Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.
Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. In this multicentre, randomised, open-label phase 2-3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1-21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5-54·9) in the chemotherapy alone group and 48·1% (43·2-52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91-1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.


Angiotensin-converting enzyme inhibitors and stroke risk: benefit beyond blood pressure reduction?
Hypertension, a leading cause of morbidity and mortality, accounts for 25-49% of all strokes. Randomized placebo-controlled trials primarily with diuretics and beta-blockers administered in patients with hypertension have demonstrated a 38% reduction in primary stroke. Placebo-controlled trials with angiotensin-converting enzyme (ACE) inhibitors have not been conducted in patients with hypertension. However, in a meta-analysis of four placebo-controlled trials of ACE inhibitors in patients with coronary heart disease and/or diabetes mellitus, the overall risk of primary stroke was significantly reduced. Results of the Heart Outcomes Prevention Evaluation trial, which produced a substantial reduction in stroke with an apparently small reduction in blood pressure, suggest that the benefit of ACE inhibitors may be related to their effects on the renin-angiotensin-aldosterone system more than on blood pressure reduction. In active-control comparisons in patients with hypertension, ACE inhibitors have demonstrated reductions in primary stroke risk similar to reductions with diuretics, beta-blockers, and calcium channel blockers. The data suggest that for primary prevention of stroke antihypertensive therapy should be individualized in patients. Relatively few data are available concerning the benefit of antihypertensive therapy in the secondary prevention of stroke. In patients who had experienced a stroke or transient ischemic attack, therapy with a diuretic or a combination of a diuretic plus an ACE inhibitor could be recommended based on available outcome studies conducted in this patient population. It is premature to conclude that the benefit of ACE inhibitor therapy in primary or secondary prevention of stroke is an effect independent of blood pressure reduction. Hypertension detection, treatment, and control in patients still must be the principal focus of clinicians for both primary and secondary prevention of stroke.


[Study on the health status of the residents near military airbases in Pyeongtaek City].
We conducted an epidemiologic survey to evaluate the effect of the aircraft noise exposure on the health of the residents near the military airbases in Pyeongtaek City. The evaluation of environmental noise level, questionnaire survey, and health examination were performed for 917 residents. The study population consisted of four groups: subjects who lived in the village close to the fighter airbase (high exposure), subjects who lived along the course of fighters (intermediate exposure), and subjects near a helicopter airbase, and the control group. The prevalence of the aircraft noise related accident and irritable bowel syndrome in the exposure groups were higher than that of the control group. The risks of noise induced hearing loss, hypertension and diabetes mellitus were higher in the exposed groups than in the control group. The prevalence of anxiety disorder and primary insomnia were higher in the exposed groups than in the control group. Prevalence odd ratios of the risk for primary insomnia after adjusting age, sex, agricultural noise, and occupation were 4.03 [95% confidence interval (95% CI) 1.56-10.47] for the subject near the helicopter airbase, 1.23 (95% CI 0.40-3.76) for those intermediately exposed to fighter noise, and 4.99 (95% CI 2.14-11.64) for those highly exposed to fighter noise. The results of the present study suggest that the aircraft noise may have adverse effects on hearing function, cardiovascular health and mental health. Therefore, it seems to be needed to take proper measures including the control of the aircraft noise and the management of the exposed people's health.


Thermoplasmatales and sulfur-oxidizing bacteria dominate the microbial community at the surface water of a CO2-rich hydrothermal spring located in Tenorio Volcano National Park, Costa Rica.
Here we report the chemical and microbial characterization of the surface water of a CO2-rich hydrothermal vent known in Costa Rica as Borbollones, located at Tenorio Volcano National Park. The Borbollones showed a temperature surrounding 60 °C, a pH of 2.4 and the gas released has a composition of ~ 97% CO2, ~ 0.07% H2S, ~ 2.3% N2 and ~ 0.12% CH4. Other chemical species such as sulfate and iron were found at high levels with respect to typical fresh water bodies. Analysis by 16S rRNA gene metabarcoding revealed that in Borbollones predominates an archaeon from the order Thermoplasmatales and one bacterium from the genus Sulfurimonas. Other sulfur- (genera Thiomonas, Acidithiobacillus, Sulfuriferula, and Sulfuricurvum) and iron-oxidizing bacteria (genera Sideroxydans, Gallionella, and Ferrovum) were identified. Our results show that CO2-influenced surface water of Borbollones contains microorganisms that are usually found in acid rock drainage environments or sulfur-rich hydrothermal vents. To our knowledge, this is the first microbiological characterization of a CO2-dominated hydrothermal spring from Central America and expands our understanding of those extreme ecosystems.


Fluorescence-activated droplet sorting of lipolytic microorganisms using a compact optical system.
Lipases are ubiquitous enzymes of great physiological significance that have been used extensively in multiple industries. Environmental microorganisms are a major source for the discovery of novel lipases with high catalytic efficiency and selectivity. However, current plate-based screening of lipase-producing strains is time consuming, labour intensive and inefficient. In this study, we developed an ultra-high throughput screening pipeline for lipase-producing strains based on fluorescence-activated droplet sorting (FADS) using a compact optical system that could be easily set up in an alignment-free manner. The pipeline includes droplet generation, droplet incubation, picoinjection of the fluorescence probe, and sorting of droplets with a throughput of 2 × 106 drops per h. We applied the pipeline to screen samples collected from different locations, including sediments from a hot spring in Tibet, soils from the Zoige wetland, contaminated soils from an abandoned oilfield, and a Chinese Daqu starter. In total, we obtained 47 lipase-producing bacterial strains belonging to seven genera, including Staphylococcus, Bacillus, Enterobacter, Serratia, Prolinoborus, Acinetobacter, and Leclercia. We believe that this FADS-based pipeline could be extended to screen various enzymes from the environment, and may find wide applications in breeding of industrial microorganisms.


Cutaneous leiomyoma in a child: A case report.
Leiomyoma is a benign tumour commonly encountered in the genitourinary and gastrointestinal organs in adults. Cutaneous leiomyomas are rare benign tumors arising from the arrector pili muscle of hair follicles. Cutaneous leiomyomas are more likely to occur in adults than in children. We describe a case of a 10-year-old female who presented with multiple, firm, red-brown masses on the back. A punch biopsy was performed. Under high-power examination, spindle cells with an eosinophilic cytoplasm were observed and immunohistochemical studies were performed; the cells stained strongly positive for smooth muscle actin (SMA). The patient was subsequently diagnosed with pilar leiomyoma and referred to a plastic surgeon for surgical treatment. Although cutaneous leiomyoma is a rare disorder, we identified a case of pilar leiomyoma in a young female. A careful clinical assessment led to the correct diagnosis and therapy in the present case. We propose that leiomyoma ought to be considered in the differential diagnosis of any cutaneous or mucosal mass in children.


DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety.
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics.


Effects of proton pump inhibitors and h(2) receptor antagonists on the ileum motility.
Objectives. To investigate the effects of proton pump inhibitors (PPIs) and H(2) receptor antagonists on ileum motility in rats with peritonitis and compare changes with control group rats. Methods. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another of 8 rats underwent a sham operation and were accepted as controls. Twenty-four hours later after the operation, the rats were killed, and their ileum smooth muscle was excised and placed in circular muscle direction in a 10 mL organ bath. Changes in amplitude and frequency of contractions were analyzed before and after PPIs and H(2) receptor blockers. Results. PPI agents decreased the motility in a dose-dependent manner in ileum in both control and intraabdominal sepsis groups. While famotidine had no significant effect on ileum motility, ranitidine and nizatidine enhanced motility in ileum in both control and intraabdominal sepsis groups. This excitatory effect of H(2) receptor antagonists and inhibitor effects of PPIs were significantly high in control group when compared to the peritonitis group. The inhibitor effect of pantoprazole on ileum motility was significantly higher than the other two PPI agents. Conclusions. It was concluded that H(2) receptor antagonists may be more effective than PPIs for recovering the bowel motility in the intraabdominal sepsis situation.


Eating out of home: energy, macro- and micronutrient intakes in 10 European countries. The European Prospective Investigation into Cancer and Nutrition.
To assess the contribution of out-of-home (OH) energy and nutrient intake to total dietary intake, and to compare out- versus in-home nutrient patterns among 27 centres in 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Between 1995 and 2000, 36,034 participants aged between 35-74 years completed a standardized 24-h dietary recall using a software programme (EPIC-Soft) that recorded the place of food/drink consumption. Eating OH was defined as the consumption of foods and beverages anywhere other than in household premises, irrespective of the place of purchase/preparation. Nutrient intakes were estimated using a standardized nutrient database. Mean intakes were adjusted for age and weighted by season and day of recall. Among women, OH eating contributed more to total fat intake than to intakes of protein and carbohydrates. Among both genders, and particularly in southern Europe, OH eating contributed more to sugar and starch intakes and less to total fibre intake. The contribution of OH eating was also lower for calcium and vitamin C intakes. The composition of diet at home was different from that consumed out of home in southern countries, but was relatively similar in the north. In northern Europe, OH and in-home eating are homogeneous, whereas southern Europeans consider OH eating as a distinctive occasion. In most centres, women selected more fat-rich items when eating out.


