Defining the transmembrane helix of M2 protein from influenza A by molecular dynamics simulations in a lipid bilayer.
Integral membrane proteins containing at least one transmembrane (TM) alpha-helix are believed to account for between 20% and 30% of most genomes. There are several algorithms that accurately predict the number and position of TM helices within a membrane protein sequence. However, these methods tend to disagree over the beginning and end residues of TM helices, posing problems for subsequent modeling and simulation studies. Molecular dynamics (MD) simulations in an explicit lipid and water environment are used to help define the TM helix of the M2 protein from influenza A virus. Based on a comparison of the results of five different secondary structure prediction algorithms, three different helix lengths (an 18mer, a 26mer, and a 34mer) were simulated. Each simulation system contained 127 POPC molecules plus approximately 3500-4700 waters, giving a total of approximately 18,000-21,000 atoms. Two simulations, each of 2 ns duration, were run for the 18mer and 26mer, and five separate simulations were run for the 34mer, using different starting models generated by restrained in vacuo MD simulations. The total simulation time amounted to 11 ns. Analysis of the time-dependent secondary structure of the TM segments was used to define the regions that adopted a stable alpha-helical conformation throughout the simulation. This analysis indicates a core TM region of approximately 20 residues (from residue 22 to residue 43) that remained in an alpha-helical conformation. Analysis of atomic density profiles suggested that the 18mer helix revealed a local perturbation of the lipid bilayer. Polar side chains on either side of this region form relatively long-lived H-bonds to lipid headgroups and water molecules.


Pilot-scale study of vertical flow constructed wetland combined with trickling filter and ferric chloride coagulation: influence of irregular operational conditions.
The aim of this study was to characterize the efficiency of an intensified process of vertical flow constructed wetland having the following particularities: (i) biological pretreatment by trickling filter, (ii) FeCl3 injection for dissolved phosphorus removal and (iii) succession of different levels of redox conditions along the process line. A pilot-scale set-up designed to simulate a real-scale plant was constructed and operated using real wastewater. The influences of FeCl3 injection and water saturation level within the vertical flow constructed wetland stage on treatment performances were studied. Three different water saturation levels were compared by monitoring: suspended solids (SS), total phosphorus (TP), dissolved chemical oxygen demand (COD), ammonium, nitrate, phosphate, iron, and manganese. The results confirmed the good overall efficiency of the process and the contribution of the trickling filter pretreatment to COD removal and nitrification. The effects of water saturation level and FeCl3 injection on phosphorus removal were evaluated by analysis of the correlations between the variables. Under unsaturated conditions, good nitrification and no denitrification were observed. Under partly saturated conditions, both nitrification and denitrification were obtained, along with a good retention of SSs. Finally, under saturated conditions, the performance was decreased for almost all parameters.


Cultural differences in visual perceptual learning.
Cultural differences in visual perceptual learning (VPL) could be attributed to differences in the way that people from individualistic and collectivistic cultures preferentially attend to local objects (analytic) or global contexts (holistic). Indeed, individuals from different cultural backgrounds can adopt distinct processing styles and learn to differentially construct meaning from the environment. Therefore, the present work investigates if cross-cultural differences in VPL can vary as a function of holistic processing. A shape discrimination task was used to investigate whether the individualistic versus collectivistic backgrounds of individuals affected the detection of global shapes embedded in cluttered backgrounds. Seventy-seven participants-including Asian (collectivistic background) and European (individualistic background) students-were trained to discriminate between radial and concentric patterns. Singelis's self-construal scale was also used to assess whether differences in learning could be attributed to independent or interdependent self-construal. Results showed that collectivists had faster learning rates and better accuracy performance than individualists following training-thereby reflecting their tendency to attend holistically when learning to extract global forms. Further, we observed a negative association between independent self-construal-which has previously been linked to analytic processing-with performance. This study provides insight into how socio-cultural backgrounds affect VPL.


Assessing the performance of prediction models: a framework for traditional and novel measures.
The performance of prediction models can be assessed using a variety of methods and metrics. Traditional measures for binary and survival outcomes include the Brier score to indicate overall model performance, the concordance (or c) statistic for discriminative ability (or area under the receiver operating characteristic [ROC] curve), and goodness-of-fit statistics for calibration.Several new measures have recently been proposed that can be seen as refinements of discrimination measures, including variants of the c statistic for survival, reclassification tables, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Moreover, decision-analytic measures have been proposed, including decision curves to plot the net benefit achieved by making decisions based on model predictions.We aimed to define the role of these relatively novel approaches in the evaluation of the performance of prediction models. For illustration, we present a case study of predicting the presence of residual tumor versus benign tissue in patients with testicular cancer (n = 544 for model development, n = 273 for external validation).We suggest that reporting discrimination and calibration will always be important for a prediction model. Decision-analytic measures should be reported if the predictive model is to be used for clinical decisions. Other measures of performance may be warranted in specific applications, such as reclassification metrics to gain insight into the value of adding a novel predictor to an established model.


Investigation of Hydrogen Embrittlement Susceptibility and Fracture Toughness Drop after in situ Hydrogen Cathodic Charging for an X65 Pipeline Steel.
The present research focuses on the investigation of an in situ hydrogen charging effect during Crack Tip Opening Displacement testing (CTOD) on the fracture toughness properties of X65 pipeline steel. This grade of steel belongs to the broader category of High Strength Low Alloy Steels (HSLA), and its microstructure consists of equiaxed ferritic and bainitic grains with a low volume fraction of degenerated pearlite islands. The studied X65 steel specimens were extracted from pipes with 19.15 mm wall thickness. The fracture toughness parameters were determined after imposing the fatigue pre-cracked specimens on air, on a specific electrolytic cell under a slow strain rate bending loading (according to ASTM G147-98, BS7448, and ISO12135 standards). Concerning the results of this study, in the first phase the hydrogen cations' penetration depth, the diffusion coefficient of molecular and atomic hydrogen, and the surficial density of blisters were determined. Next, the characteristic parameters related to fracture toughness (such as J, KQ, CTODel, CTODpl) were calculated by the aid of the Force-Crack Mouth Open Displacement curves and the relevant analytical equations.


High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma.
In approximately 5% to 10% of gastric mucosa-associated lymphoid tissue (MALT) lymphomas, evidence of Helicobacter pylori infection is absent, and their pathogenesis is poorly understood. We reviewed the clinical data and histology, and we examined t(11;18)(q21;q21) and BCL10 expression pattern in 17 such cases. In each case, the absence of H pylori was confirmed by negative serology and histology/immunohistochemistry. Five cases with stage I(E) disease were first treated with antibiotics, and none of them showed any endoscopic or histologic response. Review of the histology failed to identify any apparent difference between gastric MALT lymphomas with and without H pylori infection. Reverse transcription-polymerase chain reaction (RT-PCR) showed t(11;18)(q21;q21) in 9 (53%) of 17 cases, more frequent in lymphomas at stage II(E) or above (5 of 6) than those at stage I(E) (3 of 10). Two t(11;18)(q21;q21)-positive lymphomas were treated by partial gastrectomy and more than 16 years later showed lymphoma relapse in the gastric stump with dissemination to other mucosal sites, poorly responsive to therapy. BCL10 nuclear expression was observed in 7 of 8 t(11;18)(q21;q21)-positive cases and 4 of 7 t(11;18)(q21;q21)-negative cases, including one case suspicious for a BCL10-involved chromosomal translocation. Our results show that t(11;18)(q21;q21) occurs at a high frequency in H pylori-negative gastric MALT lymphomas. Translocation-positive gastric MALT lymphomas tend to be aggressive, and patients with such lymphomas might benefit from prompt treatment and close follow-up.


Emotion recognition in children with profound and severe deafness: do they have a deficit in perceptual processing?
Findings from several studies have suggested that deaf children have difficulties with emotion identification and that these may impact upon social skills. The authors of these studies have typically attributed such problems to delayed language acquisition and/or opportunity to converse about personal experiences with other people (Peterson & Siegal, 1995, 1998). The current study aimed to investigate emotion identification in children with varying levels of deafness by specifically testing their ability to recognize perceptual aspects of emotions depicted in upright or inverted human and cartoon faces. The findings from the study showed that, in comparison with both chronological- and mental-age-matched controls, the deaf children were significantly worse at identifying emotions. However, like controls, their performance decreased when emotions were presented on the inverted faces, thus indexing a typical configural processing style. No differences were found across individuals with different levels of deafness or in those with and without signing family members. The results are supportive of poor emotional identification in hearing-impaired children and are discussed in relation to delays in language acquisition and intergroup differences in perceptual processing.


Is mate choice in humans MHC-dependent?
In several species, including rodents and fish, it has been shown that the Major Histocompatibility Complex (MHC) influences mating preferences and, in some cases, that this may be mediated by preferences based on body odour. In humans, the picture has been less clear. Several studies have reported a tendency for humans to prefer MHC-dissimilar mates, a sexual selection that would favour the production of MHC-heterozygous offspring, who would be more resistant to pathogens, but these results are unsupported by other studies. Here, we report analyses of genome-wide genotype data (from the HapMap II dataset) and HLA types in African and European American couples to test whether humans tend to choose MHC-dissimilar mates. In order to distinguish MHC-specific effects from genome-wide effects, the pattern of similarity in the MHC region is compared to the pattern in the rest of the genome. African spouses show no significant pattern of similarity/dissimilarity across the MHC region (relatedness coefficient, R = 0.015, p = 0.23), whereas across the genome, they are more similar than random pairs of individuals (genome-wide R = 0.00185, p<10(-3)). We discuss several explanations for these observations, including demographic effects. On the other hand, the sampled European American couples are significantly more MHC-dissimilar than random pairs of individuals (R = -0.043, p = 0.015), and this pattern of dissimilarity is extreme when compared to the rest of the genome, both globally (genome-wide R = -0.00016, p = 0.739) and when broken into windows having the same length and recombination rate as the MHC (only nine genomic regions exhibit a higher level of genetic dissimilarity between spouses than does the MHC). This study thus supports the hypothesis that the MHC influences mate choice in some human populations.


