Chromomycin, an antibiotic produced by Streptomyces flaviscleroticus might play a role in the resistance to oxidative stress and is essential for viability in stationary phase.
The well-known role of antibiotics in killing sensitive organisms has been challenged by the effects they exert at subinhibitory concentrations. Unfortunately, there are very few published reports on the advantages these molecules may confer to their producers. This study describes the construction of a genetically verified deletion mutant of Streptomyces flaviscleroticus unable to synthesize chromomycin. This mutant was characterized by a rapid loss of viability in stationary phase that was correlated with high oxidative stress and altered antioxidant defences. Altered levels of key metabolites in the mutant signalled a redistribution of the glycolytic flux toward the PPP to generate NADPH to fight oxidative stress as well as reduction of ATP-phosphofructokinase and Krebs cycle enzymes activities. These changes were correlated with a shift in the preference for carbon utilization from glucose to amino acids. Remarkably, chromomycin at subinhibitory concentration increased longevity of the non-producer and restored most of the phenotypic features' characteristic of the wild type strain. Altogether these observations suggest that chromomycin may have antioxidant properties that would explain, at least in part, some of the phenotypes of the mutant. Our observations warrant reconsideration of the secondary metabolite definition and raise the possibility of crucial roles for their producers.


Soy product and isoflavone consumption in relation to prostate cancer in Japanese men.
The incidence of prostate cancer is much lower in Asian than Western populations. Environmental factors, such as dietary habits, may play a major role in the causation of prostate cancer. Although isoflavones have been suggested to show a preventive effect against prostate cancer in animal experiments, the results of epidemiologic studies are inconsistent. Here, we conducted a population-based prospective study in 43,509 Japanese men ages 45 to 74 years who generally have a high intake of isoflavones and low incidence of prostate cancer. Participants responded to a validated questionnaire, which included 147 food items. During follow-up from 1995 through 2004, 307 men were newly diagnosed with prostate cancer, of which 74 cases were advanced, 220 cases were organ localized, and 13 cases were of an undetermined stage. Intakes of genistein, daidzein, miso soup, and soy food were not associated with total prostate cancer. However, these four items decreased the risk of localized prostate cancer. In contrast, positive associations were seen between isoflavones and advanced prostate cancer. These results were strengthened when analysis was confined to men ages >60 years, in whom isoflavones and soy food were associated with a dose-dependent decrease in the risk of localized cancer, with relative risks for men in the highest quartile of genistein, daidzein, and soy food consumption compared with the lowest of 0.52 [95% confidence interval (95% CI), 0.30-0.90], 0.50 (95% CI, 0.28-0.88), and 0.52 (95% CI, 0.29-0.90), respectively. In conclusion, we found that isoflavone intake was associated with a decreased risk of localized prostate cancer.


Repeated sequential action by young children: Developmental changes in representational flexibility of task context.
A wealth of developmental research suggests that preschoolers are capable of reporting, imitating, and performing sequential actions they engage in routinely. However, few studies have explored the developmental and cognitive mechanisms required for learning how to perform such routines. A previous computational model of routines argued that a representation of task contexts underlying routines could change flexibly. This position was supported by the empirical evidence that if adults are interrupted in the course of a routine, they make fewer errors if they are interrupted just before the selection of context-dependent action than if they are interrupted earlier. Another computational model examined how efficiently adults learned to perform routines and suggested the relationship of learning efficacy with executive functions. The present study aimed to examine whether the above-mentioned models and evidence from adults can be extended to preschoolers by using an experimental task, in which children were required to play the role of a baker and repeatedly make toast for either a cat or mouse, with momentary distractions. Experiment 1 showed that earlier interruption tended to cause older children to produce more branch point errors than interruption immediately before the branch points, whereas younger children tended to be vulnerable to both interruptions. Further, across 2 experiments, this study showed that the developmental differences in how young children represent task contexts were associated with their executive functions. These findings indicate that the representational flexibility of task contexts underlies children's performance of repeated sequential actions and its association with executive functions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Attention deficit disorders in adults.
Twenty-two adults who met DSM-III criteria for "Attention Deficit Disorder, Residual Type" (ADD-RT) were evaluated in a series of clinical experiments. Although certain personality and psychological factors typified the ADD-RT group, methylphenidate blood levels, the growth hormone response to methylphenidate, and the brainstem evoked response did not distinguish subjects from matched controls. Male subjects seemed to be a more homogeneous group than female subjects. Socioeconomic status and IQ, but not severity of ADD symptoms, were found to predict outcome. ADD adults seem to be numerous and easy to identify, at least on the basis of symptoms. However, the validity of ADD-RT as a "distinct clinical entity" is open to question.


Therapeutic effects of magnetic and copper bracelets in osteoarthritis: a randomised placebo-controlled crossover trial.
To test the effectiveness of a typical magnetic wrist strap for reducing pain and stiffness, and for improving physical functioning amongst patients with osteoarthritis. A randomised double-blind placebo-controlled crossover trial. Each participant wore four devices over a 16-week period. Forty five patients with osteoarthritis were recruited from general practices in rural and urban areas of Yorkshire. Experimental device: a commercially available magnetic wrist strap. Control devices: a weak magnetic wrist strap, a demagnetised wrist strap, and a copper bracelet. The WOMAC Osteoarthritis Index, the McGill Pain Questionnaire-Pain Rating Index (PRI), a pain visual analogue scale (VAS), and medication use. No difference was observed between devices in terms of their effects on pain as measured by the primary outcome measure (WOMAC A), the PRI and the VAS. Similar results were obtained for stiffness (WOMAC B), physical function (WOMAC C), and medication use. Further analyses of the PRI subscales revealed a statistically significant difference between devices (P=0.025), which favoured the experimental device. Participants reported lower sensory pain after wearing the standard magnetic wrist strap, than when wearing control devices. However, no adjustment was made for multiple testing. Our results indicate that magnetic and copper bracelets are generally ineffective for managing pain, stiffness and physical function in osteoarthritis. Reported therapeutic benefits are most likely attributable to non-specific placebo effects. However such devices have no major adverse effects and may provide hope.


A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis.
Gene therapy approaches using adeno-associated viral vectors have been successfully tested in the equine post-traumatic osteoarthritis (PTOA) model. Owing to differences in the levels of transgene expression and adverse tissue reactions observed in published studies, we sought to identify a safe therapeutic dose of scAAVIL-1ra in an inflamed and injured joint that would result in improved functional outcomes without any adverse events. scAAVIL-1ra was delivered intra-articularly over a 100-fold range, and horses were evaluated throughout and at the end of the 10-week study. A dose-related increase in IL-1ra levels with a decrease in PGE2 levels was observed, with the peak IL-1ra concentration being observed 7 days post-treatment in all groups. Perivascular infiltration with mononuclear cells was observed within the synovial membrane of the joint treated with the highest viral dose of 5 × 1012 vg, but this was absent in the lower-dosed joints. The second-highest dose of scAAVeqIL-1ra 5 × 1011 vg demonstrated elevated IL-1ra levels without any cellular response in the synovium. Taken together, the data suggest that the 10-fold lower dose of 5 × 1011vg scAAVIL-1ra would be a safe therapeutic dose in an equine model of PTOA.


The evolution of diatoms and their biogeochemical functions.
In contemporary oceans diatoms are an important group of eukaryotic phytoplankton that typically dominate in upwelling regions and at high latitudes. They also make significant contributions to sporadic blooms that often occur in springtime. Recent surveys have revealed global information about their abundance and diversity, as well as their contributions to biogeochemical cycles, both as primary producers of organic material and as conduits facilitating the export of carbon and silicon to the ocean interior. Sequencing of diatom genomes is revealing the evolutionary underpinnings of their ecological success by examination of their gene repertoires and the mechanisms they use to adapt to environmental changes. The rise of the diatoms over the last hundred million years is similarly being explored through analysis of microfossils and biomarkers that can be traced through geological time, as well as their contributions to seafloor sediments and fossil fuel reserves. The current review aims to synthesize current information about the evolution and biogeochemical functions of diatoms as they rose to prominence in the global ocean.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'.


Systematic Review and Meta-analysis of Postexposure Prophylaxis for Crimean-Congo Hemorrhagic Fever Virus among Healthcare Workers.
We performed a systematic review and meta-analysis on the effectiveness of ribavirin use for the prevention of infection and death of healthcare workers exposed to patients with Crimean-Congo hemorrhagic fever virus (CCHFV) infection. Splashes with blood or bodily fluids (odds ratio [OR] 4.2), being a nurse or physician (OR 2.1), and treating patients who died from CCHFV infection (OR 3.8) were associated with healthcare workers acquiring CCHFV infection; 7% of the workers who received postexposure prophylaxis (PEP) with ribavirin and 89% of those who did not became infected. PEP with ribavirin reduced the odds of infection (OR 0.01, 95% CI 0-0.03), and ribavirin use <48 hours after symptom onset reduced the odds of death (OR 0.03, 95% CI 0-0.58). The odds of death increased 2.4-fold every day without ribavirin treatment. Ribavirin should be recommended as PEP and early treatment for workers at medium-to-high risk for CCHFV infection.


Arf tumor suppressor promoter monitors latent oncogenic signals in vivo.
Induction of the Arf tumor suppressor gene by elevated thresholds of mitogenic signals activates a p53-dependent transcriptional response that triggers either growth arrest or apoptosis, thereby countering abnormal cell proliferation. Conversely, Arf inactivation is associated with tumor development. Expression of Arf in tissues of adult mice is difficult to detect, possibly because its induction leads to the arrest or elimination of incipient tumor cells. We replaced coding sequences of exon 1beta of the mouse cellular Arf gene with a cDNA encoding GFP, thereby producing Arf-null animals in which GFP expression is driven by the intact Arf promoter. The Arf promoter was induced in several biologic settings previously shown to elicit mouse p19Arf expression. Inactivation of Arf in this manner led to the outgrowth of tumor cells expressing GFP, thereby providing direct evidence that the Arf promoter monitors latent oncogenic signals in vivo.