(99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis.
Aims In transthyretin amyloid (ATTR) amyloidosis various principal phenotypes have been described: cardiac, neuropathic, or a mixed cardiac and neuropathic. In addition, two different types of amyloid fibrils have been identified (type A and type B). Type B fibrils have thus far only been found in predominantly early-onset V30M and in patients carrying the Y114C mutation, whereas type A is noted in all other mutations currently examined as well as in wild-type ATTR amyloidosis. The fibril type is a determinant of the ATTR V30M disease phenotype. (99m)Tc-DPD scintigraphy is a highly sensitive method for diagnosing heart involvement in ATTR amyloidosis. The objective of this study was to determine the relationship between ATTR fibril composition and (99m)Tc-DPD scintigraphy outcome in patients with biopsy-proven ATTR amyloidosis. Methods Altogether 55 patients with biopsy-proven diagnosis of ATTR amyloidosis and amyloid fibril composition determined were examined by (99m)Tc-DPD scintigraphy. The patients were grouped and compared according to their type of amyloid fibrils. Cardiovascular evaluation included ECG, echocardiography, and cardiac biomarkers. The medical records were scrutinized to identify subjects with hypertension or other diseases that have an impact on cardiac dimensions. Results A total of 97% with type A and none of the patients with type B fibrils displayed (99m)Tc-DPD uptake at scintigraphy (p < 0.001). Findings from analyses of cardiac biomarkers, ECG, and echocardiography, though significantly different, could not differentiate between type A and B fibrils in individual patients. Conclusion In ATTR amyloidosis, the outcome of (99m)Tc-DPD scintigraphy is strongly related to the patients' transthyretin amyloid fibril composition.


Role of BMP, betaig-h3, and chitosan in early bony consolidation in distraction osteogenesis in a dog model.
The purpose of this investigation was to study the effect of bone morphogenetic protein (BMP), transforming growth factor beta-induced gene h3 (betaig-h3), and chitosan on early bony consolidation in distraction osteogenesis in a dog model. Sixteen dogs were used for this study. The lateral surface of the mandibular body was exposed in the subperiosteal plane and the vertical osteotomy on the mandibular body was extended downward. An external distraction device was applied to the mandibular body, and the mandibular distraction was started 5 days after the operation at a rate of 2 mm/day up to a 10-mm distraction after 5 days. The experimental group was then divided into a control group, a BMP group, a betaig-h3 group, and a chitosan group, depending on the type of implantation material used in the distracted area. On the same day after completing the distraction, BMP, betaig-h3, or chitosan was implanted into the distracted area. No material was implanted into the distracted area in the control group. After implanting the materials, the distraction device was left in place for 7 weeks to allow for bony consolidation. Four dogs were allocated to each group. Two dogs in each group, a total of eight dogs, were killed 4 weeks after completing the distraction and the other eight dogs were killed after 7 weeks. Serial radiographs were obtained every week after completing the distraction. New bone was generated in the distracted zone in all groups. In the BMP group, the formation of active woven bone was observed throughout the distracted zone, and the new bone appeared to be nearly normal cortical bone 7 weeks after implantation. In the betaig-h3 and chitosan groups, the development of new bone was observed in the distracted zone after 7 weeks; however, the amount was less than that in the BMP group. In the control group, the new bone was observed at the edges of the distracted zone. These findings suggest that BMP seems to be very effective in early bony consolidation in distraction osteogenesis.


Strengthening decentralized primary healthcare planning in Nigeria using a quality improvement model: how contexts and actors affect implementation.
Quality improvement models have been applied across various levels of health systems with varying success leading to scepticisms about effectiveness. Health systems are complex, influenced by contexts and characterized by numerous interests. Thus, a shift in focus from examining whether improvement models work, to understanding why, when and where they work most effectively is essential. Nigeria introduced DIVA (Diagnose-Intervene-Verify-Adjust) as a model to strengthen decentralized PHC planning. However, implementation has been poorly sustained. This article explores the role of actors and context in implementation and sustainability of DIVA in two local government areas (LGAs) in Nigeria. We employed an integrated mixed method approach in which qualitative data was used in conjunction with quantitative to understand effects of actors and contexts on implementation outcomes. We analysed policy documents and conducted interviews with PHC managers. Then using the Model for Understanding Success in Quality (MUSIQ), we measured contextual factors affecting implementation of DIVA in the selected LGAs. The LGAs scored 117.42 and 104.67 out of 168 points on the MUSIQ scale, respectively, indicating contextual barriers exist. Both have strong DIVA team attributes, but these could not independently ensure quality implementation. Although external support accounted for the greatest contextual disparities, the utmost implementation challenges relate to subnational government leadership, management, financial and technical support. Although higher levels of government may set visionary goals for PHC, interventions are potentially skewed towards donor interests at lower (implementation) levels. Thus, subnational political will is a key determinant of quality implementation. Consequently, advocacy for responsible and accountable political governance is essential in comparable decentralized contexts.


IL-6 signalling in exercise and disease.
Low-grade chronic inflammation is a feature of Type 2 diabetes and appears to play a pathogenetic role in insulin resistance. It is well known that cytokines, besides their immunoregulatory roles, are important players in metabolism. Moreover, it has become evident that skeletal muscles express several cytokines, which belong to distinct cytokine classes. IL-6 (interleukin-6) is a pleiotropic cytokine produced by virtually all multinucleated cells including skeletal myocytes where it is produced in response to contraction. IL-6 is subsequently released into the circulation, where it works in a hormone-like fashion to induce lipolysis and fat oxidation. In more recent experiments, it has been shown that IL-6 infusion increases glucose disposal during a hyperinsulinaemic euglycaemic clamp in healthy humans. IL-6 treatment of myotubes increases fatty acid oxidation, basal and insulin-stimulated glucose uptake and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increases AMPK (AMP-activated protein kinase) and the metabolic effects of IL-6 were abrogated in AMPK dominant negative-infected cells. Finally, IL-6 mediates anti-inflammatory effects by stimulating the production of anti-inflammatory cytokines and by suppressing TNFalpha (tumour necrosis factor alpha) production. We suggest that IL-6 and other muscle-derived cytokines (myokines) may play a role in defending Type 2 diabetes.


Psychological processes mediating the association between developmental trauma and specific psychotic symptoms in adults: a systematic review and meta-analysis.
Experiencing psychological trauma during childhood and/or adolescence is associated with an increased risk of psychosis in adulthood. However, we lack a clear knowledge of how developmental trauma induces vulnerability to psychotic symptoms. Understanding the psychological processes involved in this association is crucial to the development of preventive interventions and improved treatments. We sought to systematically review the literature and combine findings using meta-analytic techniques to establish the potential roles of psychological processes in the associations between developmental trauma and specific psychotic experiences (i.e., hallucinations, delusions and paranoia). Twenty-two studies met our inclusion criteria. We found mediating roles of dissociation, emotional dysregulation and post-traumatic stress disorder (PTSD) symptoms (avoidance, numbing and hyperarousal) between developmental trauma and hallucinations. There was also evidence of a mediating role of negative schemata, i.e. mental constructs of meanings, between developmental trauma and delusions as well as paranoia. Many studies to date have been of poor quality, and the field is limited by mostly cross-sectional research. Our findings suggest that there may be distinct psy-chological pathways from developmental trauma to psychotic phenomena in adulthood. Clinicians should carefully ask people with psychosis about their history of developmental trauma, and screen patients with such a history for dissociation, emotional dysregulation and PTSD symptoms. Well conducted research with prospective designs, including neurocognitive assessment, is required in order to fully understand the biopsychosocial mechanisms underlying the association between developmental trauma and psychosis.


COVID-19-Associated Mucormycosis (CAM): Case-Series and Global Analysis of Mortality Risk Factors.
Since the novel coronavirus disease (COVID-19) outbreak, the cases of COVID-19 co-infections have been increasingly reported worldwide. Mucormycosis, an opportunistic fungal infection caused by members of the Mucorales order, had been frequently isolated in severely and critically ill COVID-19 patients. Initially, the anamnestic, clinical, and paraclinical features of seven COVID-19-associated mucormycosis (CAM) cases from Egypt were thoroughly reported. Subsequently, an extensive review of the literature was carried out to describe the characteristics of CAM cases globally, aiming to explore the potential risk factors of mortality in CAM patients. Out of the seven reported patients in the case series, five (71.4%) were males, six (85.7%) had diabetes mellitus, and three (42.9%) had cardiovascular disease. All patients exhibited various forms of facial deformities under the computed tomography scanning, and two of them tested positive for Mucorales using the polymerase chain reaction (PCR) testing. Liposomal amphotericin B (LAmB) was prescribed to all cases, and none of them died until the end of the follow-up. On reviewing the literature, 191 cases were reported worldwide, of which 74.4% were males, 83.2% were from low-middle income countries, and 51.4% were aged 55 years old or below. Diabetes mellitus (79.1%), chronic hypertension (30%), and renal disease/failure (13.6%) were the most common medical comorbidities, while steroids (64.5%) were the most frequently prescribed medication for COVID-19, followed by Remdesivir (18.2%), antibiotics (12.7%), and Tocilizumab (5.5%). As the majority of the included studies were observational studies, the obtained evidence needs to be interpreted carefully. Diabetes, steroids, and Remdesivir were not associated with increased mortality risk, thus confirming that steroids used to manage severe and critical COVID-19 patients should not be discontinued. Lung involvement, bilateral manifestation, and Rhizopus isolation were associated with increased mortality risk, thus confirming that proactive screening is imperative, especially for critically ill patients. Finally, surgical management and antimycotic medications, e.g., amphotericin B and posaconazole, were associated with decreased mortality risk, thus confirming their effectiveness.


