Predicted carcass meat yield and primal cut yields in cattle divergent in genetic merit for a terminal index.
Several studies have clearly demonstrated the favorable impact of genetic selection on increasing beef cattle performance within the farm gate. Few studies, however, have attempted to quantify the value of genetic selection to downstream sectors of the beef industry, such as the meat processing sector. The objective of the current study was to characterize detailed carcass attributes of animals divergent in genetic merit for a terminal index as well as individual measures of genetic merit for carcass weight, conformation, and fat. The data used consisted of 53,674 young bulls and steers slaughtered between the years 2010 and 2013 in multiple Irish processing plants. All animals had a genetic evaluation as well as phenotypic measures of carcass characteristics. A terminal index, based on pedigree index for calving performance, feed intake, and carcass traits, calculated from the Irish national genetic evaluations, was obtained for each animal. Animals were categorized into four terminal index groups based on genetic merit estimates derived prior to the expression of the carcass phenotype by the animal. The association between genetic merit for terminal index with predicted phenotypic carcass red meat yield, carcass fat, carcass bone, and carcass composition, as well as between genetic merit for carcass weight, conformation, and fat with predicted phenotypic carcass red meat yield and composition were all quantified using linear mixed models. A greater terminal index value was associated with, on average, heavier phenotypic weights of each wholesale cut category. A greater terminal index value was also associated with a greater weight of meat and bone, but reduced carcass fat. Relative to animals in the lowest 25% genetic merit group, animals in the highest 25% genetic merit group had, on average, a greater predicted yield of very high value cuts (4.52 kg), high value cuts (13.13 kg), medium value cuts (6.06 kg), low value cuts (13.25 kg) as well as more total meat yield (37 kg). The results from the present study clearly signify a benefit to meat processers from breeding programs for terminal characteristics; coupled with the previously documented benefits to the producer, the benefits of breeding programs across the entire food production chain are obvious.


The half-lives of serum immunoglobulins in adult mice.
We determined the half-lives of several sets of murine monoclonal antibodies spanning all immunoglobulin isotypes in the serum. The antibodies in each set possess the same V region. With this approach, the differences in half-life observed between the different isotypes are independent of the V region carried by the monoclonal antibodies and therefore must relate to each other in the same way as the half-lives of each class of serum immunoglobulins. The half-life of a monoclonal antibody of the gamma 2a isotype is identical to the average half-life of serum IgG2a as previously determined (6-8 days; P. Vieira and K. Rajewsky, Eur. J. Immunol. 1986. 16:871). Therefore, the half-lives determined with monoclonal antibodies possessing the same V region represent the half-life of the serum immunoglobulins. In this way we calculated the half-life of IgM as 2 days, IgG3 and IgG1 as 6-8 days, IgG2b has a half-life of 4-6 days. IgE has a half-life of 12 h. A polymeric form of IgA was found to be eliminated from the serum with a half-life of 17-22 h.


Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies.
One of the most important factors in breast cancer (BC) mortality is treatment delay. The primary goal of this survey was to identify factors affecting the total delay time (TDT) in Turkish BC patients. A total of 1031 patients with BC were surveyed using a uniform questionnaire. The time between discovering the first symptom and signing up for the first medical visit (patient delay time; PDT) and the time between the first medical visit and the start of therapy (system delay time; SDT) were modelled separately with multilevel regression. The mean PDT, SDT and TDT were 4.8, 10.5 and 13.8 weeks, respectively. In all, 42% of the patients had a TDT >12 weeks. Longer PDT was significantly correlated with disregarding symptoms and having age of between 30 and 39 years. Shorter PDT was characteristic of patients who: had stronger self-examination habits, received more support from family and friends and had at least secondary education. Predictors of longer SDT included disregard of symptoms, distrust in success of therapy and medical system and having PDT in excess of 4 weeks. Shorter SDT was linked to the age of >60 years. Patients who were diagnosed during a periodic check-up or opportunistic mammography displayed shorter SDT compared with those who had symptomatic BC and their first medical examination was by a surgeon. TDT in Turkey is long and remains a major problem. Delays can be reduced by increasing BC awareness, implementing organized population-based screening programmes and founding cancer centres.


Genome-wide characterization and phylogenetic analysis of GSK gene family in three species of cotton: evidence for a role of some GSKs in fiber development and responses to stress.
The glycogen synthase kinase 3/shaggy kinase (GSK3) is a serine/threonine kinase with important roles in animals. Although GSK3 genes have been studied for more than 30 years, plant GSK genes have been studied only since the last decade. Previous research has confirmed that plant GSK genes are involved in diverse processes, including floral development, brassinosteroid signaling, and responses to abiotic stresses. In this study, 20, 15 (including 5 different transcripts) and 10 GSK genes were identified in G. hirsutum, G. raimondii and G. arboreum, respectively. A total of 65 genes from Arabidopsis, rice, and cotton were classified into 4 clades. High similarities were found in GSK3 protein sequences, conserved motifs, and gene structures, as well as good concordance in gene pairwise comparisons (G. hirsutum vs. G. arboreum, G. hirsutum vs. G. raimondii, and G. arboreum vs. G. raimondii) were observed. Whole genome duplication (WGD) within At and Dt sub-genomes has been central to the expansion of the GSK gene family. Furthermore, GhSK genes showed diverse expression patterns in various tissues. Additionally, the expression profiles of GhSKs under different stress treatments demonstrated that many are stress-responsive genes. However, none were induced by brassinolide treatment. Finally, nine co-expression sub-networks were observed for GhSKs and the functional annotations of these genes suggested that some GhSKs might be involved in cotton fiber development. In this present work, we identified 45 GSK genes from three cotton species, which were divided into four clades. The gene features, muti-alignment, conversed motifs, and syntenic blocks indicate that they have been highly conserved during evolution. Whole genome duplication was determined to be the dominant factor for GSK gene family expansion. The analysis of co-expressed sub-networks and tissue-specific expression profiles suggested functions of GhSKs during fiber development. Moreover, their different responses to various abiotic stresses indicated great functional diversity amongst the GhSKs. Briefly, data presented herein may serve as the basis for future functional studies of GhSKs.


On the structure and desorption dynamics of DNA bases adsorbed on gold: a temperature-programmed study.
The structure and desorption dynamics of mono- and multilayer samples of adenine, cytosine, guanine, and thymine on polycrystalline gold thin films are studied using temperature-programmed desorption-infrared reflection absorption spectroscopy (TPD-IRAS) and temperature-programmed desorption-mass spectroscopy (TPD-MS). It is shown that the pyrimidines, adenine and guanine, adsorb to gold in a complex manner and that both adhesive (adenine) and cohesive (guanine) interactions contribute the apparent binding energies to the substrate surface. Adenine displays at least two adsorption sites, including a high-energy site (210 degrees C, approximately 136 kJ/mol), wherein the molecule coordinates to the gold substrate via the NH2 group in an sp3-like, strongly perturbed, nonplanar configuration. The purines, cytosine and thymine, display a less complicated adsorption/desorption behavior. The desorption energy for cytosine (160 degrees C, approximately 122 kJ/mol) is similar to those obtained for adenine and guanine, but desorption occurs from a single site of dispersed, nonaggregated cytosine. Thymine desorbs also from a single site but at a significantly lower energy (100 degrees C, approximately 104 kJ/mol). Infrared data reveal that the monolayer architectures discussed herein are structurally very different from those observed for the bases in the bulk crystalline state. It is also evident that both pyrimidines and purines adsorb on gold with the plane of the molecule in a nonparallel orientation with respect to the substrate surface. The results of this work are discussed in the context of improving the understanding of the design of capturing oligonucleotides or DNA strands for bioanalytical applications, in particular, for gold nanoparticle-based assays.


MO-D-BRB-08: BEST IN PHYSICS (THERAPY) - A Real Time Dose Monitoring and Dose Reconstruction Tool for Patient Specific VMAT QA and Delivery.
To develop a real time dose monitoring and dose reconstruction tool to identify and quantify sources of errors during patient specific VMAT delivery and QAMethods: The VMAT delivery monitor tool called Linac Data Monitor (LDM) has been developed that connects to the linac in clinical mode and displays, records and compares real-time machine parameters to the planned parameters. A new quantity called integral error keeps a running total of leaf overshoot and undershoots errors in each leaf pair multiplied by leaf width and the amount of time during which error exists in MU delivery. Another tool reconstructs pinnacle format delivered plan based on the saved machine logfile and recalculates actual delivered dose in patient anatomy. Delivery characteristics of various standard and hypofractionation VMAT plans delivered on Elekta Axesse and Synergy linacs were quantified. The MLC and gantry errors for all the treatment sites were 0.00±0.59mm and 0.05±0.31°, indicating a good MLC gain calibration. Standard fractionation plans had a larger gantry error than hypofractionation plans due to frequent dose rate changes. On average the MLC errors were negligible but larger errors of 4-6 mm and 2.5° were seen when dose rate varied frequently. Large gantry errors occurred during the acceleration and deceleration process, and correlated well with MLC errors (p<0.0001). PTV mean, minimum, maximum dose discrepancy were 0.87±0.21%, 0.99±0.59% and 1.18±0.52%. The other OAR doses were within 2.5% except a few that showed up to 5.6% discrepancy in maximum dose. Realtime displayed normalized total positive integral error (normalized to the total MUs) correlated linearly with MLC and gantry errors (p<0.001) and dosimetric discrepancy (PTVmean: p<0.01; PTVmax: p<0.067 and PTVmax: p<0.046). Errors may exist during complex VMAT planning and delivery. LDM is capable of detecting and quantifying mechanical and dosimetric errors at various stages of planning and delivery.