Directed expression of a chimeric type II keratin partially rescues keratin 5-null mice.
The crucial role of structural support fulfilled by keratin intermediate filaments (IFs) in surface epithelia likely requires that they be organized into cross-linked networks. For IFs comprised of keratins 5 and 14 (K5 and K14), which occur in basal keratinocytes of the epidermis, formation of cross-linked bundles is, in part, self-driven through cis-acting determinants. Here, we targeted the expression of a bundling-competent KRT5/KRT8 chimeric cDNA (KRT8bc) or bundling-deficient wild type KRT8 as a control to the epidermal basal layer of Krt5-null mice to assess the functional importance of keratin IF self-organization in vivo. Such targeted expression of K8bc rescued Krt5-null mice with a 47% frequency, whereas K8 completely failed to do so. This outcome correlated with lower than expected levels of K8bc and especially K8 mRNA and protein in the epidermis of E18.5 replacement embryos. Ex vivo culture of embryonic skin keratinocytes confirmed the ability of K8bc to form IFs in the absence of K5. Additionally, electron microscopy analysis of E18.5 embryonic skin revealed that the striking defects observed in keratin IF bundling, cytoarchitecture, and mitochondria are partially restored by K8bc expression. As young adults, viable KRT8bc replacement mice develop alopecia and chronic skin lesions, indicating that the skin epithelia are not completely normal. These findings are consistent with a contribution of self-mediated organization of keratin IFs to structural support and cytoarchitecture in basal layer keratinocytes of the epidermis and underscore the importance of context-dependent regulation for keratin genes and proteins in vivo.


Natural rubber latex allergy.
Natural rubber latex (NRL) is a ubiquitous allergen as it is a component of > 40,000 products in everyday life. Latex allergy might be attributed to skin contact or inhalation of latex particles. Latex allergy is an IgE-mediated hypersensitivity to NRL, presenting a wide range of clinical symptoms such as angioedema, swelling, cough, asthma, and anaphylactic reactions. Until 1979, latex allergy appeared only as type IV delayed hypersensitivity; subsequently, the proportion of different allergy types drifted towards type IV contact allergy reactions. Several risk factors for sensitization to NRL are already known and well documented. Some authors have established a positive correlation between a history of multiple surgical interventions, atopy, spina bifida malformation, and latex allergy incidence. We suspect an increase in latex allergy incidence in association with increased atopy and sensitivity to environmental allergens in the industrial population. It is often postulated in literature that the groups of workers at risk for this allergy are essentially workers in the latex industry and healthcare professionals. In this population, direct internal and mucosal contact with NRL medical devices may be the route of sensitization as factors such as the number of procedures and use of NRL materials (catheters and tubes) were associated with increased risk of latex sensitization and allergy.


Long-Term Risk to Develop Hypertension in Women With Former Preeclampsia: A Longitudinal Pilot Study.
Women with former preeclampsia (exPE) develop chronic hypertension 4 times more often than healthy parous controls. Women, destined to develop remote chronic hypertension, had increased left ventricular mass index (LVMI) and diastolic blood pressure (BP) prior to the onset of hypertension as compared to those remaining normotensive. However, longitudinal data on the progress of this increased LVMI in women destined to develop hypertension are lacking. We included 20 women with exPE and 8 parous controls. At both 1- and 14-year postpartum (pp), we performed cardiac ultrasound and determined circulating levels of the metabolic syndrome variables. Of 14-year pp, 7 (35%) former patients had developed chronic hypertension. We compared these 7 former patients with both the 13 former patients who remained normotensive and the 8 parous controls using the Mann-Whitney U test and Kruskal-Wallis analysis. Women with hypertensive exPE differed from their normotensive counterparts by a higher incidence of early-onset preeclampsia (PE) in their index pregnancy and a higher rate of recurrence in next pregnancies. At 1-year pp, they also had high/normal BP and higher fasting insulin levels. At 14 years pp, the relative left ventricular wall thickness was higher, and the E/A ratio was lower, in the hypertensive group relative to those remaining normotensive. Women with exPE are at increased risk of developing chronic hypertension, when (1) the PE in the index pregnancy had an early-onset and/or recurred in next pregnancies and (2) the 1-year pp. Blood pressure was high normal. We also noticed that at 14 years pp, the hypertensive group showed signs of concentric left ventricular remodeling along with a decreased E/A ratio.


Housing mobility and cognitive development: Change in verbal and nonverbal abilities.
This study investigates the influence of housing instability on verbal and nonverbal cognitive development among at-risk children and adolescents involved in the child welfare system. Frequent residential changes threaten child mental health, especially among low-income families. Little is known regarding disruptions to cognitive growth, specifically the impact on verbal and nonverbal abilities. The study tests whether developmental timing of housing mobility affects cognitive development beyond individual and family risks. A nationally representative study of families (n=2,442) susceptible to housing and family instability tracked children and adolescents aged 4-14 years (M=8.95 years) over 36 months following investigation by the child welfare system. Youth completed standardized cognitive assessments while caregivers reported on behavior problems and family risk at three time points. Latent growth models examined change in cognitive abilities over time. Housing mobility in the 12 months prior to baseline predicts lower verbal cognitive abilities that improve marginally. Similar effects emerge for all age groups; however, frequent moves in infancy diminish the influence of subsequent housing mobility on verbal tasks. Housing instability threatened cognitive development beyond child maltreatment, family changes, poverty, and other risks. Findings inform emerging research on environmental influences on neurocognitive development, as well as identify targets for early intervention. Systematic assessment of family housing problems, including through the child welfare system, provides opportunities for coordinated responses to prevent instability and cognitive threats.


Autoimmune Hemolytic Anemia in Chronic Myeloid Leukemia.
Autoimmune hemolytic anemia (AIHA) might be associated with underlying hematological malignancies such as chronic lymphocytic leukemia. However, the association between AIHA and chronic myelogenous leukemia is extremely unusual. We reviewed case reports and series of 54 patients with chronic myeloid leukemia (CML) who developed autoimmune hemolysis between 1952 and 2018. Almost all the patients were in the chronic phase and were classified into transplant and non-transplant groups. The onset of autoimmune hemolysis was earlier in the transplant group and required second- and third-line therapy to control it. The etiology of hemolysis is poorly understood but attributed in the transplant group to immune reconstitution, viral infections, or CML relapse. On the other hand, it is thought to be related in the non-transplant group to CML medications, especially interferon. Key Messages: Although AIHA is uncommon in chronic myelogenous leukemia patients, it should be in the differential diagnosis list for those who develop a sudden drop in hemoglobin without a bleeding source.


Alteration of cohesin genes in myeloid diseases.
New genes involved in leukemogenesis, such as ASXL1 and TET2, have been identified recently using genomic analyses of DNA from patient samples. We have studied by array-comparative genomic hybridization (aCGH) a series of 167 samples including myelodysplastic syndromes, chronic myelomonocytic leukemias, and acute myeloid leukemias. We found a deletion of the RAD21 and STAG2 genes, which encode two components of the cohesin complex. We propose that these alterations may compromise the cohesin complex and its regulation of the transcription of genes.


Deciphering the biology of thymic epithelial tumors.
Thymic cancers arise from epithelial cells of the thymus and have a predilection for intrathoracic spread. Clinical behavior varies from relatively indolent to highly aggressive with a capacity to metastasize widely and adversely affect survival. Paraneoplastic autoimmune disorders are frequently observed in association with thymoma and have a significant impact on quality of life. Underlying immune deficits associated with thymic epithelial tumors (TETs) increase the risk for development of opportunistic infections and emergence of extrathymic malignancies. Advances in the molecular characterization of thymic tumors have revealed the lowest tumor mutation burden among all adult cancers and the occurrence of distinct molecular subtypes of these diseases. Mutations in general transcription factor IIi (GTF2I) are unique to TETs and are rarely observed in other malignancies. The infrequency of actionable mutations has created obstacles for the development of biologic therapies and has spurred research to uncover druggable genomic targets. Persistence of autoreactive T cells due to altered thymic function increases the risk for development of severe immune-related toxicity and limits opportunities for use of immune-based therapies, especially in patients with thymoma. In this paper we review emerging data on the molecular characterization and immunobiology of thymic tumors and highlight clinical implications of these discoveries.


Myocardial infarction (ST-elevation).
About one quarter of people having an acute myocardial infarction (MI) in the USA will die of it, half of them within 1 hour of the onset of symptoms. Cardiogenic shock develops in over 5% of people surviving the first hour after an acute MI, with a mortality of 50% to 80% in the first 48 hours. We conducted a systematic review and aimed to answer the following clinical questions: Which treatments improve outcomes in acute MI? Which treatments improve outcomes for cardiogenic shock after MI? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 52 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin-converting enzyme (ACE) inhibitors, aspirin, beta-blockers, calcium channel blockers, early cardiac surgery, early invasive cardiac revascularisation, glycoprotein IIb/IIIa inhibitors, intra-aortic balloon counterpulsation, nitrates (with or without thrombolysis), positive inotropes, primary percutaneous transluminal coronary angioplasty (PTCA), pulmonary artery catheterisation, thrombolysis (with or without low molecular weight heparin, with or without unfractionated heparin), vasodilators, and ventricular assistance devices and cardiac transplantation.


Geochemical evidence for mélange melting in global arcs.
In subduction zones, sediments and hydrothermally altered oceanic crust, which together form part of the subducting slab, contribute to the chemical composition of lavas erupted at the surface to form volcanic arcs. Transport of this material from the slab to the overlying mantle wedge is thought to involve discreet melts and fluids that are released from various portions of the slab. We use a meta-analysis of geochemical data from eight globally representative arcs to show that melts and fluids from individual slab components cannot be responsible for the formation of arc lavas. Instead, the data are compatible with models that first invoke physical mixing of slab components and the mantle wedge, widely referred to as high-pressure mélange, before arc magmas are generated.