A dehydration-inducible gene in the truffle Tuber borchii identifies a novel group of dehydrins.
The expressed sequence tag M6G10 was originally isolated from a screening for differentially expressed transcripts during the reproductive stage of the white truffle Tuber borchii. mRNA levels for M6G10 increased dramatically during fruiting body maturation compared to the vegetative mycelial stage. Bioinformatics tools, phylogenetic analysis and expression studies were used to support the hypothesis that this sequence, named TbDHN1, is the first dehydrin (DHN)-like coding gene isolated in fungi. Homologs of this gene, all defined as "coding for hypothetical proteins" in public databases, were exclusively found in ascomycetous fungi and in plants. Although complete (or almost complete) fungal genomes and EST collections of some Basidiomycota and Glomeromycota are already available, DHN-like proteins appear to be represented only in Ascomycota. A new and previously uncharacterized conserved signature pattern was identified and proposed to Uniprot database as the main distinguishing feature of this new group of DHNs. Expression studies provide experimental evidence of a transcript induction of TbDHN1 during cellular dehydration. Expression pattern and sequence similarities to known plant DHNs indicate that TbDHN1 is the first characterized DHN-like protein in fungi. The high similarity of TbDHN1 with homolog coding sequences implies the existence of a novel fungal/plant group of LEA Class II proteins characterized by a previously undescribed signature pattern.


Quantitative Series Enrichment Analysis (QSEA): a novel procedure for 3D-QSAR analysis.
A novel procedure is proposed for 3D-QSAR analysis. The composition of 16 published QSAR datasets has been examined using Quantitative Series Enrichment Analysis (QSEA). The procedure is based on topomer technologies. A heatmap display in combination with topomer CoMFA and a novel series trajectory analysis revealed critical information for the assembly of structures into meaningful series. Global and local centroid structures can be determined from a similarity distance matrix and build the origins for stepwise model building by increasing the similarity radius around the centroid nucleus. The results indicate that the new procedure allows determination of whether compounds belong to an emerging structure-activity relationship and which compounds can be predicted within reliable limits.


The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis.
Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC). Our sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach. In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described. A genetic influence on monoaminergic involvement in impulsivity shown by children with ADHD was found. There were trends for separate and overlapping influences on impulsive-aggressive behavior and cognitive impulsivity, where an association with PNMT (and arousal mechanisms affected by its activity) was more clearly involved in the latter. Serotonergic and dopaminergic mechanisms were implicated in both forms of impulsivity with a wider range of serotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity. These preliminary results should be followed up with an examination of environmental influences and associations with performance on tests of impulsivity in the laboratory.


Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease.
Women with a family history of breast cancer are at increased risk of the disease, but no study has been large enough to characterise reliably how, over women's lives, this risk is influenced by particular familial patterns of breast cancer. This report, on the relevance of breast cancer in first-degree relatives, is based on combined data from 52 epidemiological studies. Individual data on breast cancer in first-degree relatives (mothers, sisters, and daughters) of 58209 women with breast cancer and of 101986 controls were collected, checked, and analysed centrally. Risk ratios for breast cancer were calculated by conditional logistic regression, stratified by study, age, menopausal status, number of sisters, parity, and age when the first child was born. Breast-cancer incidence and mortality rates for particular family histories were calculated by applying age-specific risk ratios to breast-cancer rates typical for more-developed countries. Altogether 7496 (12.9%) women with breast cancer and 7438 (7.3%) controls reported that one or more first-degree relatives had a history of breast cancer: 12% of women with breast cancer had one affected relative and 1% had two or more. Risk ratios for breast cancer increased with increasing numbers of affected first-degree relatives: compared with women who had no affected relative, the ratios were 1.80 (99% CI 1.69-1.91), 2.93 (2.36-3.64), and 3.90 (2.03-7.49), respectively, for one, two, and three or more affected first-degree relatives (p<0.0001 each). The risk ratios were greatest at young ages, and for women of a given age, were greater the younger the relative was when diagnosed. The results did not differ substantially between women reporting an affected mother (9104) or sister (6386). Other factors, such as childbearing history, did not significantly alter the risk ratios associated with a family history of breast cancer. For women in more-developed countries with zero, one, or two affected first-degree relatives, the estimated cumulative incidence of breast cancer up to age 50 was 1.7%, 3.7%, and 8.0%, respectively; corresponding estimates for incidence up to age 80 were 7.8%, 13.3%, and 21.1%. Corresponding estimates for death from breast cancer up to age 80 were 2.3%, 4.2%, and 7.6%. The age when the relative was diagnosed had only a moderate effect on these estimates. Eight out of nine women who develop breast cancer do not have an affected mother, sister, or daughter. Although women who have first-degree relatives with a history of breast cancer are at increased risk of the disease, most will never develop breast cancer, and most who do will be aged over 50 when their cancer is diagnosed. In countries where breast cancer is common, the lifetime excess incidence of breast cancer is 5.5% for women with one affected first-degree relative and 13.3% for women with two.


Characterization of major surface and excretory-secretory immunogens of Trypanosoma cruzi trypomastigotes and identification of potential protective antigen.
The surface antigens of Trypanosoma cruzi trypomastigotes were identified by immunoprecipitation and were compared with metabolically labelled excretory-secretory products (ES) released by the parasites in vitro. A series of major immunogenic components in the ES antigens were revealed (160 kDa, 130 kDa and 80-110 kDa). The trypomastigote surface also bears the 130 kDa band and the 80-110 kDa complex. Competition experiments demonstrated the common antigenic structure of the ES and the surface antigens. Two-dimensional analysis of ES antigens immunoprecipitated by human Chagasic serum revealed several spots in the 80-110 kDa region with a wide range of isoelectric points (PI between 5.4 and 6.7). This reflects a charge heterogeneity of these polypeptides. The trypomastigote 85 kDa polypeptide was also identified in the ES antigens by using a monoclonal antibody against this antigen. Two-dimensional analysis of the 85 kDa proteins shed from the surface of trypomastigotes and immunoprecipitated by the monoclonal antibody 155D3 showed 2 major spots: a major part of the 85 kDa polypeptide was found at pH 6.5-6.6, whereas a substantial amount of the antigen was found at pH 5.7. An additional component with molecular weight of approximately 58 kDa and isoelectric points of 6.5 and 6.6, was also visualized. Detection of the 85 kDa polypeptide circulating in serum from patients with acute and chronic Chagas' disease was achieved using an enzyme-linked immunosorbent assay. In addition, the data obtained showed that a polyclonal antibody to the 85 kDa polypeptide could be used to passively induce a partial protection of Fischer rats against acute lethal infection. Thus, the antigens recognized by polyclonal antibody appear to play a role in the development of protective immunity against T. cruzi.


Prevention of experimental encephalomyelitis with peptides that block interaction of T cells with major histocompatibility complex proteins.
Two synthetic immunodominant and nonencephalitogenic peptides of myelin basic protein, N1-20 and AcN9-20, effectively compete with an encephalitogenic peptide, AcN1-11, in an in vitro T-cell response restricted by class II major histocompatibility complex products (I-Au). These mutant peptide constructs, which do not occur in nature, also compete with the self-antigen for the in vivo induction of T cells primed with the encephalitogen AcN1-11. By using these nonpathogenic competitor peptides, it is possible to prevent the development of a prototypic T-cell-mediated autoimmune disease, experimental allergic encephalomyelitis. These results suggest possibilities for the utilization of competitor peptides for therapy of T-cell-mediated autoimmune diseases linked to specific major histocompatibility complex genes.


Parameter-based assessment of disturbed and intact components of visual attention in children with developmental dyslexia.
People with developmental dyslexia (DD) have been shown to be impaired in tasks that require the processing of multiple visual elements in parallel. It has been suggested that this deficit originates from disturbed visual attentional functions. The parameter-based assessment of visual attention based on Bundesen's () theory of visual attention allows one to identify and quantify the underlying deficits. The present study provides the first groupwise comparison between children with DD (n = 12; mean age 9.84 years) and typically developing children (n = 12; mean age 9.87 years) with regard to intact and disturbed components of visual attention. From the performance on whole- and partial-report tasks, we derived individual parameter estimates of four different parameters: visual processing speed, storage capacity of visual short-term memory (VSTM), laterality of attentional weighting and efficiency of top-down control. Groupwise comparisons revealed that general attentional resources, processing speed and VSTM storage capacity, are impaired in children with DD compared to typically developing children. In contrast, selectivity parameters, laterality of attentional selection and attentional top-down control did not differ between these groups. Relating the current findings to previous results, obtained in highly comparable methodological settings, from single cases of children with DD, and from a group of adults with DD, we conclude that slowed perceptual processing speed is a primary visual attentional deficit in DD. Furthermore, reduced VSTM storage capacity seems to modulate the difficulties in written language processing imposed by the disorder.