Understanding principles of integration and segregation using whole-brain computational connectomics: implications for neuropsychiatric disorders.
To survive in an ever-changing environment, the brain must seamlessly integrate a rich stream of incoming information into coherent internal representations that can then be used to efficiently plan for action. The brain must, however, balance its ability to integrate information from various sources with a complementary capacity to segregate information into modules which perform specialized computations in local circuits. Importantly, evidence suggests that imbalances in the brain's ability to bind together and/or segregate information over both space and time is a common feature of several neuropsychiatric disorders. Most studies have, however, until recently strictly attempted to characterize the principles of integration and segregation in static (i.e. time-invariant) representations of human brain networks, hence disregarding the complex spatio-temporal nature of these processes. In the present Review, we describe how the emerging discipline of whole-brain computational connectomics may be used to study the causal mechanisms of the integration and segregation of information on behaviourally relevant timescales. We emphasize how novel methods from network science and whole-brain computational modelling can expand beyond traditional neuroimaging paradigms and help to uncover the neurobiological determinants of the abnormal integration and segregation of information in neuropsychiatric disorders.This article is part of the themed issue 'Mathematical methods in medicine: neuroscience, cardiology and pathology'.


A role for alpha-adrenergic receptors in extinction of conditioned fear and cocaine conditioned place preference.
Previous work has demonstrated an important role for adrenergic receptors in memory processes in fear and drug conditioning paradigms. Recent studies have also demonstrated alterations in extinction in these paradigms using drug treatments targeting beta- and alpha2-adrenergic receptors, but little is known about the role of alpha-adrenergic receptors in extinction. The current study examined whether antagonism of alpha-adrenergic receptors would impair the consolidation of extinction in fear and cocaine conditioned place preference paradigms. After contextual fear conditioning, injections of the alpha-adrenergic receptor antagonist prazosin (1.0 or 3.0 mg/kg) following nonreinforced context exposures slowed the loss of conditioned freezing over the course of 5 extinction sessions (Experiment 1). After cocaine place conditioning, prazosin had no effect on the rate of extinction over 8 nonreinforced test sessions. Following postextinction reconditioning, however, prazosin-treated mice showed a robust place preference, but vehicle-treated mice did not, suggesting that prazosin reduced the persistent effects of extinction (Experiment 2). These results confirm the involvement of the alpha-adrenergic receptor in extinction processes in both appetitive and aversive preparations.


Suitability of sorghum stalk fibers for production of particleboard.
The aim of this study was to investigate the suitability of sorghum (Sorghum bicolor) stalk (SS) as a promising raw material for particleboard manufacturing. The SS particles and industrial hardwood particles in various proportions were used as the raw materials for the surface and core layers of the three-layer particleboards. Commercial urea formaldehyde (UF) adhesive was used as a binder. Morphological and chemical characteristics of the SS were evaluated. Effects of five variable parameters on the physical (thickness swelling (TS), water absorption (WA)), and mechanical (modulus of rupture (MOR), modulus of elasticity (MOE), internal bond (IB)) properties of the particleboards were determined. Other parameters such as type of resin (UF), hardener content (1%), type of hardener (NH4Cl), press closing time (5 mm/s), board density (0.70 g/cm(3)), and press pressure (30 kg/m(2)) were held constant. Fractional factorial was used to find the optimum condition for the studied variable parameters. The morphological results showed that SS had comparable fiber length with softwoods and fiber width and wall thickness values greater than the hardwood of common forest species. They had higher hot-water solubility values, lignin and ash contents than those of the other woody materials. The experimental results showed that increasing of SS particles usage in the surface layer significantly affects the board properties. Containing 50 wt% SS particles in the surface, the MOE and MOR values exceed the minimum requirements of the European norms (EN) standards, for general purposes. All of the particleboards produced from SS had IB higher than the EN standard requirement. The presence of SS in the particleboards resulted in higher WA and TS values. All the mechanical properties of the boards decreased when the press temperature was increased from 160 to 180°C. Finally, it can be stated that SS has enough potential as a supplement fibrous material, in combination with industrial hardwood particles, for particleboard manufacturing and indoor applications.


Structural basis for DNMT3A-mediated de novo DNA methylation.
DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-ångström crystal structure of the DNMT3A-DNMT3L-DNA complex in which two DNMT3A monomers simultaneously attack two cytosine-phosphate-guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.


Borophene's tryst with stability: exploring 2D hydrogen boride as an electrode for rechargeable batteries.
Graphene's emergence can be viewed as a positive upheaval in 2D materials research. Along the same line, the realization of a related elemental 2D material, borophene, is another breakthrough. To circumvent the stability issues of borophene, which is reported to have been synthesized on metallic substrates under extreme conditions, hydrogenation of borophene (otherwise called as borophane or hydrogen boride or boron hydride) has been a plausible solution, but only proposed computationally. A recent report (H. Nishino, T. Fujita, N. T. Cuong, S. Tominaka, M. Miyauchi, S. Iimura, A. Hirata, N. Umezawa, S. Okada, E. Nishibori, A. Fujino, T. Fujimori, S. Ito, J. Nakamura, H. Hosono and T. Kondo, J. Am. Chem. Soc., 2017, 139(39), 13761-13769) brings to fore its experimental realization. Our current study delves into the possibilities of employing this intriguing 2D hydrogen boride as anodes in Li/Na ion batteries. Using first-principles density functional theory methods, we computed relevant properties such as the ion (Li/Na) adsorption behavior, the possible pathways of ionic diffusion with the estimation of barriers as well as the theoretical specific capacities and average voltages to uniquely demonstrate that this material is of particular significance for battery applications. It is noted that the use of hydrogen boride leads to a high specific capacity of 861.78 mA h g-1 for Li ions, which is remarkably higher than the value reported in relation to its computationally predicted structure. Furthermore, Na ion intercalation leads to negative voltage profiles, implying the unsuitability of 2D hydrogen boride for this particular ion. Our findings are timely and pertinent towards adding insightful details relevant to the progress of applications of 2D materials for energy storage.


Internet-Based Cognitive Behavioral Therapy for Chronic Stress: A Randomized Controlled Trial.
Prolonged exposure to stress can lead to substantial suffering, impairment and societal costs. However, access to psychological treatment is limited. Internet-based cognitive behavioral therapy (ICBT) can be effective in reducing symptoms of stress, but little is known of its effects in clinical samples. The aim of this study was to investigate the efficacy of ICBT for patients suffering from chronic stress, operationalized as adjustment disorder (AD) and exhaustion disorder (ED). A total of 100 adults diagnosed with AD or ED were randomly assigned to a 12-week ICBT (n = 50) or waitlist control condition (n = 50). Primary outcome was the level of perceived stress (PSS). Secondary outcomes included several mental health symptom domains as well as functional impairment and work ability. All outcomes were assessed at baseline, after treatment and at the 6-month follow-up. The study was preregistered at Clinicaltrials.gov: NCT02540317. Compared to the control condition, patients in the ICBT group made large and significant improvements on the PSS (d = 1.09) and moderate to large improvements in secondary symptom domains. Effects were maintained at the 6-month follow-up. There was no significant between-group effect on functional impairment or work ability. A relatively short ICBT is indicated to be effective in reducing stress-related symptoms in a clinical sample of patients with AD and ED, and has the potential to substantially increase treatment accessibility. Results must be replicated, and further research is needed to understand the relationship between symptom reduction, functional impairment and work ability.


Abasic sites in the transcribed strand of yeast DNA are removed by transcription-coupled nucleotide excision repair.
Abasic (AP) sites are potent blocks to DNA and RNA polymerases, and their repair is essential for maintaining genome integrity. Although AP sites are efficiently dealt with through the base excision repair (BER) pathway, genetic studies suggest that repair also can occur via nucleotide excision repair (NER). The involvement of NER in AP-site removal has been puzzling, however, as this pathway is thought to target only bulky lesions. Here, we examine the repair of AP sites generated when uracil is removed from a highly transcribed gene in yeast. Because uracil is incorporated instead of thymine under these conditions, the position of the resulting AP site is known. Results demonstrate that only AP sites on the transcribed strand are efficient substrates for NER, suggesting the recruitment of the NER machinery by an AP-blocked RNA polymerase. Such transcription-coupled NER of AP sites may explain previously suggested links between the BER pathway and transcription.


Alkalinizing effect of NaHCO₃ with and without glucose when administered orally to euhydrated neonatal dairy calves.
The use of oral rehydration solutions (ORS) is well established as an effective treatment to correct water-, electrolyte-, and acid-base balance in diarrheic calves. The main ingredients of a commercial ORS are Na, glucose, and alkalinizing agents, such as NaHCO3. Particular importance is attributed to the combination of glucose and Na at a specific ratio to optimize intestinal sodium, and thereby water uptake, through the sodium-glucose co-transport. Enhancing intestinal Na absorption by combining glucose and Na in an ORS has the potential to improve the alkalinizing effect of an ORS according the strong ion theory. The objective of this study was to investigate the effect of glucose on the alkalinizing effect of NaHCO3 when administered orally. Nine healthy neonatal Holstein-Friesian calves underwent 3 oral treatments with 2-L solutions of NaHCO3 (150 mmol/L), glucose (300 mmol/L), and glucose + NaHCO3 (300 mmol/L + 150 mmol/L, respectively) in randomized order. Arterial and venous blood was obtained before treatment and in 30-min intervals thereafter for blood gas analysis and determination of plasma protein and electrolyte concentrations. Urine was collected volumetrically to determine urine volume, osmolality, pH, net acid excretion, and renal Na excretion after treatment. Plasma volume changes were extrapolated from plasma protein concentration changes. Treatment and time effects were tested with repeated measures ANOVA. Only subtle differences between oral administration of NaHCO3, with and without glucose, were observed for the change of the standard HCO3 concentration relative to baseline. No differences in plasma Na, plasma volume expansion, renal Na, net base excretion, urine volume, or pH could be identified between animals treated orally with NaHCO3 with and without glucose. Similarly, no differences in blood glucose concentration, plasma volume expansion, urine volume, or renal glucose excretion were observed in the 8h after treatment when comparing oral glucose treatment with and without NaHCO3. Our results indicate that combination of NaHCO3 with glucose in a hypertonic ORS only had a minor effect on the alkalinizing effect of NaHCO3, which is unlikely to be of clinical relevance. The combination of NaHCO3 and glucose neither improved Na, glucose, nor water absorption in euhydrated neonatal dairy calves, questioning the relevance of a specific ratio between Na and glucose in ORS for calves.


