Extreme endemic radiation of the Malagasy vangas (Aves: Passeriformes).
Phylogenetic relationships of the family Vangidae and representatives of several other passeriform families were inferred from 882 base positions of mitochondrial DNA sequences of 12S and 16S rRNA genes. Results indicated the monophyly of the Vangidae, which includes the genus Tylas, hitherto often placed in the family Pycnonotidae. Our results also revealed the Malagasy endemic Newtonia, a genus never previously assigned to the Vangidae, to be a member of this family. These results suggest the occurrence of an extensive in situ radiation of this family within Madagascar, and that the extant high diversity of this family is not the result of multiple colonizations from outside. The extremely high morphological and ecological diversification of the family seems to have been enhanced through the use and ultimate occupancy of vacant niches in this island.


Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia.
Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x(L) and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x(L), Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.


Mechanisms of optical losses in Bi:SiO2 glass fibers.
The mechanisms of optical losses in bismuth-doped silica glass (Bi:SiO(2)) and fibers were studied. It was found that in the fibers of this composition the up-conversion processes occur even at bismuth concentrations lower than 0.02 at.%. Bi:SiO(2) core holey fiber drawn under oxidizing conditions was investigated. The absorption spectrum of this fiber has no bands of the bismuth infrared active center. Annealing of this fiber under reducing conditions leads to the formation of the IR absorption bands of the bismuth active center (BAC) and to the simultaneous growth of background losses. Under the realized annealing conditions (argon atmosphere, T(max) = 1100°C, duration 30 min) the BAC concentration reaches its maximum and begins to decrease in the process of excessive Bi reduction, while the background losses only increase. It was shown that the cause of these background losses is the absorption of light by nanoparticles of metallic bismuth formed in bismuth-doped glasses as a result of reduction of a part of the bismuth ions to Bi(0) and their following aggregation. The growth of background losses occurs owing to the increase of the concentration and the size of the metallic bismuth nanoparticles.


Generalized Halanay inequalities and their applications to neural networks with unbounded time-varying delays.
In this brief, we discuss some variants of generalized Halanay inequalities that are useful in the discussion of dissipativity and stability of delayed neural networks, integro-differential systems, and Volterra functional differential equations. We provide some generalizations of the Halanay inequality, which is more accurate than the existing results. As applications, we discuss invariant set, dissipative synchronization, and global asymptotic stability for the Hopfield neural networks with infinite delays. We also prove that the dynamical systems with unbounded time-varying delays are globally asymptotically stable.


Rhythmic Aortic Contractions Induced by Electrical Stimulation In Vivo in the Rat.
For over a century, the behavior of the aorta and other large arteries has been described as passive elastic tubes in which no active contraction occurs in the smooth muscle wall. In response to pulsatile pressure changes, the vessels undergo a 'passive' elastic dilatation-contraction cycle, described as a "Windkessel" effect. However, Mangel and colleagues have presented evidence that is contrary to this view. They reported that in the rabbit, the aorta undergoes rhythmic 'active' (contraction) during the cardiac cycle; but these findings have been largely ignored. In the present study, we observed spontaneous contractions in synchrony with the heartbeat in another species (rat). In addition we demonstrate that aorta contractions are of neurogenic origin. Electrical stimulation of the aorta evoked contractions that occur at a rate that is in the range of the animal's heartbeat and are suppressed by tetrodotoxin and the alpha-adrenergic receptor blocker, phentolamine. Altogether, these findings indicate that aortic contractions are under neural control from the heart.


Elucidation of the Fe(IV)=O intermediate in the catalytic cycle of the halogenase SyrB2.
Mononuclear non-haem iron (NHFe) enzymes catalyse a broad range of oxidative reactions, including halogenation, hydroxylation, ring closure, desaturation and aromatic ring cleavage reactions. They are involved in a number of biological processes, including phenylalanine metabolism, the production of neurotransmitters, the hypoxic response and the biosynthesis of secondary metabolites. The reactive intermediate in the catalytic cycles of these enzymes is a high-spin S = 2 Fe(IV)=O species, which has been trapped for a number of NHFe enzymes, including the halogenase SyrB2 (syringomycin biosynthesis enzyme 2). Computational studies aimed at understanding the reactivity of this Fe(IV)=O intermediate are limited in applicability owing to the paucity of experimental knowledge about its geometric and electronic structure. Synchrotron-based nuclear resonance vibrational spectroscopy (NRVS) is a sensitive and effective method that defines the dependence of the vibrational modes involving Fe on the nature of the Fe(IV)=O active site. Here we present NRVS structural characterization of the reactive Fe(IV)=O intermediate of a NHFe enzyme, namely the halogenase SyrB2 from the bacterium Pseudomonas syringae pv. syringae. This intermediate reacts via an initial hydrogen-atom abstraction step, performing subsequent halogenation of the native substrate or hydroxylation of non-native substrates. A correlation of the experimental NRVS data to electronic structure calculations indicates that the substrate directs the orientation of the Fe(IV)=O intermediate, presenting specific frontier molecular orbitals that can activate either selective halogenation or hydroxylation.


CoDysAn: A Telemedicine Tool to Improve Awareness and Diagnosis for Patients With Congenital Dyserythropoietic Anemia.
Congenital Dyserythropoietic Anemia (CDA) is a heterogeneous group of hematological disorders characterized by chronic hyporegenerative anemia and distinct morphological abnormalities of erythroid precursors in the bone marrow. In many cases, a final diagnosis is not achieved due to different levels of awareness for the diagnosis of CDAs and lack of use of advanced diagnostic procedures. Researchers have identified five major types of CDA: types I, II, III, IV, and X-linked dyserythropoietic anemia and thrombocytopenia (XLDAT). Proper management in CDA is still unsatisfactory, as the different subtypes of CDA have different genetic causes and different but overlapping patterns of signs and symptoms. For this reason, we developed a new telemedicine tool that will help doctors to achieve a faster diagnostic for this disease. Using open access code, we have created a responsive webpage named CoDysAn (Congenital Dyserythropoietic Anemia) that includes practical information for CDA awareness and a step-by-step diagnostic tool based on a CDA algorithm. The site is currently available in four languages (Catalan, Spanish, Italian, and English). This telemedicine webpage is available at http://www.codysan.eu.


Hearing one's own voice during phoneme vocalization--transmission by air and bone conduction.
The relationship between the bone conduction (BC) part and the air conduction (AC) part of one's own voice has previously not been well determined. This relation is important for hearing impaired subjects as a hearing aid affects these two parts differently and thereby changes the perception of one's own voice. A large ear-muff that minimized the occlusion effect while still attenuating AC sound was designed. During vocalization and wearing the ear muff the ear-canal sound pressure could be related to the BC component of a person's own voice while the AC component was derived from the sound pressure at the entrance of an open ear-canal. The BC relative to AC sensitivity of one's own voice was defined as the ratio between these two components related to the ear-canal sound pressure at hearing thresholds for BC and AC stimulation. The results of ten phonemes showed that the BC part of one's own voice dominated at frequencies between 1 and 2 kHz for most of the phonemes. The different phonemes gave slightly different results caused by differences during vocalization. However, similarities were seen for phonemes with comparable vocalization.


Effectiveness of a nasal saline gel in the treatment of recurrent anterior epistaxis in anticoagulated patients.
We believe that the use of cauterization in patients with anterior epistaxis in the absence of acute bleeding should be discouraged because it does not address the underlying cause and because it may even worsen the condition by extending the degree of mucosal disruption. This is especially true in patients who are receiving anticoagulation therapy. Therefore, we conducted a study to determine if the use of a nasal saline gel as monotherapy would be an effective alternative to invasive measures in treating recurrent epistaxis in anticoagulated patients. Our study group consisted of 74 patients-43 men and 31 women (mean age: 64.4 yr)-who had been seen in our department over an 18-month period and whose bleeding had originated in the anterior portion of the nasal vault. Most patients had been experiencing epistaxis for at least 6 months. Patients were given the saline nasal gel and taught to gently apply it to the mucosa of the anterior nasal vault with a cotton-tipped applicator at the first sign of recurrent bleeding. Patients were then followed up periodically over the next 3 months. Among the 74 patients, 69 (93.2%) had experienced a cessation of their epistaxis at 3 months. The results of our study suggest that this simple, painless technique has considerable value as a treatment option in this cohort of patients.


Effectiveness of early detection on breast cancer mortality reduction in Catalonia (Spain).
At present, it is complicated to use screening trials to determine the optimal age intervals and periodicities of breast cancer early detection. Mathematical models are an alternative that has been widely used. The aim of this study was to estimate the effect of different breast cancer early detection strategies in Catalonia (Spain), in terms of breast cancer mortality reduction (MR) and years of life gained (YLG), using the stochastic models developed by Lee and Zelen (LZ). We used the LZ model to estimate the cumulative probability of death for a cohort exposed to different screening strategies after T years of follow-up. We also obtained the cumulative probability of death for a cohort with no screening. These probabilities were used to estimate the possible breast cancer MR and YLG by age, period and cohort of birth. The inputs of the model were: incidence of, mortality from and survival after breast cancer, mortality from other causes, distribution of breast cancer stages at diagnosis and sensitivity of mammography. The outputs were relative breast cancer MR and YLG. Relative breast cancer MR varied from 20% for biennial exams in the 50 to 69 age interval to 30% for annual exams in the 40 to 74 age interval. When strategies differ in periodicity but not in the age interval of exams, biennial screening achieved almost 80% of the annual screening MR. In contrast to MR, the effect on YLG of extending screening from 69 to 74 years of age was smaller than the effect of extending the screening from 50 to 45 or 40 years. In this study we have obtained a measure of the effect of breast cancer screening in terms of mortality and years of life gained. The Lee and Zelen mathematical models have been very useful for assessing the impact of different modalities of early detection on MR and YLG in Catalonia (Spain).


Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures.
The treelike structures of many organs, including the mammary gland, are generated by branching morphogenesis, a reiterative process of branch initiation and invasion from a preexisting epithelium. Using a micropatterning approach to control the initial three-dimensional structure of mouse mammary epithelial tubules in culture, combined with an algorithm to quantify the extent of branching, we found that the geometry of tubules dictates the position of branches. We predicted numerically and confirm experimentally that branches initiate at sites with a local minimum in the concentration of autocrine inhibitory morphogens, such as transforming growth factor-beta. These results reveal that tissue geometry can control organ morphogenesis by defining the local cellular microenvironment, a finding that has relevance to control of invasion and metastasis.


The impact of natural selection on health and disease: uses of the population genetics approach in humans.
Investigations of the legacy of natural selection in the human genome have proved particularly informative, pinpointing functionally important regions that have participated in our genetic adaptation to the environment. Furthermore, genetic dissection of the intensity and type of selection acting on human genes can be used to predict involvement in different forms and severities of human diseases. We review here the progress made in population genetics studies toward understanding the effects of selection, in its different forms and intensities, on human genome diversity. We discuss some outstanding, robust examples of genes and biological functions subject to strong dietary, climatic and pathogen selection pressures. We also explore the possible relationship between cancer and natural selection, a topic that has been largely neglected because cancer is generally seen as a late-onset disease. Finally, we discuss how the present-day incidence of some diseases of modern societies may represent a by-product of past adaptation to other selective forces and changes in lifestyle. This perspective thus illustrates the value of adopting a population genetics approach in delineating the biological mechanisms that have played a major evolutionary role in the way humans have genetically adapted to different environments and lifestyles over time.


Associations of phthalates, phthalate replacements, and their mixtures with eicosanoid biomarkers during pregnancy.
Humans are exposed to complex mixtures of phthalates. Gestational exposure to phthalates has been linked to preeclampsia and preterm birth through potential pathways such as endocrine disruption, oxidative stress, and inflammation. Eicosanoids are bioactive signaling lipids that are related to a variety of homeostatic and inflammatory processes. We investigated associations between urinary phthalates and their mixtures with plasma eicosanoid levels during pregnancy using the PROTECT cohort in Puerto Rico (N = 655). After adjusting for covariates, we estimated pair-wise associations between the geometric mean of individual phthalate metabolite concentrations across pregnancy and eicosanoid biomarkers using multivariable linear regression. We used bootstrapping of adaptive elastic net regression (adENET) to evaluate phthalate mixtures associated with eicosanoids and subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual. After adjusting for false-discovery, in single-pollutant analysis, 14 of 20 phthalate metabolites or parent compound indices showed significant and primarily negative associations with multiple eicosanoids. In our mixture analysis, associations with several metabolites of low molecular weight phthalates - DEP, DBP, and DIBP - became prominent. Additionally, MEHHTP and MECPTP, metabolites of a new phthalate replacement, DEHTP, were selected as important predictors for determining the concentrations of multiple eicosanoids from different pathway groups. A unit increase in phthalate ERS derived from bootstrapping of adENET was positively associated with several eicosanoids mainly from Cytochrome P450 pathway. For example, an increase in ERS was associated with 11(S)-HETE (β = 1.6, 95% CI: 0.020, 3.180), (±)11,12-DHET (β = 2.045, 95% CI: 0.250, 3.840), 20(S)-HETE (β = 0.813, 95% CI: 0.147, 1.479), and 9 s-HODE (β = 2.381, 95% CI: 0.657, 4.104). Gestational exposure to phthalates and phthalate mixtures were associated with eicosanoid levels during pregnancy. Results from the mixture analyses underscore the complexity of physiological impacts of phthalate exposure and call for further in-depth studies to examine these relationships.


Using a web-based application to define the accuracy of diagnostic tests when the gold standard is imperfect.
Estimates of the sensitivity and specificity for new diagnostic tests based on evaluation against a known gold standard are imprecise when the accuracy of the gold standard is imperfect. Bayesian latent class models (LCMs) can be helpful under these circumstances, but the necessary analysis requires expertise in computational programming. Here, we describe open-access web-based applications that allow non-experts to apply Bayesian LCMs to their own data sets via a user-friendly interface. Applications for Bayesian LCMs were constructed on a web server using R and WinBUGS programs. The models provided (http://mice.tropmedres.ac) include two Bayesian LCMs: the two-tests in two-population model (Hui and Walter model) and the three-tests in one-population model (Walter and Irwig model). Both models are available with simplified and advanced interfaces. In the former, all settings for Bayesian statistics are fixed as defaults. Users input their data set into a table provided on the webpage. Disease prevalence and accuracy of diagnostic tests are then estimated using the Bayesian LCM, and provided on the web page within a few minutes. With the advanced interfaces, experienced researchers can modify all settings in the models as needed. These settings include correlation among diagnostic test results and prior distributions for all unknown parameters. The web pages provide worked examples with both models using the original data sets presented by Hui and Walter in 1980, and by Walter and Irwig in 1988. We also illustrate the utility of the advanced interface using the Walter and Irwig model on a data set from a recent melioidosis study. The results obtained from the web-based applications were comparable to those published previously. The newly developed web-based applications are open-access and provide an important new resource for researchers worldwide to evaluate new diagnostic tests.


Transcriptional and epigenetic signatures of zygotic genome activation during early Drosophila embryogenesis.
In all Metazoa, transcription is inactive during the first mitotic cycles after fertilisation. In Drosophila melanogaster, Zygotic Genome Activation (ZGA) occurs in two waves, starting respectively at mitotic cycles 8 (approximately 60 genes) and 14 (over a thousand genes). The regulatory mechanisms underlying these drastic transcriptional changes remain largely unknown. We developed an original gene clustering method based on discretized transition profiles, and applied it to datasets from three landmark early embryonic transcriptome studies. We identified 417 genes significantly up-regulated during ZGA. De novo motif discovery returned nine motifs over-represented in their non-coding sequences (upstream, introns, UTR), three of which correspond to previously known transcription factors: Zelda, Tramtrack and Trithorax-like (Trl). The nine discovered motifs were combined to scan ZGA-associated regions and predict about 1300 putative cis-regulatory modules. The fact that Trl is known to act as chromatin remodelling factor suggests that epigenetic regulation might play an important role in zygotic genome activation. We thus systematically compared the locations of predicted CRMs with ChIP-seq profiles for various transcription factors, 38 epigenetic marks from ModENCODE, and DNAse1 accessibility profiles. This analysis highlighted a strong and specific enrichment of predicted ZGA-associated CRMs for Zelda, CBP, Trl binding sites, as well as for histone marks associated with active enhancers (H3K4me1) and for open chromatin regions. Based on the results of our computational analyses, we suggest a temporal model explaining the onset of zygotic genome activation by the combined action of transcription factors and epigenetic signals. Although this study is mainly based on the analysis of publicly available transcriptome and ChiP-seq datasets, the resulting model suggests novel mechanisms that underly the coordinated activation of several hundreds genes at a precise time point during embryonic development.


Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes.
Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcγ receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P=0.002, OR=1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P=0.023, OR=1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.


Portage and Path Dependence.
We examine portage sites in the U.S. South, Mid-Atlantic, and Midwest, including those on the fall line, a geomorphological feature in the southeastern U.S. marking the final rapids on rivers before the ocean. Historically, waterborne transport of goods required portage around the falls at these points, while some falls provided water power during early industrialization. These factors attracted commerce and manufacturing. Although these original advantages have long since been made obsolete, we document the continuing importance of these portage sites over time. We interpret these results as path dependence and contrast explanations based on sunk costs interacting with decreasing versus increasing returns to scale.


Government funded breastfeeding peer support projects: implications for practice.
In 1999, the Government, Department of Health in England, UK established the Infant Feeding Initiative. As part of this initiative, 79 1-year infant feeding projects were selected for funding. The funded projects specifically centred upon practice innovation and evaluation in relation to promoting breastfeeding and supporting breastfeeding women in socially excluded communities. The DH recently commissioned a comprehensive evaluation of the 79 projects (DH 2003). This paper focuses upon the evaluation of the 26 DH funded projects that specifically focused upon breastfeeding peer support schemes. The evaluation illuminated many of the challenges involved in implementing community based breastfeeding peer support schemes. Lessons learnt from the most effective projects in terms of: potential to increase breastfeeding initiation and continuation rates; uptake of the service; comprehensive evaluation; and sustainability are presented here, as a series of steps required for successful operationalization of breastfeeding peer support schemes. When these steps are followed, peer support schemes offer exciting prospects for supporting breastfeeding women and increasing breastfeeding initiation and continuation rates, while respecting diversity, ensuring inclusivity and stimulating community empowerment.


Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development.
Brain-derived neurotrophic factor (BDNF), a neurotrophin, enhances the survival and differentiation of several classes of neurons in vitro. To determine its essential functions, we have mutated the BDNF gene. Most homozygote mutants die within 2 days after birth, but a fraction live for 2-4 weeks. These develop symptoms of nervous system dysfunction, including ataxia. The BDNF mutant homozygotes have substantially reduced numbers of cranial and spinal sensory neurons. Although their central nervous systems show no gross structural abnormalities, expression of neuropeptide Y and calcium-binding proteins is altered in many neurons, suggesting they do not function normally. In contrast with mice lacking the BDNF receptor TrkB, motor neurons appear normal in the BDNF mutant.