Evaluating the use of different positional strategies for sentence selection in biomedical literature summarization.
The position of a sentence in a document has been traditionally considered an indicator of the relevance of the sentence, and therefore it is frequently used by automatic summarization systems as an attribute for sentence selection. Sentences close to the beginning of the document are supposed to deal with the main topic and thus are selected for the summary. This criterion has shown to be very effective when summarizing some types of documents, such as news items. However, this property is not likely to be found in other types of documents, such as scientific articles, where other positional criteria may be preferred. The purpose of the present work is to study the utility of different positional strategies for biomedical literature summarization. We have evaluated three different positional strategies: (1) awarding the sentences at the beginning of the document, (2) preferring those at the beginning and end of the document, and (3) weighting the sentences according to the section in which they appear. To this end, we have implemented two summarizers, one based on semantic graphs and the other based on concept frequencies, and evaluated the summaries they produce when combined with each of the positional strategies above using ROUGE metrics. Our results indicate that it is possible to improve the quality of the summaries by weighting the sentences according to the section in which they appear (≈17% improvement in ROUGE-2 for the graph-based summarizer and ≈20% for the frequency-based summarizer), and that the sections containing the more salient information are the Methods and Material and the Discussion and Results ones. It has been found that the use of traditional positional criteria that award sentences at the beginning and/or the end of the document are not helpful when summarizing scientific literature. In contrast, a more appropriate strategy is that which weights sentences according to the section in which they appear.


Reliability of Computerized Neurocognitive Tests for Concussion Assessment: A Meta-Analysis.
Although widely used, computerized neurocognitive tests (CNTs) have been criticized because of low reliability and poor sensitivity. A systematic review was published summarizing the reliability of Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scores; however, this was limited to a single CNT. Expansion of the previous review to include additional CNTs and a meta-analysis is needed. Therefore, our purpose was to analyze reliability data for CNTs using meta-analysis and examine moderating factors that may influence reliability. A systematic literature search (key terms: reliability, computerized neurocognitive test, concussion) of electronic databases (MEDLINE, PubMed, Google Scholar, and SPORTDiscus) was conducted to identify relevant studies. Studies were included if they met all of the following criteria: used a test-retest design, involved at least 1 CNT, provided sufficient statistical data to allow for effect-size calculation, and were published in English. Two independent reviewers investigated each article to assess inclusion criteria. Eighteen studies involving 2674 participants were retained. Intraclass correlation coefficients were extracted to calculate effect sizes and determine overall reliability. The Fisher Z transformation adjusted for sampling error associated with averaging correlations. Moderator analyses were conducted to evaluate the effects of the length of the test-retest interval, intraclass correlation coefficient model selection, participant demographics, and study design on reliability. Heterogeneity was evaluated using the Cochran Q statistic. The proportion of acceptable outcomes was greatest for the Axon Sports CogState Test (75%) and lowest for the ImPACT (25%). Moderator analyses indicated that the type of intraclass correlation coefficient model used significantly influenced effect-size estimates, accounting for 17% of the variation in reliability. The Axon Sports CogState Test, which has a higher proportion of acceptable outcomes and shorter test duration relative to other CNTs, may be a reliable option; however, future studies are needed to compare the diagnostic accuracy of these instruments.


Super-resolution fluorescence microscopy by stepwise optical saturation.
Super-resolution fluorescence microscopy is an important tool in biomedical research for its ability to discern features smaller than the diffraction limit. However, due to its difficult implementation and high cost, the super-resolution microscopy is not feasible in many applications. In this paper, we propose and demonstrate a saturation-based super-resolution fluorescence microscopy technique that can be easily implemented and requires neither additional hardware nor complex post-processing. The method is based on the principle of stepwise optical saturation (SOS), where M steps of raw fluorescence images are linearly combined to generate an image with a [Formula: see text]-fold increase in resolution compared with conventional diffraction-limited images. For example, linearly combining (scaling and subtracting) two images obtained at regular powers extends the resolution by a factor of 1.4 beyond the diffraction limit. The resolution improvement in SOS microscopy is theoretically infinite but practically is limited by the signal-to-noise ratio. We perform simulations and experimentally demonstrate super-resolution microscopy with both one-photon (confocal) and multiphoton excitation fluorescence. We show that with the multiphoton modality, the SOS microscopy can provide super-resolution imaging deep in scattering samples.


A two-billion-year history for the lunar dynamo.
Magnetic studies of lunar rocks indicate that the Moon generated a core dynamo with surface field intensities of ~20 to 110 μT between at least 4.25 and 3.56 billion years ago (Ga). The field subsequently declined to <~4 μT by 3.19 Ga, but it has been unclear whether the dynamo had terminated by this time or just greatly weakened in intensity. We present analyses that demonstrate that the melt glass matrix of a young regolith breccia was magnetized in a ~5 ± 2 μT dynamo field at ~1 to ~2.5 Ga. These data extend the known lifetime of the lunar dynamo by at least 1 billion years. Such a protracted history requires an extraordinarily long-lived power source like core crystallization or precession. No single dynamo mechanism proposed thus far can explain the strong fields inferred for the period before 3.56 Ga while also allowing the dynamo to persist in such a weakened state beyond ~2.5 Ga. Therefore, our results suggest that the dynamo was powered by at least two distinct mechanisms operating during early and late lunar history.


Quinine localizes to a non-acidic compartment within the food vacuole of the malaria parasite Plasmodium falciparum.
The naturally fluorescent compound quinine has long been used to treat malaria infections. Although some evidence suggests that quinine acts in the parasite food vacuole, the mechanism of action of quinine has not yet been resolved. The Plasmodium falciparum multidrug resistance (pfmdr1) gene encodes a food vacuolar membrane transporter and has been linked with parasite resistance to quinine. The effect of multiple pfmdr1 copies on the subcellular localization of quinine was explored. Fluorescence microscopy was used to evaluate the subcellular localization of quinine in parasites containing different pfmdr1 copy numbers to determine if copy number of the gene affects drug localization. The acidotropic dye LysoTracker Red was used to label the parasite food vacuole. Time-lapse images were taken to determine quinine localization over time following quinine exposure. Regardless of pfmdr1 copy number, quinine overlapped with haemozoin but did not colocalize with LysoTracker Red, which labeled the acidic parasite food vacuole. Quinine localizes to a non-acidic compartment within the food vacuole possibly haemozoin. Pfmdr1 copy number does not affect quinine subcellular localization.


Physiological substrates of mammalian monogamy: the prairie vole model.
Prairie voles (Microtus ochrogaster) are described here as a model system in which it is possible to examine, within the context of natural history, the proximate processes regulating the social and reproductive behaviors that characterize a monogamous social system. Neuropeptides, including oxytocin and vasopressin, and the adrenal glucocorticoid, corticosterone, have been implicated in the neural regulation of partner preferences, and in the male, vasopressin has been implicated in the induction of selective aggression toward strangers. We hypothesize here that interactions among oxytocin, vasopressin and glucocorticoids could provide substrates for dynamic changes in social and agonistic behaviors, including those required in the development and expression of monogamy. Results from research with voles suggest that the behaviors characteristics of monogamy, including social attachments and biparental care, may be modified by hormones during development and may be regulated by different mechanisms in males and females.


Transoral mucosal excision sutured gastroplasty: a pilot study for GERD and obesity with two-year follow-up.
An outpatient transoral endoscopic procedure for gastroesophageal reflux disease (GERD) and obesity would be appealing if safe, effective, and durable. We present the first in human experience with a new system. Eight patients with GERD (3) and obesity (5) were selected according to a preapproved study protocol. All GERD patients had preprocedure manometry and pH monitoring to document GERD as well as quality of life and symptom questionnaires. Obese patients (body mass index >35) underwent a psychological evaluation and tests for comorbidities. Under general anesthesia, a procedure was performed at the gastroesophageal junction including mucosal excision, suturing of the excision beds for apposition, and suture knotting. One patient with micrognathia could not undergo the required preprocedural passage of a 60 F dilator and was excluded. The first 2 GERD patients had incomplete procedures due to instrument malfunction. The subsequent 5 subjects had a successfully completed procedure. Four patients were treated for obesity and had an average excess weight loss of 30.3% at 2-year follow-up. Of these patients, one had an 8-mm outlet at the end of the procedure recognized on video review--a correctable error--and another vomited multiple times postoperatively and loosened the gastroplasty sutures. The treated GERD patient had resolution of reflux-related symptoms and is off all antisecretory medications at 2-year follow-up. Her DeMeester score was 8.9 at 24 months. The initial human clinical experience showed promising results for effective and safe GERD and obesity therapy.


