Somatostatin regulates tight junction proteins expression in colitis mice.
Tight junction plays a critical role in intestinal defence. The alteration and perturbation of tight junction proteins could induce intestine barrier damage, and lead to the malabsorption of electrolytes and water. Previous studies had showed that colonic infection and inflammation could lead to the alteration of tight junction function, and somatostatin could protect intestinal epithelia. Thus, this study could explore that whether somatostatin could regulate tight junction in colitis mice. Colitis mice with diarrhea were induced by Citrobacter rodentium (CR) and Dextran sulfate sodium (DSS). In CR infected model, cladudin-1 and claudin-3 expression significantly decreased compared with the control mice (P<0.05); after octreotide treatment, claudin-1 and claudin-3 expression significantly increased compared with untreated CR infected mice (P<0.05). In DSS colitis model, occludin and claudin-3 expression significantly decreased compared with the control mice (P<0.05); and octreotide treatment could only significantly upregulate claudin-3 expression compared with untreated DSS colitis mice (P<0.05). To testify our results in vivo, we repeated the models in caco-2 cells by exposed with enteropathogenic Escherichia coli (E. Coli) and Tumor necrosis factor α (TNF-α). The results in vitro were consistent with in vivo study. The results suggested that somatostatin play a role in intestinal barrier protection by modulating tight junction proteins expression.


The history of tiered-effectiveness contraceptive counseling and the importance of patient-centered family planning care.
Public health workers, clinicians, and researchers have tried to increase long-acting reversible contraceptive (LARC) use by changing contraceptive counseling between patients and providers. Several major health organizations now recommend tiered-effectiveness counseling, in which the most effective methods are explained first so that patients can use information about the relative efficacy of contraceptive methods to make an informed choice. Some scholars and practitioners have raised concerns that, given histories of inequitable treatment and coercion in reproductive health care, tiered-effectiveness counseling may undermine patient autonomy and choice. This Clinical Opinion examines the development of tiered-effectiveness contraceptive counseling, how its rise mirrored the focus on promoting LARC to decrease the unintended pregnancy rate, and key considerations and the potential conflicts of a LARC-first model with patient-centered care. Finally, we discuss how reproductive justice and shared decision making can guide efforts to provide patient-centered contraceptive care.


Comparative immunological studies between canine prolactin and prolactin from other species.
Canine pituitary extracts contained material which was capable of inhibiting the binding between antisera to different prolactins and labelled non-canine prolactins. Maximum inhibition of binding was observed in the system consisting of antisera to ovine prolactin and labelled rat prolactin. This system was used to investigate the immunological activity of canine pituitary extracts and partially purified fractions. A rabbit antiserum which was raised against a canine pituitary extract and had significant immunological activity in the above system, together with labelled rat prolactin, was used to develop an assay capable of detecting material in canine pituitary extracts. This material gave parallel dose-response curves to a canine prolactin-rich fraction, D864C and purified ovine and bovine prolactin.


Role of Counterions in Molecularly Imprinted Polymers for Anionic Species.
Small-molecule oxoanions are often imprinted noncovalently as carboxylates into molecularly imprinted polymers (MIPs), requiring the use of an organic counterion. Popular species are either pentamethylpiperidine (PMP) as a protonatable cation or tetraalkylammonium (TXA) ions as permanent cations. The present work explores the influence of the TXA as a function of their alkyl chain length, from methyl to octyl, using UV/vis absorption, fluorescence titrations, and HPLC as well as MD simulations. Protected phenylalanines (Z-l/d-Phe) served as templates/analytes. While the influence of the counterion on the complex stability constants and anion-induced spectral changes shows a monotonous trend with increasing alkyl chain length at the prepolymerization stage, the cross-imprinting/rebinding studies showed a unique pattern that suggested the presence of adaptive cavities in the MIP matrix, related to the concept of induced fit of enzyme-substrate interaction. Larger cavities formed in the presence of larger counterions can take up pairs of Z-x-Phe and smaller TXA, eventually escaping spectroscopic detection. Correlation of the experimental data with the MD simulations revealed that counterion mobility, the relative distances between the three partners, and the hydrogen bond lifetimes are more decisive for the response features observed than actual distances between interacting atoms in a complex or the orientation of binding moieties. TBA has been found to yield the highest imprinting factor, also showing a unique dual behavior regarding the interaction with template and fluorescent monomer. Finally, interesting differences between both enantiomers have been observed in both theory and experiment, suggesting true control of enantioselectivity. The contribution concludes with suggestions for translating the findings into actual MIP development.


Evaluation of SAMe-TT2R2 score and other clinical factors influencing the quality of anticoagulation therapy in non-valvular atrial fibrillation: a nationwide study in Spain.
To assess the major clinical factors affecting the quality of anticoagulation and evaluate the predictive value of the SAMe-TT2R2 score to identify patients who will achieve a high average time in therapeutic range (T.T.R.) with vitamin K antagonist (V.K.A.) treatment. This observational, cross-sectional, retrospective and nationwide multicenter study included 1524 patients from the primary care setting with non-valvular atrial fibrillation receiving V.K.A. (≥12 months). We performed a bivariate analysis to identify factors individually associated with the T.T.R. and a multiple regression analysis to identify the independent predictive factors. For the validation of the SAMe-TT2R2 score, the receiver operating characteristic (R.O.C.) curve was calculated and the Hosmer-Lemeshow test was used to test calibration. A total of 94.8% of patients received acenocumarol (4.8% warfarin). A progressive decrease in mean T.T.R. was found when the SAMe-TT2R2 score increased from 0 points (72.1 ± 17.1%) to 4 points (64.1 ± 23.2%), p < 0.001. Other risk scores (CHADS2 and CHA2DS2-VASc, HAS-BLED) were also associated with the mean T.T.R. We found a significant association between low T.T.R. and the following clinical factors: female sex, three or more comorbidities, amiodarone treatment, dietary habits, bleeding history and the intake of ≥7 tablets per day besides V.K.A. (p < 0.01). Regarding SAMe-TT2R2 score validation, the R.O.C. curve showed significant capability, although not high, of discriminating good anticoagulation control (T.T.R. ≥65%) with an area under the curve of 0.562 (95% C.I. 0.533-0.592, p < 0.001) which increased, remaining modest, to 0.594 (95% C.I. 0.564-0.624, p < 0.001) when the factors not included in SAMe-TT2R2 score were added. In this cohort, the SAMe-TT2R2 score had a significant, although modest, ability to assess the likelihood of good international normalized ration (I.N.R.) control, and its predictive value might slightly improve by adding other simple clinical factors. Further research is needed to refine the predictive scales.


CYP3A variation, premenopausal estrone levels, and breast cancer risk.
Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.


Comparing the genomes of Helicobacter pylori clinical strain UM032 and Mice-adapted derivatives.
Helicobacter pylori is a Gram-negative bacterium that persistently infects the human stomach inducing chronic inflammation. The exact mechanisms of pathogenesis are still not completely understood. Although not a natural host for H. pylori, mouse infection models play an important role in establishing the immunology and pathogenicity of H. pylori. In this study, for the first time, the genome sequences of clinical H. pylori strain UM032 and mice-adapted derivatives, 298 and 299, were sequenced using the PacBio Single Molecule, Real-Time (SMRT) technology. Here, we described the single contig which was achieved for UM032 (1,599,441 bp), 298 (1,604,216 bp) and 299 (1,601,149 bp). Preliminary analysis suggested that methylation of H. pylori genome through its restriction modification system may be determinative of its host specificity and adaptation. Availability of these genomic sequences will aid in enhancing our current level of understanding the host specificity of H. pylori.


Occupational lung diseases: from old and novel exposures to effective preventive strategies.
Occupational exposure is an important, global cause of respiratory disease. Unlike many other non-communicable lung diseases, the proximal causes of many occupational lung diseases are well understood and they should be amenable to control with use of established and effective approaches. Therefore, the risks arising from exposure to silica and asbestos are well known, as are the means of their prevention. Although the incidence of occupational lung disease has decreased in many countries, in parts of the world undergoing rapid economic transition and population growth-often with large informal and unregulated workforces-occupational exposures continue to impose a heavy burden of disease. The incidence of interstitial and malignant lung diseases remains unacceptably high because control measures are not implemented or exposures arise in novel ways. With the advent of innovative technologies, new threats are continually introduced to the workplace (eg, indium compounds and vicinal diketones). In developed countries, work-related asthma is the commonest occupational lung disease of short latency. Although generic control measures to reduce the risk of developing or exacerbating asthma are well recognised, there is still uncertainty, for example, with regards to the management of workers who develop asthma but remain in the same job. In this Review, we provide recommendations for research, surveillance, and other action for reducing the burden of occupational lung diseases.


Serial analysis of gene expression.
The characteristics of an organism are determined by the genes expressed within it. A method was developed, called serial analysis of gene expression (SAGE), that allows the quantitative and simultaneous analysis of a large number of transcripts. To demonstrate this strategy, short diagnostic sequence tags were isolated from pancreas, concatenated, and cloned. Manual sequencing of 1000 tags revealed a gene expression pattern characteristic of pancreatic function. New pancreatic transcripts corresponding to novel tags were identified. SAGE should provide a broadly applicable means for the quantitative cataloging and comparison of expressed genes in a variety of normal, developmental, and disease states.


Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC).
Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members. This is the first example of a PROTAC that selectively degrades CDK9.


