A comparative study of the non-acidic chemically mediated antifoulant properties of three sympatric species of ascidians associated with seagrass habitats.
The present study investigated aspects of the antifoulant properties of three sympatric species of ascidians found in seagrass habitats of the Gulf of Mexico, Southern Atlantic Ocean, and Caribbean. Field observations in Saint Joseph Bay, Florida indicate that all three species are common and that the tunic of the solitary ascidian Molgula occidentalis is often heavily fouled, while the outer surfaces of both the colonial ascidians Amaroucium stellatum and Botryllus planus are free of fouling organisms. Antifoulant activities of a suite of increasing hydrophilic organic extracts prepared from the tunic of M. occidentalis and whole colonies of A. stellatum and B. planus were measured using both sympatric microbial (bacteria) and macroinvertebrate (cyprid larvae of Balanus amphitrite) fouling organisms in laboratory bioassays. In addition, field antifoulant assays were conducted by combining organic extracts with controlled-release resin and subsequently coating this material on to acrylic rods deployed in the field for a 72 h period. Extracts of the tunic of M. occidentalis generally did not inhibit bacterial growth. The exception was the methanol extract, which inhibited growth in one of the six marine bacteria tested. Moreover, only the highest concentrations of hexane and methanol tunic extracts tested prevented attachment of cyprid larvae. Field assays revealed no antifoulant activity on rods coated with resin containing extracts of M. occidentalis. Inhibition of both microbial growth and cyprid settlement were much more pronounced in whole-organism extracts of the two colonial ascidians. Most potent were the aqueous methanol extracts of colonies of B. planus and A. stellatum which inhibited growth in five of the six marine bacteria tested. In addition, hydrophilic and lipophilic extracts of the colonial ascidians significantly inhibited attachment of cyprid larvae, in many instances across a wide range of extract concentrations. Field antifoulant assays indicated that extracts of both colonial ascidians inhibited settlement of bryozoans and barnacles. The findings indicate that the colonial ascidians B. planus and A. stellatum possess chemical antifoulant properties. In contrast, the solitary ascidian M. occidentalis appears to either tolerate fouling or possess other non-chemical mechanisms to cope with the risks associated with epibiont overgrowth.


Towards crystal structure prediction of complex organic compounds--a report on the fifth blind test.
Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories - a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.


Chimeric Arabidopsis thaliana ribulose-1,5-bisphosphate carboxylase/oxygenase containing a pea small subunit protein is compromised in carbamylation.
A cDNA of pea (Pisum sativum L.) RbcS 3A, encoding a small subunit protein (S) of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), has been expressed in Arabidopsis thaliana under control of the cauliflower mosaic virus 35S promoter, and the transcript and mature S protein were detected. Specific antibodies revealed two protein spots for the four Arabidopsis S and one additional spot for pea S. Pea S in chimeric Rubisco amounted to 15 to 18% of all S, as judged by separation on two-dimensional isoelectric focusing/sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels from partially purified enzyme preparations and quantitation of silver-stained protein spots. The chimeric enzyme had 11 +/- 1% fewer carbamylated sites and a 11 +/- 1% lower carboxylase activity than wild-type Arabidopsis Rubisco. Whereas pea S expression, preprotein transport, and processing and assembly resulted in a stable holoenzyme, the chimeric enzyme was reproducibly catalytically less efficient. We suggest that the presence of, on average, one foreign S per holoenzyme is responsible for the altered activity. In addition, higher-plant Rubisco, unlike the cyanobacterial enzyme, seems to have evolved species-specific interactions between S and the large subunit protein that are involved in carbamylation of the active site.


Posterior Cortical Atrophy with Right Lower Egocentric Quadrantic Neglect and Lower Vertical Allocentric Neglect.
Whereas rare cases of hemispatial visual neglect have been reported in patients with a neurodegenerative disease, quadrantic visuospatial neglect has not been described. We report a patient with probable posterior cortical atrophy who demonstrated lower right-sided quadrantic visuospatial neglect, together with allocentric vertical neglect. A 68-year-old man initially noted deficits in reading and writing. Subsequently, he developed other cognitive deficits. On vertical line bisections, he deviated upward, and on horizontal line bisections, he deviated to the left. These deviations together suggest that this man's neglect might be most severe in his right (head/body-centered) lower (below eye level) visual space. When attempting to perform vertical line bisections in all four egocentric quadrants, his upward deviations were largest in the right lower quadrant. On a cancelation test, he revealed bilateral lower (ventral) allocentric neglect but not egocentric neglect. This patient's magnetic resonance imaging revealed cortical atrophy, most prominent in the left parietal lobe. Previous research in stroke patients has demonstrated that the parietal lobes are important in mediating attention to contralateral and inferior visual space. The presence of left parietal atrophy may have induced this right lower (ventral) egocentric inattention as well as bilateral ventral allocentric inattention. Although to our knowledge there have been no prior reports of a patient with right lower quadrantic and lower vertical allocentric visuospatial neglect, patients are rarely tested for these forms of neglect, and this patient illustrates the importance of evaluating patients for these and other forms of neglect.


In silico analysis of 2085 clones from a normalized rat vestibular periphery 3' cDNA library.
The inserts from 2400 cDNA clones isolated from a normalized Rattus norvegicus vestibular periphery cDNA library were sequenced and characterized. The Wackym-Soares vestibular 3' cDNA library was constructed from the saccular and utricular maculae, the ampullae of all three semicircular canals and Scarpa's ganglia containing the somata of the primary afferent neurons, microdissected from 104 male and female rats. The inserts from 2400 randomly selected clones were sequenced from the 5' end. Each sequence was analyzed using the BLAST algorithm compared to the Genbank nonredundant, rat genome, mouse genome and human genome databases to search for high homology alignments. Of the initial 2400 clones, 315 (13%) were found to be of poor quality and did not yield useful information, and therefore were eliminated from the analysis. Of the remaining 2085 sequences, 918 (44%) were found to represent 758 unique genes having useful annotations that were identified in databases within the public domain or in the published literature; these sequences were designated as known characterized sequences. 1141 sequences (55%) aligned with 1011 unique sequences had no useful annotations and were designated as known but uncharacterized sequences. Of the remaining 26 sequences (1%), 24 aligned with rat genomic sequences, but none matched previously described rat expressed sequence tags or mRNAs. No significant alignment to the rat or human genomic sequences could be found for the remaining 2 sequences. Of the 2085 sequences analyzed, 86% were singletons. The known, characterized sequences were analyzed with the FatiGO online data-mining tool (http://fatigo.bioinfo.cnio.es/) to identify level 5 biological process gene ontology (GO) terms for each alignment and to group alignments with similar or identical GO terms. Numerous genes were identified that have not been previously shown to be expressed in the vestibular system. Further characterization of the novel cDNA sequences may lead to the identification of genes with vestibular-specific functions. Continued analysis of the rat vestibular periphery transcriptome should provide new insights into vestibular function and generate new hypotheses. Physiological studies are necessary to further elucidate the roles of the identified genes and novel sequences in vestibular function.


