Inter-hemispheric oscillations in human sleep.
Sleep is generally categorized into discrete stages based on characteristic electroencephalogram (EEG) patterns. This traditional approach represents sleep architecture in a static way, but it cannot reflect variations in sleep across time and across the cortex. To investigate these dynamic aspects of sleep, we analyzed sleep recordings in 14 healthy volunteers with a novel, frequency-based EEG analysis. This approach enabled comparison of sleep patterns with low inter-individual variability. We then implemented a new probability dependent, automatic classification of sleep states that agreed closely with conventional manual scoring during consolidated sleep. Furthermore, this analysis revealed a previously unrecognized, interhemispheric oscillation during rapid eye movement (REM) sleep. This quantitative approach provides a new way of examining the dynamic aspects of sleep, shedding new light on the physiology of human sleep.


Effects of induced endometritis on uterine blood flow in cows as evaluated by transrectal Doppler sonography.
This study was conducted to evaluate the effects of induced endometritis on uterine blood flow in cows. Transrectal Doppler sonography was performed on uterine arteries of six cyclic cows before and for 4 days after inducing acute endometritis by intrauterine infusion of 720 mg of policresulen, and for 4 days of the following estrous cycle. Time-averaged maximum velocity (TAMV) increased (p < 0.001) and pulsatility index (PI) decreased (p < 0.0001) within 1 h of policresulen administration, and did not change (p > 0.05) in the next 4 days of the same cycle. TAMV and PI values in the subsequent cycle did not differ (p > 0.05) from the values measured before infusion and showed no changes (p > 0.05) within the cycle. Blood flow parameters were not related (p > 0.05) to plasma concentrations of progesterone and estrogen. All cows showed an acute endometritis determined by histopathological findings of biopsy samples taken 1 day after infusion and fibrotic endometrial alterations detected in the subsequent cycle. No relationships were observed between fibrotic changes of the endometrium and uterine blood flow during either cycle. In conclusion, acute inflammation is accompanied by a rise in uterine blood flow, but fibrotic alterations do not seem to be related to Doppler sonographic findings.


Remineralization of artificial dentinal caries lesions by biomimetically modified mineral trioxide aggregate.
Fluoride-releasing restorative materials are available for remineralization of enamel and root caries. However, remineralization of dentin is more difficult than remineralization of enamel due to the paucity of apatite seed crystallites along the lesion surface for heterogeneous crystal growth. Extracellular matrix proteins play critical roles in controlling apatite nucleation/growth in collagenous tissues. This study examined the remineralization efficacy of mineral trioxide aggregate (MTA) in phosphate-containing simulated body fluid (SBF) by incorporating polyacrylic acid and sodium tripolyphosphate as biomimetic analogs of matrix proteins for remineralizing caries-like dentin. Artificial caries-like dentin lesions incubated in SBF were remineralized over a 6 week period using MTA alone or MTA containing biomimetic analogs in the absence or presence of dentin adhesive application. Lesion depths and integrated mineral loss were monitored with microcomputed tomography. The ultrastructure of baseline and remineralized lesions was examined by transmission electron microscopy. Dentin remineralization was best achieved using MTA containing biomimetic analogs regardless of whether an adhesive was applied; dentinal tubules within the remineralized dentin were occluded by apatite. It is concluded that the version of MTA employed in this study may be doped with biomimetic analogs for remineralization of unbonded and bonded artificial caries-like lesions in the presence of SBF.


Nonlinear responses in optical metamaterials: theory and experiment.
We employed both theoretical calculations and experiments to study the nonlinear responses in optical metamaterials. The spectra of second-harmonic generations measured on a fishnet metamaterial are in quantitative agreements with calculations based on full-wave numerical simulations combined with field integrations, both exhibiting ~80 times enhancements at the magnetic resonance frequency. Our calculations explained several interesting features observed experimentally, and suggested an optimal metamaterial structure to yield the strongest nonlinear signals.


Lateral giant fibers of cray fish: location of somata by dye injection.
Using a new technique for injecting fluorescent dye, we have analyzed the intraganglionic architectutre of the lateral giant interneuron in crayfish. Each lateral giant interneuron comprises a giant axon, an ipsilateral dendritic arborization of fairly constant form, and a contralateral soma. Antidromic axon spikes produce only, small, electronic potentials in the soma; direct depolarization there fails to produce electrically excitable membrane responses and cannot discharge the main axon.


Genomic Features for Desiccation Tolerance and Sugar Biosynthesis in the Extremophile Gloeocapsopsis sp. UTEX B3054.
For tolerating extreme desiccation, cyanobacteria are known to produce both compatible solutes at intracellular level and a copious amount of exopolysaccharides as a protective coat. However, these molecules make cyanobacterial cells refractory to a broad spectrum of cell disruption methods, hindering genome sequencing, and molecular studies. In fact, few genomes are already available from cyanobacteria from extremely desiccated environments such as deserts. In this work, we report the 5.4 Mbp draft genome (with 100% of completeness in 105 contigs) of Gloeocapsopsis sp. UTEX B3054 (subsection I; Order Chroococcales), a cultivable sugar-rich and hardly breakable hypolithic cyanobacterium from the Atacama Desert. Our in silico analyses focused on genomic features related to sugar-biosynthesis and adaptation to dryness. Among other findings, screening of Gloeocapsopsis genome revealed a unique genetic potential related to the biosynthesis and regulation of compatible solutes and polysaccharides. For instance, our findings showed for the first time a novel genomic arrangement exclusive of Chroococcaceae cyanobacteria associated with the recycling of trehalose, a compatible solute involved in desiccation tolerance. Additionally, we performed a comparative genome survey and analyses to entirely predict the highly diverse pool of glycosyltransferases enzymes, key players in polysaccharide biosynthesis and the formation of a protective coat to dryness. We expect that this work will set the fundamental genomic framework for further research on microbial tolerance to desiccation and to a wide range of other extreme environmental conditions. The study of microorganisms like Gloeocapsopsis sp. UTEX B3054 will contribute to expand our limited understanding regarding water optimization and molecular mechanisms allowing extremophiles to thrive in xeric environments such as the Atacama Desert.


Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness.
Although an age-related decrease in NO bioavailability contributes to vascular stiffness, the underlying molecular mechanisms remain incompletely understood. We hypothesize that NO constrains the activity of the matrix crosslinking enzyme tissue transglutaminase (TG2) via S-nitrosylation in young vessels, a process that is reversed in aging. We sought to determine whether endothelium-dependent NO regulates TG2 activity by S-nitrosylation and whether this contributes to age-related vascular stiffness. We first demonstrate that NO suppresses activity and increases S-nitrosylation of TG2 in cellular models. Next, we show that nitric oxide synthase (NOS) inhibition leads to increased surface and extracellular matrix-associated TG2. We then demonstrate that endothelium-derived bioactive NO primarily mediates its effects through TG2, using TG2(-/-) mice chronically treated with the NOS inhibitor l-N(G)-nitroarginine methyl ester (L-NAME). We confirm that TG2 activity is modulated by endothelium-derived bioactive NO in young rat aorta. In aging rat aorta, although TG2 expression remains unaltered, its activity increases and S-nitrosylation decreases. Furthermore, TG2 inhibition decreases vascular stiffness in aging rats. Finally, TG2 activity and matrix crosslinks are augmented with age in human aorta, whereas abundance remains unchanged. Decreased S-nitrosylation of TG2 and increased TG activity lead to enhanced matrix crosslinking and contribute to vascular stiffening in aging. TG2 appears to be the member of the transglutaminase family primarily contributing to this phenotype. Inhibition of TG2 could thus represent a therapeutic target for age-associated vascular stiffness and isolated systolic hypertension.


Association of dystrophin-related protein with dystrophin-associated proteins in mdx mouse muscle.
Dystrophin is associated with a complex of muscle membrane (sarcolemmal) glycoproteins that provide a linkage to the extracellular matrix protein, laminin. The absence of dystrophin leads to a dramatic reduction of the dystrophin-associated proteins (156DAG, 59DAP, 50DAG, 43DAG and 35DAG) in the sarcolemma of patients with Duchenne muscular dystrophy and mdx mice. Here we demonstrate that dystrophin-related protein (DRP, utrophin), an autosomal homologue of dystrophin, is associated with an identical or antigenically similar complex of sarcolemmal proteins and that DRP and the dystrophin/DRP-associated proteins colocalize to the neuromuscular junction in Duchenne muscular dystrophy and mdx muscle. The DRP and dystrophin/DRP-associated proteins are found throughout the sarcolemma in small-calibre skeletal muscles and cardiac muscle of adult mdx mice. Because these muscles show minimal pathological changes, our results could provide a basis for the upregulation of DRP as a potential therapeutic approach.


Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.
The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin. Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intraoperative left ventricular epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes mellitus), hypertension (HTN) without (-) HFpEF (n=31), and HTN with (+) HFpEF (n=22). One or more of the following studies were performed on the biopsies: passive stiffness measurements to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay), collagen assays (biochemistry or histology), or titin isoform and phosphorylation assays. In comparison with controls, patients with HTN(-)HFpEF had no change in left ventricular end-diastolic pressure, myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers of inflammation (C-reactive protein, soluble ST2, tissue inhibitor of metalloproteinase 1). In comparison with both control and HTN(-)HFpEF, patients with HTN(+)HFpEF had increased left ventricular end-diastolic pressure, left atrial volume, N-terminal propeptide of brain natriuretic peptide, total, collagen-dependent, and titin-dependent stiffness, insoluble collagen, increased titin phosphorylation on PEVK S11878(S26), reduced phosphorylation on N2B S4185(S469), and increased biomarkers of inflammation. Hypertension in the absence of HFpEF did not alter passive myocardial stiffness. Patients with HTN(+)HFpEF had a significant increase in passive myocardial stiffness; collagen-dependent and titin-dependent stiffness were increased. These data suggest that the development of HFpEF depends on changes in both collagen and titin homeostasis.


Denture-induced fibrous inflammatory hyperplasia: a retrospective study in a school of dentistry.
The aim of this study was to investigate the denture-induced fibrous inflammatory hyperplasia (FIH) that occurs around the borders of an ill-fitting denture, in relation to frequency of the lesion, age and sex distribution, length of denture use, and frequency of dysplasia. A comprehensive review of FIH diagnosed in patients wearing dentures by the oral pathology diagnostic service at the University of São Paulo over 26 years (1971 to 1996) was undertaken, based on retrospective analysis of the oral histopathologic files. The frequency of FIH was 15% of the total number of pathologies diagnosed at the service of oral pathology in that period. The disorder occurred predominantly in the fifth and sixth decades of life and more often among females, at a proportion of 5:1. The frequency of FIH was higher for a length of denture use of between 1 and 10 years. Dysplasia was found in 4% of cases. The knowledge of some aspects of FIH, especially the possible histologic alteration of dysplasia, supports the importance of the diagnosis and treatment of the lesion and suggests that any excised tissue should be submitted to histopathologic evaluation. Education and regular review of patients who have worn dentures are essential if the development of FIH is to be prevented.


Interneuron cell types are fit to function.
Understanding brain circuits begins with an appreciation of their component parts - the cells. Although GABAergic interneurons are a minority population within the brain, they are crucial for the control of inhibition. Determining the diversity of these interneurons has been a central goal of neurobiologists, but this amazing cell type has so far defied a generalized classification system. Interneuron complexity within the telencephalon could be simplified by viewing them as elaborations of a much more finite group of developmentally specified cardinal classes that become further specialized as they mature. Our perspective emphasizes that the ultimate goal is to dispense with classification criteria and directly define interneuron types by function.


Exercise Capacity and Self-Efficacy are Associated with Moderate-to-Vigorous Intensity Physical Activity in Children with Congenital Heart Disease.
This study sought to determine whether exercise capacity, self-efficacy, and gross motor skills are associated with moderate-to-vigorous physical activity (MVPA) levels in children, and if these associations differ by congenital heart disease (CHD) type. Medical history was abstracted from chart review. We assessed MVPA levels (via accelerometry), percent-predicted peak oxygen consumption ([Formula: see text] cardiopulmonary exercise test), gross motor skill percentiles (test of gross motor development version-2), and self-efficacy [children's self-perceptions of adequacy and predilection for physical activity scale (CSAPPA scale)]. CHD patients (n = 137, range 4-12 years) included children with a repaired atrial septal defect (n = 31, mean ± standard deviation MVPA = 454 ± 246 min/week), transposition of the great arteries after the arterial switch operation (n = 34, MVPA = 423 ± 196 min/week), tetralogy of Fallot after primary repair (n = 37, MVPA = 389 ± 211 min/week), or single ventricle after the Fontan procedure (n = 35, MVPA = 405 ± 256 min/week). MVPA did not differ significantly between CHD groups (p = 0.68). Higher MVPA was associated with a higher percent-predicted [Formula: see text] (EST[95% CI] = 16.9[-0.2, 34] MVPA min/week per 10% increase in percent-predicted [Formula: see text] p = 0.05) and higher self-efficacy (EST[95% CI] = 5.2[1.0, 9.3] MVPA min/week per 1-unit increase in CSAPPA score, p = 0.02), after adjustment for age, sex, and testing seasonality, with no association with CHD type. Higher MVPA was not associated with gross motor skill percentile (p = 0.92). There were no significant interactions between CHD type and percent-predicted [Formula: see text] self-efficacy scores, and gross motor skill percentiles regarding their association with MVPA (p > 0.05 for all). Greater MVPA was associated with higher exercise capacity and self-efficacy, but not gross motor skills.


Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations.
The taxonomy of the family Filoviridae (marburgviruses and ebolaviruses) has changed several times since the discovery of its members, resulting in a plethora of species and virus names and abbreviations. The current taxonomy has only been partially accepted by most laboratory virologists. Confusion likely arose for several reasons: species names that consist of several words or which (should) contain diacritical marks, the current orthographic identity of species and virus names, and the similar pronunciation of several virus abbreviations in the absence of guidance for the correct use of vernacular names. To rectify this problem, we suggest (1) to retain the current species names Reston ebolavirus, Sudan ebolavirus, and Zaire ebolavirus, but to replace the name Cote d'Ivoire ebolavirus [sic] with Taï Forest ebolavirus and Lake Victoria marburgvirus with Marburg marburgvirus; (2) to revert the virus names of the type marburgviruses and ebolaviruses to those used for decades in the field (Marburg virus instead of Lake Victoria marburgvirus and Ebola virus instead of Zaire ebolavirus); (3) to introduce names for the remaining viruses reminiscent of jargon used by laboratory virologists but nevertheless different from species names (Reston virus, Sudan virus, Taï Forest virus), and (4) to introduce distinct abbreviations for the individual viruses (RESTV for Reston virus, SUDV for Sudan virus, and TAFV for Taï Forest virus), while retaining that for Marburg virus (MARV) and reintroducing that used over decades for Ebola virus (EBOV). Paying tribute to developments in the field, we propose (a) to create a new ebolavirus species (Bundibugyo ebolavirus) for one member virus (Bundibugyo virus, BDBV); (b) to assign a second virus to the species Marburg marburgvirus (Ravn virus, RAVV) for better reflection of now available high-resolution phylogeny; and (c) to create a new tentative genus (Cuevavirus) with one tentative species (Lloviu cuevavirus) for the recently discovered Lloviu virus (LLOV). Furthermore, we explain the etymological derivation of individual names, their pronunciation, and their correct use, and we elaborate on demarcation criteria for each taxon and virus.


Influence of correlated errors on the estimation of the relaxation time spectrum in dynamic light scattering.
An important step in analyzing data from dynamic light scattering is estimating the relaxation time spectrum from the correlation time function. This estimation is frequently done by regularization methods. To obtain good results with this step, the statistical errors of the correlation time function must be taken into account [J. Phys. A 6, 1897 (1973)]. So far error models assuming independent statistical errors have been used in the estimation. We show that results for the relaxation time spectrum are better if correlation between statistical errors is taken into account. There are two possible ways to obtain the error sizes and their correlations. On the one hand, they can be calculated from the correlation time function by use of a model derived by Schätzel. On the other hand, they can be computed directly from the time series of the scattered light. Simulations demonstrate that the best results are obtained with the latter method. This method requires, however, storing the time series of the scattered light during the experiment. Therefore a modified experimental setup is needed. Nevertheless the simulations also show improvement in the resulting relaxation time spectra if the error model of Schätzel is used. This improvement is confirmed when a lattice with a bimodal sphere size distribution is applied to experimental data.


PRD-Class Homeobox Genes in Bovine Early Embryos: Function, Evolution, and Overlapping Roles.
Eutherian Totipotent Cell Homeobox (ETCHbox) genes are mammalian-specific PRD-class homeobox genes with conserved expression in the preimplantation embryo but fast-evolving and highly divergent sequences. Here, we exploit an ectopic expression approach to examine the role of bovine ETCHbox genes and show that ARGFX and LEUTX homeodomain proteins upregulate genes normally expressed in the blastocyst; the identities of the regulated genes suggest that, in vivo, the ETCHbox genes play a role in coordinating the physical formation of the blastocyst structure. Both genes also downregulate genes expressed earlier during development and genes associated with an undifferentiated cell state, possibly via the JAK/STAT pathway. We find evidence that bovine ARGFX and LEUTX have overlapping functions, in contrast to their antagonistic roles in humans. Finally, we characterize a mutant bovine ARGFX allele which eliminates the homeodomain and show that homozygous mutants are viable. These data support the hypothesis of functional overlap between ETCHbox genes within a species, roles for ETCHbox genes in blastocyst formation and the change of their functions over evolutionary time.