High-throughput transcription profiling identifies putative epigenetic regulators of hematopoiesis.
Hematopoietic differentiation is governed by a complex regulatory program controlling the generation of different lineages of blood cells from multipotent hematopoietic stem cells. The transcriptional program that dictates hematopoietic cell fate and differentiation requires an epigenetic memory function provided by a network of epigenetic factors regulating DNA methylation, posttranslational histone modifications, and chromatin structure. Aberrant interactions between epigenetic factors and transcription factors cause perturbations in the blood cell differentiation program that result in various types of hematopoietic disorders. To elucidate the contributions of different epigenetic factors in human hematopoiesis, high-throughput cap analysis of gene expression was used to build transcription profiles of 199 epigenetic factors in a wide range of blood cells. Our epigenetic transcriptome analysis revealed cell type- (eg, HELLS and ACTL6A), lineage- (eg, MLL), and/or leukemia- (eg, CHD2, CBX8, and EPC1) specific expression of several epigenetic factors. In addition, we show that several epigenetic factors use alternative transcription start sites in different cell types. This analysis could serve as a resource for the scientific community for further characterization of the role of these epigenetic factors in blood development.


Free protein S level as a risk factor for coronary heart disease and stroke in a prospective cohort study of healthy United Kingdom men.
Plasma protein S (PS) levels are reportedly low in patients with venous thrombosis but high in coronary heart disease (CHD) patients. The authors examined the association between free PS concentration and CHD or stroke risk and assessed risk in combination with C-reactive protein (CRP) levels. Free PS concentration was determined in 6 annual visits among 3,052 middle-aged (49-64 years) United Kingdom men from the Second Northwick Park Heart Study, with 297 CHD events from 1989 to 2005. The highest (vs. first) quintile was associated with a significantly increased CHD risk after adjustment for all other risk factors and correction for regression dilution bias (hazard ratio = 1.85, 95% confidence interval: 1.08, 3.16; P = 0.024). Models that included all well-known risk factors plus PS quintiles improved prediction of CHD (net reclassification improvement (NRI) = 7.0% (P = 0.007), category-less NRI (>0) = 22.1% (P < 0.001)), and the likelihood ratio statistic increased significantly (P = 0.018). The increase in CHD risk was particularly strong when subjects also had high CRP levels. There was no association between free PS level and stroke risk. This study confirms the independent association of elevated free PS levels with future risk of CHD, although elevated PS levels added only modestly to prediction metrics. The novel finding of increased CHD risk, particularly when CRP and PS levels are high, requires further study.


Serum glycated albumin is inversely influenced by fat mass and visceral adipose tissue in Chinese with normal glucose tolerance.
Recent studies have revealed that body mass index (BMI) inversely influenced serum glycated albumin (GA), which may cause an underestimation of GA-monitored short-term hyperglycemic control. This study was to investigate the association between anthropometric variables (BMI and waist circumference (W)) and accurate adiposity variables (percentage of body fat (%fat), fat mass, free fat mass (FFM), subcutaneous fat area (SFA), and visceral fat area (VFA)) with serum GA. A total of 2563 subjects (1037 men, 593 premenopausal women, and 933 postmenopausal women) with normal glucose tolerance underwent bioelectrical impedance body fat content measurement and magnetic resonance imaging. Serum GA and absolute value of GA (aGA) were measured by enzymatic assay. Compared to the BMI <25.0 kg/m(2) group, the BMI ≥25.0 kg/m(2) group had significantly higher fasting plasma glucose, glycated hemoglobin A1c, and body fat parameters including W, %fat, fat mass, FFM, SFA, and VFA, but significantly lower aGA, and GA in all the three sex- and menopause-stratified groups (all P<0.05). GA decreased with the increment of fat mass for all three groups (all P for trend <0.001). In the same BMI category, men and postmenopausal women with elevated %fat (men, ≥25%; women, ≥35%) still had significantly lower GA than those with normal %fat (men, <25%; women, <35%) (all P<0.05). Multiple stepwise regression showed that %fat, fat mass, and VFA were independently associated with GA. Serum GA was inversely influenced by fat mass and visceral adipose tissue in Chinese with normal glucose tolerance.


Parental health and children's cognitive and noncognitive development: New evidence from the longitudinal survey of Australian children.
This paper examines the effects of parental health on cognitive and noncognitive development in Australian children. The underlying nationally representative panel data and a child fixed effects estimator are used to deal with unobserved heterogeneity. We find that only father's serious mental illness worsens selected cognitive and noncognitive skills of children. Maternal poor health also deteriorates some cognitive and noncognitive outcomes of children of lone mothers only. Our results demonstrate that either failing to account for parent-child fixed effects or using child noncognitive skills reported by parents could overestimate the harmful impact of poor parental health on child development.


Growth arrest-specific protein 6 attenuates neutrophil migration and acute lung injury in sepsis.
Sepsis is an acute inflammatory condition that can result in multiple organ failure and acute lung injury. Growth arrest-specific protein 6 (Gas6) is a broad regulator of the innate immune response involved with the nuclear factor κB signaling pathway. We hypothesized that Gas6 could have a protective role in attenuating the severity of acute lung injury and sepsis. Male mice were subjected to sepsis by cecal ligation and puncture (CLP) after which recombinant murine Gas6 (rmGas6; 5 μg/mouse) or normal saline (vehicle) was administered intravenously. Blood and lung tissues were collected at 20 h after CLP for various measurements. Treatment with rmGas6 significantly reduced serum levels of the injury markers aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, as well as proinflammatory cytokines interleukin 6 (IL-6) and IL-17, compared with the vehicle group (P < 0.05). The parenchyma of the lungs damaged by CLP was attenuated by rmGas6 treatment. Lung mRNA levels of tumor necrosis factor α, IL-1β, IL-6, IL-17, and macrophage inflammatory protein 2 (MIP-2) were decreased by 60%, 86%, 82%, 93%, and 82%, respectively, with rmGas6 treatment as determined by real-time reverse transcriptase-polymerase chain reaction (P < 0.05). The degradation of IκB-α induced by CLP in the lungs was inhibited by rmGas6 treatment. The number of neutrophils and myeloperoxidase activity in the lungs were significantly reduced in the rmGas6 group. Moreover, rmGas6 reduced the in vitro migration of differentiated human promyelocytic HL60 cells by 64%. Finally, the 10-day survival rate of mice subjected to CLP was increased from 31% in the vehicle group to 67% in the rmGas6 group (P < 0.05). Thus, Gas6 has potential to be developed as a novel therapeutic agent to treat patients with sepsis and acute lung injury.


Genome-wide characterization of the HD-ZIP IV transcription factor family in maize: preferential expression in the epidermis.
Transcription factors of the plant-specific homeodomain leucine zipper IV (HD-ZIP IV) family have been found from moss to higher plants, and several family members have been associated with epidermis-related expression and/or function. In maize (Zea mays), four of the five characterized HD-ZIP IV family members are expressed specifically in the epidermis, one contributes to trichome development, and target genes of another one are involved in cuticle biosynthesis. Assessing the phylogeny, synteny, gene structure, expression, and regulation of the entire family in maize, 12 novel ZmHDZIV genes were identified in the recently sequenced maize genome. Among the 17 genes, eight form homeologous pairs duplicated after the split of maize and sorghum (Sorghum bicolor), whereas a fifth duplication is shared with sorghum. All 17 ZmHDZIV genes appear to be derived from a basic module containing seven introns in the coding region. With one possible exception, all 17 ZmHDZIV genes are expressed and show preferential expression in immature reproductive organs. Fourteen of 15 ZmHDZIV genes with detectable expression in laser-dissected tissues exhibit a moderate to very strong expression preference for the epidermis, suggesting that at least in maize, the majority of HD-ZIP IV family members may have epidermis-related functions. Thirteen ZmHDZIV genes carry conserved motifs of 19 and 21 nucleotides in their 3' untranslated region. The strong evolutionary conservation and the size of the conserved motifs in the 3' untranslated region suggest that the expression of HD-ZIP IV genes may be regulated by small RNAs.


Molecular pathology of solid tumours: some practical suggestions for translating research into clinical practice.
"Molecular pathology" can be broadly defined as the use of genetic data, in addition to the standard pathological parameters, to optimise diagnosis and to indicate treatment and prognosis. The benefit to be gained from the exploitation of molecular techniques to provide additional information to aid patient management is potentially vast. Currently, molecular pathology is rarely used in clinical practice, although it is anticipated that it will eventually become a part of routine practice. However, incorporating molecular techniques into routine practice will not be straightforward because there are several issues to be resolved. Following on from a symposium held at the Royal College of Pathologists to discuss some of these issues, the establishment of a committee of molecular pathology is proposed to plan and coordinate the introduction of molecular pathology into routine clinical practice.