Effects of varied doses of psilocybin on time interval reproduction in human subjects.
Action of a hallucinogenic substance, psilocybin, on internal time representation was investigated in two double-blind, placebo-controlled studies: Experiment 1 with 12 subjects and graded doses, and Experiment 2 with 9 subjects and a very low dose. The task consisted in repeated reproductions of time intervals in the range from 1.5 to 5s. The effects were assessed by parameter kappa of the 'dual klepsydra' model of internal time representation, fitted to individual response data and intra-individually normalized with respect to initial values. The estimates kappa were in the same order of magnitude as in earlier studies. In both experiments, kappa was significantly increased by psilocybin at 90 min from the drug intake, indicating a higher loss rate of the internal duration representation. These findings are tentatively linked to qualitative alterations of subjective time in altered states of consciousness.


Outcomes after endovascular mechanical thrombectomy for low compared to high National Institutes of Health Stroke Scale (NIHSS): A multicenter study.
The role of endovascular mechanical thrombectomy (MT) in patients presenting with "minor" stroke is uncertain. We aimed to compare outcomes after MT for ischemic stroke patients presenting with National Institutes of Health Stroke Scale (NIHSS) 5 and - within the low NIHSS cohort - identify predictors of a favorable outcome, mortality, and symptomatic intracranial hemorrhage (ICH). We retrospectively analyzed a prospectively maintained, international, multicenter database. The study cohort comprised a total of 7568 patients from 29 centers. NIHSS was low (<5) in 604 patients (8%), and > 5 in 6964 (92%). Patients with low NIHSS were younger (67 + 14.8 versus 69.6 + 14.7 years, p < 0.001), more likely to have diabetes (31.5% versus 26.9%, p = 0.016), and less likely to have atrial fibrillation (26.6% versus 37.6%, p < 0.001) compared to those with higher NIHSS. Radiographic outcomes (TICI > 2B 84.6% and 84.3%, p = 0.412) and complication rates (8.1% and 7.2%, p = 0.463) were similar between the low and high NIHSS groups, respectively. Clinical outcomes at every follow up interval, including NIHSS at 24 h and discharge, and mRS at discharge and 90 days, were better in the low NIHSS group, however patients in the low NIHSS group experienced a relative decline in NIHSS from admit to discharge. Mortality was lower in the low NIHSS group (10.4% versus 24.5%, p < 0.001). Relative to patients with high NIHSS, MT is safe and effective for stroke patients with low NIHSS, and it is reasonable to offer it to appropriately selected patients presenting with minor stroke symptoms. Our findings justify efforts towards a randomized trial comparing MT versus medical management for patients with low NIHSS.


Guide to interpreting disease responses in chronic myeloid leukemia.
With the introduction of tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia, the course of the disease has been altered from an acute, rapidly progressive terminal disorder to a serious condition with high remission rates when patients are compliant with long-term treatment. The goal of therapy is to prevent transformation to the accelerated or blast crisis phases, which are associated with poor survival. Knowledge of the appropriate monitoring tests and treatment milestones, as well as the ability to interpret responses, allows advanced practitioners (APs) to effectively communicate key aspects of management to their patients. Monitoring patient responses to TKIs and identifying suboptimal responses early on offer APs the opportunity to reevaluate and adjust therapeutic treatment options. One of the causes of treatment failure is noncompliance; thus, educating patients on the importance of adhering to treatment and identifying reasons for noncompliance are of major importance. Because intolerance to TKIs may lead to discontinuation, frequent monitoring of side effects and response to treatment, open communication, patient education, and careful management are all essential in helping patients remain compliant with therapy. This review discusses the AP's role in helping patients achieve their best response to TKI therapy and optimize their long-term outcomes.


Increased accuracy of artificial selection by using the realized relationship matrix.
Dense marker genotypes allow the construction of the realized relationship matrix between individuals, with elements the realized proportion of the genome that is identical by descent (IBD) between pairs of individuals. In this paper, we demonstrate that by replacing the average relationship matrix derived from pedigree with the realized relationship matrix in best linear unbiased prediction (BLUP) of breeding values, the accuracy of the breeding values can be substantially increased, especially for individuals with no phenotype of their own. We further demonstrate that this method of predicting breeding values is exactly equivalent to the genomic selection methodology where the effects of quantitative trait loci (QTLs) contributing to variation in the trait are assumed to be normally distributed. The accuracy of breeding values predicted using the realized relationship matrix in the BLUP equations can be deterministically predicted for known family relationships, for example half sibs. The deterministic method uses the effective number of independently segregating loci controlling the phenotype that depends on the type of family relationship and the length of the genome. The accuracy of predicted breeding values depends on this number of effective loci, the family relationship and the number of phenotypic records. The deterministic prediction demonstrates that the accuracy of breeding values can approach unity if enough relatives are genotyped and phenotyped. For example, when 1000 full sibs per family were genotyped and phenotyped, and the heritability of the trait was 0.5, the reliability of predicted genomic breeding values (GEBVs) for individuals in the same full sib family without phenotypes was 0.82. These results were verified by simulation. A deterministic prediction was also derived for random mating populations, where the effective population size is the key parameter determining the effective number of independently segregating loci. If the effective population size is large, a very large number of individuals must be genotyped and phenotyped in order to accurately predict breeding values for unphenotyped individuals from the same population. If the heritability of the trait is 0.3, and N(e)=100, approximately 12474 individuals with genotypes and phenotypes are required in order to predict GEBVs of un-phenotyped individuals in the same population with an accuracy of 0.7 [corrected].


Preventive misconception and adolescents' knowledge about HIV vaccine trials.
Adolescents have had very limited access to research on biomedical prevention interventions despite high rates of HIV acquisition. One concern is that adolescents are a vulnerable population, and trials carry a possibility of harm, requiring investigators to take additional precautions. Of particular concern is preventive misconception, or the overestimation of personal protection that is afforded by enrolment in a prevention intervention trial. As part of a larger study of preventive misconception in adolescent HIV vaccine trials, we interviewed 33 male and female 16-19-year-olds who have sex with men. Participants underwent a simulated HIV vaccine trial consent process, and then completed a semistructured interview about their understanding and opinions related to enrolment in a HIV vaccine trial. A grounded theory analysis looked for shared concepts, and focused on the content and process of adolescent participants' understanding of HIV vaccination and the components of preventive misconception, including experiment, placebo and randomisation. Across interviews, adolescents demonstrated active processing of information, in which they questioned the interviewer, verbally worked out their answers based upon information provided, and corrected themselves. We observed a wide variety of understanding of research concepts. While most understood experiment and placebo, fewer understood randomisation. All understood the need for safer sex even if they did not understand the more basic concepts. Education about basic concepts related to clinical trials, time to absorb materials and assessment of understanding may be necessary in future biomedical prevention trials.


Retrospective Analysis on the Effects of House Dust Mite Specific Immunotherapy for More Than 3 Years in Atopic Dermatitis.
In extrinsic atopic dermatitis (AD), house dust mites (HDM) play a role in eliciting or aggravating allergic lesions. The nature of skin inflammation in AD has raised a growing interest in allergen-specific immunotherapy (SIT). Thus, we assessed clinical improvement and laboratory parameters for evaluation of the benefit of long-term SIT. A total of 217 AD patients who were treated with SIT for at least 3 years were retrospectively assessed, by using their investigator global assessment, pruritus scores, loss of sleep (LOS), total serum IgE, and eosinophil counts collected. Patients were additionally classified into subgroups according to age, initial AD severity and mono- or multi-sensitization to include different individual factors in the evaluation of SIT efficacy. Lastly, we compared laboratory data of good responders to SIT with that of poor responders to SIT. Improvement after SIT therapy was observed in 192 out of 217 patients (88.4%). Among these patients, 138 (63.5%) achieved excellent, near-complete or complete clinical remission. Significant reduction of pruritus, LOS, and the mean value of total serum IgE were observed (p<0.01). Better outcome was found in patients younger than 12 years of age (p=0.024). Patients with moderate to severe AD showed better treatment outcomes (p=0.036). Patients sensitized only to HDM had the better response to treatment, but SIT was also effective in multi-sensitized groups (p=1.051). No significant differences in baseline laboratory results were observed between good and poor responders (p>0.05). We emphasize the usefulness of long-term HDM SIT as a disease-modifying therapy for AD.


Functional electrical stimulation improves activity after stroke: a systematic review with meta-analysis.
To investigate the effect of functional electrical stimulation (FES) in improving activity and to investigate whether FES is more effective than training alone. Cochrane Central Register of Controlled Trials, Ovid Medline, EBSCO Cumulative Index to Nursing and Allied Health Literature, Ovid EMBASE, Physiotherapy Evidence Database (PEDro), and Occupational Therapy Systematic Evaluation of Effectiveness. Randomized and controlled trials up to June 22, 2014, were included following predetermined search and selection criteria. Data extraction occurred by 2 people independently using a predetermined data collection form. Methodologic quality was assessed by 2 reviewers using the PEDro methodologic rating scale. Meta-analysis was conducted separately for the 2 research objectives. Eighteen trials (19 comparisons) were eligible for inclusion in the review. FES had a moderate effect on activity (standardized mean difference [SMD], .40; 95% confidence interval [CI], .09-.72) compared with no or placebo intervention. FES had a moderate effect on activity (SMD, .56; 95% CI, .29-.92) compared with training alone. When subgroup analyses were performed, FES had a large effect on upper-limb activity (SMD, 0.69; 95% CI, 0.33-1.05) and a small effect on walking speed (mean difference, .08m/s; 95% CI, .02-.15) compared with control groups. FES appears to moderately improve activity compared with both no intervention and training alone. These findings suggest that FES should be used in stroke rehabilitation to improve the ability to perform activities.


