Challenges and coping strategies of parents of children with autism on the Kenyan coast.
Research on the challenges of raising a child with autism is mostly conducted in Europe, North America and Australia, and has revealed that parents have to come to terms with living with a lifelong developmental disability. In addition, parents are faced with numerous concerns, such as caring burdens, poor prognosis, and negative public attitudes. Virtually no research has been conducted in Africa on this subject. Thirty-seven interviews and eight focus group discussions were conducted with parents of children with autism and professionals in regular contact with these parents from rural and urban counties of the Kenyan coast. The study investigated challenges faced by parents and how they cope with those challenges. A purposive-convenience sampling procedure was used in selecting the study participants. A digital recorder was used to record all the interviews and focus group discussions. Transcriptions were done in Swahili, translated into English, and then imported to the NVivo software program for content analysis. The results indicate that parents of children with autism on the Kenyan coast experience common challenges including stigma, lack of appropriate treatment, financial and caring burdens regardless of their religious and cultural backgrounds. Coping strategies applied by parents comprised problem-focused aspects that involve diet management and respite care, and emotion-focused aspects that consist of beliefs in supernatural powers, prayers and spiritual healing. This qualitative study reveals a range of challenges that could have significant impact when caring for a child with autism. Coping strategies applied by parents target the physical health of the child and the psychological wellbeing of the parent. Consideration of these outcomes is vital as they could impact the initiation of a community-based rehabilitation service delivery in rural settings where parents play an active role.


Role of diet in type 2 diabetes incidence: umbrella review of meta-analyses of prospective observational studies.
To summarise the evidence of associations between dietary factors and incidence of type 2 diabetes and to evaluate the strength and validity of these associations. Umbrella review of systematic reviews with meta-analyses of prospective observational studies. PubMed, Web of Science, and Embase, searched up to August 2018. Systematic reviews with meta-analyses reporting summary risk estimates for the associations between incidence of type 2 diabetes and dietary behaviours or diet quality indices, food groups, foods, beverages, alcoholic beverages, macronutrients, and micronutrients. 53 publications were included, with 153 adjusted summary hazard ratios on dietary behaviours or diet quality indices (n=12), food groups and foods (n=56), beverages (n=10), alcoholic beverages (n=12), macronutrients (n=32), and micronutrients (n=31), regarding incidence of type 2 diabetes. Methodological quality was high for 75% (n=115) of meta-analyses, moderate for 23% (n=35), and low for 2% (n=3). Quality of evidence was rated high for an inverse association for type 2 diabetes incidence with increased intake of whole grains (for an increment of 30 g/day, adjusted summary hazard ratio 0.87 (95% confidence interval 0.82 to 0.93)) and cereal fibre (for an increment of 10 g/day, 0.75 (0.65 to 0.86)), as well as for moderate intake of total alcohol (for an intake of 12-24 g/day v no consumption, 0.75 (0.67 to 0.83)). Quality of evidence was also high for the association for increased incidence of type 2 diabetes with higher intake of red meat (for an increment of 100 g/day, 1.17 (1.08 to 1.26)), processed meat (for an increment of 50 g/day, 1.37 (1.22 to 1.54)), bacon (per two slices/day, 2.07 (1.40 to 3.05)), and sugar sweetened beverages (for an increase of one serving/day, 1.26 (1.11 to 1.43)). Overall, the association between dietary factors and type 2 diabetes has been extensively studied, but few of the associations were graded as high quality of evidence. Further factors are likely to be important in type 2 diabetes prevention; thus, more well conducted research, with more detailed assessment of diet, is needed. PROSPERO CRD42018088106.


Dextran coated bismuth-iron oxide nanohybrid contrast agents for computed tomography and magnetic resonance imaging.
Bismuth nanoparticles have been proposed as a novel CT contrast agent, however few syntheses of biocompatible bismuth nanoparticles have been achieved. We herein report the synthesis of composite bismuth-iron oxide nanoparticles (BION) that are based on a clinically approved, dextran-coated iron oxide formulation; the particles have the advantage of acting as contrast agents for both CT and MRI. BION were synthesized and characterized using various analytical methods. BION CT phantom images revealed that the X-ray attenuation of the different formulations was dependent upon the amount of bismuth present in the nanoparticle, while T2-weighted MRI contrast decreased with increasing bismuth content. No cytotoxicity was observed in Hep G2 and BJ5ta cells after 24 hours incubation with BION. The above properties, as well as the yield of synthesis and bismuth inclusion efficiency, led us to select the Bi-30 formulation for in vivo experiments, performed in mice using a micro-CT and a 9.4 T MRI system. X-ray contrast was observed in the heart and blood vessels over a 2 hour period, indicating that Bi-30 has a prolonged circulation half-life. Considerable signal loss in T2-weighted MR images was observed in the liver compared to pre-injection scans. Evaluation of the biodistribution of Bi-30 revealed that bismuth is excreted via the urine, with significant concentrations found in the kidneys and urine. In vitro experiments confirmed the degradability of Bi-30. In summary, dextran coated BION are biocompatible, biodegradable, possess strong X-ray attenuation properties and also can be used as T2-weighted MR contrast agents.


Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.
Bromodomains have been pursued intensively over the past several years as emerging targets for the development of anticancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected polypharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selective target profile is desired. Here, we report that benzo[e]pyrimido-[5,4- b]diazepine-6(11H)-ones, versatile ATP-site directed kinase pharmacophores utilized in the development of inhibitors of multiple kinases, including several previously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity, as well as how to direct selectivity toward inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first reported kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 μM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers recognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid docking studies.


The Indiana experience with artificial urinary sphincters in children and young adults.
We reviewed a 22-year single institutional experience with the artificial urinary sphincter in children and adolescents. To our knowledge this report represents the largest series in the world in children. Between 1980 and 2002, 142 patients underwent implantation of an artificial urinary sphincter, of whom 93 males and 41 females with a median age of 10 years (range 3 to 39) were available for analysis. A total of 59 patients initially received an AMS 742/792 (American Medical Systems, Inc., Minnetonka, Minnesota) artificial urinary sphincter, of whom 33 were subsequently changed to an AMS 800, while 75 initially received an AMS 800 model. Sphincter followup was terminated at device removal or at the last documented contact. The etiology of incontinence was neuropathic bladder in 107 cases (80%), the exstrophy/epispadias complex in 21 (16%) and other in 6 (4%). Outcome measures included continence, mechanical complications (leakage, tube kink and pump malfunction), functioning sphincter revisions (change in cuff size, pump repositioning and bulbar cuff placement), surgical complications (erosion, infection and misplacement) and associated surgical procedures. Mean followup of the pre-800 and 800 models was 6.9 (range 0.2 to 21.5) and 7.5 years (range 0.1 to 17.1), respectively. Fisher's exact test, Kaplan-Meier life analysis and the chi-square test were used for statistical analysis. After artificial urinary sphincter placement in the 134 patients continence was achieved in 86%, improved in 4% and not achieved in 10%. Of those with a sphincter in place 92% were continent. In terms of bladder emptying after artificial urinary sphincter insertion 22% of patients voided, 11% voided combined with clean intermittent catheterization, 48% performed clean intermittent catheterization only via the urethra, 16% performed it via a catherizable channel and 3% used urinary diversion. A mechanical complication developed in 38 of the 59 patients (64%) with pre-800 model compared with 33 of the 109 (30%) with the 800 model (p <0.0001). A mechanical complication occurred every 7.6 versus 16 patient-years for the pre-800 versus 800 models (p = 0.0001). Revision was required in 15 of the 59 patients (25%) with a pre-800 model versus 17 of the 109 (16%) with the 800 model (p = 0.103). Revision was performed every 22.7 versus 44.3 patient-years for the pre-800 versus the 800 model (p = 0.023). The artificial urinary sphincter eroded in 11 of the 59 patients (19%) with the pre-800 versus 17 of the 109 (16%) with the 800 model (p = 0.52). Ten patients experienced a total of 12 perforations of the augmented bladder after artificial urinary sphincter implantation. A total of 164 secondary surgical procedures were performed, including 38 of 134 bladder augmentations (28%). A total of 30 sphincters were permanently removed. The artificial urinary sphincter is the only bladder neck procedure that allows spontaneous voiding in the neuropathic population, obviates the need for clean intermittent catheterization and yet is compatible with it when necessary. It is also equally versatile in the 2 genders. Mechanical complications occur but they were dramatically decreased by the modifications of the AMS 800 model. In addition, secondary bladder augmentation was required in 28% of our patients. Lifelong followup is mandatory in all patients with an artificial urinary sphincter.


Transcriptome sequencing reveals maelstrom as a novel target gene of the terminal system in the red flour beetle Tribolium castaneum.
Terminal regions of the Drosophila embryo are patterned by the localized activation of the Torso-RTK pathway, which promotes the downregulation of Capicua. In the short-germ beetle Tribolium, the function of the terminal system appears to be rather different, as the pathway promotes axis elongation and, in addition, is required for patterning the extra-embryonic serosa at the anterior. Here, we show that Torso signalling also induces gene expression by relieving Capicua-mediated repression in Tribolium Given that the majority of Torso target genes remain to be identified, we established a differential gene-expression screen. A subset of 50 putative terminal target genes was screened for functions in early embryonic patterning. Of those, 13 genes show early terminal expression domains and also phenotypes were related to terminal patterning. Among others, we found the PIWI-interacting RNA factor Maelstrom to be crucial for early embryonic polarization. Tc-mael is required for proper serosal size regulation and head morphogenesis. Moreover, Tc-mael promotes growth-zone formation and axis elongation. Our results suggest that posterior patterning by Torso may be realized through Maelstrom-dependent activation of posterior Wnt domains.