Developing a behavioral model for mobile phone-based diabetes interventions.
Behavioral models for mobile phone-based diabetes interventions are lacking. This study explores the potential mechanisms by which a text message-based diabetes program affected self-management among African-Americans. We conducted in-depth, individual interviews among 18 African-American patients with type 2 diabetes who completed a 4-week text message-based diabetes program. Each interview was audio-taped, transcribed verbatim, and imported into Atlas.ti software. Coding was done iteratively. Emergent themes were mapped onto existing behavioral constructs and then used to develop a novel behavioral model for mobile phone-based diabetes self-management programs. The effects of the text message-based program went beyond automated reminders. The constant, daily communications reduced denial of diabetes and reinforced the importance of self-management (Rosenstock Health Belief Model). Responding positively to questions about self-management increased mastery experience (Bandura Self-Efficacy). Most surprisingly, participants perceived the automated program as a "friend" and "support group" that monitored and supported their self-management behaviors (Barrera Social Support). A mobile phone-based diabetes program affected self-management through multiple behavioral constructs including health beliefs, self-efficacy, and social support. Disease management programs that utilize mobile technologies should be designed to leverage existing models of behavior change and can address barriers to self-management associated with health disparities.


Bee venom ameliorates cardiac dysfunction in diabetic hyperlipidemic rats.
High levels of blood glucose and lipids are well-known risk factors for heart diseases. Bee venom is a natural product that has a potent hypoglycemic, hypolipidemic, anti-inflammatory, and antioxidant effects. The current study aimed to determine the bee venom effects on cardiac dysfunction compared to combined therapy of metformin and atorvastatin in diabetic hyperlipidemic rats. The median lethal dose of bee venom was estimated, and then 50 adult male albino rats were categorized into five groups. One group was fed a standard diet and served as a negative control, while the other groups were given nicotinamide and streptozotocin injections to induce type 2 diabetes. After confirming diabetes, the rats were fed a high-fat diet for four weeks. The four groups were divided as follows: one group served as a positive control, whereas the other three groups were treated with bee venom (0.5 mg/kg), bee venom (1.23 mg/kg), and combined therapy of metformin (60 mg/kg) and atorvastatin (10 mg/kg), respectively, for four weeks. Upon termination of the experiment, blood samples and heart tissue were obtained. Administration of bee venom using both doses (0.5 and 1.23 mg/kg) and combined therapy of metformin and atorvastatin revealed a significant decrease in the concentrations of glucose, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, troponin I, creatine kinase, and lactate dehydrogenase activities. Moreover, a significant decrease had been detedcted in malondialdehyde, nuclear factor-kappa-β levels, and relative mRNA expression of vascular cell adhesion molecule-1 and galectin-3 in heart tissue compared to the positive control (P < 0.0001). Furthermore, there was a significant increase in bodyweight levels of insulin, high-density lipoprotein cholesterol, and total antioxidant capacity in heart tissue compared to the positive control (P < 0.0001). The results indicate that bee venom can ameliorate cardiac dysfunction through attenuating oxidative stress and downregulating the NF-κβ signaling pathway.


Thermogelling chitosan lactate hydrogel improves functional recovery after a C2 spinal cord hemisection in rat.
The present study was designed to provide an appropriate micro-environment for regenerating axotomized neurons and proliferating/migrating cells. Because of its intrinsic permissive properties, biocompatibility and biodegradability, we chose to evaluate the therapeutic effectiveness of a chitosan-based biopolymer. The biomaterial toxicity was measured through in vitro test based on fibroblast cell survival on thermogelling chitosan lactate hydrogel substrate and then polymer was implanted into a C2 hemisection of the rat spinal cord. Animals were randomized into three experimental groups (Control, Lesion and Lesion + Hydrogel) and functional tests (ladder walking and forelimb grip strength tests, respiratory assessment by whole-body plethysmography measurements) were used, once a week during 10 weeks, to evaluate post-traumatic recoveries. Then, electrophysiological examinations (reflexivity of the sub-lesional region, ventilatory adjustments to muscle fatigue known to elicit the muscle metaboreflex and phrenic nerve recordings during normoxia and temporary hypoxia) were performed. In vitro results indicated that the chitosan matrix is a non-toxic biomaterial that allowed fibroblast survival. Furthermore, implanted animals showed improvements of their ladder walking scores from the 4th week post-implantation. Finally, electrophysiological recordings indicated that animals receiving the chitosan matrix exhibited recovery of the H-reflex rate sensitive depression, the ventilatory response to repetitive muscle stimulation and an increase of the phrenic nerve activity to asphyxia compared to lesioned and nonimplanted animals. This study indicates that hydrogel based on chitosan constitute a promising therapeutic approach to repair damaged spinal cord or may be used as an adjuvant with other treatments to enhance functional recovery after a central nervous system damage. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2004-2019, 2017.


Cytoskeletal organization and functional changes in monocytes from patients with chronic hepatitis B: relationship with viral replication.
Monocytes play an important role in the initiation and regulation of the antiviral immune response. These cells have a dense framework of intermediate filaments composed of vimentin monomers. In 35 patients with chronic hepatitis B, 26 healthy controls, seven patients with acute liver damage and eight patients with inactive HBsAg-negative cirrhosis, we investigated the expression of vimentin filaments, C3b and IgGFc receptors, HLA-DR molecules and the phagocytic activity in monocytes purified from venous blood. In the same subjects, we also studied the display of CD2, CD3 and CD5 on lymphocytes. In patients with chronic hepatitis B manifesting viral replication (n = 21; Group 1), the expression of vimentin filaments and the other functional monocyte parameters were decreased, whereas in patients in the nonreplicative phase of the disease (n = 14; Group 2) and in control cases with various forms of acute liver damage or inactive HBsAg-negative cirrhosis, they were similar to those found in healthy subjects. In Group 1, there was also a selective defect in the display of CD3 on lymphocytes. The expression of this molecule correlated with the functional state of monocytes. In three patients with chronic hepatitis B that changed from the replicative to the nonreplicative phase of the disease, the expression of vimentin filaments in monocytes and of CD3 on lymphocytes increased to normal levels. On the other hand, the incubation of patients' monocytes with gamma-interferon corrected the diminished expression of vimentin filaments and the other decreased functional parameters.(ABSTRACT TRUNCATED AT 250 WORDS)


Implantation: molecular basis of embryo-uterine dialogue.
Implantation is a complex developmental process that involves an intimate "cross-talk" between the embryo and uterus. Synchronized development of the embryo to the blastocyst stage and differentiation of the uterus to the receptive state are essential to this process. Successful execution of the events of implantation involves participation of steroid hormones, locally derived growth factors, cytokines, transcription factors and lipid mediators. Using gene-targeted mice and a delayed implantation model, our laboratory has been exploring potential interactions among steroid hormones, growth factors, cytokines and prostaglandins in this process. This review article highlights some of our recent observations on the roles of estrogen, catecholestrogen, the EGF family of growth factors, leukemia inhibitory factor and cyclooxygenase-2 derived prostaglandins and their interactions in embryo-uterine "cross-talk" during implantation.


Recommendations for the registration of agents to be used in the prevention and treatment of glucocorticoid-induced osteoporosis: updated recommendations from the Group for the Respect of Ethics and Excellence in Science.
The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP). Consensus discussion of the committee. With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The "prevention" and "treatment" claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year. Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO.


Comparison between ovalbumin and ovalbumin peptide 323-339 responses in allergic mice: humoral and cellular aspects.
Ovalbumin (OVA) is widely used in allergy research. OVA peptide 323-339 has been reported to be responsible for 25-35% of isolated BALB/c mouse T-cell response to intact OVA. An investigation of whether OVA and OVA 323-339 molecules can induce equivalent in vivo and in vitro immune responses was conducted. Eight-week-old BALB/c mice were randomly divided into three groups: OVA, OVA 323-339 and saline. On days 0, 7, 14, mice were intraperitoneally injected with 25 microg OVA or OVA 323-339 absorbed on 300 microg Alum, or saline; on days 21-23, all groups were challenged intranasally with either 20 microl of 1% OVA, 1% OVA 323-339 or saline. On day 28, after killing, splenocytes were isolated and cultured under the stimulus of each allergen or medium. Evaluated by hematoxylin/eosin and major basic protein immunohistochemical stainings, OVA and OVA 323-339 induced similar lung inflammation. Interestingly, significant serum total IgE and OVA-specific IgE were observed in OVA mice when compared to saline control. OVA 323-339 mice showed higher serum OVA-specific IgE, OVA 323-339-specific IgE, IL-4 and lower IFN-gamma similar to OVA mice. The proliferative response to OVA was found in cultured splenocytes of both OVA and OVA 323-339 mice, while the similar proliferative response to OVA 323-339 was only observed in the splenocytes of OVA 323-339-sensitized and challenged mice. Although OVA 323-339 induced a Th2-like response in the mouse model as did OVA, OVA 323-339 has clearly limited immunogenic potency to activate OVA-sensitized and challenged mice splenocytes, unlike OVA.


Cavity Forming Pneumonia Due to Staphylococcus aureus Following Dengue Fever.
While visiting Malaysia, a 22-year-old previously healthy Japanese man developed myalgia, headache, and fever, leading to a diagnosis of classical dengue fever. After improvement and returning to Japan after a five day hospitalization, he developed productive cough several days after defervescing from dengue. Computed tomography (CT) thorax scan showed multiple lung cavities. A sputum smear revealed leukocytes with phagocytized gram-positive cocci in clusters, and grew an isolate Staphylococcus aureus sensitive to semi-synthetic penicillin; he was treated successfully with ceftriaxone and cephalexin. This second reported case of pneumonia due to S. aureus occurring after dengue fever, was associated both with nosocomial exposure and might have been associated with dengue-associated immunosuppression. Clinicians should pay systematic attention to bacterial pneumonia following dengue fever to establish whether such a connection is causally associated.


Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´s disease - protocol for a controlled, randomized double-blinded trial.
Type 2 diabetes (DM-2) increases the risk of developing Alzheimer´s disease (AD), and patients with AD are more likely to develop DM-2. DM-2 and AD share some pathophysiological features. In AD, amyloid-β (Aβ) is accumulated as extracellular plaques in the gray matter of the brain, while in DM-2 islet amyloid polypeptide (IAPP) is accumulated in the pancreas. Premature cellular degeneration is seen in both diseases. Glucagon-like peptide-1 (GLP-1) reduces the amount of Aβ and improves cognition in animal studies. The present study tests the hypothesis that treatment with the long-acting GLP-1 receptor agonist liraglutide affects the accumulation of Aβ in patients with AD. This is a randomized, controlled, double-blinded intervention study with AD patients treated for six months with liraglutide (n = 20) or placebo (n = 20). The primary outcome is change in deposition of Aβ in the central nervous system (CNS) by Pittsburgh compound B positron emission tomography (PET). The secondary outcome is evaluation of cognition using a neuro-psychological test battery, and examination of changes in glucose uptake in the CNS by 18F-fluoro-deoxy-glucose PET. Finally, a perfusion-weighted magnetic resonance imaging with contrast will be performed to evaluate blood flow. No registered drug affects the deposition of Aβ in the brain of AD patients. Our goal is to find a new therapeutic agent that alters the pathophysiology in AD patients by decreasing the formation of Aβ plaques and thereby presumably improves the cognitive function. The trial is investigator-initiated and investigator-driven and is supported by Novo Nordisk Scandinavia. ClinicalTrials.gov: NCT01469351.


Bone histomorphometry in transiliac biopsies from 48 normal, healthy men.
Investigators and clinicians use bone histomorphometry data from iliac bone biopsies to study bone abnormalities in diseased patients, and to understand the safety and effectiveness of pharmaceutical interventions. This requires access to a high quality normal data-set to be used for comparisons, a resource that has not been adequate to date. The objective of this work is to present static and dynamic bone histomorphometry data from transilial bone biopsies performed on 48 healthy males, evenly distributed between ages 45 and 75. In addition, we compared these results with results from our earlier study in normal postmenopausal women (Recker et al., 1988 [1]). The data include bone density and anthropometric measurements, micro-CT, and a collection of serum biochemical measurements. We found that several of the histomorphometry variables were correlated with serum measurements, i.e. serum testosterone and sex hormone-binding globulin (SHBG). Micro-CT variables were correlated with the static histomorphometry variables, and were very similar. Age-related changes were observed for both histomorphometry and Micro-CT, but were surprisingly small in most cases. Comparisons with our previously reported histomorphometry data from normal women were surprisingly similar, but there was a significant age by gender interaction in the wall thickness (W.Th) measurements, i.e. there was a small increase in this variable with age in men, and a significant decline with age in women. The population selected for this study, and the prior study in normal women, were carefully chosen so as to rule out the presence of clinical, life-style or other confounding factors. While the cohort chosen herein was a convenience sample, and not a population-based sample, we believe it can be used as a reference standard with proper precautions in its interpretation and in its comparisons with diseased populations.


Prevalence of antibodies to Sarcocystis neurona in cats from Virginia and Pennsylvania.
Sarcocystis neurona is best known as the causative agent of equine protozoal myeloencephalitis of horses in the Americas. Domestic cats ( Felis domesticus ) were the first animals described as an intermediate host for S. neurona . However, S. neurona -associated encephalitis has also been reported in naturally infected cats in the United States. Thus, cats can be implicated in the life cycle of S. neurona as natural intermediate hosts. The present study examined the seroprevalence of IgG antibodies to merozoites of S. neurona in populations of domestic cats from Virginia and Pennsylvania. Overall, sera or plasma from 441 cats (Virginia = 232, Pennsylvania = 209) were tested by an indirect immunofluorescent assay at a 1ratio50 dilution. Antibodies to S. neurona were found in 32 (7%) of 441 cats. Of these, 22 (9%) of the 232 cats from Virginia and 10 (5%) of the 209 cats from Pennsylvania were seropositive for S. neurona .


Survival of human pathogenic bacteria in different types of natural mineral water.
The aim of this study was to determine the survival of human pathogens (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) in five natural mineral waters (NMWs) with different properties and mineralization levels. Five NMWs from four Spanish spas with different dry residue at 110 °C were used: A = 76,935 mg/L; B = 1,827 mg/L; C = 808.4 mg/L; D = 283.8 mg/L; and E = 170.4 mg/L. An initial inoculum of 1 × 10(6) colony forming units (cfu)/mL was used for survival studies. Distilled water, chlorinated tap water and Mueller-Hinton broth were used as controls. Colony counts in all different waters were lower than those achieved with Mueller-Hinton broth over all incubation periods. A direct effect between the bacterial survival and the level of mineralization water was observed. The NMW E with low mineralization level along with the radioactive properties showed the highest antibacterial activity among all NMWs.


Plant-pathogen interactions: disease resistance in modern agriculture.
The growing human population will require a significant increase in agricultural production. This challenge is made more difficult by the fact that changes in the climatic and environmental conditions under which crops are grown have resulted in the appearance of new diseases, whereas genetic changes within the pathogen have resulted in the loss of previously effective sources of resistance. To help meet this challenge, advanced genetic and statistical methods of analysis have been used to identify new resistance genes through global screens, and studies of plant-pathogen interactions have been undertaken to uncover the mechanisms by which disease resistance is achieved. The informed deployment of major, race-specific and partial, race-nonspecific resistance, either by conventional breeding or transgenic approaches, will enable the production of crop varieties with effective resistance without impacting on other agronomically important crop traits. Here, we review these recent advances and progress towards the ultimate goal of developing disease-resistant crops.


α-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway.
The present study investigates the effects and mechanisms of α-Lipoic acid (LA) on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in rat hearts subjected to in vivo myocardial ischemia/reperfusion (MI/R) injury. Male adult rats underwent 30 minutes of ischemia followed by 3, 24, or 72 h of reperfusion. Animals were pretreated with LA or vehicle before coronary artery ligation. The level of MI/R- induced LDH and CK release, infarct size, cardiomyocyte apoptosis and cardiac functional impairment were examined and compared. Western blot analysis was performed to elucidate the mechanism of LA pretreatment. The level of inflammatory cytokine TNF-α released to serum and accumulated in injured myocardium as well as neutrophil accumulation in injured myocardium were also examined after MI/R injury. Our results reveal that LA administration significantly reduced LDH and CK release, attenuated myocardial infarct size, decreased cardiomyocytes apoptosis, and partially preserved heart function. Western blot analysis showed that LA pretreatment up-regulated Akt phosphorylation and Nrf2 nuclear translocation while producing no impact on p38MAPK activation or nitric oxide (NO) production. LA pretreatment also increased expression of HO-1, a major target of Nrf2. LA treatment inhibited neutrophil accumulation and release of TNF-α. Moreover, PI3K inhibition abolished the beneficial effects of LA. This study indicates that LA attenuates cardiac dysfunction by reducing cardiomyoctyes necrosis, apoptosis and inflammation after MI/R. LA exerts its action by activating the PI3K/Akt pathway as well as subsequent Nrf2 nuclear translocation and induction of cytoprotective genes such as HO-1.


Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study.
Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB. We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts--those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, identifier NCT00680992. 282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3-4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5·8-21·0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9·2 months (IQR 4·2-12·9). Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB. Amgen.


Household economy, forest dependency & opportunity costs of conservation in eastern rainforests of Madagascar.
The Government of Madagascar is trying to reduce deforestation and conserve biodiversity through creating new protected areas in the eastern rainforests. While this has many benefits, forest use restriction may bring costs to farmers at the forest frontier. We explored this through a series of surveys in five sites around the Corridor Ankeniheny Zahamena new protected area and adjacent national parks. In phase one a stratified random sample of 603 households completed a household survey covering demographic and socio-economic characteristics, and a choice experiment to estimate the opportunity costs of conservation. A stratified sub-sample (n = 171) then completed a detailed agricultural survey (including recording inputs and outputs from 721 plots) and wild-harvested product survey. The data have been archived with ReShare (UK Data Service). Together these allow a deeper understanding of the household economy on the forest frontier in eastern Madagascar and their swidden agricultural system, the benefits households derive from the forests through wild-harvested products, and the costs of conservation restrictions to forest edge communities.


Montelukast and irbesartan ameliorate metabolic and hepatic disorders in fructose-induced metabolic syndrome in rats.
Metabolic syndrome (MetS) is a global health problem. Elucidation of the role of 5- lipooxygenase/leukotriene pathway and renin angiotensin system in the pathogenesis of MetS suggests a variety of potential therapies worthy of testing. The present work investigated the effect of montelukast, a leukotriene antagonist and/or irbesartan, an angiotensin II-receptor blocker, in the prevention of fructose-induced MetS in rats. Rats were allocated into 9 groups and treated for 6 weeks as follow: normal control; MetS group (received 20% fructose); MetS+montelukast groups (treated with montelukast, 5, 10, and 20 mg/kg/day, respectively); MetS+irbesartan groups (treated withirbesartan 15, 30, and 45 mg/kg/day, respectively); and MetS+montelukast+irbesartan group (co treated with montelukast 5 mg/kg plus irbesartan 15 mg/g). Metabolic parameters (visceral fat index, liver index, insulin resistance, and serum lipid profile), oxidative stress markers (malondialdehyde, reduced glutathione, and catalase), and inflammatory mediators (tumor necrosis factor-α, and uric acid) were measured. Expression of caspase-3 in hepatic tissues was detected by immunohistochemistry. Liver injury was evaluated by histopathological examination and serum alanine aminotransferase (ALT). Montelukast, irbesartan, and their combination caused significant attenuation in metabolic and hepatic disorders. Their effect was associated with attenuation of oxidative stress markers, inflammatory mediators, and caspase-3 expression. This study highlighted the protective effects of montelukast and irbesartan against fructose-induced metabolic and hepatic disorders. The protective effect of either drug relies, at least in part, on their antioxidant and antiinflammatory effect, as well as on the reduction of caspase-3 expression in hepatic tissue.