Laser beam scan enhancement through periodic aperture transfer.
A new approach to laser beam scanning is introduced which is sufficiently general to be applied to a wide variety of techniques. Periodic scan enhancement is described as a method of taking advantage of iteration or summation of contributions from individual scanning sections without imposing the progressive increase in aperture size. Vignetting at the scanning aperture is avoided, permitting employment of a multiplicity of elements whose sizes are diffraction limited. This is achieved by the interposition of alternate lenticular elements which reimage the aperture of one scanning element upon the aperture of the next. Thus, the responsibility of increased aperture size as scan progresses is transferred from the (dynamic) scanning element itself to the (static) transfer optics. Several examples illustrate application of this technique. Over-all optics is considered to approach diffraction-limited performance with minimum loss.


Complete mitochondrial genomes of ancient canids suggest a European origin of domestic dogs.
The geographic and temporal origins of the domestic dog remain controversial, as genetic data suggest a domestication process in East Asia beginning 15,000 years ago, whereas the oldest doglike fossils are found in Europe and Siberia and date to >30,000 years ago. We analyzed the mitochondrial genomes of 18 prehistoric canids from Eurasia and the New World, along with a comprehensive panel of modern dogs and wolves. The mitochondrial genomes of all modern dogs are phylogenetically most closely related to either ancient or modern canids of Europe. Molecular dating suggests an onset of domestication there 18,800 to 32,100 years ago. These findings imply that domestic dogs are the culmination of a process that initiated with European hunter-gatherers and the canids with whom they interacted.


Azocompounds as generators of defined radical species: Contributions and challenges for free radical research.
Peroxyl radicals participate in multiple processes involved in critical changes to cells, tissues, pharmacueticals and foods. Some of these reactions explain their association with degenerative pathologies, including cardiovascular and neurological diseases, as well as cancer development. Azocompounds, and particularly AAPH (2,2'-Azobis(2-methylpropionamidine) dihydrochloride), a cationic water-soluble derivative, have been employed extensively as sources of model peroxyl radicals. A considerable number of studies have reported mechanistic data on the oxidation of biologically-relevant targets, the scavenging activity of foods and natural products, and the reactions with, and responses of, cultured cells. However, despite the (supposed) experimental simplicity of using azocompounds, the chemistry of peroxyl radical production and subsequent reactions is complicated, and not always considered in sufficient depth when analyzing experimental data. The present work discusses the chemical aspects of azocompounds as generators of peroxyl (and other) radicals, together with their contribution to our understanding of biochemistry, pharmaceutical and food chemistry research. The evidence supporting a role for the formation of alkoxyl (RO•) and other radicals during thermal and photochemical decomposition of azocompounds is assessed, together with the potential influence of such species on the reactions under study.


Structure of human Niemann-Pick C1 protein.
Niemann-Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a "sterol-sensing domain" (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport.


The attraction of Zonocerus variegatus (Orthoptera: Pyrgomorphidae) to different types of lure.
Zonocerus variegatus is a common grasshopper in parts of west and equtorial Africa. The distribution in Nigeria extends from the lowland rainforest zone to the savannah in the north. The influence of lure on the behaviour of grasshopper inside cages (120 insect per cage) was investigated. Nymphs and adults of Zonocerus variegatus responded positively to intact leaves, crushed leaves and inflorescence of the common compositae weed Chromolaena odorata inside muslin bags, and intact plants. There were significant differences in the attraction recorded for starved nymphs, fed nymphs and starved adults. Attraction was more to intact leaves and is by olfaction. The increase in the attraction of starved nymphs is time dependent. Attraction to plant parts ceased after the plants were dried for 24 and 48 hours at room temperature and when plants were placed in transparent polythene bags. Gut motility and gut activity were higher during the day than at night. Nymphs, adults and egg pods placed separately inside muslin bags were not attractive to adults or nymphs.


Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly.
Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain, and in its severe form, the cerebral hemispheres fail to completely separate into two distinct halves. Although disruption of ventral forebrain induction is thought to underlie most HPE cases, a subset of HPE patients exhibits preferential dysgenesis of forebrain dorsal midline structures with unknown etiology. In this study, we show that Sonic hedgehog (Shh) lacking cholesterol moiety in one allele (ShhN/+) in mice can elicit ectopic Shh signaling in early telencephalon to induce ventral progenitor marker expression in the cortical region and impair telencephalic dorsal midline development. Prolonged ectopic ShhN signaling impaired Bmp and Wnt signaling from the dorsal patterning center through upregulation of Fgf8, leading to augmented cell proliferation, decreased cell death and impaired roof plate morphogenesis. Accordingly, ShhN/+ mutant telencephalic dorsal midline structures, including cortical hem, hippocampus and choroid plexus, either failed to form or were hypoplastic. Strikingly, ShhN/+ mutants displayed a spectrum of phenotypic features such as failure of anterior cerebral hemisphere to divide, hydrocephalus and cleft palate which have been observed in a human patient with milder HPE predicted to produce SHHN protein due to a truncation mutation in one SHH allele. We propose that elevated ectopic Shh signaling can impair dorsal telencephalic midline morphogenesis, and lead to non-cleavage of midline structures mimicking human HPE with dorsal midline defects.


Spike-driven synaptic dynamics generating working memory states.
The collective behavior of a network, modeling a cortical module of spiking neurons connected by plastic synapses is studied. A detailed spike-driven synaptic dynamics is simulated in a large network of spiking neurons, implementing the full double dynamics of neurons and synapses. The repeated presentation of a set of external stimuli is shown to structure the network to the point of sustaining working memory (selective delay activity). When the synaptic dynamics is analyzed as a function of pre- and postsynaptic spike rates in functionally defined populations, it reveals a novel variation of the Hebbian plasticity paradigm: in any functional set of synapses between pairs of neurons (e.g., stimulated-stimulated, stimulated-delay, stimulated-spontaneous), there is a finite probability of potentiation as well as of depression. This leads to a saturation of potentiation or depression at the level of the ratio of the two probabilities. When one of the two probabilities is very high relative to the other, the familiar Hebbian mechanism is recovered. But where correlated working memory is formed, it prevents overlearning. Constraints relevant to the stability of the acquired synaptic structure and the regimes of global activity allowing for structuring are expressed in terms of the parameters describing the single-synapse dynamics. The synaptic dynamics is discussed in the light of experiments observing precise spike timing effects and related issues of biological plausibility.


Hierarchical Novelty Detection for Traffic Sign Recognition.
Recent works have made significant progress in novelty detection, i.e., the problem of detecting samples of novel classes, never seen during training, while classifying those that belong to known classes. However, the only information this task provides about novel samples is that they are unknown. In this work, we leverage hierarchical taxonomies of classes to provide informative outputs for samples of novel classes. We predict their closest class in the taxonomy, i.e., its parent class. We address this problem, known as hierarchical novelty detection, by proposing a novel loss, namely Hierarchical Cosine Loss that is designed to learn class prototypes along with an embedding of discriminative features consistent with the taxonomy. We apply it to traffic sign recognition, where we predict the parent class semantics for new types of traffic signs. Our model beats state-of-the art approaches on two large scale traffic sign benchmarks, Mapillary Traffic Sign Dataset (MTSD) and Tsinghua-Tencent 100K (TT100K), and performs similarly on natural images benchmarks (AWA2, CUB). For TT100K and MTSD, our approach is able to detect novel samples at the correct nodes of the hierarchy with 81% and 36% of accuracy, respectively, at 80% known class accuracy.