Induction of cytotoxic T lymphocytes by primary in vitro stimulation with peptides.
Antigen-specific cytotoxic T cells can be generated by primary in vitro stimulation of spleen cells from C57BL/6 mice with appropriate peptide fragments. This response can be elicited without prior in vivo immunization. Chicken OVA fragmented with either cyanogen bromide (CN OVA) or trypsin (T OVA) was used as a source of mixed peptides. A synthetic peptide, NP365-380, representing the sequence 365-380 from influenza virus A/PR/8 nucleoprotein, was also used, since this contains the main determinants recognized by CTL generated from H-2b mice infected with A/PR/8 virus. The primary in vitro cytotoxic T cell response was peptide specific, since targets were lysed only in the presence of appropriate peptide antigens. Native OVA could not elicit primary effectors in vitro nor could it sensitize targets for lysis by OVA digest-specific CTL. A synthetic peptide corresponding to residues 111-122 within the OVA sequence could sensitize targets for lysis by effectors induced against T OVA. Effectors generated by in vitro stimulation were CD8+, CD4-, and H-2Db-restricted for NP365-380 and T OVA recognition. CN OVA-specific effectors were also CD8+, CD4-, but surprisingly, were able to lyse a range of H-2-different targets in an antigen-specific manner. These effectors failed to lyse a tumor line that does not express class I MHC molecules. This broad MHC restriction pattern was also apparent at the clonal level. In all cases, the antipeptide CTL generated by primary in vitro stimulation were inefficient in lysing target cells expressing endogenous forms of antigens, such as influenza virus-infected cells or cells transfected with the OVA cDNA. However, cytotoxic T cell lines generated in vitro against the NP365-380 peptide did contain a minor population of virus-reactive cells that could be selectively expanded by stimulation with A/PR/8-infected spleen cells. These results are discussed in terms of class I-restricted T cell stimulation in the absence of antigen processing by high surface densities of peptide/MHC complexes.


Metal-ligand covalency of iron complexes from high-resolution resonant inelastic X-ray scattering.
Data from Kα resonant inelastic X-ray scattering (RIXS) have been used to extract electronic structure information, i.e., the covalency of metal-ligand bonds, for four iron complexes using an experimentally based theoretical model. Kα RIXS involves resonant 1s→3d excitation and detection of the 2p→1s (Kα) emission. This two-photon process reaches similar final states as single-photon L-edge (2p→3d) X-ray absorption spectroscopy (XAS), but involves only hard X-rays and can therefore be used to get high-resolution L-edge-like spectra for metal proteins, solution catalysts and their intermediates. To analyze the information content of Kα RIXS spectra, data have been collected for four characteristic σ-donor and π-back-donation complexes: ferrous tacn [Fe(II)(tacn)2]Br2, ferrocyanide [Fe(II)(CN)6]K4, ferric tacn [Fe(III)(tacn)2]Br3 and ferricyanide [Fe(III)(CN)6]K3. From these spectra metal-ligand covalencies can be extracted using a charge-transfer multiplet model, without previous information from the L-edge XAS experiment. A direct comparison of L-edge XAS and Kα RIXS spectra show that the latter reaches additional final states, e.g., when exciting into the e(g) (σ*) orbitals, and the splitting between final states of different symmetry provides an extra dimension that makes Kα RIXS a more sensitive probe of σ-bonding. Another key difference between L-edge XAS and Kα RIXS is the π-back-bonding features in ferro- and ferricyanide that are significantly more intense in L-edge XAS compared to Kα RIXS. This shows that two methods are complementary in assigning electronic structure. The Kα RIXS approach can thus be used as a stand-alone method, in combination with L-edge XAS for strongly covalent systems that are difficult to probe by UV/vis spectroscopy, or as an extension to conventional absorption spectroscopy for a wide range of transition metal enzymes and catalysts.


Viral gametocytic hypertrophy of the Pacific oyster Crassostrea gigas in Ireland.
Viral gametocytic hypertrophy (VGH) was detected during an investigation of mortalities in Pacific oysters Crassostrea gigas from 2 separate Irish production sites. The basophilic inclusions were observed in the gonad tissue of oysters sampled in August and October 2007. The oysters involved did not show any macroscopic disease signs. Transmission electron microscopy demonstrated the presence of viral particles in these intranuclear inclusions. The particles were small, non-enveloped, icosahedral and approximately 50 nm in diameter, and thus had characteristics similar to the Papillomaviridae and Polyomaviridae families. No host defence reaction was observed. The viral particles described here appear to be similar to those described in C. virginica from the USA and Canada and to those described in C. gigas from Korea and France.


Interobserver variability in intraductal papillary mucinous neoplasm subtypes and application of their mucin immunoprofiles.
Intraductal papillary mucinous neoplasm is considered a precursor lesion to pancreatic adenocarcinoma. These are further classified into four histologic subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The first aim of this study was to assess the interobserver variability among five gastrointestinal pathologists in diagnosing intraductal papillary mucinous neoplasm subtypes by morphology alone. The second aim of the study was to compare intraductal papillary mucinous neoplasm subtypes, which received consensus diagnoses (≥80% agreement) with their respective mucin immunoprofiles (MUC1, MUC2, MUC5AC, MUC6, and CDX2). A consensus histologic subtype was reached in 58% of cases (29/50) among the five gastrointestinal pathologists. Overall there was moderate agreement (κ=0.41, P<0.01) in subtyping intraductal papillary mucinous neoplasms without the use of immunohistochemistry. The histologic subtype with the best interobserver agreement was intestinal type (κ=0.56, P<0.01) followed by pancreatobiliary, gastric, mixed, and oncocytic types (κ=0.43, P<0.01; κ=0.38, P<0.01; κ=0.17, P<0.01; κ=0.08, P<0.04, respectively). Both kappa values for mixed and oncocytic subtypes were likely artificially low due to the underrepresentation of these subtypes in this study and not a true indication of poor interobserver agreement. Following an intradepartmental consensus meeting between two gastrointestinal pathologists, 68% of cases (34/50) received a consensus intraductal papillary mucinous neoplasm subtype. Sixty-nine percent of cases (11/16) that did not receive a consensus intraductal papillary mucinous neoplasm subtype could be classified based on their respective immunoprofiles. Standardizing the use of immunohistochemistry with a mucin immunopanel (MUC1, MUC2, MUC5AC, and MUC6) may improve the agreement of diagnosing intraductal papillary mucinous neoplasm histologic subtypes.


Flexible Roles for American Indian Elders in Community-Based Participatory Research.
Community-based participatory research builds partnerships between communities and academic researchers to engage in research design, decision making, data collection, and dissemination of health promotion initiatives. Community-based participatory projects often have formal agreements or defined roles for community and academic partners. Our project (November 2012-November 2014) was designed to document life narratives of urban American Indian elders as a foundation for developing a resilience-based health promotion curriculum for urban American Indian adolescents aged 12 to 18. We used a flexible method for engaging community partners that honored the individual strengths of elders, encouraged them to describe how they wanted to contribute to the project, and provided multiple ways for elders to engage with university partners. We invited elders to participate in one or more of the following roles: as members of consensus panels to develop interview questions, as members of a community advisory board, or as participants in individual qualitative interviews. The flexibility of roles gave elders the opportunity to serve as advisors, co-developers, interviewees, or reviewers during 2 years of curriculum development. Engaging American Indian elders in the research process acknowledged the multiple layers of expertise they had as traditional leaders in the community while promoting trust in and ownership of the project. This flexible technique can be used by other communities that may not be comfortable with structured processes of engagement.


Embarrassingly Parallel Acceleration of Global Tractography via Dynamic Domain Partitioning.
Global tractography estimates brain connectivity by organizing signal-generating fiber segments in an optimal configuration that best describes the measured diffusion-weighted data, promising better stability than local greedy methods with respect to imaging noise. However, global tractography is computationally very demanding and requires computation times that are often prohibitive for clinical applications. We present here a reformulation of the global tractography algorithm for fast parallel implementation amendable to acceleration using multi-core CPUs and general-purpose GPUs. Our method is motivated by the key observation that each fiber segment is affected by a limited spatial neighborhood. In other words, a fiber segment is influenced only by the fiber segments that are (or can potentially be) connected to its two ends and also by the diffusion-weighted signal in its proximity. This observation makes it possible to parallelize the Markov chain Monte Carlo (MCMC) algorithm used in the global tractography algorithm so that concurrent updating of independent fiber segments can be carried out. Experiments show that the proposed algorithm can significantly speed up global tractography, while at the same time maintain or even improve tractography performance.


Association Between Parenting Style and Social Outcomes in Children with and Without Attention-Deficit/Hyperactivity Disorder: An 18-Month Longitudinal Study.
In a community-based sample of children with attention-deficit/hyperactivity disorder (ADHD) (n = 179) and non-ADHD controls (n = 212), this longitudinal study explored changes in parenting style over time; and whether parenting style prospectively predicts child functional outcomes. Attention-deficit/hyperactivity disorder diagnosis was assessed using the Conners ADHD index and Diagnostic Interview Schedule for Children IV. Children (70.3% boys) were assessed at baseline (mean age: 7.3 yr) and after 18 months (mean age: 8.9 yr) using a range of parent- and teacher-reported measures of child socioemotional and academic functioning. Parenting style was assessed through parent-reported measures of warmth, consistency, and anger. At 18-month follow-up, there was a small significant decline in parenting warmth and parenting anger, and an increase in parenting consistency across groups. In the ADHD group, parenting warmth at baseline was positively related to 18-month prosocial behavior and responsibility by parent report, whereas parenting consistency predicted these child outcomes by teacher report. Parenting anger was positively associated with peer problems and negatively associated with prosocial behavior, self-control, and responsibility by parent report. Associations were similar for non-ADHD controls and all associations held after adjusting for a range of family, child, and parent factors. After additional adjustment of baseline levels of child functioning, parenting warmth and consistency continued to be associated with 18-month child outcomes. Parenting style was unrelated to emotional problems and academic competence over time. Parenting style is independently related to aspects of future social outcomes of children with ADHD. Results hold implications for parenting interventions aimed at managing ADHD-related social impairments over time.