Tympanoplasty using conchal cartilage graft.
Cartilage has been used successfully as a graft in middle ear surgery. It used to be reserved for advanced pathology because of its possible detrimental effect on postoperative hearing. Recent papers however failed to prove this effect. The present study describes the authors' experience in 161 cases of conchal cartilage tympanoplasty. In tympanoplasty type I postoperative pure tone average air-bone gap was within 20 dB in 88.4% of the cases. If combined with ossiculoplasty when the stapes was intact, 72% was within 20 dB and when the stapes was absent, 54.5% was within 20 dB. Taking rate of the graft was 95.6% (154/161) with 22% (36/161) representing revision surgery. At present the author uses cartilage graft as a first choice in tympanoplastic procedures.


Mass measles vaccination in urban Burkina Faso, 1998.
To assess the impact of the National Immunization Days (NIDs) on measles vaccine coverage in Burkina Faso in 1998. During the week after the campaign, in which measles vaccine was offered to children aged 9-59 months in six cities regardless of vaccination history, a cluster survey was conducted in Ouagadougou and Bobo Dioulasso, the country's two largest cities. Interviewers visited the parents of 1267 children aged up to 59 months and examined vaccination cards. We analysed the data using cluster sample methodology for the 1041 children who were aged 9-59 months. A total of 604 (57%) children had received routine measles vaccination prior to the campaign, and 823 (79%) were vaccinated during the NIDs. Among those who had previously had a routine vaccination, 484 (81%) were revaccinated during the NIDs. Among those not previously vaccinated, 339 (78%) received one dose during the NIDs. After the campaign, 943 (91%) children had received at least one dose of measles vaccine. Better socioeconomic status was associated with a higher chance of having been vaccinated routinely, but it was not associated with NID coverage. The mass campaign enabled a substantial increase in measles vaccine coverage to be made because it reached a high proportion of children who were difficult to reach through routine methods.


Universal Mindfulness Training in Schools for Adolescents: a Scoping Review and Conceptual Model of Moderators, Mediators, and Implementation Factors.
There is evidence that universal school-based mindfulness training (SBMT) can have positive effects for young people. However, it is unknown who benefits most from such training, how training exerts effects, and how implementation impacts effects. This study aimed to provide an overview of the evidence on the mediators, moderators, and implementation factors of SBMT, and propose a conceptual model that can be used both to summarize the evidence and provide a framework for future research. A scoping review was performed, and six databases and grey literature were searched. Inclusion and exclusion criteria were applied to select relevant material. Quantitative and qualitative information was extracted from eligible articles and reported in accordance with PRISMA-ScR guidelines. The search produced 5479 articles, of which 31 were eligible and included in the review. Eleven studies assessed moderators of SBMT on pupil outcomes, with mixed findings for all variables tested. Five studies examined the mediating effect of specific variables on pupil outcomes, with evidence that increases in mindfulness skills and decreases in cognitive reactivity and self-criticism post-intervention are related to better pupil outcomes at follow-up. Twenty-five studies assessed implementation factors. We discuss key methodological shortcomings of included studies and integrate our findings with existing implementation frameworks to propose a conceptual model. Widespread interest in universal SBMT has led to increased research over recent years, exploring who SBMT works for and how it might work, but the current evidence is limited. We make recommendations for future research and provide a conceptual model to guide theory-led developments.


VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue.
Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b(+)/Gr-1(+)/CXCR4(hi) neutrophils, were observed at the site of engraftment, whereas VEGF-A-deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A-recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9-deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b(+)/Gr-1(+) neutrophils that are CXCR4(hi) and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.


Factors affecting the pharmacokinetics of parenteral chloramphenicol in enteric fever.
Chloramphenicol pharmacokinetics were studied in 29 Nepalese adults diagnosed with uncomplicated enteric fever and randomized to receive succinate ester 30 mg/kg i.v. or i.m. Serial plasma concentrations of chloramphenicol, and iothalamate (to estimate glomerular filtration rate), antipyrine (hepatocellular function) and Indocyanine Green (liver blood flow) were measured by HPLC and kinetic parameters estimated by non-compartmental analysis. In culture-positive patients (n = 16), mean residence times (MRTs) and steady-state volumes of distribution (V(d)ss) for i.v. chloramphenicol (mean +/- S.D.; 4.9 +/- 0.9 h and 1.9 +/- 0.8 L/kg; n = 7) were less than after i.m. chloramphenicol (12.3 +/- 7.3 h and 3.7 +/- 2.5 L/kg; n = 9; P < 0.05), with a higher peak plasma concentration after i.v. (16.2 +/- 9.1 versus 7.8 +/- 3.6 mg/L; P < 0.05); plasma clearance (Cl(p)) was similar in the two groups (368 +/- 172 and 310 +/- 224 mL/kg/min after i.v. and i.m. respectively). In 17 patients examined during convalescence, MRT and Vdss were less than in acute illness regardless of route chloramphenicol administration. There were similar changes in chloramphenicol kinetic parameters in culture-negative patients. Antipyrine Cl(p) and liver blood flow correlated weakly with chloramphenicol Cl(p) in culture-positive patients (P < 0.1) and were higher in convalescence; no such associations were seen for iothalamate Cl(p). These data indicate that i.v. chloramphenicol produces peak plasma concentrations which are on average twice those after i.m. injection of the same dose, due principally to a smaller V(d)ss. Cl(p) is uninfluenced by route of administration and is determined more by hepatic metabolism than renal excretion. Intramuscular treatment may result in sub-therapeutic chloramphenicol concentrations initially, but continued regular i.v. dosing is more likely to produce levels at which bone marrow toxicity occurs.


Effectiveness and efficiency of a practice accreditation program on cardiovascular risk management in primary care: study protocol of a clustered randomized trial.
Cardiovascular risk management is largely provided in primary healthcare, but not all patients with established cardiovascular diseases receive preventive treatment as recommended. Accreditation of healthcare organizations has been introduced across the world with a range of aims, including the improvement of clinical processes and outcomes. The Dutch College of General Practitioners has launched a program for accreditation of primary care practices, which focuses on chronic illness care. This study aims to determine the effectiveness and efficiency of a practice accreditation program, focusing on patients with established cardiovascular diseases. We have planned a two-arm cluster randomized trial with a block design. Seventy primary care practices will be recruited from those who volunteer to participate in the practice accreditation program. Primary care practices will be the unit of randomization. A computer list of random numbers will be generated by an independent statistician. The intervention group (n = 35 practices) will be instructed to focus improvement on cardiovascular risk management. The control group will be instructed to focus improvement on other domains in the first year of the program. Baseline and follow-up measurements at 12 months after receiving the accreditation certificate are based on a standardized version of the audit in the practice accreditation program. Primary outcomes include controlled blood pressure, serum cholesterol, and prescription of recommended preventive medication. Secondary outcomes are 15 process indicators and two outcome indicators of cardiovascular risk management, self-reported achievement of improvement goals and perceived unintended consequences. The intention to treat analysis is statistically powered to detect a difference of 10% on primary outcomes. The economic evaluation aims to determine the efficiency of the program and investigates the relationship between costs, performance indicators, and accreditation. It is important to gain more information about the effectiveness and efficiency of the practice accreditation program to assess if participation is worthwhile regarding the quality of cardiovascular risk management. The results of this study will help to develop the practice accreditation program for primary care practices.


Airway and Hypothermia Prevention: and Treatment via STEAM The System for Thermogenic Emergency Airway Management.
Military medicine has made significant advancements in decreasing mortality by addressing the lethal triad - metabolic acidosis, coagulopathy, and hypothermia. However, casualties are still succumbing to injury. Recent conflict zones have led to the development of remarkable life-saving innovations, including the management of compressible hemorrhage and whole blood transfusions. Nevertheless, hypothermia prevention and treatment techniques remain relatively unchanged. Hypothermia prevention is anticipated to become more critical in future operations due to a predicted increase in evacuation times and reliance on Prolonged Casualty Care (PCC). This is likely secondary to increasingly distanced battlespaces and the mobility challenges of operating in semi-/non-permissive environments. Innovation is essential to combat this threat via active airway rewarming in the vulnerable patient. Thus, we propose the development, fabrication, and efficacy testing of a device in which we estimate being able to control temperature and humidity at physiologic levels in the PCC setting and beyond.


Transmission dynamics and control of multidrug-resistant Klebsiella pneumoniae in neonates in a developing country.
Multidrug-resistant Klebsiella pneumoniae is an increasing cause of infant mortality in developing countries. We aimed to develop a quantitative understanding of the drivers of this epidemic by estimating the effects of antibiotics on nosocomial transmission risk, comparing competing hypotheses about mechanisms of spread, and quantifying the impact of potential interventions. Using a sequence of dynamic models, we analysed data from a one-year prospective carriage study in a Cambodian neonatal intensive care unit with hyperendemic third-generation cephalosporin-resistant K. pneumoniae. All widely-used antibiotics except imipenem were associated with an increased daily acquisition risk, with an odds ratio for the most common combination (ampicillin + gentamicin) of 1.96 (95% CrI 1.18, 3.36). Models incorporating genomic data found that colonisation pressure was associated with a higher transmission risk, indicated sequence type heterogeneity in transmissibility, and showed that within-ward transmission was insufficient to maintain endemicity. Simulations indicated that increasing the nurse-patient ratio could be an effective intervention.