Assessing the effectiveness of Enhanced Psychological Care for patients with depressive symptoms attending cardiac rehabilitation compared with treatment as usual (CADENCE): a pilot cluster randomised controlled trial.
Around 17% of people attending UK cardiac rehabilitation programmes have depression. Optimising psychological wellbeing is a rehabilitation goal, but provision of psychological care is limited. We developed and piloted an Enhanced Psychological Care (EPC) intervention embedded within cardiac rehabilitation, aiming to test key areas of uncertainty to inform the design of a definitive randomised controlled trial (RCT) and economic evaluation. An external pilot randomised controlled trial (RCT) randomised eight cardiac rehabilitation teams (clusters) to either usual care of cardiac rehabilitation provision (UC), or EPC in addition to UC. EPC comprised mental health care coordination and patient-led behavioural activation with nurse support. Adults eligible for cardiac rehabilitation following an acute coronary syndrome and identified with new-onset depressive symptoms during an initial nurse assessment were eligible. Measures were performed at baseline and 5- and 8-month follow-ups and compared between EPC and UC. Team and participant recruitment and retention rates, and participant outcomes (clinical events, depression, anxiety, health-related quality of life, patient experiences, and resource use) were assessed. Eight out of twenty teams were recruited and randomised. Of 614 patients screened, 55 were eligible and 29 took part (5%, 95% CI 3 to 7% of those screened), with 15 patient participants cluster randomised to EPC and 14 to UC. Nurse records revealed that 8/15 participants received the maximum number of EPC sessions offered; and 4/15 received no sessions. Seven out of fifteen EPC participants were referred to another NHS psychological service compared to none in UC. We followed up 27/29 participants at 5 months and 17/21 at 8 months. The mean difference (EPC minus UC) in depressive symptoms (Beck Depression Inventory) at follow-up (adjusting for baseline score) was 1.7 (95% CI - 3.8 to 7.3; N = 26) at 5 months and 4.4 (95% CI - 1.4 to 10.2; N = 17) at 8 months. While valued by patients and nurses, organisational and workload constraints are significant barriers to EPC implementation. There remains a need to develop and test new models of psychological care within cardiac rehabilitation. Our study offers important data to inform the design of future trials of similar interventions. ISRCTN34701576 . Registered on 29 May 2014. Funding details: UK NIHR HTA Programme (project 12/189/09).


Mitochondrial dysfunction and type 2 diabetes.
Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.


Mode-locking and frequency mixing at THz pulse repetition rates in a sampled-grating DBR mode-locked laser.
We report a sampled grating distributed Bragg reflector (SGDBR) laser with two different gratings which mode-lock independently at respective pulse repetition frequencies of 640 and 700 GHz. The device operates in distinct regimes depending on the bias conditions, with stable pulse trains observed at 640 GHz, 700 GHz, the mean repetition frequency of 666 GHz, and the sum frequency of 1.34 THz (due to nonlinear mixing). Performance is consistent and highly reproducible with exceptional stability observed over wide ranges of drive bias conditions. Furthermore, a monolithically integrated semiconductor optical amplifier is used to amplify the pulse trains, providing an average output power of 46 mW at 666 GHz.


Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors.
The mode of binding of four active-site directed inhibitors to human thrombin has been determined by x-ray crystallographic analysis. The inhibitors studied are benzamidine, PPACK, NAPAP, and MD-805, of which the last three are compounds evolved specifically to inhibit thrombin. Crystal structures were determined in the presence of both the inhibitor and the undecapeptide [des-amino Asp55]hirudin(55-65) which binds distant from the active site. Despite having significantly different chemical structures, NAPAP and MD-805 bind to thrombin in a very similar "inhibitor binding mode" which is not that expected by direct analogy with the binding of substrate. Both inhibitors bind to thrombin in a similar way as to trypsin, but thrombin has an extra loop, the "Tyr-Pro-Pro-Trp loop," not present in trypsin, which gives further binding interactions and is seen to move somewhat to accommodate binding of the different inhibitors. The fact that NAPAP and MD-805 require different stereochemistry for potent inhibition is demonstrated, and its structural basis clarified. The wealth of data on analogs and variants of these lead compounds is shown to be compatible with this inhibitor binding mode.


Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines.
We established a selection strategy to identify new models for an altered airway inflammatory response from a large compendium of mutant mouse lines that were systemically phenotyped in the German Mouse Clinic (GMC). As selection criteria we included published gene functional data, as well as immunological and transcriptome data from GMC phenotyping screens under standard conditions. Applying these criteria we identified a few from several hundred mutant mouse lines and further characterized the Cox4i2tm1Hutt, Ifit2tm1.1Ebsb, and Prdm11tm1.1ahl lines following ovalbumin (OVA) sensitization and repeated OVA airway challenge. Challenged Prdm11tm1.1ahl mice exhibited changes in B cell counts, CD4+ T cell counts, and in the number of neutrophils in bronchoalveolar lavages, whereas challenged Ifit2tm1.1Ebsb mice displayed alterations in plasma IgE, IgG1, IgG3, and IgM levels compared to the challenged wild type littermates. In contrast, challenged Cox4i2tm1Hutt mutant mice did not show alterations in the humoral or cellular immune response compared to challenged wild type mice. Transcriptome analyses from lungs of the challenged mutant mouse lines showed extensive changes in gene expression in Prdm11tm1.1ahl mice. Functional annotations of regulated genes of all three mutant mouse lines were primarily related to inflammation and airway smooth muscle (ASM) remodeling. We were thus able to define an effective selection strategy to identify new candidate genes for the predisposition to an altered airway inflammatory response under OVA challenge conditions. Similar selection strategies may be used for the analysis of additional genotype-envirotype interactions for other diseases.


The Generative Adversarial Brain.
The idea that the brain learns generative models of the world has been widely promulgated. Most approaches have assumed that the brain learns an explicit density model that assigns a probability to each possible state of the world. However, explicit density models are difficult to learn, requiring approximate inference techniques that may find poor solutions. An alternative approach is to learn an implicit density model that can sample from the generative model without evaluating the probabilities of those samples. The implicit model can be trained to fool a discriminator into believing that the samples are real. This is the idea behind generative adversarial algorithms, which have proven adept at learning realistic generative models. This paper develops an adversarial framework for probabilistic computation in the brain. It first considers how generative adversarial algorithms overcome some of the problems that vex prior theories based on explicit density models. It then discusses the psychological and neural evidence for this framework, as well as how the breakdown of the generator and discriminator could lead to delusions observed in some mental disorders.