The Large and Diverse Family of Mediterranean Flat Breads: A Database.
An in-depth survey was conducted by collecting information from web sources, supplemented by interviews with experts and/or bakers, to identify all the flat breads (FBs) produced in the nine Mediterranean countries involved in the FlatBreadMine Project (Croatia, Egypt, France, Greece, Italy, Jordan, Lebanon, Malta and Spain), and to have an insight into their technical and cultural features. A database with information on 143 FB types (51 single-layered, 15 double-layered, 66 garnished, 11 fried) was established. Flours were from soft wheat (67.4%), durum wheat (13.7%), corn (8.6%), rye, sorghum, chickpea, and chestnut (together 5.2%). The raising agents were compressed yeast (55.8%), sourdough (16.7%), baking powder (9.0%), but 18.6% of FBs were unleavened. Sixteen old-style baking systems were recorded, classified into baking plates and vertical ovens (tannur and tabun). Artisanal FBs accounted for 82%, while the industrial ones for 7%. Quality schemes (national, European or global) applied to 91 FBs. Fifteen FBs were rare, prepared only for family consumption: changes in lifestyle and increasing urbanization may cause their disappearance. Actions are needed to prevent the reduction of biodiversity related to FBs. Information in the database will be useful for the selection of FBs suitable to promotional activities and technical or nutritional improvement.


Comparison of two reference standards in validating two field mydriatic digital photography as a method of screening for diabetic retinopathy.
To compare two reference standards when evaluating a method of screening for referable diabetic retinopathy. Clinics at Oxford and Norwich Hospitals were used in a two centre prospective study of 239 people with diabetes receiving an ophthalmologist's examination using slit lamp biomicroscopy, seven field 35 mm stereophotography and two field mydriatic digital photography. Patients were selected from those attending clinics when the ophthalmologist and ophthalmic photographer were able to attend. The main outcome measures were the detection of referable diabetic retinopathy as defined by the Gloucestershire adaptation of the European Working Party guidelines. In comparison with seven field stereophotography, the ophthalmologist's examination gave a sensitivity of 87.4% (confidence interval 83.5 to 91.5), a specificity of 94.9% (91.5 to 98.3), and a kappa statistic of 0.80. Two field mydriatic digital photography gave a sensitivity of 80.2% (75.2 to 85.2), specificity of 96.2% (93.2 to 99.2), and a kappa statistic of 0.73. In comparison with the ophthalmologist's examination, two field mydriatic digital photography gave a sensitivity of 82.8% (78.0 to 87.6), specificity of 92.9% (89.6 to 96.2), and a kappa statistic of 0.76. Seven field stereo gave a sensitivity of 96.4% (94.0 to 98.8), a specificity of 82.9% (77.4 to 88.4), and a kappa statistic of 0.80. 15.3% of seven field sets, 1.5% of the two field digital photographs, and none of the ophthalmologist's examinations were ungradeable. An ophthalmologist's examination compares favourably with seven field stereophotography, and two field digital photography performs well against both reference standards.


Alterations in mechanical properties of the patellar tendon is associated with pain in athletes with patellar tendinopathy.
To compare tendon strain and stiffness between athletes with patellar tendinopathy and healthy controls, and explore whether the intensity of pain and dysfunction were related to the mechanical properties of the tendon. Thirty-four male athletes with patellar tendinopathy and 13 healthy controls matched by age and activity levels were recruited. The in vivo mechanical properties of the patellar tendon were examined by ultrasonography and dynamometry. In subjects with patellar tendinopathy, the intensities of self-perceived pain (maximal pain in the past 7 days and pain during a single-legged declined-squat test) using the visual analogue scale and the assessment of functional disability using the Victorian Institute of Sport Assessment-patellar questionnaire, were collected. In subjects with patellar tendinopathy, tendon strain was significantly reduced by 22% (8.9 ± 3.7 vs. 14.3 ± 4.7%, P = 0.005) when compared with healthy controls. There was no significant group difference in tendon stiffness (P = 0.27). Significant negative correlations between tendon strain and the maximal self-perceived pain over 7 days (r = -0.37, P = 0.03), and pain during a single-legged declined-squat test (r = -0.37, P = 0.03) were detected. A trend of significant positive correlation was found between tendon stiffness and pain during a single-legged declined-squat test (r = 0.30, P = 0.09). Our findings show that tendon strain is reduced in athletes with patellar tendinopathy, and a lower tendon strain is associated with a greater magnitude of pain perceived.


The eyes have it: regulatory and structural changes both underlie cichlid visual pigment diversity.
A major goal of evolutionary biology is to unravel the molecular genetic mechanisms that underlie functional diversification and adaptation. We investigated how changes in gene regulation and coding sequence contribute to sensory diversification in two replicate radiations of cichlid fishes. In the clear waters of Lake Malawi, differential opsin expression generates diverse visual systems, with sensitivities extending from the ultraviolet to the red regions of the spectrum. These sensitivities fall into three distinct clusters and are correlated with foraging habits. In the turbid waters of Lake Victoria, visual sensitivity is constrained to longer wavelengths, and opsin expression is correlated with ambient light. In addition to regulatory changes, we found that the opsins coding for the shortest- and longest-wavelength visual pigments have elevated numbers of potentially functional substitutions. Thus, we present a model of sensory evolution in which both molecular genetic mechanisms work in concert. Changes in gene expression generate large shifts in visual pigment sensitivity across the collective opsin spectral range, but changes in coding sequence appear to fine-tune visual pigment sensitivity at the short- and long-wavelength ends of this range, where differential opsin expression can no longer extend visual pigment sensitivity.


Association of Gastric Acid Suppression With Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis.
Gastric acid suppression has been associated with an increased risk of primary Clostridium difficile infection (CDI), but the risk of recurrent CDI in patients taking gastric acid suppressant medications is unclear. To perform a systematic review and meta-analysis to evaluate the association between gastric acid suppressants and recurrent CDI. MEDLINE, EMBASE, the Cochrane Central Register, the Cochrane Database, and Web of Science were searched from January 1, 1995, to September 30, 2015, for studies assessing the association between gastric acid suppressant exposure and recurrent CDI. Search terms included Clostridium difficile, pseudomembranous colitis, proton pump inhibitor, and histamine H2 blocker. Case-control studies, cohort studies, and clinical trials that included patients with CDI who did or did not receive gastric acid suppressant therapy and who were evaluated for recurrent CDI were included, with no restriction on study setting (inpatient or outpatient). The Newcastle-Ottawa scale was used to assess the methodologic quality of included studies. In this scale, case-control and cohort studies were scored on selection, comparability, and ascertainment of the outcome of interest. Data were independently abstracted to a predetermined collection form by 2 investigators. Summary odds ratio estimates with 95% CIs were calculated using the random-effects model and software to calculate the pooled effect size of studies reporting multivariate analyses. Risk of recurrent infection in patients with CDI and its association with use of gastric acid suppressant medication. Sixteen observational studies were included, together reporting 7703 patients with CDI; among these, 1525 patients (19.8%) developed recurrent CDI. The rate of recurrent CDI in patients with gastric acid suppression was 22.1% (892 of 4038 patients) compared with 17.3% (633 of 3665) in patients without gastric acid suppression, which indicated an increased risk by meta-analysis (odds ratio [OR], 1.52; 95% CI, 1.20-1.94; P < .001). There was significant heterogeneity among the studies, with an I2 value of 64%. Subgroup analyses of studies adjusting for age and potential confounders confirmed an increased risk of recurrent CDI with use of gastric acid suppressants (OR, 1.38; 95% CI, 1.08-1.76; P = .02). Meta-analyses of observational studies suggest that patients who receive gastric acid suppressants may be at increased risk for recurrent CDI. These data should be interpreted with caution because they may be confounded owing to the observational design of the individual studies. It may be reasonable to re-evaluate the need for these medications in patients with CDI.


Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma.
MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2B6 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site. MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days 1 and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m(2)) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies. Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 ( approximately 8 x 10(5), approximately 8 x 10(6), and approximately 8 x 10(7) lacZ transferring units/mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8%) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33%) patients had stable disease for > or =3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient). MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXia-P450 should undergo further clinical assessment.


Coexistence of macular corneal dystrophy types I and II in a single sibship.
Macular corneal dystrophy (MCD) is an inherited autosomal recessive disorder that has been subdivided into two primary immunophenotypes, MCD types I and II. The MCD type I gene has been localised previously to chromosome 16q22 and suggestive evidence provided that MCD type II gene is also linked to this region. Here an unusual family is reported where both MCD types I and II are found in a single sibship. Immunoreactivity to an anti-keratan sulphate monoclonal antibody (5-D-4) was evaluated in patients' serum and in corneal tissue obtained at keratoplasty. Chromosomal haplotypes were constructed using microsatellite repeat markers spanning the region of the MCD type I locus. Immunological studies demonstrated that two of the affected siblings have MCD type II while one has MCD type I. Haplotype analysis suggests that all three affected sibs inherited one identical parental haplotype. However, the two MCD types differ in their alternative chromosome with both MCD type II children sharing an identical haplotype, different from their MCD type I sibling. The findings in this study support the hypothesis that the genes for MCD types I and II co-localise to the same region of chromosome 16 and are likely to be due to allelic manifestations of the same abnormal gene.