Regulation of dendritic spines, spatial memory, and embryonic development by the TANC family of PSD-95-interacting proteins.
PSD-95 (postsynaptic density-95) is thought to play important roles in the regulation of dendritic spines and excitatory synapses, but the underlying mechanisms have not been fully elucidated. TANC1 is a PSD-95-interacting synaptic protein that contains multiple domains for protein-protein interactions but whose function is not well understood. In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. Overexpression of TANC1 and TANC2 in cultured neurons increases the density of dendritic spines and excitatory synapses in a manner that requires the PDZ (PSD-95/Dlg/ZO-1)-binding C termini of TANC proteins. TANC1-deficient mice exhibit reduced spine density in the CA3 region of the hippocampus, but not in the CA1 or dentate gyrus regions, and show impaired spatial memory. TANC2 deficiency, however, causes embryonic lethality. These results suggest that TANC1 is important for dendritic spine maintenance and spatial memory, and implicate TANC2 in embryonic development.


Inter-individual differences in resting-state functional connectivity predict task-induced BOLD activity.
The resting brain exhibits coherent patterns of spontaneous low-frequency BOLD fluctuations. These so-called resting-state functional connectivity (RSFC) networks are posited to reflect intrinsic representations of functional systems commonly implicated in cognitive function. Yet, the direct relationship between RSFC and the BOLD response induced by task performance remains unclear. Here we examine the relationship between a region's pattern of RSFC across participants and that same region's level of BOLD activation during an Eriksen Flanker task. To achieve this goal we employed a voxel-matched regression method, which assessed whether the magnitude of task-induced activity at each brain voxel could be predicted by measures of RSFC strength for the same voxel, across 26 healthy adults. We examined relationships between task-induced activation and RSFC strength for six different seed regions [Fox, M.D., Snyder, A.Z., Vincent, J.L., Corbetta, M., Van Essen, D.C., Raichle, M.E., 2005. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc. Natl. Acad. Sci. U. S. A. 102, 9673-9678.], as well as the "default mode" and "task-positive" resting-state networks in their entirety. Our results indicate that, for a number of brain regions, inter-individual differences in task-induced BOLD activity were predicted by one of two resting-state properties: (1) the region's positive connectivity strength with the task-positive network, or (2) its negative connectivity with the default mode network. Strikingly, most of the regions exhibiting a significant relationship between their RSFC properties and task-induced BOLD activity were located in transition zones between the default mode and task-positive networks. These results suggest that a common mechanism governs many brain regions' neural activity during rest and its neural activity during task performance.


Long-Term Mental Health and Quality of Life Outcomes of Neonatal Insults in Kilifi, Kenya.
We examined the mental health and quality of life (QoL) outcomes and their correlates of school-aged survivors of neonatal jaundice (NNJ), hypoxic-ischemic encephalopathy (HIE), and a comparison group. The Child Behavior Checklist and the Pediatric Quality of Life Inventory were administered to assess the mental health and QoL of 375 children (134 with NNJ, 107 with HIE, and 134 comparison group) aged 6 to 12 years [Median age 9 (interquartile range 7 to 11)]. The results showed that survivors of NNJ and HIE have mental health problems and QoL similar to the comparison group. Maternal mental health was the predominant covariate of mental health and QoL in survivors of NNJ and HIE. This result could indicate that mothers with mental health problems are more likely to have children with mental health issues, but also that caring for children with these adversities may affect mental health well-being of the caregivers. There is a need for early mental health screening and psychosocial intervention for caregivers and their children to enhance both their mental health and QoL.


Practising midwifery independently: for the majority of midwives?
This paper explores the proposition that all midwives can practice independently regardless of their place of practice or employment status. That independence can be defined by the way in which the midwife practises is discussed. The theory of midwifery as a partnership is reviewed and its effects on midwifery as a profession will be explored. How this relates to Victoria and the absence of regulations will also be discussed. The need for continuity of care and women centred practice will be analysed in this context. Advocacy, as used by midwives, will be examined, as will midwife empowerment of the woman and the midwife.


Visual inspection with acetic acid for cervical cancer screening outside of low-resource settings.
To assess visual inspection with acetic acid (VIA) as a screening tool for use in a well-equipped health center in Peru, to evaluate VIA as an alternative or adjunct to the Papanicolaou (Pap) smear, and to determine if VIA can play a role in settings other than low-resource ones. This was a prospective study of 1 921 asymptomatic women living in Lima, Peru, carried out in 1999 and 2000. The study was performed at a cancer center equipped with the latest-generation technology and highly trained oncologists. The women underwent a complete clinical evaluation, including a Pap smear and VIA. Participants with any positive test were referred for colposcopy and biopsy. More women tested positive by VIA than on the Pap smear (6.9% vs. 4.2%; P = 0.0001). There were 35 women with histologic cervical intraepithelial neoplasia grade 1 (CIN 1); of these, 15 were detected by Pap and 20 by VIA (P = 0.4). A diagnosis of CIN 2 or 3 (CIN 2-3) was confirmed in a total of 13 cases; Pap detected 5 of the cases and VIA 11 of the cases (P = 0.06). The positive predictive value for detection of CIN 2+ was 8.3% for VIA and 6.3% for Pap (P = 0.5). Most importantly, while only 2.3% of patients with a positive VIA were lost to follow-up before colposcopy, that was true for 26.3% of the women with a positive Pap smear (P < 0.0001). VIA is useful for detection of precursor lesions of cervical cancer not only in low-resource settings but also in well-equipped health centers and cancer centers. In these non-low-resource settings, VIA has a positive predictive value comparable to the conventional Pap smear, but it is more likely to achieve earlier diagnosis, follow-up, and treatment than cytology-based screening.


Synthesis and reactivity of 5-polyfluoroalkyl-5-deazaalloxazines.
Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence of pyridine and subsequent cyclization with concentrated H2SO4 gave the corresponding 1,3-dialkyl-5-(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones (5-polyfluoroalkyl-5-deazaalloxazines). The reactivity of these compounds towards nucleophilic reagents, such as sodium cyanoborohydride, acetophenone, nitromethane, potassium cyanide, indole and p-thiocresol, as well as Suzuki and Sonogashira couplings are described. The nucleophilic addition takes place at the 5-position of the 5-deazaalloxazine system and is in many cases irreversible to give 5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione derivatives in good to excellent yields.


Functional compensation in the ventromedial prefrontal cortex improves memory-dependent decisions in older adults.
Everyday consumer choices frequently involve memory, as when we retrieve information about consumer products when making purchasing decisions. In this context, poor memory may affect decision quality, particularly in individuals with memory decline, such as older adults. However, age differences in choice behavior may be reduced if older adults can recruit additional neural resources that support task performance. Although such functional compensation is well documented in other cognitive domains, it is presently unclear whether it can support memory-guided decision making and, if so, which brain regions play a role in compensation. The current study engaged younger and older humans in a memory-dependent choice task in which pairs of consumer products from a popular online-shopping site were evaluated with different delays between the first and second product. Using functional imaging (fMRI), we found that the ventromedial prefrontal cortex (vmPFC) supports compensation as defined by three a priori criteria: (1) increased vmPFC activation was observed in older versus younger adults; (2) age-related increases in vmPFC activity were associated with increased retrieval demands; and (3) increased vmPFC activity was positively associated with performance in older adults-evidence of successful compensation. Extending these results, we observed evidence for compensation in connectivity between vmPFC and the dorsolateral PFC during memory-dependent choice. In contrast, we found no evidence for age differences in value-related processing or age-related compensation for choices without delayed retrieval. Together, these results converge on the conclusion that age-related decline in memory-dependent choice performance can be minimized via functional compensation in vmPFC.


Chemical sensing with nanoparticles as optical reporters: from noble metal nanoparticles to quantum dots and upconverting nanoparticles.
A wide variety of biological and medical analyses are based on the use of optical signals to report specific molecular events. Thanks to advances in nanotechnology, various nanostructures have been extensively used as optical reporters in bio- and chemical assays. This review describes recent progress in chemical sensing using noble metal nanoparticles (gold and silver), quantum dots and upconverting nanoparticles. It provides insights into various nanoparticle-based sensing strategies including fluorescence/luminescence resonance energy transfer nanoprobes as well as activatable probes sensitive to specific changes in the biological environment. Finally we list some research challenges to be overcome in order to accelerate the development of applications of nanoparticle bio- and chemical sensors.


Phenotypic and Functional Analysis of Human NK Cell Subpopulations According to the Expression of FcεRIγ and NKG2C.
Human memory-like NK cells are commonly defined by either a lack of FcεRIγ or gain of NKG2C expression. Here, we investigated the heterogeneity of human CD56dim NK cell subpopulations according to the expression of FcεRIγ and NKG2C in a large cohort (n = 127). Although the frequency of FcεRIγ- and NKG2C+ NK cells positively correlated, the FcεRIγ- and NKG2C+ NK cell populations did not exactly overlap. The FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were only evident after HCMV infection, but each had distinct characteristics. Among the subpopulations, FcεRIγ-NKG2C+ NK cells exhibited the most restricted killer immunoglobulin-like receptor repertoire, suggesting clonal expansion. Moreover, FcεRIγ-NKG2C+ NK cells exhibited the lowest Ki-67 and highest Bcl-2 expression, indicating the long-lived quiescent memory-like property. Functionally, FcεRIγ-NKG2C+ NK cells had weak natural effector function against K562 but strong effector functions by CD16 engagement, whereas FcεRIγ+NKG2C+ NK cells had strong effector functions in both settings. Anatomically, the FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were present in multiple human peripheral organs. In conclusion, we demonstrate the heterogeneity of memory-like NK cells stratified by FcεRIγ and NKG2C and suggest both markers be utilized to better define these cells.


