Major life events and major chronic difficulties are differentially associated with history of major depressive episodes.
Major life events have been found to precede onsets of a 1st lifetime episode of depression more commonly than subsequent recurrences. Despite general empirical support for this finding, few data directly address how the role of major life events may change over successive recurrences. Further, little research has examined major chronic difficulties in relation to a 1st lifetime episode versus a recurrence of depression. The present study tested the associations between major life events and major difficulties in relation to lifetime history of depressive episodes in a sample of 96 individuals diagnosed with major depression. Using investigator-based measures of life stress, the authors found that, whereas major life events were associated with fewer lifetime episodes, major chronic difficulties were related to more prior episodes. These findings are discussed in terms of underlying mechanisms that may account for the changing role of major life stress over successive recurrences of depression.


Expression of Serum Sialic Acid, Early Antigen-IgA, and Viral Capsid Antigen-IgA in Nasopharynx Cancer Patients: The Diagnostic Implication of Combined Assays.
BACKGROUND Ebstein-Barr virus (EBV) plays a critical role in nasopharynx cancer, which can be effectively monitored by serum levels of early antigen antibody (EA-IgA) and viral capsid antigen antibody (VCA-IgA). This study explored the diagnostic value of combined assays of sialic acid (SA), EA-IgA, and VCA-IgA via the expressional assay. MATERIAL AND METHODS A total of 42 nasopharynx cancer patients and 42 benign rhinitis and healthy controls were recruited in this study. Serum EA-IgA and VCA-IgA were tested by enzyme-linked immunosorbent assay (ELISA) and enzymatic assay of serum SA. Specificity and sensitivity of those 3 assays were compared. The diagnostic value of each parameter was evaluated by ROC curves. RESULTS All 3 indexes (SA, EA-IgA and VCA-IgA) showed elevated serum levels in nasopharynx cancer patients when compared to those with rhinitis, who had higher levels than healthy individuals. Concentrations of these factors were also positively correlated with the TNM staging of cancer. The sensitivity and specificity were 30.95% and 83.33% (in SA), 57.14% and 95.24% (in EA-IgA), and 76.19% and 92.86% (in VCA-IgA), respectively. VCA-IgA had the highest sensitivity among all 3 indexes. The combined assay increased the diagnostic sensitivity to 92.86% without compromising specificity. CONCLUSIONS SA, EA-IgA, and VCA-IgA levels were significantly elevated in nasopharynx patients' serum. The combined assay may have clinical value in diagnosis and monitoring.


Immunological elimination of infected cells as the candidate mechanism for tumor protection in polyomavirus-infected mice.
The uniformly lethal development of mammary tumors in polyomavirus-infected adult female nude mice was prevented by adoptive cell transfer of polyomavirus-immune splenocytes or peritoneal cells. Transferred immune cells also lowered the growth rate of emerging tumors. The induction of other relatively less frequent tumors of the skin and bone was decreased as well. Using in situ hybridization of whole-body sections as well as hybridization of nucleic acids from the mammary glands, we show for the first time that transferred immune cells, but not normal cells, virtually eliminated virus signal in the whole mouse and in the mammary glands. Since infected and tumorous mammary glands produce very little infectious virus, it appears that a major mechanism mediating the prevention of polyomavirus oncogenesis involves the immunological elimination of nonproductively and persistently infected cells.


The specificity landscape of bacterial ribonuclease P.
Developing quantitative models of substrate specificity for RNA processing enzymes is a key step toward understanding their biology and guiding applications in biotechnology and biomedicine. Optimally, models to predict relative rate constants for alternative substrates should integrate an understanding of structures of the enzyme bound to 'fast' and 'slow' substrates, large datasets of rate constants for alternative substrates, and transcriptomic data identifying in vivo processing sites. Such data are either available or emerging for bacterial ribonucleoprotein RNase P a widespread and essential tRNA 5' processing endonuclease, thus making it a valuable model system for investigating principles of biological specificity. Indeed, the well-established structure and kinetics of bacterial RNase P enabled the development of high throughput measurements of rate constants for tRNA variants and provided the necessary framework for quantitative specificity modeling. Several studies document the importance of conformational changes in the precursor tRNA substrate as well as the RNA and protein subunits of bacterial RNase P during binding, although the functional roles and dynamics are still being resolved. Recently, results from cryo-EM studies of E. coli RNase P with alternative precursor tRNAs are revealing prospective mechanistic relationships between conformational changes and substrate specificity. Yet, extensive uncharted territory remains, including leveraging these advances for drug discovery, achieving a complete accounting of RNase P substrates, and understanding how the cellular context contributes to RNA processing specificity in vivo.


Nitric oxide charged catheters as a potential strategy for prevention of hospital acquired infections.
Catheter-Associated Hospital-Acquired Infections (HAI's) are caused by biofilm-forming bacteria. Using a novel approach, we generated anti-infective barrier on catheters by charging them with Nitric Oxide (NO), a naturally-produced gas molecule. NO is slowly released from the catheter upon contact with physiological fluids, and prevents bacterial colonization and biofilm formation onto catheter surfaces. The aim of the study was to assess the anti-infective properties of NO-charged catheters exposed to low concentration (up to 103 CFU/ml) of microbial cells in-vitro. We assessed NO-charged tracheal tubes using Pseudomonas aeruginosa, dialysis and biliary catheters using Escherichia coli, and urinary catheters using E. coli, Candida albicans or Enterococcus faecalis. Safety and tolerability of NO-charged urinary catheters were evaluated in a phase 1 clinical study in 12 patients. Six patients were catheterized with NO-charged catheters (NO-group), followed by 6 patients catheterized with regular control catheters (CT-group). Comparison of safety parameters between the study groups was performed. NO-charged tracheal, dialysis biliary and urinary catheters prevented P. aeruginosa, E. coli and C. albicans attachment and colonization onto their surfaces and eradicated corresponding planktonic microbial cells in the surrounding media after 24-48 hours, while E. faecalis colonization onto urinary catheters was reduced by 1 log compared to controls. All patients catheterized with an NO-charged urinary catheter successfully completed the study without experiencing NO-related AE's or serious AE's (SAE's). These data highlight the potential of NO-based technology as potential platform for preventing catheter-associated HAI's.


Participation Mediates the Relationship Between Postconcussive Symptoms and Suicidal Ideation Among Veterans.
Veterans with mild traumatic brain injury (mTBI) and associated symptoms are at risk for suicide. Postconcussive symptoms (PCS) may heighten risk for suicidal thoughts by limiting veterans' participation. To investigate whether participation mediates the relationship between PCS and suicidal ideation. Cross-sectional, exploratory design. Structural equation models were used to investigate whether participation mediated the relationship between PCS and suicidal ideation. Community. Veterans with mTBI (N = 145). The Ohio State University TBI Identification Method was used to establish mTBI diagnosis. We identified latent variables for PCS and participation using the Neurobehavioral Symptom Inventory and select domains of the Medical Outcomes Study Short Form-36, respectively. We used the Beck Scale for Suicide Ideation to measure the presence of suicidal ideation. Participation mediated the relationship between PCS and the presence of suicidal ideation (odds ratio [OR] = 1.09, p = .011). More severe PCS were associated with lesser participation (β = -.86, p < .001); greater participation was associated with lower odds of suicidal ideation (OR = 0.92, p = .007). PCS may heighten risk for suicidal thoughts among veterans by limiting successful participation, a primary target of occupational therapy intervention. Thus, the results suggest that occupational therapy practitioners can play a substantial role in suicide prevention services for veterans with mTBI. Preventive services could mitigate suicide risk among veterans with mTBI by enabling sustained engagement in meaningful and health-promoting activity (e.g., reasons for living) and targeting PCS. What This Article Adds: Researchers have proposed that occupational therapy practitioners can help prevent veteran suicide by supporting their engagement in meaningful, health-promoting activity and by targeting suicide risk factors within their scope of practice. To the best of our knowledge, this is the first study to offer empirical support for such proposed suicide prevention efforts. Although additional research is needed, these results are promising and highlight a distinct role for occupational therapy in suicide prevention.


Tooth loss and periodontal bone level in individuals of Jönköping County. A comparison between two adult populations living in the city and in the surrounding area.
Cross-sectional and longitudinal studies were performed in the community (in this paper changed to city) of Jönköping, Sweden, over a period of 20 years to follow changes in oral health and oral health behaviour. To widen our knowledge about dental health and dental care among the adult population, we expanded the study in 1993 to cover the whole county. The specific aim of the present study was to describe tooth loss (excluding third molars) and periodontal bone level in adult residents of Jönköping County and to compare these two parameters in adults living in the city of Jönköping with the same in adults living in the rest of the county. Random samples of individuals 30, 40, 50, 60, and 70 years old were selected. A total of 484 persons from the city and 1219 subjects from the rest of the county were examined. A total of 32 (7%) and 27 (2%) persons were completely edentulous in the examined populations from the city and from the rest of the county, respectively. A majority belonged to the older age groups, 60 and 70 years, with 17% of the subjects in the city being edentulous compared with 13% in the rest of the county. The mean number of missing teeth in subjects in the city versus subjects in the rest of the county was 0.75/0.95, 1.37/1.60, 3.34/2.43, 6.34/7.40, and 9.95/10.26 in 30-, 40-, 50-, 60-, and 70-year-olds, respectively. Of all the different tooth types, the average number of molars per person decreased the most with increasing age from an average of 7.79/7.83 (city/county) to 3.06/3.09 (city/county) for 30- and 70-year-olds, respectively. The proportion of subjects without molars was higher in the older age groups in both the city and the rest of the county with 4.8/10.7% and 15.6/22.0% of the 60- and 70-year-olds, respectively, lacking molars. In both populations, the mean periodontal bone level decreased with age. It was concluded that no important differences in tooth loss and periodontal health could be seen between the two populations. When organising dental care, dental health administrators could apply the findings from the population in the city to the entire county.