Incomplete response to artificial tears is associated with features of neuropathic ocular pain.
Artificial tears are first-line therapy for patients with dry eye symptoms. It is not known, however, which patient factors associate with a positive response to therapy. The purpose of this study was to evaluate whether certain ocular and systemic findings are associated with a differential subjective response to artificial tears. Cross-sectional study of 118 individuals reporting artificial tears use (hypromellose 0.4%) to treat dry eye-associated ocular pain. An evaluation was performed to assess dry eye symptoms (via the dry eye questionnaire 5 and ocular surface disease index), ocular and systemic (non-ocular) pain complaints and ocular signs (tear osmolarity, tear breakup time, corneal staining, Schirmer testing with anaesthesia, and eyelid and meibomian gland assessment). The main outcome measures were factors associated with differential subjective response to artificial tears. By self-report, 23 patients reported no improvement, 73 partial improvement and 22 complete improvement in ocular pain with artificial tears. Patients who reported no or partial improvement in pain with artificial tears reported higher levels of hot-burning ocular pain and sensitivity to wind compared with those with complete improvement. Patients were also asked to rate the intensity of systemic pain elsewhere in the body (other than the eye). Patients who reported no or incomplete improvement with artificial tears had higher systemic pain scores compared with those with complete improvement. Both ocular and systemic (non-ocular) pain complaints are associated with a differential subjective response to artificial tears.


Discovery and validation of blood microRNAs as molecular biomarkers of epilepsy: Ways to close current knowledge gaps.
There is a major unmet need for biomarkers of epilepsy. Biofluids such as blood offer a potential source of molecular biomarkers. MicroRNAs (miRNAs) fulfill several key requirements for a blood-based molecular biomarker being enriched in the brain and dysregulated in epileptic brain tissue, and manipulation of miRNAs can have seizure-suppressive and disease-modifying effects in preclinical models. Biofluid miRNAs also possess qualities that are favorable for translation, including stability and easy and cheap assay techniques. Herein we review findings from both clinical and animal models. Studies have featured a mix of unbiased profiling and hypothesis-driven efforts. Blood levels of several brain-enriched miRNAs are altered in patients with epilepsy and in patients with drug-resistant compared to drug-responsive seizures, with encouraging receiver-operating characteristic (ROC) curve analyses, both in terms of sensitivity and specificity. Both focal and generalized epilepsies are associated with altered blood miRNA profiles, and associations with clinical parameters including seizure burden have been reported. Results remain preliminary, however. There is a need for continued discovery and validation efforts that include multicenter studies and attention to study design, sample collection methodology, and quality control. Studies focused on epileptogenesis as well as associations with covariables such as sex, etiology, and timing of sampling remain limited. We identify 10 knowledge gaps and propose experiments to close these. If adequately addressed, biofluid miRNAs may be an important future source of diagnostic biomarkers that could also support forthcoming trials of antiepileptogenesis or disease-modifying therapies.


A meta-analysis epidemiological assessment of neurodevelopmental disorders following vaccines administered from 1994 through 2000 in the United States.
Thimerosal is an ethylmercury-containing compound (49.6% mercury by weight) used as at the preservative level in vaccines (0.005% to 0.01%). Statistical modeling in a meta-analysis epidemiological assessment of the Vaccine Adverse Event Reporting System (VAERS) for neurodevelopment disorders (NDs) reported following Diphtheria-Tetanus-whole-cell-Pertussis (DTP) vaccines in comparison to Diphtheria-Tetanus-whole-cell-Pertussis-Haemophilus Influenzae Type b (DTPH) vaccines (administered: 1994-1997) and following Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP), vaccines in comparison to Thimerosal-free DTaP vaccines (administered: 1997-2000), was undertaken. Significantly increased adjusted (sex, age, vaccine type, vaccine manufacturer) risks of autism, speech disorders, mental retardation, personality disorders, thinking abnormalities, ataxia, and NDs in general, with minimal systematic error or confounding, were associated with TCV exposure. It is clear from the results of the present epidemiological study and other recently published data associating mercury exposure with childhood NDs, additional ND research should be undertaken in the context of evaluating mercury-associated exposures, especially from Thimerosal-containing vaccines.


Middle East Respiratory Syndrome.
Middle East respiratory syndrome (MERS) emerged in the Arabian Peninsula in 2012, and subsequently spread to other countries in Europe and Asia, and to the United States. As of August 2015, the disease has infected 1,400 patients, of whom 500 have died, yielding a 36% mortality rate. The exact mode of transmission is unknown and there are no proven treatments. While the overall case rate for MERS has been low, its presence in countries that house US troops, unknown mode of transmission, and high mortality rate make it a significant health concern among US military personnel.


In vivo macrophage suppression of delayed hypersensitivity in the guinea-pig.
The nature of the suppressive activity in the peritoneal exudate cells (PEC) of guinea-pigs immunized with dinitrophenyl bovine gamma globulin (DNP50-BGG) was investigated. A method was developed to isolate from the peritoneal exudate large numbers of macrophages. Using density gradient centrifugation on Percoll it was possible to obtain a population of cells which contained over 90% macrophages. This macrophage preparation was found to respond to lymphokine but to be incapable of passively transferring delayed hypersensitivity reactions. When these immune macrophages were transferred into antigen immunized animals, which had been pretreated with cyclophosphamide (CY), the skin reactions were suppressed to the same extent as when the total PEC was transferred. PEC from guinea-pigs immunized with ovalbumin in Freund's incomplete adjuvant did not suppress the skin reactions in CY-pretreated DNP50BGG immunized animals. However, in contrast, macrophages from these animals did suppress the skin reactions in the recipient guinea-pigs indicating that the macrophage suppression was not antigen specific.


Predictors of Vaccination Card Retention in Children 12-59 months old in Karachi, Pakistan.
To determine the factors associated with retaining the vaccination card among care takers of 12-59 months old children in Karachi, Pakistan. This was an analytical cross-sectional study in Karachi. Households were randomly selected throughout a multistage cluster sampling technique. Data was collected for 504 children of 12- 59 months of age. Questionnaire was administered to caretakers to gather information regarding the children's vaccination status, socio-demographic characteristics and reviewing their vaccination cards. Statistical analysis was done by SPSS 19 using logistic regression. Among 462 vaccinated children, caretakers of 33% provided vaccination cards. Odds of card retention decrease if the caretaker has a large household i.e., >5 people sharing one room (AOR 0.277, 95% CI: 0.096, 0.797) and if the child is of four to five years of age (AOR 0.544, 95% CI: 0.305, 0.970). Gender of the child, and the caretaker's education and access to electronic media were not significant predictors of vaccination card retention in our study. Our study showed that vaccination card retention for children 12-59 months of age was low (33%) in Karachi. There is a need to educate caretakers of young children regarding the importance of keeping vaccination card and to disseminate this information through healthcare providers. Improving vaccination card retention is one of the key measures which will help towards accurately estimating coverage and to inform health policy decisions.


Explaining socioeconomic inequalities in self-rated health: a systematic review of the relative contribution of material, psychosocial and behavioural factors.
Material, psychosocial and behavioural factors are important explanatory pathways for socioeconomic inequalities in health. The aim of this systematic review was to summarise the available evidence on empirical studies and to analyse the relative contribution of these factors for explaining inequalities in self-rated health. The study was performed in compliance with PRISMA guidelines. The literature search was conducted in the electronic databases PubMed and Web of Science (1996-2016) as well as by screening of reference lists of obtained articles. Two reviewers performed the search and critical appraisal of the studies. All studies that focus on explaining socioeconomic inequalities in self-rated health, including at least 2 of the 3 main pathways and analysing the relative contribution of these approaches in separate and joint models, were included. Eleven publications were included. Separate analyses showed that material, psychosocial and behavioural factors contribute to the explanation of socioeconomic inequalities in self-rated health. However, the combined analyses revealed that material factors contributed most to differences in self-rated health because of their higher independent (direct) effect and additional shared (indirect) effect (through psychosocial and behavioural factors). These results were largely independent of age, gender and indicator of socioeconomic status. The evidence presented might be used for policymakers to identify and to justify prioritisation in terms of prevention and health promotion. The findings show that multiple factors are important for tackling social inequalities in health. Strategies for reducing these inequalities should focus on material/structural living conditions as they shape conditions of psychosocial resources and health behaviour.