Fibrin sealant improves graft adherence in a porcine full-thickness burn wound model.
Autograft take and rapid wound closure is essential for the survival of severely burned patients. Loss of skin grafts typically occurs during the first few days after coverage, mainly due to shear forces and inadequate contact with the wound bed. Slow-clotting fibrin sealant, applied with a spray-on device, has been shown to improve healing of skin grafts in large wounds. However, its use in burn wounds has not been studied so far. To evaluate the effectiveness of sprayed fibrin sealant in excised and grafted full-thickness burns. Ten female Yorkshire pigs (30-45 kg) received a full-thickness contact burn of approximately 15% total body surface area. The burns were excised to the level of the muscular fascia after 24 h and covered with meshed skin autograft (mesh ratio 1:3). Wounds were randomized to either fibrin sealant (n=20) or standard skin staples (n=16) for graft fixation. Fibrin sealant was used as a slow-clotting spray (4 IU thrombin/ml). Outcome measurements included clinical scoring at days 2, 5, 9 and 14 postoperatively, planimetric analysis of wound closure, and histological examination of epidermal and dermal thickness 14 days after autografting. In the fibrin sealant group, graft adherence scores were significantly increased (p<0.02) and graft dislocation scores significantly decreased (p<0.01) at days 2 and 5 postoperatively, when compared to controls. Planimetric analysis of remaining open mesh interstices showed acceleration of wound closure in the fibrin sealant group but did not reach statistical significance (day 14 p=0.04 at significance level p<0.025). Wound contraction, occurrence of hematoma, and dermal as well as epidermal thickness were not different between the groups at 14 days postoperatively. The results indicate that the use of slow-clotting fibrin sealant spray for autograft fixation is advantageous over skin staples. Easy handling and reduced graft dislocation at early time points are key qualities of this method.


Patient-clinician relationship seems to affect adherence to analgesic use in cancer patients: a cross sectional study in a Taiwanese population.
Patient satisfaction can provide a measure of service quality and serve as a predictor of health-related behaviors. Little is known about how patients' satisfaction with clinician-patient interactions affects their adherence to taking analgesics. The purposes of this study were to (1) investigate the predictors of patients' satisfaction with clinicians, and (2) examine whether patients' satisfaction with their clinicians can improve adherence to analgesic use. A cross-sectional and descriptive design was used. Outpatient oncology clinic at a medical center in Taiwan. A convenience sample (N = 309) was recruited. The Medical Interview Satisfaction Scale 21 - Chinese Version, Short Version of the Barriers Questionnaire - Taiwan Form, Taiwanese version of the Morisky Medication Adherence Measure, and Interpersonal Physician Trust Scale - Chinese version, and Brief Pain Inventory Chinese Version. Variables that could significantly predict patients' satisfaction were patient age and trust in clinicians, which together accounted for 33% of the total variance. Patients' satisfaction with their clinicians significantly predicted patients' adherence to medication use (OR = 3.10, P < 0.05). There was an interactive effect (OR = 0.12, P < 0.05) between patients' satisfaction and barriers to analgesic use. Correlation coefficients between barriers to analgesic use and patients' adherence are -0.52 (P < 0.001) and -0.13 (P = 0.20) in the higher satisfaction and lower satisfaction patients, respectively. Patients' satisfaction with their clinicians can have a positive effect on changing analgesics adherence behaviors when patients hold incorrect beliefs about analgesics. Patients' satisfaction has an important role in enhancement of analgesics adherence behaviors.


ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-Guided Analysis.
Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in recurrent glioblastoma patients receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts. In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and overall survival (OS). Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Bi-weekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REMARK criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker post-immunotherapy. Lower median p-ERK+ cell density was observed compared to prior studies, likely due to tissue handling variances. Nonetheless, high p-ERK was associated with prolonged OS, particularly in IDH wild-type glioblastomas (P=0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P=0.011). Meta-analysis across three cohorts (n=65) supported the survival benefit of elevated tumor p-ERK levels (P=0.0424). This study strengthens the role of p-ERK as a predictive biomarker for OS in glioblastoma patients on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.


Association of CYP17A1 Genetic Polymorphisms and Susceptibility to Essential Hypertension in the Southwest Han Chinese Population.
BACKGROUND The CYP17A1 gene encodes for cytochrome P450 enzyme CYP17A1, which is involved with the steroidogenic pathway including mineralocorticoids. The CYP17A1 polymorphisms might affect enzyme activity, then leading to a state of mineralocorticoid 11-deoxycorticosterone excess characterized by hypertension, suppressed plasma renin activity, and low aldosterone concentrations. The aim of this study was to investigate the contribution of CYP17A1 polymorphisms in inducing the susceptibility to essential hypertension among the Southwest Han Chinese population. MATERIAL AND METHODS Eight single nucleotide polymorphisms of CYP17A1 were genotyped in a case-control study for samples by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS The polymorphisms rs11191548 and rs4919687 were significantly associated with hypertension risk, which was confirmed by systolic and diastolic blood pressure distribution analyses between different genotype groups, and these two polymorphisms were found in linkage disequilibrium. The rs4919687 polymorphism was estimated to cause the destruction of exonic splicing silencer (ESR and Motif 3) sites and to transform the transcription factor AREB6 binding site, respectively, in the bioinformatics analyses. The haplotypes rs4919686A-rs3740397G -rs4919687C-rs743572C-rs11191548C and rs4919686A-rs3740397G-rs4919687T-rs743572C- rs11191548T were found to be susceptible to essential hypertension. CONCLUSIONS Our findings suggest that the CYP17A1 polymorphisms could be a genetic risk factor for essential hypertension among the Yunnan Han Chinese population, which would have implications for the treatment of this complex disorder.


[Hydroxyurea and HIV infection].
Hydroxyurea is an anticancerous product, used recently in the treatment of HIV-1 infection thanks to its inhibitory action in viral replication, potentialization of the nucleosides activity (particularly ddI or didanosine) and its cytostatic properties on CD4 and CD8 lymphocytes. Many studies showed its efficiency, as further drug, in initial regimen of a tritherapy (containing ddI) and salvage therapy. The dosage of 500 mg bid seems tolerated well by adults, and 20 mg/kg by children. Long-term tolerance remains unknown. With ddI, it could be proposed in developing countries.


Short-Term and Long-Term Outcomes Following Transhiatal versus Right Thoracoabdominal Resection of Siewert Type II Adenocarcinoma of the Esophagogastric Junction.
Few studies have evaluated the outcomes of transhiatal and right thoracoabdominal resection of Siewert type II adenocarcinoma of the esophagogastric junction. This study investigated the relative effect of these two methods in the surgical treatment of Siewert type II adenocarcinoma of the esophagogastric junction. Clinical data for 211 Siewert type II cancer patients were collected and classified into transhiatal group (n = 181) and right thoracoabdominal group (n = 30) according to surgical approach. Short-term outcomes were compared between these two groups. A 1:1 propensity score matching was performed using a logistic regression model. Recurrence-free survival and overall survival were compared between the matched groups. The right thoracoabdominal group had significantly greater intraoperative blood loss and longer operative time compared with transhiatal group. Complications corresponding to Clavien-Dindo grade III or higher were 4.4% in transhiatal group and 30% in right thoracoabdominal group (P < 0.05). The right thoracoabdominal group exhibited greater blood loss, longer operative time, longer hospitalization, and a smaller number of lymph nodes retrieved than the transhiatal group as evidenced by PSM analysis, and patients in transhiatal group also experienced significantly better survival than patients in right thoracoabdominal group. In this study, the transhiatal approach was associated with more favorable short-term and oncological outcomes than the right thoracoabdominal group approach for Siewert type II adenocarcinoma of the esophagogastric junction. The transhiatal approach with total gastrectomy appears to be an optional choice for this type of tumor, especially for esophagus invasion ≤2 cm. Well-designed randomized control trials are necessary to validate our findings.


Nuclear magnetic resonance of hydrogen molecules trapped inside C70 fullerene cages.
We present a solid-state NMR study of H2 molecules confined inside the cavity of C70 fullerene cages over a wide range of temperatures (300 K to 4 K). The proton NMR spectra are consistent with a model in which the dipole-dipole coupling between the ortho-H2 protons is averaged over the rotational/translational states of the confined quantum rotor, with an additional chemical shift anisotropy δ(H)(CSA)=10.1 ppm induced by the carbon cage. The magnitude of the chemical shift anisotropy is consistent with DFT estimates of the chemical shielding tensor field within the cage. The experimental NMR data indicate that the ground state of endohedral ortho-H2 in C70 is doubly degenerate and polarized transverse to the principal axis of the cage. The NMR spectra indicate significant magnetic alignment of the C70 long axes along the magnetic field, at temperatures below ~10 K.


Long-term dietary supplementation with low-dose nobiletin ameliorates hepatic steatosis, insulin resistance, and inflammation without altering fat mass in diet-induced obesity.
We evaluated the long-term effect of low-dose nobiletin (NOB), a polymethoxylated flavone, on diet-induced obesity and related metabolic disturbances. C57BL/6J mice were fed a high-fat diet (HFD, 45 kcal% fat) with or without NOB (0.02%, w/w) for 16 weeks. NOB did not alter food intake or body weight. Despite increases in fatty acid oxidation-related genes expression and enzymes activity in adipose tissue, NOB did not affect adipose tissue weight due to simultaneous increases in lipogenic genes expression and fatty acid synthase activity. However, NOB significantly decreased not only pro-inflammatory genes expression in adipose tissue but also proinflammatory cytokine levels in plasma. NOB-supplemented mice also showed improved glucose tolerance and insulin resistance, along with decreased levels of plasma insulin, free fatty acids, total cholesterol, non-HDL-cholesterol, and apolipoprotein B. In addition, NOB caused significant decreases in hepatic lipid droplet accumulation and triglyceride content by activating hepatic fatty acid oxidation-related enzymes. Hepatic proinflammatory TNF-α mRNA expression, collagen accumulation, and plasma levels of aminotransferases, liver damage indicators, were also significantly lower in NOB-supplemented mice. These findings suggest that long-term supplementation with low-dose NOB can protect against HFD-induced inflammation, insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease, without ameliorating adiposity.