The many faces and functions of β-catenin.
β-Catenin (Armadillo in Drosophila) is a multitasking and evolutionary conserved molecule that in metazoans exerts a crucial role in a multitude of developmental and homeostatic processes. More specifically, β-catenin is an integral structural component of cadherin-based adherens junctions, and the key nuclear effector of canonical Wnt signalling in the nucleus. Imbalance in the structural and signalling properties of β-catenin often results in disease and deregulated growth connected to cancer and metastasis. Intense research into the life of β-catenin has revealed a complex picture. Here, we try to capture the state of the art: we try to summarize and make some sense of the processes that regulate β-catenin, as well as the plethora of β-catenin binding partners. One focus will be the interaction of β-catenin with different transcription factors and the potential implications of these interactions for direct cross-talk between β-catenin and non-Wnt signalling pathways.


CaM kinase II: a protein kinase with extraordinary talents germane to insulin exocytosis.
CaM kinase II, a multifunctional Ca2+/calmodulin-dependent protein kinase, is expressed in the pancreatic beta-cell and is activated by glucose and other secretagogues in a manner correlating with insulin secretion. It is proposed that the activation of CaM kinase II mediates some of the actions of Ca2+ on the exocytosis of insulin secretory granules. This suggestion is supported by the localization of CaM kinase II to the insulin secretory granule and by the identification of two secretory-relevant proteins, MAP-2 and synapsin I, as endogenous substrates in the beta-cell. Mechanistically, CaM kinase II appears to be involved in secretory steps proximal to granule fusion at the plasmalemma, and may facilitate protracted secretion through control of the interaction of granules with the cell cytoskeleton and their mobilization from intracellular synthesis sites. Through its unique regulatory properties, however, CaM kinase II is predicted to serve in more specialized aspects of the secretory process. In particular, the ability of CaM kinase II to remain active after cell stimulation is suggested to represent a mechanism by which releasable pools of granules are replenished between stimuli.


Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.
PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.


Developmental exposure to cannabidiol (CBD) alters longevity and health span of zebrafish (Danio rerio).
Consumption of cannabinoid-containing products is on the rise, even during pregnancy. Unfortunately, the long-term, age-related consequences of developmental cannabidiol (CBD) exposure remain largely unknown. This is a critical gap given the established Developmental Origins of Health and Disease (DOHaD) paradigm which emphasizes that stressors, like drug exposure, early in life can instigate molecular and cellular changes that ultimately lead to adverse outcomes later in life. Thus, we exposed zebrafish (Danio rerio) to varying concentrations of CBD (0.02, 0.1, 0.5 μM) during larval development and assessed aging in both the F0 (exposed generation) and their F1 offspring 30 months later. F0 exposure to CBD significantly increased survival (~ 20%) and reduced size (wet weight and length) of female fish. While survival was increased, the age-related loss of locomotor function was unaffected and the effects on fecundity varied by sex and dose. Treatment with 0.5 μM CBD significantly reduced sperm concentration in males, but 0.1 μM increased egg production in females. Similar to other model systems, control aged zebrafish exhibited increased kyphosis as well as increased expression markers of senescence, and inflammation (p16ink4ab, tnfα, il1b, il6, and pparγ) in the liver. Exposure to CBD significantly reduced the expression of several of these genes in a dose-dependent manner relative to the age-matched controls. The effects of CBD on size, gene expression, and reproduction were not reproduced in the F1 generation, suggesting the influence on aging was not cross-generational. Together, our results demonstrate that developmental exposure to CBD causes significant effects on the health and longevity of zebrafish.


Barriers to free antiretroviral treatment access among kothi-identified men who have sex with men and aravanis (transgender women) in Chennai, India.
The Indian government provides free antiretroviral treatment (ART) for people living with HIV. To assist in developing policies and programs to advance equity in ART access, we explored barriers to ART access among kothis (men who have sex with men [MSM] whose gender expression is feminine) and aravanis (transgender women, also known as hijras) living with HIV in Chennai. In the last quarter of 2007, we conducted six focus groups and four key-informant interviews. Data were explored using framework analysis to identify categories and derive themes. We identified barriers to ART access at the family/social-level, health care system-level, and individual-level; however, we found these barriers to be highly interrelated. The primary individual-level barrier was integrally linked to the family/social and health care levels: many kothis and aravanis feared serious adverse consequences if their HIV-positive status were revealed to others. Strong motivations to keep one's HIV-positive status and same-sex attraction secret were interconnected with sexual prejudice against MSM and transgenders, and HIV stigma prevalent in families, the health care system, and the larger society. HIV stigma was present within kothi and aravani communities as well. Consequences of disclosure, including rejection by family, eviction from home, social isolation, loss of subsistence income, and maltreatment (although improving) within the health care system, presented powerful disincentives to accessing ART. Given the multi-level barriers to ART access related to stigma and discrimination, interventions to facilitate ART uptake should address multiple constituencies: the general public, health care providers, and the kothi and aravani communities. India needs a national policy and action plan to address barriers to ART access at family/social, health care system, and individual levels for aravanis, kothis, other subgroups of MSM and other marginalized groups.


Semi-supervised Learning Predicts Approximately One Third of the Alternative Splicing Isoforms as Functional Proteins.
Alternative splicing acts on transcripts from almost all human multi-exon genes. Notwithstanding its ubiquity, fundamental ramifications of splicing on protein expression remain unresolved. The number and identity of spliced transcripts that form stably folded proteins remain the sources of considerable debate, due largely to low coverage of experimental methods and the resulting absence of negative data. We circumvent this issue by developing a semi-supervised learning algorithm, positive unlabeled learning for splicing elucidation (PULSE; http://www.kimlab.org/software/pulse), which uses 48 features spanning various categories. We validated its accuracy on sets of bona fide protein isoforms and directly on mass spectrometry (MS) spectra for an overall AU-ROC of 0.85. We predict that around 32% of "exon skipping" alternative splicing events produce stable proteins, suggesting that the process engenders a significant number of previously uncharacterized proteins. We also provide insights into the distribution of positive isoforms in various functional classes and into the structural effects of alternative splicing.


Fluorescent-labeled growth factor molecules serve as probes for receptor binding and endocytosis.
In this report, we describe the applicability of fluorescein-labeled EGF (FITC-EGF) in monitoring the interaction between EGF and its cellular receptor in real time. This work takes advantage of previous studies that demonstrated that EGF may be labeled at its amino terminus with FITC without significant deleterious effects on the binding of the growth factor to its receptor or on the ability of the growth factor to activate the intrinsic tyrosine kinase activity of the receptor. When suspended human epidermoid carcinoma (A431) cells were treated with FITC-EGF, a biphasic quenching of the FITC fluorescence was observed. Both phases were blocked when the experiments were performed in the presence of excess unlabeled EGF. The first phase, in which the FITC emission was quenched by 8-10%, was complete within 30 s. This rapid quenching was attributed to changes in the rotational mobility of the EGF molecule that accompany its binding to receptors. The slower phase required 20-30 min for completion and resulted in the further quenching of the FITC fluorescence by 30-40%. This slower phase appeared to reflect the internalization of the receptor and its routing to acidic intracellular compartments. The rapid fluorescence decay phase was used to determine the rate constants (k(on) and k-off)) for the interaction of FITC-EGF with receptors on the surface of cells.


Treat-and-extend bevacizumab for neovascular age-related macular degeneration: the importance of baseline characteristics.
To evaluate the factors affecting visual and anatomical outcomes and the number of intravitreal bevacizumab injections required in the treatment of neovascular age-related macular degeneration using a treat-and-extend regimen. Retrospective consecutive case series. The charts of subjects treated with intravitreal bevacizumab for neovascular age-related macular degeneration using a treat-and-extend regimen over a 12-month period were reviewed. The key variables explored were patient age, phakic status, posterior vitreous detachment status, baseline best-corrected visual acuity (BCVA), baseline central macular thickness (CMT), and type of chorodial neovascularization. The primary outcome measures were improvement in BCVA of 3 logMAR lines or more, maintenance of BCVA within 3 logMAR lines of baseline, number of intravitreal injections delivered over a 12-month period, and final CMT on optical coherence tomography. A total of 230 eyes met the criteria. Mean presenting BCVA was Snellen 20/55 (0.44 logMAR) and mean final BCVA was Snellen 20/44 (0.35 logMAR) (P < 0.001). A total of 23.5% (95% confidence interval [CI], 18.5-29.4%) of the subjects demonstrated an improvement in BCVA of 3 or more logMAR lines, whereas 96.5% (95% CI, 93.3-98.2%) of the subjects lost fewer than 3 logMAR lines. Mean CMT on optical coherence tomography changed from a baseline average of 373.1 μm (95%CI, 360.3-386.1 μm) to a final average of 305.5 μm (95% CI, 290.0-316.0 μm). The average number of injections during the 12-month period was 9.2 (95% CI, 9.0-9.4). Posterior vitreous detachment was associated with fewer injections on univariate and multivariate analysis (8.7 injections in the posterior vitreous detachment group versus 9.8 in the non-posterior vitreous detachment group, P < 0.001). Patients with poorer presenting BCVA and greater baseline CMTs were more likely to demonstrate a 3 or more logMAR line improvement in BCVA. Thinner final CMTs were independently associated with thinner presenting CMTs and fewer injections. Favorable visual and anatomical outcomes may be achieved with intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration using a treat-and-extend regimen. Our study suggests that posterior vitreous detachment may play a role in the efficacy of intravitreal bevacizumab during the treatment of neovascular age-related macular degeneration.


A prospective cohort and extended comprehensive-cohort design provided insights about the generalizability of a pragmatic trial: the ProtecT prostate cancer trial.
Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability. Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive-cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct. The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa. The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice.


Histamine release from gut mast cells from patients with inflammatory bowel diseases.
Inflammatory mediators from intestinal mast cells may serve as initiators of acute and delayed inflammation. Mast cell histamine release was measured in 19 patients with inflammatory bowel diseases using gut mast cells from enzymatically dispersed endoscopic forceps biopsy specimens of macroscopically inflamed and normal tissue. Mast cells and corresponding basophils were challenged with anti-IgE, anti-IgG, subclass anti-IgG4, and formyl-methionyl-leucyl-phenylalanine (FMLP) and results were compared with those from nine patient control subjects. The mast cell count in patients with ulcerative colitis was increased compared with that in control subjects and patients with Crohn's disease, and the mast cell count obtained from inflamed tissue was greater than that of normal tissue. The study also shows the heterogeneity of the responsiveness of the histamine releasing cells to various secretagogues. Thus, mast cells released 0.4 (0.0-2.0) (median (range)) ng histamine per sample at anti-IgE challenge, and basophils were also anti-IgE responsive. In contrast, mast cells did not respond to FMLP but the corresponding basophils did. Gut mast cells released 0.3 (0.0-1.0) (median (range)) ng histamine per sample at anti-IgG4 challenge; however, the corresponding basophils did not respond to anti-IgG4. In addition, the anti-IgG4 mediated histamine release was primarily confined to patients with inflammatory bowel disease. This study substantiates previous histopathological findings that mast cells may play a functional role in the inflammatory process of inflammatory bowel diseases and provides evidence for a possible role of subclass IgG4 as a reaginic antibody.


Structural behavior of competitive temperature and pH-responsive tethered polymer layers.
Herein, we develop a molecular theory to examine a class of pH and temperature-responsive tethered polymer layers. The response of pH depends on intramolecular charge repulsion of weakly acidic monomers and the response of temperature depends on hydrogen bonding between polymer monomers and water molecules akin to the behavior of water-soluble polymers such as PEG (poly-ethylene glycol) or NIPAAm (n-isopropylacrylamide). We investigate the changes in structural behavior that result for various end-tethered copolymers: pH/T responsive monomers alone, in alternating sequence with hydrophobic monomers, and as 50/50 diblocks with hydrophobic monomers. We find that the sequence and location of hydrophobic units play a critical role in the thermodynamic stability and structural behavior of these responsive polymer layers. Additionally, the polymers exhibit tunable collapse when varying the surface coverage, location and sequence of hydrophobic units as a function of temperature and pH. As far as we know, our results present the first molecularly detailed theory for end-tethered polymers that are both pH and temperature-responsive via hydrogen bonding. We propose that this work holds predictive power for the guided design of future biomaterials.


A randomized controlled trial of Kung Fu training for metabolic health in overweight/obese adolescents: the "martial fitness" study.
Twenty overweight/obese adolescents underwent six months of Kung Fu or placebo (Tai Chi) training, 3x.wk(-1). Outcomes included fasting insulin and insulin resistance, lipids, glucose and HbA(1c), and C-reactive protein (CRP). CRP decreased significantly (p = 0.03) in both groups over time at six months. Although insulin sensitivity did not change, HbA(1c) tended to decrease over time (p = 0.09), again with no group difference (p = 0.60). Reduced CRP was related to increased upper body strength (p = 0.01). Increased lean body mass was related to reductions in HbA(1c), insulin resistance, triglycerides, and total cholesterol. Improvements in lean body mass appear to have a potential role in favorable metabolic outcomes, independent of changes in fat mass. Further research in this area is warranted before definite conclusions can be drawn about the efficacy of martial arts training for metabolic outcomes in this cohort.


Analysis of conformational variation in macromolecular structural models.
Experimental conditions or the presence of interacting components can lead to variations in the structural models of macromolecules. However, the role of these factors in conformational selection is often omitted by in silico methods to extract dynamic information from protein structural models. Structures of small peptides, considered building blocks for larger macromolecular structural models, can substantially differ in the context of a larger protein. This limitation is more evident in the case of modeling large multi-subunit macromolecular complexes using structures of the individual protein components. Here we report an analysis of variations in structural models of proteins with high sequence similarity. These models were analyzed for sequence features of the protein, the role of scaffolding segments including interacting proteins or affinity tags and the chemical components in the experimental conditions. Conformational features in these structural models could be rationalized by conformational selection events, perhaps induced by experimental conditions. This analysis was performed on a non-redundant dataset of protein structures from different SCOP classes. The sequence-conformation correlations that we note here suggest additional features that could be incorporated by in silico methods to extract dynamic information from protein structural models.


A New Pipeline for the Normalization and Pooling of Metabolomics Data.
Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples' originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.


Periodontal pathogens invade gingiva and aortic adventitia and elicit inflammasome activation in αvβ6 integrin-deficient mice.
The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin β6(-/-) mouse model to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum to colonize the periodontium and induce local and systemic inflammatory responses. Polymicrobially infected Itgβ6(-/-) mice demonstrate greater susceptibility to gingival colonization/infection, with severe gingival inflammation, apical migration of the junctional epithelium, periodontal pocket formation, alveolar bone resorption, osteoclast activation, bacterial invasion of the gingiva, a greater propensity for the bacteria to disseminate hematogenously, and a strong splenic T cell cytokine response. Levels of atherosclerosis risk factors, including serum nitric oxide, oxidized low-density lipoprotein, serum amyloid A, and lipid peroxidation, were significantly altered by polybacterial infection, demonstrating an enhanced potential for atherosclerotic plaque progression. Aortic gene expression revealed significant alterations in specific Toll-like receptor (TLR) and nucleotide-binding domain- and leucine-rich-repeat-containing receptor (NLR) pathway genes in response to periodontal bacterial infection. Histomorphometry of the aorta demonstrated larger atherosclerotic plaques in Itgβ6(-/-) mice than in wild-type (WT) mice but no significant difference in atherosclerotic plaque size between mice with polybacterial infection and mice with sham infection. Fluorescence in situ hybridization demonstrated active invasion of the aortic adventitial layer by P. gingivalis. Our observations suggest that polybacterial infection elicits distinct aortic TLR and inflammasome signaling and significantly increases local aortic oxidative stress. These results are the first to demonstrate the mechanism of the host aortic inflammatory response induced by polymicrobial infection with well-characterized periodontal pathogens.


VINCENT: A visual analytics system for investigating the online vaccine debate.
This paper reports and describes VINCENT, a visual analytics system that is designed to help public health stakeholders (i.e., users) make sense of data from websites involved in the online debate about vaccines. VINCENT allows users to explore visualizations of data from a group of 37 vaccine-focused websites. These websites differ in their position on vaccines, topics of focus about vaccines, geographic location, and sentiment towards the efficacy and morality of vaccines, specific and general ones. By integrating webometrics, natural language processing of website text, data visualization, and human-data interaction, VINCENT helps users explore complex data that would be difficult to understand, and, if at all possible, to analyze without the aid of computational tools. The objectives of this paper are to explore A) the feasibility of developing a visual analytics system that integrates webometrics, natural language processing of website text, data visualization, and human-data interaction in a seamless manner; B) how a visual analytics system can help with the investigation of the online vaccine debate; and C) what needs to be taken into consideration when developing such a system. This paper demonstrates that visual analytics systems can integrate different computational techniques; that such systems can help with the exploration of online public health debates that are distributed across a set of websites; and that care should go into the design of the different components of such systems.


Atlantic forcing of persistent drought in West Africa.
Although persistent drought in West Africa is well documented from the instrumental record and has been primarily attributed to changing Atlantic sea surface temperatures, little is known about the length, severity, and origin of drought before the 20th century. We combined geomorphic, isotopic, and geochemical evidence from the sediments of Lake Bosumtwi, Ghana, to reconstruct natural variability in the African monsoon over the past three millennia. We find that intervals of severe drought lasting for periods ranging from decades to centuries are characteristic of the monsoon and are linked to natural variations in Atlantic temperatures. Thus the severe drought of recent decades is not anomalous in the context of the past three millennia, indicating that the monsoon is capable of longer and more severe future droughts.


Risk factors for typhoid outbreak in Sungai Congkak Recreational Park, Selangor 2009.
Typhoid fever continues to pose public health problems in Selangor where cases are found sporadically with occasional outbreaks reported. In February 2009, Hospital Tengku Ampuan Rahimah (HTAR) reported a cluster of typhoid fever among four children in the pediatric ward. We investigated the source of the outbreak, risk factors for the infection to propose control measures. We conducted a case-control study to identify the risk factors for the outbreak. A case was defined as a person with S. typhi isolated from blood, urine or stool and had visited Sungai Congkak recreational park on 27th January 2010. Controls were healthy household members of cases who have similar exposure but no isolation of S. typhi in blood, urine or stool. Cases were identified from routine surveillance system, medical record searching from the nearest clinic and contact tracing other than family members including food handlers and construction workers in the recreational park. Immediate control measures were initiated and followed up. Twelve (12) cases were identified from routine surveillance with 75 household controls. The Case-control study showed cases were 17 times more likely to be 12 years or younger (95% CI: 2.10, 137.86) and 13 times more likely to have ingested river water accidentally during swimming (95% CI: 3.07, 58.71). River water was found contaminated with sewage disposal from two public toilets which effluent grew salmonella spp. The typhoid outbreak in Sungai Congkak recreational park resulted from contaminated river water due to poor sanitation. Children who accidentally ingested river water were highly susceptible. Immediate closure and upgrading of public toilet has stopped the outbreak.


Understanding nonrenewable resource supply behavior.
Decisions concerned with finding, developing, and extracting nonrenewable resources are dynamically interrelated in complex ways. Economic theory provides a description of this process that yields useful insights, but there are gaps between theory and empirical applications that hinder our understanding of how supply responds to changes in economic incentives. Consequently, many questions concerning market efficiency as opposed to government intervention remain open.


Management of infants born with severe neonatal alloimmune thrombocytopenia: the role of platelet transfusions and intravenous immunoglobulin.
Neonatal alloimmune thrombocytopenia (NAIT) is a fetomaternal incompatibility most commonly induced by maternal anti-HPA-1a alloantibodies. Transfusion of immunologically compatible platelets (PLTs) to prevent cerebral hemorrhage, the most severe complication in affected newborns, is usually recommended. Such PLT concentrates, however, are often not readily available. The efficacy of random-donor PLT transfusions and intravenous immunoglobulin (IVIG) for the management of 17 neonates across four centers with unexpected, severe NAIT was evaluated. Neonates were treated with random-donor PLTs alone (n=7), random-donor PLTs with IVIG (n=8), or matched HPA-1bb PLTs (n=2). All but one patient (treated with random PLTs and IVIG) achieved a posttransfusion PLT count of higher than 30 × 10(9) /L after the first PLT transfusion. The PLT count remained higher than 30 × 10(9) /L for longer than 24 hours in five of seven, seven of eight, and two of four newborns who received random-donor PLTs alone, random-donor PLTs with IVIG, or matched HPA-1bb PLTs, respectively. None of the newborns developed major bleeding or intracranial hemorrhage. IVIG did not appear to improve either posttransfusion PLT counts or total PLT transfusion requirements. Transfusion of random-donor PLTs alone was effective at correcting critically low PLT counts and should be considered as first-line treatment of newborns with unexpected severe NAIT.


Are teachers' judgements of pupils' ability influenced by body shape?
Evidence indicates that teachers can judge pupils on the basis of their physical appearance, including their body shape. Teacher bias towards obese pupils has been suggested as a potential pathway through which obese children attain relatively lower academic levels. The aim of this study was to investigate whether teachers' judgements of pupils' ability are influenced by the body shape of the child. The sample includes English, singleton children in state schools from the Millennium Cohort Study. The data were taken from the fourth wave of data collection, when the children were approximately 7 years old. In all, 5086/5072 children had teacher ability ratings of reading and maths. Logistic regression analyses were used to test whether teachers' perceptions of the child's reading and mathematics ability were influenced by the pupil's waist circumference, conditional upon cognitive test scores of reading and maths ability. After adjustment for cognitive test scores, no significant overall relationship was found between the pupil's waist circumference and the teacher's judgements of ability. No statistically significant differences were observed in the probability of being judged as above average after further adjustments were made for potential confounders. There is little evidence that teachers' judgements of pupils' ability are influenced by obesity.


Effects of molting and environmental factors on trace metal body-burdens and hemocyanin concentrations in the American lobster, Homarus americanus.
Hemocyanin concentrations in the hemolymph of marine crustacea are dependent on the molt cycle and on environmental conditions. Studies in our laboratories have found that hemocyanin levels in blue crabs are reduced after ecdysis and under conditions of environmental stress (Engel, Brouwer, & McKenna, 1993. Hemocyanin concentrations in marine crustaceans as a function of environmental conditions. Marine Ecology Progress Series, 93, 233-244). We have extended those studies to include the American lobster, Homarus americanus. Hemolymph and digestive gland tissues from Long Island Sound lobsters were analyzed for hemocyanin, copper, and zinc during different stages of the molt cycle. Hemocyanin, copper and zinc in the hemolymph were highest in premolt stages (D1-D4), and lowest in the postecdysal papershell stages (B1-B2). Concomitantly, copper in digestive glands decreased significantly following ecdysis, but no significant changes in the metals bound to metallothionein (MT) were observed. Copper-MT was the predominant form throughout the molt cycle, presumably because lobsters were obtained from copper-contaminated areas. To examine the effects of environmental factors, intermolt lobsters were collected from locations of different environmental quality along the Atlantic coast, and were analyzed for hemocyanin and trace metals. In general, animals from areas with a history of contamination showed the highest hemocyanin concentrations.


Phoretic motion of colloids in a phase separating medium.
The enhanced motion of dispersed particles driven by a concentration gradient is the basis for diffusiophoresis. Here we present the dynamics of colloids in a phase separating medium probed by X-Ray Photon Correlation Spectroscopy (XPCS) in the ultra-small angle scattering range. Charge stabilized silica colloids suspended in a binary mixture of 3-methylpyridine and water/heavy water are preferentially wetted by 3-methylpyridine and consequently display a phoretic motion towards that phase upon demixing. This activity lasts for hundreds of seconds before the phase separation is complete and the enhanced motion is arrested as the colloids return to normal diffusive dynamics.


ERNICA Consensus Conference on the Management of Patients with Esophageal Atresia and Tracheoesophageal Fistula: Follow-up and Framework.
Improvements in care of patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) have shifted the focus from mortality to morbidity and quality-of-life. Long-term follow-up is essential, but evidence is limited and standardized protocols are scarce. Nineteen representatives of the European Reference Network for Rare Inherited Congenital Anomalies (ERNICA) from nine European countries conducted a consensus conference on the surgical management of EA/TEF. The conference was prepared by item generation (including items of surgical relevance from the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN)-The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines on follow-up after EA repair), item prioritization, formulation of a final list containing the domains Follow-up and Framework, and literature review. Anonymous voting was conducted via an internet-based system. Consensus was defined as ≥75% of those voting with scores of 6 to 9. Twenty-five items were generated in the domain Follow-up of which 17 (68%) matched with corresponding ESPGHAN-NASPGHAN statements. Complete consensus (100%) was achieved on seven items (28%), such as the necessity of an interdisciplinary follow-up program. Consensus ≥75% was achieved on 18 items (72%), such as potential indications for fundoplication. There was an 82% concordance with the ESPGHAN-NASPGHAN recommendations. Four items were generated in the domain Framework, and complete consensus was achieved on all these items. Participants of the first ERNICA conference reached significant consensus on the follow-up of patients with EA/TEF who undergo primary anastomosis. Fundamental statements regarding centralization, multidisciplinary approach, and involvement of patient organizations were formulated. These consensus statements will provide the cornerstone for uniform treatment protocols and resultant optimized patient care.


Metabolism of isothiocyanates in individuals with positive and null GSTT1 and M1 genotypes after drinking watercress juice.
Isothiocyanates (ITCs) derived from cruciferous vegetables have been shown to be promising agents against cancer in human cell culture, animal models, and in epidemiological studies. Several epidemiological studies have demonstrated an inverse relationship between intake of dietary isothiocyanates and the risk of cancers, particularly lung, colon, and breast. More importantly, the protective effects of dietary ITCs appear to be influenced by glutathione S-transferase (GST) genotype; specifically, individuals with glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase Mu 1 (GSTM1) null are better protected than those with GSTT1 and M1 positive. Although the majority of studies, especially those conducted in populations exposed to ITC rich diets, demonstrated such effects, there are a few studies that showed opposite or no association. While evidence for the interactions of dietary ITCs with GST genes is relatively strong, the reasons for the differential effects remain unclear. In this study, we examined one possible mechanism: whether subjects with null genotypes excrete ITCs at a slower rate than those with positive genotypes after drinking watercress juice, a rich source of ITCs. A total of 48 subjects, 28 GSTT1 and M1 positive and 20 null genotypes were enrolled in the study. The rates of excretion were determined using five urine samples collected over a period of 24 h after drinking watercress juice. No statistically significant differences in the rates of isothiocyanate excretion and the time of peak excretion were observed between the two tested groups having positive and null genotypes. GSTT1 and M1 genotypes are not likely to be involved in the rate of excretion of ITCs in watercress. The demonstrated differences in protection among subjects with the two genotypes are not likely due to differences in overall ITC excretion rates, however, excretion rates of ITCs other than PEITC need to be investigated. Other yet to be identified mechanism(s) may underlie the diet and gene interactions between dietary ITCs and GST genotypes in human cancer prevention. Further research is needed to evaluate the protective mechanisms of isothiocyanates against cancer.


Results of the 2015 Scoliosis Research Society Survey on Single Versus Dual Attending Surgeon Approach for Adult Spinal Deformity Surgery.
An electronic survey administered to Scoliosis Research Society (SRS) membership. To characterize surgeon practices and views regarding the use of two attending surgeons for adult spinal deformity (ASD) surgery. The use of two experienced attending surgeons can decrease the operative time, estimated blood loss, and perioperative complication rates. However, the current practice patterns for the use of two attending surgeons remains unknown. An electronic, 27-question survey regarding single/dual attending surgeons was administered to the SRS membership. Determinants included: surgeon/practice demographics, assistant type/level of training, and questions regarding use of two attending surgeons. Overall reporting and comparisons between groups were made: US versus international, academic versus private practice, and experience <15 years versus >15 years. A total of 199 surgeons responded from 27 different countries. Overall and between the groups, the respondents significantly reported believing that two attending spine surgeons improves safety, decreases complications, and improves outcomes (P < 0.01). Approximately, 67.3% reported using a second attending ≤25% of the time (33.2% do not), and 24.1% use one ≥51% of the time (similar between groups); 51.1% that have a second attending feel it's limited by reimbursement and access concerns and 71.9% have difficulty getting the second attending reimbursed. 72.3% use a second attending for ALL of the following reasons (no difference between groups): "it's safer/reduces complications," "it decreases operative time," "it decreases blood loss," "it results in improved outcomes," "it's less work and stress for me." If reimbursement was equal/assured for a second attending, 67.5% would use one "more often" or "always." The respondents feel that having a second attending surgeon improves patient care, however most do not use one often. Reasons include reimbursement/access concerns and the majority would use one if reimbursement was equal and assured. Based on the current literature and these results, there is a need for working with third party payers to improve dual surgeon reimbursement rates in complex cases. 5.


Legal challenges in neurological practice.
Clinical neuroscience has made tremendous advances over the last century. Neurology as a discipline is still considered challenging and at times risky due to the natural history and progressive course of few of the neurological diseases. Encouragingly, the patient and their caregivers are now increasingly willing to be actively involved in making decisions. The patients' relationship with the doctor is a reflection of the society. A society that is orienting itself toward "rating" and "feedback" has made this doctor-patient relationship, a consumer-service provider relationship. This perhaps is due to commercialization of health that usually accompanies globalization. Moreover, a rapid influx of information from potential erroneous sources such as the Internet has also made patient and caregivers not being hesitant to taking legal course in the case of adverse events during treatment or simply because of dissatisfaction. The purpose of the legal process initiated by patients with neurological ailments is more often to compensate for the income lost, physical and psychological anguish that accompanies disease and its treatment, and to fund treatment or rehabilitation requirements. However, it is not clearly established if monetary benefits acquired lead to better opportunities for recovery of the patient. The consumer protection act and commercialization of medical services may well have an adverse effect on the doctor and patient relationship. Hence, there is a great need for all medical professionals to mutually complement and update each other. This review examines legal (litigation) processes with special interest on medicolegal system in patients with neurological ailments and the challenges faced by the neurologist during day-to-day clinical practice.


Identification of RNA-binding surfaces in iron regulatory protein-1.
Post-transcriptional regulation of mRNA translation and stability in iron metabolism involves the interaction between the trans-acting cytoplasmic iron regulatory proteins (IRP-1 and IRP-2) and cis-acting iron-responsive elements (IREs) in mRNA 5'- or 3'-untranslated regions. IRP-1 can adopt two conformations: one with a [4Fe-4S]-cluster, unable to bind IREs, which functions as a cytoplasmic aconitase; one lacking this cluster, which accumulates in iron-deprived cells and binds mRNA firmly. We investigated which surfaces of IRP-1 interact with IREs. Surface areas were predicted on the basis of the crystallized porcine mitochondrial aconitase structure. We selected nine sequences absent or different in mitochondrial and Escherichia coli aconitases, both being devoid of RNA-binding properties. Mutations in two regions of domain 4 of IRP-1 lowered the affinity for a wild-type IRE up to 7-fold in vitro, whereas the aconitase activity, a control for structural integrity, was not affected. Scatchard plot analysis with mutant IREs indicated that domain 4 is involved in the binding specificity. This conclusion was confirmed with hybrid proteins in which IRP-1 surface loops were grafted into IRP-2. The results indicate that arginines 728 and 732 contact the IRE bulge, whereas region 685-689 is necessary for recognition of the IRE loop.


Characterisation of utrophin modulator SMT C1100 as a non-competitive inhibitor of firefly luciferase.
Firefly luciferase (FLuc) is a powerful tool for molecular and cellular biology, and popular in high-throughput screening and drug discovery. However, FLuc assays have been plagued with positive and negative artefacts due to stabilisation and inhibition by small molecules from a range of chemical classes. Here we disclose Phase II clinical compound SMT C1100 for the treatment of Duchenne muscular dystrophy as an FLuc inhibitor (KD of 0.40 ± 0.15 µM). Enzyme kinetic studies using SMT C1100 and other non-competitive inhibitors including resveratrol and NFκBAI4 identified previously undescribed modes of inhibition with respect to FLuc's luciferyl adenylate intermediate. Employing a photoaffinity strategy to identify SMT C1100's binding site, a photolabelled SMT C1100 probe instead underwent FLuc-dependent photooxidation. Our findings support novel binding sites on FLuc for non-competitive inhibitors.


Flexible polarimeter architecture based on a birefringent grating.
A polarimeter architecture is presented based on a birefringent grating displayed onto a parallel-aligned liquid crystal (LC) on silicon display (PAL-LCoS). The system is compact and flexible, since the size of the image can be adjusted by means of the period of the grating. The LCoS grating permits simultaneously measuring two orthogonal states of polarization (SOPs). By adding a wave plate, different couples of orthogonal SOPs can be detected. First, a basic proof of concept is presented using one quarter-wave and one half-wave plate with fixed retardances, which permit measuring the six SOPs classically used in polarimetry (linear states at 0°, 45°, 90°, and 135°, and R and L circular states). Next, the system is made fully programmable by incorporating a variable LC retarder (LCR). The LCR orientation and retardance values are optimized by means of the condition number indicator, in order to provide equivalent optimal accuracy. Experimental results of calibration images and test images are presented, showing the potentials of this architecture.


Outcome-based quality improvement in home health care: the OASIS indicators.
The outcomes movement in home health care is expanding rapidly, with strong support from both the industry and Medicare. The Federal government has proposed requiring all Medicare-certified agencies to collect data items from the Outcome and Assessment Information Set (OASIS) to form the basis for standardized risk-adjusted outcome reporting as part of a systematic outcome-based quality improvement (OBQI) approach. In addition to contributing to improving patient outcomes, OASIS data items, when combined with other assessment information, utilization data, and cost information, can provide home health care agencies with a powerful integrated information set for internal management and strategic planning.


Outsmarting the liars: the benefit of asking unanticipated questions.
We hypothesised that the responses of pairs of liars would correspond less with each other than would responses of pairs of truth tellers, but only when the responses are given to unanticipated questions. Liars and truth tellers were interviewed individually about having had lunch together in a restaurant. The interviewer asked typical opening questions which we expected the liars to anticipate, followed by questions about spatial and/or temporal information which we expected suspects not to anticipate, and also a request to draw the layout of the restaurant. The results supported the hypothesis, and based on correspondence in responses to the unanticipated questions, up to 80% of liars and truth tellers could be correctly classified, particularly when assessing drawings.


Quasi-periodic gratings: diffraction orders accelerate along curves.
Light diffracting to different diffraction orders of a periodic grating generally propagates along a set of straight trajectories. Here we show that certain quasi-periodic gratings can produce curved diffraction orders. These curved lobes are created by the caustic interference of the originally straight diffraction orders and manifest themselves as accelerating beams. Both numerical simulations and experimental results demonstrate the validity of multiple accelerating beam generation with a single binary grating. Our work makes a quantitative link between the quasi-periodicity of a grating and the resulting caustic diffraction orders. Furthermore, the use of binary devices has important applications in acoustics, x-ray optics, and electron beam engineering and is also useful when high optical power is needed.


Clusters of bioactive compounds target dynamic endomembrane networks in vivo.
Endomembrane trafficking relies on the coordination of a highly complex, dynamic network of intracellular vesicles. Understanding the network will require a dissection of cargo and vesicle dynamics at the cellular level in vivo. This is also a key to establishing a link between vesicular networks and their functional roles in development. We used a high-content intracellular screen to discover small molecules targeting endomembrane trafficking in vivo in a complex eukaryote, Arabidopsis thaliana. Tens of thousands of molecules were prescreened and a selected subset was interrogated against a panel of plasma membrane (PM) and other endomembrane compartment markers to identify molecules that altered vesicle trafficking. The extensive image dataset was transformed by a flexible algorithm into a marker-by-phenotype-by-treatment time matrix and revealed groups of molecules that induced similar subcellular fingerprints (clusters). This matrix provides a platform for a systems view of trafficking. Molecules from distinct clusters presented avenues and enabled an entry point to dissect recycling at the PM, vacuolar sorting, and cell-plate maturation. Bioactivity in human cells indicated the value of the approach to identifying small molecules that are active in diverse organisms for biology and drug discovery.


Drug resistance in cancer: molecular evolution and compensatory proliferation.
Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP.


C-ski cDNAs are encoded by eight exons, six of which are closely linked within the chicken genome.
The c-ski locus extends a minimum of 65 kb in the chicken genome and is expressed as multiple mRNAs resulting from alternative exon usage. Four exons comprising approximately 1.5 kb of cDNA sequence have been mapped within the chicken c-ski locus. However, c-ski cDNAs include almost 3 kb of sequence for which the exon structure was not defined. From our studies using the polymerase chain reaction and templates of RNA and genomic DNA, it is clear that c-ski cDNAs are encoded by a minimum of eight exons. A long 3' untranslated region is contiguous in the genome with the distal portion of the ski open reading frame such that exon 8 is composed of both coding and noncoding sequences. Exons 2 and 3 are separated by more than 25 kb of genomic sequence. In contrast, exons 3 through 8, representing more than half the length of c-ski cDNA sequences, are closely linked within 10 kb in the chicken genome.


[The 2004 Pelotas birth cohort: methods and description].
To describe a birth cohort which started in 2004, aiming to assess pre and perinatal conditions of the newborns, infant morbimortality, early life characteristics and outcomes, and access, use and financing of health care. All children born in the urban area of Pelotas and Capão do Leão municipalities (Southern Brazil) in 2004 were identified and their mothers invited to join the study. In the first year of the study the children were seen at birth, at three and 12 months of age. These visits involved the application of a questionnaire to the mothers including questions on health; life style; use of health services; socioeconomic situation; estimation of gestational age; anthropometric measurements on the newborn (weight, length, head, chest and abdominal circumferences); anthropometric measurements on the mother (weight and height) and assessment of infant development. Out of the eligible infants (4,558), more than 99% were recruited to the study at birth. Follow-up rates were 96% at three months and 94% at 12 months of age. Among the initial results we highlight the following. Infant mortality rate was 19.7 per thousand, with 66% of infant deaths occurring in the neonatal period. There were frequencies of 15% premature babies and 10% low birthweight. Cesarean sections represented 45% of deliveries. The third Pelotas birth cohort showed an infant mortality rate similar to that of 11 years ago, with most deaths occurring in the neonatal period. The rates of prematurity and cesarean sections increased substantially.


Limb alterations in brachypodism mice due to mutations in a new member of the TGF beta-superfamily.
The mutation brachypodism (bp) alters the length and number of bones in the limbs of mice but spares the axial skeleton. It illustrates the importance of specific genes in controlling the morphogenesis of individual skeletal elements in the tetrapod limb. We now report the isolation of three new members of the transforming growth factor-beta (TGF-beta) superfamily (growth/differentiation factors (GDF) 5,6 and 7) and show by mapping, expression patterns and sequencing that mutations in Gdf5 are responsible for skeletal alterations in bp mice. GDF5 and the closely related GDF6 and GDF7 define a new subgroup of factors related to known bone- and cartilage-inducing molecules, the bone morphogenetic proteins (BMPs). Studies of Bmp5 mutations in short ear mice have shown that at least one other BMP gene is also required for normal skeletal development. The highly specific skeletal alterations in bp and short ear mice suggest that different members of the BMP family control the formation of different morphological features in the mammalian skeleton.


Recombinant Protein Production and Purification of Insoluble Proteins.
Proteins are synthesized in heterologous systems because of the impossibility to obtain satisfactory yields from natural sources. The efficient production of soluble and functional recombinant proteins is among the main goals in the biotechnological field. In this context, it is important to point out that under stress conditions, protein folding machinery is saturated and this promotes protein misfolding and, consequently, protein aggregation. Thus, the selection of the optimal expression organism and its growth conditions to minimize the formation of insoluble protein aggregates should be done according to the protein characteristics and downstream requirements. Escherichia coli is the most popular recombinant protein expression system despite the great development achieved so far by eukaryotic expression systems. Besides, other prokaryotic expression systems, such as lactic acid bacteria and psychrophilic bacteria, are gaining interest in this field. However, it is worth mentioning that prokaryotic expression system poses, in many cases, severe restrictions for a successful heterologous protein production. Thus, eukaryotic systems such as mammalian cells, insect cells, yeast, filamentous fungus, and microalgae are an interesting alternative for the production of these difficult-to-express proteins.


A silicon-based hybrid plasmonic waveguide with a metal cap for a nano-scale light confinement.
A hybrid plasmonic waveguide with a metal cap on a silicon-on-insulator rib (or slab) is presented. There is a low-index material nano-layer between the Si layer and the metal layer. The field enhancement in the nano-layer provides a nano-scale confinement of the optical field (e.g., 50 nm x 5 nm) when operates at the optical wavelength lambda = 1550 nm. The theoretical investigation also shows that the present hybrid plasmonic waveguide has a low loss and consequently a relatively long propagation distance (on the order of several tens of lambda).


Relation of nutrient intake to microalbuminuria in nondiabetic middle-aged men and women: International Population Study on Macronutrients and Blood Pressure (INTERMAP).
Microalbuminuria (MA) is a risk factor for cardiovascular and renal disease. However, little is known about the relation of nutritional factors to MA, especially in individuals without diabetes. Data collected by the International Population Study on Macronutrients and Blood Pressure from 1997 to 1999 were used to assess relations of multiple dietary factors (energy intake, macronutrients, and micronutrients) independent of lifestyle-related cardiovascular risk factors to MA (urinary albumin excretion, 30 to <300 mg/24 h). The study population included 4,381 Chinese, Japanese, UK, and US men and women without diabetes aged 40 to 59 years (17 population samples) without macroalbuminuria. MA prevalences ranged from 3.1% to 5.5% for men and 2.6% to 4.6% for women in the 4 countries. With adjustment for age and country, the following nutrients considered singly (of 29) were related in logistic regression analyses to MA prevalence ( P < 0.05): for men, inversely, iron, vitamin C and E, estimated total simple sugar, omega-6 fatty acid, polyunsaturated fatty acid, and calcium (all expressed as caloric density) intake; for women, directly, 24-hour urinary sodium excretion and alcohol intake. In multivariate analyses, sugar, iron, polyunsaturated fats, and vitamin C and E intake (in men) and alcohol intake (women only) remained associated with MA ( P < 0.05). MA also was related directly to body mass index ( P < 0.05), blood pressure ( P < 0.001), and smoking ( P > 0.05) and inversely to education ( P < 0.05 in women). In cross-sectional analyses, several nutrients were related to MA among men. Additional studies are required to confirm these findings.


Disruption of gut integrity and permeability contributes to enteritis in a fish-parasite model: a story told from serum metabolomics.
In the animal production sector, enteritis is responsible for serious economic losses, and intestinal parasitism is a major stress factor leading to malnutrition and lowered performance and animal production efficiency. The effect of enteric parasites on the gut function of teleost fish, which represent the most ancient bony vertebrates, is far from being understood. The intestinal myxozoan parasite Enteromyxum leei dwells between gut epithelial cells and causes severe enteritis in gilthead sea bream (Sparus aurata), anorexia, cachexia, growth impairment, reduced marketability and increased mortality. This study aimed to outline the gut failure in this fish-parasite model using a multifaceted approach and to find and validate non-lethal serum markers of gut barrier dysfunction. Intestinal integrity was studied in parasitized and non-parasitized fish by immunohistochemistry with specific markers for cellular adhesion (E-cadherin) and tight junctions (Tjp1 and Cldn3) and by functional studies of permeability (oral administration of FITC-dextran) and electrophysiology (Ussing chambers). Serum samples from parasitized and non-parasitized fish were analyzed using non-targeted metabolomics and some significantly altered metabolites were selected to be validated using commercial kits. The immunodetection of Tjp1 and Cldn3 was significantly lower in the intestine of parasitized fish, while no strong differences were found in E-cadherin. Parasitized fish showed a significant increase in paracellular uptake measured by FITC-dextran detection in serum. Electrophysiology showed a decrease in transepithelial resistance in infected animals, which showed a diarrheic profile. Serum metabolomics revealed 3702 ions, from which the differential expression of 20 identified compounds significantly separated control from infected groups in multivariate analyses. Of these compounds, serum inosine (decreased) and creatine (increased) were identified as relevant and validated with commercial kits. The results demonstrate the disruption of tight junctions and the loss of gut barrier function, a metabolomic profile of absorption dysfunction and anorexia, which further outline the pathophysiological effects of E. leei.


Pentamidine blocks hepatotoxic injury in mice.
Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells. VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922-935).