Large scale cardiac modeling on the Blue Gene supercomputer.
Multi-scale, multi-physical heart models have not yet been able to include a high degree of accuracy and resolution with respect to model detail and spatial resolution due to computational limitations of current systems. We propose a framework to compute large scale cardiac models. Decomposition of anatomical data in segments to be distributed on a parallel computer is carried out by optimal recursive bisection (ORB). The algorithm takes into account a computational load parameter which has to be adjusted according to the cell models used. The diffusion term is realized by the monodomain equations. The anatomical data-set was given by both ventricles of the Visible Female data-set in a 0.2 mm resolution. Heterogeneous anisotropy was included in the computation. Model weights as input for the decomposition and load balancing were set to (a) 1 for tissue and 0 for non-tissue elements; (b) 10 for tissue and 1 for non-tissue elements. Scaling results for 512, 1024, 2048, 4096 and 8192 computational nodes were obtained for 10 ms simulation time. The simulations were carried out on an IBM Blue Gene/L parallel computer. A 1 s simulation was then carried out on 2048 nodes for the optimal model load. Load balances did not differ significantly across computational nodes even if the number of data elements distributed to each node differed greatly. Since the ORB algorithm did not take into account computational load due to communication cycles, the speedup is close to optimal for the computation time but not optimal overall due to the communication overhead. However, the simulation times were reduced form 87 minutes on 512 to 11 minutes on 8192 nodes. This work demonstrates that it is possible to run simulations of the presented detailed cardiac model within hours for the simulation of a heart beat.


Differentiation between focal malignant marrow-replacing lesions and benign red marrow deposition of the spine with T2*-corrected fat-signal fraction map using a three-echo volume interpolated breath-hold gradient echo Dixon sequence.
To assess the feasibility of T2*-corrected fat-signal fraction (FF) map by using the three-echo volume interpolated breath-hold gradient echo (VIBE) Dixon sequence to differentiate between malignant marrow-replacing lesions and benign red marrow deposition of vertebrae. We assessed 32 lesions from 32 patients who underwent magnetic resonance imaging after being referred for assessment of a known or possible vertebral marrow abnormality. The lesions were divided into 21 malignant marrow-replacing lesions and 11 benign red marrow depositions. Three sequences for the parameter measurements were obtained by using a 1.5-T MR imaging scanner as follows: three-echo VIBE Dixon sequence for FF; conventional T1-weighted imaging for the lesion-disc ratio (LDR); pre- and post-gadolinium enhanced fat-suppressed T1-weighted images for the contrast-enhancement ratio (CER). A region of interest was drawn for each lesion for parameter measurements. The areas under the curve (AUC) of the parameters and their sensitivities and specificities at the most ideal cutoff values from receiver operating characteristic curve analysis were obtained. AUC, sensitivity, and specificity were respectively compared between FF and CER. The AUCs of FF, LDR, and CER were 0.96, 0.80, and 0.72, respectively. In the comparison of diagnostic performance between the FF and CER, the FF showed a significantly larger AUC as compared to the CER (p = 0.030), although the difference of sensitivity (p = 0.157) and specificity (p = 0.157) were not significant. Fat-signal fraction measurement using T2*-corrected three-echo VIBE Dixon sequence is feasible and has a more accurate diagnostic performance, than the CER, in distinguishing benign red marrow deposition from malignant bone marrow-replacing lesions.


DNA damage phenotype and prostate cancer risk.
The capacity of an individual to process DNA damage is considered a crucial factor in carcinogenesis. The comet assay is a phenotypic measure of the combined effects of sensitivity to a mutagen exposure and repair capacity. In this paper, we evaluate the association of the DNA repair kinetics, as measured by the comet assay, with prostate cancer risk. In a pilot study of 55 men with prostate cancer, 53 men without the disease, and 71 men free of cancer at biopsy, we investigated the association of DNA damage with prostate cancer risk at early (0-15 min) and later (15-45 min) stages following gamma-radiation exposure. Although residual damage within 45 min was the same for all groups (65% of DNA in comet tail disappeared), prostate cancer cases had a slower first phase (38% vs. 41%) and faster second phase (27% vs. 22%) of the repair response compared to controls. When subjects were categorized into quartiles, according to efficiency of repairing DNA damage, high repair-efficiency within the first 15 min after exposure was not associated with prostate cancer risk while higher at the 15-45 min period was associated with increased risk (OR for highest-to-lowest quartiles=3.24, 95% CI=0.98-10.66, p-trend=0.04). Despite limited sample size, our data suggest that DNA repair kinetics marginally differ between prostate cancer cases and controls. This small difference could be associated with differential responses to DNA damage among susceptible individuals.


Surgeons opinions of legal practice in bile duct injury following cholecystectomy.
Litigation for bile duct injury following laparoscopic cholecystectomy places financial strain on the health service, causes significant patient morbidity and adversely affects the patient and surgeon. Claimants argue that the injury itself is evidence of negligence. A questionnaire addressing views on BDI causation was sent to members of AUGIS working in the National Health Service, UK. Response themes and responses were compared between groups of surgeons. Of 117 respondents, 45% experienced BDI and 22% had medicolegal experience. 47% of respondents identified factors outside the surgeons control as being relevant to BDI. Those that had experienced BDI from their own surgery were less likely to identify surgeon/systems errors as the primary cause for BDI than those that had not (34% vs 74%, p < 0.001). Medicolegal expert surgeons were more likely to report that substandard technique should be presumed (50% vs 19%, p = 0.002), however, 25% of medicolegal experts indicated that not all BDIs caused by their own surgery could have been avoided. A significant number of experienced surgeons indicated that BDI following LC should not be assumed to result from surgeon negligence or institutional failure. This suggests that negligence should not be inferred from the act of BDI alone.


What Is the Origin of Livestock-Associated Methicillin-Resistant Staphylococcus aureus Clonal Complex 398 Isolates from Humans without Livestock Contact? An Epidemiological and Genetic Analysis.
Fifteen percent of all methicillin-resistant Staphylococcus aureus (MRSA) clonal complex 398 (CC398) human carriers detected in The Netherlands had not been in direct contact with pigs or veal calves. To ensure low MRSA prevalence, it is important to investigate the likely origin of this MRSA of unknown origin (MUO). Recently, it was shown that CC398 strains originating from humans and animals differ in the presence of specific mobile genetic elements (MGEs). We hypothesized that determining these specific MGEs in MUO isolates and comparing them with a set of CC398 isolates of various known origin might provide clues to their origin. MUO CC398 isolates were compared to MRSA CC398 isolates obtained from humans with known risk factors, a MRSA CC398 outbreak isolate, livestock associated (LA) MRSA CC398 isolates from pigs, horses, chickens, and veal calves, and five methicillin-susceptible Staphylococcus aureus (MSSA) CC398 isolates of known human origin. All strains were spa typed, and the presence or absence of, scn, chp, φ3 int, φ6 int, φ7 int, rep7, rep27, and cadDX was determined by PCRs. The MRSA CC398 in humans, MUO, or MRSA of known origin (MKO) resembled MRSA CC398 as found in pigs and not MSSA CC398 as found in humans. The distinct human MSSA CC398 spa type, t571, was not present among our MRSA CC398 strains; MRSA CC398 was tetracycline resistant and carried no φ3 bacteriophage with scn and chp. We showed by simple PCR means that human MUO CC398 carriers carried MRSA from livestock origin, suggestive of indirect transmission. Although the exact transmission route remains unknown, direct human-to-human transmission remains a possibility as well.


Dietary Intake in Relation to Military Dietary Reference Values During Army Basic Combat Training; a Multi-center, Cross-sectional Study.
The military dietary reference intakes (MDRIs), outlined in Army Regulation 40-25, OPNAVINST 10110.1/MCO10110.49, AFI 44-141, establish standards intended to meet the nutrient requirements of Warfighters. Therefore, the purpose of this study was to comprehensively compare the revised MDRIs, published in 2017, with estimated dietary intakes in U.S. military personnel. During this cross-sectional study, Block food frequency questionnaires were administered at the end of the 9-week basic combat training course to estimate dietary intake during basic combat training in male (n = 307) and female (n = 280) recruits. The cut-point method was used to determine nutrient adequacy in comparison to the MDRIs. This study was approved by the Institutional Review Board of the U.S. Army Research Institute of Environmental Medicine. Recruits consumed an adequate amount of vitamins A, C and K, as well as the B-vitamins, and phosphorus, selenium, zinc, and protein and carbohydrate as a percentage of total calories when compared with MDRI standards. Vitamin D was the short-fall nutrient affecting the greatest number of participants, as 55 and 70% of males and females, respectively, consumed less than 33% of the MDRI. In addition, less than 50% of males met the MDRI for linoleic and α-linolenic acid, fiber, vitamin E, magnesium, and potassium, and less than 50% of females met the MDRI for α-linolenic acid, fiber, vitamin E, calcium, iron, magnesium, and potassium. In contrast, fat and sodium were over-consumed by both males (78 and 87%, respectively) and females (73 and 72%, respectively). The main findings of this study were that vitamins D and E, magnesium, potassium, α-linolenic acid, and fiber were under consumed by male and female recruits while males also did not consume adequate linoleic acid and females did not consume adequate calcium and iron. Future prospective research studies are needed to determine possible health and performance impacts that may be associated with suboptimal intake of these nutrients.


Predictors of decline in IADL functioning among older survivors following the Great East Japan earthquake: A prospective study.
We described associations between the type of disaster experience and change in instrumental activities of daily living among older adult survivors before-after a terrible disaster. The study took advantage of a "natural experiment" afforded by the Japan Gerontological Evaluation Study (JAGES), a nationwide cohort study established in 2010, seven months prior to the earthquake and tsunami. A follow-up survey was conducted in 2013. This study was conducted in Iwanuma, which was directly struck by tsunami. Our sample comprised community-dwelling aged survivors in Iwanuma who responded to questions about personal circumstances and functional status both before and after the disaster (N = 3547). Personal experiences of earthquake and tsunami damage was used as an exposure variable. The outcome was changes in self-reported 13-item instrumental activities of daily living (IADL), which was assessed both before and after the disaster. Among the participants, 931 reported losing family member(s) to the disaster, while a further 549 reported losing friend(s). More than half of the participants reported any damage to their houses while approximately 1 in 8 lost their car(s). The multivariable OLS regression revealed that complete house loss and disruption of internal medicine were associated with significantly worse IADL: -0.67 points (95%CI: -0.99, -0.34) for entirely destroyed homes; -0.40 points (95% CI: -0.71, -0.092) for disruption of internal medicine. By contrast, loss of family/friends/pets/cars and disruption to the other medical service were not associated with decline in IADL. Complete house loss and disruption of access to internal medicine after a disaster were associated with significant adverse impact on decline in physical and cognitive functions 2.5 years after the disaster, while loss of family/friends was not.


Inflammation-mediated abrogation of androgen signaling: an in vitro model of prostate cell inflammation.
As a link between inflammation and cancer has been reported in many studies, we established an in vitro model of prostatic inflammation to investigate the loss of androgen receptor (AR)-mediated signaling in androgen responsive prostate cell lines. First, the U937 monocyte cell line was differentiated into macrophages using phorbol acetate (PMA), and cells were induced with lipopolysaccharide (LPS) for cytokine secretion. Next, the cytokine levels (TNFα, IL-6, and IL1β) in conditioned media (CM) were analyzed. Prostate cells were then fed with CM containing varying concentrations of TNFα, and IkB degradation, nuclear factor kappa B (NFκB) translocation and transactivation, and the expression of matrix metalloproteinase-8 (MMP8) and matrix metalloproteinase-9 (MMP9) were then assessed. As a result of CM treatment, ubiquitin-mediated AR degradation, which was restored using anti-TNFα antibody neutralization, led to both a decrease in KLK4, PSA, and NKX3.1 expression levels and the upregulation of GPX2. In addition to the loss of AR, acute and chronic CM exposure resulted in p53 degradation and consequent p21 downregulation, which was also restored by either androgen administration or ectopic NKX3.1 expression via the stabilization of MDM2 levels in LNCaP cells. Additionally, CM treatment enhanced H2AX((S139)) phosphorylation (a hallmark of DNA damage) and genetic heterogeneity in the absence of androgens in prostate cells without activating mitochondrial apoptosis. Thus, the data suggest that inflammatory cytokine exposure results in the loss of AR and p53 signaling in prostate cells and facilitates genetic heterogeneity via ROS accumulation to promote prostate carcinogenesis.


Increasing patient engagement in rehabilitation exercises using computer-based citizen science.
Patient motivation is an important factor to consider when developing rehabilitation programs. Here, we explore the effectiveness of active participation in web-based citizen science activities as a means of increasing participant engagement in rehabilitation exercises, through the use of a low-cost haptic joystick interfaced with a laptop computer. Using the joystick, patients navigate a virtual environment representing the site of a citizen science project situated in a polluted canal. Participants are tasked with following a path on a laptop screen representing the canal. The experiment consists of two conditions: in one condition, a citizen science component where participants classify images from the canal is included; and in the other, the citizen science component is absent. Both conditions are tested on a group of young patients undergoing rehabilitation treatments and a group of healthy subjects. A survey administered at the end of both tasks reveals that participants prefer performing the scientific task, and are more likely to choose to repeat it, even at the cost of increasing the time of their rehabilitation exercise. Furthermore, performance indices based on data collected from the joystick indicate significant differences in the trajectories created by patients and healthy subjects, suggesting that the low-cost device can be used in a rehabilitation setting for gauging patient recovery.


RNA sequencing: the teenage years.
Over the past decade, RNA sequencing (RNA-seq) has become an indispensable tool for transcriptome-wide analysis of differential gene expression and differential splicing of mRNAs. However, as next-generation sequencing technologies have developed, so too has RNA-seq. Now, RNA-seq methods are available for studying many different aspects of RNA biology, including single-cell gene expression, translation (the translatome) and RNA structure (the structurome). Exciting new applications are being explored, such as spatial transcriptomics (spatialomics). Together with new long-read and direct RNA-seq technologies and better computational tools for data analysis, innovations in RNA-seq are contributing to a fuller understanding of RNA biology, from questions such as when and where transcription occurs to the folding and intermolecular interactions that govern RNA function.


Linking prenatal maternal adversity to developmental outcomes in infants: the role of epigenetic pathways.
Prenatal exposure to maternal stress, anxiety, and depression can have lasting effects on infant development with risk of psychopathology. Although the impact of prenatal maternal distress has been well documented, the potential mechanisms through which maternal psychosocial variables shape development have yet to be fully elucidated. Advances in molecular biology have highlighted the role of epigenetic mechanisms in regulating gene activity, neurobiology, and behavior and the potential role of environmentally induced epigenetic variation in linking early life exposures to long-term biobehavioral outcomes. In this article, we discuss evidence illustrating the association between maternal prenatal distress and both fetal and infant developmental trajectories and the potential role of epigenetic mechanisms in mediating these effects. Postnatal experiences may have a critical moderating influence on prenatal effects, and we review findings illustrating prenatal-postnatal interplay and the developmental and epigenetic consequences of postnatal mother-infant interactions. The in utero environment is regulated by placental function and there is emerging evidence that the placenta is highly susceptible to maternal distress and a target of epigenetic dysregulation. Integrating studies of prenatal exposures, placental function, and postnatal maternal care with the exploration of epigenetic mechanisms may provide novel insights into the pathophysiology induced by maternal distress.


Molecular Epidemiology of Staphylococcus epidermidis Implicated in Catheter-Related Bloodstream Infections at an Academic Hospital in Pretoria, South Africa.
Staphylococcus epidermidis is one of the most prevalent pathogens implicated in catheter-related bloodstream infections (CRBSI) at an academic hospital in Pretoria, South Africa. Little is known about the clonality and the prevalence of antibiotic resistance and virulence genes in S. epidermidis (e.g., icaAB, IS256, mecA, and qacA/B). A total of 508 intravascular catheters (IVCs) from 331 patients were submitted for culture from May to October 2013. Only 50% (n = 253/508) of the IVCs were accompanied by blood cultures (BCs) taken within 48 h. Forty-four percent (44%; n = 112/253) of IVCs were colonised, of which 26% (n = 65/253) were associated with a CRBSI. We identified S. epidermidis as the causal agent in 31% (n = 20/65) of the CRBSI cases. Fifty-nine S. epidermidis isolates were obtained, 23 isolates were cultured from 22 IVCs and 36 isolates were cultured from 36 BCs. All S. epidermidis isolates were resistant to β-lactams (100%; n = 59/59), followed by high levels of resistance toward erythromycin (86%; n = 51/59) and gentamicin (81%; n = 49/59). The mecA gene was prevalent in all the (100%, n = 59/59) isolates. Isolates contained the IS256 element (83%, n = 49/59), the icaAB gene (81%, n = 48/59) and, the qacA/B gene (81%, n = 48/59). All 48 isolates were qacA positive upon restriction enzyme digestion of the qacA/B amplicons. Phenotypic resistance toward 0.5% (m/v) chlorhexidine was not observed. Staphylococcal Cassette Chromosome (SCC) mec typing showed that SCCmec type IV (31%; n = 18/59) was the most prevalent. The remaining SCCmec elements were highly diverse. Pulsed-field gel electrophoresis (PFGE) showed that S. epidermidis isolates from individual patients were mostly clonal. Multilocus sequencing typing (MLST) of 10 sequenced isolates showed that sequence type (ST) 2 (40%; n = 4/10) was the most frequently detected, followed by ST54 (20%; n = 2/10), ST28 (10%; n = 1/10), ST59 (10%; n = 1/10) and ST490 (10%; 1/10). One isolate was newly assigned to ST596. These S. epidermidis infections can be attributed to patients' skin microflora or to poor infection control practices. Currently, S. epidermidis strains circulating in the studied hospital are multidrug-resistant and highly adaptive to environmental changes.


Basal body movements orchestrate membrane organelle division and cell morphogenesis in Trypanosoma brucei.
The defined shape and single-copy organelles of Trypanosoma brucei mean that it provides an excellent model in which to study how duplication and segregation of organelles is interfaced with morphogenesis of overall cell shape and form. The centriole or basal body of eukaryotic cells is often seen to be at the centre of such processes. We have used a combination of electron microscopy and electron tomography techniques to provide a detailed three-dimensional view of duplication of the basal body in trypanosomes. We show that the basal body duplication and maturation cycle exerts an influence on the intimately associated flagellar pocket membrane system that is the portal for secretion and uptake from this cell. At the start of the cell cycle, a probasal body is positioned anterior to the basal body of the existing flagellum. At the G1-S transition, the probasal body matures, elongates and invades the pre-existing flagellar pocket to form the new flagellar axoneme. The new basal body undergoes a spectacular anti-clockwise rotation around the old flagellum, while its short new axoneme is associated with the pre-existing flagellar pocket. This rotation and subsequent posterior movements results in division of the flagellar pocket and ultimately sets parameters for subsequent daughter cell morphogenesis.


Firearm safety counseling in primary care pediatrics: a randomized, controlled trial.
Physicians have been encouraged to counsel families about risks associated with gun ownership, but the effectiveness of physician counseling regarding gun safety is unknown. To determine the effectiveness of gun safety counseling during well-child care visits. Group randomized, controlled trial. Physicians, nurse practitioners, and physician assistants were randomized to either the intervention group or a control group. Group Health Cooperative, a staff-model health maintenance organization. Patients. Consecutive sample of families (n = 1295) seen for a scheduled appointment for well-child care for a child <18 years of age. Of the families originally scheduled for a visit, 80. 3% were seen and completed the outcomes surveys. Each family in the intervention group was given a 60-second message by their practitioner that depended on the presence of guns in the home. Families without guns were informed of the health risks associated with gun ownership and given a standard information pamphlet. Families with guns were given the same information about risks and were told that if they chose to keep a gun, they should store it locked and unloaded. They were given instructions on storage and a folder with material, including the same pamphlet, a letter from the police department, written storage guidelines, and discount coupons for gun storage devices. Changes in the following self-reported events: 1) acquisition of a safe storage device; 2) removal of firearms from the home; and 3) acquisition of firearms. Results. There were no important differences between intervention and control groups in the rate of acquisition of new guns (intervention: 1.3% vs control:.9%) after the intervention. Among households with guns at baseline, there were also no differences between groups in the removal of guns (intervention: 6.7% vs control: 5.7%), but there was a fairly large nonsignificant difference in the proportion who purchased trigger locks (intervention: 8.0% vs control: 2.5%). A single firearm safety-counseling session during well-child care, combined with economic incentives to purchase safe storage devices, did not lead to changes in household gun ownership and did not lead to statistically significant overall changes in storage patterns.


Estrogen-receptor-directed neoadjuvant therapy for breast cancer: results of a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy.
We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively. Two hundred ten patients with primary breast cancer (T1-T4, N0, N1-2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m2), mitozantrone (7 mg/m2) and mitomycin (7 mg/m2) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months. With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% +/- 4.7% (neoadjuvant) and 87% +/- 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T1 and T2 tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence. In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond.


Comparative analysis of Phytophthora genes encoding secreted proteins reveals conserved synteny and lineage-specific gene duplications and deletions.
Comparative analysis of two Phytophthora genomes revealed overall colinearity in four genomic regions consisting of a 1.5-Mb sequence of Phytophthora sojae and a 0.9-Mb sequence of P. ramorum. In these regions with conserved synteny, the gene order is largely similar; however, genome rearrangements also have occurred. Deletions and duplications often were found in association with genes encoding secreted proteins, including effectors that are important for interaction with host plants. Among secreted protein genes, different evolutionary patterns were found. Elicitin genes that code for a complex family of highly conserved Phytophthora-specific elicitors show conservation in gene number and order, and often are clustered. In contrast, the race-specific elicitor gene Avrlb-1 appeared to be missing from the region with conserved synteny, as were its five homologs that are scattered over the four genomic regions. Some gene families encoding secreted proteins were found to be expanded in one species compared with the other. This could be the result of either repeated gene duplications in one species or specific deletions in the other. These different evolutionary patterns may shed light on the functions of these secreted proteins in the biology and pathology of the two Phytophthora spp.


Monoamine transporters: structure, intrinsic dynamics and allosteric regulation.
Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain neurotransmitter homeostasis. As targets of a wide range of compounds, including antidepressants, substances of abuse and drugs for neuropsychiatric and neurodegenerative disorders, their mechanism of action and their modulation by small molecules have long been of broad interest. Recent advances in the structural characterization of dopamine and serotonin transporters have opened the way for structure-based modeling and simulations, which, together with experimental data, now provide mechanistic understanding of their transport function and interactions. Here we review recent progress in the elucidation of the structural dynamics of MATs and their conformational landscape and transitions, as well as allosteric regulation mechanisms.


Isolation and perivascular localization of mesenchymal stem cells from mouse brain.
Although originally isolated from the bone marrow, mesenchymal stem cells (MSCs) have recently been detected in other tissues. However, little is known about MSCs in the brain. To determine the extent to which cells with the features of MSCs exist in normal brain tissue and to determine the location of these cells in the brain. Single-cell suspensions from mouse brains were cultured according to the same methods used for culturing bone marrow-derived MSCs (BM-MSCs). These brain-derived cells were analyzed by fluorescence-activated cell sorting for surface markers associated with BM-MSCs (stem cell antigen 1 [Sca-1+], CD9+, CD45-, CD11b-, and CD31-). Brain-derived cells were exposed to mesenchymal differentiation conditions. To determine the locations of these cells within the brain, sections of normal brains were analyzed by immunostaining for Sca-1, CD31, and nerve/glial antigen 2. Cells morphologically similar to mouse BM-MSCs were identified and called brain-derived MSCs (Br-MSCs). Fluorescence-activated cell sorting indicated that the isolated cells had a surface marker profile similar to BM-MSCs, ie, Sca-1V+, CD9+, CD45-, and CD11b-. Like BM-MSCs, Br-MSCs were capable of differentiation into adipocytes, osteocytes, and chondrocytes. Immunostaining indicated that Sca-1+ Br-MSCs are located around blood vessels and may represent progenitor cells that serve as a source of mesenchymal elements (eg, pericytes) within the brain. Our results indicate that cells similar to BM-MSCs exist in the brain. These Br-MSCs appear to be located within the vascular niche and may provide the mesenchymal elements of this niche. Because MSCs may be part of the cellular response to tissue injury, Br-MSCs may represent targets in the therapy of pathological processes such as stroke, trauma, and tumorigenesis.


No effect of acute beetroot juice ingestion on oxygen consumption, glucose kinetics, or skeletal muscle metabolism during submaximal exercise in males.
Beetroot juice, which is rich in nitrate (NO3 (-)), has been shown in some studies to decrease oxygen consumption (V̇o2) for a given exercise workload, i.e., increasing efficiency and exercise tolerance. Few studies have examined the effect of beetroot juice or nitrate supplementation on exercise metabolism. Eight healthy recreationally active males participated in three trials involving ingestion of either beetroot juice (Beet; ∼8 mmol NO3 (-)), Placebo (nitrate-depleted Beet), or Beet + mouthwash (Beet+MW), all of which were performed in a randomized single-blind crossover design. Two-and-a-half hours later, participants cycled for 60 min on an ergometer at 65% of V̇o2 peak. [6,6-(2)H]glucose was infused to determine glucose kinetics, blood samples obtained throughout exercise, and skeletal muscle biopsies that were obtained pre- and postexercise. Plasma nitrite [NO2 (-)] increased significantly (∼130%) with Beet, and this was attenuated in MW+Beet. Beet and Beet+MW had no significant effect on oxygen consumption, blood glucose, blood lactate, plasma nonesterified fatty acids, or plasma insulin during exercise. Beet and Beet+MW also had no significant effect on the increase in glucose disposal during exercise. In addition, Beet and Beet+MW had no significant effect on the decrease in muscle glycogen and phosphocreatine and the increase in muscle creatine, lactate, and phosphorylated acetyl CoA carboxylase during exercise. In conclusion, at the dose used, acute ingestion of beetroot juice had little effect on skeletal muscle metabolism during exercise.


Vulnerable road users are at greater risk during Ramadan -- results from road traffic surveillance data.
To assess how the frequency, nature and outcome of road traffic crashes differ during the fasting month of Ramadan. The retrospective study was conducted in Karachi and comprised data from the Road Traffic Injury Surveillance Project which entailed information on all road traffic injury victims presenting to Emergency Departments in the city between September 2006 and September 2011. Data was analysed to find the frequency of road traffic crashes according to time of incident, road user group and survival. Ramadan and Non-Ramadan groups were compared with respect to time and frequency of incidents, road user group and mortality. SPSS 16 was used for statistical analysis. There were 163,022 subjects from whom 13,640(8.36%) came during Ramadan and 149,382 (91.6%) during the non-Ramadan months. Frequency of road traffic crashes did not change significantly during Ramadan, but was clustered around the breaking of Fast and the Taravih prayers. The most commonly affected road user group was motorbike riders followed by pedestrians. Overall survival of the RTI victims was 96.1% with a mortality rate of 4.1% which was higher than the figure of 3.5% in the non-Ramadan period. Vulnerable road users were more frequently involved in road traffic injuries during Ramadan. Moreover, the frequency of crashes increased around evening which requires more careful planning of traffic controls, especially for the vulnerable road users.


4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection.
Previous studies have identified the inhibitory role that the programmed death 1 (PD-1) pathway plays during chronic infection. Blockade of this pathway results in rescue of viral-specific CD8 T cells, as well as reduction of viral loads in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). We tested the effect of combining PD ligand 1 (PD-L1) blockade with an agonistic regimen that induces 4-1BB costimulation during chronic LCMV infection. There is a boosting effect in the rescue of LCMV-specific CD8 T cell responses after dual treatment with PD-L1 blockade and 4-1BB agonistic Abs when the amount and timing of 4-1BB costimulation are carefully controlled. When PD-L1-blocking Abs are given together with a single low dose of anti-4-1BB agonistic Abs, there is an enhanced and stable expansion of viral-specific CD8 T cells. Conversely, when blocking Abs to PD-L1 are given with a repetitive high dose of anti-4-1BB, there is an initial synergistic expansion of viral-specific CD8 T cells by day 7, followed by dramatic apoptosis by day 14. Viral control paralleled CD8 T cell kinetics after dual treatment. By day 7 posttreatment, viral titers were lower in both of the combined regimens (compared with PD-L1 blockade alone). However, whereas the high dose of anti-4-1BB plus PD-L1 blockade resulted in rebound of viral titers to original levels, the low dose of anti-4-1BB plus PD-L1 blockade resulted in a stable reduction of viral loads. These findings demonstrate the importance of carefully manipulating the balance between activating and inhibitory signals to enhance T cell responses during chronic infection.


Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia.
Altered metabolism is a hallmark of cancer. However, the role of genomic changes in metabolic genes driving the tumour metabolic shift remains to be elucidated. Here, we have investigated the genomic and transcriptomic changes underlying this shift across ten different cancer types. A systematic pan-cancer analysis of 6538 tumour/normal samples covering ten major cancer types identified a core metabolic signature of 44 genes that exhibit high frequency somatic copy number gains/amplifications (>20 % cases) associated with increased mRNA expression (ρ > 0.3, q < 10(-3)). Prognostic classifiers using these genes were confirmed in independent datasets for breast and kidney cancers. Interestingly, this signature is strongly associated with hypoxia, with nine out of ten cancer types showing increased expression and five out of ten cancer types showing increased gain/amplification of these genes in hypoxic tumours (P ≤ 0.01). Further validation in breast and colorectal cancer cell lines highlighted squalene epoxidase, an oxygen-requiring enzyme in cholesterol biosynthesis, as a driver of dysregulated metabolism and a key player in maintaining cell survival under hypoxia. This study reveals somatic genomic alterations underlying a pan-cancer metabolic shift and suggests genomic adaptation of these genes as a survival mechanism in hypoxic tumours.


Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype.
Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking? Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment. Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction. Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case-control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking. Women with PCOS, age 18-40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA. Overall, self-report of smoking in the nested case-control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels <15 ng/ml compared with 90% of past smokers and 6% of current smokers). There were minor changes in smoking status as determined by serum cotinine levels over time, with the greatest change found in the smoking groups (past or current smokers). In the larger cohort, hirsutism scores at baseline were lower in the never smokers compared with past smokers. Total testosterone levels at baseline were also lower in the never smokers compared with current smokers. At end of study follow-up insulin levels and homeostatic index of insulin resistance increased in the current smokers (P < 0.01 for both) compared with baseline and with non-smokers. The chance for ovulation was not associated with smoking status, but live birth rates were increased (non-significantly) in never or past smokers. The limitations include the selection bias involved in our nested case-control study, the possibility of misclassifying exposure to second hand smoke as smoking and our failure to capture self-reported changes in smoking status after enrollment in the trial. Because self-report of smoking is accurate, further testing of smoking status is not necessary in women with PCOS. Because smoking status is unlikely to change during infertility treatment, extra attention should be focused on smoking cessation in current or recent smokers who seek or who are receiving infertility treatment. Sponsored by the Eugene Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health. ClinicalTrials.gov numbers, NCT00068861 and NCT00719186.


Application of an optosensing chip based on molecularly imprinted polymer coated quantum dots for the highly selective and sensitive determination of sesamol in sesame oils.
A novel optosensing chip was constructed by anchoring the fluorescence sensing material layer based on molecularly imprinted polymer (MIP) coated CdSe/ZnS quantum dots (QDs) on a chip for highly selective and sensitive optosensing of sesamol in sesame oil. Many factors that affected the performance of the optosensing chip based on MIP-coated QDs are discussed. Under optimized conditions, the relative fluorescence intensity of the optosensing chip decreased linearly (r(2) > 0.99) with increasing sesamol concentration in the range from 2.4 × 10(-6) to 1.2 × 10(-3) mol L(-1) with a detection limit of 7.2 × 10(-8) mol L(-1). The relative standard deviation for five replicate detections of 4.8 × 10(-4) mol L(-1) sesamol was 2.2%. Recoveries of 94.8-102.3% were achieved by direct detection when the optosensing chip was used for the selective detection of sesamol in sesame oil. Practically, the optosensing approach showed high sensitivity, good selectivity, and excellent reproducibility for the detection of sesamol in real oil samples.


Marfan Syndrome and Quality of Life in the GenTAC Registry.
Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL. This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data. QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity. In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL. In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity.


Lettuce cultivar mediates both phyllosphere and rhizosphere activity of Escherichia coli O157:H7.
Plant roots and leaves can be colonized by human pathogenic bacteria, and accordingly some of the largest outbreaks of foodborne illness have been associated with salad leaves contaminated by E. coli O157. Integrated disease management strategies often exploit cultivar resistance to provide a level of protection from economically important plant pathogens; however, there is limited evidence of whether the genotype of the plant can also influence the extent of E. coli O157 colonization. To determine cultivar-specific effects on colonization by E. coli O157, we used 12 different cultivars of lettuce inoculated with a chromosomally lux-marked strain of E. coli O157:H7. Lettuce seedlings grown gnotobiotically in vitro did exhibit a differential cultivar-specific response to E. coli O157 colonization, although importantly there was no relationship between metabolic activity (measured as bioluminescence) and cell numbers. Metabolic activity was highest and lowest on the cultivars Vaila-winter gem and Dazzle respectively, and much higher in endophytic and tightly bound cells than in epiphytic and loosely bound cells. The cultivar effect was also evident in the rhizosphere of plants grown in compost, which suggests that cultivar-specific root exudate influences E. coli O157 activity. However, the influence of cultivar in the rhizosphere was the opposite to that in the phyllosphere, and the higher number and activity of E. coli O157 cells in the rhizosphere may be a consequence of them not being able to gain entry to the plant as effectively. If metabolic activity in the phyllosphere corresponds to a more prepared state of infectivity during human consumption, leaf internalization of E. coli O157 may pose more of a public health risk than leaf surface contamination alone.


Complementary analysis of the Mycobacterium tuberculosis proteome by two-dimensional electrophoresis and isotope-coded affinity tag technology.
Classical proteomics combined two-dimensional gel electrophoresis (2-DE) for the separation and quantification of proteins in a complex mixture with mass spectrometric identification of selected proteins. More recently, the combination of liquid chromatography (LC), stable isotope tagging, and tandem mass spectrometry (MS/MS) has emerged as an alternative quantitative proteomics technology. We have analyzed the proteome of Mycobacterium tuberculosis, a major human pathogen comprising about 4,000 genes, by (i) 2-DE and mass spectrometry (MS) and by (ii) the isotope-coded affinity tag (ICAT) reagent method and MS/MS. The data obtained by either technology were compared with respect to their selectivity for certain protein types and classes and with respect to the accuracy of quantification. Initial datasets of 60,000 peptide MS/MS spectra and 1,800 spots for the ICAT-LC/MS and 2-DE/MS methods, respectively, were reduced to 280 and 108 conclusively identified and quantified proteins, respectively. ICAT-LC/MS showed a clear bias for high M(r) proteins and was complemented by the 2-DE/MS method, which showed a preference for low M(r) proteins and also identified cysteine-free proteins that were transparent to the ICAT-LC/MS method. Relative quantification between two strains of the M. tuberculosis complex also revealed that the two technologies provide complementary quantitative information; whereas the ICAT-LC/MS method quantifies the sum of the protein species of one gene product, the 2-DE/MS method quantifies at the level of resolved protein species, including post-translationally modified and processed polypeptides. Our data indicate that different proteomic technologies applied to the same sample provide complementary types of information that contribute to a more complete understanding of the biological system studied.


Identifying Dendritic Processing.
In system identification both the input and the output of a system are available to an observer and an algorithm is sought to identify parameters of a hypothesized model of that system. Here we present a novel formal methodology for identifying dendritic processing in a neural circuit consisting of a linear dendritic processing filter in cascade with a spiking neuron model. The input to the circuit is an analog signal that belongs to the space of bandlimited functions. The output is a time sequence associated with the spike train. We derive an algorithm for identification of the dendritic processing filter and reconstruct its kernel with arbitrary precision.


Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
The objectives of this study are to test the hypothesis that the fatigue and accompanying symptoms of Chronic Myalgic Encephalomyelitis/Fatigue Syndrome are in part due to defects in energy provision at the cellular level, and to understand the pathophysiology of the defects so that effective medical intervention can be implemented. We performed an audit of 138 patients (ages 18-65) diagnosed with ME/CFS and attending a private practice. The patients and 53 normal, healthy controls had the ATP Profile test carried out on neutrophils from a 3-ml venous blood sample. This test yields 6 numerical factors that describe the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria. Other biomedical measurements, including the concentration of cell-free DNA in plasma, were made. The results of the audit are compared with the controls and a previous cohort of 61 patients. We find that all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness. The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction. Comparisons with exercise studies suggest that the dysfunction in neutrophils also occurs in other cells. This is confirmed by the cell-free DNA measurements which indicate levels of tissue damage up to 3.5 times the normal reference range. The major immediate causes of the dysfunction are lack of essential substrates and partial blocking of the translocator protein sites in mitochondria. The ATP Profile is a valuable diagnostic tool for the clinical management of ME/CFS.


Common genetic polymorphisms and haplotypes of fibrinogen alpha, beta, and gamma chains affect fibrinogen levels and the response to proinflammatory stimulation in myocardial infarction survivors: the AIRGENE study.
This study was designed to investigate whether single nucleotide polymorphisms (SNPs) and haplotypes of the fibrinogen gene-cluster (fibrinogen chains alpha [FGA], beta [FGB], and gamma [FGG]) could explain the inter- and intraindividual variability of fibrinogen levels in patients with atherosclerosis. We also searched for genetic determinants affecting the responses of fibrinogen genes to proinflammatory stimulation. The mechanisms regulating fibrinogen levels are not fully understood, and they are likely to be regulated by complex gene-environment interactions. In the AIRGENE study, 895 survivors of myocardial infarction from 5 European cities were followed prospectively for 6 to 8 months, and plasma fibrinogen, interleukin (IL)-6, and C-reactive protein levels were determined monthly. We analyzed 21 SNPs and the corresponding haplotypes in the 3 fibrinogen genes. Eight SNPs in FGA and FGB were significantly associated with fibrinogen levels. Similarly, 2 different haplotypes in FGA and 3 in FGB were also associated with mean fibrinogen levels. The IL-6 levels had a significant impact on the associations between SNPs/haplotypes in FGA/FGB and fibrinogen levels. We also identified SNPs and haplotypes in FGA and FGB with strong impact on the intraindividual variability of fibrinogen during the follow-up period. We identified common SNPs and haplotypes on FGA/FGB genes, explaining the interindividual and intraindividual variability of fibrinogen levels, in patients with a history of myocardial infarction. We have also identified for the first time, SNPs/haplotypes on FGA/FGB whose effects on fibrinogen expression are modified by the underlying IL-6 levels. These findings may have an impact on risk stratification and the design of genetically guided therapeutic approaches in patients with advanced atherosclerosis.


Antigen-induced Ca2+ signaling and desensitization in B cells.
Cross-linking of B cell surface Ig (sIg) by anti-Ig results in transmembrane signaling. However, the capacity of a thymus-dependent (TD) Ag to mediate B cell signal transduction has been less well documented. Therefore, we examined Ag-induced intracellular free calcium concentration [( Ca2+]) in B cells by using TD Ag that would be expected to either cross-link or not cross-link sIgM and/or induce the coupling of sIgM to FcR. Stimulation of mouse TA3 hybridoma B cell transfectants that express the SP6 anti-TNP specific sIgM with either TNP-OVA or anti-IgM antibodies resulted in a maximal fourfold increase in [Ca2+]i. The net increase in [Ca2+]i in response to TNP-OVA was dependent upon both the Ag dose and the TNP:OVA molar ratio. Because occupancy of several cell-surface receptor types leads to a loss of response to subsequent stimulation by ligand (homologous desensitization), we examined the ability of Ag to induce homologous desensitization of sIgM in these B cells. TNP1-OVA at all concentrations tested (up to 500 micrograms/ml) did not lead to any change in [Ca2+]i or desensitization. Cross-linking of TNP1-OVA (10 micrograms/ml) with F(ab')2 of anti-OVA antibody induced both a rise in [Ca2+]i and homologous desensitization of sIg, suggesting that cross-linking of sIgM by Ag is sufficient to induce both these processes. TNP6-OVA at a concentration of 10 micrograms/ml induced changes in [Ca2+]i and partially desensitized TNP-specific B cells to stimulation by anti-IgM. Interestingly, a high dose (180 micrograms/ml) of TNP6-OVA stimulated minimal changes in [Ca2+]i yet did not lead to desensitization. However, cross-linking of TNP6-OVA at this high dose with F(ab')2 of rabbit anti-OVA elevated [Ca2+]i and elicited partial desensitization. Complete desensitization of sIgM by Ag was achieved when intact (Fc-containing) anti-OVA antibody was used, suggesting that the FcR can play a role in desensitization. Ag- and antibody-mediated desensitization was not caused by steric hindrance of sIg. Thus, we have observed two forms of Ag-induced desensitization of sIgM, both of which involve sIg cross-linking and one of which is mediated by the physiologic coupling of sIg to FcR.


Caffeine ingestion and fluid balance: a review.
Caffeine and related methylxanthine compounds are recognized as having a diuretic action, and consumers are often advised to avoid beverages containing these compounds in situations where fluid balance may be compromised. The aim of this review is to evaluate the available literature concerning the effect of caffeine ingestion on fluid balance and to formulate targeted and evidence-based advice on caffeinated beverages in the context of optimum hydration. A literature search was performed using the Medline database of articles published in the medical and scientific literature for the period of January 1966-March 2002. Subject headings and key words used in this search were: tea, coffee, caffeine, diuresis, fluid balance and water-electrolyte balance. A secondary search was performed using the bibliographies of publications identified in the initial search. The available literature suggests that acute ingestion of caffeine in large doses (at least 250-300 mg, equivalent to the amount found in 2-3 cups of coffee or 5-8 cups of tea) results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks. A profound tolerance to the diuretic and other effects of caffeine develops, however, and the actions are much diminished in individuals who regularly consume tea or coffee. Doses of caffeine equivalent to the amount normally found in standard servings of tea, coffee and carbonated soft drinks appear to have no diuretic action. The most ecologically valid of the published studies offers no support for the suggestion that consumption of caffeine-containing beverages as part of a normal lifestyle leads to fluid loss in excess of the volume ingested or is associated with poor hydration status. Therefore, there would appear to be no clear basis for refraining from caffeine containing drinks in situations where fluid balance might be compromised.


MR imaging of hindbrain deformity in Chiari II patients with and without symptoms of brainstem compression.
We examined the MR appearance of the hindbrain deformity, including the upper cervical spinal canal and craniovertebral junction, in 33 patients with Chiari II malformation. In this disorder, there is impaction at birth of the medulla and cerebellar vermis into the upper cervical spine, resulting in obliteration of the subarachnoid space and scalloping of the dens. Spinal canal enlargement during the child's growth, combined with dorsal displacement of neural tissue, eventually causes marked widening of the precervical subarachnoid space. This enlargement may simulate an intradural mass. Our series documents the changes seen at birth and the progression of the widened precervical space through the first and second decades. Twelve (36%) of the 33 patients studied were symptomatic, with brainstem or longtract symptomatology, and 11 of these required surgery. This group was compared with the remaining 21 asymptomatic Chiari II patients to identify MR features associated with clinical deterioration. The level of descent of the hindbrain hernia was critical; eight of 12 symptomatic patients had a cervicomedullary kink at C4 or lower, while no asymptomatic patients had a fourth ventricle, medulla, or kink below C3-C4. The precervical cord subarachnoid space was slightly wider in asymptomatic patients, although there was great overlap. In five patients with follow-up scans, this space was seen to increase in width after laminectomy. A CSF flow void was present in the precervical space in about 25% of patients in both groups. In nine of 12 symptomatic patients, C1 arch indentation of the dura (causing significant compression) was confirmed surgically. However, seven (33%) of the 21 asymptomatic patients also had this appearance. Absolute measurement of the anteroposterior diameter of the canal at C1 ranged from 11 to 25 mm in both groups. Retrocollis, which persisted despite sedation for MR, was seen in two patients, both symptomatic. Recognition of the vermis, medullary kink, cervical cord, C1 arch, fourth ventricle, and precervical space in Chiari II patients is fundamental to the analysis of symptoms in


A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes.
BRAF35, a structural DNA-binding protein, initially was identified as a component of a large BRCA2-containing complex. Biochemical analysis revealed the presence of a smaller core-BRAF35 complex devoid of BRCA2. Here we report the isolation of a six-subunit core-BRAF35 complex with the capacity to deacetylate histones, termed the BRAF-histone deacetylase complex (BHC), from human cells. BHC contains polypeptides reminiscent of the chromatin-remodeling complexes SWI/SNF and NuRD (nucleosome remodeling and deacetylating). Similar to NuRD, BHC contains an Mi2-like subunit, BHC80, and a PHD zinc-finger subunit as well as histone deacetylases 1/2 and an MTA-like subunit, the transcriptional corepressor CoREST. We show that BHC mediates repression of neuron-specific genes through the cis-regulatory element known as the repressor element 1 or neural restrictive silencer (RE1/NRS). Chromatin-immunoprecipitation experiments demonstrate the recruitment of BHC by the neuronal repressor REST. Expression of BRAF35 containing a single point mutation in the HMG domain of the protein abrogated REST-mediated transcriptional repression. These results demonstrate a role for core-BRAF35-containing complex in the regulation of neuron-specific genes through modulation of the chromatin structure.


Distal tibial fractures: evaluation of different fixation techniques.
The purpose of this study was the comparison of the most commonly used surgical techniques (external fixation, intramedullary nailing, and plate fixation) for the treatment of distal tibial fractures (AO/OTA classification 42-A, B, C or 43-A, B1). A retrospective cohort study of patients who underwent surgical treatment for distal tibial fractures between 1992 and 2011 was performed. A total of 93 patients (52 male/41 female) met inclusion criteria. Statistically significant differences were found regarding the consolidation time of the intramedullary-nailing (147.32 ± 91.16 days) and the plate-fixation group (135.75 ± 110.75 days) versus the external-fixation group (163.12 ± 96.79 days; P = 0.001; P = 0.01). Significant differences were also observed in the range of motion (ROM) of the ankle joint in the intramedullary-nailing and plate-fixation group versus the ROM in the external-fixation group (P = 0.044; P = 0.025). The overall complication rate was 13/93 (14 %). Out of 66 patients treated with intramedullary nailing, 8 (12 %) suffered from complications. Out of the 15 patients treated with plate and 12 patients with external fixation, 2 (13 %) and 3 (25 %) showed complications, respectively. Our results demonstrate advantages in terms of shorter mobilization time and a better ROM of the ankle joint for intramedullary nailing and plate fixation compared with external fixation. Due to our results, we suggest internal fixation (intramedullary nailing or plate fixation) whenever patient's condition and the local fracture situation allow it.