Lacticaseibacillus casei Strain T21 Attenuates Clostridioides difficile Infection in a Murine Model Through Reduction of Inflammation and Gut Dysbiosis With Decreased Toxin Lethality and Enhanced Mucin Production.
Clostridioides difficile is a major cause of diarrhea in patients with antibiotic administration. Lacticaseibacillus casei T21, isolated from a human gastric biopsy, was tested in a murine C. difficile infection (CDI) model and colonic epithelial cells (Caco-2 and HT-29). Daily administration of L. casei T21 [1 × 108 colony forming units (CFU)/dose] for 4 days starting at 1 day before C. difficile challenge attenuated CDI as demonstrated by a reduction in mortality rate, weight loss, diarrhea, gut leakage, gut dysbiosis, intestinal pathology changes, and levels of pro-inflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, macrophage inflammatory protein 2 (MIP-2), and keratinocyte chemoattractant (KC)] in the intestinal tissue and serum. Conditioned media from L. casei T21 exerted biological activities that fight against C. difficile as demonstrated in colonic epithelial cells by the following: (i) suppression of gene expression and production of IL-8, an important chemokine involved in C. difficile pathogenesis, (ii) reduction in the expression of SLC11A1 (solute carrier family 11 member 1) and HuR (human antigen R), important genes for the lethality of C. difficile toxin B, (iii) augmentation of intestinal integrity, and (iv) up-regulation of MUC2, a mucosal protective gene. These results supported the therapeutic potential of L. casei T21 for CDI and the need for further study on the intervention capabilities of CDI.


A hybrid rhOP-1 delivery system enhances new bone regeneration and consolidation in a rabbit model of distraction osteogenesis.
The effect of an early single injection of biodegradable core-shell nanoparticles (NPs) loaded with various low doses of recombinant human bone morphogenetic protein-7 (rhBMP-7/rhOP-1) on new bone regeneration and consolidation in a rabbit model of tibial distraction osteogenesis (DO) was investigated. The Regenerate bone was examined using soft radiography, densitometry, micro-computed tomography and histomorphometry. Compared to control, higher bone fill scores and a two- to three-fold increase in the quantity of mineralized tissue were prominent in the 1.0 and 5.0 microg OP-1/NPs groups, 3 weeks post-injections (P>0.05). Histologically, the distraction gap was completely ossified and the osteotomy margins poorly demarcated in those groups, one week into the consolidation phase. An up-regulation of various growth factors, ligands, and receptors was observed using immunohistochemistry. This novel hybrid delivery system maintains the bioactivity of the encapsulant, minimizes the therapeutic doses of rhOP-1, and accelerates DO via its localized, release-controlled, osteogenic, and naturally biocompatible polymeric properties.


On the content of sensorimotor representations after actual and motor imagery practice.
We examined the similarities between actual and motor imagery practice with regard to the development of sensorimotor representations. Participants had to reproduce knee joint positions (15 or 150 trials) in visuo-proprioceptive or proprioceptive conditions (Experiment 1) or in visual, proprioceptive or visuo-proprioceptive imagery conditions (Experiment 2), before being transferred in a proprioceptive condition. A familiarization session in a proprioceptive condition was performed before imagery practice only (Experiment 2). Results showed that the effect of vision withdrawal varied according to actual or motor imagery practice: performance accuracy in transfer decreased after actual visuo-proprioceptive practice while it increased after visuo-proprioceptive imagery practice. These results suggest that different movement representations can be developed following actual or imagery practice. They also suggest that information from previous experience could be stored in a sensorimotor memory and could be fundamental for the efficiency of motor imagery practice.


Validation of human behavioral tests using ethanol as a CNS depressant model.
This study evaluated the sensitivity of a battery of tests proposed for use in determining the depressant effects of chemicals on human central nervous system (CNS) function. The first step in the development of such tests was to determine if the tests could detect the effects produced by a known CNS depressant, ethanol. Five behavioral tests, digit span memory, simple reaction time, tachistoscopic perception, flicker fusion and anticipation timing (velocity estimation) were evaluated to determine their sensitivity to the effects of ethanol at blood levels between 0.05-0.06%. Thirty-one adult male volunteers received 0 and 1.4 ml 100 proof vodka/kg body weight according to a double-blind crossover design. Tests were conducted before treatment and between 30 and 70 minutes after an ethanol or control drink was ingested. Multivariate analysis of variance (MANOVA), using composite scores representing the individual tests, indicated that the battery as a whole detected statistically significant ethanol effects. Repeated measures analysis of variance (ANOVA) comparing performance after drinking ethanol to control performance on each of the individual tests indicated a significant decrement in reaction time, tachistoscopic perception and anticipation timing.


Methodology investigation of expirograms for enabling contact free breath alcohol analysis.
The present techniques for breath alcohol determination have usability limitations concerning practical use and the time and effort required for the test person. The rationale of the physiological assumptions in a recently demonstrated technique for breath analysis without a mouthpiece is investigated in this paper. Expirograms quantifying ethanol, carbon dioxide (CO(2)) and water (H(2)O) from 30 test subjects were analysed, with respect to the influence of individual variations in end-expiratory CO(2) and H(2)O concentrations, and possible benefits from simultaneous measurement of CO(2) or H(2)O. Both healthy subjects and patients suffering from pulmonary diseases performed breath tests with small and maximum volume expiration. The breath tests were recorded basically with a standard evidential instrument using infrared absorption spectroscopy, and equipped with a mouthpiece. Average concentrations were significantly higher for the maximum than for the small expirations. For the maximum expirations, the healthy subjects had a significantly higher end-expired PCO(2) of 4.4 ± 0.5 kPa (mean ± standard deviation) than the patients (3.9 ± 0.7 kPa). The corresponding values for H(2)O were 39 ± 1 and 38 ± 1 mg l(-1). The results indicate that the CO(2) variability is consistent with the requirements of accuracy for alcohol ignition interlocks. In addition, CO(2) as tracer gas is preferable to H(2)O due to its low concentration in ambient air. In instruments for evidential purposes H(2)O may be required as tracer gas for increased accuracy. Furthermore, the study provides support for early determination of breath alcohol concentration, indicating that determination after 2 s will introduce an additional random error of 0.02 mg l(-1) or less.


Mapping the burden of onchocercal skin disease.
Onchocerciasis is a neglected tropical disease caused by a nematode parasite, Onchocerca volvulus, and transmitted by bites of Simulium blackflies which breed near fast-flowing rivers. In humans, thousands of microfilariae (immature worms) migrate to the skin and eyes where they cause pathology. Historically, much research was devoted to the serious effect of blindness, from which the disease earns its alternative name of 'river blindness'. Mapping the burden of onchocercal skin disease (OSD) was expedited by the development of a clinical classification and grading system that facilitated comparison of data from different countries. After successful field testing in Nigeria, the classification scheme was used in a multicountry study in seven endemic sites, to estimate the true burden of OSD across Africa. High levels of OSD were found, affecting 28% of the population. A new control programme, the African Programme for Onchocerciasis Control (APOC) was launched in 20 countries using annual doses of ivermectin, donated by Merck & Co., Inc. The multicountry study also found a close correlation between the levels of itching and OSD with the level of endemicity, as determined by the prevalence of onchocercal nodules. This enabled APOC to use Rapid Epidemiological Mapping of Onchocerciasis, which entailed identifying likely vector breeding sites near rivers, then sampling 50 adult males in nearby villages to determine the prevalence of nodules and delineate which villages required treatment. Onchocerciasis is now targeted for elimination in Africa, and the challenge is to complete Onchocerciasis Elimination Mapping of hypoendemic areas using serology.


[Situation of maternal mortality in Peru, 2000 - 2012].
We perform an analysis concerning the situation of maternal mortality in Peru, based on the information of the System of Epidemiologic Surveillance of Maternal Mortality of the General Directorate of Epidemiology of the Ministry of Health and the Family and Health Demographic Survey. We can see a decrease in the rates of maternal mortality between 2000 and 2012. The direct causes are the same but in different proportions according to the natural regions, being the hemorrhage the first cause of maternal mortality. The coverage of birth attention in health establishments has increased in the last years but it is still necessary to improve the capacity of quick response and the quality of the health services. Maternal mortality in Peru is related to inequity and lack of women empowerment to excerpt their rights, specially the sexual and reproductive rights. It is necessary to strengthen the strategies that have been implemented in order to accomplish of the reduction in maternal mortality in Peru.


Semantic network array processor and its applications to image understanding.
The problems in computer vision range from edge detection and segmentation at the lowest level to the problem of cognition at the highest level. This correspondence describes the organization and operation of a semantic network array processor (SNAP) as applicable to high level computer vision problems. The architecture consists of an array of identical cells each containing a content addressable memory, microprogram control, and a communication unit. The applications discussed in this correspondence are the two general techniques, discrete relaxation and dynamic programming. While the discrete relaxation is discussed with reference to scene labeling and edge interpretation, the dynamic programming is tuned for stereo.