Growth disorders in type 1 diabetes: an Indian experience.
Though children with type 1 diabetes mellitus (T1DM) are often tall at the time of diagnosis, they may experience growth retardation, pubertal delay or both, which may be due to poor glycemic control, associated diseases or chronic complications. Factors affecting growth include: gender, genetic environment, age at diagnosis, diabetes duration, puberty, metabolic control, and status of growth hormone (GH), insulin-like growth factors (IGFs), and IGF binding proteins (IGFBPs). Insulin regulates expression of hepatic GH receptors, affects IGFs and IGFBPs synthesis by modulating GH postreceptor events, and significantly increases IGF-I bioactivity. Low portal insulin seen in T1DM leads to GH hypersecretion, low circulating IGF-I and IGFBP-3, and high circulating IGFBP-1. Newly diagnosed T1DM patients have decreased GHBP which can be restored with insulin therapy. Growth velocity should be appropriate for the age of the child/adolescent, and the mid-parental height. Height, weight and blood pressure (BP) should be measured and plotted on a growth chart at least 2-3 times a year. Puberty should also be assessed annually. Following precautions are to be taken in T1DM children: checking for pubertal onset and ensuring it is not delayed, testing early when growth falters (hypothyroidism/celiac disease/puberty/other conditions), aiming for best possible metabolic control (multidose regimens, regardless of type of insulin), and encouraging dietary calcium and protein, exposure to sunlight, Vitamin D supplements and exercise.


Widespread patterns of gene loss in the evolution of the animal kingdom.
The animal kingdom shows an astonishing diversity, the product of over 550 million years of animal evolution. The current wealth of genome sequence data offers an opportunity to better understand the genomic basis of this diversity. Here we analyse a sampling of 102 whole genomes including >2.6 million protein sequences. We infer major genomic patterns associated with the variety of animal forms from the superphylum to phylum level. We show that a remarkable amount of gene loss occurred during the evolution of two major groups of bilaterian animals, Ecdysozoa and Deuterostomia, and further loss in several deuterostome lineages. Deuterostomes and protostomes also show large genome novelties. At the phylum level, flatworms, nematodes and tardigrades show the largest reduction of gene complement, alongside gene novelty. These findings paint a picture of evolution in the animal kingdom in which reductive evolution at the protein-coding level played a major role in shaping genome composition.


Melatonin enhances the cadmium tolerance of mushrooms through antioxidant-related metabolites and enzymes.
Many wild mushroom species are known to immune heavy metals. However, the mechanism by which this occurs remains largely unsolved. Melatonin (MT) has been proven to play an important defensive role against various abiotic stresses in plants and animals. This study reports on the presence of MT in edible fungi and its role in the response to cadmium (Cd)-induced stress. We found that melatonin was widely distributed in all experimental species and could also relieve Cd-induced damage in the Volvariella volvacea. Comparative metabolic and proteome analyses reveal that tryptophan/proline/tyrosine metabolism, the citrate cycle, nitrogen and glutathione metabolism, and oxidation-reduction processes were enriched after Cd and/or MT addition, indicating an antioxidant mechanism was aroused. Finally, different MT and cadmium treatments were studied for their effects on the expression and activity of oxidation-related enzymes (superoxide dismutase, catalase, peroxidase, etc), which further verified the ameliorative influence of MT on Cd-induced oxidative stress.


Is the self a higher-order or fundamental function of the brain? The "basis model of self-specificity" and its encoding by the brain's spontaneous activity.
What is the self? This is a question that has long been discussed in (Western) philosophy where the self is traditionally conceived a higher-order function at the apex or pinnacle of all functions. This tradition has been transferred to recent neuroscience where the self is often considered to be a higher-order cognitive function reflected in memory and other high-level judgements. However, other lines of research demonstrate a close and intimate relationship between self-specificity and more basic functions like perceptions, emotions and reward. This paper focuses on the relationship between self-specificity and other basic functions relating to emotions, reward and perception. I propose the basis model that conceives self-specificity as a fundamental feature of the brain's spontaneous activity. This is supported by recent findings showing rest-self overlap in midline regions as well as findings demonstrating that the resting state can predict subsequent degrees of self-specificity. I conclude that such self-specificity in the brain's spontaneous activity may be central in linking the self to either internal or external stimuli. This may also provide the basis for coding the self as subject in relation to internal (i.e., self-consciousness) or external (i.e., phenomenal consciousness) mental events.


Epidemiology and outcomes of non-compressible torso hemorrhage.
Non-compressible torso hemorrhage (NCTH) is the leading cause of potentially preventable death in military trauma, but the civilian epidemiology is unknown. The aim of this study is to apply a military definition of NCTH, which incorporates anatomic and physiological criteria, to a civilian population treated at trauma centers in the US. Patients (age >16 y) from 197 Level 1 trauma centers (approximately 95% of all US Level 1 centers) in the National Trauma Data Bank 2007-2009 that sustained a named torso vessel injury, pulmonary injury, grade IV solid organ injury, or pelvic fracture with ring disruption were included. Of these, patients with a systolic blood pressure <90 mmHg were considered to have NCTH. Multivariable logistic regression was used to identify patient and injury factors associated with NCTH and mortality after adjusting for the following covariates: patient (age, gender, ethnicity, and insurance status), injury (Glasgow Coma Scale, injury type, Injury Severity Score, anatomic region), and clinical (major surgical procedure, need for transfusion, and intensive care unit admission) characteristics. Of the 1.8 million patients in the 2007-2009 National Trauma Data Bank, 249,505 met the anatomic criteria for non-compressible torso injury (NCTI). Of these, 20,414 (8.2%) patients had associated hemorrhage. The rate of pulmonary and torso vessel injury was similar (53.4% and 50.6%, respectively), with solid organ injury identified in 27.0% of patients and pelvic injury in 8.9%. The overall mortality rate of patients with NCTI and NCTH was 6.8% and 44.6%, respectively. The most lethal injury was major torso vessel injury (OR 1.54, 95% CI 1.33-1.78), followed by pulmonary injury (OR 1.32, 95% CI 1.18-1.48). Lower mortality was found in patients with pelvic injury (OR 0.80, 95% CI 0.65-0.98). The military definition of NCTH can be usefully applied to civilians to identify patients with lethal injuries and high resource needs. Investigating the implications of NCTH on patient triage is recommended.


Successful Intracoronary Thrombolysis in Acute ST Elevation Myocardial Infarction Patient With Uncorrected Tetralogy of Fallot.
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease that has low survival rate without surgical correction. This report is about a rare case of acute ST elevation myocardial infarction in a 46-year-old patient with uncorrected TOF that was successfully treated with low-dose intracoronary thrombolysis.


Second-harmonic generation in zinc tris(thiourea) sulfate.
The linear and second-order nonlinear optical properties of single-crystal zinc tris(thiourea) sulfate, or ZTS, are determined. The deduced nonlinear coefficients are |d(31)| = 0.31, |d(32)| = 0.35, and |d(33)| = 0.23 pm/V compared with a |d(14)| value of 0.39 pm/V for potassium dihydrogen phosphate. Because it exhibits a low angular sensitivity (deltaDeltak/deltatheta), ZTS may prove useful for type-II second-harmonic generation from 1.06 to 1.027 microm. We present the phase-matching measurement data for ZTS and compare the calculated frequency conversion efficiency for ZTS with that of several other well-characterized materials.


Infectious salmon anaemia virus in wild fish from Scotland.
Following the outbreak of infectious salmon anaemia (ISA) at salmon farms in Scotland, UK, a survey was established to determine the extent of infection in wild fish. All fish tested were free from the clinical symptoms of ISA. Isolations of ISAV were made from 5 sea trout within areas where ISA affected salmon farms were located. Evidence for ISAV in other sea trout was provided by ISA RT-PCR diagnostic tests. Results from ISA RT-PCR tests reveal evidence for ISAV being present in salmon parr, adult salmon and juvenile brown trout in rivers distant from salmon farms and indicate that, at the time of the survey (1998-1999), ISAV may have been widely distributed. Nucleotide sequence analysis of segments 2 and 8 showed that for most sequences from wild fish there was 100% homology with ISAV isolated from clinically affected farmed fish although evidence is presented which indicates variability in ISAV sequences from wild fish. Modelling the RT-PCR findings indicates that ISAV among salmonid fish was spatially non-random. Brown trout, sea trout and salmon (adult and parr) show a pattern of occasionally large numbers of positive samples against a background of very low numbers.


Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia.
Cubilin is a 460-kDa protein functioning as an endocytic receptor for intrinsic factor vitamin B(12) complex in the intestine and as a receptor for apolipoprotein A1 and albumin reabsorption in the kidney proximal tubules and the yolk sac. In the present study, we report the identification of cubilin as a novel transferrin (Tf) receptor involved in catabolism of Tf. Consistent with a cubilin-mediated endocytosis of Tf in the kidney, lysosomes of human, dog, and mouse renal proximal tubules strongly accumulate Tf, whereas no Tf is detectable in the endocytic apparatus of the renal tubule epithelium of dogs with deficient surface expression of cubilin. As a consequence, these dogs excrete increased amounts of Tf in the urine. Mice with deficient synthesis of megalin, the putative coreceptor colocalizing with cubilin, also excrete high amounts of Tf and fail to internalize Tf in their proximal tubules. However, in contrast to the dogs with the defective cubilin expression, the megalin-deficient mice accumulate Tf on the luminal cubilin-expressing surface of the proximal tubule epithelium. This observation indicates that megalin deficiency causes failure in internalization of the cubilin-ligand complex. The megalin-dependent, cubilin-mediated endocytosis of Tf and the potential of the receptors thereby to facilitate iron uptake were further confirmed by analyzing the uptake of (125)I- and (59)Fe-labeled Tf in cultured yolk sac cells.


Antibacterial Effect of Luma apiculata (DC.) Burret Extracts in Clinically Important Bacteria.
Nosocomial infections caused by bacteria are one of the main public health problems. Moreover, the resistance to antibiotics by these bacteria makes it necessary to find new treatments to fight them. Objective. To evaluate the antibacterial activity of Luma apiculata (DC.) Burret extracts on bacteria of clinical importance. Materials and Methods. In this study, extracts were obtained at room temperature by successive extraction of L. apiculata leaves, flowers, and branches and treated separately with solvents of ascending polarity (i.e., hexane, methylene dichloride, ethyl acetate, ethanol, methanol, and water) to extract the compounds depending on their polarity. Then, the extract's antibacterial activity was tested against Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Enterococcus sp, Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli. Results. The hexane extract of L. apiculata leaves resulted to be active against all bacteria tested. Among them, S. aureus showed to be the more susceptible, showing a minimum inhibitory concentration (MIC) of 120 μg/ml. In addition, a growth curve was performed, and colonies were counted. A decrease in bacterial growth was observed when the hexane extract of L. apiculata leaves was added. Besides, the hexane extracts of L. apiculata flowers resulted to be active against all Gram-positive tested bacteria. However, at higher concentrations, this extract resulted inactive for the Gram-negative bacteria tested. The hexane extract of L. apiculata branches resulted to be inactive in all cases. The extracts obtained treating separately leaves, flowers, or branches with solvents of major polarity than the hexane in a successive extraction of ascending polarity methodology resulted also to be inactive as an antimicrobial against all bacteria tested. Discussion/Conclusion. The hexane extract of L. apiculata leaves showed the lower MIC against S. aureus when compared with extracts obtained from other parts of the plant. The growth curve and the colonies count suggest a bacteriostatic activity of the L. apiculata leaves extract against Staphylococcus aureus.


Didgeridoo playing and singing to support asthma management in Aboriginal Australians.
Asthma affects over 15% of Australian Aboriginal people. Compliance in asthma management is poor. Interventions that will increase compliance are required. The purpose of the study was to determine whether Aboriginal children, adolescents and adults would engage in music lessons to increase their knowledge of asthma and support management of their asthma. Participants were recruited from schools and through the local Aboriginal Medical Service. All participants identified as Aborigines and were diagnosed as being asthmatic. The intervention was a 6-month program of once weekly music lessons using a culturally significant wind instrument, the didgeridoo, for males and singing lessons for females. High school students enthusiastically engaged and had excellent retention in what they considered to be a most enjoyable program. Respiratory function improved significantly in both junior and senior boys who also reported a noticeable improvement in their health. Similar but less significant improvement was seen in the high school girls, although like the boys, they too perceived an improvement in their asthma. The project demonstrated that music has great potential for engaging and thus supporting asthma. Furthermore, cultural awareness was increased by those playing the didgeridoo and social skills were noticeably improved in the girls. Similar culturally appropriate activities have applications far beyond Aboriginal communities in Australia.


Influence of steviol glycosides on the stability of vitamin C and anthocyanins.
A high level of sweetness and health-promoting properties make steviol glycosides an interesting alternative to sugars or artificial sweeteners. The radical oxygen species scavenging activity of these compounds may influence the stability of labile particles present in food. Model buffer solutions containing steviol glycosides, a selected food antioxidant (vitamin C or anthocyanins), and preservative were analyzed during storage. The addition of steviol glycosides at concentrations of 50, 125, and 200 mg/L increased the stability of both ascorbic and dehydroascorbic acid (degradation rates decreased up to 3.4- and 4.5-fold, respectively); the effect was intensified by higher sweetener concentrations and higher acidity of the solutions. Glycosides used alone did not affect the stability of anthocyanins; however, they enhanced the protective effect of sugars; half-life times increased by ca. 33% in the presence of sucrose (100 g/L) and by ca. 52% when both sucrose (100 g/L) and glycosides (total 200 mg/L) were used. Steviol glycosides concentrations remained stable during experiments.


On the structure of prilocaine in aqueous and amphiphilic solutions.
The solvation of prilocaine has been investigated in pure water and in an amphiphilic methanol/water solution using a combination of neutron diffraction with isotopic substitution augmented by Empirical Potential Structure Refinement (EPSR) simulations. This combination of techniques allows for details of the solvation structure on the atomic scale to be unravelled. The hydration of prilocaine is significantly altered relative to when this molecule is in pure water (as a hydrochloride salt) or in an amphiphilic environment (as a freebase compound). Interestingly, there is not a significant change in hydration around the amine group on prilocaine hydrochloride compared with prilocaine as a freebase. Despite this group being an ammonium group in water and an amine group in methanol/water solutions, the hydration of this motif remains largely intact. The changes in hydration between prilocaine as a free base and prilocaine·HCl instead appears to arise from a change in hydration around the aromatic ring and the amide group in the prilocaine molecule.


First Detection of an Enterovirus C99 in a Captive Chimpanzee with Acute Flaccid Paralysis, from the Tchimpounga Chimpanzee Rehabilitation Center, Republic of Congo.
Enteroviruses, members of the Picornaviridae family, are ubiquitous viruses responsible for mild to severe infections in human populations around the world. In 2010 Pointe-Noire, Republic of Congo recorded an outbreak of acute flaccid paralysis (AFP) in the humans, caused by wild poliovirus type 1 (WPV1). One month later, in the Tchimpounga sanctuary near Pointe-Noire, a chimpanzee developed signs similar to AFP, with paralysis of the lower limbs. In the present work, we sought to identify the pathogen, including viral and bacterial agents, responsible for this illness. In order to identify the causative agent, we evaluated a fecal specimen by PCR and sequencing. A Human enterovirus C, specifically of the EV-C99 type was potentially responsible for the illness in this chimpanzee. To rule out other possible causative agents, we also investigated the bacteriome and the virome using next generation sequencing. The majority of bacterial reads obtained belonged to commensal bacteria (95%), and the mammalian virus reads matched mainly with viruses of the Picornaviridae family (99%), in which enteroviruses were the most abundant (99.6%). This study thus reports the first identification of a chimpanzee presenting AFP most likely caused by an enterovirus and demonstrates once again the cross-species transmission of a human pathogen to an ape.


Mapping the coordination and cooperation mechanisms of risk communication on feed/food safety in the EU.
The mapping of the EU coordination and cooperation mechanisms of risk communication in the field of food safety (i.e. encompassing all matters pertaining to the feed and food chain) was conducted for the European Food Safety Authority (EFSA), following a mandate by the European Commission, to inform the General Plan for Risk Communication that the Commission will set out. This study focuses on communication activities in 'peacetime' situations (i.e. non-crisis) on the published outputs of risk assessment and risk management. This is a specific part of the risk communication process defined in the General Food Law. Data were collected through an online survey of competent authority organisations involved in risk communication at national and regional levels in the EU-27 Member States and Norway; and interviews with selected organisations at Member State, EU and international levels. Based on these data, this report provides an overview of the current information flow of risk communication, in terms of whether and how organisations at all levels receive, produce, and disseminate risk communication material. The existing flows in each country are described and mapped in flow charts. Flows are also presented for each of the EU/international organisations involved in risk communication on food safety. A number of relevant networks are identified that actively engage in sharing/exchanges of risk communication material on food safety, including networks managed by EFSA. This project also highlighted certain challenges in current risk communication systems, and recommendations are made to address them. At national level, these are: an increase in resources dedicated to coordinating communication on EU food safety issues, to improve capacity to undertake this task; strengthen the cooperation and coordination between authorities involved in risk communication activities to ensure a more proactive approach. In addition, recommendations are provided to enhance further collaboration of communication activities at all levels (between Member States and with EFSA; between EU Agencies), so that the coordination of risk communication at EU level follows a partnership approach.