Postoperative bezoar ileus after early enteral feeding.
Postoperative enteral nutrition is a widely accepted route of application for nutrition formulas due to a low complication rate, a good acceptance by patients. and a favorable cost-effectiveness. We report three cases of bezoar ileus after early postoperative enteral nutrition, using a fine needle jejunostomy (FNJ) in two cases and a nasoduodenal tube in one case. A male patient who underwent gastric resection for a gastrointestinal stroma tumor and was nourished through an fine needle jejunostomy developed an acute abdomen on the seventh postoperative day. Surgical exploration revealed a mechanical ileus caused by denaturated nutrition formula distal to the catheter tip. The second case, a female patient, underwent gastric resection for a gastric cancer and on the fourth postoperative day developed acute onset of abdominal pain. Intraoperative findings were the same as described in the first case. The third case, a male patient with necrotizing cholecystitis, underwent open cholecystectomy. Postoperative enteral feeding was performed using a nasoduodenal tube. He developed a small bowel obstruction on the 17th postoperative day that was caused by an intraluminal bezoar. In conclusion, bezoar formation represents an underestimated complication of postoperative enteral feeding. Acute onset of abdominal pain and the development of small bowel obstruction are the main clinical symptoms of this severe complication. The pathogenesis of bezoar formation remains unclear.


Genetic variability, stability and heritability for quality and yield characteristics in provitamin A cassava varieties.
Cassava is widely consumed in many areas of Africa, including Ghana, and is a major part of most household diets. These areas are characterized by rampant malnutrition, because the tuberous roots are low in nutritional value. Provitamin A biofortified cassava varieties have been developed by the International Institute for Tropical Agriculture, but adoption of these varieties in Ghana will largely depend on their agronomic performance, including fresh root yield, dry matter content, resistance to major pests and diseases, mealiness, starch content and the stability of these traits. Eight provitamin A varieties with two white checks were planted in three environments for two seasons to determine stability and variability among the varieties for important traits. There were significant variations in performance between varieties and between environments for cassava mosaic disease, root number, fresh root yield and starch content. High broad-sense heritability and genetic advance were observed in all traits, except for storage root number, and could be exploited through improvement programs. This study identified the best performing enhanced provitamin A varieties for traits that are key drivers of variety adoption in Ghana. In view of this, some varieties can be recommended for varietal release after on-farm testing. The study also showed the possibility of tapping heterosis after careful selection of parents.


Delta(9)-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo.
Delta(9)-tetrahydrocannabinol (THC), the main psychoactive component of marijuana has been shown to suppress the immune response. However, the exact mechanism of THC-induced immunosuppression remains unclear. In the current study, we tested the hypothesis that exposure to THC leads to the induction of apoptosis in lymphocyte populations. Splenocytes of C57BL/6 mice cultured in the presence of 10 microM or greater concentrations of THC showed significantly reduced proliferative response to mitogens, including anti-CD3 monoclonal antibodies (mAbs), concanavalin A (Con A), and lipopolysaccharide (LPS) in vitro. Thymocytes and naive and activated splenocytes exposed to 10 microM or 20 microM THC showed significantly increased levels of apoptosis. Treatment with CB2 antagonist inhibited THC-induced apoptosis in thymocytes and activated splenocytes. Administration of 10 mg/kg body weight of THC into C57BL/6 mice led to thymic and splenic atrophy as early as 6 h after treatment. This effect could be partially inhibited by treatment with a caspase inhibitor in vivo. THC exposure led to reductions in the numbers of all subpopulations of splenocytes and thymocytes examined. Functional studies revealed that splenocytes from THC-treated mice had significantly reduced proliferative response to anti-CD3 mAbs, Con A, and LPS in vitro. Finally, thymocytes and splenocytes exposed to THC in vivo exhibited apoptosis upon in vitro culture. Together, these results suggest that in vivo exposure to THC can lead to significant suppression of the immune response by induction of apoptosis.


With great power comes great responsibility: the importance of rejection, power, and editors in the practice of scientific publishing.
Peer review is an important element of scientific communication but deserves quantitative examination. We used data from the handling service manuscript Central for ten mid-tier ecology and evolution journals to test whether number of external reviews completed improved citation rates for all accepted manuscripts. Contrary to a previous study examining this issue using resubmission data as a proxy for reviews, we show that citation rates of manuscripts do not correlate with the number of individuals that provided reviews. Importantly, externally-reviewed papers do not outperform editor-only reviewed published papers in terms of visibility within a 5-year citation window. These findings suggest that in many instances editors can be all that is needed to review papers (or at least conduct the critical first review to assess general suitability) if the purpose of peer review is to primarily filter and that journals can consider reducing the number of referees associated with reviewing ecology and evolution papers.


Effect of intravenous hydration in patients receiving bisphosphonate therapy.
Patients with advanced cancers are at high risk for bone metastases, which accelerate bone resorption and skeletal complications. Therefore, bisphosphonates, which are strong inhibitors of bone resorption, are widely used to prevent pathological fractures, pain and tumour-induced hypercalcaemia. Intravenous infusion of bisphosphonate is associated with dose- and infusion rate-dependent adverse renal effects. The present study investigated the effect of hydration on bisphosphonate efficacy and safety. The 600-bed CHOV Hospital (Neufchâteau, France) and the Université de Lorraine (Nancy, France). Patients who received pamidronate or zoledronic acid treatments were identified: 50 patients [16 of whom were hydrated and 34 of whom were non-hydrated]. Data on serum calcium levels, creatinine clearance and clinical tolerance were collected. Main outcome measure The impact of hydration on these parameters was analysed between day 1 and day 7. Bisphosphonate normalized calcaemia and hydration did not induce further reduction of calcium levels. Patient kidneys were significantly preserved by hydration in both groups (median clearance: +6.2%), whereas dehydrated patients had lower creatinine clearance (median clearance: -1.1%). Hydration did not influence other clinical or biological parameters tested. Hydration plays an important role in the treatment of hypercalcaemia by pamidronate and zoledronic acid: it enhances kidney protection (i.e., creatinine clearance).


A multicenter study of oral malignant tumors from Thailand.
Oral malignant tumors in Thailand have not been extensively studied. Hence the following study was conducted. To determine the prevalence and clinicopathologic data of the oral malignant tumors from Thailand. Biopsy records of the Oral Pathology Department, Chulalongkorn University; Department of Oral Biology and Diagnostic Sciences, Chiang Mai University; Department of Oral Diagnosis, Khon Kaen University and Department of Stomatology, Prince of Songkla University, were reviewed for lesions diagnosed in the category of oral malignant tumors from 2005-2014. Demographic data and site of the lesions were collected. Data were analyzed by descriptive statistics using SPSS software version 17.0. Of the 22,639 accessioned cases, 1411 cases (6.23%) were diagnosed as oral malignant tumors. The mean age of the patients was 59.13 ± 17.32 years. A total of 651 cases (46.14%) were diagnosed in males, whereas 759 cases (53.79%) were diagnosed in females. The male-to-female ratio was 0.86:1. The sites of predilection for oral malignant tumors were the gingiva, followed by tongue and alveolar mucosa. The three most common oral malignant tumors in the descending order of frequency were squamous cell carcinoma, non-Hodgkin lymphoma and mucoepidermoid carcinoma. This study provides extensive data on the oral malignant tumors from several university biopsy services located in virtually all parts of Thailand. The data from the present study show some similarities with previous studies; however, differences such as gender and site of predilection still exist.


Effect of Roux-en-Y gastric bypass and diet-induced weight loss on diabetic kidney disease in the Zucker diabetic fatty rat.
Reductions in urinary protein excretion after Roux-en-Y gastric bypass (RYGB) surgery in patients with diabetic kidney disease have been reported in multiple studies. To determine the weight loss dependence of the effect of RYGB on urinary protein excretion by comparing renal outcomes in Zucker diabetic fatty rats undergoing either gastric bypass surgery or a sham operation with or without weight matching. University laboratories. Zucker diabetic fatty rats underwent surgery at 18 weeks of age. A subgroup of sham operated rats were weight matched to RYGB operated rats by restricting food intake. Urinary protein excretion was assessed at baseline and at postoperative weeks 4 and 12. Renal histology and macrophage-associated inflammation were assessed at postoperative week 12. Progressive urinary protein excretion was attenuated by both RYGB and diet-induced weight loss, albeit to a lesser extent by the latter. Both weight loss interventions produced equivalent reductions in glomerulomegaly, glomerulosclerosis, and evidence of renal macrophage infiltration. Weight loss per se improves renal structure and attenuates renal inflammatory responses in an experimental animal model of diabetic kidney disease. Better glycemic control post-RYGB may in part explain the greater reductions in urinary protein excretion after gastric bypass surgery.


RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate.
RNA is sensed by Toll-like receptor 7 (TLR7) and TLR8 or by the RNA helicases LGP2, Mda5 and RIG-I to trigger antiviral responses. Much less is known about sensors for DNA. Here we identify a novel DNA-sensing pathway involving RNA polymerase III and RIG-I. In this pathway, AT-rich double-stranded DNA (dsDNA) served as a template for RNA polymerase III and was transcribed into double-stranded RNA (dsRNA) containing a 5'-triphosphate moiety. Activation of RIG-I by this dsRNA induced production of type I interferon and activation of the transcription factor NF-kappaB. This pathway was important in the sensing of Epstein-Barr virus-encoded small RNAs, which were transcribed by RNA polymerase III and then triggered RIG-I activation. Thus, RNA polymerase III and RIG-I are pivotal in sensing viral DNA.


Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury.
Dapagliflozin, a new type of drug used to treat diabetes mellitus (DM), is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although some studies showed that SGLT2 inhibition attenuated reactive oxygen generation in diabetic kidney the role of SGLT2 inhibition is unknown. We evaluated whether SLT2 inhibition has renoprotective effects in ischemia-reperfusion (IR) models. We evaluated whether dapagliflozin reduces renal damage in IR mice model. In addition, hypoxic HK2 cells were treated with or without SGLT2 inhibitor to investigate cell survival, the apoptosis signal pathway, and the induction of hypoxia-inducible factor 1 (HIF1) and associated proteins. Dapagliflozin improved renal function. Dapagliflozin reduced renal expression of Bax, renal tubule injury and TUNEL-positive cells and increased renal expression of HIF1 in IR-injured mice. HIF1 inhibition by albendazole negated the renoprotective effects of dapagliflozin treatment in IR-injured mice. In vitro, dapagliflozin increased the expression of HIF1, AMP-activated protein kinase (AMPK), and ERK and increased cell survival of hypoxic HK2 cells in a dose-dependent manner. In conclusion, dapagliflozin attenuates renal IR injury. HIF1 induction by dapagliflozin may play a role in renoprotection against renal IR injury.


Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase sigma.
Protein tyrosine phosphatase sigma (PTP-sigma, encoded by the Ptprs gene) is a member of the LAR subfamily of receptor-like protein tyrosine phosphatases that is highly expressed during mammalian embryonic development in the germinal cell layer lining the lateral ventricles of the developing brain, dorsal root ganglia, Rathke's pouch, olfactory epithelium, retina and developing lung and heart. On the basis of its expression and homology with the Drosophila melanogasterorthologues DPTP99 and DPTP100A (refs 5,6), which have roles in the targeting of axonal growth cones, we hypothesized that PTP-sigma may also have a modulating function in cell-cell interactions, as well as in axon guidance during mammalian embryogenesis. To investigate its function in vivo, we generated Ptprs-deficient mice. The resulting Ptprs-/-animals display retarded growth, increased neonatal mortality, hyposmia and hypofecundity. Anatomical and histological analyses showed a decrease in overall brain size with a severe depletion of luteinizing hormone-releasing hormone (LHRH)-immunoreactive cells in Ptprs-/- hypothalamus. Ptprs-/- mice have an enlarged intermediate pituitary lobe, but smaller anterior and posterior lobes. These results suggest that tyrosine phosphorylation-dependent signalling pathways regulated by PTP-sigma influence the proliferation and/or adhesiveness of various cell types in the developing hypothalamo-pituitary axis.


1,25-Dihydroxyvitamin D3 inhibits directly human osteoclastogenesis by down-regulation of the c-Fms and RANK expression.
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a key molecule to maintain calcium homeostasis and bone metabolism. It was recently reported that 1,25(OH)2D3 directly inhibited osteoclast differentiation in mouse bone marrow cells and human bone marrow-derived colony-forming unit granulocyte macrophage (CFU-GM) cells. However, the direct effects of 1,25(OH)2D3 and its affecting mechanisms on the osteoclast differentiation of human osteoclast precursors remain largely unknown. In this study, we examined the direct effects of 1,25(OH)2D3 on the osteoclastogenesis of human peripheral blood (PB) osteoclast precursors. In vitro osteoclastogenesis assays were performed using osteoclast precursors from normal PB. The gene expressions were analyzed using real-time PCR. The cell surface proteins, including c-Fms and RANK, were measured by flow cytometry. 1,25(OH)2D3 strongly inhibited osteoclast differentiation and it suppressed the expression of RANK in the human PB osteoclast precursors. One mechanism of RANK inhibition by 1,25(OH)2D3 is down-regulation of the M-CSF receptor c-Fms, which is required for the expression of RANK. In contrast to the previous reports on mouse osteoclast precursors, 1,25(OH)2D3 did not affect the expression of c-Fos. Parallel to the inhibition of osteoclastogenesis, 1,25(OH)2D3 increased the expression and phosphorylation of CCAAT enhancer-binding protein β (C/EBPβ), which is a recently discovered inhibitor of osteoclastogenesis. Our results show that 1,25(OH)2D3 inhibits human osteoclastogenesis by decreasing the RANK+ osteoclast precursors, and we suggest that 1,25(OH)2D3 may be a powerful therapeutic agent for treating inflammation-induced bone disease that shows excessive osteoclast activation.


Failure of normalization of CA19-9 following resection for pancreatic cancer is tantamount to metastatic disease.
Multidisciplinary therapy for pancreatic cancer involves radical resection followed by gemcitabine-based chemotherapy. Carbohydrate antigen 19-9 (CA19-9), when elevated preoperatively, is a useful marker to monitor disease status following resection. However, little has been reported on outcomes of patients in whom CA19-9 never normalizes. We hypothesize that failure of CA19-9 normalization within 6 months is prognostically equivalent to metastatic disease. From our pancreatectomy database, we identified 93 patients with pancreatic adenocarcinoma and elevated CA19-9 prior to resection with levels recorded postoperatively. Patients were grouped based on normalization or persistent elevation of CA19-9 at 6 months after resection. CA19-9 levels normalized (≤35 u/ml) after resection in 38 (41%) and remained elevated in 55 (59%). Clinicopathologic characteristics were compared using Student's t-test and contingency table analyses. Survival curves were constructed using Kaplan-Meier method and compared by log-rank analysis. Cox regression was used to determine predictors of survival. The two groups had comparable clinicopathologic characteristics except for nodal status and perineural invasion, which were higher in patients with persistently elevated CA19-9. Persistent CA19-9 conferred shorter median overall survival of 10.8 months compared with 23.8 months in patients with normalization (p < 0.001), which persisted when controlling for nodal status. Multivariate analysis demonstrated persistently elevated CA19-9 as the sole statistically significant negative predictor of survival [hazard ratio (HR) 2.20, p = 0.002]. Persistent CA19-9 elevation after pancreatectomy correlates with shorter survival analogous to unresected or metastatic disease and should be regarded as persistent disease regardless of radiographic findings. These patients should be considered for accrual to clinical trials or initiation of alternative therapy.


Orthographic and associative neighborhood density effects: what is shared, what is different?
Words with many orthographic neighbors elicit a larger N400 than words with few orthographic neighbors. This has been interpreted as stronger overall semantic activation due to orthographic neighbors activating their semantic representations. To investigate this claim, we manipulated the number of associates of words (NoA), a variable directly affecting overall semantic activation, and compared this to the ERP effect of the number of orthographic neighbors (N) in a lexical decision task. Words with high NoA and with high N produced a very similar increase of the N400. In addition, a higher N increased the amplitude of the Late Positive Complex. The common N400 effect suggests that N affects semantic activation, like NoA does. The late positive effect specific to N could occur because words with few orthographic neighbors initially elicit little activity in the orthographic system, thereby resembling nonwords, which leads to distinct processing.


Management of failures of total ankle replacement with the agility total ankle arthroplasty.
Few studies have focused on treatment following failed total ankle replacement. The purpose of this study was to report the outcomes of patients undergoing revision total ankle replacement and to propose a talar component subsidence grading system that may be helpful in making decisions regarding how to revise failed total ankle replacements in the future. A retrospective review was performed of fifty-three patients who underwent revision total ankle replacement and had been followed for a minimum of two years. Patients were assessed radiographically and with outcome scores. The rates of conversion to amputation or fusion were also assessed. The mean follow-up period was 49.1 months after the revision arthroplasty. The average time from primary total ankle replacement to revision was fifty-one months. Forty-one of the fifty-three patients (77%) were available for follow-up. The revision arthroplasty had been converted to an arthrodesis in five of the forty-one patients, and two additional patients had undergone amputation. The most common indication for revision total ankle replacement was talar subsidence (63%; twenty-six of forty-one). Twenty-two patients (54%) had a subtalar arthrodesis performed at the time of the revision arthroplasty, with nineteen of those having a custom-designed long-stem talar component placed simultaneously. The mean radiographic measurements of component position did not change significantly postoperatively. The mean postoperative scores for the thirty-four patients with a retained total ankle replacement were: 4.4 of 10 possible points on a visual analog pain scale (VAS), 65 of 100 possible points on the American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot scale, 93.5 of 100 possible points on the Short-Form 12 (SF-12), 137.9 of 204 possible points on the Revised Foot Function Index (FFI-R), and 64 of 180 possible points on the Ankle Osteoarthritis Scale (AOS). The mean arc of motion radiographically was 18° preoperatively and 23° postoperatively, with all improvement occurring in plantar flexion. A lesser amount of preoperative talar subsidence was a significant predictor of a good outcome based on the AOFAS hindfoot score (p < 0.03) and the AOS (p < 0.01) score. Revision arthroplasty may be considered as an alternative to arthrodesis when treating patients with a failed Agility total ankle implant.


Dietary amelioration of Helicobacter infection.
We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability, and cultural acceptability. This review, therefore, highlights specific foods, food components, and food products, grouped as follows: bee products (eg, honey and propolis); probiotics; dairy products; vegetables; fruits; oils; essential oils; and herbs, spices, and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and preclinical evidence must now be followed up with rationally designed, unambiguous human trials.


Ethnopharmacy of the ethnic Albanians (Arbëreshë) of northern Basilicata, Italy.
Intercultural studies about the methods of use and perceptions of traditional remedies in Europe are strategically important in understanding how pharmaceutical means in our multicultural modern societies are differently accepted by diverse ethnic groups. In this survey, we analysed the biological means traditionally used in the ethnomedicine of three Arbëreshë (ethnic Albanians) communities in the Vulture area (northern Lucania, southern Italy). The majority of remedies are represented by plants belonging to 54 botanical taxa. A few of the recorded species have a traditional therapeutic use that has never previously been reported in southern Italy. Other means-especially used in the past-are comprised of mineral, animal and industrial derived materials. In specific cases, some of these materials and even plants are neither applied externally or internally, but are instead utilised as symbolic ritual objects in spiritual healing ceremonies. Ethnopharmacological and anthropological considerations about these usages are discussed.


Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries.
Acute lung injury (ALI), which is associated with a mortality of 30-40%, is attributable to inflammation that develops rapidly across the lung's vast vascular surface, involving an entire lung or even both lungs. No specific mechanism explains this extensive inflammatory spread, probably because of the lack of approaches for detecting signal conduction in lung capillaries. Here, we addressed this question by applying the photolytic uncaging approach to induce focal increases in Ca2+ levels in targeted endothelial cells of alveolar capillaries. Uncaging caused Ca2+ levels to increase not only in the targeted cell, but also in vascular locations up to 150 microm from the target site, indicating that Ca2+ was conducted from the capillary to adjacent vessels. No such conduction was evident in mouse lungs lacking endothelial connexin 43 (Cx43), or in rat lungs in which we pretreated vessels with peptide inhibitors of Cx43. These findings provide the first direct evidence to our knowledge that interendothelial Ca2+ conduction occurs in the lung capillary bed and that Cx43-containing gap junctions mediate the conduction. A proinflammatory effect was evident in that induction of increases in Ca2+ levels in the capillary activated expression of the leukocyte adherence receptor P-selectin in venules. Further, peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases. Together, our findings reveal a novel role for Cx43-mediated gap junctions, namely as conduits for the spread of proinflammatory signals in the lung capillary bed. Gap junctional mechanisms require further consideration in the understanding of ALI.


Finding the missing link: Resolving the Coryneliomycetidae within Eurotiomycetes.
Species belonging to the Coryneliaceae and parasitizing Podocarpaceae hosts were collected from different locations in South Africa and studied morphologically by light microscopy and molecularly by obtaining partial nrDNA (ITS-1/5.8S/ITS-2, 18S and 28S) gene sequences. The position of the Coryneliaceae within the Eurotiomycetidae was not confirmed and a new subclass, Coryneliomycetidae, was introduced. While Eurotiomycetidae usually form cleistothecia/gymnothecia with evanescent, unitunicate asci, and Chaetothyriomycetidae mostly perithecia with bitunicate/fissitunicate to evanescent asci, Coryneliomycetidae form pseudothecial mazaedial ascomata, initially with double-walled asci with the outer layer deliquescing, resulting in passive ascospore release. The Coryneliomycetidae thus occupies a unique position in the Eurotiomycetes. Furthermore, epitypes were designated for Corynelia uberata, the type species of Corynelia (type genus of the family, order and subclass), Lagenulopsis bispora, the type species of Lagenulopsis, and Tripospora tripos the type species of Tripospora, with Lagenulopsis and Tripospora confirmed as belonging to the Coryneliaceae. Corynelia uberata resolved into three clades, one on Afrocarpus (= Podocarpus) falcatus and A. gracilior, and two clades occurring on P. latifolius, herein described as C. africana and C. fructigena. Morphologically these three species are not readily distinguishable, although they differ in spore dimensions, ascomata shape, ornamentation and DNA phylogeny. It is likely that several more species from other parts of the world are currently erroneously placed in C. uberata.


Predictors of micronutrient status among six- to twelve-month-old breast-fed Ghanaian infants.
This study describes the factors associated with hemoglobin and plasma ferritin, zinc and retinol concentrations and erythrocyte riboflavin status among 208 Ghanaian infants who participated in a complementary feeding intervention trial from 6 to 12 mo of age. Anthropometric, morbidity and dietary data were collected regularly from 1 to 12 mo; blood samples were collected at 6 and 12 mo. The prevalence of low micronutrient status at 6 and 12 mo, respectively, was as follows: hemoglobin <100 g/L, 30 and 34%; plasma ferritin <12 microg/L, 17 and 43%; plasma zinc <10.7 micromol/L, 4 and 6%; plasma retinol <0.7 micromol/L, 26 and 26%; erythrocyte riboflavin <200 umol/L of packed red cells, 14 and 10%. Multiple regression was used to identify factors significantly associated with micronutrient status. From 6 to 12 mo, fever prevalence was associated with a decrease in hemoglobin, but an increase in erythrocyte riboflavin concentrations, and diarrhea prevalence was related to a decrease in plasma retinol. Seasonal differences were evident for most of the indicators of micronutrient status, and elevated C-reactive protein levels (indicative of recent infection) were related to lower hemoglobin, retinol and zinc concentrations but higher ferritin and erythrocyte riboflavin concentrations. Weight at birth or at 1 mo of age was positively related to iron, zinc and vitamin A status, but a more rapid weight gain was associated with depletion of iron stores. Socioeconomic status was related to higher hemoglobin, riboflavin and zinc concentrations. The feeding of a micronutrient-fortified food was positively associated with plasma ferritin and retinol concentrations at 12 mo. These results suggest that prenatal factors, socioeconomic status, dietary intake and morbidity all influence infant micronutrient status, and that fortification of complementary foods is one potential avenue for preventing deficiencies.


Case Study: Innovation Procurement for a Digital Services Platform.
This case describes a design contest strategy to procure a solution to coordination of care transitions across healthcare programs to strengthen patient outcomes. The fit of the vendors' approach with the organization and the potential for building a strong relationship with the vendor teams were evaluated. A consortium of small Canadian companies was selected to proceed to a proof-of-concept phase and full implementation of the digital solution across the region. This design contest approach resulted in a successful vendor partnership for the organization to co-design, develop, implement and scale an innovative solution to support care transitions across the region.


Acquisition of murine major histocompatibility complex gene products by schistosomula of Schistosoma mansoni.
Schistosoma mansoni schistosomula recovered from the lungs of inbred mice were shown to possess serologically detectable alloantigens on their tegumental surfaces. Using appropriate antisera and infected congenic and recombinant mice as worm donors, gene products of the K and I subregions of the major histocompatibility complex were demonstrated among these alloantigens acquired by the parasites. In contrast, other cell surface alloantigens, such as Thy 1, Ly 1, and H-Y and the serum proteins albumin, C3 and Ig, could not be detected on the surface of lung schistosomula by means of comparable techniques. In another series of experiments, schistosomula recovered from the lungs of mice and reinjected into allogeneic recipients were shown to exchange their alloantigens during an 87-h period of examination. Similarly, lung schistosomula cocultured with allogeneic lymphocytes were shown to acquire major histocompatibility complex (MHC) coded antigens from the cells. It is possible that as acquired host molecules, MHC gene products may disguise the surface of schistosome parasites thereby rendering them insusceptible to immune attack.


Atracurium--a post-marketing surveillance study: methods and U.S. experience.
Two companion post-marketing studies have evaluated the frequency of adverse events amongst patients receiving atracurium. In this first report, we describe the study methods used in both centres and the findings of the study conducted at the Group Health Co-operative of Puget Sound, U.S.A. In this study, the frequency of adverse events in 1013 patients receiving atracurium was substantially the same as that in 851 patients receiving other neuromuscular blocking agents. In both groups there were no instances of cardiac arrest, anaphylaxis or death, no adverse effects associated with failure to antagonize neuromuscular block, and no instances of previously unreported types of adverse effects. We conclude that the safety profile of atracurium is similar to that of other neuromuscular blocking agents and that this type of observational study of anaesthetic agents may prove a useful tool for surveillance of new drugs used primarily in hospitals.


Dietary lipids and thrombosis. Relationships to atherosclerosis.
A high intake of saturated fatty acids and cholesterol is associated with a high incidence of occlusive arterial lesions involving both atherosclerosis and thrombosis. The evidence is based on epidemiological, experimental, and clinical studies. Such dietary habits increase serum low density lipoprotein cholesterol, a main risk factor for atherosclerosis. The mechanisms by which dietary saturated fatty acids are connected to arterial thrombogenesis are only partly known. Experimental and epidemiological studies also indicate an association between dietary saturated fatty acids and venous thrombosis; however, the chain of evidence lacks documentation from prospective clinical studies. When unsaturated fatty acids of the (n-9), (n-6), or (n-3) families replace saturated fatty acids in the diet, risk factors related to atherosclerosis may be reduced and the development of atherosclerosis, inhibited. This potential is related both to the reduction of saturated fatty acids and, in varying degrees, to the individual unsaturated fatty acids. The very long-chain fatty acids of the (n-3) family and probably also linoleic acid of the (n-6) family have the potential to inhibit thrombogenesis. In this respect, the effect of the individual fatty acids seems even more important. To obtain an optimal dietary lipid composition for the prevention of atherosclerosis and thrombosis, it is important to appreciate the metabolic and structural effects of the individual fatty acids. The interaction between the various dietary fatty acids and their effects on lipid biosynthesis is still only partly known. The present nutritional recommendations include a low intake of saturated fatty acids and cholesterol and a balanced content of the unsaturated fatty acids and represent a well-documented approach to the prevention of both processes.


Obesity and biochemical outcome following radical prostatectomy for organ confined disease with negative surgical margins.
We have previously shown that men with a body mass index (BMI) greater than 35 kg/m2 had higher rates of positive surgical margins and significantly higher biochemical recurrence rates following radical prostatectomy (RP). To determine whether the higher prostate specific antigen (PSA) recurrence rates were due solely to the higher positive margin rate, we examined whether obesity was an independent predictor of biochemical failure among men with negative surgical margins. We examined data from 1,250 men treated with RP between 1988 and 2003 at 5 equal access medical centers, of whom 731 had pathologically organ confined disease and negative surgical margins. Multivariate Cox proportional hazards analysis was used to determine if BMI was a significant independent predictor of biochemical recurrence. Mean BMI significantly increased over time (p = 0.010). Black men were significantly more likely to be obese than white or nonwhite-nonblack men. After controlling for all preoperative characteristics, body mass index was a significant predictor of biochemical failure with moderately and severely obese men (BMI 35 kg/m2 or greater) having greater than a 4-fold increased risk of PSA failure (p = 0.035). After controlling for the higher pathological Gleason grades among obese men, body mass index remained a significant predictor of biochemical failure with moderately and severely obese men (BMI 35 kg/m2 or greater) having nearly a 4-fold increased risk for PSA failure (p = 0.036). BMI 35 kg/m2 or greater was associated with higher grade tumors and worse outcome following RP in a cohort of men with favorable pathological findings. Thus, surgical technique (margin status) cannot fully explain the worse outcomes among obese men, suggesting that obesity may be associated with a biologically more aggressive form of prostate cancer.