Roseomonas terrae sp. nov.
A Gram-negative, non-motile, coccobacilli-shaped bacterium, DS-48T, was isolated from soil from Dokdo, Korea, and its taxonomic position was investigated by means of a polyphasic study. Strain DS-48T grew optimally at 25 degrees C and pH 7.0-8.0 in the presence of 0.5% (w/v) NaCl. It contained Q-10 as the predominant ubiquinone and C18:1omega7c and C18:1 2-OH as the major fatty acids. The DNA G+C content was 69.3 mol%. A phylogenetic analysis based on 16S rRNA gene sequences showed that strain DS-48T fell within the genus Roseomonas, clustering with Roseomonas lacus TH-G33T (at a bootstrap confidence level of 100%). The levels of similarity between the 16S rRNA gene sequence of strain DS-48T and those of the type strains of recognized Roseomonas species were in the range 93.2-98.0%. DNA-DNA relatedness data and differential phenotypic properties, together with the phylogenetic distinctiveness of DS-48T, revealed that this strain differs from recognized Roseomonas species. On the basis of phenotypic, phylogenetic and genetic data, therefore, strain DS-48T represents a novel species within the genus Roseomonas, for which the name Roseomonas terrae sp. nov. is proposed. The type strain is DS-48T (=KCTC 12874T=JCM 14592T).


Effects of long-term fluoride exposure are associated with oxidative biochemistry impairment and global proteomic modulation, but not genotoxicity, in parotid glands of mice.
Fluoride has become widely used in dentistry because of its effectiveness in caries control. However, evidence indicates that excessive intake interferes with the metabolic processes of different tissues. Thus, this study aimed to investigate the effects of long-term exposure to F on the parotid salivary gland of mice, from the analysis of oxidative, proteomic and genotoxic parameters. The animals received deionized water containing 0, 10 or 50 mg/L of F, as sodium fluoride, for 60 days. After, parotid glands were collected for analysis of oxidative biochemistry, global proteomic profile, genotoxicity assessment and histopathological analyses. The results revealed that exposure to fluoride interfered in the biochemical homeostasis of the parotid gland, with increased levels of thiobarbituric acid reactive species and reduced glutathione in the exposed groups; as well as promoted alteration of the glandular proteomic profile in these groups, especially in structural proteins and proteins related to oxidative stress. However, genotoxic assessment demonstrated that exposure to fluoride did not interfere with DNA integrity in these concentrations and durations of exposure. Also, it was not observed histopathological alterations in parotid gland. Thus, our results suggest that long-term exposure to fluoride promoted modulation of the proteomic and biochemical profile in the parotid glands, without inducing damage to the genetic component. These findings reinforce the importance of rationalizing the use of fluorides to maximize their preventative effects while minimizing the environmental risks.


A comparison of Bayesian adaptive randomization and multi-stage designs for multi-arm clinical trials.
When several experimental treatments are available for testing, multi-arm trials provide gains in efficiency over separate trials. Including interim analyses allows the investigator to effectively use the data gathered during the trial. Bayesian adaptive randomization (AR) and multi-arm multi-stage (MAMS) designs are two distinct methods that use patient outcomes to improve the efficiency and ethics of the trial. AR allocates a greater proportion of future patients to treatments that have performed well; MAMS designs use pre-specified stopping boundaries to determine whether experimental treatments should be dropped. There is little consensus on which method is more suitable for clinical trials, and so in this paper, we compare the two under several simulation scenarios and in the context of a real multi-arm phase II breast cancer trial. We compare the methods in terms of their efficiency and ethical properties. We also consider the practical problem of a delay between recruitment of patients and assessment of their treatment response. Both methods are more efficient and ethical than a multi-arm trial without interim analyses. Delay between recruitment and response assessment attenuates this efficiency gain. We also consider futility stopping rules for response adaptive trials that add efficiency when all treatments are ineffective. Our comparisons show that AR is more efficient than MAMS designs when there is an effective experimental treatment, whereas if none of the experimental treatments is effective, then MAMS designs slightly outperform AR.


Shifting the pH Optima of (R)-Selective Transaminases by Protein Engineering.
Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. However, wild-type ATAs usually show pH optima at slightly alkaline values and exhibit low catalytic activity under physiological conditions. For efficient asymmetric synthesis ATAs are commonly used in combination with lactate dehydrogenase (LDH, optimal pH: 7.5) and glucose dehydrogenase (GDH, optimal pH: 7.75) to shift the equilibrium towards the synthesis of the target chiral amine and hence their pH optima should fit to each other. Based on a protein structure alignment, variants of (R)-selective transaminases were rationally designed, produced in E. coli, purified and subjected to biochemical characterization. This resulted in the discovery of the variant E49Q of the ATA from Aspergillus fumigatus, for which the pH optimum was successfully shifted from pH 8.5 to 7.5 and this variant furthermore had a two times higher specific activity than the wild-type protein at pH 7.5. A possible mechanism for this shift of the optimal pH is proposed. Asymmetric synthesis of (R)-1-phenylethylamine from acetophenone in combination with LDH and GDH confirmed that the variant E49Q shows superior performance at pH 7.5 compared to the wild-type enzyme.


What does it mean to 'live' and 'die'? A cross-linguistic analysis of parent-child conversations in English and Indonesian.
Previous work on children's intuitive knowledge about the natural world has documented their difficulty in acquiring an overarching concept of biological life that includes plants as well as humans and non-human animals. It has also suggested that the acquisition of fundamental biological concepts like alive and die may be influenced by the language used to describe them, as evidenced by differences between English- and Indonesian-speaking children's performance in tasks involving these concepts. Here, we examine one particularly important source of linguistic information available to children during this acquisition process: everyday conversations with their parents. We take a cross-linguistic approach in analysing the evidence available to English- and Indonesian-speaking children as they acquire meanings for words corresponding to the concepts alive and die. Our analysis illustrates that young children acquiring English and Indonesian are faced with distinct problems, but that parental input in both languages does little to support the acquisition of broad, inclusive biological concepts.


Numerical modeling and practical experience of Xuxi River's natural restoration using biological treatment.
Considering the successful application of biological treatment in several restoration works in China, this study is aimed to complete the previous numerical modeling and practical observation of the stream restoration. The results obtained from the restoration of the Xuxi River, Wuxi City, China, show that the technology of bacteria offers new solution for restoring the polluted urban streams. Although a considerable increase in the concentration of nutrients may have enhanced the algae problem during the treatment, the Xuxi River is now clearer and contains aquatic life. In addition to showing good agreement with the observed data for selected calibrated parameters, the developed model also may be used for estimating missing values. Because of a lack of data, the model can only be validated using data collected from the Gankeng River, Shenzhen City. Based on the results, the model is able to fit the observed data under a broader range of field situations.


Development of a family-based pulmonary rehabilitation programme: an exploratory study.
This study explored the expectations of patients with chronic obstructive pulmonary disease (COPD) and family members about a family-based pulmonary rehabilitation (PR) programme; developed and implemented a family-based PR programme and explored the impacts of the intervention on patients and family members. Patients with COPD and family members were interviewed. A family-based PR programme was designed. Patients' breathlessness, muscle strength, exercise tolerance, functional balance and health-related quality of life were collected pre/post-programme. Family coping and adjustment to illness were measured in patients and family members. Focus groups were conducted after the programme. Patients (n = 35; 69 ± 10 years; FEV1 62 ± 15% predicted) and family members (n = 35; 57 ± 12 years) had similar expectations/needs about a PR programme. Nine dyads participated. Patients' quadriceps strength, exercise tolerance and functional balance improved significantly (all p values < 0.023). Patients and family members seem to use more positive coping behaviours (p = 0.026; p = 0.011). Patients (n = 7; 78%) and family members (n = 8; 89%) considered having more knowledge about COPD and its management. Patients felt more functional (n = 9; 100%) and reported their family members to be more active (n = 3; 38%). In family members' perspective, their relationship with the care receiver was enhanced (n = 2; 22%). PR programmes, if inclusive of family members, may enhance the skills of the whole family to manage COPD. Implications for Rehabilitation Patients with chronic obstructive pulmonary disease (COPD) and their family members have similar expectations and needs about a family-based pulmonary rehabilitation (PR) programme. A family-based PR programme is feasible to implement within primary care. PR programmes, if inclusive of family members, may enhance the skills of the whole family to manage COPD.


Early coordinated multidisciplinary intervention to prevent sickness absence and labour market exclusion in patients with low back pain: study protocol of a randomized controlled trial.
Musculoskeletal disorders account for one third of the long-term absenteeism in Denmark and the number of individuals sick listed for more than four weeks is increasing. Compared to other diagnoses, patients with musculoskeletal diseases, including low back pain, are less likely to return to work after a period of sick leave. It seems that a multidisciplinary intervention, including cooperation between the health sector, the social sector and in the work place, has a positive effect on days off work due to musculoskeletal disorders and particularly low back pain. It is a challenge to coordinate this type of intervention, and the implementation of a return-to-work (RTW)-coordinator is suggested as an effective strategy in this process. The purpose of this paper is to describe the study protocol and present a new type of intervention, where the physiotherapist both has the role as RTW-coordinator and treating the patient. A randomized controlled trial (RCT) is currently on-going. The RCT includes 770 patients with low back pain of minimum four weeks who are referred to an outpatient back centre. The study population consists of patients, who are sick-listed or at risk of sick-leave due to LBP. The control group is treated with usual care in a team of a physiotherapist, a chiropractor, a rheumatologist and a social worker employed at the centre. The Intervention group is treated with usual care and in addition intervention of a psychologist, an occupational physician, an ergonomist, a case manager from the municipal sickness benefit office, who has the authority in the actual case concerning sickness benefit payment and contact to the patients employer/work place. The treating physiotherapist is the RTW-coordinator. Outcome will be reported at the end of treatment as well as 6 and 12 months follow up. The primary outcome is number of days off work. Secondary outcomes are disability, pain, and quality of life. The study will follow the recommendations in CONSORT-statement in designing and reporting RCTs. This large RCT is testing the effectiveness of a preventive intervention targeting patients on short term sick leave or at risk being sick listed because of low back pain. We have developed a novel multidisciplinary team structure using the treating physiotherapist as the return to work coordinator, and having the case manager from the municipal sickness benefit office participating in team meetings. The study has the potential to contribute to the knowledge about how to target the challenges in the treatment of LBP. The aim is to prevent sickness absence and labour market exclusion--both on the individual level and economic costs at community level. Short term results will be available in 2014.This study is approved by the Danish Regional Ethics Committee (J.nr: H-C-2008-112) and is registered at ClinicalTrials.gov: NCT01690234.