Identification of the sequence required for expression of the 2H4 epitope on the human leukocyte common antigens.
The anti-2H4 antibody, which subdivides the T4+ population of human T lymphocytes into T4+, 2H4+ suppressor-inducer cells and T4+, 2H4- helper cells, recognizes an epitope on a subset of the human leukocyte common antigens (LCAs). LCAs are a family of cell surface glycoproteins generated from a single gene by the differential usage of three exons near the NH2-terminus. Using cDNA clones corresponding to four of the different forms of LCA molecules, extracellular domains of the LCA molecules were synthesized in vitro. Immunoprecipitation of these molecules with the anti-2H4 antibody demonstrated that exon A is required for the expression of the 2H4 epitope.


Effects of High-Speed Power Training on Neuromuscular and Gait Functions in Frail Elderly with Mild Cognitive Impairment Despite Blunted Executive Functions: A Randomized Controlled Trial.
Physical frailty and impaired executive function of the brain show similar pathophysiology. Both of these factors lead to dysfunction of neuromuscular and abilities in elderly. High-speed power training (HSPT) has been determined to have positive effects on neuromuscular function and gait performance, as well as executive function in the elderly. The purpose of this study was to investigate the effects of 8-week HSPT on neuromuscular, gait and executive functions in frail elderly with mild cognitive impairment (MCI). We performed a randomized controlled trial of frail elderly from community and medical center in republic of Korea. Forty-two physically frail elderly with MCI were randomly allocated to control (n=22, age=74.22±4.46) and intervention groups (n=18, age=73.77±4.64). The intervention group was subjected to HSPT, 3 times weekly for 8 weeks. Isometric contraction of knee extension and flexion with electromyography (EMG) was measured to determine the neuromuscular function such as knee extensor strength, rate of torque development, movement time, pre-motor time, motor time, rate of EMG rise, and hamstrings antagonist co-activation. Additionally, the 4.44-meter gait and timed up-and-go (TUG) test were administered to assess gait performance. A frontal assessment battery was measured in this study. The 8-week HSPT regimen improved the knee extensor strength from 1.13±0.08 to 1.25±0.07 (p<0.05), the 200-ms RTD from 3.01±0.3 to 3.55±0.24 (p<0.05) and the rate of EMG rise from 166.48±13.31 to 197.94±11.51 (p<0.05), whereas the movement time and motor time were statistically decreased from 921.69±40.10 to 799.51±72.84, and 271.40±19.29 to 181.15±38.08 (p<0.05), respectively. The 4.44-m gait speed and TUG significantly decreased from 6.39±0.25 to 5.5±0.24, and 11.05±0.53 to 9.17±0.43 respectively (p<0.05). The findings of this study suggest the favorable effects of 8-week HSPT on the neuromuscular function and the gait performance in the frail elderly with MCI without increase in the executive function.


Prevalence and risk factors of undercorrected refractive errors among Singaporean Malay adults: the Singapore Malay Eye Study.
To describe the prevalence and the risk factors of undercorrected refractive error in an adult urban Malay population. This population-based, cross-sectional study was conducted in Singapore in 3280 Malay adults, aged 40 to 80 years. All individuals were examined at a centralized clinic and underwent standardized interviews and assessment of refractive errors and presenting and best corrected visual acuities. Distance presenting visual acuity was monocularly measured by using a logarithm of the minimum angle of resolution (logMAR) number chart at a distance of 4 m, with the participants wearing their "walk-in" optical corrections (spectacles or contact lenses), if any. Refraction was determined by subjective refraction by trained, certified study optometrists. Best corrected visual acuity was monocularly assessed and recorded in logMAR scores using the same test protocol as was used for presenting visual acuity. Undercorrected refractive error was defined as an improvement of at least 0.2 logMAR (2 lines equivalent) in the best corrected visual acuity compared with the presenting visual acuity in the better eye. The mean age of the subjects included in our study was 58 +/- 11 years, and 52% of the subjects were women. The prevalence rate of undercorrected refractive error among Singaporean Malay adults in our study (n = 3115) was 20.4% (age-standardized prevalence rate, 18.3%). More of the women had undercorrected refractive error than the men (21.8% vs. 18.8%, P = 0.04). Undercorrected refractive error was also more common in subjects older than 50 years than in subjects aged 40 to 49 years (22.6% vs. 14.3%, P < 0.001). Non-spectacle wearers were more likely to have undercorrected refractive errors than were spectacle wearers (24.4% vs. 14.4%, P < 0.001). Persons with primary school education or less were 1.89 times (P = 0.03) more likely to have undercorrected refractive errors than those with post-secondary school education or higher. In contrast, persons with a history of eye disease were 0.74 times (P = 0.003) less likely to have undercorrected refractive errors. The proportion of undercorrected refractive error among the Singaporean Malay adults with refractive errors was higher than that of the Singaporean Chinese adults with refractive errors. Undercorrected refractive error is a significant cause of correctable visual impairment among Singaporean Malay adults, affecting one in five persons.


Collagen-glycosaminoglycan matrix implantation promotes angiogenesis following surgical brain trauma.
Surgical brain injury (SBI) is unavoidable during many neurosurgical procedures intrinsically linked to postoperative neurological deficits. We have previously demonstrated that implantation of collagen glycosaminoglycan (CG) following surgical brain injury could significantly promote functional recovery and neurogenesis. In this study we further hypothesized that this scaffold may provide a microenvironment by promoting angiogenesis to favor neurogenesis and subsequent functional recovery. Using the rodent model of surgical brain injury as we previously established, we divided Sprague-Dawley male rats (weighting 300-350 g) into three groups: (1) sham (2) surgical injury with a lesion (L), and (3) L with CG matrix implantation (L + CG). Our results demonstrated that L + CG group showed a statistically significant increase in the density of vascular endothelial cells and blood vessels over time. In addition, tissue concentrations of angiogenic growth factors (such as VEGF, FGF2, and PDGF) significantly increased in L + CG group. These results suggest that implantation of a CG scaffold can promote vascularization accompanied by neurogenesis. This opens prospects for use of CG scaffolds in conditions such as brain injury including trauma and ischemia.