Are mechanics different between male and female runners with patellofemoral pain?
Patellofemoral pain (PFP) has often been attributed to abnormal hip and knee mechanics in females. To date, there have been few investigations of the hip and knee mechanics of males with PFP. The purpose of this study was to compare the lower extremity mechanics and alignment of male runners with PFP with healthy male runners and female runners with PFP. We hypothesized that males with PFP would move with greater varus knee mechanics compared with male controls and compared with females with PFP. Furthermore, it was hypothesized that males with PFP would demonstrate greater varus alignment. A gait and single-leg squat analysis was conducted on each group (18 runners per group). Measurement of each runner's tibial mechanical axis was also recorded. Motion data were processed using Visual 3D (C-Motion, Bethesda, MD). ANOVAs were used to analyze the data. Males with PFP ran and squatted in greater peak knee adduction and demonstrated greater peak knee external adduction moment compared with healthy male controls. In addition, males with PFP ran and squatted with less peak hip adduction and greater peak knee adduction compared with females with PFP. The static measure of mechanical axis of the tibial was not different between groups. However, a post hoc analysis revealed that males with PFP ran with greater peak tibial segmental adduction. Males with PFP demonstrated different mechanics during running and during a single-leg squat compared with females with PFP and with healthy males. Based upon the results of this study, therapies for PFP may need to be sex specific.


ENSO as an integrating concept in earth science.
The El Niño-Southern Oscillation (ENSO) cycle of alternating warm El Niño and cold La Niña events is the dominant year-to-year climate signal on Earth. ENSO originates in the tropical Pacific through interactions between the ocean and the atmosphere, but its environmental and socioeconomic impacts are felt worldwide. Spurred on by the powerful 1997-1998 El Niño, efforts to understand the causes and consequences of ENSO have greatly expanded in the past few years. These efforts reveal the breadth of ENSO's influence on the Earth system and the potential to exploit its predictability for societal benefit. However, many intertwined issues regarding ENSO dynamics, impacts, forecasting, and applications remain unresolved. Research to address these issues will not only lead to progress across a broad range of scientific disciplines but also provide an opportunity to educate the public and policy makers about the importance of climate variability and change in the modern world.


Deaths Attributed to Respiratory Syncytial Virus in Young Children in High-Mortality Rate Settings: Report from Child Health and Mortality Prevention Surveillance (CHAMPS).
Lower respiratory tract infections are a leading cause of death in young children, but few studies have collected the specimens needed to define the role of specific causes. The Child Health and Mortality Prevention Surveillance (CHAMPS) platform aims to investigate causes of death in children aged <5 years in high-mortality rate settings, using postmortem minimally invasive tissue sampling and other advanced diagnostic techniques. We examined findings for deaths identified in CHAMPS sites in 7 countries in sub-Saharan Africa and south Asia to evaluate the role of respiratory syncytial virus (RSV). We included deaths that occurred between December 2016 and December 2019. Panels determined causes of deaths by reviewing all available data including pathological results from minimally invasive tissue sampling, polymerase chain reaction screening for multiple infectious pathogens in lung tissue, nasopharyngeal swab, blood, and cerebrospinal fluid samples, clinical information from medical records, and verbal autopsies. We evaluated 1213 deaths, including 695 in neonates (aged <28 days), 283 in infants (28 days to <12 months), and 235 in children (12-59 months). RSV was detected in postmortem specimens in 67 of 1213 deaths (5.5%); in 24 deaths (2.0% of total), RSV was determined to be a cause of death, and it contributed to 5 other deaths. Younger infants (28 days to <6 months of age) accounted for half of all deaths attributed to RSV; 6.5% of all deaths in younger infants were attributed to RSV. RSV was the underlying and only cause in 4 deaths; the remainder (n = 20) had a median of 2 (range, 1-5) other conditions in the causal chain. Birth defects (n = 8) and infections with other pathogens (n = 17) were common comorbid conditions. RSV is an important cause of child deaths, particularly in young infants. These findings add to the substantial body of literature calling for better treatment and prevention options for RSV in high-mortality rate settings.


Do negative life events promote gerotranscendence in the second half of life?
Gerotranscendence has been defined as a developmental shift in meta-perspective from a materialistic and pragmatic view to a more cosmic and transcendent view. Although gerotranscendence has been argued to increase with age and life experiences, the results have been mixed and based on cross-sectional studies. We use a longitudinal setting to investigate the role of negative life events, age, and gender on change in one dimension of gerotranscendence, cosmic transcendence. 1569 individuals (ages 58-89) answered a questionnaire on cosmic transcendence in two cycles of the Longitudinal Aging Study Amsterdam in 1995-1996 (time 1) and 1998-1999 (time 2). Controlling for education, marital status, religious affiliation, chronic diseases, functional limitations, depressive symptoms, and social support, change models based on structural equation modeling were fitted to the data to test whether negative life events, age, and gender were associated with change in cosmic transcendence. A higher number of negative life events, especially negative life events other than deaths of others, were associated with increased cosmic transcendence, whereas experiencing no negative life events was associated with decreased cosmic transcendence. The level of cosmic dimension was higher at older than younger ages. Cosmic transcendence decreased over time among the older participants and women, whereas it increased among the younger participants and men. Experiencing negative life events has the potential to promote the development of cosmic transcendence, even when controlling for age and gender. In the absence of negative life events, however, cosmic transcendence was observed to decline with aging.


The focal adhesion protein PINCH-1 associates with EPLIN at integrin adhesion sites.
PINCH-1 is a LIM-only domain protein that forms a ternary complex with integrin-linked kinase (ILK) and parvin (to form the IPP complex) downstream of integrins. Here, we demonstrate that PINCH-1 (also known as Lims1) gene ablation in the epidermis of mice caused epidermal detachment from the basement membrane, epidermal hyperthickening and progressive hair loss. PINCH-1-deficient keratinocytes also displayed profound adhesion, spreading and migration defects in vitro that were substantially more severe than those of ILK-deficient keratinocytes indicating that PINCH-1 also exerts functions in an ILK-independent manner. By isolating the PINCH-1 interactome, the LIM-domain-containing and actin-binding protein epithelial protein lost in neoplasm (EPLIN, also known as LIMA1) was identified as a new PINCH-1-associated protein. EPLIN localized, in a PINCH-1-dependent manner, to integrin adhesion sites of keratinocytes in vivo and in vitro and its depletion severely attenuated keratinocyte spreading and migration on collagen and fibronectin without affecting PINCH-1 levels in focal adhesions. Given that the low PINCH-1 levels in ILK-deficient keratinocytes were sufficient to recruit EPLIN to integrin adhesions, our findings suggest that PINCH-1 regulates integrin-mediated adhesion of keratinocytes through the interactions with ILK as well as EPLIN.


A large-scale distribution of milk-based fortified spreads: evidence for a new approach in regions with high burden of acute malnutrition.
There are 146 million underweight children in the developing world, which contribute to up to half of the world's child deaths. In high burden regions for malnutrition, the treatment of individual children is limited by available resources. Here, we evaluate a large-scale distribution of a nutritional supplement on the prevention of wasting. A new ready-to-use food (RUF) was developed as a diet supplement for children under three. The intervention consisted of six monthly distributions of RUF during the 2007 hunger gap in a district of Maradi region, Niger, for approximately 60,000 children (length: 60-85 cm). At each distribution, all children over 65 cm had their Mid-Upper Arm Circumference (MUAC) recorded. Admission trends for severe wasting (WFH<70% NCHS) in Maradi, 2002-2005 show an increase every year during the hunger gap. In contrast, in 2007, throughout the period of the distribution, the incidence of severe acute malnutrition (MUAC<110 mm) remained at extremely low levels. Comparison of year-over-year admissions to the therapeutic feeding program shows that the 2007 blanket distribution had essentially the same flattening effect on the seasonal rise in admissions as the 2006 individualized treatment of almost 60,000 children moderately wasted. These results demonstrate the potential for distribution of fortified spreads to reduce the incidence of severe wasting in large population of children 6-36 months of age. Although further information is needed on the cost-effectiveness of such distributions, these results highlight the importance of re-evaluating current nutritional strategies and international recommendations for high burden areas of childhood malnutrition.


Different levels of Notch signaling regulate quiescence, renewal and differentiation in pancreatic endocrine progenitors.
Genetic studies have implicated Notch signaling in the maintenance of pancreatic progenitors. However, how Notch signaling regulates the quiescent, proliferative or differentiation behaviors of pancreatic progenitors at the single-cell level remains unclear. Here, using single-cell genetic analyses and a new transgenic system that allows dynamic assessment of Notch signaling, we address how discrete levels of Notch signaling regulate the behavior of endocrine progenitors in the zebrafish intrapancreatic duct. We find that these progenitors experience different levels of Notch signaling, which in turn regulate distinct cellular outcomes. High levels of Notch signaling induce quiescence, whereas lower levels promote progenitor amplification. The sustained downregulation of Notch signaling triggers a multistep process that includes cell cycle entry and progenitor amplification prior to endocrine differentiation. Importantly, progenitor amplification and differentiation can be uncoupled by modulating the duration and/or extent of Notch signaling downregulation, indicating that these processes are triggered by distinct levels of Notch signaling. These data show that different levels of Notch signaling drive distinct behaviors in a progenitor population.


Detection of Helicobacter pylori in dental plaque by reverse transcription-polymerase chain reaction.
To investigate whether the oral cavity is a potential reservoir and possible sanctuary for Helicobacter pylori, supragingival and subgingival plaques were analyzed by a Helicobacter genus-specific reverse transcriptase-polymerase chain reaction based on the sequence data of H. pylori 16S rRNA. The amplified 500-bp DNA fragment was identified by ethidium bromide staining after agarose gel electrophoresis and by Southern hybridization. Twenty-five dyspeptic patients were studied. Histologic examination of gastric biopsy specimens revealed that 18 had H. pylori gastritis and 7 did not. For seven of the 18 (38.8%) patients with proven H. pylori gastritis, H. pylori was also identified in their dental plaque. None of the patients without H. pylori gastritis had H. pylori in their dental plaque. The detection of H. pylori in dental plaque suggests that this H. pylori colonization is not restricted to the gastric mucosa and that this ecological niche may serve as a possible sanctuary which may be responsible for reinoculation of the stomach after topical anti-H. pylori therapies such as bismuth.