Advanced echocardiography in adult zebrafish reveals delayed recovery of heart function after myocardial cryoinjury.
Translucent zebrafish larvae represent an established model to analyze genetics of cardiac development and human cardiac disease. More recently adult zebrafish are utilized to evaluate mechanisms of cardiac regeneration and by benefiting from recent genome editing technologies, including TALEN and CRISPR, adult zebrafish are emerging as a valuable in vivo model to evaluate novel disease genes and specifically validate disease causing mutations and their underlying pathomechanisms. However, methods to sensitively and non-invasively assess cardiac morphology and performance in adult zebrafish are still limited. We here present a standardized examination protocol to broadly assess cardiac performance in adult zebrafish by advancing conventional echocardiography with modern speckle-tracking analyses. This allows accurate detection of changes in cardiac performance and further enables highly sensitive assessment of regional myocardial motion and deformation in high spatio-temporal resolution. Combining conventional echocardiography measurements with radial and longitudinal velocity, displacement, strain, strain rate and myocardial wall delay rates after myocardial cryoinjury permitted to non-invasively determine injury dimensions and to longitudinally follow functional recovery during cardiac regeneration. We show that functional recovery of cryoinjured hearts occurs in three distinct phases. Importantly, the regeneration process after cryoinjury extends far beyond the proposed 45 days described for ventricular resection with reconstitution of myocardial performance up to 180 days post-injury (dpi). The imaging modalities evaluated here allow sensitive cardiac phenotyping and contribute to further establish adult zebrafish as valuable cardiac disease model beyond the larval developmental stage.


Abundance of house dust mites in relation to climate in contrasting agricultural settlements in Israel.
The correlation between climatic conditions and mite numbers in houses from rural areas was studied in 13 agricultural communities (kibbutzim and moshavim) in nine geo-climatic subregions of Israel. Mites were present in 97% of the dust samples. The average number of mites per gram of dust in the different localities ranged between 84 and 2053. The maximum number of mites (7440/g dust) was found in a carpet from a house in Geva Carmel in the northern coastal region. The most prevalent species of mites were Dermatophagoides pteronyssinus and Dermatophagoides farinae, which were found in 85.6% and 71.3% of the samples, respectively. The house dust mites D. pteronyssinus, D. farinae and Euroglyphus maynei constituted 94.8% of the mites. Most of the mites were isolated from the carpets and sofas (37.0% and 33.7%, respectively), and a smaller number from beds (29.3%). The smallest number of mites (< or = 250/g dust) were found at a minimum relative humidity (RH) of 30% and lower, with a maximum temperature of 32 degrees C and higher, i.e. in the Jordan valley and Negev mountains. A greater number of mites (250-500/g dust) were found at a minimum ambient RH of 35-40% and a maximum temperature of 32 degrees C and higher, i.e. the Hula valley. A large number of mites (500-1000/g dust) were found at a minimum RH of 35-40% with a maximum temperature of 30 degrees C and lower, i.e. in the Judean and Samarian range, as well as in upper Galilee. The largest number of mites (1000-2000/g dust) was found at a minimum RH of 45% and higher, with a maximum temperature ranging between 30 and 32 degrees C. These conditions occur in the coastal strip, the coastal plain and in the Judean and Samarian foothills. A monthly examination of two houses in Zova, a kibbutz in the Judean hills next to Jerusalem, and two houses from Palmachim, a kibbutz in the coastal region, revealed that the highest prevalence of mites was found in the months April-November and May-November, respectively. In Zova, the highest number of mites were found during the months of June and July while the highest concentrations of D. pteronyssinus-antigen (Der p I) were measured during the month of September. A positive correlation between mite numbers and the quantity of Der p I in house dust was found.


Accurate modeling of replication rates in genome-wide association studies by accounting for Winner's Curse and study-specific heterogeneity.
Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human traits, but only a fraction of variants identified in discovery studies achieve significance in replication studies. Replication in genome-wide association studies has been well-studied in the context of Winner's Curse, which is the inflation of effect size estimates for significant variants due to statistical chance. However, Winner's Curse is often not sufficient to explain lack of replication. Another reason why studies fail to replicate is that there are fundamental differences between the discovery and replication studies. A confounding factor can create the appearance of a significant finding while actually being an artifact that will not replicate in future studies. We propose a statistical framework that utilizes genome-wide association studies and replication studies to jointly model Winner's Curse and study-specific heterogeneity due to confounding factors. We apply this framework to 100 genome-wide association studies from the Human Genome-Wide Association Studies Catalog and observe that there is a large range in the level of estimated confounding. We demonstrate how this framework can be used to distinguish when studies fail to replicate due to statistical noise and when they fail due to confounding.


Optimization of a fluoroscope to reduce radiation exposure in pediatric imaging.
A new children's hospital provided the impetus to investigate radiation dose and image quality in a fluoroscope that was specially engineered for pediatric fluoroscopy. Radiation protection management recommends radiation exposures that are as low as reasonably achievable, while still maintaining diagnostic image quality. To obtain comparative phantom imaging data on radiation exposure and image quality from a newly installed fluoroscope before and after optimization for pediatric imaging. Images were acquired from various thickness phantoms, simulating differing patient sizes. The images were evaluated for visualization of high- and low-contrast objects and for radiation exposure. Effects due to use of the image intensifier anti-scatter grid were also investigated. The optimization of the new fluoroscope for pediatric operation reduced radiation exposure by about 50% (compared to the originally installed fluoroscope), with very little loss of image quality. Pulsed fluoroscopy was able to lower radiation dose to less than 10% of continuous fluoroscopy, while still maintaining acceptable phantom image quality. Radiation exposure in pediatric fluoroscopy can be reduced to values well below the exposure settings that are typically found on unoptimized fluoroscopes. Pulsed fluoroscopy is considered a requisite for optimal pediatric fluoroscopy.


[Legionella pneumophila serogroup 3 isolated from a patient of pneumonia developed after drowning in bathtub of a hot spring spa].
A 71-year-old Japanese female, was found unconscious by drawing, in a hot spring spa, at around noon of 20 October 1994. She recovered by emergency cardiopulmonary resuscitation, and admitted to the Takinomiya General Hospital, with adult respiratory distress syndrome (ARDS). Although she recovered from ARDS within 4 days after her admission, she developed severe pneumonia accompanied with the second attack of ARDS. Ordinary bacteriological culture of her respiratory specimens failed to yield any significant pathogen for her pneumonia, and neither cefazolin nor imipenem/cilastatin was effective. Thus minocyclin was given on the 7th hospital-day and this was effective for blood gas and C-reactive protein (CRP) levels. Intratracheal exsudate inoculated on BCYE alpha agar plate yielded grayish white colonies. Cells of the colonies were clearly agglutinated by anti-Legionella pneumophila serogroup (SG) 3 serum. Antibody titers of patient's paired sera against the strain L. pneumophila SG3 Bloomington-2 and the patient's strain (Y-1) were determined by microplate agglutination test, and a significant rise from 1:20 to 1:320 was demonstrated. Patient recovered by erythromycin treatment and was discharged on the 59th hospital day. L. pneumophila SG3 organisms were again isolated from the spa water where the patient drawn. From these findings described above, we diagnosed the patient as pneumonia due to L. pneumophila SG3, and the spa water was the most probable source of infection.


Caveolin-1 gene knockout impairs nitrergic function in mouse small intestine.
Caveolin-1 is a plasma membrane-associated protein that is responsible for caveolae formation. It plays an important role in the regulation of the function of different signaling molecules, among which are the different isoforms of nitric oxide synthase (NOS). Nitric oxide (NO) is known to be an important inhibitory mediator in the mouse gut. Caveolin-1 knockout mice (Cav1(-/-)) were used to examine the effect of caveolin-1 absence on the NO function in the mouse small intestine (ileum and jejunum) compared to their genetic controls and BALB/c controls. Immunohistochemical staining showed loss of caveolin-1 and NOS in the jejunal smooth muscles and myenteric plexus interstitial cells of Cajal (ICC) of Cav1(-/-) mice; however, nNOS immunoreactive nerves were still present in myenteric ganglia. Under nonadrenergic noncholinergic (NANC) conditions, small intestinal tissues from Cav1(-/-) mice relaxed to electrical field stimulation (EFS), as did tissues from control mice. Relaxation of tissues from control mice was markedly reduced by N-omega-nitro-L-arginine (10(-4) M), but relaxation of Cav1(-/-) animals was affected much less. Also, Cav1(-/-) mice tissues showed reduced relaxation responses to sodium nitroprusside (100 microM) compared to controls; yet there were no significant differences in the relaxation responses to 8-bromoguanosine-3': 5'-cyclic monophosphate (100 microM). Apamin (10(-6) M) significantly reduced relaxations to EFS in NANC conditions in Cav1(-/-) mice, but not in controls. The data from this study suggest that caveolin-1 gene knockout causes alterations in the smooth muscles and the ICC, leading to an impaired NO function in the mouse small intestine that could possibly be compensated by apamin-sensitive inhibitory mediators.