Chronic green tea catechins administration prevents oxidative stress-related brain aging in C57BL/6J mice.
As the organism ages, production of reactive oxygen species (ROS) increases while antioxidants defense capability declines, leading to oxidative stress in critical cellular components, which further enhances ROS production. In the brain, this vicious cycle is more severe as brain is particularly vulnerable to oxidative damage. In our study, 14-month-old female C57BL/6J mice were orally administered 0.05% green tea catechins (GTC, w/v) in drinking water for 6 months. We found that GTC supplementation prevented the decrease in total superoxide dismutase and glutathione peroxidase activities in serum as well as reduced the thiobarbituric acid reactive substances and protein carbonyl contents in the hippocampus of aged mice. The activation of transcriptional factor nuclear factor-kappa B and lipofuscin formation in pyramidal cells of hippocampal CA1 region, which are all related to oxidative stress, was also reduced after GTC treatment. We also found that long-term GTC treatment prevented age-related reductions of two representative post-synaptic proteins post-synaptic density 95 and N-methyl-d-aspartate receptor 1 in the hippocampus. These results demonstrated that chronic 0.05% green tea catechins administration may prevent oxidative stress related brain aging in female C57BL/6J mice.


Pneumonia care and the nursing home: a qualitative descriptive study of resident and family member perspectives.
Nursing home residents are frequently sent to hospital for diagnostic tests or to receive acute health care services. These transfers are both costly and for some, associated with increased risks. Although improved technology allows long-term care facilities to deliver more complex health care on site, if this is to become a trend then residents and family members must see the value of such care. This qualitative study examined resident and family member perspectives on in situ care for pneumonia. A qualitative descriptive study design was used. Participants were residents and family members of residents treated for pneumonia drawn from a larger randomized controlled trial of a clinical pathway to manage nursing home-acquired pneumonia on-site. A total of 14 in-depth interviews were conducted. Interview data were analyzed using the editing style, described by Miller and Crabtree, to identify key themes. Both residents and family members preferred that pneumonia be treated in the nursing home, where possible. They both felt that caring and attention are key aspects of care which are more easily accessible in the nursing home setting. However, residents felt that staff or doctors should make the decision whether to hospitalize them, whereas family members wanted to be consulted or involved in the decision-making process. These findings suggest that interventions to reduce hospitalization of nursing home residents with pneumonia are consistent with resident and family member preferences.


Anatomical circuitry of lateral inhibition in the eye of the horseshoe crab, Limulus polyphemus.
Lengthy uninterrupted series of sections of the neural plexus in the compound eye of the horseshoe crab, Limulus polyphemus, have been used to reconstruct all the arborizations and their synaptic interconnections in a neuropil knot. This one microglomerulus contains the axons of 19 retinular cells, which pass by without contacts; 13 efferent fibres with 44 synapses to and from eccentric cell collaterals; and arborizations from 54 eccentric cells with 577 synapses. Eccentric cell axons are devoid of synaptic input. Their collaterals ramify in synaptic knots and subserve both pre- and postsynaptic functions simultaneously. Arborizations near the axon of origin have a highly branched pattern (up to 20 bifurcations), a high synaptic input: output ratio (up to about 9:1), and high synaptic density (a maximum of 12 per micrometre of neurite length). The opposite extreme is represented by sparsely branched eccentric cell collaterals distant from their axons of origin with very little synaptic input and sparse output. Spatially graded lateral inhibition is the apparent outcome of a radially decreasing distribution of inhibitory synapses on the arborizations of eccentric cell collaterals combined with possible decremental signal transmission in the plexus. The synaptic analysis has a bearing on most physiological aspects of lateral inhibition that have been studied in the Limulus eye. Implied in the results is the suggestion that synapse formation is an intrinsic property of the presynaptic element, but that the connectivity is governed by the electrical activity of target neurons.


Experimental Inhibition of Periostin Attenuates Kidney Fibrosis.
Periostin is responsible for tissue regeneration, fibrosis, and wound healing via its interaction with integrin. Recently, the role of periostin has been shown to contribute to fibrosis in chronic kidney disease. We investigated the role of periostin and the effect of periostin blockade in renal fibrogenesis. We investigated the function of periostin in vivo in wild-type and periostin-null mice (Postn-KO) in a unilateral ureteral obstruction (UUO) model. For the in vitro experiments, primary cultured inner medullary collecting duct cells from the wild-type and Postn-KO mice were used. Periostin expression was strongly induced by UUO in the wild-type mice. UUO induced renal fibrosis and morphological changes in the obstructed kidney of wild-type mice, whereas global knockout of periostin reduced fibrosis induced by UUO and improved kidney structure. Fibrosis- and inflammation-related mRNA were significantly induced in the wild-type mice and were decreased in the Postn-KO mice. Additionally, α-smooth muscle actin expression was increased following the administration of recombinant periostin in vitro. The effect of periostin blockade was examined using 2 methods. The integrin blockade peptide decreased fibrosis-related gene expression in in vitro experiments. Anti-periostin polyclonal antibody attenuated renal fibrosis induced by UUO through changes in transforming growth factor-β signaling and the inflammatory and apoptotic pathways. Periostin is a marker of renal fibrosis and may augment the progression of fibrogenesis as an extracellular matrix protein. Periostin blockade effectively attenuated renal fibrogenesis. Thus, periostin inhibition may be a therapeutic strategy for the amelioration of renal disease progression.


Role of imaging in current acute ischemic stroke workflow for endovascular therapy.
Ischemic stroke is caused by a thrombus that blocks an intracranial artery. Brain tissue beyond the blocked artery survives for a variable period of time because of blood and nutrients received through tiny vessels called collaterals. Imaging the brain and the vasculature that supplies it is therefore a vital first step in treating patients with acute ischemic stroke. In this review, we focus on current evidence for imaging selection of patients for endovascular therapy in the context of the recently positive clinical trials, such as Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing Computed Tomography to Recanalization Times (ESCAPE), Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME), and Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA). We discuss evidence for and use of the various imaging paradigms available. We discuss how to set up quick and efficient imaging protocols for patient selection and address common concerns about the use of imaging, including time spent, contrast, radiation, and other advantages and disadvantages. Finally, we briefly comment on how imaging can integrate itself within various health systems of care in the future, thereby potentially improving patient outcomes further.


Comparison of sire breed solutions for growth traits adjusted by mean expected progeny differences to a 1993 base.
Records on growth traits were obtained from five Midwestern agricultural experiment stations as part of a beef cattle crossbreeding project (NC-196). Records on birth weight (BWT, n =3,490), weaning weight (WWT, n = 3,237), and yearling weight (YWT, n = 1,372) were analyzed within locations and pooled across locations to obtain estimates of breed of sire differences. Solutions for breed of sire differences were adjusted to the common base year of 1993. Then, factors to use with within-breed expected progeny differences (EPD) to obtain across-breed EPD were calculated. These factors were compared with factors obtained from similar analyses of records from the U. S. Meat Animal Research Center (MARC). Progeny of Brahman sires mated to Bos taurus cows were heaviest at birth and among the lightest at weaning. Simmental and Gelbvieh sires produced the heaviest progeny at weaning. Estimates of heritability pooled across locations were .34, .19, and .07 for BWT, WWT, and YWT, respectively. Regression coefficients of progeny performance on EPD of sire were 1.25+/-.09, .98+/-.13, and .62+/-.18 for BWT, WWT, and YWT, respectively. Rankings of breeds of sire generally did not change when adjusted for sire sampling. Rankings were generally similar to those previously reported for MARC data, except for Limousin and Charolais sires, which ranked lower for BWT and WWT at NC-196 locations than at MARC. Adjustment factors used to obtain across-breed EPD were largest for Brahman for BWT and for Gelbvieh for WWT. The data for YWT allow only comparison of Angus with Simmental and of Gelbvieh with Limousin.