Identification and characterization of a locus (RTM1) that restricts long-distance movement of tobacco etch virus in Arabidopsis thaliana.
Screens of Arabidopsis thaliana for susceptibility to tobacco etch virus (TEV) revealed that each of 10 ecotypes were able to support genome replication and cell-to-cell movement in inoculated leaves. However, only four ecotypes, including C24 and La-er, supported complete infections in which TEV was able to replicate and move from cell to cell and long distances through the vasculature. The rates of cell-to-cell movement of a reporter-tagged TEV strain (TEV-GUS) in inoculated leaves of C24 and Columbia (Col-3) were similar, and infection foci continued to expand in both ecotypes through 10 days post-inoculation. No visible or microscopic hypersensitive or cell death responses were evident in inoculated leaves of Col-3 plants. Infection of neither C24 nor Col-3 plants with TEV-GUS resulted in induction of PR-1a gene expression, which is normally associated with active defence responses and systemic acquired resistance. The genetic basis for the restriction of long-distance movement of TEV-GUS in Columbia was investigated using C24 x Col-3 crosses and backcrosses and using La-er x Col-0 recombinant inbred lines. A dominant locus conditioning the restricted TEV infection phenotype was identified on chromosome 1 between markers ATEAT1 and NCC1 at approximately 14 cM in both genetic analyses. This locus was designated RTM1 (restricted TEV movement 1). It is proposed that RTM1 mediates a restriction of long-distance movement through a mechanism that differs substantially from those conditioned by the dominant resistance genes normally associated with gene-for-gene interactions.


Simultaneous alignment and surface regression using hybrid 2D-3D networks for 3D coherent layer segmentation of retinal OCT images with full and sparse annotations.
Layer segmentation is important to quantitative analysis of retinal optical coherence tomography (OCT). Recently, deep learning based methods have been developed to automate this task and yield remarkable performance. However, due to the large spatial gap and potential mismatch between the B-scans of an OCT volume, all of them were based on 2D segmentation of individual B-scans, which may lose the continuity and diagnostic information of the retinal layers in 3D space. Besides, most of these methods required dense annotation of the OCT volumes, which is labor-intensive and expertise-demanding. This work presents a novel framework based on hybrid 2D-3D convolutional neural networks (CNNs) to obtain continuous 3D retinal layer surfaces from OCT volumes, which works well with both full and sparse annotations. The 2D features of individual B-scans are extracted by an encoder consisting of 2D convolutions. These 2D features are then used to produce the alignment displacement vectors and layer segmentation by two 3D decoders coupled via a spatial transformer module. Two losses are proposed to utilize the retinal layers' natural property of being smooth for B-scan alignment and layer segmentation, respectively, and are the key to the semi-supervised learning with sparse annotation. The entire framework is trained end-to-end. To the best of our knowledge, this is the first work that attempts 3D retinal layer segmentation in volumetric OCT images based on CNNs. Experiments on a synthetic dataset and three public clinical datasets show that our framework can effectively align the B-scans for potential motion correction, and achieves superior performance to state-of-the-art 2D deep learning methods in terms of both layer segmentation accuracy and cross-B-scan 3D continuity in both fully and semi-supervised settings, thus offering more clinical values than previous works.


The effect of intestinal microflora on the enterohepatic circulation of mercapturic acid pathway metabolites.
The metabolism of four xenobiotics, pentachloromethylthiobenzene, 2-chloro-n-iso-propylacetanilide, 2-acetamido-4-(chloromethyl) thiazole and 2,4',5-trichlorobiphenyl, which are known to be metabolized via the mercapturic acid pathway, was examined in germfree and conventional rats. An essential role for the intestinal flora in the metabolism of the above compounds and in the production of certain metabolites was established. Mechanisms for the formation of these latter metabolites from the mercapturates are proposed. These mechanisms involve enterohepatic circulation and metabolism by the intestinal flora. The significance of xenobiotic metabolism by the intestinal microflora is discussed.


Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau.
Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 × 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.


Genital infections with Chlamydia trachomatis and Neisseria gonorrhoeae in Ghanaian women.
Women who attended the gynaecology clinic or were admitted to the postpartum ward of Korle Bu Hospital, Accra, Ghana were tested for infection with Chlamydia trachomatis and Neisseria gonorrhoeae. Eight (4.9%) of 162 gynaecological patients were infected with C trachomatis and five (3.1%) with N gonorrhoeae, and respective prevalences among 148 postpartum women were 7.7% (3/39) and 3.4% (5/148). Among 40 gynaecological patients who were not pregnant and whose principal complaint was of lower abdominal pain, 4 (10%) were infected with C trachomatis and none with N gonorrhoeae. Antibodies against serovars D, E, F, and G were common, and three typable isolates were serovar G. C trachomatis would appear to be more common than N gonorrhoeae in obstetric and gynaecological patients in Ghana.


De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.
To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.


Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases.
Over 90 000 people are expected to be diagnosed with melanoma in the United States this year. The development of brain metastases is particularly difficult to manage. Over the past few years, melanoma patients with multiple unresectable brain metastases for which stereotactic surgery might also not be a viable option have fortunately experienced a dramatic expansion in available management options given improvements made to targeted agents, immunotherapy, and radiotherapy. Whole-brain radiation therapy (WBRT) is a long-standing radiation technique that has become increasingly sophisticated. In this review, we summarize retrospective and prospective studies on individual advances in targeted agents, immunotherapy, and WBRT, highlighting important variables such as overall survival, intracranial progression-free survival, control and response rates, and toxicities. We also discuss the recent integration of these therapies into a multimodality approach, which has shown promise in the clinical setting although toxicities have not been insignificant. Finally, we describe ongoing prospective trials relevant to melanoma with brain metastases, and we conclude with our own thoughts on the optimal approach for these patients.


Acyclovir treatment of varicella in otherwise healthy adolescents. The Collaborative Acyclovir Varicella Study Group.
To determine whether orally administered acyclovir is of therapeutic benefit for varicella in otherwise healthy adolescents, and to compare the severity of the disease in adolescents with that in younger children. Multicenter, randomized, placebo-controlled, double-blind trial. Patients' homes and university hospital clinics. Sixty-eight adolescents between 13 and 18 years of age with varicella entered the study. Of the 62 adolescents with laboratory-confirmed varicella who were included in the final analysis, 31 received acyclovir and 31 received placebo. Placebo or an 800 mg acyclovir tablet was given orally four times daily for 5 days, beginning within 24 hours of onset of rash. Acyclovir recipients had significant reductions in times to cessation of new lesion formation (p less than 0.001), maximum number of lesions (p = 0.019), and defervescence (p = 0.045). Mean constitutional illness score was significantly reduced on day 4 (0.5 vs 1.5, p = 0.05), as was the mean number of residual hypopigmented lesions present on 28-day follow-up examination (22.7 vs 92.7, p = 0.018). Two complications, both bacterial superinfections, occurred in placebo recipients. Adverse experiences and varicella-zoster virus antibody titers measured 28 days after enrollment were similar in both treatment groups. Comparison of placebo recipients with children 2 to 12 years of age participating in a companion study indicated that varicella is more severe in adolescents: mean maximum total lesions (421 vs 347, p = 0.003), mean maximum constitutional illness score (3.1 vs 2.2, p = 0.032), and mean number of residual lesions (92.7 vs 33.2, p = 0.01) were all greater in the adolescent population. Oral acyclovir therapy is safe and effective for treatment of varicella in otherwise healthy adolescents; this may be an appropriate subgroup for treatment with antiviral drugs because the disease is more severe in them than in younger children.


Five-year experience with temporary pacemaker therapy in the coronary care unit.
The clinical course of 1,022 consecutive patients who received a temporary transvenous pacemaker in the coronary care unit during a 5-year period between January 1976 and January 1981 was reviewed. The route of pacemaker insertion was identified in 942 patients (92.2%) and included antecubital vein cutdown in 606 patients (59.3%), subclavian venipuncture in 177 patients (17.3%), right internal jugular venipuncture in 111 patients (10.9%), and femoral venipuncture in 48 patients (4.7%). Pacemaker-related complications occurred in 140 instances (13.7% morbidity), without associated mortality. The most common complication was the development of a new pericardial rub (54 patients, 5.3%). The right internal jugular approach was associated with the lowest complication rate. On the basis of these findings, it is our practice to insert temporary pacemakers via the right internal jugular or subclavian route.


[Membranous nephropathy associated with kidney amyloidosis].
15 kidney biopsies from 13 patients with a combination of membranous nephropathy and amyloidosis were studied. Membranous nephropathy is shown to precede the development of amyloidosis which possesses all the properties of the acquired one (AA-amyloid). Transformation of membranous nephropathy into amyloidosis is due to the deficiency of the immune system characteristic of both processes. This combination is not considered as a special type of amyloidosis but as a peculiar feature of membranous nephropathy.


Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial.
Gastroesophageal reflux disease (GERD) is a chronic, relapsing disease with symptoms that have negative effects on daily life. Two treatment options are long-term medication or surgery. To evaluate optimized esomeprazole therapy vs standardized laparoscopic antireflux surgery (LARS) in patients with GERD. The LOTUS trial, a 5-year exploratory randomized, open, parallel-group trial conducted in academic hospitals in 11 European countries between October 2001 and April 2009 among 554 patients with well-established chronic GERD who initially responded to acid suppression. A total of 372 patients (esomeprazole, n = 192; LARS, n = 180) completed 5-year follow-up. Interventions Two hundred sixty-six patients were randomly assigned to receive esomeprazole, 20 to 40 mg/d, allowing for dose adjustments; 288 were randomly assigned to undergo LARS, of whom 248 actually underwent the operation. Time to treatment failure (for LARS, defined as need for acid suppressive therapy; for esomeprazole, inadequate symptom control after dose adjustment), expressed as estimated remission rates and analyzed using the Kaplan-Meier method. Estimated remission rates at 5 years were 92% (95% confidence interval [CI], 89%-96%) in the esomeprazole group and 85% (95% CI, 81%-90%) in the LARS group (log-rank P = .048). The difference between groups was no longer statistically significant following best-case scenario modeling of the effects of study dropout. The prevalence and severity of symptoms at 5 years in the esomeprazole and LARS groups, respectively, were 16% and 8% for heartburn (P = .14), 13% and 2% for acid regurgitation (P < .001), 5% and 11% for dysphagia (P < .001), 28% and 40% for bloating (P < .001), and 40% and 57% for flatulence (P < .001). Mortality during the study was low (4 deaths in the esomeprazole group and 1 death in the LARS group) and not attributed to treatment, and the percentages of patients reporting serious adverse events were similar in the esomeprazole group (24.1%) and in the LARS group (28.6%). This multicenter clinical trial demonstrated that with contemporary antireflux therapy for GERD, either by drug-induced acid suppression with esomeprazole or by LARS, most patients achieve and remain in remission at 5 years. clinicaltrials.gov Identifier: NCT00251927.


Eukaryotic genomes from a global metagenomic data set illuminate trophic modes and biogeography of ocean plankton.
Metagenomics is a powerful method for interpreting the ecological roles and physiological capabilities of mixed microbial communities. Yet, many tools for processing metagenomic data are neither designed to consider eukaryotes nor are they built for an increasing amount of sequence data. EukHeist is an automated pipeline to retrieve eukaryotic and prokaryotic metagenome-assembled genomes (MAGs) from large-scale metagenomic sequence data sets. We developed the EukHeist workflow to specifically process large amounts of both metagenomic and/or metatranscriptomic sequence data in an automated and reproducible fashion. Here, we applied EukHeist to the large-size fraction data (0.8-2,000 µm) from Tara Oceans to recover both eukaryotic and prokaryotic MAGs, which we refer to as TOPAZ (Tara Oceans Particle-Associated MAGs). The TOPAZ MAGs consisted of >900 environmentally relevant eukaryotic MAGs and >4,000 bacterial and archaeal MAGs. The bacterial and archaeal TOPAZ MAGs expand upon the phylogenetic diversity of likely particle- and host-associated taxa. We use these MAGs to demonstrate an approach to infer the putative trophic mode of the recovered eukaryotic MAGs. We also identify ecological cohorts of co-occurring MAGs, which are driven by specific environmental factors and putative host-microbe associations. These data together add to a number of growing resources of environmentally relevant eukaryotic genomic information. Complementary and expanded databases of MAGs, such as those provided through scalable pipelines like EukHeist, stand to advance our understanding of eukaryotic diversity through increased coverage of genomic representatives across the tree of life.IMPORTANCESingle-celled eukaryotes play ecologically significant roles in the marine environment, yet fundamental questions about their biodiversity, ecological function, and interactions remain. Environmental sequencing enables researchers to document naturally occurring protistan communities, without culturing bias, yet metagenomic and metatranscriptomic sequencing approaches cannot separate individual species from communities. To more completely capture the genomic content of mixed protistan populations, we can create bins of sequences that represent the same organism (metagenome-assembled genomes [MAGs]). We developed the EukHeist pipeline, which automates the binning of population-level eukaryotic and prokaryotic genomes from metagenomic reads. We show exciting insight into what protistan communities are present and their trophic roles in the ocean. Scalable computational tools, like EukHeist, may accelerate the identification of meaningful genetic signatures from large data sets and complement researchers' efforts to leverage MAG databases for addressing ecological questions, resolving evolutionary relationships, and discovering potentially novel biodiversity.


Cancer in the older woman: diagnosis and prevention.
Progestogens should be added to estrogen replacement therapy, not only to prevent endometrial cancer in women with a uterus, but also to reduce the risk of breast cancer in some women. Smoking should be discouraged to reduce the risk for both lung cancer and heart disease. Recommendations should be made to increase fiber intake to lessen the risk for carcinoma of the colon. Reducing fat intake also decreases risk for colon cancer, as well as carcinoma of the breast. Postmenopausal bleeding must be investigated for early diagnosis of endometrial cancer and, when endometrial hyperplasia is the finding, it should be treated with progestogens to prevent adenocarcinoma. The progestogen challenge test is recommended for all women with a uterus, and if bleeding occurs, the progestogen should be continued for 13 days each month. Use of mammograms and other diagnostic modalities should be increased to make the earliest possible diagnosis of breast cancer.


Multiple primary pulmonary malignancy.
The diagnosis of multiple primary pulmonary malignancy can be difficult; and the criteria for such tumours may arise simultaneously or consecutively, be unilateral or bilateral and have similar or different histology. Resection remains the treatment of choice and, despite the gloomy outlook, no patient should be assumed inoperable. To achieve early diagnosis of a consecutively occurring tumour, regular and prolonged follow up of every patient who has had a first tumour resected is recommended.


A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel.
This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors. Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m(2) paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations. Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma. The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m(2) paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.


Gating information by two-state membrane potential fluctuations.
Two-state voltage fluctuations between a hyperpolarized down-state and a depolarized up-state have been observed experimentally in a wide variety of neurons across brain regions. Using a biophysical model, we show that synaptic input by NMDA receptors can cause such membrane potential fluctuations. In this model, when a neuron is driven by two input pathways with different AMPA/NMDA receptor content, the NMDA-rich input causes up-state transitions, whereas the AMPA-rich input generates spikes only in the up-state. Therefore the NMDA-rich pathway can gate input from an AMPA pathway in an all-or-none fashion by switching between different membrane potential states. Furthermore, once in the up-state, the NMDA-rich pathway multiplicatively increases the gain of a neuron responding to AMPA-rich input. This proposed mechanism for two-state fluctuations directly suggests specific computations, such as gating and gain modulation based on the distinct receptor composition of different neuronal pathways. The dynamic gating of input by up- and down-states may be an elementary operation for the selective routing of signals in neural circuits, which may explain the ubiquity of two-state fluctuations across brain regions.


Shear-induced integrin signaling in platelet phosphatidylserine exposure, microvesicle release, and coagulation.
It is currently unclear why agonist-stimulated platelets require shear force to efficiently externalize the procoagulant phospholipid phosphatidylserine (PS) and release PS-exposed microvesicles (MVs). We reveal that integrin outside-in signaling is an important mechanism for this requirement. PS exposure and MV release were inhibited in β3-/- platelets or by integrin antagonists. The impaired MV release and PS exposure in β3-/- platelets were rescued by expression of wild-type β3 but not a Gα13 binding-deficient β3 mutant (E733EE to AAA), which blocks outside-in signaling but not ligand binding. Inhibition of Gα13 or Src also diminished agonist/shear-dependent PS exposure and MV release, further indicating a role for integrin outside-in signaling. PS exposure in activated platelets was induced by application of pulling force via an integrin ligand, which was abolished by inhibiting Gα13-integrin interaction, suggesting that Gα13-dependent transmission of mechanical signals by integrins induces PS exposure. Inhibition of Gα13 delayed coagulation in vitro. Furthermore, inhibition or platelet-specific knockout of Gα13 diminished laser-induced intravascular fibrin formation in arterioles in vivo. Thus, β3 integrins serve as a shear sensor activating the Gα13-dependent outside-in signaling pathway to facilitate platelet procoagulant function. Pharmacological targeting of Gα13-integrin interaction prevents occlusive thrombosis in vivo by inhibiting both coagulation and platelet thrombus formation.


A novel nonribose agonist, LUF5834, engages residues that are distinct from those of adenosine-like ligands to activate the adenosine A(2a) receptor.
The recent publication of both the antagonist- and agonist-bound structures of the adenosine A(2A) receptor have revealed much about how a ligand may bind to a receptor and cause the conformational changes associated with agonist-mediated activation. In particular, the agonist-bound structure revealed key interactions between the ribose group of adenosine-derived agonists and amino acids in the receptor binding pocket that lead to receptor activation. However, agonists without a ribose group also exist, and we wondered whether such compounds occupy the same agonist binding site. Therefore we used a mutagenesis approach in this study to investigate the mode of binding of 2-amino-4-(4-hydroxyphenyl)- 6-(1H-imidazol-2-ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (LUF5834), a potent partial agonist without a ribose moiety, compared with the adenosine-derived reference agonist 2-[p-(2-carboxyethyl)phenyl-ethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). Mutation of the orthosteric residue Phe168 to alanine abrogated the function of both agonists. However, mutation to alanine of residues Thr88 and Ser277 shown by the crystal structures to interact with the ribose group of adenosine-like ligands had no effect on the potency of LUF5834. Furthermore, alanine mutation of Asn253, which makes a hydrogen-bonding interaction with the exocyclic nitrogen of the adenine ring, had minimal effect on LUF5834 affinity but removed agonist activity of this ligand. Mutation of other residues, such as the highly conserved Trp246 or Glu13, had significant deleterious effects on the function of CGS21680 but little effect on LUF5834. In summary, our findings suggest that this class of agonist interacts with distinct residues to activate the receptor compared with classic adenosine derived agonists.


[Predictors of bacterial excretion in patients with infiltrative pulmonary tuberculosis].
An association of bacterial excretion with the magnitude of the X-ray and clinical symptoms of infiltrative pulmonary tuberculosis, with the intensity of concomitant anxiety-depression disorders and the results of complex laboratory peripheral blood tests was studied in 100 patients with this condition. The fact that M. tuberculosis was present in the sputum was shown to be linked to the significant increase in the size of tuberculous infiltrates, the extent of decay in the latter, their connection with the root of the lung, the spread of excretion foci, and the intensity of cough and bloody expectoration. The similar trend was demonstrated in the degree of situational anxiety, depressive indecision, and pessimism, as well as in the values of leukocytosis and erythrocyte sedimentation rate. The predictive informative value of a set of findings is illustrated by the discriminant function equation that allows the correct prediction of bacterial excretion in 76.8% of cases.


Oral Health Knowledge and Behaviors among Adolescents with Type 1 Diabetes.
Early onset and more advanced periodontal disease has been reported for children with diabetes. We surveyed oral health knowledge, attitudes, and behaviors among adolescents with diabetes in order to inform potential intervention strategies. Study subjects were youth (ages 12-19 years) with type 1 diabetes (N = 90) participating in a cohort study investigating determinants of periodontal disease at a regional pediatric diabetes specialty clinic. Over 90% of the youth had been instructed on how to brush and floss and had preventive dental care in the past year. However, 44% knew that periodontal disease is associated with diabetes and 32% knew that it can start in childhood with bleeding gums. Despite being at high risk for developing periodontal disease, the mean toothbrushing frequency was once per day and 42% did not floss. Significant opportunity exists for improving periodontal disease knowledge and adoption of preventive oral hygiene behaviors in adolescents with diabetes.


Complete plastome sequences from Glycine syndetika and six additional perennial wild relatives of soybean.
Organelle sequences have a long history of utility in phylogenetic analyses. Chloroplast sequences when combined with nuclear data can help resolve relationships among flowering plant genera, and within genera incongruence can point to reticulate evolution. Plastome sequences are becoming plentiful because they are increasingly easier to obtain. Complete plastome sequences allow us to detect rare rearrangements and test the tempo of sequence evolution. Chloroplast sequences are generally considered a nuisance to be kept to a minimum in bacterial artificial chromosome libraries. Here, we sequenced two bacterial artificial chromosomes per species to generate complete plastome sequences from seven species. The plastome sequences from Glycine syndetika and six other perennial Glycine species are similar in arrangement and gene content to the previously published soybean plastome. Repetitive sequences were detected in high frequencies as in soybean, but further analysis showed that repeat sequence numbers are inflated. Previous chloroplast-based phylogenetic trees for perennial Glycine were incongruent with nuclear gene-based phylogenetic trees. We tested whether the hypothesis of introgression was supported by the complete plastomes. Alignment of complete plastome sequences and Bayesian analysis allowed us to date putative hybridization events supporting the hypothesis of introgression and chloroplast "capture."


CORESS Feedback: Cases from the Confidential Reporting System for Surgery.
CORESS is an independent charity, supported by the AXA Health, the MDU and the WPA Benevolent Foundation We are grateful to those who have provided the material for these reports. The online reporting form is available on the website (www.coress.org.uk), which also includes previous Feedback reports. Published cases will be acknowledged by a Certificate of Contribution, which may be included in the contributor's record of continuing professional development or may form part of appraisal or annual review of competence progression (ARCP) portfolio documentation. Trainee contributions are particularly welcome.


Synthesis and biological evaluation of (-)-dictyostatin and stereoisomers.
Total syntheses of (-)-dictyostatin, 6,16-bis-epi-dictyostatin, 6,14,19-tris-epi-dictyostatin and a number of other isomers and analogs are reported. Three main fragments-top, middle and bottom-were first assembled and then joined by olefination or anionic addition reactions. After appending the two dienes at either end of the molecule, macrolactonization and deprotection completed the syntheses. The work proves both the relative and absolute configurations of (-)-dictyostatin. The compounds were evaluated by cell-based measurements of increased microtubule mass and antiproliferative activity, and in vitro tubulin polymerization assays as well as competitive assays with paclitaxel for its binding site on microtubules. These assays showed dictyostatin to be the most potent of the agents and further showed that the structural alterations caused from 20- to >1000-fold decreases in activity.


Performance of modeling and balancing approach methods when using weights to estimate treatment effects in observational time-to-event settings.
In observational studies weighting techniques are often used to overcome bias due to confounding. Modeling approaches, such as inverse propensity score weighting, are popular, but often rely on the correct specification of a parametric model wherein neither balance nor stability are targeted. More recently, balancing approach methods that directly target covariate imbalances have been proposed, and these allow the researcher to explicitly set the desired balance constraints. In this study, we evaluate the finite sample properties of different modeling and balancing approach methods, when estimating the marginal hazard ratio, through Monte Carlo simulations. The use of the different methods is also illustrated by analyzing data from the Swedish stroke register to estimate the effect of prescribing oral anticoagulants on time to recurrent stroke or death in stroke patients with atrial fibrillation. In simulated scenarios with good overlap and low or no model misspecification the balancing approach methods performed similarly to the modeling approach methods. In scenarios with bad overlap and model misspecification, the modeling approach method incorporating variable selection performed better than the other methods. The results indicate that it is valuable to use methods that target covariate balance when estimating marginal hazard ratios, but this does not in itself guarantee good performance in situations with, e.g., poor overlap, high censoring, or misspecified models/balance constraints.


Assessment of the groundwater salinity monitoring network of the Tehran region: application of the discrete entropy theory.
In this paper, a new entropy-based approach is developed for assessing the location of salinity monitoring stations in the Tehran Aquifer, Tehran, Iran. To find the optimal distance among stations, the measure of Transinformation in the Entropy Theory is used. Then a Transinformation-Distance (T-D) curve is developed and used in a multi-objective GA-based optimization model, which provides the best locations for monitoring stations. Because of the large area of the Tehran aquifer and significant spatial variations of the Electrical Conductivity (EC) of the groundwater in the study area, the C-means clustering method is used to classify the study area to some homogenous zones. The optimization model is applied to each zone to find the optimal location of monitoring stations. The results show the applicability and the efficiency of the model in assessing the groundwater monitoring systems.


Dynamic modeling of environmental risk associated with drilling discharges to marine sediments.
Drilling discharges are complex mixtures of base-fluids, chemicals and particulates, and may, after discharge to the marine environment, result in adverse effects on benthic communities. A numerical model was developed to estimate the fate of drilling discharges in the marine environment, and associated environmental risks. Environmental risk from deposited drilling waste in marine sediments is generally caused by four types of stressors: oxygen depletion, toxicity, burial and change of grain size. In order to properly model these stressors, natural burial, biodegradation and bioturbation processes were also included. Diagenetic equations provide the basis for quantifying environmental risk. These equations are solved numerically by an implicit-central differencing scheme. The sediment model described here is, together with a fate and risk model focusing on the water column, implemented in the DREAM and OSCAR models, both available within the Marine Environmental Modeling Workbench (MEMW) at SINTEF in Trondheim, Norway.


Attachment styles as predictors of empathy in nursing students.
Previous studies have traced a relationship between the attachment styles of nurses working as in healthcare teams and their empathy which is an essential characteristic required of people concerned with managing relationships, supporting social events, and improving the of nurse-patient relationships. Since determining the effective variables in the quality of nurse-patient relationships in clinical settings is of paramount importance, current investigation is an effort to examine the relationship between attachment styles and empathy in nursing students. 260 university students (male = 130 and female = 130) were chosen as the sample of the study based upon specific inclusion criteria. All participants completed the Attachment Style Questionnaire (ASQ) and the Interpersonal Reactivity Index (IRI). Data was collected and analyzed using Pearson correlation coefficient and regression analysis with SPSS (v.18). The results showed that secure and insecure attachment styles have significant positive and negative correlation with empathy respectively. Based on the results of regression analysis, it was shown that secure attachment style is predicting 53% of the variance empathy variable, whereas insecure attachment styles are explaining up to 76% of the variance empathy variable collectively. The increase of attention to instructions that focus on empathetic relationships with patients and that are based upon the secure attachment style can result in positive changes in the area of nurse-patient relations and in increasing attention to medical ethics. Findings are consistent with prediction derived from attachment theory and add to our understanding of relationship between attachment styles with empathy in nursing students. The meaning and limitations of this study and suggestions for further research are also discussed.


Peptide Tethering: Pocket-Directed Fragment Screening for Peptidomimetic Inhibitor Discovery.
Constrained peptides have proven to be a rich source of ligands for protein surfaces, but are often limited in their binding potency. Deployment of nonnatural side chains that access unoccupied crevices on the receptor surface offers a potential avenue to enhance binding affinity. We recently described a computational approach to create topographic maps of protein surfaces to guide the design of nonnatural side chains [J. Am. Chem. Soc. 2017, 139, 15560]. The computational method, AlphaSpace, was used to predict peptide ligands for the KIX domain of the p300/CBP coactivator. KIX has been the subject of numerous ligand discovery strategies, but potent inhibitors of its interaction with transcription factors remain difficult to access. Although the computational approach provided a significant enhancement in the binding affinity of the peptide, fine-tuning of nonnatural side chains required an experimental screening method. Here we implement a peptide-tethering strategy to screen fragments as nonnatural side chains on conformationally defined peptides. The combined computational-experimental approach offers a general framework for optimizing peptidomimetics as inhibitors of protein-protein interactions.


The effect of protein structural conformation on nanoparticle molecular imprinting of ribonuclease A using miniemulsion polymerization.
One of the major difficulties faced in the molecular imprinting of proteins is the inherently fragile and flexible nature of the protein template which makes it incompatible with most polymerization systems. Miniemulsion polymerization is a possible approach for preparing molecularly imprinted nanoparticles, and in this study, the method of initiation, the high-shear homogenization, and the surfactant used for the polymerization reaction had been considered as possible factors that can denature the template protein, ribonuclease A (RNase A). The conformation of the protein in a miniemulsion was studied using circular dichroism (CD). It was found that redox initiation was more suitable for protein imprinting and that the addition of poly(vinyl alcohol) (PVA) as a co-surfactant had proved to be effective in preserving the template protein structural integrity. On the basis of the results of the study, polymeric nanoparticles imprinted with RNase A were prepared via miniemulsion polymerization using methyl methacrylate (MMA) and ethylene glycol dimethacrylate (EGDMA) as the functional and cross-linker monomers, respectively, with the conditions of the polymerization system optimized to best preserve the integrity of the protein template. In the subsequent investigation for the recognition properties of the prepared nanoparticles through batch and competitive rebinding tests, the imprinted nanoparticles prepared through the conventional (nonoptimized) miniemulsion polymerization lacked the target specificity as displayed by those prepared under the optimized conditions. This illustrated the importance of protein structural integrity in protein imprinting.


Urethral recurrence following neobladder in bladder cancer patients.
Risk factors of urethral recurrence after neobladder in bladder cancer patients were studied. Between 1977 and 2001, 73 patients (male 58, female 15) underwent neobladder as a treatment for bladder cancer. The observation time after cystectomy ranged from 2 to 254 months (median 60.5). Ten (17.2%) of 58 male patients had urethral recurrence and of the 10, 8 patients had multiple bladder cancers including bladder neck. Urethral recurrence was found by macrohematuria, follow-up cystourethroscopy, and inguinal lymph node swelling. Only one who complained of macrohematuria had positive urinary cytology. Of 58 male patients, 5 underwent total nephroureterectomy for renal pelvic or ureteral cancer before radical cystectomy, and 3 of the 5 had urethral recurrence. Two of 10 patients with urethral recurrence died with cancer, and they had renal pelvic or ureteral cancer. The five-year cause specific survival was 83% for patients with urethral recurrence, and 79% for those without urethral recurrence, respectively. Urethral recurrence did not have a significant effect on survival. The patients with multiple bladder cancers including bladder neck, and renal pelvic or ureteral cancer before radical cystectomy, have high risks for urethral recurrence. Urinary cytology has limited value for the detection of urethral recurrence.


[Accessory nuclei of the primary erythroid cells of chick embryos: the kinetics of their formation and the relationship to the synthesis of extra DNA].
Kinetics of formation of accessory nuclei (AN), synthesis and accumulation of DNA in AN and main nuclei (MN) of the chick embryo primary erythroid cells (PEC) (2-7 days of development) and interdependence of these processes were studied using cytomorphology, autoradiography and differential cytophotometry. The earlier data on the existence of AN in primary erythrocytes (EC) were confirmed, and it was shown for the first time that the formation of AN accompanied the primary erythropoiesis from the very beginning of the proerythroblast (PEB) stage. The number of AN-bearing cells increases as erythropoiesis proceeds to reach the value of 50% PEC. The AN are formed in diploid, tetraploid, as well as in binuclear cells. The DNA content in AN may vary from 1-2 to 80% of the 2c value and has a tendency of increasing during erythropoiesis, while that in MN is always 2c or multiple thereof. Formed at early stages of PEC proliferation as pieces of segregated Feulgen-positive material, the AN are preserved during mitosis, taking no part in mitotic rearrangements of the chromosomes and being eventually involved in one of the daughter cells. Clusters of metaphase, anaphase and telophase chromosomes contain strictly 4c or 2c + 2c DNA. DNA synthesis in MN and AN may proceed in parallel and independently. It is frequently observed in AN of terminally differentiated PEC-reticulocytes (RC) and EC, whose MN no longer incorporate 3H-thymidine.(ABSTRACT TRUNCATED AT 250 WORDS)


Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem.
Hereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.


Costs of flexible sigmoidoscopy screening for colorectal cancer in the United Kingdom.
Colorectal cancer is one of the most commonly occurring cancers in industrialized countries, yet appears to be amenable to screening. Amongst the many possible protocols is once-only screening by means of flexible sigmoidoscopy. This protocol is currently being investigated in a UK multicenter trial and the study provides estimates of the expected resource costs. The direct health care costs of sigmoidoscopy and of all subsequent procedures were estimated from an audit of resource use of approximately 40,000 patients at thirteen centers. Patient-borne costs were estimated from the results of surveys conducted at twelve of these centers. The health service costs of a flexible sigmoidoscopy was estimated at pounds 56. The total costs of screening (including private costs) averaged pounds 82 per person screened, although costs varied by center. The total health service costs of screening and subsequent management averaged approximately pounds 91 per person screened, again with variations between centers. Even within a strict trial protocol, intercenter variation in costs can be detected, ascribable to variability in local management practices, local yield, and local patient-borne costs. Other recent estimates of flexible sigmoidoscopy costs vary widely. As these costs form the basis of technology assessment simulation models which, in turn, inform policy obtaining realistic cost estimates within the appropriate health care setting is of paramount importance.


Blood Flow Into Basilar Tip Aneurysms: A Predictor for Recanalization After Coil Embolization.
Hemodynamic forces may play a role in the recanalization of coiled aneurysms. The purpose of this study was to investigate the influence of presurgical hemodynamics on the efficacy of coil embolization for basilar tip aneurysms. We identified 82 patients who underwent endovascular coil embolization for basilar tip aneurysms with a follow-up of >1 year. Presurgical hemodynamics were investigated using computational fluid dynamics with 3-dimensional data derived from rotational angiography. During postprocessing, we quantified the rate of net flow entering the aneurysm through its neck and calculated the proportion of the aneurysmal inflow rate to the basilar artery flow rate. In addition, we investigated the correlation between the basilar bifurcation configuration and the hemodynamics. Twenty-five of the 82 patients were excluded because of difficult vascular geometry reconstruction. Among the 57 examined patients, angiographic recanalization was observed in 19 patients (33.3%). The proportion of the aneurysmal inflow rate to the basilar artery flow rate and a coil packing density <30% were independent and significant predictors for the recanalization of coiled aneurysms. Additional investigation revealed that a small branch angle formed by the basilar artery and the posterior cerebral artery increased blood flow into the aneurysm. The proportion of the aneurysmal inflow rate to the basilar artery flow rate, influenced by the basilar bifurcation configuration, was an independent and significant predictor for recanalization after coil embolization in basilar tip aneurysms.


[Occupational allergies to cellulases].
In the 1960s an increasing number of occupational allergies in the detergent industry against the proteolytic enzyme Subtilisin were observed. In this context the high sensitization potential of enzyme dusts attracted attention. The present evaluation of literature data confirms that this is also true for cellulases. These enzymes--mostly of fungal origin--are frequently used in biotechnology. Several cases of specific airway sensitization caused by cellulases are verified by a number of studies. As symptoms, results of skin prick tests, detection of specific IgE-antibodies and results of specific bronchoprovocation tests are consistent, an immunologic mechanism seems to be confirmed.


Thymidine salvage in Pseudomonas stutzeri and Pseudomonas aeruginosa provided by heterologous expression of Escherichia coli thymidine kinase gene.
Unlike enteric bacteria, Pseudomonas spp. generally lack thymidine phosphorylase and thymidine kinase activities, thus preventing their utilization of exogenous thymine or thymidine and precluding specific radioactive labeling of their DNA in vivo. To overcome this limitation, a DNA fragment encoding thymidine kinase (EC 18.104.22.168) from Escherichia coli was cloned into pKT230, a small, broad-host-range plasmid derived from plasmid RSF1010. From transformed E. coli colonies, the recombinant plasmid bearing the thymidine kinase gene was conjugally transferred to Pseudomonas stutzeri, Pseudomonas aeruginosa, Pseudomonas mendocina, Pseudomonas alcaligenes, and Pseudomonas pseudoalcaligenes. Thymidine kinase activity was expressed in all of these species, and all gained the ability to incorporate exogenous [2-14C]thymidine into their DNA. Thymidine incorporation into P. stutzeri was enhanced 12-fold more in mutants lacking thymidylate synthetase activity. These mutants produced higher levels of thymidine kinase and were thymidine auxotrophs; thymineless death resulted from removal of thymidine from a growing culture.


[Automated analysis of the cerebral cortex using a television image analyzer].
In the context of the development of approaches to a quantitative automated analysis of neural tissue, the use of television image analyzers seems to be fairly promising. A complex of programmes for the television analysis system (TAS) by "Leitz Company" has been developed to implement an automated analysis of cerebral cortex sections. At the first stage of investigation, the operator sets a plan of scanning the object in the interactive regimen and with a small magnification of the microscope. The second stage involves the focusing and discrimination of images, selection of objects for analysis and measurement of the principal stereological parameters of neurons with a large magnification and at an automatic regimen. The curves obtained of changes of the stereological characteristics of the cortex in relation to the distance to the surface are in good agreement with the cytoarchitectonic pattern observed. Thus, the use of the TAS allows for the effective automated processing of neuromorphological preparations.


Proposed carbohydrate antigen 19-9 (CA19-9) cut-off values for the detection of pancreatic cancer in patients with poorly controlled diabetes: a real-world study.
CA19-9 is a tumor marker for pancreatic cancer (PC), and the nondiabetic cut-off level is 37 U/mL. CA19-9 levels are said to rise in patients with tumors like PC and intraductal papillary mucinous neoplasm (IPMN). CA19-9 levels have also been shown to be related to HbA1c levels. We hypothesized that the CA19-9 cut-off levels would differ between patients with poorly controlled diabetes. This real-world trial was designed to test our hypotheses. This was a retrospective cohort study. All inpatients with poorly controlled diabetes had mean HbA1c levels of 10.0% and were divided into three groups: those with pancreatic cancer (PC group, N = 20), those with IPMN (IPMN group, N = 55), and those with neither (NC group, N = 985). Serum CA19-9 levels in the PC group were significantly higher than in the IPMN and NC groups (p < 0.001). CA19-9 levels did not differ statistically between the IPMN and NC groups. According to the receiver operating characteristic (ROC) analysis, serum CA19-9 levels of 98.4 U/mL had the highest sensitivity and specificity to detect PC, when comparing PC to IPMN + NC groups. Using this cut-off, the sensitivity and specificity of CA19-9 for PC were 70.0% and 96.5%, respectively, with a 0.81 area under the ROC curve. CA19-9 levels in two inpatients were >98.4 U/mL, most likely due to hepatocellular carcinoma and esophageal cancer. CA19-9 cut-off levels were thought to be 98.4 U/mL. However, we should keep in mind that the sensitivity and specificity were not 100%.


A spatial model of antipredator vigilance.
Many species of animals have to perform two contradictory tasks: feeding, and avoiding becoming food for others. A large number of theoretical and empirical studies have investigated the trade-off between feeding and antipredator vigilance, especially in birds. An important factor which has been neglected in these studies is that of the area occupied by the flock. If individuals feed close together, competition increases and feeding rates decrease. However, if individuals space themselves widely, then vigilance efficiency goes down and there is an increased predation risk. We develop a vigilance model which allows birds to control the area the flock occupies as well as their vigilance rate. The optimal strategy is found for the birds under a variety of environmental conditions. In particular the effect of each environmental parameter on this optimum is considered in turn. How the model can be adapted for different bird species is also investigated.


Vepoloxamer Enhances Fibrinolysis of tPA (Tissue-Type Plasminogen Activator) on Acute Ischemic Stroke.
Background and Purpose- Thrombolytic treatment of acute ischemic stroke with tPA (tissue-type plasminogen activator) is hampered by its narrow therapeutic window and potential hemorrhagic complication. Vepoloxamer is a nonionic surfactant that exerts potent hemorheologic and antithrombotic properties in various thrombotic diseases. The current study investigated the effect of vepoloxamer on tPA treatment in a rat model of embolic stroke. Methods- Male Wistar rats subjected to embolic middle cerebral artery occlusion were treated with the combination of vepoloxamer and tPA, vepoloxamer alone, tPA alone, or saline initiated 4 hours after middle cerebral artery occlusion. Results- Monotherapy with tPA did not reduce infarct volume, and adversely potentiated microvascular thrombosis and vascular leakage compared with the saline treatment. Vepoloxamer monotherapy reduced infarct volume by 25% and improved brain perfusion. However, the combination treatment with vepoloxamer and tPA significantly reduced infarct volume by 32% and improved neurological function, without increasing the incidence of gross hemorrhage. Compared with vepoloxamer alone, the combination treatment with vepoloxamer and tPA robustly reduced secondary thrombosis and tPA-augmented microvascular leakage and further improved brain perfusion, which was associated with substantial reductions of serum active PAI-1 (plasminogen activator inhibitor-1) level and tPA-upregulated PAI-1 in the ischemic brain. Mechanistically, exosomes derived from platelets of ischemic rats treated with tPA-augmented cerebral endothelial barrier permeability and elevated protein levels of PAI-1 and TF (tissue factor) in the endothelial cells, whereas exosomes derived from platelets of rats subjected to the combination treatment with vepoloxamer and tPA diminished endothelial permeability augmented by tPA and fibrin and reduced PAI-1 and TF levels in the endothelial cells. Conclusions- The combination treatment with vepoloxamer and tPA exerts potent thrombolytic effects in rats subjected to acute ischemic stroke. Vepoloxamer reduces tPA-aggravated prothrombotic effect of platelet-derived exosomes on cerebral endothelial cells, which may contribute to the therapeutic effect of the combination treatment.


Development of a solute and defect concentration dependant Ising model for the study of transmutation induced segregation in neutron irradiated W-(Re, Os) systems.
In this study, radiation-induced precipitation of transmutation products is addressed via the development of a new solute and vacancy concentration dependant Ising model for the W-Re-Os system. This new model includes interactions between both Os and Re atoms with vacancies, thus facilitating more representative simulations of transmutation in fusion reactor components. Local solute concentration dependencies are introduced for the W-Re, W-Os and Re-Os pair interactions. The model correctly accounts for the repulsion between small clusters of vacancies and the attraction between larger clusters/voids, via the introduction of local vacancy concentration dependant interaction coefficients between pairs of atoms and vacancies. To parameterise the pair interactions between atoms and/or vacancies, the enthalpy of mixing, ΔHmix, for various configurations and solute/defect concentrations, was calculated using density functional theory, within 6 binary systems: W-Re, W-Os, Re-Os, W-vacancy, Re-vacancy and Os-vacancy. The new energy model was implemented into the SPPARKS Monte Carlo code, and successfully used to predict the formation of voids decorated with Re and Os solute atoms. Analysis suggests that there is a strong thermodynamic tendency for Os to bind to these voids with a comparatively weaker binding from Re atoms. The binding energies of various solute/vacancy clusters were calculated and showed that Re and Os solute atoms tend to stabilise small clusters of vacancies, increasing the attractive binding energy between the constituents.


The assessment of placental blood vessels by three-dimensional power Doppler ultrasound.
This study was performed in order to compare the performance of classical two dimensional (2D) and three dimensional (3D) ultrasound, both with power Doppler technology, in the visualization of the placental vascular network during ongoing pregnancy. 15 pregnant volunteers in the third trimester of pregnancy were examined by 2D and 3D power Doppler ultrasound. The aim of the study was to follow the branching of the main stem vessel as far as possible distally in the placenta. In addition, we assessed the visualization rate of terminal parts of uteroplacental circulation, radial and spiral arteries. There was no difference in the visualization of primary placental stem vessels by 2D and 3D power Doppler. However, 3D power Doppler performs better distally, with statistically significant differences at the level of secondary stem (p = 0.03), and even more prominent differences at the level of tertiary stem vessels (p = 0.0008). There was no difference in the visualization rate of radial and spiral arteries (p > 0.05). We found 3D superior to 2D ultrasound with power Doppler technology in the determination of the distal vascular branches of the fetal placental blood vessels.


Lymphoma: variations in time to diagnosis and treatment.
This study examines illness trajectories of patients with lymphoma and assesses whether UK government targets to reduce waiting time for diagnosis and treatment are achievable and appropriate. One hundred and ninety-four patients, residents in West Yorkshire, aged more than 25 years and newly diagnosed with lymphoma during 2000 were included. Data collected from interviews, primary care and hospital records were used to examine time between critical events on the illness trajectory and characteristics of patients not meeting proposed targets. Forty-two per cent of patients did not receive a hospital appointment within 2 weeks of general practitioner referral, 26% were not treated within 1 month of diagnosis and 64% were not treated within 2 months of referral. Target achievement differed by diagnostic group, and trends were seen by age and deprivation. The interval from onset of symptoms to treatment averaged more than 1 year and approximately half of this occurred before first medical contact. Results suggest that significant improvements are needed to achieve targets. Although existing targets particularly address referral and treatment intervals, these were the shortest intervals on the trajectory. Generalized targets may be inappropriate and unachievable for lymphoma as they do not consider individual disease characteristics or allow for variations in the urgency with which treatment is needed.


MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation.
Serum response factor and its transcriptional cofactor MKL1 are critical for megakaryocyte maturation and platelet formation. We show that MKL2, a homologue of MKL1, is expressed in megakaryocytes and plays a role in megakaryocyte maturation. Using a megakaryocyte-specific Mkl2 knockout (KO) mouse on the conventional Mkl1 KO background to produce double KO (DKO) megakaryocytes and platelets, a critical role for MKL2 is revealed. The decrease in megakaryocyte ploidy and platelet counts of DKO mice is more severe than in Mkl1 KO mice. Platelet dysfunction in DKO mice is revealed by prolonged bleeding times and ineffective platelet activation in vitro in response to adenosine 5'-diphosphate. Electron microscopy and immunofluorescence of DKO megakaryocytes and platelets indicate abnormal cytoskeletal and membrane organization with decreased granule complexity. Surprisingly, the DKO mice have a more extreme thrombocytopenia than mice lacking serum response factor (SRF) expression in the megakaryocyte compartment. Comparison of gene expression reveals approximately 4400 genes whose expression is differentially affected in DKO compared with megakaryocytes deficient in SRF, strongly suggesting that MKL1 and MKL2 have both SRF-dependent and SRF-independent activity in megakaryocytopoiesis.


Annotated 18S and 28S rDNA reference sequences of taxa in the planktonic diatom family Chaetocerotaceae.
The species-rich diatom family Chaetocerotaceae is common in the coastal marine phytoplankton worldwide where it is responsible for a substantial part of the primary production. Despite its relevance for the global cycling of carbon and silica, many species are still described only morphologically, and numerous specimens do not fit any described taxa. Nowadays, studies to assess plankton biodiversity deploy high throughput sequencing metabarcoding of the 18S rDNA V4 region, but to translate the gathered metabarcodes into biologically meaningful taxa, there is a need for reference barcodes. However, 18S reference barcodes for this important family are still relatively scarce. We provide 18S rDNA and partial 28S rDNA reference sequences of 443 morphologically characterized chaetocerotacean strains. We gathered 164 of the 216 18S sequences and 244 of the 413 28S sequences of strains from the Gulf of Naples, Atlantic France, and Chile. Inferred phylogenies showed 84 terminal taxa in seven principal clades. Two of these clades included terminal taxa whose rDNA sequences contained spliceosomal and Group IC1 introns. Regarding the commonly used metabarcode markers in planktonic diversity studies, all terminal taxa can be discriminated with the 18S V4 hypervariable region; its primers fit their targets in all but two species, and the V4-tree topology is similar to that of the 18S. Hence V4-metabarcodes of unknown Chaetocerotaceae are assignable to the family. Regarding the V9 hypervariable region, most terminal taxa can be discriminated, but several contain introns in their primer targets. Moreover, poor phylogenetic resolution of the V9 region affects placement of metabarcodes of putative but unknown chaetocerotacean taxa, and hence, uncertainty in taxonomic assignment, even of higher taxa.


Evaluation of Anterior Segment's Structures in Tilted Disc Syndrome.
Purpose. To evaluate anterior segment's structures by Pentacam in patients with tilted disc syndrome (TDS). Methods. Group 1 included forty-six eyes of forty-six patients who have the TDS. Group 2 including forty-six eyes of forty-six cases was the control group which was equal to the study group in age, gender, and refraction. A complete ophthalmic examination was performed in both groups. All cases were evaluated by Pentacam. The axial length (AL) of eyes was measured by ultrasound. Quantitative data obtained from these measurements were compared between two groups. Results. There was no statistically significant difference for age, gender, axial length, and spherical equivalent measurements between two groups (p = 0.625, p = 0.830, p = 0.234, and p = 0.850). There was a statistically significant difference for central corneal thickness (CCT), corneal volume (CV), anterior chamber angle (ACA), and pupil size measurements between two groups (p = 0.001, p = 0.0001, p = 0.003, and p = 0.001). Also, there was no statistically significant difference for anterior chamber depth (ACD), anterior chamber volume (ACV), and lens thickness (LT) measurements between two groups (p = 0.130, p = 0.910, and p = 0.057). Conclusion. We determined that CCT was thinner, CV was less, and ACA was narrower in patients with TDS. There are some changes in the anterior segment of the eyes with tilted disc.


Ginkgo biloba exocarp extracts inhibits angiogenesis and its effects on Wnt/β-catenin-VEGF signaling pathway in Lewis lung cancer.
A fruit of Ginkgo biloba L. also known as Ginkgo biloba, can be used for the treatment of cancer in Chinese traditional medicine. The scientific name of succulent skin, which is the episperm of Ginkgo nuts, is exocarp. Experiment shows that Ginkgo biloba exocarp extracts (GBEE) has the effects of immune promotion, cancer inhibition and etc. Study on the activity of GBEE against Lewis lung cancer (LLC) angiogenesis and its partial molecular mechanism. The effect of GBEE on proliferation of LLC cells was detected by MTT method in vitro. The metastasis model of LLC was set up. The C57BL/6J mice were randomly separated into normal control, model control, positive control and GBEE (50, 100, 200mg/kg) treatment groups, n=10. The mice in normal group and model group were both intragastric gavage (i.g.) normal saline (NS) in a volume of 0.1mL/10g (b.w.), positive group were intraperitoneal (i.p.) injection cyclophosphamide (CPA) at a dose of 20mg/kg (b.w.) , the GBEE treatment groups were respectively i.g. GBEE 50, 100, and 200mg/kg (b.w.), once a day for 20d. After treatment, we calculated the tumor inhibition rate and anti-metastasis rate. The microvessel density (MVD) was measured by immunohistochemistry method in transplanted tumor. The expression levels of vascular en-dothelial growth factor (VEGF) and VEGFR2 mRNA or Wnt3a, β-catenin, VEGF, VEGFR2 and p-Akt/Akt protein expression were respectively tested by Quantitative Reverse transcription Polymerase chain reaction (qRT-PCR) or western blot in vitro and vivo. GBEE suppressed the growth of LLC cells in a dose-dependent way at the dose of 5, 10, 20, 40, 80 and 160µg/mL in vitro. It can suppressed Wnt3a and β-catenin protein expression and the content of mRNA of VEGF and VEGFR2 in LLC cells significantly. In vivo, we discovered GBEE can retard the growth of LLC transplanted tumor in a dose-dependent way at the dose of 50, 100, 200mg/kg, suppressing tumor lung metastasis. The expression of CD34 was reduced, which means MVD was inhibited and so do β-catenin, VEGF, VEGFR2 and p-AKT/AKT protein expression and VEGF and VEGFR2 mRNA expression levels in LLC transplanted tumor of C57BL/6 mice. GBEE played the effects of anti-tumor and anti-metastatic depending upon the inhibition of tumor angiogenesis, which may be closely relevant to its effect in blockage of Wnt /β-catenin-VEGF signaling pathway in LLC.


The transition from a phytopathogenic smut ancestor to an anamorphic biocontrol agent deciphered by comparative whole-genome analysis.
Pseudozyma flocculosa is related to the model plant pathogen Ustilago maydis yet is not a phytopathogen but rather a biocontrol agent of powdery mildews; this relationship makes it unique for the study of the evolution of plant pathogenicity factors. The P. flocculosa genome of ~23 Mb includes 6877 predicted protein coding genes. Genome features, including hallmarks of pathogenicity, are very similar in P. flocculosa and U. maydis, Sporisorium reilianum, and Ustilago hordei. Furthermore, P. flocculosa, a strict anamorph, revealed conserved and seemingly intact mating-type and meiosis loci typical of Ustilaginales. By contrast, we observed the loss of a specific subset of candidate secreted effector proteins reported to influence virulence in U. maydis as the singular divergence that could explain its nonpathogenic nature. These results suggest that P. flocculosa could have once been a virulent smut fungus that lost the specific effectors necessary for host compatibility. Interestingly, the biocontrol agent appears to have acquired genes encoding secreted proteins not found in the compared Ustilaginales, including necrosis-inducing-Phytophthora-protein- and Lysin-motif- containing proteins believed to have direct relevance to its lifestyle. The genome sequence should contribute to new insights into the subtle genetic differences that can lead to drastic changes in fungal pathogen lifestyles.


Systematic Evaluation of HLA-G 3'Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome.
Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3' untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3'UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3'UTR haplotypes (UTR-1-UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3'UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients.


Reimagining Physician Assistant Education.
The physician assistant (PA) profession has successfully flourished for over 50 years, demand for graduates remains strong, and there is a wealth of research on the quality of care that PA graduates provide. Nevertheless, health care and education are constantly changing, and we must change with them. We must continually scan the horizon and consider how best to adapt to current issues like the clinical sites crisis, as well as evolutions in technology, pedagogy, and in our students themselves. The Physician Assistant Education Association Presidents Commission, a group of past presidents, sought to stimulate a conversation on "reimagining PA education" through the lens of advances in our knowledge of the neuroscience of learning and changes in technology, including simulation, and a broader focus on innovation and "thinking outside the box." Through interviews with PA faculty and leaders, we provide some examples of areas of innovation in education, especially on the possibilities presented by a more flexible approach to innovation from the accreditation body than many PA faculty might perceive. One initial conclusion is that PA educators should focus more on helping students to "think like clinicians" from the start of their education. This paper is primarily intended to stimulate dialog, and we encourage all PA educators to form-and more importantly, share-their own thoughts and questions, through the PAEA professional learning communities and Digital Learning Hub (PAEAlearning.org/learn/digital-learning-hub/).


Army flight medic performance of paramedic level procedures: indicated vs. performed.
There is great disparity in the education, experience, and staffing requirements for civilian and Army aeromedical transports (AMT). This study sought to determine if medical skills beyond the standard training for Army flight medics were indicated and being performed on Army AMT missions. As a secondary measure, the percentage of indicated interventions performed by basic Emergency Medical Technician (EMT-B) and paramedic (EMT-P) flight medics were compared. This was a retrospective review of Army AMT charts including patients transported by an EMT-B-staffed unit in Iraq and an EMT-P-staffed unit in Afghanistan from July 2008 to June 2009. Charts were reviewed independently by two Emergency Medicine board-certified Army flight surgeons. Of 984 interventions found to be indicated on the 406 charts that met inclusion criteria, 36% were rated as EMT-P level. Seventeen percent were indicated but not performed. EMT-Bs failed to perform indicated procedures 35% of the time vs. 3% in the EMT-P group (p < 0.001). For paramedic-level procedures, EMT-Bs failed to make 76% of appropriate interventions, compared to <1% in the EMT-P group (p < 0.001). There seems to be a substantial number of procedures beyond the scope of standard Army flight medic training being required for Army AMT missions. It seems that when advance interventions are indicated, those trained to the EMT-P level perform them significantly more often than those trained to Army standard. Based on the findings of this study, the authors suggest the Army consider adopting the standards required for civilian AMT.


Invasive chronic inflammatory monocyte phenotype in subjects with high HIV-1 viral load.
Human immunodeficiency virus type 1 (HIV-1)-infected monocytes trafficking into the central nervous system are a risk factor for HIV-1-associated dementia. We performed global gene expression analysis on CD14+ monocytes isolated from HIV-1-infected individuals and controls to identify HIV-1-related changes in monocyte phenotype. Monocytes from subjects with high viral load (HVL) had a significant increase in monocytes expressing CD16, CCR5, and MCP-1. There was also an increase in sialoadhesin, a macrophage marker of chronic inflammation. Expression of proinflammatory cytokine genes IL-1, IL-6, and TNF-alpha was unchanged in individuals with HIV-1 compared to control CD14+ monocytes. Differential gene expression identified by DNA microarray analysis was confirmed with reverse transcription polymerase chain reaction (RT-PCR), while increased protein expression was characterized by immunofluorescence. We concluded that there is a circulating CD14+ macrophage hybrid phenotype in subjects with HVL.


Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial.
BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol. Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition. This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).


Reducing health disparities in depressive disorders outcomes between non-Hispanic Whites and ethnic minorities: a call for pragmatic strategies over the life course.
There are significant disparities in treatment process and symptomatic and functional outcomes in depressive disorders for racial and ethnic minority patients. Using a life-course perspective, the authors conducted a systematic review of the literature to identify modifiable mechanisms and effective interventions for prevention and treatment at specific points -- system, community, provider, and individual patient -- in health care settings. Multicomponent chronic disease management interventions have produced improvements in depression outcomes for ethnic minority populations. Case management appears to be a key component of effective interventions. Socioculturally tailored treatment and prevention interventions may be more efficacious than standard treatment programs. Future research should focus on identifying key components of case management and sociocultural tailoring that are essential for effective interventions and developing new low-cost dissemination mechanisms for treatment and preventive programs that could be tailored to racial and ethnic minorities.


Formation of Polyion Complex Aggregate Formed from a Cationic Block Copolymer and Anionic Polysaccharide.
Block copolymers (PmMn; P20M101 and P100M98) comprising poly(2-(methacryloyloxy)ethylphosphorylcholine) (PMPC, P) containing biocompatible phosphorylcholin pendants and cationic poly((3-acryloylaminopropyl) trimethylammonium chloride) (PMAPTAC, M) were synthesized via a controlled radical polymerization method. The degrees of polymerization of the PMPC and PMAPTAC segments are denoted by subscripts (PmMn). The mixture of cationic PmMn and anionic sodium chondroitin sulfate C (CS) with the pendant anionic carboxylate and sulfonate groups formed polyion complex (PIC) aggregates in phosphate-buffered saline. A charge-neutralized mixture of P20M101 with CS formed P20M101/CS PIC vesicles with a hydrodynamic radius (Rh) of 97.2 nm, zeta potential of ca. 0 mV, and aggregation number (Nagg) of 23,044. PMPC shells covered the surface of the PIC vesicles. The mixture of P100M98 and CS formed PIC spherical micelles with the PIC core and hydrophilic PMPC shells. The Rh, zeta potential, and Nagg of the PIC micelles were 26.4 nm, ca. 0 mV, and 404, respectively. At pH < 4, the carboxylate anions in CS were protonated. Thus, the charge balance in the PIC micelles shifted to decrease the core density owing to the electrostatic repulsions of the excess cations in the core. The PIC micelles dissociated at a NaCl concentration ≥0.6 M owing to the charge screening effect. The positively charged PIC micelles with excess P100M98 can encapsulate anionic dyes owing to electrostatic interaction.


Cystic lesions of the prostate gland. A sonographic--pathologic correlation.
277 patients underwent biplane transrectal ultrasonography. Twenty-two patients (7.9%) showed evidence of one or more intraprostatic cystic lesions. Histologic correlation was available with total prostatectomy specimens in six patients and surgical drainage in two patients. Sonographically, 11 patients showed one, 6 patients two, and 5 patients three or more intraprostatic cystic lesions. The size of the lesions ranged from 2 to 30 mm, and the majority of lesions were located within the central portion of the gland or at the junction of central and peripheral regions of the gland. Histologically, among the eight pathologically confirmed patients the lesions corresponded to cystically dilated, epitheliallined prostatic glands, a reepithelialized cyst related to previous biopsy, a dilated utricle, and two intraprostatic abscesses. The cystic lesions in our series were not associated with carcinoma of the prostate, but represented either a growth phenomenon related to the presence of benign prostatic hypertrophy, inflammatory conditions (abscesses), or anatomical variants (utricle).


Mechanism of Ethylene Addition to Nickel Bis(oxothiolene) and Nickel Bis(dioxolene) Complexes.
The electrochemically reversible binding of olefins by nickel bis(dithiolene) has been extensively studied, both theoretically and computationally. To optimize a catalyst for this process, we have investigated all possible reaction pathways of ethylene addition onto the related complex nickel bis(dioxolene), and the two isomers (cis and trans) of nickel bis(oxothiolene). Modern DFT calculations predict that the nickel bis(dioxolene) complex has limited practical use due to high barriers to binding. However, each of the two isomers of the nickel bis(oxothiolene) complexes display enhanced properties versus the original nickel bis(dithiolene) complex. Specifically, in nickel bis(dithiolene), the intraligand binding of olefins leads to decomposition, whereas interligand binding is required for reversibility; the two nickel bis(oxothiolene) complexes have greater selectivity toward the formation of the desired interligand adducts. For the full reaction pathways, the new complexes' binding mechanisms are contrasted with the mechanism of the original catalyst.


Acute self-limiting hepatitis C after possible sexual exposure: sequence analysis of the E-2 region of the infected patient and sexual partner.
We describe a case of symptomatic acute infection with HCV in a woman whose sexual partner had chronic hepatitis C. The patient cleared HCV RNA 8 weeks after the onset of acute hepatitis and was found to be persistently HCV-RNA negative during 90 weeks of follow-up. Part of the E-2 region of HCV was directly sequenced in the patient and her sexual partner. Four local controls with subtype-1a infection and 9 1a isolates obtained from GenBank were analyzed. The average nucleotide divergence between the sequences of the infected patient and her sexual partner was 5.1%, compared with an average nucleotide divergence of 19.4% (range 16.6-21.8%) between the sequences of the patient and those of controls. Comparison of the phylogenetic trees in the partial E-2 region showed that the sequence of the patient was closely related to that of her sexual partner. Our findings suggest that the infection was transmitted to the patient from her sexual partner. The resolution of acute hepatitis C in this case was probably related to the host rather than to intrinsic characteristics of the HCV genome.