Multiple markers of inflammation and weight status: cross-sectional analyses throughout childhood.
Inflammatory markers such as C-reactive protein (CRP) are related to obesity in adults, but the association is less clear in children. Our objective was to examine relationships between multiple markers of inflammation and children's weight status; we hypothesized that the prevalence of inflammatory markers would increase as weight status increased. We conducted a cross-sectional analysis of children in the United States aged 1 to 17 years in the National Health and Nutrition Examination Survey, 1999-2006. Children were categorized using weight-for-length when age <2 years and BMI for > or =2 years, as very obese (> or =99th percentile), obese (<99th and > or =95th percentile), overweight (<95th and > or =85th percentile), and healthy weight (>5th to < or =85th percentile) according to expert consensus. Our main outcome measures were high-sensitivity CRP and absolute neutrophil count, in addition to a novel third measure: ferritin controlled for iron status using a ferritin/transferrin ratio. We used Cox proportional hazards models to examine risk of abnormal values of inflammatory markers according to weight. Increased risk of a CRP level of >1.0 mg/L was evident among very obese children from ages 3 to 5 years (hazard ratio [HR]: 2.29; P < .01) through 15 to 17 years (HR: 4.73; P < .01). Increased risk of abnormal neutrophil count among very obese children began at 6 to 8 years (HR: 2.00; P = .049), and increased prevalence of abnormal ferritin/transferrin ratio began at 9 to 11 years (HR: 7.06; P < .001). Multiple inflammatory markers are strongly and positively associated with increasing weight status in children, and this relationship starts as young as age 3. Elevated inflammatory markers in very young obese children are particularly concerning, because inflammation may cause long-term, cumulative vascular damage. This deserves additional research via longitudinal design.


Directional sexual selection on chroma and within-pattern colour contrast in Labeotropheus fuelleborni.
Speciation via intersexual selection on male nuptial colour pattern is thought to have been a major force in promoting the explosive speciation of African haplochromine cichlids, yet there is very little direct empirical evidence of directional preferences within populations. In this study, we used objective spectrophotometry and analyses based on visual physiology to determine whether females of the Katale population of Labeotropheus fuelleborni, a Lake Malawi haplochromine, prefer males that have higher chroma and more within-pattern colour contrast. In paired male preference tests, female Katale L. fuelleborni showed increasing preferences for males with more relatively saturated colours on their flanks. They also showed increasing preferences for males with relatively higher contrast levels among flank elements. This is the first empirical evidence, to our knowledge, for male colour as a directionally sexually selected trait within a haplochromine cichlid population.


Eye disorders in old people.
Visual impairment is one of a major public health problem among elderly people. Aim of this study was determining the prevalence of visual impairment in median and old peoples in Qazvin (Iran). In this cross sectional study, with a simple random sampling, 446 patients older than 5o years who were referred to outpatient ophthalmology clinics at Avecina hospital of Qazvin (a province of Iran) in 2010 were enrolled. Participants first complete a questionnaire with 25 questions toward demographic and past medical history and then were examined by ophthalmologist. These examinations includes direct and indirect ophthalmoscopy, slit lamp examination, measurement of uncorrected visual acuity and visual acuity with current glasses, lensometery of the previous glasses, refraction with and without the use of cycloplegic and determining the best corrected visual acuity. All slit lamp examinations were performed by the same ophthalmologist. Data were analyzed with SPSS16 with use of Chi - Square test with Pvalue <0.05. In this study 446 patients were examined that 54.7% were male. Mean age of study population was 62+-9.3 years old. 96.4% of participants had refractory disorder. Prevalence of myopia, hyperopia and astigmatism were 33.6%, 45.9% and 16.8% respectively. Of patients 17.4% had diabetes. Of participants 28.9% had temporal headache, 37% red eye, 41.2% flashing, 27.3% and 28% had dryness and discharge of eye respectively. 31.1% of participants had eyelide problem, 4.7% Color Vision Deficiency (CVD) and 3.8% had family history of CVD. Of total 4.5% had glaucoma, 3.3% macular degeneration and 21.7% had hypertension. 0.6% of population had macular degeneration, 0.4% of population had glaucoma Of 892 eyes (446 individuals), 36.2% had visual acuity less than 7/10, 1.7% light perception (LP) and 0.22% no light perception (NLP) and 2.7% finger count. Refractory errors, cataract and amblyopia were most important eye disorders in older people in Qazvin.


Use of Intervention Mapping for Occupational Risk Prevention and Health Promotion: A Systematic Review of Literature.
Aim: Intervention mapping (IM) is a method to systematically design interventions that is applied regularly within the public health domain. This study investigates whether IM is effectively used within the occupational safety and health domain as well. Specifically, this study explores the relation between the fidelity regarding the use of the IM protocol for intervention development, the implementation process and the effectiveness of the occupational risk prevention and health promotion interventions. Methods: A systematic review was conducted including articles on development, implementation, and effects of occupational risk prevention and health promotion interventions that were developed according to the IM-protocol. By means of a checklist, two authors reviewed the articles and rated them on several indicators regarding the fidelity of the IM-protocol, the implementation process, and the intervention effect. Results: A literature search resulted in a total of 12 interventions as described in 38 articles. The fidelity to the IM-protocol was relatively low for participation throughout the development process and implementation planning. No relationship was found between fidelity of the IM-protocol and the intervention effect. A theory-based approach (as one of the core elements of IM) appears to be positively related to a successful implementation process. Conclusion: Results of the review suggest that organizing a participative approach and implementation planning is difficult in practice. In addition, results imply that conducting matrices of change objectives as part of the intervention development, although challenging and time-consuming, may ultimately pay off, resulting in a tailored intervention that matches the target group.


Concluding embryogenesis after diaspora: seed germination in Illicium parviflorum.
Albuminous seeds, dispersed with a minimally developed embryo surrounded by nutrient storage tissue, are pervasive across extinct and extant early diverging angiosperm lineages. Typically, seed ontogenic studies have focused on the time between fertilization and seed release, but in albuminous seeds, embryogenesis is incomplete at the time of seed dispersal. Here, I studied the morphological and nutritional relationships between the embryo and the endosperm after seed dispersal in Illicium parviflorum (Austrobaileyales). Seeds of I. parviflorum germinate over a period of three months. Different stages during the germination process were anatomically evaluated using a combination of histochemistry and immunocytochemistry. At dispersal, the seeds of Illicium contain a tiny achlorophyllous embryo with minimal histological differentiation surrounded by copious amounts of lipo-protein globules stored in the endosperm within cell walls rich in un-esterified pectins. Six weeks later, the embryo expanded and differentiated the vascular tissues prior to the emergence of the radicle through the seed coat, as the stored lipids and proteins coalesced within cells. Six weeks later, the cotyledons contained starch and complex lipids intracellularly and accumulated low-esterified pectins in their cell walls. The proteolipid-rich albuminous seeds of Illicium exemplify how woody angiosperms of the Austrobaileyales, Amborellales, and many magnoliids release seeds with high-energy storage compounds that are reprocessed by embryos that complete development during germination. Seedlings of these lineages thrive in the understory of tropical environments, which match with the predicted environments where angiosperms evolved.


Extending the methods used to screen the WHO drug safety database towards analysis of complex associations and improved accuracy for rare events.
Post-marketing drug safety data sets are often massive, and entail problems with heterogeneity and selection bias. Nevertheless, quantitative methods have proven a very useful aid to help clinical experts in screening for previously unknown associations in these data sets. The WHO international drug safety database is the world's largest data set of its kind with over three million reports on suspected adverse drug reaction incidents. Since 1998, an exploratory data analysis method has been in routine use to screen for quantitative associations in this data set. This method was originally based on large sample approximations and limited to pairwise associations, but in this article we propose more accurate credibility interval estimates and extend the method to allow for the analysis of more complex quantitative associations. The accuracy of the proposed credibility intervals is evaluated through comparison to precise Monte Carlo simulations. In addition, we propose a Mantel-Haenszel-type adjustment to control for suspected confounders.


Bis(1,3-benzothia-zol-2-amine-κN)silver(I) nitrate acetone solvate.
In the title compound, [Ag(C(7)H(6)N(2)S)(2)]NO(3)·C(3)H(6)O, the Ag(I) ion is coordinated to two benzothia-zol-2-amine ligands via the thia-zole N atoms in an approximately linear arrangement. The dihedral angle between the mean planes of the two 1,3-benzothia-zole groups is 5.9 (3)°. Both amine groups on the ligands are oriented in the same direction and are engaged in N-H⋯O hydrogen bonding with the nitrate counter-anion, forming one-dimensional columns along the b-axis direction. Voids created by inefficient crystal packing are occupied by acetone solvent mol-ecules which are disordered over two sites with occupancies of 0.563 (11) and 0.437 (11).