Enhancement technology improves palatability of normal and callipyge lambs.
The objective of this research was to determine if BPI Processing Technology (BPT) improved palatability of normal (NN) and callipyge (CN) lamb meat and to determine the mechanism by which palatability was improved. Ten ewe and 10 wether lambs of each phenotype were slaughtered, and carcass traits were assessed by a trained evaluator. The LM was removed at 2 d postmortem. Alternating sides served as controls (CON) or were treated with BPT. Muscles designated BPT were injected to a target 120% by weight with a patented solution containing water, ammonium hydroxide, carbon monoxide, and salt. Muscle pH, cooking loss, Warner-Bratzler shear force (WBS), sarcomere length, cooked moisture retention, and desmin degradation were measured. A trained sensory panel and a take-home consumer panel evaluated LM chops. Callipyge had a heavier BW and HCW, less adjusted fat thickness, reduced yield grades, and greater conformation scores than NN (P < 0.05). For LM, NN had shorter sarcomeres, smaller WBS values, greater juiciness ratings, more off-flavors, reduced consumer ratings for raw characteristics (like of portion size, like of color, like of leanness, overall like of appearance) and greater consumer ratings for eating characteristics (like of juiciness, like of flavor) than CN (P < 0.05). For LM, BPT had greater cooked moisture retention, smaller WBS values, greater juiciness ratings, less off-flavors, and greater consumer ratings for raw characteristics (like of portion size, like of color, overall like of appearance) and eating characteristics (like of juiciness, like of flavor) than CON (P < 0.05). Significant phenotype × treatment interactions occurred for LM muscle pH, desmin degradation, tenderness, consumer like of texture/tenderness, and consumer overall like of eating quality (P < 0.05). For LM, BPT increased muscle pH more for NN than CN (P < 0.01) and increased desmin degradation for NN but decreased desmin degradation for CN (P < 0.01). The BPT enhancement improved LM tenderness ratings for CN more than NN (P < 0.05). For consumer like of texture/tenderness, BPT improved ratings for CN more than NN (P < 0.01). For consumer overall like of eating quality, BPT improved ratings for CN more than NN (P < 0.05). In summary, BPT had little to no effect on sarcomere length and desmin degradation, but improved palatability of NN and CN lamb by increasing cooked moisture retention, improving consumer acceptability of CN to near-normal levels.


Bactericidal efficacy of non-thermal plasma activation against Aeromonas hydrophila and immunological responses of koi (Cyprinus carpio haematopterus).
In the aquaculture industry, an efficient and safe water purification system is important to prevent mass mortality by virulent pathogens. As extensive use of traditional methods (e.g.: povidone-iodine, ozone, ultraviolet irradiation, formalin, and chlorine dioxide) have adverse effects on cultured fish, an appropriate and alternative water purification method is vital for the sustainability of the industry. Non-thermal plasma technology has been successfully used for various biomedical purposes (e.g: food sterilization, medical device disinfection, wound healing, cancer therapy, etc.) and has great potential to be used as a sterilizing system. However, few studies have been conducted on its usefulness in the aquaculture industry. In this study, we investigated the bactericidal efficacy of plasma-activated water induced by non-thermal plasma and its histopathological as well as immunological adverse effects on koi. A highly virulent Aeromonas hydrophila SNU HS7, which caused massive mortality of koi, was used for this study. Non-thermal plasma was applied for 10 min to the fish tanks with 1.2 × 109 CFU/mL SNU HS7 using PLMB-20 system to confirm the sterilization efficacy and to observe the survival and immunological reaction of koi for 14 days. As a result, gross pathological, histopathological, and immunological investigations did not reveal any significant adverse effects in fish as compared to the control groups. To the best of our knowledge, this is the first study showing that non-thermal plasma can be used for sterilization of rearing water without giving significant physiological damage to the fish, even under the assumption of extreme situations. As plasma can effectively sterilize not only bacteria but also other unknown pathogens, the results of this study are showing a promising future in purifying water in aquaculture practice.


Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5.
Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.


Genetic mapping in Eucalyptus urophylla and Eucalyptus grandis using RAPD markers.
Two single-tree linkage maps were constructed for Eucalyptus urophylla and Eucalyptus grandis, based on the segregation of 480 random amplified polymorphic DNA (RAPD) markers in a F1 interspecific progeny. A mixture of three types of single-locus segregations were observed: 244 1:1 female, 211 1:1 male, and 25 markers common to both, segregating 3:1. Markers segregating in the 1:1 ratio (testcross loci) were used to establish separate maternal and paternal maps, while markers segregating in the 3:1 ratio were used to identify homology between linkage groups of the two species maps. An average of 2.8 polymorphic loci were mapped for each arbitrary decamer primer used in the polymerase chain reaction. The mean interval size beween framework markers on the maps was 14 cM. The maps comprised 269 markers covering 1331 cM and 236 markers covering 1415 cM, in 11 linkage groups, for E. urophylla (2n = 2x = 22) and E. grandis (2n = 2x = 22), respectively. A comparative mapping analysis with two other E. urophylla and E. grandis linkage maps showed that RAPDs could be reliable markers for establishing a consensus species map. RAPD markers were automatically and quantitatively scored with an imaging analyzer. They were classified into four categories based on their optical density. A fragment intensity threshold is proposed to optimize the selection of reliable RAPD markers for future mapping experiments. Key words : genetic linkage map, Eucalyptus urophylla, Eucalyptus grandis, random amplified polymorphic DNA, RAPD, automated data collection.


Variation in residual feed intake in Holstein-Friesian dairy heifers in southern Australia.
Feed conversion efficiency of dairy cattle is an important component of the profitability of dairying, given that the cost of feed accounts for much of total farm expenses. Residual feed intake (RFI) is a useful measure of feed conversion efficiency, as it can be used to compare individuals with the same or differing levels of production during the period of measurement. If genetic variation exists in RFI among dairy cattle, selection for lower RFI could improve profitability. In this experiment, RFI was defined as the difference between an animal's actual feed intake and its expected feed intake, which was determined by regression of dry matter (DM) intake against mean body weight (BW) and growth rate. Nine hundred and three Holstein-Friesian heifer calves, aged between 5 and 7 mo, were measured for RFI in 3 cohorts of approximately 300 animals. Calves were housed under feedlot style conditions in groups of 15 to 20 for 85 to 95 d and had ad libitum access to a cubed alfalfa hay. Intakes of individual animals were recorded via an electronic feed recording system and BW gain was determined by weighing animals once or twice weekly, over a period of 60 to 70 d. Calves had DM intake (mean ± SD) of 8.3±1.37 kg of DM/d over the measurement period with BW gains of 1.1±0.17 kg/d. In terms of converting feed energy for maintenance and growth, the 10% most efficient calves (lowest RFI) ate 1.7 kg of DM less each day than the 10% least efficient calves (highest RFI) for the same rate of growth. Low-RFI heifers also had a significantly lower rate of intake (g/min) than high-RFI heifers. The heritability estimate of RFI (mean ± SE) was 0.27 (±0.12). These results indicate that substantial genetic variation in RFI exists, and that the magnitude of this variation is large enough to enable this trait to be considered as a candidate trait for future dairy breeding goals. A primary focus of future research should be to ensure that calves that are efficient at converting feed energy for maintenance and growth also become efficient at converting feed energy to milk. Future research will also be necessary to identify the consequences of selection for RFI on other traits (especially fertility and other fitness traits) and if any interactions exist between RFI and feeding level.


Parent Perceptions of Caregiver-Mediated Telemedicine Tools for Assessing Autism Risk in Toddlers.
Telemedicine tools have potential for increasing access to diagnostic services for children with autism spectrum disorder (ASD). Past work has utilized tele-assessment procedures in which remote psychologists observe administration of interactive screening instruments by trained, on-site providers. Although promising, this approach relies on two clinicians, limiting its efficiency and scalability. The present study examined the use, acceptability, and parents' perceptions of two caregiver-mediated tools for assessing ASD risk in toddlers, in which remote clinicians guided parents to complete interactive screening activities with their children. Most parents found tele-assessment to be comfortable, and many reported liking the parent-led nature of these tools. Parents also offered constructive feedback, which was used to modify the tele-assessment process for future study.


Macrophage activation syndrome in the course of monogenic autoinflammatory disorders.
An overwhelming activation of cytotoxic T cells and well-differentiated macrophages leading to systemic overload of inflammatory mediators characterizes the so-called macrophage activation syndrome (MAS); this potentially life-threatening clinical entity may derive from several genetic defects involved in granule-mediated cytotoxicity but has been largely observed in patients with juvenile idiopathic arthritis, many rheumatologic diseases, infections, and malignancies. The occurrence of MAS in the natural history or as the revealing clue of monogenic autoinflammatory disorders (AIDs), rare conditions caused by disrupted innate immunity pathways with overblown release of proinflammatory cytokines, has been only reported in few isolated patients with cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome since 2001. All these patients displayed various clinical, laboratory, and histopathologic features of MAS and have often required intensive care support. Only one patient has died due to MAS. Defective cytotoxic cell function was documented in a minority of patients. Corticosteroids were the first-line treatment, but anakinra was clinically effective in three refractory cases. Even if MAS and AIDs share multiple clinical features as well as heterogeneous pathogenetic scenes and a potential response to anti-interleukin-1 targeted therapies, MAS requires a prompt specific recognition in the course of AIDs due to its profound severity and high mortality rate.


