor-site morbidity and facilitate stump-length preservation or limb salvage.

Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis. Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral) therapy, and that CsA exposure early post-transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration-controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough-level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time-concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12-h dosage interval (AUC[0-12]) (p = 0.0068), AUC over the first 4 h of the 12-h dosage interval (AUC[0-4]) (p = 0.0014) or 2h post-dose (C2) CsA level (p = 0.0027). Day 3 dose- and weight-corrected C2 values (EMIT equivalent) separated patients into low (< 200 microg/L/mg/kg dose), intermediate (200-350 microg/L/mg/kg dose) and high absorber categories (> 350 microg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500 microg/L by day 3 post-transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using C0 levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single-point C2 concentrations which accurately predict individual AUC[0-4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose- and weight-corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (C0) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.