Speciation of arsenic and selenium by capillary electrophoresis.
Capillary electrophoresis (CE) with direct UV detection, both on-capillary and with a high-sensitivity detection cell (HSDC), were used for the simultaneous determination of arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), selenate [Se(VI)], selenite [Se(IV)], selenocystine (SeC), selenomethionine (SeM) and selenocystamine (SeCM). These anionic and cationic species were separated with negative separation voltage polarity in a capillary coated with poly(diallydimethylammonium chloride) (PDDAC). The background electrolyte (BGE) providing optimal separation was 15 mM phosphate buffer at pH 10.6. Arsenic and selenium species were detected at 195 and 200 nm, respectively. The limit of detection (LOD) values with on-capillary detection (75 microm i.d.) for the individual analytes were 1.02, 1.50, 1.08, 1.35, 19.5, 0.36, 0.32, 1.11 and 1.47 mg/L, respectively (expressed as arsenic or selenium). The method precision for peak area was from 2.1 to 3.4% relative standard deviation. HSDC was applied to increase the detection sensitivity and gave LOD improvement factors from 4.7 to 8.2, yielding LODs for the individual target analytes ranging from 0.049 to 2.38 mg/L. When the normal sample stacking mode was employed using a sample plug up to 4.6% of capillary volume, both the cationic and anionic analytes were stacked simultaneously with LOD improvement factors of 2.6-4.5 yielding LODs for the individual analytes ranging from 0.11 to 7.42 mg/L. The method was applied for the speciation of arsenic in sediment and determination of SeM in a selenium nutrition supplement. The achieved separation selectivity also gives the method a more general application potential for simultaneous arsenic and selenium speciation when hyphenated with inductively coupled plasma MS.


Primary care consultations about medically unexplained symptoms: how do patients indicate what they want?
Patients with medically unexplained physical symptoms (MUS) are often thought to deny psychological needs when they consult general practitioners (GPs) and to request somatic intervention instead. We tested predictions from the contrasting theory that they are transparent in communicating their psychological and other needs. To test predictions that what patients tell GPs when they consult about MUS is related transparently to their desire for (1) emotional support, (2) symptom explanation and (3) somatic intervention. Prospective naturalistic study. Before consultation, patients indicated what they wanted from it using a self-report questionnaire measuring patients' desire for: emotional support, explanation and reassurance, and physical investigation and treatment. Their speech during consultation was audio-recorded, transcribed and coded utterance-by-utterance. Multilevel regression analysis tested relationships between what patients sought and what they said. Patients (N = 326) consulting 33 GPs about symptoms that the GPs designated as MUS. Patients who wanted emotional support spoke more about psychosocial problems, including psychosocial causes of symptoms and their need for psychosocial help. Patients who wanted explanation and reassurance suggested more physical explanations, including diseases, but did not overtly request explanation. Patients' wish for somatic intervention was associated only with their talk about details of such interventions and not with their requests for them. In general, patients with medically unexplained symptoms provide many cues to their desire for emotional support. They are more indirect or guarded in communicating their desire for explanation and somatic intervention.


Aripiprazole and pregnancy: A retrospective, multicentre study.
Aripiprazole is a second generation antipsychotic medication that has been a useful addition to the treatment of severe mental illness due to its low metabolic and sedation risk profile. Pregnancy is a time of high risk of metabolic complications such as gestational diabetes and the postpartum period is often a time when sedation can compromise infant care. To date there is limited data in pregnancy on the safety of aripiprazole use. While available data do not suggest an elevated malformation risk in pregnancy, there is less information available on pregnancy and neonatal complications. This study presents preliminary data on pregnancy and neonatal complications on 26 women who took aripiprazole in pregnancy. These women attended at antenatal clinics for women with severe mental illness at two hospitals in Australia. Overall aripiprazole was not associated with an increased risk of gestational diabetes. However, use of aripiprazole in pregnancy was associated with an increased risk of pregnancy hypertension, lower birth weight, shorter gestation at birth and higher rates of admission of the neonate than the expected population rates. These findings need to be replicated in a larger, well-designed study to ensure they do not reflect confounding factors. Findings demonstrate that aripiprazole is unlikely to pose a metabolic risk in pregnancy but other pregnancy complications including hypertension, need to be examined in further studies.


Current issues in dietary acrylamide: formation, mitigation and risk assessment.
Acrylamide (AA) is known as a neurotoxin in humans and it is classified as a probable human carcinogen by the International Agency of Research on Cancer. AA is produced as by-product of the Maillard reaction in starchy foods processed at high temperatures (>120 °C). This review includes the investigation of AA precursors, mechanisms of AA formation and AA mitigation technologies in potato, cereal and coffee products. Additionally, most relevant issues of AA risk assessment are discussed. New technologies tested from laboratory to industrial scale face, as a major challenge, the reduction of AA content of browned food, while still maintaining its attractive organoleptic properties. Reducing sugars such as glucose and fructose are the major contributors to AA in potato-based products. On the other hand, the limiting substrate of AA formation in cereals and coffee is the free amino acid asparagine. For some products the addition of glycine or asparaginase reduces AA formation during baking. Since, for potatoes, the limiting substrate is reducing sugars, increases in sugar content in potatoes during storage then introduce some difficulties and potentially quite large variations in the AA content of the final product. Sugars in potatoes may be reduced by blanching. Levels of AA in different foods show large variations and no general upper limit is easily applicable, since some formation will always occur. Current policy is that practical measures should be taken voluntarily to reduce AA formation in vulnerable foods since AA is considered a health risk at the concentrations found in foods.


Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer.
Altered immune, inflammatory, and angiogenesis responses are observed in patients with head and neck squamous cell carcinoma (HNSCC), and many of these responses have been linked with aggressive malignant behavior and a decrease in prognosis. In this study, we examined the hypothesis that HNSCC cells produce cytokines that regulate immune, inflammatory, and angiogenesis responses. We identified important regulatory cytokines in supernatants of well-defined and freshly cultured HNSCC cell lines by ELISA and determined whether these cytokines are detected in tumor cell lines and tissue specimens by immunohistochemistry. The serum concentration of the cytokines and cytokine-dependent acute phase inflammatory responses (i.e., fibrinogen, C-reactive protein, and erythrocyte sedimentation rate) from patients with HNSCC was determined, and the potential relationship of serum cytokine levels to tumor volume was analyzed. Cytokines interleukin (IL)-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor were detected in similar concentration ranges in the supernatants of a panel of established University of Michigan squamous cell carcinoma (UM-SCC) cell lines and supernatants of freshly isolated primary HNSCC cultures. Evidence for the expression of IL-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and VEGF in HNSCC cells within tumor specimens in situ was obtained by immunohistochemistry. In a prospective comparison of the cytokine level and cytokine-inducible acute-phase proteins in serum, we report that cytokines IL-6, IL-8, and VEGF were detected at higher concentrations in the serum of patients with HNSCC compared with patients with laryngeal papilloma or age-matched control subjects (at P < 0.05). The serum concentrations of IL-8 and VEGF were found to be weakly correlated with large primary tumor volume (R2 = 0.2 and 0.4, respectively). Elevated IL-1- and IL-6-inducible acute-phase responses were also detected in cancer patients but not in patients with papilloma or control subjects (at P < 0.05). We therefore conclude that cytokines important in proinflammatory and proangiogenic responses are detectable in cell lines, tissue specimens, and serum from patients with HNSCC. These cytokines may increase the pathogenicity of HNSCC and prove useful as biomarkers or targets for therapy.