A mathematical model gives insights into the effects of vitamin B-6 deficiency on 1-carbon and glutathione metabolism.
We experimented with a mathematical model for 1-carbon metabolism and glutathione (GSH) synthesis to investigate the effects of vitamin B-6 deficiency on the reaction velocities and metabolite concentrations in this metabolic network. The mathematical model enabled us to independently alter the activities of each of the 5 vitamin B-6-dependent enzymes and thus determine which inhibitions were responsible for the experimentally observed consequences of a vitamin B-6 deficiency. The effect of vitamin B-6 deficiency on serine and glycine concentrations in tissues and plasma was almost entirely due to its effects on the activity of glycine decarboxylase. The effect of vitamin B-6 restriction on GSH concentrations appeared to be indirect, arising from the fact that vitamin B-6 restriction increases oxidative stress, which, in turn, affects several enzymes in 1-carbon metabolism as well as the GSH transporter. Vitamin B-6 restriction causes an abnormally high and prolonged homocysteine response to a methionine load test. This effect appeared to be mediated solely by its effects on cystathionine beta-synthase. Reduction of the enzymatic activity of serine hydroxymethyltransferase (SHMT) had negligible effects on most metabolite concentrations and reaction velocities. Reduction or total elimination of cytoplasmic SHMT had a surprisingly moderate effect on metabolite concentrations and reaction velocities. This corresponds to the experimental findings that a reduction in the enzymatic activity of SHMT has little effect on 1-carbon metabolism. Our simulations showed that the primary function of SHMT was to increase the rate by which the glycine-serine balance was reequilibrated after a perturbation.


Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health.
The indigenous intestinal microflora are involved in a variety of processes within the human body, and are important for maintaining host health. As such, interindividual differences in the ability to harbor certain intestinal bacteria might be associated with interindividual differences in health and/or disease susceptibility. In the last decade there has been considerable interest in phytoestrogen intakes in relation to human health. Daidzein, an isoflavone phytoestrogen found in soy, is metabolized to equol and O-desmethylangolensin (O-DMA) by intestinal bacteria. The specific bacterium/bacteria responsible for equol and O-DMA production in humans have yet to be identified definitively, but in vitro and animal studies have suggested that equol and O-DMA are more biologically active than their precursor daidzein. Interestingly, substantial interindividual differences in daidzein metabolism exist; following soy or daidzein consumption, approximately 30%-50% of the human population produce equol, and approximately 80%-90% produce O-DMA. Observational and intervention studies in humans have suggested that the ability to produce equol and O-DMA may be associated with reduced risk of certain diseases including breast and prostate cancers. However, relatively few studies have been conducted to date. In this review, we discuss the available evidence for a relationship between daidzeinmetabolizing phenotypes and human health, and suggest potential mechanisms for some of the reported relationships.


Bringing narratives from physicians, patients and caregivers together: a scoping review of published research.
Patients and family caregivers tell different stories about their illness and care experiences than their physicians do. Better understanding of the relationships among these narratives could offer insight into intersections and disconnections in patient, caregiver and physician perceptions of illness and care. Such understanding could support enhanced patient-centred care in medical education and practice. Narrative writing is increasingly common among physicians, patients and caregivers and uniquely positioned to reveal matters of concern to these groups. We conducted a scoping review to identify literature in which first-person narratives from more than one group (physicians, patients and/or caregivers) were considered as 'data'. A search strategy involving nine databases located 6337 citations. Two reviewers independently screened titles and abstracts. Full-text screening followed (n=82), along with handsearching of grey literature and bibliographies. Of these, 22 met inclusion criteria. Most pieces analysed narratives by patients and caregivers (n=13), followed by patients, caregivers and physicians (n=7) and patients and physicians (n=2). Only nine pieces compared perspectives among any of these groups. The rest combined narratives for analysis, largely patient and caregiver stories (n=12). Most of the 22 papers used descriptive content analysis to derive themes. Themes of humanity, identity, agency and communication intersect between groups but often manifest in unique ways. What is absent, however, is a more interpretive narrative analysis of structure, orientation and characterisation within these narratives, which may reveal even more than their content. This scoping review offers a cautionary tale of lost potential. Many narratives are gathered and analysed but usually only thematically and rarely comparatively. We call for researchers to explore the potential of comparative analysis and the power of narrative inquiry in the field. Comparative narrative analysis may enrich understanding of how differences between perspectives come to be and what they mean for the experience of illness and care.


Fitting HIV Prevalence 1981 Onwards for Three Indian States Using the Goals Model and the Estimation and Projection Package.
Models are designed to provide evidence for strategic program planning by examining the impact of different interventions on projected HIV incidence. We employed the Goals Model to fit the HIV epidemic curves in Andhra Pradesh, Maharashtra and Tamil Nadu states of India where HIV epidemic is considered to have matured and in a declining phase. Input data in the Goals Model consisted of demographic, epidemiological, transmission-related and risk group wise behavioral parameters. The HIV prevalence curves generated in the Goals Model for each risk group in the three states were compared with the epidemic curves generated by the Estimation and Projection Package (EPP) that the national program is routinely using. In all the three states, the HIV prevalence trends for high-risk populations simulated by the Goals Model matched well with those derived using state-level HIV surveillance data in the EPP. However, trends for the low- and medium-risk populations differed between the two models. This highlights the need to generate more representative and robust data in these sub-populations and consider some structural changes in the modeling equation and parameters in the Goals Model to effectively use it to assess the impact of future strategies of HIV control in various sub-populations in India at the sub-national level.


Tiresias: Context-sensitive Approach to Decipher the Presence and Strength of MicroRNA Regulatory Interactions.
MicroRNAs (miRNAs) are short non-coding RNAs that regulate expression of target messenger RNAs (mRNAs) post-transcriptionally. Understanding the precise regulatory role of miRNAs is of great interest since miRNAs have been shown to play an important role in development, diseases, and other biological processes. Early work on miRNA target prediction has focused on static sequence-driven miRNA-mRNA complementarity. However, recent research also utilizes expression-level data to study context-dependent regulation effects in a more dynamic, physiologically-relevant setting. Methods: We propose a novel artificial neural network (ANN) based method, named Tiresias, to predict such targets in a context-dependent manner by combining sequence and expression data. In order to predict the interacting pairs among miRNAs and mRNAs and their regulatory weights, we develop a two-stage ANN and present how to train it appropriately. Tiresias is designed to study various regulation models, ranging from a simple linear model to a complex non-linear model. Tiresias has a single hyper-parameter to control the sparsity of miRNA-mRNA interactions, which we optimize using Bayesian optimization. Results: Tiresias performs better than existing computational methods such as GenMiR++, Elastic Net, and PIMiM, achieving an F1 score of >0.8 for a certain level of regulation strength. For the TCGA breast invasive carcinoma dataset, Tiresias results in the rate of up to 82% in detecting the experimentally-validated interactions between miRNAs and mRNAs, even if we assume that true regulations may result in a low level of regulation strength. Conclusion: Tiresias is a two-stage ANN, computational method that deciphers context-dependent microRNA regulatory interactions. Experiment results demonstrate that Tiresias outperforms existing solutions and can achieve a high F1 score. Source code of Tiresias is available at https://bitbucket.org/cellsandmachines/.


Regulation of renal blood flow by plasma chloride.
Micropuncture studies have shown that glomerular filtration rate (GFR) falls in response to a rise in Na(+) or Cl(-) concentrations in the loop of Henle, whereas studies in isolated kidneys have shown that GFR falls in response to osmotic diuresis. To define the separate effects of an acute increase in plasma sodium (P(Na)), chloride (P(Cl)) or osmolality (P(osmol)), changes in renal blood flow (RBF) and GFR were measured during intrarenal infusions of hypertonic NaCl, NaHCO(3), Na acetate, dextrose, NH(4)Cl or NH(4)acetate to denervated kidneys. The infusions raised P(osmol) at the experimental kidney by 30-45 mosmol. RBF increased abruptly by 10-30% with all hypertonic infusions indicating that an acute increase in plasma tonicity causes renal vasodilatation. Renal vasodilatation persisted or increased further during infusion of dextrose, NaHCO(3) and Na acetate, but GFR was unchanged. In contrast, during infusion of the two Cl-containing solutions, vasodilatation was reversed after 1-5 min and RBF and GFR decreased (P < 0.01) below preinfusion levels. Prior salt depletion doubled the vasoconstriction seen with hypertonic NaCl infusions. Overall, changes in RBF were unrelated to changes in P(Na) or fractional Na or fluid reabsorption but correlated with changes in P(Cl) (r = -0.91) and fractional Cl(-) reabsorption (r = 0.94). The intrafemoral arterial infusion of the two Cl-containing solutions did not increase femoral vascular resistance. In conclusion, hyperchloremia produces a progressive renal vasoconstriction and fall in GFR that is independent of the renal nerves, is potentiated by prior salt depletion and is related to tubular Cl(-) reabsorption. Chloride-induced vasoconstriction appears specific for the renal vessels.


Time- and segment-related changes of postresected intestine: a 4-dimensional model of intestinal adaptation.
The aim of the present study was to investigate the segment- and time-related changes in rat short bowel syndrome and construct a 4-dimensional (4D) geometrical model of intestinal adaptation. Sprague-Dawley rats were divided into 3 groups: 2-day, 7-day, and 15-day postresection groups in which 75% of the jejunoileum was removed. Histological and morphometrical parameters in the remaining proximal to distal intestinal segments, from the jejunum to the distal colon, were comparatively evaluated in the groups. The data were used to construct a 4D geometric model in which villi were considered as cylinders, and their surface area was expressed as cylinder lateral area. Major adaptive changes were observed in the ileum consisting of an increase in both the diameter of base and the height of villi. A parallel reduction in their number/mm was observed. The resulting ileal architecture was characterized by a limited number of large villi. An opposite pattern was observed in the jejunum whose postresection structure consisted of an increased number of villi. No changes were observed in the colon. Postresection restructuring was early and faster in the ileum than in the jejunum resulting in an increase in absorptive area of 81.5% and 22.5% in the ileum and jejunum, respectively. Postresection adaptation is intestinal segment-specific because all of the major changes occur in the ileum rather than in the jejunum. Sparing ileal segments during resection may improve the outcome of patients undergoing extensive intestinal resection. Our 4D model can be used to test interventions aimed at optimizing postresection intestinal adaptation.