Prospective evaluation of an internet-linked handheld computer critical care knowledge access system.
Critical care physicians may benefit from immediate access to medical reference material. We evaluated the feasibility and potential benefits of a handheld computer based knowledge access system linking a central academic intensive care unit (ICU) to multiple community-based ICUs. Four community hospital ICUs with 17 physicians participated in this prospective interventional study. Following training in the use of an internet-linked, updateable handheld computer knowledge access system, the physicians used the handheld devices in their clinical environment for a 12-month intervention period. Feasibility of the system was evaluated by tracking use of the handheld computer and by conducting surveys and focus group discussions. Before and after the intervention period, participants underwent simulated patient care scenarios designed to evaluate the information sources they accessed, as well as the speed and quality of their decision making. Participants generated admission orders during each scenario, which were scored by blinded evaluators. Ten physicians (59%) used the system regularly, predominantly for nonmedical applications (median 32.8/month, interquartile range [IQR] 28.3-126.8), with medical software accessed less often (median 9/month, IQR 3.7-13.7). Eight out of 13 physicians (62%) who completed the final scenarios chose to use the handheld computer for information access. The median time to access information on the handheld handheld computer was 19 s (IQR 15-40 s). This group exhibited a significant improvement in admission order score as compared with those who used other resources (P = 0.018). Benefits and barriers to use of this technology were identified. An updateable handheld computer system is feasible as a means of point-of-care access to medical reference material and may improve clinical decision making. However, during the study, acceptance of the system was variable. Improved training and new technology may overcome some of the barriers we identified.


Non-invasive induction of plasticity in the human cortex: uses and limitations.
The last couple of decades have seen the development of a number of non-invasive brain stimulation (NIBS) techniques that are capable of inducing short-lasting plasticity in the human cortex. Importantly, the induction of lasting plastic changes can, under some conditions, reversibly modify behaviour and interact with learning. These techniques have provided novel opportunities to study human cortical plasticity and examine the role of cortical regions in behaviour. In this review we briefly summarise current NIBS techniques, outline approaches to characterise and quantify cortical plastic change, and describe mechanisms that are implicated in the induced plastic changes. We then outline the areas in which these techniques might be useful, namely, investigating the mechanisms of human cortical plasticity, the characterisation of influences on plasticity, and the investigation of the role of cortical regions in behaviour. Finally, we conclude by highlighting some current limitations of the techniques and suggest that further development of the current NIBS paradigms and more focussed targeting should further enhance the utility of these powerful non-invasive techniques for the investigation of the cortical plasticity and pathophysiology.


Importance of water entropy in rotation mechanism of F1-ATPase.
We briefly review our theoretical study on the rotation scheme of F1-ATPase. In the scheme, the key factor is the water entropy which has been shown to drive a variety of self-assembly processes in biological systems. We decompose the crystal structure of F1-ATPase into three sub-complexes each of which is composed of the γ subunit, one of the β subunits, and two α subunits adjacent to them. The βE, βTP, and βDP subunits are involved in the sub-complexes I, II, and III, respectively. We calculate the hydration entropy of each sub-complex using a hybrid of the integral equation theory for molecular liquids and the morphometric approach. It is found that the absolute value of the hydration entropy follows the order, sub-complex I > sub-complex II > sub-complex III. Moreover, the differences are quite large, which manifests highly asymmetrical packing of F1-ATPase. In our picture, this asymmetrical packing plays crucially important roles in the rotation of the γ subunit. We discuss how the rotation is induced by the water-entropy effect coupled with such chemical processes as ATP binding, ATP hydrolysis, and release of the products.


Mechanistic studies of the yeast polyamine oxidase Fms1: kinetic mechanism, substrate specificity, and pH dependence.
The flavoprotein oxidase Fms1 from Saccharomyces cerevisiae catalyzes the oxidation of spermine and N(1)-acetylspermine to yield spermidine and 3-aminopropanal or N-acetyl-3-aminopropanal. The kinetic mechanism of the enzyme has been determined with both substrates. The initial velocity patterns are ping-pong, consistent with reduction being kinetically irreversible. Reduction of Fms1 by either substrate is biphasic. The rate constant for the rapid phase varies with the substrate concentration, with limiting rates for reduction of the enzyme of 126 and 1410 s(-1) and apparent K(d) values of 24.3 and 484 μM for spermine and N(1)-acetylspermine, respectively. The rapid phase is followed by a concentration-independent phase that is slower than turnover. The reaction of the reduced enzyme with oxygen is monophasic, with a rate constant of 402 mM(-1) s(-1) with spermine at 25 °C and 204 mM(-1) s(-1) with N(1)-acetylspermine at 4 °C and pH 9.0. This step is followed by rate-limiting product dissociation. The k(cat)/K(amine)-pH profiles are bell-shaped, with an average pK(a) value of 9.3 with spermine and pK(a) values of 8.3 and 9.6 with N(1)-acetylspermine. Both profiles are consistent with the active forms of substrates having two charged nitrogens. The pH profiles for the rate constant for flavin reduction show pK(a) values of 8.3 and 7.2 for spermine and N(1)-acetylspermine, respectively, for groups that must be unprotonated; these pK(a) values are assigned to the substrate N4. The k(cat)/K(O(2))-pH profiles show pK(a) values of 7.5 for spermine and 6.8 for N(1)-acetylspermine. With both substrates, the k(cat) value decreases when a single residue is protonated.


Rough set soft computing cancer classification and network: one stone, two birds.
Gene expression profiling provides tremendous information to help unravel the complexity of cancer. The selection of the most informative genes from huge noise for cancer classification has taken centre stage, along with predicting the function of such identified genes and the construction of direct gene regulatory networks at different system levels with a tuneable parameter. A new study by Wang and Gotoh described a novel Variable Precision Rough Sets-rooted robust soft computing method to successfully address these problems and has yielded some new insights. The significance of this progress and its perspectives will be discussed in this article.


Revisiting the Dependence of Cu K-Edge X-ray Absorption Spectra on Oxidation State and Coordination Environment.
X-ray absorption spectroscopy (XAS) at the Cu K-edge is an important tool for probing the properties of copper centers in transition-metal chemistry and catalysis. However, the interpretation of experimental XAS spectra requires a detailed understanding of the dependence of spectroscopic features on the local geometric and electronic structure, which can be established by theoretical X-ray spectroscopy. Here, we present a systematic computational study of the Cu K-edge XAS spectra of selected Cu complexes based on time-dependent density-functional theory in combination with a molecular orbital analysis of the relevant transitions. For a series of Cu ammine model complexes as well as a comprehensive test set of 12 Cu(I) and 5 Cu(II) complexes, we revisit the dependence of the pre-edge region in Cu K-edge XAS spectra on oxidation state and coordination geometry. While our calculations confirm earlier experimental assignments, we can also reveal additional signatures of the ligand orbitals and identify the underlying orbital interactions. The comprehensive picture revealed by this study will provide a reliable basis for the interpretation of in situ Cu K-edge XAS spectra of catalytic intermediates.


Continuous-time symmetric Hopfield nets are computationally universal.
We establish a fundamental result in the theory of computation by continuous-time dynamical systems by showing that systems corresponding to so-called continuous-time symmetric Hopfield nets are capable of general computation. As is well known, such networks have very constrained Lyapunov-function controlled dynamics. Nevertheless, we show that they are universal and efficient computational devices, in the sense that any convergent synchronous fully parallel computation by a recurrent network of n discrete-time binary neurons, with in general asymmetric coupling weights, can be simulated by a symmetric continuous-time Hopfield net containing only 18n + 7 units employing the saturated-linear activation function. Moreover, if the asymmetric network has maximum integer weight size w(max) and converges in discrete time t*, then the corresponding Hopfield net can be designed to operate in continuous time Theta(t*/epsilon) for any epsilon > 0 such that w(max)2(12n) </= epsilon2(1/epsilon). In terms of standard discrete computation models, our result implies that any polynomially space-bounded Turing machine can be simulated by a family of polynomial-size continuous-time symmetric Hopfield nets.


Age-Specific Serum Total and Free Estradiol Concentrations in Healthy Men in US Nationally Representative Samples.
To report age-specific serum estradiol concentration in nonsmoking, lean US men without comorbidities. We provide concentrations from 30 and 15 to 20 years ago given previously described declines in serum estradiol in US men over time. We used data from the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1991) and continuous NHANES (1999 to 2004). Serum estradiol and SHBG were previously measured by competitive electrochemiluminescence immunoassays. Free estradiol was estimated from estradiol, SHBG, and albumin. By age, we calculated median concentrations overall and for nonsmoking, lean (body mass index <25 kg/m2 and waist <102 cm) men without diabetes, cardiovascular disease, or cancer. Overall, respective total estradiol medians for men ages 20 to 39, 40 to 59, and ≥60 years old were 37.0, 33.9, and 33.5 pg/mL in NHANES III and 31.3, 30.5, and 27.0 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective total estradiol medians were 32.0, 32.1, and 32.0 pg/mL in NHANES III and 29.1, 22.7, and 26.1 pg/mL in continuous NHANES. Overall, respective free estradiol medians were 0.82, 0.72, and 0.64 pg/mL in NHANES III and 0.67, 0.61, and 0.47 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective free estradiol medians were 0.64, 0.67, and 0.62 pg/mL in NHANES III and 0.58, 0.42, and 0.40 pg/mL continuous NHANES. We report US nationally representative serum estradiol concentrations in healthy men, which could be used for targeting estradiol during testosterone supplementation and for general good health.