Spatial working memory deficits represent a core challenge for rehabilitating neglect.
Left neglect following right hemisphere injury is a debilitating disorder that has proven extremely difficult to rehabilitate. Traditional models of neglect have focused on impaired spatial attention as the core deficit and as such, most rehabilitation methods have tried to improve attentional processes. However, many of these techniques (e.g., visual scanning training, caloric stimulation, neck muscle vibration) produce only short-lived effects, or are too uncomfortable to use as a routine treatment. More recently, many investigators have begun examining the beneficial effects of prism adaptation for the treatment of neglect. Although prism adaptation has been shown to have some beneficial effects on both overt and covert spatial attention, it does not reliably alter many of the perceptual biases evident in neglect. One of the challenges of neglect rehabilitation may lie in the heterogeneous nature of the deficits. Most notably, a number of researchers have shown that neglect patients present with severe deficits in spatial working memory (SWM) in addition to their attentional impairments. Given that SWM can be seen as a foundational cognitive mechanism, critical for a wide range of other functions, any deficit in SWM memory will undoubtedly have severe consequences. In the current review we examine the evidence for SWM deficits in neglect and propose that it constitutes a core component of the syndrome. We present preliminary data which suggest that at least one current rehabilitation method (prism adaptation) has no effect on SWM deficits in neglect. Finally, we end by reviewing recent work that examines the effectiveness of SWM training and how SWM training may prove to be a useful avenue for future rehabilitative efforts in patients with neglect.


To posture or not to posture after macular hole surgery.
To evaluate the anatomic and functional success of phacovitrectomy and intraocular gas tamponade for macular hole surgery with only first night face down posturing. This was a nonrandomized observational prospective trial over 9 months, with data collection on 28 eyes of 26 consecutive patients who underwent phacovitrectomy, internal limiting membrane peel, and intraocular gas tamponade (C2F6) for stage 2, 3, and 4 macular holes. Data included sex, age, hole latency and Gass stage, preoperative and postoperative visual acuity and ocular coherence tomography, refractive outcome, ocular comorbidity, first postoperative day gas fill, and intraocular pressure. Postoperatively, all patients were postured face down overnight. Thereafter, patients with more than 70% gas fill (beyond the inferior retinal vascular arcade) were asked to stop posturing, although they were advised not to lie flat on their backs at night for 10 days. The sample was divided into patients who did and did not need to posture postoperatively, depending on first day gas fill. Twenty patients did not need posturing and 8 patients needed postoperative posturing for 10 days. The mean macular hole duration was 10.5 months. A total of 87.5% compared to 100% achieved hole closure in the posture and nonposture group, respectively. The mean postoperative visual acuity was 0.5 +/- 0.25 LogMAR. Statistical analysis revealed no significant difference in age, hole duration, preoperative and postoperative visual acuities, intraocular pressure measured 24 hours postoperatively, or refractive error between the two samples. Phacovitrectomy for macular hole surgery without postoperative face down posture is a reasonable approach, as long as the eye has more than 70% gas fill (beyond the inferior retinal vascular arcade) on the first postoperative day. This study showed no statistically significant difference between patients who postured and those who did not posture. The combination of phacoemulsification, pars plana vitrectomy, internal limiting membrane, and gas tamponade in macular hole surgery reduces the difficulty of posturing in elderly patients. This technique saves the patient from exposure to a second intraocular intervention to remove a cataract which will commonly develop after vitrectomy and gas tamponade alone.


Iron status and stores decline with age in Lewis rats.
In the context of a larger study examining the interaction of vitamin A (VA) status and age on immune function, we examined age-related changes in hematologic and iron status variables in male Lewis rats. Animals were fed a nutritionally adequate purified diet containing either 0.35 (marginal), 4.0 (control) or 50 (supplemented) mg retinol equivalents (as retinyl palmitate) per kg of diet from the time of weaning until killing at 8-10 (middle-aged) or 20-22 (old) mo of age. Neither VA nor VA and age interaction effects were significant for most iron variables examined. After controlling for body weight, old rats had significantly lower hemoglobin, hematocrit and plasma iron than middle-aged rats. This decrease in hematologic and transport iron variables was not accompanied by a shift of iron into other storage compartments. Old rats also had significantly lower total iron content and iron concentration in liver, spleen and bone marrow. Hemosiderin iron in marrow smears correlated significantly (r = 0.43-0.76, P: < 0.05) with chemical estimates of iron in storage, transport and functional pools. Old rats also tended to have less stained iron in femur marrow smears. Thus, body iron in functional, transport and storage compartments, namely the liver, spleen and bone marrow, were significantly lower in old than in middle-aged rats. Although iron stores and status are usually considered to increase with advancing age, our data show a consistent pattern of lower hematologic and storage iron variables in old than in middle-aged Lewis rats. Future research is indicated to understand the biology and functional consequences of the observed age-associated decline in body iron.


Evaluation of different recruitment and randomisation methods in a trial of general practitioner-led interventions to increase physical activity: a randomised controlled feasibility study with factorial design.
Interventions promoting physical activity by General Practitioners (GPs) lack a strong evidence base. Recruiting participants to trials in primary care is challenging. We investigated the feasibility of (i) delivering three interventions to promote physical activity in inactive participants and (ii) different methods of participant recruitment and randomised allocation. We recruited general practices from Devon, Bristol and Coventry. We used a 2-by-2 factorial design for participant recruitment and randomisation. Recruitment strategies were either opportunistic (approaching patients attending their GP surgery) or systematic (selecting patients from practice lists and approaching them by letter). Randomisation strategies were either individual or by practice cluster. Feasibility outcomes included time taken to recruit the target number of participants within each practice. Participants were randomly allocated to one of three interventions: (i) written advice (control); (ii) brief GP advice (written advice plus GP advice on physical activity), and (iii) brief GP advice plus a pedometer to self-monitor physical activity during the trial. Participants allocated to written advice or brief advice each received a sealed pedometer to record their physical activity, and were instructed not to unseal the pedometer before the scheduled day of data collection. Participant level outcomes were reported descriptively and included the mean number of pedometer steps over a 7-day period, and European Quality of Life (EuroQoL)-5 dimensions (EQ-5D) scores, recorded at 12 weeks' follow-up. We recruited 24 practices (12 using each recruitment method; 18 randomising by cluster, 6 randomising by individual participant), encompassing 131 participants. Opportunistic recruitment was associated with less time to target recruitment compared with systematic (mean difference (days) -54.9, 95% confidence interval (CI) -103.6; -6.2) but with greater loss to follow up (28.8% versus. 6.9%; mean difference 21.9% (95% CI 9.6%; 34.1%)). There were differences in the socio-demographic characteristics of participants according to recruitment method. There was no clear pattern of change in participant level outcomes from baseline to 12 weeks across the three arms. Delivering and trialling GP-led interventions to promote physical activity is feasible, but trial design influences time to participant recruitment, participant withdrawal, and possibly, the socio-demographic characteristics of participants. ISRCTN73725618.


BCL9L expression in pancreatic neoplasia with a focus on SPN: a possible explanation for the enigma of the benign neoplasia.
Solid pseudopapillary neoplasms of the pancreas (SPN) are rare tumors affecting mainly women. They show an activating mutation in CTNNB1, the gene for β-catenin, and consequently an overactivation of the Wnt/β-catenin pathway. This signaling pathway is implied in the pathogenesis of various aggressive tumors, including pancreatic adenocarcinomas (PDAC). Despite this, SPN are characterized by an unusually benign clinical course. Attempts to explain this lack of malignancy have led to the discovery of an aberrant expression of the transcription factor FLI1 in SPN. In 42 primary pancreatic tumors the RNA-expression of the FLI1 targets DKK1, INPP5D, IGFBP3 and additionally two members of the Wnt/β-catenin pathway, namely BCL9 and BCL9L, was investigated using quantitative real time PCR. Expression of these genes was evaluated in SPN (n = 18), PDAC (n = 12) and the less aggressive intraductal papillary mucinous neoplasm IPMN (n = 12) and compared to normal pancreatic tissue. Potential differences between the tumor entities were evaluated using students t-test. The results demonstrated a differential RNA-expression of BCL9L with a lack of expression in SPN (p < 0.001), RNA levels similar to normal tissue in IPMN and increased expression in PDAC (p < 0.04). Further, overexpression of the cyclin D1 inhibitor INPP5D in IPMN (p < 0.0001) was found. PDAC, on the other hand, showed the highest expression of IGFBP3 (p < 0.00001) with the gene still being significantly overexpressed in IPMN (p < 0.001). Nevertheless the difference in expression was significant between PDAC and IPMN (p < 0.05) and IGFBP3 RNA levels were significantly higher in PDAC and IPMN than in SPN (p < 0.0001 and p < 0.02, resp.). This study demonstrates a significantly decreased expression of the β-catenin stabilizing gene BCL9L in SPN as a first clue to the possible reasons for the astonishingly benign behavior of this entity. In contrast, high expression of the gene was detected in PDAC supporting the connection between BCL9L expression and tumor malignancy in pancreas neoplasias. IPMN, accordingly, showed intermediate expression of BCL9L, but instead demonstrated a high expression of the cyclin D1 inhibitor INPP5D, possibly contributing to the better prognosis of this neoplasia compared to PDAC.


Molecular Epidemiology and Evolution of European Bat Lyssavirus 2.
Bat rabies cases in Europe are mainly attributed to two lyssaviruses, namely European Bat Lyssavirus 1 (EBLV-1) and European Bat Lyssavirus 2 (EBLV-2). Prior to the death of a bat worker in Finland in 1985, very few bat rabies cases were reported. Enhanced surveillance in the two subsequent years (1986-1987) identified 263 cases (more than a fifth of all reported cases to date). Between 1977 and 2016, 1183 cases of bat rabies were reported, with the vast majority (>97%) being attributed to EBLV-1. In contrast, there have been only 39 suspected cases of EBLV-2, of which 34 have been confirmed by virus typing and presently restricted to just two bat species; Myotis daubentonii and Myotis dasycneme. The limited number of EBLV-2 cases in Europe prompted the establishment of a network of European reference laboratories to collate all available viruses and data. Despite the relatively low number of EBLV-2 cases, a large amount of anomalous data has been published in the scientific literature, which we have here reviewed and clarified. In this review, 29 EBLV-2 full genome sequences have been analysed to further our understanding of the diversity and molecular evolution of EBLV-2 in Europe. Analysis of the 29 complete EBLV-2 genome sequences clearly corroborated geographical relationships with all EBLV-2 sequences clustering at the country level irrespective of the gene studied. Further geographical clustering was also observed at a local level. There are high levels of homogeneity within the EBLV-2 species with nucleotide identities ranging from 95.5-100% and amino acid identities between 98.7% and 100%, despite the widespread distribution of the isolates both geographically and chronologically. The mean substitution rate for EBLV-2 across the five concatenated genes was 1.65 × 10-5, and evolutionary clock analysis confirms the slow evolution of EBLV-2 both between and within countries in Europe. This is further supported by the first detailed EBLV-2 intra-roost genomic analysis whereby a relatively high sequence homogeneity was found across the genomes of three EBLV-2 isolates obtained several years apart (2007, 2008, and 2014) from M. daubentonii at the same site (Stokesay Castle, Shropshire, UK).


Single-cell Spatial Proteomic Revelations on the Multiparametric MRI Heterogeneity of Clinically Significant Prostate Cancer.
Multiparametric MRI (mpMRI) has become an indispensable radiographic tool in diagnosing prostate cancer. However, mpMRI fails to visualize approximately 15% of clinically significant prostate cancer (csPCa). The molecular, cellular, and spatial underpinnings of such radiographic heterogeneity in csPCa are unclear. We examined tumor tissues from clinically matched patients with mpMRI-invisible and mpMRI-visible csPCa who underwent radical prostatectomy. Multiplex immunofluorescence single-cell spatial imaging and gene expression profiling were performed. Artificial intelligence-based analytic algorithms were developed to examine the tumor ecosystem and integrate with corresponding transcriptomics. More complex and compact epithelial tumor architectures were found in mpMRI-visible than in mpMRI-invisible prostate cancer tumors. In contrast, similar stromal patterns were detected between mpMRI-invisible prostate cancer and normal prostate tissues. Furthermore, quantification of immune cell composition and tumor-immune interactions demonstrated a lack of immune cell infiltration in the malignant but not in the adjacent nonmalignant tissue compartments, irrespective of mpMRI visibility. No significant difference in immune profiles was detected between mpMRI-visible and mpMRI-invisible prostate cancer within our patient cohort, whereas expression profiling identified a 24-gene stromal signature enriched in mpMRI-invisible prostate cancer. Prostate cancer with strong stromal signature exhibited a favorable survival outcome within The Cancer Genome Atlas prostate cancer cohort. Notably, five recurrences in the 8 mpMRI-visible patients with csPCa and no recurrence in the 8 clinically matched patients with mpMRI-invisible csPCa occurred during the 5-year follow-up post-prostatectomy. Our study identified distinct molecular, cellular, and structural characteristics associated with mpMRI-visible csPCa, whereas mpMRI-invisible tumors were similar to normal prostate tissue, likely contributing to mpMRI invisibility.


Underreporting of deaths in the maternal deaths surveillance system in one region of Morocco.
To assess the reliability of maternal deaths surveillance system (MDSS) and to determine the factors that influence its completeness in one region of Morocco. We conducted a retrospective survey in "Gharb Chrarda Bni Hssen" region (GCBH) between January the 1st, 2013 and September the 30th, 2014 using multiple sources approach. All deaths of women of reproductive age (WRA) were investigated using certificates with medical cause, medical records and interviews with household members and relatives to ascertain a pregnancy-related or maternal death. An External Expert Committee reviewed the information collected to assign a cause for each death. Our results were compared to those reported in the same period by the MDSS. Our study identified 690 deaths of WRA and 69 maternal deaths of which 34.8% occurred outside health facilities. The MDSS recorded during the study period 538 deaths of WRA and 29 maternal deaths (including only one outside health facility) representing respectively an underreporting of 22.0% and 58.0%. Late maternal deaths represented 11.4% of all deaths of women with a registered pregnancy within 12 months prior to the death, while the MDSS identified none. The maternal mortality ratio (MMR) was estimated at 103, approximately 2.5 times higher than that reported in the MDSS. Our study has shown weaknesses in the current notification system for maternal deaths in the region of GCBH. Therefore, more attention must be given to the regional committees in charge of auditing the cases and defining actions to be implemented to prevent further maternal deaths.


ACE gene is associated with Alzheimer's disease and atrophy of hippocampus and amygdala.
Despite biological support for a role of angiotensin converting enzyme (ACE) in Alzheimer's disease (AD), studies assessing the ACE I/D polymorphism in AD are conflicting. We re-evaluated this association in the Rotterdam Study, a population-based cohort study. The mechanism of association was further explored by adjusting for vascular factors, and by analysing atrophy, white matter lesions and infarcts on MRI in non-demented individuals. Genotypes were available for 6488 participants. During average follow-up of 6 years 250 subjects developed AD. MRI data were available for 494 non-demented participants. Homozygosity for the I-allele conferred a slightly increased risk of AD compared to carrying a D-allele (RR 1.12 (95% CI 0.99-1.25)). This increase was only significant in women, and independent of vascular factors (RR 1.39 (95% CI 1.14-1.69)). Non-demented women with the II genotype had smaller hippocampal and amygdalar volumes. Vascular pathology was not significantly associated with ACE. This suggests a modest but significant increase in risk of AD and early AD pathology in women homozygous for the ACE I-allele independent of vascular factors.


Inhibition of Na+/K(+)-ATPase may be one mechanism contributing to potassium efflux and cell shrinkage in CD95-induced apoptosis.
To investigate the involvement of K+ efflux in apoptotic cell shrinkage, we monitored efflux of the K+ congener, 86Rb+, and cell volume during CD95-mediated apoptosis in Jurkat cells. An anti-CD95 antibody caused apoptosis associated with intracellular GSH depletion, a significant increase in 86Rb+ efflux, and a decrease in cell volume compared with control cells. Preincubating Jurkat cells with Val-Ala-Asp-chloromethylketone (VAD-cmk), an inhibitor of caspase proteases, prevented the observed 86Rb+ efflux and cell shrinkage induced by the anti-CD95 antibody. A wide range of inhibitors against most types of K+ channels could not inhibit CD95-mediated efflux of 86Rb+, however, the uptake of 86Rb+ by Jurkat cells was severely compromised when treated with anti-CD95 antibody. Uptake of 86Rb+ in Jurkat cells was sensitive to ouabain (a specific Na+/K(+)-ATPase inhibitor), demonstrating Na+/K(+)-ATPase dependent K+ uptake. Ouabain induced significant 86Rb+ efflux in untreated cells, as well as it seemed to compete with 86Rb+ efflux induced by the anti-CD95 antibody, supporting a role for Na+/K(+)-ATPase in the CD95-mediated 86Rb+ efflux. Ouabain treatment of Jurkat cells did not cause a reduction in cell volume, although together with the anti-CD95 antibody, ouabain potentiated CD95-mediated cell shrinkage. This suggests that the observed inhibition of Na+/K(+)-ATPase during apoptosis may also facilitate apoptotic cell shrinkage.


Bimolecular Fluorescence Complementation (BiFC) Analysis: Advances and Recent Applications for Genome-Wide Interaction Studies.
Complex protein networks are involved in nearly all cellular processes. To uncover these vast networks of protein interactions, various high-throughput screening technologies have been developed. Over the last decade, bimolecular fluorescence complementation (BiFC) assay has been widely used to detect protein-protein interactions (PPIs) in living cells. This technique is based on the reconstitution of a fluorescent protein in vivo. Easy quantification of the BiFC signals allows effective cell-based high-throughput screenings for protein binding partners and drugs that modulate PPIs. Recently, with the development of large screening libraries, BiFC has been effectively applied for genome-wide PPI studies and has uncovered novel protein interactions, providing new insight into protein functions. In this review, we describe the development of reagents and methods used for BiFC-based screens in yeast, plants, and mammalian cells. We also discuss the advantages and drawbacks of these methods and highlight the application of BiFC in large-scale studies.


A framework to account for the effects of visual loss on human auditory abilities.
Until recently, a commonly held view was that blindness resulted in enhanced auditory abilities, underpinned by the beneficial effects of cross-modal neuroplasticity. This viewpoint has been challenged by studies showing that blindness results in poorer performance for some auditory spatial tasks. It is now clear that visual loss does not result in a general increase or decrease in all auditory abilities. Although several hypotheses have been proposed to explain why certain auditory abilities are enhanced while others are degraded, these are often limited to a specific subset of tasks. A comprehensive explanation encompassing auditory abilities assessed in fully blind and partially sighted populations and spanning spatial and non-spatial cognition has not so far been proposed. The current article proposes a framework comprising a set of nine principles that can be used to predict whether auditory abilities are enhanced or degraded. The validity of these principles is assessed by comparing their predictions with a wide range of empirical evidence concerning the effects of visual loss on spatial and non-spatial auditory abilities. Developmental findings and the effects of early- versus late-onset visual loss are discussed. Ways of improving auditory abilities for individuals with visual loss and reducing auditory spatial deficits are summarized. A new Perceptual Restructuring Hypothesis is proposed within the framework, positing that the auditory system is restructured to provide the most accurate information possible given the loss of the visual signal and utilizing available cortical resources, resulting in different auditory abilities getting better or worse according to the nine principles. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


FMLRC: Hybrid long read error correction using an FM-index.
Long read sequencing is changing the landscape of genomic research, especially de novo assembly. Despite the high error rate inherent to long read technologies, increased read lengths dramatically improve the continuity and accuracy of genome assemblies. However, the cost and throughput of these technologies limits their application to complex genomes. One solution is to decrease the cost and time to assemble novel genomes by leveraging "hybrid" assemblies that use long reads for scaffolding and short reads for accuracy. We describe a novel method leveraging a multi-string Burrows-Wheeler Transform with auxiliary FM-index to correct errors in long read sequences using a set of complementary short reads. We demonstrate that our method efficiently produces significantly more high quality corrected sequence than existing hybrid error-correction methods. We also show that our method produces more contiguous assemblies, in many cases, than existing state-of-the-art hybrid and long-read only de novo assembly methods. Our method accurately corrects long read sequence data using complementary short reads. We demonstrate higher total throughput of corrected long reads and a corresponding increase in contiguity of the resulting de novo assemblies. Improved throughput and computational efficiency than existing methods will help better economically utilize emerging long read sequencing technologies.


Understanding perceptions of HIV risk among adolescents in KwaZulu-Natal.
Risk perception has been theorized to be an important antecedent for adopting protective behavior. It is a key construct of research applying the Health Belief Model and other behavior change models. In relation to HIV, risk perception is an indicator of perceived susceptibility to infection, a measure for one's understanding of AIDS transmission as well as willingness to consider behavioral changes. However, there remains much we do not know about what drives risk perception, especially among youth. This study identifies factors that influence the calculation of HIV-risk perception among a group of adolescents in South Africa. Data, collected in 1999 from 2,716 adolescents aged 14-22, are used to explore factors predicting risk perception. Logistic regression models suggest connectedness to parents and community for males and females, self-efficacy to use a condom among males, and living in a household with a chronically ill member for females are associated with HIV risk perception. We conclude that a greater understanding of the connection of adolescents to their communities and adults in their lives is needed, and ways in which programs can alter the environments in which adolescents form opinions, make choices, and act should be incorporated into program design.


A common microstructure in behavioral hearing thresholds and stimulus-frequency otoacoustic emissions.
Behavioral hearing thresholds and otoacoustic emission (OAE) spectra often exhibit quasiperiodic fluctuations with frequency. For behavioral and OAE responses to single tones-the latter referred to as stimulus-frequency otoacoustic emissions (SFOAEs)-this microstructure has been attributed to intracochlear reflections of SFOAE energy between its region of generation and the middle ear boundary. However, the relationship between behavioral and SFOAE microstructures, as well as their presumed dependence on the properties of the SFOAE-generation mechanism, have yet to be adequately examined. To address this, behavioral thresholds and SFOAEs evoked by near-threshold tones were compared in 12 normal-hearing female subjects. The microstructures observed in thresholds and both SFOAE amplitudes and delays were found to be strikingly similar. SFOAE phase accumulated an integer number of cycles between the frequencies of microstructure maxima, consistent with a dependence of microstructure periodicity on SFOAE propagation delays. Additionally, microstructure depth was correlated with SFOAE magnitude in a manner resembling that predicted by the intracochlear reflection framework, after assuming reasonable values of parameters related to middle ear transmission. Further exploration of this framework may yield more precise estimates of such parameters and provide insight into their frequency dependence.


Coronary artery disease in patients with human immunodeficiency virus infection.
The life expectancy of people infected with human immunodeficiency virus (HIV) is rising due to better access to combination anti-retroviral therapy (ART). Although ART has reduced acquired immune deficiency syndrome (AIDS) related mortality and morbidity, there has been an increase in non-AIDS defining illnesses such as diabetes mellitus, hypercholesterolemia and coronary artery disease (CAD). HIV is a disease marked by inflammation which has been associated with specific biological vascular processes increasing the risk of premature atherosclerosis. The combination of pre-existing risk factors, atherosclerosis, ART, opportunistic infections and coagulopathy contributes to rising CAD incidence. The prevalence of CAD has emerged as a major contributor of morbidity in these patients due to longer life expectancy. However, ART has been associated with lipodystrophy, dyslipidemia, insulin resistance, diabetes mellitus and CAD. These adverse effects, along with drug-drug interactions when ART is combined with cardiovascular drugs, result in significant challenges in the care of this group of patients. Exercise tolerance testing, echocardiography, myocardial perfusion imaging, coronary computed tomography angiography and magnetic resonance imaging help in the diagnosis of CAD and heart failure and help predict cardiovascular outcomes in a manner similar to non-infected individuals. This review will highlight the pathogenesis and factors that link HIV to CAD, presentation and treatment of HIV-patients presenting with CAD and review briefly the cardiac imaging modalities used to identify this entity and help prognosticate future outcomes.


Drought sensitivity of an N2 -fixing tree may slow temperate deciduous forest recovery from disturbance.
Increased drought intensity and frequency due to climate change may reduce the abundance and activity of nitrogen (N2 )-fixing plants, which supply new N to terrestrial ecosystems. As a result, drought may indirectly reduce ecosystem productivity through its effect on the N cycle. Here, we manipulated growing season net rainfall across a series of plots in an early successional mesic deciduous forest to understand how drought affects the aboveground productivity of the N2 -fixing tree Robinia pseudoacacia and three co-occurring nonfixing tree species. We found that lower soil moisture was associated with reduced productivity of R. pseudoacacia but not of nonfixing trees. As a result, the relative biomass and density of R. pseudoacacia declined in drier soils over time. Greater aboveground biomass of R. pseudoacacia was also associated with greater total soil N, extractable inorganic N, N mineralization rates, and productivity of nonfixing trees. These soil N effects may reflect current N2 fixation by R. pseudoacacia saplings, or the legacy effect of former trees in the same location. Our results suggest that R. pseudoacacia promotes the growth of nonfixing trees in early succession through its effect on the N cycle. However, the sensitivity of R. pseudoacacia to dry soils may reduce N2 fixation under scenarios of increasing drought intensity and frequency, demonstrating a mechanism by which drought may indirectly diminish potential forest productivity and recovery rate from disturbance.


Contrasting strategies for anoxic brain survival--glycolysis up or down.
Anoxia-tolerant turtles and carp (Carassius) exhibit contrasting strategies for anoxic brain survival. In the turtle brain, the energy consumption is deeply depressed to the extent of producing a comatose-like state. Brain metabolic depression is brought about by activating channel arrest to reduce ion flux and through the release of inhibitory gamma-aminobutyric acid (GABA) and the upregulation of GABAA receptors. Key glycolytic enzymes are down-regulated during prolonged anoxia. The result is a suppression of neurotransmission and a substantial depression in brain electrical activity. By contrast, Carassius remain active during anoxia, though at a reduced level. As in the turtle, there is an adenosine-mediated increase in brain blood flow but, in contrast to the turtle, this increase is sustained throughout the anoxic period. Key glycolytic enzymes are up-regulated and anaerobic glycolysis is enhanced. There is no evidence of channel arrest in Carassius brain. The probable result is that electrical activity in the brain is not suppressed but instead maintained at a level sufficient to regulate and control the locomotory and sensory activities of the anoxic carp. The key adaptations permitting the continued high level of glycolysis in Carassius are the production and excretion of ethanol as the glycolytic end-product, which avoids self-pollution by lactate produced during glycolysis that occurs in other vertebrates.


Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.
Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).


Photonic crystal fibers with squeezed hexagonal lattice.
We study the birefringence and polarization coupling in the index-guiding photonic crystal fibers (PCFs) with squeezed hexagonal crystal lattice. The sign of form birefringence in such photonic crystal fibers can be changed as the wavelength changes, which is reported for the first time to our knowledge. A PCF-based polarization splitter with squeezed hexagonal lattice is proposed to achieve excellent extinction ratio and a simpler structure than those reported previously.


MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues, and it exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. Here, we demonstrate that MANF is abundantly expressed in normal corneal epithelial cells; however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in streptozotocin-induced type 1 diabetic C57BL/6 mice. Recombinant human MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycemia-induced endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific small interfering RNA (siRNA). Finally, we reveal that the subconjunctival injection of MANF-specific siRNA prevents corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK.


DNA sequence assembly and genetic algorithms new results and puzzling insights.
Applying genetic algorithms to DNA sequence assembly is not a straightforward process. Significantly improved results in terms of performance, quality of results, and the scaling of applicability have been realized through non-standard and even counter-intuitive parameter settings. Specifically, the solution time for a 10kb data set was reduced by an order of magnitude, and a 20kb data set that was previously unsolved by the genetic algorithm was solved in a time that represents only a linear increase from the 10kb data set. Additionally, significant progress has been made on a 35kb data set representing real biological data. A single contig solution was found for a 752 fragment subset of the data set, and a 15 contig solution was found for the full data set. This paper discusses the new results, the modifications to the previous genetic algorithm used in this study, the experimental design process by which the new results were obtained, the questions raised by these results, and some preliminary attempts to explain these results.


Strontium speciation during reaction of kaolinite with simulated tank-waste leachate: bulk and microfocused EXAFS analysis.
Radioactive strontium (90Sr) is an important constituent of the complex wastes from past nuclear weapons production and has been stored in underground tanks at U.S. DOE sites (e.g., Hanford, WA). Using bulk and microfocused EXAFS spectroscopy, we examined temporal changes in solid-phase Sr speciation in kaolinite samples reacted for 1-369 d with high-pH, high ionic strength synthetic tank-waste leachate containing Sr(2+) and Cs(+) at 10(-3) mol kg(-1). Analyses of bulk EXAFS spectra showed that Sr initially forms a precipitate by 7 d with a local structure similar to SrCO(3-) (s). At 33 d, microfocused EXAFS of individual particles in one sample revealed a mixture of hydrated and dehydrated Sr associated with neoformed sodalite-type phases. At aging times of 93 d and longer, bulk EXAFS spectra and supporting characterizations indicated nonexchangeable Sr with a local structure consistent with incorporation into increasingly crystalline aluminosilicate particles, particularly sodalite. These experimental studies suggest that irreversible trapping of radionuclides occurs if they are present during the formation and aging of feldspathoid alteration products of local Si-bearing sediment minerals. This may serve as an effective contaminant sequestration mechanism at sites such as Hanford.


Hydrothermal synthesis of nanostructured TiO2 particles and characterization of their photocatalytic antimicrobial activity.
Nanostructured titania particles were synthesized by using hydrothermal processing and the photocatalytic antimicrobial activities were characterized. Both sol-gel synthesized and commercial TiO2 (anatase) samples were processed with two step hydrothermal treatments, under alkaline and neutral conditions. Scanning Electron Microscope (SEM) images showed that alkaline treatment yields nanofibers and lamellar structured particles from the commercial anatase and sol-gel synthesized samples respectively. Further treatment of nanofibers and nanostructured lamellar particles with distilled water results with crystal growth and the formation of nano structured bipyramidal crystalline particles. The photocatalytic antimicrobial activities of the samples were determined against Escherichia coil under irradiation. It was observed that the samples treated under alkaline conditions have improved activity than the original anatase samples. Limited activity and resulting time lag in bacterial inactivation were observed for hydrothermally treated samples with distilled water. However, a post treatment comprising the UV irradiation in aqueous conditions enhanced the photocatalytic activity.


Phase locking of a 275 W high power all-fiber amplifier seeded by two categories of multi-tone lasers.
Multi-tone radiation is a promising technique to suppress stimulated Brillouin scattering (SBS) effects and improve the ultimate output power of the fiber laser/amplifier. Coherent beam combining of fiber lasers/ amplifiers is another feasible way to increase the output laser power from single gain medium while simultaneously maintaining good beam quality. In this paper, we combine the multi-tone driven all-fiber amplifiers and active phase compensation to demonstrate high power phase locking for coherent beam combining. First, we present the theory of coherent beam combining of multi-tone lasers. Second, we optimize the all-fiber power amplifier oscillator power-amplifier (MOPA) system with high scalability and flexibility based on compact, high efficiency Yb-doped fiber amplifier chains. Then, two categories of multi-tone master oscillators are used to driven the amplifier chains. The first category is two coupled single-frequency lasers and the second is a frequency modulated single-frequency laser. The output powers are all boosted to 275 W without any distinct SBS. Last, phase locking of the amplifier chains are implemented using stochastic parallel gradient descent (SPGD) algorithm. Scaling this configuration to a higher power involves increasing the power per chain and adding the number of amplifier channels.


catena-Poly[[[aqua-(1,10-phenanthroline-κN,N')cadmium(II)]-μ-pyridine-2,3-dicarboxyl-ato-κN,O:O,O] dihydrate].
The title complex, {[Cd(C(7)H(3)NO(4))(C(12)H(8)N(2))(H(2)O)]·2H(2)O}(n), is a one-dimensional coordination polymer, wherein the Cd atom is seven-coordinated by two 1,10-phenanthroline N atoms, one N and three O atoms from two different pyridine-2,3-dicarboxyl-ate ligands, and one water mol-ecule. It is further extended to a two-dimensional layer structure by hydrogen bonds and π-π stacking inter-actions [centroid-centroid distances of 3.560 (2) and 3.666 (2) Å]. There is a C4 water chain in the structure whose repeat unit contains four water mol-ecules with O⋯O distances in the range 2.748 (3)-2.795 (4) Å. One of the two H atoms of each water of hydration is statistically distributed over two positions with equal occupancy.


Human papilloma virus E1-specific T cell immune response is associated with the prognosis of cervical cancer patients with squamous cell carcinoma.
Cervical cancer is attributable to human papilloma virus (HPV) infection in the majority cases. E1, an HPV derived-protein, plays an important role in the initiation and development of cervical cancer. Our study aims to investigate the HPV E1-specific T cell response in patients with cervical squamous cell carcinoma (CSCC). A total of 66 CSCC patients with FIGO stage IIB-IIIB and 60 healthy controls were enrolled. Enzyme-Linked ImmunoSpot (ELISPOT) assays was used to measure the HPV E1-specific T cell response in the peripheral blood of these patients before treatment. The patients were treated with chemotherapy and/or radiotherapy and followed up clinically for three years. The relationship between the T cell response, various clinical characteristics and the prognosis were studied with univariate analysis, multivariate analysis and survival curve analysis. The frequency of HPV E1-specific T cell response in peripheral blood of cervical cancer patients was 59.09%, with mean response intensity 24.56 SFC/106 PBMCs. The frequency and intensity of HPV E1-specific T cell response in patients were higher than healthy controls(p < 0.001; p = 0.009). The intensity of HPV E1-specific T cell responses were higher in the stage IIB patients and patients with no pelvic lymph node metastasis (p = 0.038; p = 0.044). Univariate analysis showed that HPV E1 specific T cell response was associated with progression-free survival (PFS) and overall survival (OS) (PFS: p = 0.021; OS: p = 0.004). Multivariate analysis showed that HPV E1-specific T cell response was an independent prognostic factor influencing PFS and OS among all the factors included in our study (PFS: HR = 7.252, 95%CI = 1.690-31.126, p = 0.008; OS: HR = 7.499, 95%CI = 1.661-33.856, p = 0.009). The survival curves showed that the rate of PFS and OS in patients with HPV E1 specific T cell response was significantly higher than those who did not response. Our study demonstrated that the level of HPV E1-specific T cell response was correlated with the survival of advanced patients with CSCC. Patients who displayed no HPV E1-specific T cell response were more likely to be those with poor prognosis.


Sex estimation in a contemporary Spanish population: cranial and dental anthropometry.
Sex estimation of skeletal remains is an essential step in the reconstruction of the biological profile of unknown individuals in medico-legal death investigations and archaeological contexts. However, the skeletons are often incomplete. When the pelvis is absent, the skull is widely considered to be the second-best indicator of sex. However, debate persists, and there is evidence that postcranial bones have more discriminatory power than the cranium. The present study was undertaken to determine the accuracy and reliability of a combination of skull and dental measurements for sex estimation in comparison with the cranial and dental methods separately, and to provide evidence as to whether the combination of these cranial measurements is more effective than postcranial bones alone for estimating sex when the pelvis is not available. The study sample comprised 70 individuals from the San José cemetery in Granada (Spain). Thirty cranial measurements and 44 dental measurements were examined using logistic regression analyses. These data showed that the combination of neurocranial and maxillary canine measurements provide the key dimensions as significant predictors of sex in this sample. For the pooled sexes, the overall correct sex allocation accuracies ranged from 76.0% to 92.3%. The present study shows that when using metric data, there is no evidence that the skull measures are better than those of the postcranial bones to estimate the sex. Only the combination of skull and maxillary canine measures provide similar sex discriminatory power to those of the postcranial skeleton.


Toxicity of fullerene (C60) to sediment-dwelling invertebrate Chironomus riparius larvae.
An environmentally realistic method to test fullerene (C(60) ) toxicity to the benthic organism Chironomus riparius was created by allowing suspended fullerenes to settle down, making a layer on top of the sediment. To test the hypothesis that higher food concentrations will reduce toxic responses, two food concentrations were tested (0.5 and 0.8% Urtica sp.) in sediment containing fullerene masses of 0.36 to 0.55 mg/cm(2) using a 10-d chronic test. In the 0.5% food level treatments, there were significant differences in all growth-related endpoints compared with controls. Fewer effects were observed for the higher food treatment. Fullerene agglomerates were observed by electron microscopy in the gut, but no absorption into the gut epithelial cells was detected. In the organisms exposed to fullerenes, microvilli were damaged and were significantly shorter. The potential toxicity of fullerene to C. riparius appears to be caused by morphological changes, inhibiting larval growth.


Omega-3 polyunsaturated fatty acid regulation of gene expression.
This review describes the mechanisms by which polyunsaturated fatty acids regulate the activity of the nuclear transcription factors, peroxisome proliferator-activated receptor and sterol regulatory element binding protein-1, and it describes the role that the peroxisome proliferator-activated receptor and sterol regulatory element binding protein-1 play in coordinating the regulation of lipid synthesis, lipid oxidation, and thermogenesis. Finally, the requirement for dietary polyunsaturated fatty acids, particularly n-3 fatty acids, is defined in terms of the effects polyunsaturated fatty acids exert on gene expression and the role that these effects play in overall energy balance.


Geometrical recombination operators for real-coded evolutionary MCMCs.
Markov chain Monte Carlo (MCMC) algorithms are sampling methods for intractable distributions. In this paper, we propose and investigate algorithms that improve the sampling process from multi-dimensional real-coded spaces. We present MCMC algorithms that run a population of samples and apply recombination operators in order to exchange useful information and preserve commonalities in highly probable individual states. We call this class of algorithms Evolutionary MCMCs (EMCMCs). We introduce and analyze various recombination operators which generate new samples by use of linear transformations, for instance, by translation or rotation. These recombination methods discover specific structures in the search space and adapt the population samples to the proposal distribution. We investigate how to integrate recombination in the MCMC framework to sample from a desired distribution. The recombination operators generate individuals with a computational effort that scales linearly in the number of dimensions and the number of parents. We present results from experiments conducted on a mixture of multivariate normal distributions. These results show that the recombinative EMCMCs outperform the standard MCMCs for target distributions that have a nontrivial structural relationship between the dimensions.


Large-Scale Brain Simulation and Disorders of Consciousness. Mapping Technical and Conceptual Issues.
Modeling and simulations have gained a leading position in contemporary attempts to describe, explain, and quantitatively predict the human brain's operations. Computer models are highly sophisticated tools developed to achieve an integrated knowledge of the brain with the aim of overcoming the actual fragmentation resulting from different neuroscientific approaches. In this paper we investigate the plausibility of simulation technologies for emulation of consciousness and the potential clinical impact of large-scale brain simulation on the assessment and care of disorders of consciousness (DOCs), e.g., Coma, Vegetative State/Unresponsive Wakefulness Syndrome, Minimally Conscious State. Notwithstanding their technical limitations, we suggest that simulation technologies may offer new solutions to old practical problems, particularly in clinical contexts. We take DOCs as an illustrative case, arguing that the simulation of neural correlates of consciousness is potentially useful for improving treatments of patients with DOCs.


Analysis of phase sensitivity for binary computer-generated holograms.
A binary diffraction model is introduced to study the sensitivity of the wavefront phase of binary computer-generated holograms on groove depth and duty-cycle variations. Analytical solutions to diffraction efficiency, diffracted wavefront phase functions, and wavefront sensitivity functions are derived. The derivation of these relationships is obtained by using the Fourier method. Results from experimental data confirm the analysis. Several phase anomalies were discovered, and a simple graphical model of the complex fields is applied to explain these phenomena.


Respective Roles of Hematopoietic and Nonhematopoietic Nod2 on the Gut Microbiota and Mucosal Homeostasis.
NOD2 mutations are associated with Crohn's disease (CD). Both CD (in human) and Nod2 deficiency (in mice) are characterized by increased mucosal CD4 T-cells, an altered permeability and a microbial dysbiosis. However, the respective roles of the gut epithelial and immune compartments on the phenotype are not known. Microbial composition, epithelial peptide secretion, intestinal permeability, and immune cell composition of Peyer patches were studied in Nod2 knock-out mice transplanted with wild-type bone marrow cells and vice versa. The nonhematopoietic cells control the microbiota composition and epithelial secretion of mucins and antimicrobial peptides. These parameters are correlated with recurrent associations between bacterial species and luminal products. In contrast, Nod2 in the hematopoietic compartment regulates the epithelial permeability and the gut-associated lymphoid tissue independently of the bacterial composition. The immune system and the gut permeability in one hand and the microbial and epithelial peptide compositions in the other hand are separate couples of interdependent parameters, both controlled by Nod2 in either the hematopoietic or nonhematopoietic lineages.


Impact of genetic and environmental factors on hsCRP concentrations and response to therapeutic agents.
Inflammation plays an instrumental role in all stages of atherosclerosis. High-sensitivity C-reactive protein (hsCRP), a systemic inflammatory marker, has been gaining recognition as an independent risk factor for cardiovascular disease (CVD). Both baseline hsCRP concentrations and drug-induced hsCRP changes are highly variable and potentially subject to genetic regulation. This review summarizes the current studies examining the effect of genetic and environmental factors on baseline plasma hsCRP concentrations, with a main focus on C-reactive protein, pentraxin-related (CRP) genetic polymorphisms and various dietary components that affect hsCRP concentrations. We also address the association of CRP genetic variations with CVD risk, a relationship that may support or refute the causality of CRP in the atherosclerotic process. Moreover, we discuss the impact of CRP genetic polymorphisms on hsCRP changes in response to 3-week fenofibrate treatment in the genetic intervention of the Genetics of Lipid Lowering Drugs and Diet Network study. Genetic variants on the CRP locus and other loci and dietary and lifestyle factors are responsible for the interindividual variability of plasma hsCRP concentrations. CRP genetic variants further influence differing plasma hsCRP response after 3-week fenofibrate treatment in patients with metabolic syndrome. Future studies focusing on the influence and interaction of genetic variation on the hsCRP response to dietary and other behavior modification as well as drug treatment could have important implications for the development of more personalized preventive and therapeutic approaches to reduce CVD.


Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: A prospective cohort study.
Almost all studies that have investigated the immune response to trauma have analysed blood samples acquired post-hospital admission. Thus, we know little of the immune status of patients in the immediate postinjury phase and how this might influence patient outcomes. The objective of this study was therefore to comprehensively assess the ultra-early, within 1-hour, immune response to trauma and perform an exploratory analysis of its relationship with the development of multiple organ dysfunction syndrome (MODS). The immune and inflammatory response to trauma was analysed in 89 adult trauma patients (mean age 41 years, range 18-90 years, 75 males) with a mean injury severity score (ISS) of 24 (range 9-66), from whom blood samples were acquired within 1 hour of injury (mean time to sample 42 minutes, range 17-60 minutes). Within minutes of trauma, a comprehensive leukocytosis, elevated serum pro- and anti-inflammatory cytokines, and evidence of innate cell activation that included neutrophil extracellular trap generation and elevated surface expression of toll-like receptor 2 and CD11b on monocytes and neutrophils, respectively, were observed. Features consistent with immune compromise were also detected, notably elevated numbers of immune suppressive CD16BRIGHT CD62LDIM neutrophils (82.07 x 106/l ± 18.94 control versus 1,092 x 106/l ± 165 trauma, p < 0.0005) and CD14+HLA-DRlow/- monocytes (34.96 x 106/l ± 4.48 control versus 95.72 x 106/l ± 8.0 trauma, p < 0.05) and reduced leukocyte cytokine secretion in response to lipopolysaccharide stimulation. Exploratory analysis via binary logistic regression found a potential association between absolute natural killer T (NKT) cell numbers and the subsequent development of MODS. Study limitations include the relatively small sample size and the absence of data relating to adaptive immune cell function. Our study highlighted the dynamic and complex nature of the immune response to trauma, with immune alterations consistent with both activation and suppression evident within 1 hour of injury. The relationship of these changes, especially in NKT cell numbers, to patient outcomes such as MODS warrants further investigation.


Surface waves in defocusing thermal media.
We predict that the interface of materials with defocusing thermal nonlinearities supports stable fundamental and higher-order surface waves when the opposite edges of the medium are maintained at different temperatures. Such surface waves exist due to the interplay between repulsion from the interface and the defocusing thermal nonlinearity that deflects light beams from the bulk of the medium toward its edges.


A neglected case of giant synovial chondromatosis in knee joint.
Synovial chondromatosis is a rare benign condition arising from the synovial membrane of the joints, synovial sheaths or bursae around the joints. Primary synovial chondromatosis typically affects the large joints in the third to fifth decade of life. The purpose of this case report is to document this rare synovial pathology, which required open synovectomy and debridement to eradicate it. In our case, the biggest sized SOC was 20x19x6 cm, although there were many joint mice. Our case had the biggest SOC ever extracted, which to the best of my knowledge has not been reported earlier.


PRKDC mutations in a SCID patient with profound neurological abnormalities.
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs; encoded by PRKDC) functions in DNA non-homologous end-joining (NHEJ), the major DNA double strand break (DSB) rejoining pathway. NHEJ also functions during lymphocyte development, joining V(D)J recombination intermediates during antigen receptor gene assembly. Here, we describe a patient with compound heterozygous mutations in PRKDC, low DNA-PKcs expression, barely detectable DNA-PK kinase activity, and impaired DSB repair. In a heterologous expression system, we found that one of the PRKDC mutations inactivated DNA-PKcs, while the other resulted in dramatically diminished but detectable residual function. The patient suffered SCID with reduced or absent T and B cells, as predicted from PRKDC-deficient animal models. Unexpectedly, the patient was also dysmorphic; showed severe growth failure, microcephaly, and seizures; and had profound, globally impaired neurological function. MRI scans revealed microcephaly-associated cortical and hippocampal dysplasia and progressive atrophy over 2 years of life. These neurological features were markedly more severe than those observed in patients with deficiencies in other NHEJ proteins. Although loss of DNA-PKcs in mice, dogs, and horses was previously shown not to impair neuronal development, our findings demonstrate a stringent requirement for DNA-PKcs during human neuronal development and suggest that high DNA-PK protein expression is required to sustain efficient pre- and postnatal neurogenesis.


Insight into the redox regulation of the phosphoglucan phosphatase SEX4 involved in starch degradation.
Starch is the major carbohydrate reserve in plants, and is degraded for growth at night. Starch breakdown requires reversible glucan phosphorylation at the granule surface by novel dikinases and phosphatases. The dual-specificity phosphatase starch excess 4 (SEX4) is required for glucan desphosphorylation; however, regulation of the enzymatic activity of SEX4 is not well understood. We show that SEX4 switches between reduced (active) and oxidized (inactive) states, suggesting that SEX4 is redox-regulated. Although only partial reactivation of SEX4 was achieved using artificial reductants (e.g. dithiothreitol), use of numerous chloroplastic thioredoxins recovered activity completely, suggesting that thioredoxins could reduce SEX4 in vivo. Analysis of peptides from oxidized and reduced SEX4 identified a disulfide linkage between the catalytic cysteine at position 198 (Cys198) and the cysteine at position 130 (Cys130) within the phosphatase domain. The position of these cysteines was structurally analogous to that for known redox-regulated dual-specificity phosphatases, suggesting a common mechanism of reversible oxidation amongst these phosphatases. Mutation of Cys130 renders SEX4 more sensitive to oxidative inactivation and less responsive to reductive reactivation. Together, these results provide the first biochemical evidence for a redox-dependent structural switch that regulates SEX4 activity, which represents the first plant phosphatase known to undergo reversible oxidation via disulfide bond formation like its mammalian counterparts.