Internet gratifications and internet addiction: on the uses and abuses of new media.
Internet addiction has been identified as a pathological behavior, but its symptoms may be found in normal populations, placing it within the scope of conventional theories of media attendance. The present study drew upon fresh conceptualizations of gratifications specific to the Internet to uncover seven gratification factors: Virtual Community, Information Seeking, Aesthetic Experience, Monetary Compensation, Diversion, Personal Status, and Relationship Maintenance. With no parallel in prior research, Virtual Community might be termed a "new" gratification. Virtual Community, Monetary Compensation, Diversion, and Personal Status gratifications accounted for 28% of the variance in Internet Addiction Tendency. The relationship between Internet addiction and gratifications was discussed in terms of the formation of media habits and the distinction between content and process gratifications.


Increasing educational inequality in preterm birth in Quebec, Canada, 1981-2006.
Few studies have evaluated the relationship between preterm birth (PTB) and maternal education over time. We sought to determine whether educational inequalities in PTB have increased in Québec, Canada. The authors analysed 2,124,909 singleton live births from 1981 to 2006, and computed the Relative Index of Inequality (RII) and Slope Index of Inequality (SII) with 95% CIs for the relationship between maternal education and extreme, very or moderate PTB (≤27, 28-31, and 32-36 completed weeks of gestation, respectively) for five periods (1981-1985, 1986-1990, 1991-1995, 1996-2000, 2001-2006), adjusting for maternal age, marital status, birthplace, language spoken at home, parity and infant sex. Average rates of extreme and moderate PTB increased over time but decreased for very PTB. A statistically significant increase in the RII over time was present for extreme and moderate PTB. The adjusted RII for extreme PTB increased from 1.58 (95% CI 1.24 to 2.01) in 1981-1985 to 3.11 (95% CI 2.54 to 3.81) in 2001-2006. For moderate PTB, the corresponding RIIs were 1.53 (95% CI 1.44 to 1.61) and 1.91 (95% CI 1.81 to 2.01). Absolute differences in the PTB proportion between the least and most educated mothers increased from 1981 to 2006 for extreme (adjusted SII 0.11% vs 0.28%) and moderate PTB (adjusted SII 1.67% vs 3.11%). Absolute differences in the proportion very PTB did not increase. Relative and absolute educational inequalities in extreme and moderate PTB have increased over time in Québec. Relative increases were largest for extreme PTB, and absolute increases were largest for moderate PTB.


Nitration transforms a sensitive peroxiredoxin 2 into a more active and robust peroxidase.
Peroxiredoxins (Prx) are efficient thiol-dependent peroxidases and key players in the mechanism of H2O2-induced redox signaling. Any structural change that could affect their redox state, oligomeric structure, and/or interaction with other proteins could have a significant impact on the cascade of signaling events. Several post-translational modifications have been reported to modulate Prx activity. One of these, overoxidation of the peroxidatic cysteine to the sulfinic derivative, inactivates the enzyme and has been proposed as a mechanism of H2O2 accumulation in redox signaling (the floodgate hypothesis). Nitration of Prx has been reported in vitro as well as in vivo; in particular, nitrated Prx2 was identified in brains of Alzheimer disease patients. In this work we characterize Prx2 tyrosine nitration, a post-translational modification on a noncatalytic residue that increases its peroxidase activity and its resistance to overoxidation. Mass spectrometry analysis revealed that treatment of disulfide-oxidized Prx2 with excess peroxynitrite renders mainly mononitrated and dinitrated species. Tyrosine 193 of the YF motif at the C terminus, associated with the susceptibility toward overoxidation of eukaryotic Prx, was identified as nitrated and is most likely responsible for the protection of the peroxidatic cysteine against oxidative inactivation. Kinetic analyses suggest that tyrosine nitration facilitates the intermolecular disulfide formation, transforming a sensitive Prx into a robust one. Thus, tyrosine nitration appears as another mechanism to modulate these enzymes in the complex network of redox signaling.


Plasma membrane compartmentalization of D2 dopamine receptors.
Plasma membrane microcompartments could allow different signaling pathways to operate more efficiently and prevent cross-talk. We utilized a novel in-cell biotin transfer assay to demonstrate that the majority of plasma membrane-expressed D2 dopamine receptor (D2R) is microcompartmentalized within detergent-resistant structures. Conversely, a minority of D2R existed in a detergent-soluble form and interacted in a relatively unrestricted manner with other cellular proteins. The microcompartmentalization of D2R had functional consequences because dopamine-induced internalization of D2R was largely restricted to the compartmentalized receptor. The D2R-containing microcompartments did not correspond to putative detergent-resistant lipid raft structures. First, the detergent-insoluble D2R structures were significantly denser than detergent-resistant membrane fragments containing flotillin, a widely utilized lipid raft marker protein. Second, the detergent solubility of D2R was unaffected by treatment of cells with the cholesterol chelating agent, methyl-β-cyclodextrin, that is thought to disrupt lipid rafts. Finally, the in-cell biotinylation assay did not provide any evidence for the membrane compartmentalization of peptide motifs thought to target to lipid rafts. Thus, our observations form one of the first demonstrations, in living cells, of plasma membrane microcompartments defined by the ability of the compartment structure to broadly restrict the interaction of resident molecules with other cellular proteins.


Can we use shorter constructs while maintaining satisfactory sagittal plane alignment for adult spinal deformity?
Issues with spinopelvic fixation for adult spinal deformity (ASD) include loss of the physiological mobility of the entire lumbar spine, perioperative complications, and medical costs. Little is known about the factors associated with successful short fusion for ASD. The authors evaluated radiographic and clinical outcomes after shorter fusion for different subtypes of ASD at 2 years postoperatively and examined factors associated with successful short fusion. This was a single-center study of 37 patients who underwent short fusion and a minimum 2 years of follow-up for ASD in which lumbar kyphosis was the main deformity. The exclusion criteria were 1) age < 40 years, 2) previous lumbar vertebral fracture, 3) severe osteoporosis, 4) T10-L2 kyphosis > 20°, 5) scoliotic deformity with an upper end vertebra (UEV) above T12, and 6) concomitant Parkinson's disease or neurological disease. The surgical procedures, radiographic course, and Oswestry Disability Index (ODI) were assessed, and correlations between radiographic parameters and postoperative ODI at 2 years were analyzed. A mean of 3.5 levels were fused. The mean radiographic parameters preoperatively, at 2 weeks, and at 2 years, respectively, were as follows: coronal Cobb angle: 22.9°, 11.5°, and 12.6°; lumbar lordosis (LL): 12.9°, 35.8°, and 32.2°; pelvic incidence (PI) minus LL: 35.5°, 14.7°, and 19.2°; pelvic tilt: 29.4°, 23.1°, and 25.0°; and sagittal vertical axis 85.3, 36.7, and 59.2 mm. Abnormal proximal junctional kyphosis occurred in 8 cases. Revision surgery was performed to extend the length of fusion from a lower thoracic vertebra to the pelvis in 2 cases. The mean ODI scores preoperatively and at 2 years were 50.7% and 24.1%, respectively. Patient age, number of fused intervertebral segments, and radiographic parameters were analyzed by the stepwise method to identify factors contributing to the ODI score at 2 years, preoperative PI, and sagittal vertical axis at 2 years. On receiver operating characteristic curve analysis of the minimal clinically important difference of ODI (15%) and preoperative PI, the cutoff value of the preoperative PI was 47° (area under the curve 0.75). In terms of subtypes of ASD in which lumbar kyphosis is the main deformity, if the PI is < 47°, then the use of short fusion preserving mobile intervertebral segments can produce adequate LL for the PI, improving both postoperative global spinal alignment and quality of life.


Use of an early disease-modifying drug adherence measure to predict future adherence in patients with multiple sclerosis.
Patients with multiple sclerosis (MS) who are adherent to their treatment regimens are less likely to experience relapses and the cost associated with relapse. Pharmacists whose practice involves these specialty pharmaceuticals used to treat MS are striving for ways to improve outcomes by achieving treatment adherence in their patients. Specialty pharmacies have reported higher adherence rates than traditional pharmacies, which may translate to improved outcomes. Identifying patients who warrant increased adherence intervention is critical. Models using administrative health care claims to predict adherence have typically included demographic characteristics, comorbidities, and/or previous consumption of health care resources. Addition of a measure of early adherence may improve the ability to predict future adherence outcomes. To evaluate early adherence with disease-modifying drugs (DMDs) as a predictor of future adherence in patients with MS. The first DMD claim (i.e., index event) for adult MS patients (aged ≥18 years and aged ≤ 65 years) who received self-injected DMDs between January 1, 2006, and May 31, 2010, was identified in a national U.S. managed care database. Patients were required to have continuous eligibility for 12 months pre- and 24 months post-index. Multiple regression models were used to predict future adherence as measured by the proportion of days covered (PDC). The base model included age, gender, a medication intensity measure, presence of a non-MS-related hospitalization pre-index, and markers for physical difficulty, forgetfulness, or depression/stress. Models adding early DMD adherence as a covariate were analyzed using incrementing 30-day periods predicting the subsequent 360 days. There were 4,606 patients included with an average age of 46.0 (SD 9.4) years, and 78.7% were female. Average PDC in the first 360 days post-index was 80.0% (SD 26.0). Using the first 60 days of early adherence as the only predictor in the model showed an R2 of 20.6%. The base model (i.e., no early adherence measure but other covariates included) yielded an adjusted R2 of only 2.3%. As the time period of early adherence is increased (from 60 to 360 days), the explained variance as measured by adjusted R2 values increased from 20.6% to 53.5% (early adherence-only models). Addition of the covariates, other than early adherence, increased the R2 by 1% to 2%. Statistical predictive models that include early adherence with DMDs were able to explain the variance in future adherence outcomes to a greater extent than models based solely on baseline characteristics. The efficiency of an adherence intervention in reaching its intended target can be improved by using models such as these with enhanced specificity and selectivity.