[Abundance, population structure and growth of the Atrina maura (Bivalvia: Pinnidae) in a tropical lagoon of the Mexican Pacific coast ].
The abundance, population structure, and growth of the Pen-shell Atrina maura in the Corralero-Alotengo tropical lagoon system in Oaxaca, Mexico, were studied from February to September of 1997. An abundance analysis showed significant temporal and spatial differences (Kruskal-Wallis, p < 0.001). Two spatial groups of abundance were found in the area, one from the mouth of the lagoon system to the middle of the Pen-shell bank, and the other between the middle of the Pen-shell bank and the head of the system. Three temporal periods of abundance were found (February-April-May; July-August; March-June-September). The distribution of population size showed that benthic recruitment of A. maura occurred from February to July. Length frequency of A. maura is commonly wide-ranging; nevertheless, in this study Pen-shell organisms with a valve length of 15 cm were frequently found. The growth rate length was 3.7 cm/month during the dry season (February to May), and 3.5 cm/month during the rainy season (June to September). Sex ratio was maintained at 1:1 from February to May, but males were dominant from June to August, and the minimum length for reproduction was registered at 10 cm valve length.


An Extrudable Partially Demineralized Allogeneic Bone Paste Exhibits a Similar Bone Healing Capacity as the "Gold Standard" Bone Graft.
Autologous bone grafts (BGs) remain the reference grafting technique in various clinical contexts of bone grafting procedures despite their numerous peri- and post-operative limitations. The use of allogeneic bone is a viable option for overcoming these limitations, as it is reliable and it has been widely utilized in various forms for decades. However, the lack of versatility of conventional allogeneic BGs (e.g., blocks, powders) limits their potential for use with irregular or hard-to-reach bone defects. In this context, a ready- and easy-to-use partially demineralized allogeneic BG in a paste form has been developed, with the aim of facilitating such bone grafting procedures. The regenerative properties of this bone paste (BP) was assessed and compared to that of a syngeneic BG in a pre-clinical model of intramembranous bone healing in critical size defects in rat calvaria. The microcomputed tridimensional quantifications and the histological observations at 7 weeks after the implantation revealed that the in vivo bone regeneration of critical-size defects (CSDs) filled with the BP was similar to syngeneic bone grafts (BGs). Thus, this ready-to-use, injectable, and moldable partially demineralized allogeneic BP, displaying equivalent bone healing capacity than the "gold standard," may be of particular clinical relevance in the context of oral and maxillofacial bone reconstructions.


Acute clinical recovery from sport-related concussion.
Concussion is a highly prevalent injury in contact and collision sports that has historically been poorly understood. An influx of sport-concussion research in recent years has led to a dramatic improvement in our understanding of the injury's defining characteristics and natural history of recovery. In this review, we discuss the current state of knowledge regarding the characteristic features of concussion and typical acute course of recovery, with an emphasis on the aspects of functioning most commonly assessed by clinicians and researchers (e.g., symptoms, cognitive deficits, postural stability). While prototypical clinical recovery is becoming better understood, questions remain regarding what factors (e.g., injury severity, demographic variables, history of prior concussions, psychological factors) may explain individual variability in recovery. Although research concerning individual differences in response to concussion is relatively new, and in many cases limited methodologically, we discuss the evidence about several potential moderators of concussion recovery and point out areas for future research. Finally, we describe how increased knowledge about the negative effects of and recovery following concussion has been translated into clinical guidelines for managing concussed athletes.


Economical spectrophotometric method for estimation of zaltoprofen in pharmaceutical formulations.
A simple, rapid, precise, and economical spectrophotometric method has been developed for quantitative analysis of zaltoprofen (ZLT) in pharmaceutical formulations. A mixture of methanol and water was used as a solvent. Initial stock solution of ZLT was prepared in methanol and subsequent dilution was done in water. The standard solution of ZLT in water showed two absorption maxima, one at 243.5 nm and another at 338.0 nm. The drug obeyed Beer-Lambert's law in the concentration range of 1-40 μg/mL with regression 0.9999 at 243.5 nm and 5-100 μg/mL with regression 0.9999 at 338.0 nm. The overall % recovery was found to be 99.53% and 99.77% at 243.5 nm and 338.0 nm, respectively, which reflect that the method is free from interference of the impurities and other additives used in tablet formulation. Relative standard deviations of absorbance from six measurements were always less than 2%. The results of analysis have been validated as per ICH guidelines. Both the wavelengths can be adopted in routine analysis of ZLT in tablet dosage form.


Studies of peripheral blood T-and B-lymphocytes in acute infections.
E-binding (T) and immunoglobulin-bearing (B) lymphocytes were determined in 22 patients with acute infections. The percentage of T-cells was depressed in most patients in the early stages of disease, whereas the B-cell proportion was usually elevated compared with convalescence and controls. The B-cell increase occurred earlier in a small group of viral or mycoplasmal infections than in bacterial infections. Four patients with unusually high numbers of B-cells had no corresponding increase in EAC3-binding lymphocytes. Almost all lymphocytes from pleural effusion in a patient with tuberculosis were found to be T-cells.


Isoflurane preconditioning confers cardioprotection by activation of ALDH2.
The volatile anesthetic, isoflurane, protects the heart from ischemia/reperfusion (I/R) injury. Aldehyde dehydrogenase 2 (ALDH2) is thought to be an endogenous mechanism against ischemia-reperfusion injury possibly through detoxification of toxic aldehydes. We investigated whether cardioprotection by isoflurane depends on activation of ALDH2.Anesthetized rats underwent 40 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups: untreated controls, isoflurane preconditioning with and without an ALDH2 inhibitor, the direct activator of ALDH2 or a protein kinase C (PKCε) inhibitor. Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide. Isolated neonatal cardiomyocytes were treated with hypoxia followed by reoxygenation. Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2. In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2. Activation of ALDH2 and cardioprotection by isoflurane were substantially blocked by the PKCε inhibitor. Activation of ALDH2 by mitochondrial PKCε plays an important role in the cardioprotection of isoflurane in myocardium I/R injury.


Anion and Cation Permeability of the Mouse TMEM16F Calcium-Activated Channel.
TMEM16F is involved in several physiological processes, such as blood coagulation, bone development and virus infections. This protein acts both as a Ca2+-dependent phospholipid scramblase and a Ca2+-activated ion channel but several studies have reported conflicting results about the ion selectivity of the TMEM16F-mediated current. Here, we have performed a detailed side-by-side comparison of the ion selectivity of TMEM16F using the whole-cell and inside-out excised patch configurations to directly compare the results. In inside-out configuration, Ca2+-dependent activation was fast and the TMEM16F-mediated current was activated in a few milliseconds, while in whole-cell recordings full activation required several minutes. We determined the relative permeability between Na+ and Cl¯ (PNa/PCl) using the dilution method in both configurations. The TMEM16F-mediated current was highly nonselective, but there were differences depending on the configuration of the recordings. In whole-cell recordings, PNa/PCl was approximately 0.5, indicating a slight preference for Cl¯ permeation. In contrast, in inside-out experiments the TMEM16F channel showed a higher permeability for Na+ with PNa/PCl reaching 3.7. Our results demonstrate that the time dependence of Ca2+ activation and the ion selectivity of TMEM16F depend on the recording configuration.


The seroprevalence of hepatitis B, hepatitis C and human immunodeficiency virus infections in paediatric oncology patients in Turkey.
One hundred and two newly diagnosed children with malignancy followed up at the Pediatric Oncology Department of Ankara Oncology Hospital were investigated for hepatitis B, hepatitis C and human immunodeficiency virus markers. The ages ranged between seven months and 17 years with a median of 10 years; 62 were male. Twenty-four patients had Hodgkin's disease, 11 had non-Hodgkin's lymphoma and 67 patients had other solid tumours. Four patients had positive HBs-Ag, 15 developed immunity against hepatitis B and had anti-HBs antibodies. One patient had a previous infection with positive anti-HBc. Hepatitis C virus antibodies were positive in only one patient. HIV serology was negative in all patients. These results show the high prevalence of hepatitis B virus infection in paediatric oncology patients. In countries where hepatitis B is endemic, strict screening of blood donors, usage of disposable equipment and vaccination of patients is recommended. Although the incidence of hepatitis C and human immunodeficiency virus infections are rising, infection with hepatitis B is still by far the most common.


Novel educational approaches to enhance learning and interest in nephrology.
The number of U.S. medical graduates pursuing careers in nephrology has declined over the last several years. Some of the proposed reasons for this declining interest include difficult-to-understand or unstimulating kidney pathophysiology courses in medical school; disheartening inpatient elective experiences; and few opportunities to experience the other aspects of nephrology careers such as outpatient nephrology clinics, outpatient dialysis, and kidney transplantation. Novel and alternative educational approaches should be considered by the nephrology training community to enhance the understanding of nephrology from medical school to fellowship training. Newer teaching methods and styles should also be incorporated to adapt to today's learner. These innovative educational approaches may not only increase interest in nephrology careers, but they may also enhance and maintain interest during nephrology fellowship. In this article, we will review several educational approaches that may enhance teaching and learning in nephrology.


Fusion plasma turbulence described by modified sandpile dynamics.
Transport in fusion plasmas is investigated with modified sandpile models. Based on results from more complete simulations, the sandpile model is modified in steps. Models with a constant source are obtained by coupling two sandpiles. Decoupling the mean field from the bursts allows one to develop a reduced model which captures some of the key features of flux-driven simulations. In the latter sandpile model, turbulent transport is mediated by the burst field while the mean-field gradient governs the transfer to the bursts. This allows one to investigate spreading, namely turbulent transport into stable regions, and transport barriers, regions where the transfer from the mean field to turbulence is reduced. Both cases are found to exhibit intermittent behaviors when the system undergoes spontaneous transitions between different transport regimes. Finally, one couples to the sandpile algorithm a species evolution algorithm that assigns a quality factor to each site. The latter appears to self-generate corrugations, or micro-barriers. These are found to naturally cluster radially in structures that are large enough to impact confinement. The mechanisms introduced to alleviate the clustering, destabilization of the corrugation by overloading and by secondary instabilities at critical radial extents, are shown to generate long-range relaxation events in space and in time with quasiperiodic reorganization of the corrugation pattern.