Pressure ulcer-related pelvic osteomyelitis: evaluation of a two-stage surgical strategy (debridement, negative pressure therapy and flap coverage) with prolonged antimicrobial therapy.
A two-stage surgical strategy (debridement-negative pressure therapy (NPT) and flap coverage) with prolonged antimicrobial therapy is usually proposed in pressure ulcer-related pelvic osteomyelitis but has not been widely evaluated. Adult patients with pressure ulcer-related pelvic osteomyelitis treated by a two-stage surgical strategy were included in a retrospective cohort study. Determinants of superinfection (i.e., additional microbiological findings at reconstruction) and treatment failure were assessed using binary logistic regression and Kaplan-Meier curve analysis. Sixty-four pressure ulcer-related pelvic osteomyelitis in 61 patients (age, 47 (IQR, 36-63)) were included. Osteomyelitis was mostly polymicrobial (73%), with a predominance of S. aureus (47%), Enterobacteriaceae spp. (44%) and anaerobes (44%). Flap coverage was performed after 7 (IQR, 5-10) weeks of NPT, with 43 (68%) positive bone samples among which 39 (91%) were superinfections, associated with a high ASA score (OR, 5.8; p = 0.022). An increased prevalence of coagulase negative staphylococci (p = 0.017) and Candida spp. (p = 0.003) was observed at time of flap coverage. An ESBL Enterobacteriaceae spp. was found in 5 (12%) patients, associated with fluoroquinolone consumption (OR, 32.4; p = 0.005). Treatment duration was as 20 (IQR, 14-27) weeks, including 11 (IQR, 8-15) after reconstruction. After a follow-up of 54 (IQR, 27-102) weeks, 15 (23%) failures were observed, associated with previous pressure ulcer (OR, 5.7; p = 0.025) and Actinomyces spp. infection (OR, 9.5; p = 0.027). Pressure ulcer-related pelvic osteomyelitis is a difficult-to-treat clinical condition, generating an important consumption of broad-spectrum antibiotics. The lack of correlation between outcome and the debridement-to-reconstruction interval argue for a short sequence to limit the total duration of treatment.


Spectrum sharing in cognitive radio networks--an auction-based approach.
Cognitive radio is emerging as a promising technique to improve the utilization of the radio frequency spectrum. In this paper, we consider the problem of spectrum sharing among primary (or "licensed") users (PUs) and secondary (or "unlicensed") users (SUs). We formulate the problem based on bandwidth auction, in which each SU makes a bid for the amount of spectrum and each PU may assign the spectrum among the SUs by itself according to the information from the SUs without degrading its own performance. We show that the auction is a noncooperative game and that Nash equilibrium (NE) can be its solution. We first consider a single-PU network to investigate the existence and uniqueness of the NE and further discuss the fairness among the SUs under given conditions. Then, we present a dynamic updating algorithm in which each SU achieves NE in a distributed manner. The stability condition of the dynamic behavior for this spectrum-sharing scheme is studied. The discussion is generalized to the case in which there are multiple PUs in the network, where the properties of the NE are shown under appropriate conditions. Simulations were used to evaluate the system performance and verify the effectiveness of the proposed algorithm.


Measurement of Transport Properties of Aerosolized Nanomaterials.
Airborne engineered nanomaterials such as single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs), functionalized MWCNT, graphene, fullerene, silver and gold nanorods were characterized using a tandem system of a differential mobility analyzer and an aerosol particle mass analyzer to obtain their airborne transport properties and understand their relationship to morphological characteristics. These nanomaterials were aerosolized using different generation methods such as electrospray, pneumatic atomization, and dry aerosolization techniques, and their airborne transport properties such as mobility and aerodynamic diameters, mass scaling exponent, dynamic shape factor, and effective density were obtained. Laboratory experiments were conducted to directly measure mobility diameter and mass of the airborne nanomaterials using tandem mobility-mass measurements. Mass scaling exponents, aerodynamic diameters, dynamic shape factors and effective densities of mobility-classified particles were obtained from particle mass and the mobility diameter. Microscopy analysis using Transmission Electron Microscopy (TEM) was performed to obtain morphological descriptors such as envelop diameter, open area, aspect ratio, and projected area diameter. The morphological information from the TEM was compared with measured aerodynamic and mobility diameters of the particles. The results showed that aerodynamic diameter is smaller than mobility diameter below 500 nm by a factor of 2 to 4 for all nanomaterials except silver and gold nanorods. Morphologies of MWCNTs generated by liquid-based method, such as pneumatic atomization, are more compact than those of dry dispersed MWCNTs, indicating that the morphology depends on particle generation method. TEM analysis showed that projected area diameter of MWCNTs appears to be in reasonable agreement with mobility diameter in the size range from 100 - 400 nm. Principal component analysis of the obtained airborne particle properties also showed that the mobility diameter-based effective density and aerodynamic diameter are eigenvectors and can be used to represent key transport properties of interest.


Bilateral Sensory Changes and High Burden of Disease in Patients With Chronic Pain and Unilateral Nondermatomal Somatosensory Deficits: A Quantitative Sensory Testing and Clinical Study.
Widespread sensory deficits resembling hemihypoesthesia occur in 20% to 40% of chronic pain patients on the side of pain, independent of pain etiology, and have been termed nondermatomal sensory deficits (NDSDs). Sensory profiles have rarely been investigated in NDSDs. Quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS) was performed in the face, hand, and foot of the painful body side and in contralateral regions in chronic pain patients. Twenty-five patients with NDSDs and 23 without NDSDs (termed the pain-only group) were included after exclusion of neuropathic pain. Comprehensive clinical and psychiatric evaluations were carried out. NDSD in chronic pain was associated with high burden of disease and more widespread pain. Only in the NDSD group were significantly higher thresholds for mechanical and painful stimuli found in at least 2 of 3 regions ipsilateral to pain. In addition, we found a bilateral loss of function for temperature and vibration detection, and a gain of function for pressure pain in certain regions in patients with NDSD. Sensory loss and gain of function for pressure pain correlated with pain intensity in several regions. This may indicate a distinct sensory profile in chronic non-neuropathic pain and NDSD, probably attributable to altered central pain processing and sensitization. The presence of NDSD in chronic non-neuropathic pain may be regarded as a marker for higher burden of pain disease.


Determination of bleb capsule porosity with an experimental glaucoma drainage device and measurement system.
Control of intraocular pressure after implantation of a glaucoma drainage device (GDD) depends on the porosity of the capsule that forms around the plate of the GDD. To compare capsular porosity after insertion of 2 different GDDs using a novel implant and measurement system. We performed an experimental interventional study at an eye research facility in a tertiary eye care center. Testing was performed on 22 adult New Zealand white rabbits that received the experimental GDD or an existing GDD. A new experimental GDD, the Center for Eye Research Australia (CERA) implant, was created using computer-aided design and a 3-dimensional printer. The CERA GDDs were implanted in the eyes of rabbits randomized into 1 of the following 3 groups: with no connection to the anterior chamber (n = 7), with connection to the anterior chamber for 1 week (n = 5), and with connection to the anterior chamber for 4 weeks (n = 5). In a control group (n = 5), a pediatric GDD was implanted without connection to the anterior chamber. We measured the capsular porosity using a pressure-gated picoliter pump at a driving pressure of 12 mm Hg. The animals were killed humanely for histologic study. Porosity of the fibrous capsule around the implant. We found no difference in mean (SEM) capsular porosity between the CERA (3.39 [0.76; 95% CI, 1.43-5.48] µL/min) and pediatric (4.52 [0.52; 95% CI, 3.19-5.95] µL/min) GDDs (P = .28, unpaired t test) at 4 weeks without aqueous exposure. Mean (SEM) capsular porosity of CERA GDDs connected to the anterior chamber at 1 week was 2.46 (0.36; 95% CI, 1.55-3.44) µL/min but decreased to 0.67 (0.07; 95% CI, 0.49-0.86) µL/min at 4 weeks (P = .001, unpaired t test). Our experimental method permits direct measurement of capsular porosity of an in situ GDD. In a comparison between an experimental (CERA) and an existing GDD, no differences were identified in capsular porosity or histologic reaction between the implants. These results suggest that the CERA GDD model can be used to test key components of glaucoma surgery and implant design.


Non-CpG methylation by DNMT3B facilitates REST binding and gene silencing in developing mouse hearts.
The dynamic interaction of DNA methylation and transcription factor binding in regulating spatiotemporal gene expression is essential for embryogenesis, but the underlying mechanisms remain understudied. In this study, using mouse models and integration of in vitro and in vivo genetic and epigenetic analyses, we show that the binding of REST (repressor element 1 (RE1) silencing transcription factor; also known as NRSF) to its cognate RE1 sequences is temporally regulated by non-CpG methylation. This process is dependent on DNA methyltransferase 3B (DNMT3B) and leads to suppression of adult cardiac genes in developing hearts. We demonstrate that DNMT3B preferentially mediates non-CpG methylation of REST-targeted genes in the developing heart. Downregulation of DNMT3B results in decreased non-CpG methylation of RE1 sequences, reduced REST occupancy, and consequently release of the transcription suppression during later cardiac development. Together, these findings reveal a critical gene silencing mechanism in developing mammalian hearts that is regulated by the dynamic interaction of DNMT3B-mediated non-CpG methylation and REST binding.


Pollination and airflow patterns around conifer ovulate cones.
Wind-tunnel studies indicate that the geometry of Pinus ovulate cones may enhance the probability of pollen entrapment by aerodynamically predetermining airflow patterns around scale-bract complexes. Pollination experiments reveal that pollen from a particular species has the highest probability of reaching the ovules of its own species. The phenomenon of species-specific pollination appears to be related to the specific morphometry of scale-bract complexes and the terminal settling velocity of pollen of the same species. These data are interpreted as evidence for a reciprocity between the aerodynamic characteristics of airborne pollen and ovulate cones of some conifer species.


GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease.
Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study. Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls. Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 × 10(-7)), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 × 10(-8); Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 × 10(-4); OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 × 10(-2), OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 × 10(-3), OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 × 10(-3), OR = 1.13, 95% CI:1.042, 1.215). We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations.