Combining location and expression data for principled discovery of genetic regulatory network models.
We develop principled methods for the automatic induction (discovery) of genetic regulatory network models from multiple data sources and data modalities. Models of regulatory networks are represented as Bayesian networks, allowing the models to compactly and robustly capture probabilistic multivariate statistical dependencies between the various cellular factors in these networks. We build on previous Bayesian network validation results by extending the validation framework to the context of model induction, leveraging heuristic simulated annealing search algorithms and posterior model averaging. Using expression data in isolation yields results inconsistent with location data so we incorporate genomic location data to guide the model induction process. We combine these two data modalities by allowing location data to influence the model prior and expression data to influence the model likelihood. We demonstrate the utility of this approach by discovering genetic regulatory models of thirty-three variables involved in S. cerevisiae pheromone response. The models we automatically generate are consistent with the current understanding regarding this regulatory network, but also suggest new directions for future experimental investigation.


Folic acid-coupled nano-paclitaxel liposome reverses drug resistance in SKOV3/TAX ovarian cancer cells.
Chemotherapy could be used as an effective treatment for ovarian cancer and subsequent peritoneal metastasis. Administration of chemoagents in a targeted manner may bring the advantage of higher efficiency and lower drug resistance. In the present study, folate receptor (FR)-targeted nano-paclitaxel formulations were generated and tested for cytotoxicity in a peritoneal xenograft model of paclitaxel-resistant ovarian cancer and SKOV3/TAX cell lines. Immunocytochemical staining confirmed the expression of FR in both SKOV3 and SKOV3/TAX cells. The enrichment of the folic acid-coupled PEGylated nano-paclitaxel liposome (FA-NP) in FR-positive cells was visualized with fluorescence. The uptake of the FA-NP peaked at 4 h and was more robust than nontargeted PEGylated nano-paclitaxel liposome (NP). FA-NP but not NP markedly inhibited the growth of ovarian cancer cells and induced a two-fold increase in the doubling time. The cytotoxic effects of FA-NP were more potent than NP in both SKOV3 cells [50% of inhibition concentration (IC50), 5.67 vs. 50.2 μg/ml, FA-NP vs. NP] and SKOV3/TAX cells (IC50, 0.38 vs. >200 μg/ml, FA-NP vs. NP). FA-NP caused more G2-M cell cycle arrest and apoptotic changes in ovarian cancer cells than NP or regular paclitaxel. However, these effects were blunted in the presence of free FA, which competitively inhibited the receptor-mediated uptake of FA-NP particles. Intraperitoneal (i.p.) administration of FA-NP but not regular paclitaxel, NP, or vehicle significantly prolonged the survival and reduced tumor nodule number (2.9±0.3) in BALB/c nude mice. FA-NP also markedly enhanced the percentage of apoptotic cells in peritoneal xenografts of paclitaxel-resistant ovarian cancer cells (44.6±8.5 vs. 3.2±1.1% for vehicle, 22.4±5.9% for regular paclitaxel, and 35.2±7.7% for NP; P<0.05). However, intravenous administration of FA-NP at the same dose failed to induce apoptosis (20.1±6.2%; P<0.05) and inhibit tumor nodule number to the same extent as intraperitoneal administration. FA-NP reversed the drug resistance in paclitaxel-resistant SKOV3/TAX ovarian cancer cells both in vitro and in vivo. Localized and targeted administration of the FR-targeted chemoagents might prolong the survival time in patients with drug-resistant ovarian cancer.


Regulatory effects of WRAP53 on radiosensitivity of laryngeal squamous cell carcinoma cells.
Telomere length is closely associated with cellular radiosensitivity and WRAP53 is required for telomere addition by telomerase. In this research we assessed radiosensitivity of laryngeal squamous cell carcinoma Hep-2 cell lines after WRAP53 inhibition, and analyzed the molecular mechanisms. phWRAP53-siRNA and pNeg-siRNA were constructed and transfected into Hep-2 cells with lipofectamine. Expression of WRAP53 was analyzed by RT-PCR and Western-blottin, radiosensitivity of Hep-2 cells was assessed colony formation assay, and the relative length of telomeres was measured by QPCR. The data revealed that the plasmid of phWRAP53-siRNA was constructed successfully, and the mRNA and protein levels of WRAP53 were both obviously reduced in the Hep-2 cell line transfected with phWRAP53-siRNA. After Hep-2 cells were irradiated with X-rays, the D0 and SF2 were 2.481 and 0.472, respectively, in the phWRAP53-siRNA group, much lower than in the control group (D0 and SF2 of 3.213 and 0.592) (P<0.01). The relative telomere length in the phWRAP53-siRNA group was 0.185±0.01, much lower than in the untreated group (0.523±0.06) and the control group (0.435±0.01). Decreasing the expression of WRAP53 using RNA interference technique can enhance the radiosensitivity of Hep-2 cell lines by influencing the telomere length. WRAP53 is expected to be a new target to regulate the radiosensitization of tumor cells.


Phenotypic characterisation of Saccharomyces spp. yeast for tolerance to stresses encountered during fermentation of lignocellulosic residues to produce bioethanol.
During industrial fermentation of lignocellulose residues to produce bioethanol, microorganisms are exposed to a number of factors that influence productivity. These include inhibitory compounds produced by the pre-treatment processes required to release constituent carbohydrates from biomass feed-stocks and during fermentation, exposure of the organisms to stressful conditions. In addition, for lignocellulosic bioethanol production, conversion of both pentose and hexose sugars is a pre-requisite for fermentative organisms for efficient and complete conversion. All these factors are important to maximise industrial efficiency, productivity and profit margins in order to make second-generation bioethanol an economically viable alternative to fossil fuels for future transport needs. The aim of the current study was to assess Saccharomyces yeasts for their capacity to tolerate osmotic, temperature and ethanol stresses and inhibitors that might typically be released during steam explosion of wheat straw. Phenotypic microarray analysis was used to measure tolerance as a function of growth and metabolic activity. Saccharomyces strains analysed in this study displayed natural variation to each stress condition common in bioethanol fermentations. In addition, many strains displayed tolerance to more than one stress, such as inhibitor tolerance combined with fermentation stresses. Our results suggest that this study could identify a potential candidate strain or strains for efficient second generation bioethanol production. Knowledge of the Saccharomyces spp. strains grown in these conditions will aid the development of breeding programmes in order to generate more efficient strains for industrial fermentations.


Does anonymity increase the reporting of mental health symptoms?
There is no doubt that the perceived stigma of having a mental disorder acts as a barrier to help seeking. It is possible that personnel may be reluctant to admit to symptoms suggestive of poor mental health when such data can be linked to them, even if their personal details are only used to help them access further care. This may be particularly relevant because individuals who have a mental health problem are more likely to experience barriers to care and hold stigmatizing beliefs. If that is the case, then mental health screening programmers may not be effective in detecting those most in need of care. We aimed to compare mental health symptom reporting when using an anonymous versus identifiable questionnaire among UK military personnel on deployment in Iraq. Survey among UK military personnel using two questionnaires, one was anonymous (n = 315) and one collected contact details (i.e. identifiable, n = 296). Distribution was by alternate allocation. Data were collected in Iraq during January-February 2009. No significant difference in the reporting of symptoms of common mental disorders was found (18.1% of identifiable vs. 22.9% of anonymous participants). UK military personnel were more likely to report sub-threshold and probable PTSD when completing questionnaires anonymously (sub-threshold PTSD: 2.4% of identifiable vs. 5.8% of anonymous participants; probable PTSD: 1.7% of identifiable vs. 4.8% of anonymous participants). Of the 11 barriers to care and perceived social stigma statements considered, those completing the anonymous questionnaire compared to those completing the identifiable questionnaire were more likely to endorse three statements: "leaders discourage the use of mental health services" (9.3% vs. 4.6%), "it would be too embarrassing" (41.6% vs. 32.5%) and "I would be seen as weak" (46.6% vs. 34.2%). We found a significant effect on the reporting of sub-threshold and probable PTSD and certain stigmatizing beliefs (but not common mental disorders) when using an anonymous compared to identifiable questionnaire, with the anonymous questionnaire resulting in a higher prevalence of PTSD and increased reporting of three stigmatizing beliefs. This has implications for the conduct of mental health screening and research in the US and UK military.


Thermodynamic interference with bile acid demicelleization reduces systemic entry and injury during cholestasis.
Bile acids (BA), with their large hydrophobic steroid nucleus and polar groups are amphipathic molecules. In bile, these exist as micelles above their critical micellar concentration (CMC). In blood at low concentrations, these exist as monomers, initiating cellular signals. This micellar to monomer transition may involve complex thermodynamic interactions between bile salts alone or with phospholipids, i.e. mixed micelles and the aqueous environment. We therefore went on to test if therapeutically relevant changes in temperature could influence micellar behavior of bile salts, and in turn whether this affected the biological responses in cells, and in vivo. Sodium taurocholate (STC) belongs to a major class of bile salts. STC has a CMC in the 5-8 mM range and its infusion into the pancreatic duct is commonly used to study pancreatitis. We thus studied micellar breakdown of STC using isothermal titration calorimetry (ITC), dynamic light scattering and cryogenic transmission electron microscopy. Under conditions relevant to the in vivo environment (pH 7.4, Na 0.15 M), ITC showed STC to have a U shaped reduction in micellar breakdown between 37 °C and 15 °C with a nadir at 25 °C approaching ≈90% inhibition. This temperature dependence paralleled pancreatic acinar injury induced by monomeric STC. Mixed micelles of STC and 1-palmitoyl, 2-oleyl phosphatidylcholine, a phospholipid present in high proportions in bile, behaved similarly, with ≈75% reduction in micellar breakdown at 25 °C compared to 37 °C. In vivo pancreatic cooling to 25 °C reduced the increase in circulating BAs after infusion of 120 mM (5%) STC into the pancreatic duct, and duct ligation. Lower BA levels were associated with improved cardiac function, reduced myocardial damage, shock, lung injury and improved survival independent of pancreatic injury. Thus micellar breakdown of bile salts is essential for their entry into the systemic circulation, and thermodynamic interference with this may reduce their systemic entry and consequent injury during cholestasis, such as from biliary pancreatitis.


Antigen recognized by monoclonal antibodies to mesencephalic neural crest and to ciliary ganglion neurons is involved in the high affinity choline uptake mechanism in these cells.
High-affinity choline uptake mechanisms are among the characteristics of cholinergic neurons such as the ciliary and choroid subpopulations in the ciliary ganglion (Barald and Berg, 1979). We have produced three monoclonal antibodies (Mabs), two of which were made to 8-day embryonic chick ciliary ganglion (CG) neurons (CG-1, CG-4) (Barald, 1982) and one of which was made to cultured mesencephalic neural crest (NC) cells (CG-14) removed from the embryo 31 hr after incubation. We have shown that all three Mabs label a common 75 kD antigen present on the cell surface of both CG neurons and NC cells (Barald, 1988). Here we report that the CG-1 and CG-4 antibodies, used in the same ratios in which they are synergistically cytotoxic for both the CG and NC cells (Barald, 1988), and Mab CG-14 alone, have specific effects on the high-affinity choline uptake mechanism (HACU) of CG neurons and isolated antigen-positive NC cells in the absence of complement. CG-1 and CG-4 in ratios of 8/1 (the same ratios that are used to kill the CG and the NC subpopulation), but neither singly, inhibit the HACU of CG neurons by 40% and that of isolated antigen-positive NC cells by 75%. However, CG-14 alone, at 1 microgram/ml, inhibits the HACU of both CG neurons and isolated NC cells by 95%. None of the antibodies had an effect on numbers of ouabain binding sites (a measure of the Na+/K+ ATPase) or cell surface acetylcholinesterase (AChE) of CG neurons or NC cells isolated by "no-flow" fluorescence cytometry with a Meridian Instruments ACAS470 cytometer. CG or NC cells grown in the presence of the antibodies without complement grow and remain healthy for many weeks. They exhibit no difference in morphology, protein content, lactate dehydrogenase activity (LDH), or division time from untreated sister cultures. Therefore, the antigen recognized by all three Mabs may be involved in a high-affinity choline uptake mechanism, a common characteristic of cholinergic neurons. The Mabs themselves may possibly label some element of the high-affinity transporter or a proximal membrane component. This implies that such a high-affinity uptake mechanism is present in the subpopulation of NC cells at early times in development. If these cells in fact are destined to contribute to the avian CG, these characteristics are present in the subpopulation before the NC cells take on a neuronal morphology.


Linking white matter and deep gray matter alterations in premanifest Huntington disease.
Huntington disease (HD) is a fatal progressive neurodegenerative disorder for which only symptomatic treatment is available. A better understanding of the pathology, and identification of biomarkers will facilitate the development of disease-modifying treatments. HD is potentially a good model of a neurodegenerative disease for development of biomarkers because it is an autosomal-dominant disease with complete penetrance, caused by a single gene mutation, in which the neurodegenerative process can be assessed many years before onset of signs and symptoms of manifest disease. Previous MRI studies have detected abnormalities in gray and white matter starting in premanifest stages. However, the understanding of how these abnormalities are related, both in time and space, is still incomplete. In this study, we combined deep gray matter shape diffeomorphometry and white matter DTI analysis in order to provide a better mapping of pathology in the deep gray matter and subcortical white matter in premanifest HD. We used 296 MRI scans from the PREDICT-HD database. Atrophy in the deep gray matter, thalamus, hippocampus, and nucleus accumbens was analyzed by surface based morphometry, and while white matter abnormalities were analyzed in (i) regions of interest surrounding these structures, using (ii) tractography-based analysis, and using (iii) whole brain atlas-based analysis. We detected atrophy in the deep gray matter, particularly in putamen, from early premanifest stages. The atrophy was greater both in extent and effect size in cases with longer exposure to the effects of the CAG expansion mutation (as assessed by greater CAP-scores), and preceded detectible abnormalities in the white matter. Near the predicted onset of manifest HD, the MD increase was widespread, with highest indices in the deep and posterior white matter. This type of in-vivo macroscopic mapping of HD brain abnormalities can potentially indicate when and where therapeutics could be targeted to delay the onset or slow the disease progression.


Activation of gelatinolytic/collagenolytic activity in dentin by self-etching adhesives.
Mild acids are known to activate dentin matrix metalloproteinase (MMPs). All self-etching dental adhesives are acidic (pH 1.5-2.7) and may activate dentin MMPs. The purpose of this study was to compare the ability of several all-in-one adhesives to activate gelatinolytic and collagenolytic activities in powdered mineralized dentin. Powdered dentin made from human teeth was mixed with all-in-one adhesives (Clearfil Tri-S Bond, G-Bond, Adper Prompt L-Pop) or a self-etching primer (Clearfil SE Bond primer) for varying times and then the reaction was stopped by extracting the adhesives using acetone. Fresh untreated mineralized dentin powder had a gelatinolytic activity of 3.31 +/- 0.39 relative fluorescent units (RFU) per mg dry weight (24 h) that increased, over storage time, to 87.5 RFU mg(-1) (24 h) after 6-8 wk. When fresh powder was treated with acidic Tri-S Bond, the gelatinolytic activity increased from 3.24 +/- 0.70 RFU mg(-1) to > 112.5 RFU mg(-1) (24 h) after 20 min and then remained unchanged. Monomers with lower pH values produced less activity. There was a significant, direct correlation between gelatinolytic activity and pH, with Tri-S giving the highest activity. Coating dentin powder with Tri-S resin prevented fluorescent substrates from gaining access to the enzyme, even though it activated the enzyme. In conclusion, self-etch adhesives may activate latent MMP and increase the activity to near-maximum levels and contribute to the degradation of resin-dentin bonds over time.


Recommendations for research design and reporting in computer-assisted diagnosis to facilitate meta-analysis.
Computer-assisted diagnosis (CAD) describes a diverse, heterogeneous range of applications rather than a single entity. The aims and functions of CAD systems vary considerably and comparing studies and systems is challenging due to methodological and design differences. In addition, poor study quality and reporting can reduce the value of some publications. Meta-analyses of CAD are therefore difficult and may not provide reliable conclusions. Aiming to determine the major sources of heterogeneity and thereby what CAD researchers could change to allow this sort of assessment, this study reviews a sample of 147 papers concerning CAD used with imaging for cancer diagnosis. It discusses sources of variability, including the goal of the CAD system, learning methodology, study population, design, outcome measures, inclusion of radiologists, and study quality. Based upon this evidence, recommendations are made to help researchers optimize the quality and comparability of their trial design and reporting.


Global Reconstruction of Naturalized River Flows at 2.94 Million Reaches.
Spatiotemporally continuous global river discharge estimates across the full spectrum of stream orders are vital to a range of hydrologic applications, yet they remain poorly constrained. Here we present a carefully designed modeling effort (Variable Infiltration Capacity land surface model and Routing Application for Parallel computatIon of Discharge river routing model) to estimate global river discharge at very high resolutions. The precipitation forcing is from a recently published 0.1° global product that optimally merged gauge-, reanalysis-, and satellite-based data. To constrain runoff simulations, we use a set of machine learning-derived, global runoff characteristics maps (i.e., runoff at various exceedance probability percentiles) for grid-by-grid model calibration and bias correction. To support spaceborne discharge studies, the river flowlines are defined at their true geometry and location as much as possible-approximately 2.94 million vector flowlines (median length 6.8 km) and unit catchments are derived from a high-accuracy global digital elevation model at 3-arcsec resolution (~90 m), which serves as the underlying hydrography for river routing. Our 35-year daily and monthly model simulations are evaluated against over 14,000 gauges globally. Among them, 35% (64%) have a percentage bias within ±20% (±50%), and 29% (62%) have a monthly Kling-Gupta Efficiency ≥0.6 (0.2), showing data robustness at the scale the model is assessed. This reconstructed discharge record can be used as a priori information for the Surface Water and Ocean Topography satellite mission's discharge product, thus named "Global Reach-level A priori Discharge Estimates for Surface Water and Ocean Topography". It can also be used in other hydrologic applications requiring spatially explicit estimates of global river flows.


Hydrodynamically Coupled Brownian Dynamics: A coarse-grain particle-based Brownian dynamics technique with hydrodynamic interactions for modeling self-developing flow of polymer solutions.
We present a novel coarse-grain particle-based simulation technique for modeling self-developing flow of dilute and semi-dilute polymer solutions. The central idea in this paper is the two-way coupling between a mesoscopic polymer model and a phenomenological fluid model. As our polymer model, we choose Responsive Particle Dynamics (RaPiD), a Brownian dynamics method, which formulates the so-called "conservative" and "transient" pair-potentials through which the polymers interact besides experiencing random forces in accordance with the fluctuation dissipation theorem. In addition to these interactions, our polymer blobs are also influenced by the background solvent velocity field, which we calculate by solving the Navier-Stokes equation discretized on a moving grid of fluid blobs using the Smoothed Particle Hydrodynamics (SPH) technique. While the polymers experience this frictional force opposing their motion relative to the background flow field, our fluid blobs also in turn are influenced by the motion of the polymers through an interaction term. This makes our technique a two-way coupling algorithm. We have constructed this interaction term in such a way that momentum is conserved locally, thereby preserving long range hydrodynamics. Furthermore, we have derived pairwise fluctuation terms for the velocities of the fluid blobs using the Fokker-Planck equation, which have been alternatively derived using the General Equation for the Non-Equilibrium Reversible-Irreversible Coupling (GENERIC) approach in Smoothed Dissipative Particle Dynamics (SDPD) literature. These velocity fluctuations for the fluid may be incorporated into the velocity updates for our fluid blobs to obtain a thermodynamically consistent distribution of velocities. In cases where these fluctuations are insignificant, however, these additional terms may well be dropped out as they are in a standard SPH simulation. We have applied our technique to study the rheology of two different concentrations of our model linear polymer solutions. The results show that the polymers and the fluid are coupled very well with each other, showing no lag between their velocities. Furthermore, our results show non-Newtonian shear thinning and the characteristic flattening of the Poiseuille flow profile typically observed for polymer solutions.


Development and Reporting of Prediction Models: Guidance for Authors From Editors of Respiratory, Sleep, and Critical Care Journals.
Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.


The Breast Cancer Working Group presentation was divided into three sections: the epidemiology, pathology and treatment of breast cancer.
EPIDEMIOLOGY OF BREAST CANCER: The incidence and mortality of breast cancer are lower in Asia than in the West, particularly in post-menopausal women, but they are increasing. The age patterns of the incidence of breast cancer in Asia differ from in the West: in most Asian countries the peak incidence of breast cancer is at about age 45-50, whereas in western countries the incidence continues to increase even at older ages. Mortality is decreasing in western countries, whereas it is still increasing in Asian nations. There are many epidemiological factors involved in breast cancer, and important known risk factors include diet, obesity and diabetes. Asian studies found that high intake of isoflavones reduced the risk of breast cancer. PATHOLOGY OF BREAST CANCER: With regard to the pathology of breast cancer, for the molecular subtype, luminal A and luminal B are being used, while HER2 expression and rapid proliferation are also employed. Study results showed a somewhat higher prevalence of luminal A in Japanese compared with Americans. Ductal carcinoma in situ breast cancer is less frequent in Asian breast cancer patients than in Americans. The Working Group resolved to establish an international committee for pathological assessment of breast cancer in Asia. TREATMENT OF BREAST CANCER: Pharmacokinetics-pharmacodynamics studies are needed between ethnic backgrounds, investigating aromatase inhibitors and tamoxifen (endoxifen), as well as the effects of demographic factors such as diet, medical care, body mass index, etc. Correlations between adverse events and the clinical outcome also need to be studied.


The nonpolymorphic MHC class II isotype, HLA-DQA2, is expressed on the surface of B lymphoblastoid cells.
The more centromeric of the two human MHC class II DQA genes, DQA2, has not previously been shown to express a protein product. However, its high degree of sequence similarity to DQA1, the fact that it is highly evolutionarily conserved, and the recent demonstration of its transcription in some cell lines suggest that a DQA2 alpha-chain may be expressed. Polyclonal anti-peptide antisera were generated and shown to be specific for DQA2 in Western blotting of Triton X-114 preparations of B lymphoblastoid cell lines. DQA2 expression is variable, although always at least threefold less than that of DQA1, and is found in all haplotypes examined. Immunoprecipitations of biotin-labeled cell surface proteins reveal that DQA2 appears at the cell surface. In keeping with others' findings, no evidence for an expressed DQB2 beta-chain was found, prompting investigation of the means by which DQA2 gains access to the cell surface. Antisera specific for allotypic and isotypic MHC class II beta-chains were used in sequential immunoprecipitation experiments to search for a beta-chain partner for DQA2, and a transfectant system was established in an attempt to promote pairing of DQA2 with a selected DQB1 (*0501) chain. In neither case was DQA2 found to dimerize with an MHC class II beta-chain. Despite this, DQA2 is capable of forming a complex with invariant chain.


Task difficulty modulates brain activation in the emotional oddball task.
Previous functional magnetic resonance imaging (fMRI) studies have reported that task-irrelevant, emotionally salient events can disrupt target discrimination, particularly when attentional demands are low, while others demonstrate alterations in the distracting effects of emotion in behavior and neural activation in the context of attention-demanding tasks. We used fMRI, in conjunction with an emotional oddball task, at different levels of target discrimination difficulty, to investigate the effects of emotional distractors on the detection of subsequent targets. In addition, we distinguished different behavioral components of target detection representing decisional, nondecisional, and response criterion processes. Results indicated that increasing target discrimination difficulty led to increased time required for both the decisional and nondecisional components of the detection response, as well as to increased target-related neural activation in frontoparietal regions. The emotional distractors were associated with activation in ventral occipital and frontal regions and dorsal frontal regions, but this activation was attenuated with increased difficulty. Emotional distraction did not alter the behavioral measures of target detection, but did lead to increased target-related frontoparietal activation for targets following emotional images as compared to those following neutral images. This latter effect varied with target discrimination difficulty, with an increased influence of the emotional distractors on subsequent target-related frontoparietal activation in the more difficult discrimination condition. This influence of emotional distraction was in addition associated specifically with the decisional component of target detection. These findings indicate that emotion-cognition interactions, in the emotional oddball task, vary depending on the difficulty of the target discrimination and the associated limitations on processing resources.


A Comparison of Sound Levels in Open Plan Versus Pods in a Neonatal Intensive Care Unit.
The objective of this study was to compare the noise levels recorded in two different neonatal intensive care unit (NICU) settings: a pod and an open plan NICU located in the same hospital. The NICU is a busy environment with ambient noise levels that often exceed established recommendations. This noise deleteriously affects the physiological stability and developmental outcomes of sick and preterm infants. Pods have reduced numbers of cots (in this case, 6) compared to open plan NICUs (in this case, 11), yet the noise levels in pods have not been reported. This study compared real-time decibel (dB) levels in an A-weighted scale, captured continuously by sound dosimeters mounted in both NICU settings for a period of 4 weeks: a pod setting and an open plan NICU. Researchers also collected observational data. The average noise level recorded in the pod was 3 dBs less than in the open plan NICU. This result was statistically significant. However, dB recordings in both areas were over the recommended limits by 4-6 dBs, with isolated peaks between 74.5 dBs (NICU) and 75.9 dBs (pod). Observational data confirmed this correlation. Further research to evaluate interventions to decrease the noise levels in both settings are needed, especially during times of peak activity. Staff working in these settings need to be more aware that control of acoustic levels is important in the neuroprotection of neonates. Coupling this with careful consideration to structural components and evidence-based design planning may contribute to lowering dB levels in the NICU environment.


Modified Harada-Mori and simple wet mount to determine hookworm infections in Yo Island urban area, Songkhla, Southern Thailand.
Hookworm was a previously dominant parasitic infection in Southern Thailand. The changing population to an aging society in Yo Island has never been investigated for intestinal parasites. This study aimed to estimate the prevalence of hookworm and intestinal parasitic infections on Yo Island, a small island in Songkhla Province of southern Thailand. A cross-sectional study was conducted among volunteers aged 15 and above to give one stool sample that was screened by wet mount for intestinal parasites and the modified Harada-Mori culture (mHMFPC) which is adapted from HMFPC, using local plastic bag containers instead of test tubes for hookworm detection. Two hundred forty-seven volunteers (females = 160) gave one stool. The highest participation was in age group higher than 60 years. Most were Buddhism (89.1%), agriculturist (71.4%), non-education (87.9%), and income lower than 9000 baht (50.2%). The prevalence of intestinal parasites was 13/247 (5.3%) of which 6/247 (2.4%) were positive for hookworm species Necator americanus. One volunteer was coinfected with hookworm and Strongyloides stercoralis and another with Endolimax nana and Blastocystis hominis. The mHMFPC detected more positive stool samples than wet mount and wet mount: 5 vs. 2. Parasite prevalence was low in this urban community of mostly low-income village dwellers. The mHMFPC appeared better at detecting hookworm but numbers were small. Combined techniques are suitable for field use.


Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates.
Exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological complications. Exchange transfusion is not without risk and intravenous immunoglobulin has been suggested as an alternative therapy for isoimmune haemolytic jaundice to reduce the need for exchange transfusion. To assess whether the use of intravenous immunoglobulin, in newborn infants with isoimmune haemolytic jaundice, is effective in reducing the need for exchange transfusion. The search strategy of the Cochrane Neonatal Review group was used. Searches were made of MEDLINE 1966-2002, EMBASE Drugs and Pharmacology 1990-2002, Cochrane Controlled Trials Register, The Cochrane Library, Issue 1, 2002, expert informants, review articles, cross references, and hand searching of abstracts and conference proceedings of the annual meetings of The Society for Pediatric Research 1990-2001 and The European Society for Paediatric Research 1990-2001. All randomised and quasi-randomised controlled trials of the use of intravenous immunoglobulin in the treatment of isoimmune haemolytic disease were considered. The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Studies were assessed for inclusion and quality by two reviewers working independently, with the second reviewer blinded to trial author, institution and journal of publication. Data were extracted independently by the two reviewers. Any differences of opinion were discussed and a consensus reached. Investigators were contacted for additional or missing information. For categorical outcomes, the relative risk (RR), risk difference (RD) and the number needed to treat (NNT) were calculated. For continuous variables, the weighted mean difference (WMD) was calculated. Seven studies were identified. Three of these fulfilled the inclusion criteria and included a total of 189 infants. Term and preterm infants and infants with rhesus and ABO incompatibility were included. The use of exchange transfusion decreased significantly in the immunoglobulin treated group (typical RR 0.28, 95% CI 0.17, 0.47; typical RD -0.37, 95% CI -0.49, -0.26; NNT 2.7). The mean number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (WMD -0.52, 95% CI -0.70, -0.35). None of the studies assessed long term outcomes. Although the results show a significant reduction in the need for exchange transfusion in those treated with intravenous immunoglobulin, the applicability of the results is limited. The number of studies and infants included is small and none of the three included studies was of high quality. The protocols of two of the studies mandated the use of early exchange transfusion, limiting the generalizability of the results. Further well designed studies are needed before routine use of intravenous immunoglobulin can be recommended for the treatment of isoimmune haemolytic jaundice.


Functional MRI of emotional memory in adolescent depression.
Major Depressive Disorder (MDD) is a leading cause of disease burden worldwide. Mood-congruent biases in memory tasks are frequently reported in MDD patients, with facilitated memory for negative stimuli. Most functional MRI studies to date have examined the neural correlates of these biases in depressed adults, with fewer studies in adolescents with MDD. Investigation of MDD in adolescence may aid greater understanding of the aetiology and development of the disorder. Cognitive biases were investigated in 56 MDD patients aged 11-17 years and a matched group of 30 healthy control participants with a self-referential memory task. Behavioural performance and BOLD fMRI data were collected during both encoding and retrieval stages. The neural response to encoding in adolescents with MDD was found to differ significantly from controls. Additionally, neural responses during encoding and retrieval showed differential relationships with age between patient and control groups, specifically in medial, temporal, and prefrontal regions. These findings suggest that during adolescence neurophysiological activity associated with emotional memory differs in those with depression compared to controls and may be age sensitive.


Hydrogen gas is ineffective in moderate and severe neonatal hypoxia-ischemia rat models.
Hydrogen gas (H(2)) has been shown to ameliorate brain injury in experimental adult rat focal ischemia and in a mild neonatal hypoxia-ischemia (HI, 90 min hypoxia) rat model. In this study we tested H(2) in moderate (120 min hypoxia) and severe (150 min hypoxia) neonatal HI rat models. We hypothesized that H(2) would improve outcomes after neonatal HI by scavenging free radicals. Two hundred (200) unsexed Sprague-Dawley rats at day 10 of life (p10) underwent neonatal HI with the Rice-Vannucci model. Multiple treatment protocols were studied, including pre-ischemic treatment, intra-ischemic treatment, and post-ischemic treatment (Sham n=32, HI n=82, HI+H(2)n=86). We also tested H(2) in middle cerebral artery occlusion (MCAO) in adult rats (MCAO n=9, MCAO+H(2)n=7) for comparison. Analysis at 24 h included infarction volume, measurement of brain concentration of malondialdehyde (MDA) (an end-product of lipid peroxidation), daily weight, Nissl histology, and mortality. In moderate and severe neonatal HI models, hydrogen gas therapy (2.9% concentration H(2)) was not associated with decreased volume of infarction or decreased concentration of MDA. H(2) gas pretreatment (2.9%) was associated with increased infarction volume in neonatal HI. In MCAO in adult rats, H(2) gas therapy demonstrated a trend of beneficial effect. Exposure of H(2) gas to non-ischemic neonates resulted in a significant increase in brain concentration of MDA. We conclude that 2.9% H(2) gas therapy does not ameliorate moderate to severe ischemic damage in neonatal hypoxia-ischemia.


Vulnerable and Grandiose Narcissism Are Differentially Associated With Ability and Trait Emotional Intelligence.
We examined the association between two types of narcissism, grandiose and vulnerable, and self-reported as well as ability emotional intelligence (EI). Grandiose narcissism is characterized by high self-esteem, interpersonal dominance and a tendency to overestimate one's capabilities, whereas vulnerable narcissism presents defensive, avoidant and hypersensitive attitude in interpersonal relations. In the current study (n = 249) we found that vulnerable narcissism was significantly and negatively associated with trait (self-reported) EI; however, it did not correlate with ability (performance) EI. Grandiose narcissism was significantly positively connected with trait EI. Moreover, when the two EI scores were analyzed together in a single model, they were associated with grandiose narcissism in opposite directions. Specifically, trait EI showed a positive relation with grandiose narcissism, while ability EI negatively predicted this type of narcissism. The latter results are consistent with previous findings showing that individuals with high level of grandiose narcissism tend to overestimate their abilities. Vulnerable narcissism is probably connected with more realistic self-perception of emotional abilities.


Inflammatory response markers in rats undergoing abdominal surgical procedures.
The aim of this study was to determine the effectiveness of cortisol, interleukin (IL)-6, C-reactive protein (CRP), and white blood cell (WBC) count as inflammatory markers to evaluate the postoperative inflammatory response associated with various abdominal surgical procedures in rats. Wistar albino rats (N=152) were randomly assigned to 7 groups: control, hepatectomy, splenectomy, nephrectomy, colectomy, gastrectomy, and sham. Apart from the control group, each group was then divided into 3 subgroups: 6th, 24th and 48th h. Thus, a total of 19 groups were defined, each including 8 rats. At the 6th, 24th and 48th h following the surgical procedures blood samples from each rat were collected. The plasma concentrations of IL- 6, cortisol, CRP, and WBC were measured. Both the surgery category and the elapsed time after the surgery had a significant effect on IL-6 levels (P<0.0001). Blood CRP levels were primarily determined by the surgery category (P<0.0001). Neither surgery nor the elapsed time had a significant effect on the cortisol levels. The elapsed time after surgery was the major factor that influenced the differences in WBC count among the surgery groups (P<0.0001). Our results cumulatively indicate that the levels of IL-6, CRP, and cortisol and WBC count change at different time points after several abdominal surgical procedures. Cortisol level is not related to the type of surgical procedure or the elapsed time, while WBC count decreases with the elapsed time. None of the changes in the markers investigated in this study is specifically related to the category of abdominal surgical procedure.


Vitamins and minerals: issues associated with too low and too high population intakes.
There is an ongoing increase in the availability of foods fortified with micronutrients and dietary supplements. This may result in differing intakes of micronutrients within the population and perhaps larger differences in intakes. Insight into population micronutrient intakes and evaluation of too low or too high intakes is required to see whether there are potential problems regarding inadequacy or excessive intakes. Too low population intakes are evaluated against an estimated average requirement; potential too high population intakes are evaluated against a tolerable upper intake level (UL). Additional health effects, seriousness, and incidence of these health effects are not considered but these can be taken into account in a benefit-risk assessment. Furthermore, authorities would like to regulate food fortification and supplementation in such a way that most of the population is not at risk of potentially high intakes. Several models are available for estimating maximum levels of micronutrients for food fortification and dietary supplements. Policy makers and risk managers need to decide how to divide the 'free space' between food fortification and/or dietary supplements, while protecting populations from adverse health effects.


Different Patterns of Correlation between Grey and White Matter Integrity Account for Behavioral and Psychological Symptoms in Alzheimer's Disease.
Behavioral disorders and psychological symptoms (BPSD) in Alzheimer's disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: Mood (i.e., anxiety and depression; ADmood), Frontal (i.e., dishinibition and elation; ADfrontal), and Psychotic (delusions and hallucinations; ADpsychotic) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD.


"Practice so that the skill does not disappear": mixed methods evaluation of simulator-based learning for midwives in Uganda.
Postpartum hemorrhage and neonatal asphyxia are leading causes of maternal and neonatal mortality, respectively, that occur relatively rarely in low-volume health facilities in sub-Saharan Africa. Rare occurrence of cases may limit the readiness and skills that individual birth attendants have to address complications. Evidence suggests that simulator-based training and practice sessions can help birth attendants maintain these life-saving skills; one approach is called "low-dose, high-frequency" (LDHF). The objective of this evaluation is to determine the facilitating factors and barriers to participation in LDHF practice, using qualitative and quantitative information. A trial in 125 facilities in Uganda compared three strategies of support for LDHF practice to improve retention of skills in prevention and treatment of postpartum hemorrhage and neonatal asphyxia. Birth attendants kept written logs of their simulator-based practice sessions, which were entered into a database, then analyzed using Stata to compare frequency of practice by the study arm. The evaluation also included 29 in-depth interviews and 19 focus group discussions with birth attendants and district trainers. Transcripts were entered in Atlas.ti software for coding, then analyzed using content analysis to identify factors that motivated or discouraged simulator-based practice. Practice log data indicated that simulator-based practice sessions occurred more frequently in facilities where one or two practice coordinators helped schedule and lead the practice sessions and in health centers compared to hospitals. The qualitative data suggest that birth attendants who practiced more were motivated by a desire to maintain skills and be prepared for emergencies, external recognition, and establishing a set schedule. Barriers to consistent practice included low staffing levels, heavy workloads, and a sense that competency can be maintained through routine clinical care alone. Some facilities described norms around continuing education and some did not. Designating practice coordinators to lead their peers in simulator-based practice led to more consistent skills practice within frontline health facilities. Ongoing support, scheduling of practice sessions, and assessment and communication of motivation factors may help sustain LDHF practice and similar forms of continuing professional development. Registered with clinicaltrials.gov #NCT03254628 on August 18, 2018 (registered retrospectively).


IL-13-driven alterations in hepatic cholesterol handling contributes to hypercholesterolemia in a rat model of minimal change disease.
Circulating factors have been implicated in the pathogenesis of minimal change disease (MCD), and may have direct effects on cholesterol metabolism. This study investigated the pathogenesis of hypercholesterolemia in an IL-13 overexpression rat model of MCD prior to the onset of proteinuria, so as to establish the direct contribution of IL-13, especially with regard to hepatic cholesterol handling. In this model of MCD, the temporal relationship between hypercholesterolemia and proteinuria was first identified. Plasma proprotein convertase subtilisin/kexin type 9 (Pcsk9) and liver ATP-binding cassette sub-family G member 5 (Abcg5) were measured using ELISA. Liver Ldlr and liver X receptor alpha (Lxra) were quantified with Western blot. Abcg5-mediated cholesterol efflux in IL-13-stimulated rat primary hepatocytes was measured using taurocholate as cholesterol acceptor. The role of Lxra was validated using a luciferase assay in Lxre-luciferase-transfected IL-13-stimulated hepatocytes. IL-13-transfected rats developed hypercholesterolemia prior to proteinuria, with 35% of rats hypercholesterolemic but only 11% proteinuric by Day 20 (P = 0.04). These pre-proteinuric hypercholesterolemic rats showed elevations in total and LDL-cholesterol, but not hypertriglyceridemia or hepatic steatosis. The hypercholesterolemia was associated with increased hepatic Pcsk9 synthesis and enhanced circulating Pcsk9 levels, which correlated strongly with plasma total cholesterol (r = 0.73, P<0.001). The hypercholesterolemia was also contributed by decreased Abcg5 expression and activity, due to reduced Lxra expression. Lxra expression correlated with plasma total cholesterol levels (r = -0.52, P = 0.01), and overexpression of pLxra in rat hepatocytes abrogated the IL-13-mediated down-regulation of Lxre-driven gene expression. In conclusion, we have shown that IL-13 induced changes in hepatic cholesterol handling in a cytokine-induced rat model of MCD, resulting in hypercholesterolemia which can precede the onset of proteinuria.


Understanding the mechanisms of a combined physical and psychological intervention for people with neurogenic claudication: protocol for a causal mediation analysis of the BOOST trial.
Conservative treatments such as exercise are recommended for the management of people with neurogenic claudication from spinal stenosis. However, the effectiveness and mechanisms of effect are unknown. This protocol outlines an a priori plan for a secondary analysis of a multicentre randomised controlled trial of a physiotherapist-delivered, combined physical and psychological intervention (Better Outcomes for Older people with Spinal Trouble (BOOST) programme). We will use causal mediation analysis to estimate the mechanistic effects of the BOOST programme on the primary outcome of disability (measured by the Oswestry Disability Index). The primary mechanism of interest is walking capacity, and secondary mediators include fear-avoidance behaviour, walking self-efficacy, physical function, physical activity and/or symptom severity. All mediators will be measured at 6 months and the outcome will be measured at 12 months from randomisation. Patient characteristics and possible confounders of the mediator-outcome effect will be measured at baseline. Sensitivity analyses will be conducted to evaluate the robustness of the estimated effects to varying levels of residual confounding. Ethical approval was given on 3 March 2016 (National Research Ethics Committee number: 16/LO/0349). The results of this analysis will be disseminated in peer-reviewed journals and at relevant scientific conferences. ISRCTN12698674.


Serum total and HDL cholesterol and risk of prostate cancer.
Studies suggest a decreased risk of high-grade prostate cancer in men with lower circulating total cholesterol and that statins may protect against aggressive disease. Confirmation in additional populations and examination of associations for lipoprotein subfractions are needed. We examined prostate cancer risk and serum total and HDL cholesterol in the ATBC Study cohort (n = 29,093). Cox proportional hazards models were used to estimate the relative risk of total (n = 2,041), non-aggressive (n = 829), aggressive (n = 461), advanced (n = 412), and high-grade (n = 231) prostate cancer by categories of total and HDL cholesterol. After excluding the first 10 years of follow-up, men with higher serum total cholesterol were at increased risk of overall (≥240 vs. <200 mg/dl: HR = 1.22, 95% CI 1.03-1.44, p-trend = 0.01) and advanced (≥240 vs. <200 mg/dl: HR = 1.85, 95% CI 1.13-3.03, p-trend = 0.05) prostate cancer. Higher HDL cholesterol was suggestively associated with a decreased risk of prostate cancer regardless of stage or grade. In this population of smokers, high serum total cholesterol was associated with higher risk of advanced prostate cancer, and high HDL cholesterol suggestively reduced the risk of prostate cancer overall. These results support previous studies and, indirectly, support the hypothesis that statins may reduce the risk of advanced prostate cancer by lowering cholesterol.


Poly(3-hexylthiophene) nanowires in porous alumina: internal structure under confinement.
We study the structure of poly(3-hexylthiophene) (P3HT) subjected to nanoscale confinement in two dimensions (2D) as imposed by the rigid walls of nanopore anodic aluminum oxide (AAO) templates. P3HT nanowires with aspect ratios (length-to-diameter) above 1000 and diameters ranging between 15 nm and 350 nm are produced in the pores of the AAO templates via two processing routes. These are, namely, drying a solution or cooling from the melt. Our study focuses on the effects of nanoconfinement on the semicrystalline nature of the nanowires, the orientation of crystals, and the evolution of the structures that P3HT might develop under confinement, which we investigate by combining imaging (SEM), spectroscopic (FTIR, photoluminescence) and structural characterization (WAXS, DSC) techniques. Solution-processed P3HT nanowires are essentially amorphous and porous, whereas melt-processed nanowires are semicrystalline, and present a more compact morphology and smoother surfaces. In the latter case, the orientation of crystals was found to strongly depend on the pore diameter. In large diameter nanowires (250 nm and 120 nm), crystals are oriented laying the π-π stacking direction parallel to the nanowire axis. In contrast, in small diameter nanowires, the π-π stacking direction is mainly perpendicular to the nanowires, as crystals are likely to nucleate at pore walls. The structural evolution of P3HT upon heating into weakly (250 nm in diameter) and strongly (15 nm in diameter) confining pores has been studied. A complex set of structures is observed, i.e., crystals, a solid layered mesophase, a nematic/smectic mesophase, and the isotropic melt. Interestingly, a rare crystal polymorph (form II) is also observed under strong confinement conditions together with the usual lamellar crystal form I. Furthermore, we show that nanoconfinement stabilizes form II: such crystals are still present at 210 °C while in the bulk they get converted to form I crystals at around 50 °C.


Bilateral first rib resection and scalenectomy is effective for treatment of thoracic outlet syndrome.
Because of the small numbers of thoracic outlet syndrome (TOS) patients treated with bilateral first rib resection and scalenectomy (FRRS), this patient subset has not been well studied. We examined a large cohort of TOS patients who underwent bilateral FRRS to evaluate patient characteristics and outcomes. Patients treated with bilateral FRRS at Johns Hopkins Medical Institutions from 2003 to 2012 were identified by review of a prospectively maintained database. Statistical analysis compared patients with unilateral and bilateral FRRS and bilateral patients with different TOS indications. Fifty-three patients underwent bilateral FRRS with a mean follow-up of 11.4 months. Average time between operations was 17.0 months (range, 5.1-59.8 months). Compared with 408 unilateral FRRS patients, bilateral patients were younger (30 vs 35 years; P = .012), with no significant difference in gender. Among patients with dual-sided FRRS, 25 (47%) had bilateral neurogenic symptoms, 2 (4%) had bilateral arterial symptoms, and 26 (49%) had venous symptoms with the first side due to intermittent compression in 5 (second side: four, intermittent compression; one, neurogenic) and effort thrombosis in 21 (second side: 9, effort thrombosis; 8, intermittent compression; 4, neurogenic). Ten patients had prophylactic FRRS to prevent contralateral venous or arterial thrombosis, and eight had cervical ribs. Compared with neurogenic patients, venous patients were younger (25 vs 35 years; P < .001), with a trend toward more competitive athletes (seven venous vs two neurogenic). Symptomatic restenosis requiring dilation occurred after four FRRS for venous symptoms at a mean of 32.4 months, and rethrombosis occurred after four FRRS at a mean of 4 weeks (one treated with warfarin, three with tissue plasminogen activator), all on the primary side. Overall, 88% of FRRS for symptomatic TOS led to resolved symptoms at last follow-up. Bilateral FRRS is an effective method for treatment of TOS. Venous bilateral patients more often are younger, are competitive athletes, and require close postoperative monitoring for recurrent stenosis and thrombosis.


The Role of Laparoscopy in Penetrating Abdominal Trauma: Our Initial Experience.
Diagnostic and therapeutic laparoscopy is a known approach in managing patients with penetrating abdominal trauma (PAT). However, multiple controversies exist on indications, contraindications, and its appropriateness. The aim of this study was to evaluate the appropriateness of diagnostic and therapeutic laparoscopy in patients with PAT at Dr George Mukhari Academic Hospital, Pretoria, South Africa. This was a retrospective, observational study. All patients with PAT managed by diagnostic and therapeutic laparoscopy during 2012-2013 were included. Recorded indications and contraindications, the mechanism of injury, the anatomical location of injury, intraoperative findings, reasons for conversion, and adverse outcomes (complications, reoperations and mortality) were analyzed in every case. One hundred fourteen patients were included. Stab injuries were sustained by 81 (71%) patients, and 33 (29%) patients sustained gunshot wounds (GSW) to the abdomen. The conversion rate was 7%. The operation was completed laparoscopically in 106 patients: 79 with stab wounds (74.5%) and 27 with GSW (25.5%). Laparoscopy was diagnostic for 44 patients (41.5%) and therapeutic for 62 patients (58.5%). In total, 13 patients (12%) required re-intervention, and 2 patients died (1.9%). The complications were not specific to the laparoscopic approach. No missed injuries were reported in the study. Diagnostic and therapeutic laparoscopy in patients with PAT is an appropriate management in hemodynamically stable patients or those responsive to initial resuscitation. The location of injuries is not a limiting factor, although it affects placement of ports. The conversion is not a complication but rather the correct way of completing the operation in an appropriate situation. It should be considered in patients with extensive intraabdominal bleeding suggesting the possibility of major vessel injury, a significant deterioration of the patient, and the complexity of injuries requiring a prolonged laparoscopic procedure.


Tracking of obesity-related behaviours from childhood to adulthood: A systematic review.
Obesity in childhood carries a wide range of physical, psychological and social disbenefits and also increases the risk of adult obesity with its well-recognised, enhanced risk of several common complex diseases as well as adverse socioeconomic and psychosocial sequelae. Understanding the tracking of the two key modifiable behaviours, food consumption and physical activity, between childhood and adulthood may illuminate the childhood determinants of adult obesity and contribute to the development of effective interventions. We performed a systematic review of the available literature on tracking of both physical activity and of dietary intake between childhood and adulthood by searching MEDLINE, EMBASE, CINAHL, PSYCInfo, Google and Google Scholar. For inclusion, studies had to report baseline measurements when the children were less than, or equal to, 18 years and to report follow-up for at least 5 years to any age over 18 years. After removal of duplicates, 9625 search hits were screened by title and/or abstract and 79 potentially relevant papers were identified and full papers obtained. In total 39 papers were included in this analysis. Of these, 11 papers (from 5 studies) reported data on tracking of diet from childhood to adulthood and 28 papers (from 16 studies) reported data on tracking of physical activity or inactivity. Despite the diversity of study design and measurement methodology, we found evidence of tracking of both physical activity and of diet between childhood and adulthood with estimates of strength of tracking of a similar order for both behaviours. Because of the inherent methodological difficulties in quantifying habitual behaviour, it is likely that the reported estimates of strength of tracking under-estimate the true degree of tracking. The evidence of tracking reported here may give greater impetus to the development of interventions aimed to prevent the persistence of obesity from childhood into adulthood and its attendant adverse socioeconomic, psychosocial and health sequelae.


Multiple thoracic vertebral fractures as a complication of cardiopulmonary resuscitation: A case report.
A 50-year-old man experienced cardiac arrest. The patient underwent standard cardiopulmonary resuscitative measures for approximately 20 minutes before spontaneous circulation returned. He was diagnosed with variant angina, and subsequent imaging for evaluation of upper back pain revealed fractures of the fifth through eighth thoracic vertebrae. Multiple thoracic vertebral fractures are extremely rare. Here we report a case of multiple thoracic vertebral fractures as a complication of cardiopulmonary resuscitation.


Comparative Genomics of the Listeria monocytogenes ST204 Subgroup.
The ST204 subgroup of Listeria monocytogenes is among the most frequently isolated in Australia from a range of environmental niches. In this study we provide a comparative genomics analysis of food and food environment isolates from geographically diverse sources. Analysis of the ST204 genomes showed a highly conserved core genome with the majority of variation seen in mobile genetic elements such as plasmids, transposons and phage insertions. Most strains (13/15) harbored plasmids, which although varying in size contained highly conserved sequences. Interestingly 4 isolates contained a conserved plasmid of 91,396 bp. The strains examined were isolated over a period of 12 years and from different geographic locations suggesting plasmids are an important component of the genetic repertoire of this subgroup and may provide a range of stress tolerance mechanisms. In addition to this 4 phage insertion sites and 2 transposons were identified among isolates, including a novel transposon. These genetic elements were highly conserved across isolates that harbored them, and also contained a range of genetic markers linked to stress tolerance and virulence. The maintenance of conserved mobile genetic elements in the ST204 population suggests these elements may contribute to the diverse range of niches colonized by ST204 isolates. Environmental stress selection may contribute to maintaining these genetic features, which in turn may be co-selecting for virulence markers relevant to clinical infection with ST204 isolates.


The effect of a pedometer-based community walking intervention "Walking for Wellbeing in the West" on physical activity levels and health outcomes: a 12-week randomized controlled trial.
Recent systematic reviews have suggested that pedometers may be effective motivational tools to promote walking. However, studies tend to be of a relatively short duration, with small clinical based samples. Further research is required to demonstrate their effectiveness in adequately powered, community based studies. Using a randomized controlled trial design, this study assessed the impact of a 12-week graduated pedometer-based walking intervention on daily step-counts, self-reported physical activity and health outcomes in a Scottish community sample not meeting current physical activity recommendations. Sixty-three women and 16 men (49.2 years +/- 8.8) were randomly assigned to either an intervention (physical activity consultation and 12-week pedometer-based walking program) or control (no action) group. Measures for step-counts, 7-day physical activity recall, affect, quality of life (n = 79), body mass, BMI, % body fat, waist and hip circumference (n = 76), systolic/diastolic blood pressure, total cholesterol and HDL cholesterol (n = 66) were taken at baseline and week 12. Analyses were performed on an intention to treat basis using 2-way mixed factorial analyses of variance for parametric data and Mann Whitney and Wilcoxon tests for non-parametric data. Significant increases were found in the intervention group for step-counts (p < .001), time spent in leisure walking (p = .02) and positive affect (p = .027). Significant decreases were found in this group for time spent in weekday (p = .003), weekend (p = .001) and total sitting (p = .001) with no corresponding changes in the control group. No significant changes in any other health outcomes were found in either group. In comparison with the control group at week 12, the intervention group reported a significantly greater number of minutes spent in leisure time (p = .008), occupational (p = .045) and total walking (p = .03), and significantly fewer minutes in time spent in weekend (p = .003) and total sitting (p = .022). A pedometer-based walking program, incorporating a physical activity consultation, is effective in promoting walking and improving positive affect over 12 weeks in community based individuals. The discussion examines possible explanations for the lack of significant changes in health outcomes. Continued follow-up of this study will examine adherence to the intervention and possible resulting effects on health outcomes.


Ethnic differences in the relationships between diabetes, early age adiposity and mortality among breast cancer survivors: the Breast Cancer Health Disparities Study.
The contribution of type 2 diabetes and obesity on mortality in breast cancer (BC) patients has not been well studied among Hispanic women, in whom these exposures are highly prevalent. In a multi-center population-based study, we examined the associations between diabetes, multiple obesity measures, and mortality in 1180 Hispanic and 1298 non-Hispanic white (NHW) women who were diagnosed with incident invasive BC from the San Francisco Bay Area, New Mexico, Utah, Colorado, and Arizona. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards regression models. The median follow-up time from BC diagnosis to death was 10.8 years. In ethnic-stratified results, the association for BC-specific mortality among Hispanics was significantly increased (HR 1.85 95 % CI 1.11, 3.09), but the ethnic interaction was not statistically significant. In contrast, obesity at age 30 increased BC-specific mortality risk in NHW women (HR 2.33 95 % CI 1.36, 3.97) but not Hispanics (p-interaction = 0.045). Although there were no ethnic differences for all-cause mortality, diabetes, obesity at age 30, and post-diagnostic waist-hip ratio were significantly associated with all-cause mortality in all women. This study provides evidence that diabetes and adiposity, both modifiable, are prognostic factors among Hispanic and NHW BC patients.


Microbiome Differences Between Human Head and Body Lice Ecotypes Revealed by 16S RRNA Gene Amplicon Sequencing.
Human head lice and body lice (Pediculus humanus) are neglected ectoparasites. Head lice continue to be prevalent in children worldwide, and insecticide resistance in these insects has complicated their treatment. Meanwhile, body lice, which are most common in the developing world, are resurging among marginalized populations in developed nations. Today, the microbiome is being increasingly recognized as a key mediator of insect physiology. However, the microbial communities that inhabit human lice have remained unknown beyond only a few species of bacteria. Knowledge of the microbiomes of head and body lice could improve our understanding of the observed physiological differences between the 2 ecotypes and potentially inform the development of novel interventions against lice infestations and louse-borne infectious diseases. Toward these goals, here we performed 16S rRNA gene amplicon sequencing to characterize the microbiomes of both head and body lice and identify patterns of interest among these communities. Our data reveal that head and body lice harbor limited but distinct communities of bacteria that include known intracellular endosymbionts ("Candidatus Riesia pediculicola"), extracellular bacteria that may be horizontally acquired from the host environment, and a number of taxa of known or potential public health significance. Notably, in body lice, the relative abundance of vertically transmitted endosymbionts is lower than in head lice, which is a significant driver of greater alpha diversity. Further, several differentially abundant non-endosymbiont taxa and differences in beta diversity were observed between head lice and body lice. These findings support the hypothesis that microbiome differences could contribute to the divergence between human louse ecotypes and underscore the need for future studies to better comprehend the acquisition and physiological roles of human lice microbiomes.


Effect of salpingectomy on ovarian response to hyperstimulation during in vitro fertilization: a meta-analysis.
To compare ovarian response to hyperstimulation during IVF between patients who did and did not undergo salpingectomy. Meta-analysis. University-affiliated teaching hospital. Patients undergoing IVF who did and did not undergo salpingectomy. None. The total dose of gonadotropin, duration of hyperstimulation, E level on the day of hCG injection, number of oocytes retrieved, and basal FSH level were evaluated because these reflect ovarian response. Twenty-five studies were identified through searches conducted on PubMed, Cochrane Libraries, Ovid, Web of Science, Science Direct, China National Knowledge Infrastructure, and Wanfang Database through October 2015. The 25 studies included 1,935 patients who underwent salpingectomy and 2,893 who did not. Fixed-effects and random-effects models were used to calculate the overall combined risk estimates. The results of the meta-analysis suggest that salpingectomy impairs ovarian response to hyperstimulation. The total dose of gonadotropin was significantly increased after combined salpingectomy (inverse variance [IV] 0.10 [95% confidence interval (CI) 0.03, 0.16]; I(2) = 30%) and bilateral salpingectomy (IV [95% CI] 0.23 [0.09, 0.37]; I(2) = 36%). The number of oocytes retrieved decreased significantly after unilateral salpingectomy (IV [95% CI] -0.17 [-0.27, -0.06]; I(2) = 31%) and bilateral salpingectomy (IV [95% CI] -0.20 [-0.32, -0.08]; I(2) = 48%). In addition, a statistically significant reduction was found between the number of oocytes retrieved from the ipsilateral and contralateral ovary (IV [95% CI] 0.25 [-0.40, -0.10]; I(2) = 48%). Finally, bilateral salpingectomy may lead to an increase in the FSH level (IV [95% CI] 0.39 [0.20, 0.59]; I(2) = 0%). Heterogeneity moderators were identified by performing subgroup and sensitivity analyses. No evidence of publication bias was observed. This meta-analysis indicated that salpingectomy may impair ovarian response to hyperstimulation during IVF. Further high-quality research is needed to confirm our findings and to develop therapeutic methods that are alternatives to salpingectomy for maternal well-being.


Predicting mostly disordered proteins by using structure-unknown protein data.
Predicting intrinsically disordered proteins is important in structural biology because they are thought to carry out various cellular functions even though they have no stable three-dimensional structure. We know the structures of far more ordered proteins than disordered proteins. The structural distribution of proteins in nature can therefore be inferred to differ from that of proteins whose structures have been determined experimentally. We know many more protein sequences than we do protein structures, and many of the known sequences can be expected to be those of disordered proteins. Thus it would be efficient to use the information of structure-unknown proteins in order to avoid training data sparseness. We propose a novel method for predicting which proteins are mostly disordered by using spectral graph transducer and training with a huge amount of structure-unknown sequences as well as structure-known sequences. When the proposed method was evaluated on data that included 82 disordered proteins and 526 ordered proteins, its sensitivity was 0.723 and its specificity was 0.977. It resulted in a Matthews correlation coefficient 0.202 points higher than that obtained using FoldIndex, 0.221 points higher than that obtained using the method based on plotting hydrophobicity against the number of contacts and 0.07 points higher than that obtained using support vector machines (SVMs). To examine robustness against training data sparseness, we investigated the correlation between two results obtained when the method was trained on different datasets and tested on the same dataset. The correlation coefficient for the proposed method is 0.14 higher than that for the method using SVMs. When the proposed SGT-based method was compared with four per-residue predictors (VL3, GlobPlot, DISOPRED2 and IUPred (long)), its sensitivity was 0.834 for disordered proteins, which is 0.052-0.523 higher than that of the per-residue predictors, and its specificity was 0.991 for ordered proteins, which is 0.036-0.153 higher than that of the per-residue predictors. The proposed method was also evaluated on data that included 417 partially disordered proteins. It predicted the frequency of disordered proteins to be 1.95% for the proteins with 5%-10% disordered sequences, 1.46% for the proteins with 10%-20% disordered sequences and 16.57% for proteins with 20%-40% disordered sequences. The proposed method, which utilizes the information of structure-unknown data, predicts disordered proteins more accurately than other methods and is less affected by training data sparseness.


Knowledge and attitudes of tuberculosis management in San Juan de Lurigancho district of Lima, Peru.
Expansion of the health care workforce in Peru to combat tuberculosis (TB) includes both professional health care providers (HCPs) such as doctors and nurses, and non-professional HCPs such as community health workers (CHWs). We describe the knowledge and attitudes of these HCPs, and identify modifiable barriers to appropriate anti-tuberculosis treatment. We surveyed HCPs practicing in 30 clinical settings (hospitals, community health centers, and health posts) in the San Juan de Lurigancho district of Eastern Lima, Peru. Multiple-choice questions were used to assess knowledge of TB. A five-item Likert scale was created to assess attitudes toward the community, patients, and clinics. Linear regression was used to identify predictors of mean knowledge score, and analysis of variance was used to test differences in HCP score. Of the 73 HCPs surveyed, 15% were professionals (doctors or nurses). The remaining 85% were health technicians, community health workers (CHWs) or students. The mean knowledge score was 10.0 +/- 1.9 (maximum 14) with professional HCPs scoring higher than other HCPs (11.7 +/- 1.1 vs. 9.7 +/- 1.9), p < .01). Knowledge gaps included identification of patients at high risk for TB, assessment of treatment outcomes, and consequences of treatment failure. The most commonly cited modifiable barriers were structural, including laboratory facilities and staffing of TB clinics, with 52.1% and 62.5% of HCPs, respectively, citing these as problematic. Efforts to improve knowledge of TB HCPs in Peru should focus on the specific gaps we have identified. Further research is needed to evaluate whether these knowledge gaps correlate with TB control.


Effect of occupational exposure to cobalt blue dyes on the thyroid volume and function of female plate painters.
It has previously been shown that long-term oral exposure to cobalt can cause goiter and myxedema. The effect of industrial cobalt exposure on thyroid volume and function was determined for 61 female plate painters exposed to cobalt blue dyes in two Danish porcelain factories and 48 unexposed referents. Thyroid volume was determined by ultrasonography. The cobalt blue dyes were used in one of two forms, cobalt aluminate (insoluble) and cobalt-zinc silicate (semisoluble). Only the subjects exposed to semisoluble cobalt had a significantly increased urinary cobalt content (1.17 micrograms.mmol-1 versus 0.13 micrograms.mmol-1, P less than 0.0001). These subjects also had increased levels of serum thyroxine (T4) and free thyroxine (FT4I) (P = 0.0001 and 0.0029, respectively), unaltered serum thyroid stimulating hormone (TSH), and marginally reduced 3,5,3'-triiodothyronine (T3), whereas thyroid volume tended to be lower (P = 0.14). The group exposed to insoluble cobalt did not differ significantly in any thyroid-related parameters. No correlation between urinary cobalt and FT4I or thyroid volume was found. The study demonstrates an effect of cobalt on thyroid hormone metabolism.


Presence of multiple subpopulations of lipoproteins of intermediate density in normal subjects.
Analysis of human plasma by gradient gel electrophoresis (GGE) revealed multiple distinct bands in the size range between very low density (VLDL) and low density lipoproteins (LDL). GGE of intermediate density lipoproteins (IDL) from normal subjects consistently showed two major bands with particle diameters in the range of 275 to 300 A. The larger, usually predominant subspecies was designated IDL-1, and the smaller, IDL-2. GGE also demonstrated two sizes of subpopulations in the VLDL density range in all subjects. A discontinuous nonequilibrium density gradient ultracentrifugation technique was devised to isolate a series of fractions containing progressively smaller lipoproteins. Successive fractions showed progressive enrichment in cholesteryl-esters, depletion of triglyceride, slower migration on agarose, and depletion of apo E and the C apolipoproteins relative to apo B. The IDL-1 and IDL-2 subspecies appeared to represent two distributions of lipoproteins overlapping in size (particle diameter 280-300 A and 268-284 A, respectively) and buoyant density (d = 1.008-1.022 g/ml and d = 1.013-1.028 g/ml, respectively). Plasma from two patients with dysbetalipoproteinemia showed predominant increases in fractions normally containing small VLDL and IDL-1, while patients with severe hypertriglyceridemia had increases primarily in levels of larger VLDL. Heterogeneity of lipoprotein precursors could account for the discrete subspecies of LDL observed in human plasma.


Carotenoids and carotenoids plus vitamin E protect against ultraviolet light-induced erythema in humans.
Carotenoids and tocopherols, known to be efficient antioxidants and capable of scavenging reactive oxygen species generated during photooxidative stress, may protect the skin from ultraviolet light-induced erythema. beta-Carotene is widely used as an oral sun protectant but studies on its protective effects are scarce. The objective of this study was to investigate the protective effects of oral supplementation with carotenoids and a combination of carotenoids and vitamin E against the development of erythema in humans. A carotenoid supplement (25 mg total carotenoids/d) and a combination of the carotenoid supplement and vitamin E [335 mg (500 IU) RRR-alpha-tocopherol/d] were given for 12 wk to healthy volunteers. Erythema was induced by illumination with a blue-light solar simulator. Serum beta-carotene and alpha-tocopherol concentrations and skin carotenoid levels were assessed by HPLC and reflection photometry. Serum beta-carotene and alpha-tocopherol concentrations increased with supplementation. Erythema on dorsal skin (back) was significantly diminished (P < 0.01) after week 8, and erythema suppression was greater with the combination of carotenoids and vitamin E than with carotenoids alone. The antioxidants used in this study provided protection against erythema in humans and may be useful for diminishing sensitivity to ultraviolet light.


Integration of Podiatric Medicine Within the Fracture Liaison Services Model.
Underlying bone metabolic disorders are often neglected when managing acute fractures. The term fracture liaison services (FLS) refers to models of care with the designated responsibility of comprehensive fracture management, including the diagnosis and treatment of osteoporosis. Although there is evidence of the effectiveness of FLS in reducing health-care costs and improving patient outcomes, podiatric practitioners are notably absent from described FLS models. The integration of podiatric practitioners into FLS programs may lead to improved patient care and further reduce associated health-care costs.


Living in the Hospital: The Vulnerability of Children with Chronic Critical Illness.
The number of children with chronic critical illness (CCI) is a growing population in the United States. A defining characteristic of this population is a prolonged hospital stay. Our study assessed the proportion of pediatric patients with chronic critical illness in U.S. hospitals at a specific point in time, and identified a subset of children whose hospital stay lasted for months to years. The potential harms of a prolonged hospitalization for children with CCI, which include over treatment, infection, disruption of family life, and the intensive utilization of resources-combined with the moral distress experienced by the clinicians who care for the children, suggest the need for ethical analysis of this growing issue to identify actions that could be taken at the clinical and health systems levels to reduce the harms associated with prolonged hospital stay. In this article we present three real cases from our study that involved a very long hospital stay. We applied a framework developed by Mackenzie, Rogers, and Dodds to analyze inherent, situational, and pathogenic vulnerabilities to examine the ways that interventions intended to remedy one source of harm for the children in our cohort inadvertently created other harms. We examined the complex ways that children with protracted hospitalization are vulnerable to the choices made by their family and clinicians, as well as by healthcare systems and communities. Finally, we used this analysis to summarize actions and ethical responses to this growing patient population. Such an understanding is essential to make clinical and ethical decisions that arise for children who are at risk for a very long stay in the hospital.


Full-field heterodyne interference microscope with spatially incoherent illumination.
A heterodyne interference microscope arrangement for full-field imaging is described. The reference and object beams are formed with highly correlated, time-varying laser speckle patterns. The speckle illumination confers a confocal transfer function to the system, and by temporal averaging, the coherence noise that often degrades coherent full-field microscope images is suppressed. The microscope described is similar to a Linnik-type microscope and allows the use of high-numerical-aperture objective lenses, but the temporal coherence of the illumination permits the use of a low-power achromatic doublet in the reference arm. The use of a doublet simplifies alignment of the microscope and can reduce the cost. Preliminary results are presented that demonstrate full-field surface height precision of 1 nm rms.


Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis.
Magnetic resonance (MR) techniques are of value in following the pathological process of multiple sclerosis in vivo. They are widely applied to monitor the disease natural history and its modification by treatment. However, serial studies of lesion measures have yielded generally disappointing correlations with the development of clinical disability. A potential explanation for this is the presence of abnormalities, beyond the visible lesions, in the normal appearing white matter (NAWM) and grey matter (NAGM). Quantitative structural MR techniques, including measures of magnetisation transfer, diffusion, relaxation times and spectroscopic metabolite concentrations, reveal that there are abnormalities in NAWM and NAGM. These are present from clinical onset and become more pronounced with clinical progression, increasing disability and increasing lesion load. Furthermore, functional MRI (fMRI) studies of motor and visual paradigms has identified a range of responses suggesting that cortical plasticity exists; such modified responses are seen in the earliest stages of disease and in the absence of visible lesions, but are more pronounced with disease progression and increasing lesion load and abnormality in the NAWM. Limited reproducibility and sensitivity to change can pose methodological limitations for MR studies of NAWM and NAGM, especially when follow up intervals are relatively short. Whilst existing quantitative MR measures from normal appearing tissues provide valuable information to understand the natural history and monitor treatment effects in MS, none of them fully or even predominantly accounts for the patient's functional state nor can be relied on as a definitive surrogate measure of treatment effect. Better resolution of the abnormalities is needed especially in grey matter where pathological foci are known to be abundant. Studies correlating structural MR and fMRI parameters with measures of function in well defined anatomical pathways should further elucidate the pathogenic role of abnormality in the normal appearing tissues. In future, new imaging modalities are needed that provide a more specific measure of histopathological and cellular aspects of the disease process in vivo.


In-Situ Effects of Simulated Overfishing and Eutrophication on Benthic Coral Reef Algae Growth, Succession, and Composition in the Central Red Sea.
Overfishing and land-derived eutrophication are major local threats to coral reefs and may affect benthic communities, moving them from coral dominated reefs to algal dominated ones. The Central Red Sea is a highly under-investigated area, where healthy coral reefs are contending against intense coastal development. This in-situ study investigated both the independent and combined effects of manipulated inorganic nutrient enrichment (simulation of eutrophication) and herbivore exclosure (simulation of overfishing) on benthic algae development. Light-exposed and shaded terracotta tiles were positioned at an offshore patch reef close to Thuwal, Saudi Arabia and sampled over a period of 4 months. Findings revealed that nutrient enrichment alone affected neither algal dry mass nor algae-derived C or N production. In contrast, herbivore exclusion significantly increased algal dry mass up to 300-fold, and in conjunction with nutrient enrichment, this total increased to 500-fold. Though the increase in dry mass led to a 7 and 8-fold increase in organic C and N content, respectively, the algal C/N ratio (18±1) was significantly lowered in the combined treatment relative to controls (26±2). Furthermore, exclusion of herbivores significantly increased the relative abundance of filamentous algae on the light-exposed tiles and reduced crustose coralline algae and non-coralline red crusts on the shaded tiles. The combination of the herbivore exclusion and nutrient enrichment treatments pronounced these effects. The results of our study suggest that herbivore reduction, particularly when coupled with nutrient enrichment, favors non-calcifying, filamentous algae growth with high biomass production, which thoroughly outcompetes the encrusting (calcifying) algae that dominates in undisturbed conditions. These results suggest that the healthy reefs of the Central Red Sea may experience rapid shifts in benthic community composition with ensuing effects for biogeochemical cycles if anthropogenic impacts, particularly overfishing, are not controlled.


Using Data Linkage to Investigate Inconsistent Reporting of Self-Harm and Questionnaire Non-Response.
The objective of this study was to examine agreement between self-reported and medically recorded self-harm, and investigate whether the prevalence of self-harm differs in questionnaire responders vs. non-responders. A total of 4,810 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) completed a self-harm questionnaire at age 16 years. Data from consenting participants were linked to medical records (number available for analyses ranges from 205-3,027). The prevalence of self-harm leading to hospital admission was somewhat higher in questionnaire non-responders than responders (2.0 vs. 1.2%). Hospital attendance with self-harm was under-reported on the questionnaire. One third reported self-harm inconsistently over time; inconsistent reporters were less likely to have depression and fewer had self-harmed with suicidal intent. Self-harm prevalence estimates derived from self-report may be underestimated; more accurate figures may come from combining data from multiple sources.


Acutely Administered Leptin Increases [Ca2+] i and BK Ca Currents But Does Not Alter Chemosensory Behavior in Rat Carotid Body Type I Cells.
Obesity related pathologies are the health care crisis of our generation. The fat cell derived adipokine leptin has been shown to be a central stimulant of respiration. Very high levels of leptin, however, are associated with the depressed ventilatory phenotype observed in obesity hypoventilation syndrome. Leptin receptors have been identified on carotid body type I cells but how their activation might influence the physiology of these cells is not known.The acute application of leptin evoked calcium signaling responses in isolated type I cells. Cells increased their Fura 2 ratio by 0.074 ± 0.010 ratio units (n = 39, P < 0.001). Leptin also increased the peak membrane currents in 6 of 9 cells increasing the peak macroscopic currents at +10 mV by 61 ± 14 % (p < 0.02). Leptin administered in the presence of the selective BK(Ca) channel inhibitor Paxilline (0.5 μM) failed to increase membrane currents (n = 5). Interestingly, leptin did not significantly alter the resting membrane potential of isolated type I cells (n = 9) and anoxic/acidic depolarizations were unaffected by leptin (n = 7, n = 6).These data suggest that leptin receptors are functional in type I cells but that their acute activation does not alter chemosensory properties. Future studies will use chronic models of leptin dysregulation.


The clinico-radiological paradox of cognitive function and MRI burden of white matter lesions in people with multiple sclerosis: A systematic review and meta-analysis.
Moderate correlation exists between the imaging quantification of brain white matter lesions and cognitive performance in people with multiple sclerosis (MS). This may reflect the greater importance of other features, including subvisible pathology, or methodological limitations of the primary literature. To summarise the cognitive clinico-radiological paradox and explore the potential methodological factors that could influence the assessment of this relationship. Systematic review and meta-analysis of primary research relating cognitive function to white matter lesion burden. Fifty papers met eligibility criteria for review, and meta-analysis of overall results was possible in thirty-two (2050 participants). Aggregate correlation between cognition and T2 lesion burden was r = -0.30 (95% confidence interval: -0.34, -0.26). Wide methodological variability was seen, particularly related to key factors in the cognitive data capture and image analysis techniques. Resolving the persistent clinico-radiological paradox will likely require simultaneous evaluation of multiple components of the complex pathology using optimum measurement techniques for both cognitive and MRI feature quantification. We recommend a consensus initiative to support common standards for image analysis in MS, enabling benchmarking while also supporting ongoing innovation.


Timescale-invariant representation of acoustic communication signals by a bursting neuron.
Acoustic communication often involves complex sound motifs in which the relative durations of individual elements, but not their absolute durations, convey meaning. Decoding such signals requires an explicit or implicit calculation of the ratios between time intervals. Using grasshopper communication as a model, we demonstrate how this seemingly difficult computation can be solved in real time by a small set of auditory neurons. One of these cells, an ascending interneuron, generates bursts of action potentials in response to the rhythmic syllable-pause structure of grasshopper calls. Our data show that these bursts are preferentially triggered at syllable onset; the number of spikes within the burst is linearly correlated with the duration of the preceding pause. Integrating the number of spikes over a fixed time window therefore leads to a total spike count that reflects the characteristic syllable-to-pause ratio of the species while being invariant to playing back the call faster or slower. Such a timescale-invariant recognition is essential under natural conditions, because grasshoppers do not thermoregulate; the call of a sender sitting in the shade will be slower than that of a grasshopper in the sun. Our results show that timescale-invariant stimulus recognition can be implemented at the single-cell level without directly calculating the ratio between pulse and interpulse durations.


Follicular free fatty acid metabolic signatures and their effects on oocyte competence in non-obese PCOS patients.
Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility in women. This study identified changes in free fatty acids profiles in the follicular fluid that may lead to better diagnosis and management of infertility in PCOS women. Polycystic ovary syndrome (PCOS) is a heterogeneous disease characterized by various endocrine/metabolic disorders and impaired reproductive potential. Alterations in oocyte competence are considered potentially causative factors for infertility in PCOS women and analyzing the composition of follicular fluid in these patients may help to identify which changes have the potential to alter oocyte quality. In this study, free fatty acid metabolic signatures in follicular fluid were performed to identify changes that may impact oocyte competence in non-obese PCOS women. Sixty-four non-obese women (32 with PCOS and 32 age- and BMI-matched controls) undergoing in vitro fertilization were recruited. Embryo quality was morphologically assessed. Free fatty acid metabolic profiling in follicular fluid was performed using gas/liquid chromatography-mass spectrometry. Principal component analysis and orthogonal partial least squares-discriminant analysis models were further constructed. Nine free fatty acids and 24 eicosanoids were identified and several eicosanoids synthesized by the cyclooxygenase pathway were significantly elevated in PCOS patients compared to controls. The combination of PGE2, PGF2α, PGJ2, and TXB2 had an area under the curve of 0.867 (0.775-0.960) for PCOS discrimination. Furthermore, follicular fluid levels of PGE2 and PGJ2 were negatively correlated with high-quality embryo rate in PCOS patients (P < 0.05). Metabolomic analysis revealed that follicular fluid lipidomic profiles undergo changes in non-obese PCOS women, which suggests that identifying changes in important metabolic signatures may give us a better understanding of the pathogenesis of PCOS. Furthermore, elevated PGE2 and PGJ2 concentrations may contribute to impaired oocyte competence in non-obese PCOS patients.


X-ray absorption studies of the Cu-dependent phenylalanine hydroxylase from Chromobacterium violaceum. Comparison of the copper coordination in oxidized and dithionite-reduced enzymes.
The coordination chemistry of the Cu sites of phenylalanine hydroxylase (PAH) from Chromobacterium violaceum has been studied by X-ray absorption spectroscopy (XAS). The EXAFS of the Cu(II) form of the enzyme resembles that of other non-blue copper proteins such as plasma amine oxidases and dopamine-beta-hydroxylase and is characteristic of a mixed N/O coordination shell containing histidine ligation. Detailed simulations of the raw EXAFS data have been carried out using full curved-wave restrained refinement methodologies which allow imidazole ligands to be treated as structural units. The results suggest a Cu(II) coordination of two histidines and two additional O/N-donor groups. A reasonable fit to both data sets can be obtained by assuming that the non-imidazole first-shell donor atoms are derived from solvent (H2O or OH-). The EXAFS of the reduced enzyme shows major differences. The amplitude of the first shell in the Fourier transform is only 50% of that of the oxidized enzyme, indicative of a substantial reduction in coordination number. In addition, the first shell of the transform is split into two components. Simulations of the reduced data can be obtained by either two histidines at a long distance of 2.08 A and an O ligand at a short distance of 1.88 A or two histidines at a short distance of 1.90 A and one second-row scatterer such as S or Cl at 2.20 A. Comparison of absorption edge data on the reduced enzyme with data from Cu(I) bis- and tris(1,2-dimethylimidazole) complexes suggests a pseudo-three-coordinate structure.