Characterization of a novel synapse-specific protein. II. cDNA cloning and sequence analysis of the F1-20 protein.
The F1-20 protein is a novel neuronal-specific, synapse-associated protein that is expressed nonuniformly in mouse brain. Expression of the F1-20 protein is developmentally regulated in a pattern coincident with active synaptogenesis and synaptic maturation. Here we report the cloning of the cDNA sequence for the F1-20 protein. We found two distinct isoforms of F1-20 cDNA that differed by the presence of 15 additional nucleotides, which does not interrupt the open reading frame. RNase protection analysis and PCR amplification of mouse brain RNA revealed that both isoforms are present in cellular RNA. It is likely that the two F1-20 mRNA isoforms are derived from RNA splicing events utilizing alternative 3' acceptor sites. Analysis of the deduced amino acid sequence for the complete open reading frame revealed that the predominant F1-20 mRNA encodes an 896 amino acid polypeptide with a molecular weight of 91,319 Da. The deduced amino acid sequence does not contain a signal sequence, or any extensive hydrophobic regions. The deduced amino acid sequence does contain a number of consensus sequences for protein kinases. Searches of the protein and nucleic acid sequence data bases revealed that the F1-20 protein has not been previously characterized at the primary structure level, although a weak similarity was found between rabbit calpastatin and the C-terminal portion of the F1-20 protein. We then determined biochemically that the F1-20 protein is a substrate for Ca(2+)-dependent proteolysis, which is specifically inhibited by calpain inhibitors in vitro. This indicates that the F1-20 protein is a substrate for neuronal calpain. We observed that treatment of a synaptosomal lysate with alkaline phosphatase led to an increase in the electrophoretic mobility of the F1-20 protein, as well as to an increase in the sharpness of the electrophoretic band. This indicates that the F1-20 protein is phosphorylated in vivo.


Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages.
Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighboring surviving cells. In epithelial cells of Drosophila imaginal discs, the Caspase-9 ortholog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Here we show that caspase-induced activation of JNK during AiP depends on an inflammatory response. This is mediated by extracellular reactive oxygen species (ROSs) generated by the NADPH oxidase Duox in epithelial disc cells. Extracellular ROSs activate Drosophila macrophages (hemocytes), which in turn trigger JNK activity in epithelial cells by signaling through the tumor necrosis factor (TNF) ortholog Eiger. We propose that in an immortalized ("undead") model of AiP, signaling back and forth between epithelial disc cells and hemocytes by extracellular ROSs and TNF/Eiger drives overgrowth of the disc epithelium. These data illustrate a bidirectional cell-cell communication pathway with implication for tissue repair, regeneration, and cancer.


Symptomatic progression of asymptomatic rotator cuff tears: a prospective study of clinical and sonographic variables.
The purposes of this study were to identify changes in tear dimensions, shoulder function, and glenohumeral kinematics when an asymptomatic rotator cuff tear becomes painful and to identify characteristics of individuals who develop pain compared with those who remain asymptomatic. A cohort of 195 subjects with an asymptomatic rotator cuff tear was prospectively monitored for pain development and examined annually for changes in various parameters such as tear size, fatty degeneration of the rotator cuff muscle, glenohumeral kinematics, and shoulder function. Forty-four subjects were found to have developed new pain, and the parameters before and after pain development were compared. The forty-four subjects were then compared with a group of fifty-five subjects who remained asymptomatic over a two-year period. With pain development, the size of a full-thickness rotator cuff tear increased significantly, with 18% of the full-thickness tears showing an increase of >5 mm, and 40% of the partial-thickness tears had progressed to a full-thickness tear. In comparison with the assessments made before the onset of pain, the American Shoulder and Elbow Surgeons scores for shoulder function were significantly decreased and all measures of shoulder range of motion were decreased except for external rotation at 90° of abduction. There was an increase in compensatory scapulothoracic motion in relation to the glenohumeral motion during early shoulder abduction with pain development. No significant changes were found in external rotation strength or muscular fatty degeneration. Compared with the subjects who remained asymptomatic, the subjects who developed pain were found to have significantly larger tears at the time of initial enrollment. Pain development in shoulders with an asymptomatic rotator cuff tear is associated with an increase in tear size. Larger tears are more likely to develop pain in the short term than are smaller tears. Further research is warranted to investigate the role of prophylactic treatment of asymptomatic shoulders to avoid the development of pain and loss of shoulder function.


Synthesis and reactivity of potential toxic metabolites of tamoxifen analogues: droloxifene and toremifene o-quinones.
Tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer. However, tamoxifen has been shown to increase the risk of endometrial cancer which has stimulated research for new effective antiestrogens, such as droloxifene and toremifene. In this study, the potential for these compounds to cause cytotoxic effects was investigated. One potential cytotoxic mechanism could involve metabolism of droloxifene and toremifene to catechols, followed by oxidation to reactive o-quinones. Another cytotoxic pathway could involve the oxidation of 4-hydroxytoremifene to an electrophilic quinone methide. Comparison of the amounts of GSH conjugates formed from 4-hydroxytamoxifen, droloxifene, and 4-hydroxytoremifene suggested that 4-hydroxytoremifene is more effective at formation of a quinone methide. However, all three substrates formed similar amounts of o-quinones. Both the tamoxifen-o-quinone and toremifene-o-quinone reacted with deoxynucleosides to give corresponding adducts. However, the toremifene-o-quinone was shown to be considerably more reactive than the tamoxifen-o-quinone in terms of both kinetic data as well as the yield and type of deoxynucleoside adducts formed. Since thymidine formed the most abundant adducts with the toremifene-o-quinone, sufficient material was obtained for characterization by (1)H NMR, COSY-NMR, DEPT-NMR, and tandem mass spectrometry. Cytotoxicity studies with tamoxifen, droloxifene, 4-hydroxytamoxifen, 4-hydroxytoremifene, and their catechol metabolites were carried out in the human breast cancer cell lines S30 and MDA-MB-231. All of the metabolites tested showed cytotoxic effects that were similar to the parent antiestrogens which suggests that o-quinone formation from tamoxifen, droloxifene, and 4-hydroxytoremifene is unlikely to contribute to their cytotoxicity. However, the fact that the o-quinones formed adducts with deoxynucleosides in vitro implies that the o-quinone pathway might contribute to the genotoxicity of the antiestrogens in vivo.


Predicting perturbation patterns from the topology of biological networks.
High-throughput technologies, offering an unprecedented wealth of quantitative data underlying the makeup of living systems, are changing biology. Notably, the systematic mapping of the relationships between biochemical entities has fueled the rapid development of network biology, offering a suitable framework to describe disease phenotypes and predict potential drug targets. However, our ability to develop accurate dynamical models remains limited, due in part to the limited knowledge of the kinetic parameters underlying these interactions. Here, we explore the degree to which we can make reasonably accurate predictions in the absence of the kinetic parameters. We find that simple dynamically agnostic models are sufficient to recover the strength and sign of the biochemical perturbation patterns observed in 87 biological models for which the underlying kinetics are known. Surprisingly, a simple distance-based model achieves 65% accuracy. We show that this predictive power is robust to topological and kinetic parameter perturbations, and we identify key network properties that can increase up to 80% the recovery rate of the true perturbation patterns. We validate our approach using experimental data on the chemotactic pathway in bacteria, finding that a network model of perturbation spreading predicts with ∼80% accuracy the directionality of gene expression and phenotype changes in knock-out and overproduction experiments. These findings show that the steady advances in mapping out the topology of biochemical interaction networks opens avenues for accurate perturbation spread modeling, with direct implications for medicine and drug development.


A roller coaster of emotions and sense--coping with the perceived psychosocial consequences of a false-positive screening mammography.
To explore coping with the perceived psychosocial consequences of a false-positive screening mammography. Mammographic screening has been found effective to decrease breast cancer (BC) mortality, yet there are adverse effects. Psychosocial consequences of false-positive mammographic screening have mainly been investigated from a population-based perspective. A call for qualitative studies to further explore these consequences has thus been postulated. To date, qualitative studies have elucidated women's experiences following their recall breast examinations, but their coping with perceived psychosocial consequences of a false-positive screening mammography has not yet been explored. An explorative qualitative study. Face-to-face interviews were held with a purposive heterogeneous sample of 13 Swedish-speaking women with a false-positive screening mammography. The transcripts were analysed by the use of an inductive content analysis. Coping with the perceived psychosocial consequences of a false-positive screening mammography implied a roller coaster of emotion and sense. Women described how they imagined the worst and were in a state of uncertainty feeling threatened by a fatal disease. Conversely, they felt protected, surrounded by their families and being professionally taken care of, which together with perceived sisterhood and self-empowerment evoked strength and hope. Being aware of family responsibility became a crucial matter. Experiencing false-positive screening raised thoughts of thankfulness and reappraisal of life, although an ounce of BC anxiety remained. Consequently, gained awareness about BC screening and values in life surfaced. Experiencing a false-positive screening mammography triggers agonising experiences evoking a variety of coping strategies. Provision of screening raises the issue of responsibility for an impact on psychosocial well-being among healthy women. Gained knowledge might provide a basis for interventions to prevent psychosocial consequences of false-positive mammographic screening and provide support for women with a potentially compromised ability to overcome such consequences.


An ERP study of good production vis-à-vis poor perception of tones in Cantonese: implications for top-down speech processing.
This study investigated a theoretically challenging dissociation between good production and poor perception of tones among neurologically unimpaired native speakers of Cantonese. The dissociation is referred to as the near-merger phenomenon in sociolinguistic studies of sound change. In a passive oddball paradigm, lexical and nonlexical syllables of the T1/T6 and T4/T6 contrasts were presented to elicit the mismatch negativity (MMN) and P3a from two groups of participants, those who could produce and distinguish all tones in the language (Control) and those who could produce all tones but specifically failed to distinguish between T4 and T6 in perception (Dissociation). The presence of MMN to T1/T6 and null response to T4/T6 of lexical syllables in the dissociation group confirmed the near-merger phenomenon. The observation that the control participants exhibited a statistically reliable MMN to lexical syllables of T1/T6, weaker responses to nonlexical syllables of T1/T6 and lexical syllables of T4/T6, and finally null response to nonlexical syllables of T4/T6, suggests the involvement of top-down processing in speech perception. Furthermore, the stronger P3a response of the control group, compared with the dissociation group in the same experimental conditions, may be taken to indicate higher cognitive capability in attention switching, auditory attention or memory in the control participants. This cognitive difference, together with our speculation that constant top-down predictions without complete bottom-up analysis of acoustic signals in speech recognition may reduce one's sensitivity to small acoustic contrasts, account for the occurrence of dissociation in some individuals but not others.


Anomalomermis ephemerophagis n. g., n. sp. (Nematoda: Mermithidae) parasitic in the mayfly Ephemerella maculata Traver (Ephermeroptera: Ephermerellidae) in California, USA.
A new nematode, Anomalomermis ephemerophagis n. g., n. sp. (Nematoda: Mermithidae) is described from the mayfly Ephemerella maculata Traver (Ephermeroptera: Ephermerellidae) in California. The new species is characterised by six cephalic papillae and four additional disk papillae located on the head between the cephalic papillae and stoma. Additional diagnostic characters are: a terminal mouth opening; absence of X-fibers in the cuticle of both postparasitic juveniles and adults; paired, curved, medium-sized spicules; a straight barrow-shaped vagina and large eggs. Two infectious agents were present in some specimens. This is the first description of an adult nematode from a mayfly.


Xianglian Pill ameliorates antibiotic-associated diarrhea by restoring intestinal microbiota and attenuating mucosal damage.
Xianglian Pill (XLP), a traditional Chinese pharmaceutical preparation for the treatment of gastrointestinal disease, possessing anti-inflammatory, anti-microbial and analgesic activities, may represent a promising candidate for the treatment of antibiotic-associated diarrhea (AAD). This study aimed to unravel the underlying mechanism of XLP on the amelioration of AAD. AAD was induced by intragastric administration of a mixture of cefuroxime and levofoxacin (300 mg/kg. bw + 200 mg/kg. bw) for five consecutive days. Then AAD mice were treated with XLP at the dose of 500, 1000 and 2000 mg/kg. bw, respectively for 5 days. The physical manifestations, diarrhea status were monitored during the drug delivery. Histopathology of colon, intestinal microbiota, inflammatory cytokines, tight junction protein and short chain fat acids (SCFAs) were determined. Mice received cefuroxime and levofoxacin for 5 days developed medium to severe diarrhea. XLP treatment, however, mitigated the diarrhea status. Further evaluation revealed that XLP promoted the recovery of mucosa, maintained the integrity of tight junction, attenuated the inflammatory disorders, restored intestinal microbiota and increased SCFAs level in feces. XLP ameliorates AAD by restoring intestinal microbiota and attenuating mucosal damage.


Exposure to extreme stress impairs contextual odour discrimination in an animal model of PTSD.
Post-traumatic stress disorder (PTSD) patients respond to trauma-related danger cues even in objectively safe environments as if they were in the original event, seemingly unable to adequately modulate their responses based on the contextual cues present. In order to model this inability to utilize contextualized memory, in an animal model of PTSD, a novel experimental paradigm of contextual cue processing was developed--the differential contextual odour conditioning (DCOC) paradigm--and tested in trauma-exposed animals and controls. In the DCOC paradigm, animals encountered cinnamon odour in both an aversive environment and a rewarding (safe) environment. Response (freezing) to cinnamon odour was tested in a third, neutral environment to examine the ability of animals to modulate their responses based on the contextual cues. The effect of exposure to traumatic stressors, e.g. predator scent stress (PSS) and underwater trauma (UWT), on contextual cue discrimination was assessed. Rats trained in the DCOC paradigm acquired the ability to modulate their behavioural responses to odour cue based on contextual cues signalling safe vs. dangerous environment. The PSS and UWT stressors abolished the ability to modulate their responses based on contextual cues, both when exposure preceded DCOC training, and when it followed successfully completed training. The DCOC paradigm offers a promising model for studying the neurobiological basis of contextual modulation of response to potential threat in animals, a process that is disrupted by exposure to severe stress/trauma, and thus might be particularly salient for the study of PTSD.


Molecular adaptation of telomere associated genes in mammals.
Placental mammals display a huge range of life history traits, including size, longevity, metabolic rate and germ line generation time. Although a number of general trends have been proposed between these traits, there are exceptions that warrant further investigation. Species such as naked mole rat, human and certain bat species all exhibit extreme longevity with respect to body size. It has long been established that telomeres and telomere maintenance have a clear role in ageing but it has not yet been established whether there is evidence for adaptation in telomere maintenance proteins that could account for increased longevity in these species. Here we carry out a molecular investigation of selective pressure variation, specifically focusing on telomere associated genes across placental mammals. In general we observe a large number of instances of positive selection acting on telomere genes. Although these signatures of selection overall are not significantly correlated with either longevity or body size we do identify positive selection in the microbat species Myotis lucifugus in functionally important regions of the telomere maintenance genes DKC1 and TERT, and in naked mole rat in the DNA repair gene BRCA1. These results demonstrate the multifarious selective pressures acting across the mammal phylogeny driving lineage-specific adaptations of telomere associated genes. Our results show that regardless of the longevity of a species, these proteins have evolved under positive selection thereby removing increased longevity as the single selective force driving this rapid rate of evolution. However, evidence of molecular adaptations specific to naked mole rat and Myotis lucifugus highlight functionally significant regions in genes that may alter the way in which telomeres are regulated and maintained in these longer-lived species.


Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial.
Hypoglycemia is a leading risk of glucose-lowering therapy. Treatment with insulin glargine compared with standard care early in the course of dysglycemia in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial provides information on the frequency and predictors of hypoglycemia in this setting. A total of 12,537 people with high cardiovascular risk and dysglycemia treated with one or no oral glucose-lowering agents were randomized to add glargine titrated to a fasting glucose level of ≤5.3 mmol/L (≤95 mg/dL) or to use standard therapies. Independent associations of both nonsevere hypoglycemia (symptomatic and confirmed with a glucose level of ≤3 mmol/L [≤54 mg/dL]) and severe hypoglycemia with characteristics at baseline, treatment allocation, and average HbA1c were assessed by Cox proportional hazards models. During a median follow-up period of 6.2 years, 28% of participants reported nonsevere hypoglycemia, and 3.8% reported severe hypoglycemia. Prior use of a sulfonylurea and allocation to glargine independently predicted a higher risk for both categories of participants. Nonsevere events were independently associated with younger age, lower BMI, the presence of diabetes, and higher baseline HbA1c level. Severe events were associated with older age, hypertension, higher serum creatinine level, and lower cognitive function, but not baseline glycemic status. Progressively higher on-treatment HbA1c level was associated with a lower risk of nonsevere events in both treatment groups; a lower risk of severe events in the glargine group, and a higher risk of severe events with standard care. Hypoglycemia was relatively uncommon in the ORIGIN trial, but was more frequent with sulfonylurea use at baseline and allocation to glargine. Nonsevere and severe events were associated with different clinical characteristics, awareness of which may guide individualized therapy.


Vibrio vulnificus biogroup 2: new biogroup pathogenic for eels.
Clinical and nonclinical isolates of the lactose-positive Vibrio vulnificus were compared with Vibrio strains isolated from lesions on eels (Anguilla japonica) cultured commercially in Japan. Strains were compared phenotypically and antigenically, for pathogenicity to mice and eels, and for genetic relatedness. The strains isolated from diseased eels differed phenotypically from the original species description of V. vulnificus in that they were negative for indole production, ornithine decarboxylase activity, growth at 42 degrees C, and acid production from mannitol and sorbitol. No relationship between the surface antigens of V. vulnificus strains from environmental and clinical sources and the strains from diseased eels was observed. Typical V. vulnificus strains and the eel isolates were pathogenic to mice; however, only those strains originally isolated from diseased eels were found to be pathogenic to eels. Results of DNA-DNA competition experiments revealed that there was greater than 90% relative reassociation between clinical and nonclinical V. vulnificus and strains from diseased eels. Based on the results of the DNA-DNA competition experiments, we conclude that the strains isolated from diseased eels were V. vulnificus; however, the differences in phenotypic characteristics and eel pathogenicity indicated that these strains represent a different biogroup. Therefore, we propose that strains phenotypically similar to the type strain of the species (ATCC 27562) be classified as V. vulnificus biogroup 1 and the strains phenotypically similar to those isolated from diseased eels be classified as V. vulnificus biogroup 2 represented by the reference strain ATCC 33148.


Autoradiographic study of smooth muscle cell proliferation in spontaneously hypertensive rats.
1. The rate of smooth muscle cell proliferation in age-matched 1-4-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was compared using autoradiography. 2. Labelling index, defined as labelled cells/sum of labelled and unlabelled cells x 1000, was obtained from perfusion-fixed superior mesenteric and large mesenteric arteries. 3. In the large mesenteric arteries, the smooth muscle cell labelling indices were similar between the SHR and WKY at all age groups, except at 1 week of age when the smooth muscle labelling index was higher in the SHR. 4. In the superior mesenteric arteries, labelling indices were similar between the rat strains at all age groups. 5. We conclude that, in the SHR, a rapid proliferation of smooth muscle cells in the large mesenteric arteries occurred during the first week of life. This resulted in a higher number of smooth muscle cell layers in the media of muscular arteries. 6. The increased proliferation may play a role in the subsequent development of hypertension in the SHR.


Carbohydrate CuAAC click chemistry for therapy and diagnosis.
Carbohydrates are important as signaling molecules and for cellular recognition events, therefore offering scope for the development of carbohydrate-mimetic diagnostics and drug candidates. As a consequence, the construction of carbohydrate-based bioactive compounds and sensors has become an active research area. While the advent of click chemistry has greatly accelerated the progress of medicinal chemistry and chemical biology, recent literature has seen an extensive use of such approaches to construct functionally diverse carbohydrate derivatives. Here we summarize some of the progress, covering the period 2010 to mid-2015, in Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition CuAAC "click chemistry" of carbohydrate derivatives, in the context of potential therapeutic and diagnostic tool development.


Self-harm subscale of the Schedule for Nonadaptive and Adaptive Personality (SNAP): predicting suicide attempts over 8 years of follow-up.
We examined the predictive power of the self-harm subscale of the Schedule for Nonadaptive and Adaptive Personality (SNAP) to identify suicide attempters in the Collaborative Longitudinal Study of Personality Disorders (CLPS). The SNAP, a self-report personality inventory, was administered to 733 CLPS participants at baseline, of whom 701 (96%) had at least 6 months of follow-up data. Cox proportional hazards regression analyses were performed to examine the SNAP-self-harm subscale (SNAP-SH) in predicting the 129 suicide attempters over 8 years of follow-up. Possible moderators of prediction were examined, including borderline personality disorder, major depressive disorder (MDD), and substance use disorder. We also compared baseline administration of the SNAP-SH to subsequent administrations more proximal to the suicide attempt, and to a higher-order SNAP-negative temperament (SNAP-NT) subscale. Receiver operating characteristic analyses were conducted using suicide attempts (n = 58) over the first year of follow-up to provide reference points for sensitivity and specificity. The SNAP-SH demonstrated good predictive power for suicide attempts (hazard ratio = 1.28, P < .001) and appeared relatively consistent across borderline personality disorder, MDD, and substance use disorder diagnoses. Using more proximal scores did not increase predictive power. The SNAP-SH compared favorably to the predictive power of the higher-order SNAP-NT. Receiver operating characteristic analyses indicate several cutoff scores on the SNAP-SH that yield moderate to high sensitivity and specificity for predicting suicide attempts over the first year of follow-up. The SNAP-SH may be a useful screening instrument for risk of suicide attempts in nonpsychotic psychiatric patients.


Sequence and gene expression evolution of paralogous genes in willows.
Whole genome duplications (WGD) have had strong impacts on species diversification by triggering evolutionary novelties, however, relatively little is known about the balance between gene loss and forces involved in the retention of duplicated genes originating from a WGD. We analyzed putative Salicoid duplicates in willows, originating from the Salicoid WGD, which took place more than 45 Mya. Contigs were constructed by de novo assembly of RNA-seq data derived from leaves and roots from two genotypes. Among the 48,508 contigs, 3,778 pairs were, based on fourfold synonymous third-codon transversion rates and syntenic positions, predicted to be Salicoid duplicates. Both copies were in most cases expressed in both tissues and 74% were significantly differentially expressed. Mean Ka/Ks was 0.23, suggesting that the Salicoid duplicates are evolving by purifying selection. Gene Ontology enrichment analyses showed that functions related to DNA- and nucleic acid binding were over-represented among the non-differentially expressed Salicoid duplicates, while functions related to biosynthesis and metabolism were over-represented among the differentially expressed Salicoid duplicates. We propose that the differentially expressed Salicoid duplicates are regulatory neo- and/or subfunctionalized, while the non-differentially expressed are dose sensitive, hence, functionally conserved. Multiple evolutionary processes, thus drive the retention of Salicoid duplicates in willows.


Optogenetic stimulation of a hippocampal engram activates fear memory recall.
A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.


Genetic variants in microRNAs and breast cancer risk in African American and European American women.
MicroRNAs (miRNAs) are an integral part of the post-transcriptional machinery of gene expression and have been implicated in the carcinogenic cascade. Single nucleotide polymorphisms (SNPs) in miRNAs and risk of breast cancer have been evaluated in populations of European or Asian ancestry, but not among women of African ancestry. Here we examined 145 SNPs in six miRNA processing genes and in 78 miRNAs which target genes known to be important in breast cancer among 906 African American (AA) and 653 European American (EA) cases and controls enrolled in the Women's Circle of Health Study. Allele frequencies of most SNPs (87 %) differed significantly by race. We found a number of SNPs in miRNAs and processing genes in association with breast cancer overall or stratified by estrogen receptor (ER) status. Several associations were significantly different by race, with none of the associations being significant in both races. Using a polygenic risk score to combine the effects of multiple SNPs, we found significant associations with the score in each subgroup analysis. For ER-positive cancer, each unit increment of the risk score was associated with a 51 % increased risk in AAs (OR = 1.51, 95 % CI = 1.30-1.74, p = 3.3 × 10(-8)) and a 73 % increased risk in EAs (OR = 1.73, 95 % CI = 1.45-2.06, p = 1.4 × 10(-9)). These data show, for the first time, that miRNA-related genetic variations may underlie the etiology of breast cancer in both populations of African and European ancestries. Future studies are needed to validate our findings and to explore the underlying mechanisms.


On the benefits of populations for noisy optimization.
It is known that, in the absence of noise, no improvement in local performance can be gained from retaining candidate solutions other than the best one. Yet, it has been shown experimentally that, in the presence of noise, operating with a non-singular population of candidate solutions can have a marked and positive effect on the local performance of evolution strategies. So as to determine the reasons for the improved performance, we have studied the evolutionary dynamics of the (micro ,lambda)-ES in the presence of noise. Considering a simple, idealized environment, we have developed a moment-based approach that uses recent results involving concomitants of selected order statistics. This approach yields an intuitive explanation for the performance advantage of multi-parent strategies in the presence of noise. It is then shown that the idealized dynamic process considered does bear relevance to optimization problems in high-dimensional search spaces.


[Mycobacterial infections in HIV-infected patients in Cali, Colombia].
The prevalence of mycobacterial infections was determined in a sample of 155 individuals infected with human immunodeficiency virus (HIV) who were treated in the Social Security Institute (SSI) of Cali, Colombia. A tuberculin test (2 TU PPD RT23) was used, and the presence of mycobacteria was checked through direct microscopy and culturing blood, urine, feces, and gastric aspirate. When clinically indicated, samples of cerebrospinal fluid, bone marrow, and sputum were also examined and cultivated. The absence of reactivity to tuberculin was significantly more frequent in the patients than in the controls (91.3%, compared to 57.4%; chi 2 = 33, P = 0). The prevalence of tuberculosis was 6.5%, in comparison with 0.04% among a group of HIV-negative ISS members (exact binomial 95% confidence interval: 0.0313% to 0.1154%). Nontuberculous mycobacteria (NTM), present in 43 patients, were significantly more frequent than Mycobacterium tuberculosis (27.7%, versus 6.5%; chi 2 = 24.78, P = 0.000,001), but they caused illness only in some cases. The most common species were those of the M. avium-intracellulare complex. M. avium-intracellulare and M. fortuitum had a total prevalence of 7.1% and were the most-prevalent NTM that caused disease in these patients (4.5%); they were also responsible for three cases of disseminated infection. Clinical disease caused by M. tuberculosis or NTM and complete tuberculin anergy were associated with stage-IV HIV infection and with CD4 lymphocyte counts < or = 400/microL. However, the lack of immunocellular response, shown by limited tuberculin reactivity, was found beginning with the asymptomatic HIV carrier stage. The progressive deterioration of the immune system of HIV-positive patients is the determining factor in the high morbidity and mortality with mycobacteria infections and requires prompt chemoprophylaxis or treatment.


Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover study.
Many human studies report that nitric oxide (NO) improves sport performance. This is because NO is a potential modulator of blood flow, muscle energy metabolism, and mitochondrial respiration during exercise. L-Citrulline is an amino acid present in the body and is a potent endogenous precursor of L-arginine, which is a substrate for NO synthase. Here, we investigated the effect of oral L-citrulline supplementation on cycling time trial performance in humans. A double-blind randomized placebo-controlled 2-way crossover study was employed. Twenty-two trained males consumed 2.4 g/day of L-citrulline or placebo orally for 7 days. On Day 8 they took 2.4 g of L-citrulline or placebo 1 h before a 4-km cycling time trial. Time taken to complete the 4 km cycle, along with power output/VO2 ratio (PO/VO2), plasma nitrite and nitrate (NOx) and amino acid levels, and visual analog scale (VAS) scores, was evaluated. L-Citrulline supplementation significantly increased plasma L-arginine levels and reduced completion time by 1.5 % (p < 0.05) compared with placebo. Moreover, L-citrulline significantly improved subjective feelings of muscle fatigue and concentration immediately after exercise. Oral L-citrulline supplementation reduced the time take to complete a cycle ergometer exercise trial. Current Controlled Trials UMIN000014278.