Quantification of Bufadienolides in Bryophyllum pinnatum Leaves and Manufactured Products by UHPLC-ESIMS/MS.
A quantitative assay for determination of the main bufadienolides bersaldegenin-1-acetate (1), bersaldegenin-3-acetate (2), bryophyllin A (3), and bersaldegenin-1,3,5-orthoacetate (4) in Bryophyllum pinnatum leaves and manufactured products was developed and validated. The assay involved extraction by pressurised liquid extraction, followed by quantification by ultrahigh performance liquid chromatography-tandem mass spectroscopy. The ultrahigh performance liquid chromatography-tandem mass spectroscopy method was applied to various batches of leaves harvested on several dates from plants grown at two locations (Brazil and Germany). In addition, press juices prepared from plants cultivated in Germany and Brazil were analysed. The total bufadienolide content ranged from 16.28 to 40.50 mg/100 g dry weight in leaves from plants grown in Brazil. The total content of these four bufadienolides was significantly lower in plants cultivated in Germany (3.78-12.49 mg/100 g dry weight, resp.). The total amounts of bufadienolides were 0.091-0.163 mg/100 mL and 0.89-1.16 mg/100 mL in press juices obtained from plants cultivated in Germany and Brazil, respectively. When analysing single leaves from individual plants, the content of bufadienolides was markedly higher in young leaves. For comparative purposes, the content of these bufadienolides was also determined in Bryophyllum daigremontianum and Bryophyllum tubiflorum. Bersaldegenin-1,3,5-orthoacetate (4) was predominant in the leaves of B. daigremontianum and in the stems of B. tubiflorum, while the leaves of B. tubiflorum contained very low amounts of 1-4.


Tuning quantum electron and phonon transport in two-dimensional materials by strain engineering: a Green's function based study.
Novel two-dimensional (2D) materials show unusual physical properties which combined with strain engineering open up the possibility of new potential device applications in nanoelectronics. In particular, transport properties have been found to be very sensitive to applied strain. In the present work, using a density-functional based tight-binding (DFTB) method in combination with Green's function (GF) approaches, we address the effect of strain engineering of the transport setup (contact-device(scattering)-contact regions) on the electron and phonon transport properties of two-dimensional materials, focusing on hexagonal boron-nitride (hBN), phosphorene, and MoS2 monolayers. Considering unstretched contact regions, we show that the electronic bandgap displays an anomalous behavior and the thermal conductance continuously decreases after increasing the strain level in the scattering region. However, when the whole system (contact and device regions) is homogeneously strained, the bandgap for hBN and MoS2 monolayers decreases, while for phosphorene it first increases and then tends to zero with larger strain levels. Additionally, the thermal conductance shows specific strain dependence for each of the studied 2D materials. These effects can be tuned by modifying the strain level in the stretched contact regions.


The role of cats in the eco-epidemiology of spotted fever group diseases.
Mediterranean Spotted Fever (MSF), whose etiological agent is R. conorii, is one of the oldest described vector-borne infectious diseases. Although it is endemic in the Mediterranean area, clinical cases have also been reported in other regions. R. massiliae-Bar29 is related to MSF cases. This strain is distributed worldwide. R. conorii and R. massiliae-Bar29 are transmitted by ticks. Dogs are considered the sentinel of R. conorii infection. Cats could also be involved in their transmission. Rickettsia felis, etiological agent of Flea-borne spotted fever, is mainly transmitted by the cat flea, Ctenocephalides felis. Up to now, the role of cats in its transmission is not entirely elucidated. The aim of the study is to analyze the infection in cats by these microorganisms. The study was undertaken in Northeastern Spain. Twenty municipalities of seven regions participated in the study. 212 cats (pets and stray cats) were analyzed. Variables surveyed were: date of collection, age, sex, municipality, source, living place, outdoor activities, health status, type of disease, contact with other animals, and ectoparasite infestation. Sera were evaluated by indirect immunofluorescence antibody assay (IFA). Molecular detection (real-time PCR and sequencing) and cultures were performed on blood samples. There were 59 (27.8%) cats seroreactive to one or more microorganisms. Considering cross-reactions, the seroprevalences were 15.6%-19.5% (R. massiliae-Bar29), 1.9%-6.2% (R. conorii), and 5.2%-7.5% (R. felis). A weak association was observed between SFG seropositivity and tick infestation. Ticks found on seropositive cats were Rhipicephalus pusillus, R. sanguineus and R. turanicus. DNA of Rickettsia was detected in 23 cats. 21 of them could be sequenced. Sequences obtained were identical to those sequences of SFG rickettsiae similar to R. conorii and R. massiliae. No amplification of R. felis was obtained. Cats can be infected by SFG rickettsiae and produce antibodies against them. Cats may play a role in the transmission cycle of R. conorii and R. massiliae-Bar29, although the role in the R. felis cycle needs further analysis.


Common harms from amoxicillin: a systematic review and meta-analysis of randomized placebo-controlled trials for any indication.
When prescribing antibiotics for common indications, clinicians need information about both harms and benefits, information that is currently available only from observational studies. We quantified the common harms of the most frequently prescribed antibiotic, amoxicillin, from randomized placebo-controlled trials. For this systematic review, we searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, without language restriction, for any randomized, participant-blinded, placebo-controlled trials of amoxicillin or amoxicillin-clavulanic acid for any indication, in any setting. Our main outcome was any reported adverse event. Of 730 studies identified, we included 45 trials: 27 involving amoxicillin, 17 involving amoxicillin-clavulanic acid and 1 involving both. The indications for antibiotic therapy were variable. The risk of bias was low, although only 25 trials provided data suitable for assessment of harms, which suggested under-reporting. Diarrhea was attributed to amoxicillin only in the form of amoxicillin-clavulanic acid (Peto odds ratio [OR] 3.30, 95% confidence interval [CI] 2.23-4.87). The OR for candidiasis (3 trials) was significantly higher (OR 7.77, 95% CI 2.23-27.11). Rashes, nausea, itching, vomiting and abnormal results on liver function tests were not significantly increased. The results were not altered by sensitivity analyses, nor did funnel plots suggest publication bias. The number of courses of antibiotics needed to harm was 10 (95% CI 6-17) for diarrhea with amoxicillin-clavulanic acid and 27 (95% CI 24-42) for candidiasis with amoxicillin (with or without clavulanic acid). Diarrhea was caused by use of amoxicillin-clavulanic acid, and candidiasis was caused by both amoxicillin and amoxicillin-clavulanic acid. Harms were poorly reported in most trials, and their true incidence may have been higher than reported. Nevertheless, these rates of common harms associated with amoxicillin therapy may inform decisions by helping clinicians to balance harms against benefits.


Mental Health Determinants Among a Psychiatric Outpatient Sample of Vietnamese Migrants in Germany.
Background: Mental health risk-factors for Asian migrants have been studied almost exclusively in the US, Canada, and Australia but not in European countries. Therefore, we aimed to identify sociodemographic, clinical, and migration-surrounding factors associated with experienced mental distress among Vietnamese migrants in Germany. Method: 305 Vietnamese migrants utilizing Germany's first Vietnamese psychiatric outpatient clinic filled out at admission the Brief-Symptom-Inventory 18 (BSI-18) as well as a questionnaire on 22 potential mental health determinants. Using a multiple linear regression model, we identified those sociodemographic, clinical, and migration-surrounding factors that were significantly related to the Global Severity Index (GSI) of the BSI-18. Results: The factors unemployment (B = -6.32, p = 0.014), financial problems (B = -10.71, p < 0.001), no or only little religious involvement (B = -3.23, p = 0.002), no psychiatric precontact (B = -7.35, p = 0.004), previous migration experiences (B = 8.76, p = 0.002), and perceived discrimination (B = 6.58, p = 0.011) were found to significantly increase the level of mental distress according to the BSI-GSI. Conclusion: Based on these results, we were able to construct a mental health risk-profile for Vietnamese migrants in Germany, which aims to detect candidates for psychiatric problems earlier and supply them with customized prevention and therapy options.


Syringohydromyelia in Cavalier King Charles spaniels.
Syringohydromyelia secondary to foramen magnum overcrowding is described in seven Cavalier King Charles spaniels. Clinical signs were consistent with a central spinal cord lesion. The most common signs were persistent scratching at the shoulder region with apparent neck, thoracic limb, or ear pain and thoracic limb lower motor neuron deficits. The diagnosis was made by magnetic resonance imaging. The syringohydromyelia is postulated to be a consequence of an occipital bone malformation resulting in a small caudal fossa and cerebellar herniation. Clinical signs improved but did not completely resolve when the dogs received treatment with corticosteroids or nonsteroidal anti-inflammatory drugs.


Associations between Respiratory Diseases and Dietary Patterns Derived by Factor Analysis and Reduced Rank Regression.
The study aims to identify children's dietary patterns and explore the relationship between dietary patterns and respiratory diseases. Subjects were 2,397 fourth graders in 14 Taiwanese communities who participated in the Taiwan Children Health Study. This study is based on an evaluation of dietary patterns, performed from April until June 2011. Information pertaining to respiratory disease was obtained by The International Study of Asthma and Allergies in Childhood questionnaire, and dietary intake data obtained by food frequency questionnaire. Factor analysis and reduced rank regression (RRR) were both used to analyze dietary patterns. Using factor analysis, it was found that children on a high-protein, high-fat, Western diet had a significantly higher risk of allergic rhinitis (OR 1.10, 95% CI 1.01-1.20). Lower ORs were noted for current wheezing, ever asthma and bronchitis in children eating a healthy diet than those on a high-protein, high-fat, Western diet. Using RRR, it was found that children on a high-protein, high-fat diet had significantly higher risks of allergic rhinitis (OR 1.17, 95% CI 1.07-1.27), current wheezing (OR 1.23, 95% CI 1.04-1.45) and bronchitis (OR 1.26, 95% CI 1.09-1.46). A diet rich in fat and protein may increase the risk of respiratory disease in children.