BMP-2, hypoxia, and COL1A1/HtrA1 siRNAs favor neo-cartilage hyaline matrix formation in chondrocytes.
Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets.


Different indicators of socioeconomic status and their relative importance as determinants of health in old age.
Socioeconomic status has been operationalised in a variety of ways, most commonly as education, social class, or income. In this study, we also use occupational complexity and a SES-index as alternative measures of socioeconomic status. Studies show that in analyses of health inequalities in the general population, the choice of indicators influence the magnitude of the observed inequalities. Less is known about the influence of indicator choice in studies of older adults. The aim of this study is twofold: i) to analyse the impact of the choice of socioeconomic status indicator on the observed health inequalities among older adults, ii) to explore whether different indicators of socioeconomic status are independently associated with health in old age. We combined data from two nationally representative Swedish surveys, providing more than 20 years of follow-up. Average marginal effects were estimated to compare the association between the five indicators of SES, and three late-life health outcomes: mobility limitations, limitations in activities of daily living (ADL), and psychological distress. All socioeconomic status indicators were associated with late-life health; there were only minor differences in the effect sizes. Income was most strongly associated to all indicators of late-life health, the associations remained statistically significant when adjusting for the other indicators. In the fully adjusted models, education contributed to the model fits with 0-3% (depending on the outcome), social class with 0-1%, occupational complexity with 1-8%, and income with 3-18%. Our results indicate overlapping properties between socioeconomic status indicators in relation to late-life health. However, income is associated to late-life health independently of all other variables. Moreover, income did not perform substantially worse than the composite SES-index in capturing health variation. Thus, if the primary objective of including an indicator of socioeconomic status is to adjust the model for socioeconomic differences in late-life health rather than to analyse these inequalities per se, income may be the preferable indicator. If, on the other hand, the primary objective of a study is to analyse specific aspects of health inequalities, or the mechanisms that drive health inequalities, then the choice of indicator should be theoretically guided.


Mesothelioid reaction following talc pleurodesis: a case report.
Talc pleurodesis is a well-established procedure performed to obliterate the pleural space to prevent recurrent pleural effusion and/or recurrent pneumothorax. Pleurodesis is commonly accomplished by draining the pleural fluid, if present, followed by either a mechanical procedure, such as abrasion, pleurectomy, or instillation of a chemical irritant into the pleural space, which results in inflammation and fibrosis which obliterates the pleural space. The reported complications of talc pleurodesis are hypoxemia, hypotension, tachycardia, dyspnea, chest pain, and fever. Herein, we present a case of a 43-year-old female patient who developed an intense mesothelioid reaction which occurred 7 years following talc pleurodesis. This case represents a unique mesothelioid reaction which became manifested several years after recurrent talc pleurodesis. Such a mesothelioid reaction can clinically and radiographically mimic malignant mesothelioma. We conclude that Talc pleurodesis played a causative role in this patient developing an intense mesothelioid reaction. A mesothelioid reaction should be included in the differential diagnosis in patients with pleural thickening/pleural plaque formation who have previously been treated with talc pleurodesis.


Vitamin D3 effects on lipids differ in statin and non-statin-treated humans: superiority of free 25-OH D levels in detecting relationships.
Inverse associations between 25-OH vitamin D levels and cardiovascular morbidity and mortality have been reported. Our goals were to 1) investigate effects of correcting inadequate D status on lipids, 2) determine whether free 25-OH D is better correlated with lipids than total 25-OH D. A randomized, double-blind placebo-controlled trial was performed. Participants resided in the general community. Adults with inadequate D status were randomized to D3: 14 men, 12 women, age 60 ± 8 years (mean ± SD) or placebo: 12 men, 11 women: 59 ±12 years. Responses to 12-week oral vitamin D3 titrated (1000-3000 IU/d) to achieve 25-OH D levels ≥25 ng/mL were compared to placebo. Measurements were 25-OH D (tandem mass spectometry), free 25-OH D (direct immunoassay), lipids (directly measured triglyceride, cholesterol, and subfractions; plant sterols and cholesterol synthesis precursors), and safety labs before and after 6 and 12 weeks D3 or placebo. Data were analyzed by repeated measures ANOVA and linear regression. Vitamin D3 was titrated to 1000 IU/d in 15/26 (58%), to 2000 IU/d in 10, and 3000 IU/d in one patient. D3 had no effect on cholesterol or cholesterol subfractions except for trends for decreases in atorvastatin-treated patients (cholesterol, P = .08; low-density lipoprotein [LDL] cholesterol, P = .05). Decreased campesterol concentrations (P = .05) were seen with D3 but not placebo in statin-treated patients. Relationships between total 25-OH D and lipids were not detected, but inverse linear relationships were detected between free 25-OH D and triglycerides (P = .03 for all participants [n = 49], P = .03 in all statin-treated [n = 19], and P = .0009 in atorvastatin-treated [n = 11]), and between free 25-OH D and LDL cholesterol (P = .08 overall, P = .02 in all statin-treated, and P = .03 for atorvastatin-treated), and total cholesterol (P = .09 overall; P = .04 for all statin-treated, and P = .05 for atorvastatin-treated). Vitamin D lipid-lowering effects appear limited to statin-treated patients and are likely due to decreased cholesterol absorption. Relationships between lipids and D metabolites were only detected when free 25-OH D was measured, suggesting the superiority of determining free 25-OH D levels compared to total 25-OH vitamin D levels when analyzing biologic responses.


Parent perspectives on oncology team communication regarding neurocognitive impacts of cancer therapy and school reentry.
Neurocognitive deficits are common after childhood cancer and impact academic performance. Parents need to be knowledgeable of long-term complications impacting school and the resources necessary to support educational achievement. The oncology team plays an important role in preparing parents for the challenges of returning to school after treatment. An online survey developed by parents and stakeholders was used to assess parent experiences and preferences associated with oncology team support around neurocognitive deficits and school transition. Recruitment included social media sites, foundation contacts, and clinic/event flyers. Topics included information content, timing, and frequency of information; and utility or perceived value of information. Inclusion criteria included respondent identifying as a parent (caregiver) of child treated for cancer who has returned to school. Surveys from 203 parents were completed representing diverse geographic locations. Nearly half (48%) did not recall receiving information about neurocognitive deficits. The most frequently reported time to receive this information was at diagnosis, but parents reported a need for conversations throughout the cancer trajectory, especially at transition to survivorship and school reentry. In addition, half of the parents (51%) felt inadequately prepared for the return to school. Information about neuropsychological testing, resources for learning difficulties, educational terms, and legal rights related to school services were the topics most inadequately provided. Parents feel inadequately prepared by their oncology team for their child's return to school. Research is needed to identify effective oncology team approaches to fill the gaps in knowledge around school reentry after cancer treatment.


Influence of baseline variables on changes in International Prostate Symptom Score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms: 4-year results of the CombAT study.
To examine, using post hoc analysis, the influence of baseline variables on changes in international prostate symptom score (IPSS), maximum urinary flow rate (Qmax ) and IPSS quality of life (QoL) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with either the α-blocker tamsulosin or the dual 5-alpha reductase inhibitor dutasteride, alone or in combination, as part of the 4-year Combination of Avodart and Tamsulosin (CombAT) study. CombAT was a 4-year, multicentre, randomized, double-blind, parallel-group study in 4844 men ≥50 years of age with a clinical diagnosis of BPH by medical history and physical examination, an IPSS ≥12 points, prostate volume (PV) ≥30 mL, total serum PSA level ≥1.5 ng/mL, and Qmax >5 mL/s and ≤15 mL/s with a minimum voided volume ≥125 mL. Eligible subjects were randomized to receive oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. Baseline variable subgroups analysed were as follows: PV (30 to <40; 40 to <60; 60 to <80; ≥80 mL), PSA level (1.5 to <2.5; 2.5 to <4; ≥4 ng/mL), age (median: <66, ≥66 years), IPSS (median: <16, ≥16; IPSS thresholds, <20, ≥20), IPSS QoL score (question 8, Q8) (median: <4, ≥4), Qmax (median: <10.4, ≥10.4 mL/s), BPH impact index (BII) (median: <5, ≥5) and body mass index (BMI, median: <26.8, ≥26.8 kg/m(2) ). Within each baseline variable subgroup, changes in IPSS, Qmax and IPSS QoL Q8 from baseline were evaluated using a generalized linear model with effects for baseline IPSS, Qmax or IPSS QoL Q8 and treatment group at each post-baseline assessment up to and including the month 48 visit using a last observation carried forward approach. The treatment comparisons of combination therapy vs dutasteride and combination therapy vs tamsulosin were performed from the general linear model with statistical significance defined as P ≤ 0.01. Combination therapy resulted in a significantly greater improvement from baseline IPSS at 48 months vs tamsulosin monotherapy across all baseline subgroups. The benefit of combination therapy over dutasteride was confined to groups with lower baseline PV (<60 mL) and PSA (<4 ng/mL). In groups with baseline PV ≥60 mL and PSA ≥4 ng/mL, dutasteride and combination therapy show similar improvements in symptoms. Combination therapy resulted in significantly improved Qmax compared with tamsulosin but not dutasteride monotherapy. Qmax improvement appeared to increase with PV and PSA level in combination therapy subjects. The proportion of subjects with an IPSS QoL ≤2 (at least mostly satisfied) at 48 months was significantly higher with combination therapy than with dutasteride for subgroups with PV 40-60 mL and PSA level <4 ng/mL and than with tamsulosin for all PSA subgroups and PV subgroups ≥40 mL. CombAT data support the use of long-term combination therapy with dutasteride and tamsulosin in patients considered at risk for progression of BPH, as determined by high PV (≥30 mL) and high PSA (≥1.5 ng/mL). Combination therapy, dutasteride monotherapy and tamsulosin monotherapy all improved Qmax , but to different extents (combination therapy > dutasteride >> tamsulosin), suggesting that dutasteride contributes most to the Qmax benefit in combination therapy. Combination therapy provided consistent improvement over tamsulosin in LUTS across all analysed baseline variables at 48 months. Compared with dutasteride, the superiority of combination therapy at 48 months was shown in patients with PV <60 mL or PSA <4 ng/mL.