Cell mechanotactic and cytotoxic response to zinc oxide nanorods depends on substrate stiffness.
Bio-nanomaterials offer promise in the field of tissue engineering. Specifically, environmental cues such as the material chemistry, topography and rigidity of the surface to which cells adhere to, can alter and dictate cell shape, proliferation, migration, and gene expression. How deeply each factor (topographical, chemical and mechanical) drives cell response remains incompletely understood. To illustrate cell sensitivities to different factors, we herein present ZnO nanorods (ZnO-Nrds) coated on glass and polydimethylsiloxane (PDMS) substrates and analyzed cell viability and proliferation. The work presented here shows a clear response of various cell lines (mouse embryonic fibroblasts 3T3, human cervix carcinoma HeLa and human osteoblast-like cells MG63) to the rigidity of the underlying surface. The chemical counterpart, given by the presence of ZnO-Nrds, strongly reduced the cell viability of all cell lines. However, the substrate underlying the ZnO coating impacted cell spreading and viability. The substrates exhibited a better ability to neglect cell attachment and proliferation with the ZnO coating and pro-apoptoticity specifically with the PDMS as the underlying substrate which exhibited a "softer" environment with respect to a glass substrate. The results also revealed that the few cells that adhered to the ZnO-Nrds on PDMS and glass showed a rounded morphology. On the basis of these observations, we can correlate common features of phenomenological cell response to chemotactic and durotactic cues. The work presented herein reinforces the response of cells to changes in substrate rigidity. These observations provide a foundation for a potentially promising approach to decrease cell adhesion and thus as an optimal substrate for different applications such as prosthesis design, tissue engineering, anti-bio fouling materials and diagnostics.


Rehydration after exercise with fresh young coconut water, carbohydrate-electrolyte beverage and plain water.
This is to cross-over study to assess the effectiveness of fresh young coconut water (CW), and carbohydrate-electrolyte beverage (CEB) compared with plain water (PW) for whole body rehydration and blood volume (BV) restoration during a 2 h rehydration period following exercise-induced dehydration. Eight healthy male volunteers (mean age and VO2max of 22.4 +/- 3.3 years and 45.8 +/- 1.5 ml min kg-1 respectively) exercised at 60% of VO2max in the heat (31.1 +/- 0.03 degrees C, 51.4 +/- 0.1% rh) until 2.78 +/- 0.06% (1.6 +/- 0.1 kg) of their body weight (BW) was lost. After exercise, the subjects sat for 2 h in a thermoneutral environment (22.5 +/- 0.1 degrees C; 67.0 +/- 1.0% rh) and drank a volume of PW, CW and CEB on different occasions representing 120% of the fluid loss. A blood and urine sample, and the body weight of each subject was taken before and after exercise and at 30 min intervals throughout a rehydration period. Each subject remained fasted throughout rehydration. Each fluid was consumed in three portions in separate trials representing 50% (781 +/- 47 ml), 40% (625 +/- 33 ml) and 30% (469 +/- 28 ml) of the 120% fluid loss at 0, 30 and 60 min of the 2 h rehydration period, respectively. The drinks given were randomised. In all the trials the subjects were somewhat hypohydrated (range 0.08-0.18 kg BW below euhydrated BW; p > 0.05) after a 2 h rehydration period since additional water and BW were lost as a result of urine formation, respiration, sweat and metabolism. The percent of body weight loss that was regained (used as index of percent rehydration) during CW, PW, and CEB trials was 75 +/- 5%, 73 +/- 5% and 80 +/- 4% respectively, but was not statistically different between trials. The rehydration index, which provided an indication of how much of what was actually ingested was used for body weight restoration, was again not different statistically between trials (1.56 +/- 0.14, 1.36 +/- 0.13 and 1.71 +/- 0.21 for CW, CEB and PW respectively). Although BV restoration was better with CW, it was not statistically different from CEB and PW. Cumulative urine output was similar in all trials. There were no difference at any time in serum Na+ and Cl-, serum osmolality, and net fluid balance between the three trials. Urine osmolality decreased after 1 h during the rehydration period and it was lowest in the PW trial. Plasma glucose concentrations were significantly higher compared with PW ingestion when CW and CEB were ingested during the rehydration period. CW was significantly sweeter, caused less nausea, fullness and no stomach upset and was also easier to consume in a larger amount compared with CEB and PW ingestion. In conclusion, ingestion of fresh young coconut water, a natural refreshing beverage, could be used for whole body rehydration after exercise.


Moxalactam plus ticarcillin or tobramycin for treatment of febrile episodes in neutropenic cancer patients.
Moxalactam disodium in combination with ticarcillin disodium or tobramycin sulfate was used to treat 445 episodes of suspected or confirmed infection in patients with cancer. The majority had leukemia and neutropenia. The rate of cures during the 231 confirmed infections was 65% for moxalactam and ticarcillin and 64% for moxalactam and tobramycin. Both regimens were comparable against aerobic gram-negative and polymicrobial infections. In gram-positive infections, the response rate for moxalactam and ticarcillin was 73% and for moxalactam and tobramycin, 53%. Only three of nine enterococcal infections responded to treatment. Thirteen percent of all organisms recovered were resistant to moxalactam. Side effects occurred infrequently; the most important was coagulopathy due to moxalactam. Nephrotoxic effects occurred in six patients receiving moxalactam and tobramycin and in none of those receiving moxalactam and ticarcillin. In 39 patients, a superinfection was confirmed. Fourteen were fungal, three were due to enterococcus, and one due to Klebsiella species. Eleven of the 14 fungal episodes occurred in the moxalactam-ticarcillin group. Moxalactam with ticarcillin and moxalactam with tobramycin are equally active for the initial treatment of presumed infection in patients with neutropenia.


Dietary Patterns in Relation to Cardiovascular Disease Incidence and Risk Markers in a Middle-Aged British Male Population: Data from the Caerphilly Prospective Study.
Dietary behaviour is an important modifiable factor in cardiovascular disease (CVD) prevention. The study aimed to identify dietary patterns (DPs) and explore their association with CVD incidence and risk markers. A follow-up of 1838 middle-aged men, aged 47-67 years recruited into the Caerphilly Prospective Cohort Study at phase 2 (1984-1988) was undertaken. Principal component analysis identified three DPs at baseline, which explained 24.8% of the total variance of food intake. DP1, characterised by higher intakes of white bread, butter, lard, chips and sugar-sweetened beverages and lower intake of wholegrain bread, was associated with higher CVD (HR 1.35: 95% CI: 1.10, 1.67) and stroke (HR 1.77; 95% CI: 1.18, 2.63) incidence. DP3, characterised by higher intakes of sweet puddings and biscuits, wholegrain breakfast cereals and dairy (excluding cheese and butter) and lower alcohol intake, was associated with lower CVD (HR 0.76; 95% CI: 0.62, 0.93), coronary heart disease (HR: 0.68; 95% CI: 0.52, 0.90) and stroke (HR: 0.68; 95% CI: 0.47, 0.99) incidence and a beneficial CVD profile at baseline, while DP1 with an unfavourable profile, showed no clear associations after 12 years follow-up. Dietary pattern 2 (DP2), characterised by higher intake of pulses, fish, poultry, processed/red meat, rice, pasta and vegetables, was not associated with the aforementioned outcomes. These data may provide insight for development of public health initiatives focussing on feasible changes in dietary habits.


Sound policy trumps politics: states should expand Medicaid.
By virtue of the Supreme Court's decision on the constitutionality of the Patient Protection and Affordable Care Act, states may reject the law's expansion of Medicaid without losing all Medicaid funding from the federal government. The Court's ruling potentially permits a range of Medicaid options for states, including some that may be very attractive from state officials' political perspectives. In the context of the presidential campaign, the uncompensated care problem, and their concerns about costs of expansion, state officials are weighing their options, and some have already pledged to opt out of expansion. We argue that despite the politics, expansion is in fact good for patients, providers, and taxpayers, and states should therefore comply.


Determinants for acceptance of preventive treatment against heart disease - a web-based population survey.
Patients' perception of risk and their lifestyle choices are of major importance in the treatment of common chronic diseases. This study reveals determinants for and knowledge about why people accept or reject preventive medical interventions against heart disease. A representative sample of 40-60-year-old Danish inhabitants was invited to participate in a web-based survey. The respondents were presented with a hypothetical scenario and asked to imagine that they were at an increased risk of heart disease, and subsequently presented with an offer of a preventive medical intervention. The aim was to elicit preference structures when potential patients are presented with different treatment conditions. About one third of the respondents were willing to accept preventive medical treatment. Respondents with personal experience with heart disease were more likely to accept treatment than respondents with family members with heart disease or no prior experience with heart disease. The willingness to accept treatment was similar for both genders, and when adjusting for experience with heart disease, age was not associated with willingness to accept treatment. Socioeconomic status in terms of lower education was positively associated with acceptance. The price of treatment reduced willingness to accept for the lower income groups, whereas it had no effect in the highest income group. Some 57% of respondents who were willing to accept treatment changed their decision following information on potential side effects. In accordance with our pre-study hypothesis, individuals with low income were more sensitive to price than individuals with high income. Thus, if the price of preventive medication increases above certain limits, a substantial proportion of the population may refrain from treatment. More than half of the respondents who were initially willing to accept treatment changed their decision when informed about the presence of potential side effects. This is an important observation in relation to risk communication, since most side effects occur very seldom, and a skewed assessment of treatment efficacy compared to risk of side effects may refrain some patients from treatment. Thus, more research is needed to better allow patients to compare treatment efficacy with risk of side effects in quantitative terms.


Disease variant prediction with deep generative models of evolutionary data.
Quantifying the pathogenicity of protein variants in human disease-related genes would have a marked effect on clinical decisions, yet the overwhelming majority (over 98%) of these variants still have unknown consequences1-3. In principle, computational methods could support the large-scale interpretation of genetic variants. However, state-of-the-art methods4-10 have relied on training machine learning models on known disease labels. As these labels are sparse, biased and of variable quality, the resulting models have been considered insufficiently reliable11. Here we propose an approach that leverages deep generative models to predict variant pathogenicity without relying on labels. By modelling the distribution of sequence variation across organisms, we implicitly capture constraints on the protein sequences that maintain fitness. Our model EVE (evolutionary model of variant effect) not only outperforms computational approaches that rely on labelled data but also performs on par with, if not better than, predictions from high-throughput experiments, which are increasingly used as evidence for variant classification12-16. We predict the pathogenicity of more than 36 million variants across 3,219 disease genes and provide evidence for the classification of more than 256,000 variants of unknown significance. Our work suggests that models of evolutionary information can provide valuable independent evidence for variant interpretation that will be widely useful in research and clinical settings.


[Drug resistance profile of Mycobacterium tuberculosis in the state of Mato Grosso do Sul, Brazil, 2000-2006].
To determine the drug resistance profile of Mycobacterium tuberculosis in the state of Mato Grosso do Sul, Brazil, between 2000 and 2006. Descriptive study of reported tuberculosis cases in the Brazilian Case Registry Database. We included only those cases in which M. tuberculosis culture was positive and sensitivity to drugs (rifampicin, isoniazid, streptomycin and ethambutol) was tested. Löwenstein-Jensen and Ogawa-Kudoh solid media were used for cultures, as was an automated liquid medium system. Sensitivity tests were based on the proportion method. Among the 783 cases evaluated, males predominated (69.7%), as did patients in the 20-49 year age bracket (70%), a diagnosis of pulmonary tuberculosis (94.4%) and positive HIV serology (8.6%); 645 (82.4%) were new cases, and 138 (17.6%) had previously been treated. Resistance to at least one drug was found in 143 cases (18.3%). The primary resistance (PR) rate was, respectively, 8.1%, 1.6%, 2.8% and 12.4%, for monoresistance, multidrug resistance (MDR), other patterns of resistance and resistance to at least one drug, whereas the acquired resistance (AR) rate was 14.5%, 20.3%, 10.9% and 45.7%, respectively, and the combined resistance (CR) rate was 9.2%, 4.9%, 4.2% and 18.3%, respectively. In PR, streptomycin was the most common drug, whereas isoniazid was the most common in AR and CR (7.2% and 3.7%, respectively). These high levels of resistance undermine the efforts for tuberculosis control in Mato Grosso do Sul. Acquired MDR was 12.7 times more common than was primary MDR, demonstrating that the previous use of drug therapy is an indicator of resistance. These levels reflect the poor quality of the health care provided to these patients, showing the importance of using the directly observed treatment, short course strategy, as well as the need to perform cultures and sensitivity tests for the early diagnosis of drug resistance.


First Report of Damping-off Caused by Alternaria japonica on Chinese Cabbage Seedlings in China.
In May 2011, samples of Chinese cabbage (Brassica campestris L. subsp. chinensis Markino) seedlings at the two-to four-leaf stage with damping-off symptoms were collected from greenhouses in the Tibet Autonomous Region of China. Infected stems of the seedlings were constricted at or near the soil surface. On diseased stems, a light to dark brown coloration was demarcated from healthy tissue. Damping-off and death of seedlings occurred as the lesions enlarged, resulting in a significant reduction of seedlings. Diseased stems were cut into 3-mm-long segments, surface-sterilized with 3.5% sodium hypochlorite for 1 min, and rinsed in sterilized water three times before being placed on water agar. A fungus frequently isolated from diseased plants was hyphal tipped under a dissecting microscope and transferred onto potato dextrose agar (PDA) to obtain a pure culture. The isolate grew slowly on PDA at 25°C with a 12-h photoperiod. The colony was white at first and gradually turned gray or grayish-green. No conidia or chlamydospores developed. However, conidia were produced on potato-carrot agar. Conidia were yellow-brown, obpyriform or obpyriform with beaks, had two to eight transverse septa, one to three vertical or oblique septa, and were produced solitarily or often in chains of two or three and measured 43.5 to 85.2 × 21.5 to 28.0 μm. A few conidia without beaks were also present and were nearly round and slightly smaller than the conidia with beaks. Several adjacent chlamydospores with thickened walls were often intercalary. The isolate was tentatively identified as Alternaria japonica based on its morphological characteristics (1,2). For molecular analyses, the internal transcribed spacer (ITS) regions of ribosomal DNA from the isolate were amplified with universal primers ITS1 and ITS4. The resulting sequence (Accession No. JN654465) submitted to GenBank had a 99% identity to that of A. japonica (Accession No. AY154703.1) isolated from leaves of Raphanus sativus. To confirm the pathogenicity of A. japonica, nine healthy 10-day-old Chinese cabbage seedlings were inoculated at the stem base with one PDA plug from a 6-day-old culture, with nine noninoculated (PDA plus only) seedlings serving as controls. Two days after inoculation, symptoms similar to those on the naturally infected plants developed on the inoculated seedlings. No symptoms developed on the controls. The pathogen was reisolated from the stems of inoculated and diseased seedlings. To our knowledge, this is the first report of A. japonica leading to damping off on Chinese cabbage seedlings in China. References: (1) M. P. Corlett and M. E. Corlett. Can. J. Plant Pathol. 21:298, 1999. (2) T. Y. Zhang. Flora Fungorum Sinicorum: Alternaria (in Chinese) Vol. 16. Science Press, Beijing, 2003.


Population viability and harvest sustainability for Madagascar lemurs.
Subsistence hunting presents a conservation challenge by which biodiversity preservation must be balanced with safeguarding of human livelihoods. Globally, subsistence hunting threatens primate populations, including Madagascar's endemic lemurs. We used population viability analysis to assess the sustainability of lemur hunting in Makira Natural Park, Madagascar. We identified trends in seasonal hunting of 11 Makira lemur species from household interview data, estimated local lemur densities in populations adjacent to focal villages via transect surveys, and quantified extinction vulnerability for these populations based on species-specific demographic parameters and empirically derived hunting rates. We compared stage-based Lefkovitch with periodic Leslie matrices to evaluate the impact of regional dispersal on persistence trajectories and explored the consequences of perturbations to the timing of peak hunting relative to the lemur birth pulse, under assumptions of density-dependent reproductive compensation. Lemur hunting peaked during the fruit-abundant wet season (March-June). Estimated local lemur densities were roughly inverse to body size across our study area. Life-history modeling indicated that hunting most severely threatened the species with the largest bodies (i.e., Hapalemur occidentalis, Avahi laniger, Daubentonia madagascariensis, and Indri indi), characterized by late-age reproductive onsets and long interbirth intervals. In model simulations, lemur dispersal within a regional metapopulation buffered extinction threats when a majority of local sites supported growth rates above the replacement level but drove regional extirpations when most local sites were overharvested. Hunt simulations were most detrimental when timed to overlap lemur births (a reality for D. madagascariensis and I. indri). In sum, Makira lemurs were overharvested. Regional extirpations, which may contribute to broad-scale extinctions, will be likely if current hunting rates persist. Cessation of anthropogenic lemur harvest is a conservation priority, and development programs are needed to help communities switch from wildlife consumption to domestic protein alternatives.


Easing semantically enriched information retrieval-An interactive semi-automatic annotation system for medical documents.
Mapping medical concepts from a terminology system to the concepts in the narrative text of a medical document is necessary to provide semantically accurate information for further processing steps. The MetaMap Transfer (MMTx) program is a semantic annotation system that generates a rough mapping of concepts from the Unified Medical Language System (UMLS) Metathesaurus to free medical text, but this mapping still contains erroneous and ambiguous bits of information. Since manually correcting the mapping is an extremely cumbersome and time-consuming task, we have developed the MapFace editor.The editor provides a convenient way of navigating the annotated information gained from the MMTx output, and enables users to correct this information on both a conceptual and a syntactical level, and thus it greatly facilitates the handling of the MMTx program. Additionally, the editor provides enhanced visualization features to support the correct interpretation of medical concepts within the text. We paid special attention to ensure that the MapFace editor is an intuitive and convenient tool to work with. Therefore, we recently conducted a usability study in order to create a well founded background serving as a starting point for further improvement of the editor's usability.


Torsion and curvature of FtsZ filaments.
FtsZ filaments participate in bacterial cell division, but it is still not clear how their dynamic polymerization and shape exert force on the underlying membrane. We present a theoretical description of individual filaments that incorporates information from molecular dynamic simulations. The structure of the crystallized Methanococcus jannaschii FtsZ dimer was used to model a FtsZ pentamer that showed a curvature and a twist. The estimated bending and torsion angles between monomers and their fluctuations were included in the theoretical description. The MD data also permitted positioning the curvature with respect to the protein coordinates and allowed us to explore the effect of the relative orientation of the preferred curvature with respect to the surface plane. We find that maximum tension is attained when filaments are firmly attached and oriented with their curvature perpendicular to the surface and that the twist serves as a valve to release or to tighten the tension exerted by the curved filaments on the membrane. The theoretical model also shows that the presence of torsion can explain the shape distribution of short filaments observed by Atomic Force Microscopy in previously published experiments. New experiments with FtsZ covalently attached to lipid membranes show that the filament on-plane curvature depends on lipid head charge, confirming the predicted monomer orientation effects. This new model underlines the fact that the combination of the three elements, filament curvature, twist and the strength and orientation of its surface attachment, can modulate the force exerted on the membrane during cell division.


Hydroxycut-induced Liver Toxicity.
In the recent era, use of various nutritional supplements is highly encouraged amongst the people of United States. Weight loss supplements are major part of the nutritional supplements and their usage is unregulated in the US. Obesity is a major health concern in the US and Americans spend around $30 billion a year for weight loss supplements. At times, these supplements can be responsible for documented or undocumented adverse drug effects. The health consequences related to these supplements are often overlooked by the general public, even though FDA issues advisories regarding them. One common supplement used for weight loss was Hydroxycut (Iovate Health Sciences Research, Oakville, Ontario, Canada). Hydroxycut was recalled from the market after a FDA warning in May 2009 because of 23 reports of serious health problems ranging from jaundice and elevated liver enzymes to liver damage. 1 This case report adds evidence for Hydroxycut - induced hepatotoxicity. A 27 year old man with right upper quadrant pain and jaundice was found to have elevated liver enzymes and was taking Hydroxycut along with other supplements. Liver biopsy showed drug induced hepatotoxicity. Discontinuation of Hydroxycut dramatically improved liver functions and related symptoms.