Interpersonal closeness and morality predict feelings of being moved.
The emotion commonly labeled in English as being moved or touched is widely experienced but only tacitly defined, and has received little systematic attention. Based on a review of conceptualizations from various disciplines, we hypothesize that events appraised as an increase in interpersonal closeness, or as moral acts, when sufficiently intense, elicit a positive emotion typically labeled "being moved," and characterized by tears, goosebumps, and a feeling of warmth in the chest. We predicted this to be true for events a person participates in, as well as for events they observe. In Study 1, we elicited reports of recent episodes of weeping evoked by something positive, and also weeping because of something negative; we measured emotion terms, bodily sensations, and appraisals in a U.S. We discovered that events of positive tears, rather than negative tears, were associated with self-reported being moved or touched, with goosebumps, with feelings of chest warmth, and with the appraisals of increased closeness and moral acts. These appraisals mediated the difference in being moved between positive and negative events. We further found that appraisal patterns for personally experienced events were similar to the patterns for observed events. Finally, the 2 appraisals were more closely associated with being moved than with other emotion labels. This was corroborated in Study 2 in the U.S. and Norway, where we induced being moved, sadness, anxiety, and happiness through videos and measured these emotions, plus the appraisals and sensations from Study 1. (PsycINFO Database Record


Conjugated linoleic acid (CLA) prevents body fat accumulation and weight gain in an animal model.
Conjugated linoleic acid (CLA) has been shown to reduce body fat and increase lean body mass in mice, rats, and pigs. A recent human trial indicated that CLA may work more effectively if used for prevention of body fat deposition and weight gain. To test this hypothesis, we conducted 2 experiments using relatively old mice (older than 6 mo): experiment 1, supplementation of CLA during dietary restriction and experiment 2, supplementation during ad libitum feeding followed by restriction. In experiment 1, there were significant effects of diet restriction and CLA supplementation on body composition, while CLA decreased body fat content in ad libitum diet but not significantly during diet restriction. In experiment 2, CLA fed animals had body weights similar to restricted animals and CLA significantly reduced body fat (significantly lower than prior to and post restriction, or pair fed). This suggests that CLA exerted modulation of body fat independent of reduced food intake. Based on these results, we concluded that CLA may be more effective at protecting against fat mass regain following weight loss than as a weight loss treatment.


beta-Carotene supplementation results in an increased serum and colonic mucosal concentration of beta-carotene and a decrease in alpha-tocopherol concentration in patients with colonic neoplasia.
The aim of this study was to evaluate the colonic mucosal beta-carotene (BC) concentration following supplementation with BC and to determine if an increase in BC concentration influences vitamin E (alpha-tocopherol) status. The concentration of BC and alpha-tocopherol was assessed in serum and colonic tissue obtained from subjects with a history of colonic polyps or resected cancer (Dukes A, B1, or B2). Serum and mucosal biopsy samples were obtained prior to and following 3 months daily p.o. supplementation with 30 mg of BC or placebo. The concentration of BC was significantly increased in serum and colonic mucosa from both polyp and cancer subjects following supplementation as compared to presupplementation values and values from subjects receiving a placebo. The concentration of alpha-tocopherol in serum from cancer subjects was significantly decreased in samples obtained at the end of 3 months of BC supplementation as compared to placebo-matched controls. In BC-supplemented polyp subjects the tissue concentration of alpha-tocopherol was also significantly decreased relative to presupplementation values. The results indicate that BC supplementation does result in a significant accumulation of BC in the colonic mucosa but that the alpha-tocopherol concentration in both serum and colonic tissue may be compromised by an increased intake of BC. The mechanism for the decrease in alpha-tocopherol in conjunction with the increase in BC will require further study in order to develop strategies which will prevent vitamin E deficiency in BC-supplemented individuals.


Structural basis of tRNA modification with CO2 fixation and methylation by wybutosine synthesizing enzyme TYW4.
Wybutosine (yW), one of the most complicated modified nucleosides, is found in the anticodon loop of eukaryotic phenylalanine tRNA. This hypermodified nucleoside ensures correct codon recognition by stabilizing codon-anticodon pairings during the decoding process in the ribosome. TYW4 is an S-adenosylmethionine (SAM)-dependent enzyme that catalyzes the final step of yW biosynthesis, methylation and methoxycarbonylation. However, the structural basis for the catalytic mechanism by TYW4, and especially that for the methoxycarbonylation, have remained elusive. Here we report the apo and cofactor-bound crystal structures of yeast TYW4. The structures revealed that the C-terminal domain folds into a beta-propeller structure, forming part of the binding pocket for the target nucleoside. A comparison of the apo, SAM-bound, and S-adenosylhomocysteine-bound structures of TYW4 revealed a drastic structural change upon cofactor binding, which may sequester solvent from the catalytic site during the reaction and facilitate product release after the reaction. In conjunction with the functional analysis, our results suggest that TYW4 catalyzes both methylation and methoxycarbonylation at a single catalytic site, and in the latter reaction, the methoxycarbonyl group is formed through the fixation of carbon dioxide.


Gabapentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons.
Neuropathic pain following injury to peripheral sensory neurons is a common clinical problem and frequently difficult to treat. Gabapentin (GBP), a novel anticonvulsant, has significant analgesic effects in clinical neuropathic states and in relevant preclinical models, but its mechanism of action remains unclear. Because calcium currents play a significant role in neuronal function, this study was designed to assess the effect of GBP on the membrane voltage-activated inward calcium currents (I(Ca)) in dorsal root ganglia (DRG) primary afferent neurons of neuropathic versus control rats. Male rats were prepared according to the chronic constriction injury (CCI) model. The L4 and L5 dorsal root ganglia of those selected as CCI or control after appropriate behavioral testing were removed, and neurons were enzymatically dissociated. Fluorescent dye (DiI) placed at the injury site allowed identification of neurons projecting to that site. These were acutely studied using whole-cell, perforated (with beta-escin) patch-clamp recordings. Additionally, neurons from sham or nonoperated rats were also studied. Although there was marked variability among cells, concentrations of GBP ranging from 0.1 to 300 micromol/L decreased neuronal peak ICa in midsized neurons (30 to 40 microm) of both sham and neuropathic rats, in a fast, reversible, and concentration-dependent manner. Intergroup differences were not significant, however the concentration-response EC50s were 2.7 micromol/L for the sham and 16.5 micromol/L for the CCI neurons. The drug suppressed I(Ca) in nonoperated rats to a lesser degree, but changes did not differ significantly from the operated groups. Calcium currents in either small or large diameter neurons were also variably decreased by 10 micromol/L of GBP in sham and CCI neurons. Current inhibition by GBP was partly voltage dependent. GBP, at clinically relevant concentrations, results in significant reduction of I(Ca) in both sham and neuropathic neurons, while in nonoperated rats reduced I(Ca) to a smaller degree. Sensitivity to drug was not affected by neuropathy. This current inhibition is partly voltage dependent. Depression of I(Ca) may be partly related to the binding of the drug to the alpha(2)delta modulatory subunit of the voltage activated calcium channels (VACC). Analgesia may be due to diminished release of neurotransmitter by sensory neurons, a Ca(2+)-dependent process.


Ligand-independent activation of pituitary ER: dependence on PKA-stimulated pathways.
In pituitary and other target tissues, estrogen acts through ERs, which are ligand-activated nuclear transcription factors. ERs can also be activated by intracellular signaling pathways in a ligand-independent manner in some cells. Because the pituitary is the target of several cAMP-activating factors, we examined the ability of cAMP to activate ERs in the alphaT3 gonadotrope cell line. Forskolin, 8-bromo-cAMP, and pituitary adenylate cyclase-activating polypeptide all enhanced ER-dependent promoter activity, which was inhibited by antiestrogen or a pituitary-specific inhibitory ER variant. Activation was PKA dependent and was blocked by the PKA inhibitor H89 or cotransfection of the inhibitor PKI. Although cAMP activated MAPK in alphaT3 cells, inhibition of MAPK with the MEK inhibitor PD98059 did not prevent forskolin-induced ER activation. Similarly, epidermal growth factor did not stimulate ER activity, although it increased MAPK activation. Forskolin-induced activation of ER was enhanced by cotransfection of steroid receptor coactivator-1 and was inhibited by the repressor of ER action, suggesting that cAMP does not alter the normal interactions between ER and cofactors. In contrast to results with estrogen, cAMP treatment did not decrease ER protein levels. These results demonstrate that in the pituitary, cAMP activates ER in a ligand-independent manner exclusively through PKA.


GLOSSary: the GLobal Ocean 16S subunit web accessible resource.
Environmental metagenomics is a challenging approach that is exponentially spreading in the scientific community to investigate taxonomic diversity and possible functions of the biological components. The massive amount of sequence data produced, often endowed with rich environmental metadata, needs suitable computational tools to fully explore the embedded information. Bioinformatics plays a key role in providing methodologies to manage, process and mine molecular data, integrated with environmental metagenomics collections. One such relevant example is represented by the Tara Ocean Project. We considered the Tara 16S miTAGs released by the consortium, representing raw sequences from a shotgun metagenomics approach with similarities to 16S rRNA genes. We generated assembled 16S rDNA sequences, which were classified according to their lengths, the possible presence of chimeric reads, the putative taxonomic affiliation. The dataset was included in GLOSSary (the GLobal Ocean 16S Subunit web accessible resource), a bioinformatics platform to organize environmental metagenomics data. The aims of this work were: i) to present alternative computational approaches to manage challenging metagenomics data; ii) to set up user friendly web-based platforms to allow the integration of environmental metagenomics sequences and of the associated metadata; iii) to implement an appropriate bioinformatics platform supporting the analysis of 16S rDNA sequences exploiting reference datasets, such as the SILVA database. We organized the data in a next-generation NoSQL "schema-less" database, allowing flexible organization of large amounts of data and supporting native geospatial queries. A web interface was developed to permit an interactive exploration and a visual geographical localization of the data, either raw miTAG reads or 16S contigs, from our processing pipeline. Information on unassembled sequences is also available. The taxonomic affiliations of contigs and miTAGs, and the spatial distribution of the sampling sites and their associated sequence libraries, as they are contained in the Tara metadata, can be explored by a query interface, which allows both textual and visual investigations. In addition, all the sequence data were made available for a dedicated BLAST-based web application alongside the SILVA collection. GLOSSary provides an expandable bioinformatics environment, able to support the scientific community in current and forthcoming environmental metagenomics analyses.


Global control regions and regulatory landscapes in vertebrate development and evolution.
During the course of evolution, many genes that control the development of metazoan body plans were co-opted to exert novel functions, along with the emergence or modification of structures. Gene amplification and/or changes in the cis-regulatory modules responsible for the transcriptional activity of these genes have certainly contributed in a major way to evolution of gene functions. In some cases, these processes led to the formation of groups of adjacent genes that appear to be controlled by both global and shared mechanisms.


Surgical reconstruction of the musculocutaneous nerve in traumatic brachial plexus injuries.
Over the last 16 years, 345 surgical reconstructions of the brachial plexus were performed using nerve grafting or neurotization techniques in the Neurosurgical Department at the Nordstadt Hospital, Hannover, Germany. Sixty-five patients underwent graft placement between the C-5 and C-6 root and the musculocutaneous nerve to restore the flexion of the arm. A retrospective study was conducted, including statistical evaluation of the following pre- and intraoperative parameters in 54 patients: 1) time interval between injury and surgery; 2) choice of the donor nerve (C-5 or C-6 root); and 3) length of the grafts used for repairs between the C-5 or C-6 root and the musculocutaneous nerve. The postoperative follow-up interval ranged from 9 months to 14.6 years, with a mean +/- standard deviation of 4.4 +/- 3 years. Reinnervation of the biceps muscle was found in 61% of the patients. Comparison of the different preoperative time intervals (1-6 months, 7-12 months, and > 12 months) showed a significantly better outcome in those patients with a preoperative delay of less than 7 months (p < 0.05). Reinnervation of the musculocutaneous nerve was demonstrated in 76% of the patients who underwent surgery within the first 6 months postinjury, in 60% of the patients with a delay of between 6 and 12 months, and in only 25% of the patients who underwent surgery after 12 months. Comparison of the final outcome according to the root (C-5 or C-6) that was used for grafting the musculocutaneous nerve showed no statistical difference. Furthermore, statistical analysis (regression test) of the length of the grafts between the donor (C-5 or C-6 root) nerve and the musculocutaneous nerve displayed an inverse relationship between the graft length and the postoperative outcome. Together, these results provide additional information to enhance the functional outcome of brachial plexus surgery.


Site-specific phosphorylation of the human immunodeficiency virus type-1 Rev protein accelerates formation of an efficient RNA-binding conformation.
Phosphorylation is important in the regulation of many cellular processes, yet the precise role of protein phosphorylation for many RNA-binding protein substrates remains obscure. In this report, we demonstrate that phosphorylation of a recombinant human immunodeficiency virus type-1 Rev protein promotes rapid formation of an efficient RNA-binding state. The apparent dissociation constant for ligand binding is enhanced 7-fold for the protein following phosphorylation; however, phosphate addition leads to a 1. 6-fold decrease in RNA ligand-protein complex stability. RNA ligand binding stimulates slow formation of an equally competent binding state for the unphosphorylated protein, indicating that the addition of phosphate or ligand binding promotes a similar conformational change in Rev. Phosphorylation directly alters the conformation of Rev, as revealed by modification experiments that monitor the solvent accessibility of cysteines in the protein. These biochemical properties are attributed to the addition of phosphate at one of two serine residues (Ser-54 or Ser-56) that lie within the multimerization domain adjacent to the RNA-binding helix. Glutaraldehyde-mediated cross-linking experiments revealed that phosphorylation of Rev does not affect Rev multimerization activity. The Rev protein from the less pathogenic HIV-2 isolate lacks this phosphorylation site in the amino acid sequence; thus, the described biochemical properties of the phosphorylated protein may contribute to Rev activity and possibly to HIV-1 virulence during natural infection.


Extensively drug resistant tuberculosis (XDR-TB): A potential threat.
Emergence of extensively drug resistant tuberculosis (XDR-TB) has been reported by more than 55 countries. XDR-TB is considered as untreatable and highly fatal disease. In developing countries like India, number of cases of multi-drug resistant tuberculosis (MDR-TB) and XDR-TB are increasing. Emergence of resistance to Isoniazid and Rifampicin, the two most effective and well tolerated agents, coupled with resistance to second line agents pose limited treatment options for XDR-TB. The present minireview provides information about the seriousness of XDR-TB and the drugs available for its treatment. Although considered a fatal disorder, judicious use of combination of drugs, retaining their antimycobacterial activity, can improve the clinical outcome of XDR-TB. Only such an approach can provide some hope for the patients of XDR-TB.


The International Stroke Trial database.
We aimed to make individual patient data from the International Stroke Trial (IST), one of the largest randomised trials ever conducted in acute stroke, available for public use, to facilitate the planning of future trials and to permit additional secondary analyses. For each randomised patient, we have extracted data on the variables assessed at randomisation, at the early outcome point (14-days after randomisation or prior discharge) and at 6-months and provide them as an analysable database. The IST dataset includes data on 19 435 patients with acute stroke, with 99% complete follow-up. Over 26.4% patients were aged over 80 years at study entry. Background stroke care was limited and none of the patients received thrombolytic therapy. The IST dataset provides a source of primary data which could be used for planning further trials, for sample size calculations and for novel secondary analyses. Given the age distribution and nature of the background treatment given, the data may be of value in planning trials in older patients and in resource-poor settings.


Axial resolution enhancement for planar Airy beam light-sheet microscopy via the complementary beam subtraction method.
Airy beam light-sheet illumination can extend the field of view (FOV) of light-sheet fluorescence microscopy due to the unique propagation properties of non-diffraction and self-acceleration. However, the side lobes create undesirable out-of-focus background, leading to poor axial resolution and low image contrast. Here, we propose an Airy complementary beam subtraction (ACBS) method to improve the axial resolution while keeping the extended FOV. By scanning the optimized designed complementary beam that has two main lobes (TML), the generated complementary light-sheet has almost identical intensity distribution to that of the planar Airy light-sheet except for the central lobe. Subtraction of the two images acquired by double exposure respectively using the planar Airy light-sheet and the planar TML light-sheet can effectively suppress the influence of the out-of-focus background. The axial resolution improves from ∼4µm to 1.2 µm. The imaging performance was demonstrated by imaging specimens of aspergillus conidiophores and GFP labeled mouse brain section. The results show that the ACBS method enables the Airy beam light-sheet fluorescence microscopy to obtain better imaging quality.