Characterization of CDH3-Related Congenital Hypotrichosis With Juvenile Macular Dystrophy.
Congenital hypotrichosis with juvenile macular dystrophy (HJMD) is a rare disorder presenting in childhood and adolescence with central visual disturbance and sparse scalp hair. Reported retinal imaging is lacking, and whether the condition is progressive remains unclear. To investigate a series of patients with HJMD due to biallelic mutations in CDH3 and thereby characterize the disorder. Ten patients from 10 families underwent detailed clinical assessment, including serial retinal imaging and electrophysiologic evaluation, at Moorfields Eye Hospital, St James's University Hospital, and Calderdale Royal Infirmary. Patients ranged in age from 3 to 17 years at onset and 5 to 57 years at last assessment. The molecular genetic investigation included bidirectional Sanger sequencing of all exons and intron-exon boundaries of CDH3 and whole-exome sequencing in 2 patients. The study was conducted from June 5, 2013, to January 15, 2016, with final follow-up completed on December 15, 2015. Results of clinical assessment and molecular genetic testing. All 10 patients (7 male and 3 female) presented with central visual disturbance in childhood and had lifelong sparse scalp hair with normal facial hair. Fundus examination revealed chorioretinal atrophy of the posterior pole contiguous with the disc in all but 1 patient that was associated with marked loss of autofluorescence on fundus autofluorescence imaging. Optical coherence tomography (OCT) demonstrated variable degrees of atrophy of the outer retina, retinal pigment epithelium, and choroid, with outer retinal tubulations frequently observed. One patient had mild disruption of the inner segment ellipsoid band on OCT and additional mild digit abnormalities. Electrophysiologic evaluation in 5 patients demonstrated macular dysfunction with additional mild, generalized retinal dysfunction in 2 patients. Eight patients had more than 1 evaluation; of these, 5 patients showed deterioration of visual acuity over time, 1 patient remained stable, and 2 patients had severe visual loss at presentation that precluded assessment of visual deterioration. The area of atrophy did not progress with time, but retinal thickness decreased on OCT. Electrophysiologic evaluation in 1 patient found deterioration of macular function after 13 years of follow-up, but the mild, generalized photoreceptor dysfunction remained stable. Biallelic mutations were identified in all patients, including 6 novel mutations. These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole. The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair. Patients may have additional limb abnormalities.


Liver specific, systemic and genetic contributors to alcohol-related liver disease progression.
Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.


Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell-derived ADAM9.
Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a predominant role in tumor metastasis; however, the molecular mechanisms involved remain elusive. Here, we demonstrate that genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet α6β1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of α6β1 on both human and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this receptor directly binds to platelet α6β1. In vivo studies showed that the interplay between platelet α6β1 and tumor cell-expressed ADAM9 promotes efficient lung metastasis. The integrin α6β1-dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting α6β1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin α6β1 represents a promising target for antimetastatic therapies.


Ovarian hormone loss impairs excitatory synaptic transmission at hippocampal CA3-CA1 synapses.
Premature and long-term ovarian hormone loss following ovariectomy (OVX) is associated with cognitive impairment. This condition is prevented by estradiol (E2) therapy when initiated shortly following OVX but not after substantial delay. To determine whether these clinical findings are correlated with changes in synaptic functions, we used adult OVX rats to evaluate the consequences of short-term (7-10 d, OVXControl) and long-term (∼5 months, OVXLT) ovarian hormone loss, as well as subsequent in vivo E2 treatment, on excitatory synaptic transmission at the hippocampal CA3-CA1 synapses important for learning and memory. The results show that ovarian hormone loss was associated with a marked decrease in synaptic strength. E2 treatment increased synaptic strength in OVXControl but not OVXLT rats, demonstrating a change in the efficacy for E2 5 months following OVX. E2 also had a more rapid effect: within minutes of bath application, E2 acutely increased synaptic strength in all groups except OVXLT rats that did not receive in vivo E2 treatment. E2's acute effect was mediated postsynaptically, and required Ca(2+) influx through the voltage-gated Ca(2+) channels. Despite E2's acute effect, synaptic strength of OVXLT rats remained significantly lower than that of OVXControl rats. Thus, changes in CA3-CA1 synaptic transmission associated with ovarian hormone loss cannot be fully reversed with delayed E2 treatment. Given that synaptic strength at CA3-CA1 synapses is related to the ability to learn hippocampus-dependent tasks, these findings provide additional insights for understanding cognitive impairment-associated long-term ovarian hormone loss and ineffectiveness for delayed E2 treatment to maintain cognitive functions.


Hospital admission volume does not impact the in-hospital mortality of acute pancreatitis.
Multiple factors influence mortality in Acute Pancreatitis (AP). To evaluate the association of demographic, clinical, and hospital factors with the in-hospital mortality of AP using a population-based administrative database. The Maryland HSCRC database was queried for adult (≥18 years) admissions with primary diagnosis of AP between 1/94-12/10. Organ failure (OF), interventions, hospital characteristics and referral status were evaluated. There were 72,601 AP admissions across 48 hospitals in Maryland with 885 (1.2%) deaths. A total of 1657 (2.3%) were transfer patients, of whom 101 (6.1%) died. Multisystem OF was present in 1078 (1.5%), of whom 306 (28.4%) died. On univariable analysis, age, male gender, transfer status, comorbidity, OF, all interventions, and all hospital characteristics were significantly associated with mortality; however, only age, transfer status, OF, interventions, and large hospital size were significant in the adjusted analysis. Patients with commercial health insurance had significantly less mortality than those with other forms of insurance (OR 0.65, 95% CI: 0.52, 0.82, p = 0.0002). OF is the strongest predictor of mortality in AP after adjusting for demographic, clinical, and hospital characteristics. Admission to HV or teaching hospital has no survival benefit in AP after adjusting for OF and transfer status.


Application of an Individual-Based Transmission Hazard Model for Estimation of Influenza Vaccine Effectiveness in a Household Cohort.
Household cohort studies are an important design for the study of respiratory virus transmission. Inferences from these studies can be improved through the use of mechanistic models to account for household structure and risk as an alternative to traditional regression models. We adapted a previously described individual-based transmission hazard (TH) model and assessed its utility for analyzing data from a household cohort maintained in part for study of influenza vaccine effectiveness (VE). Households with ≥4 individuals, including ≥2 children <18 years of age, were enrolled and followed during the 2010-2011 influenza season. VE was estimated in both TH and Cox proportional hazards (PH) models. For each individual, TH models estimated hazards of infection from the community and each infected household contact. Influenza A(H3N2) infection was laboratory-confirmed in 58 (4%) subjects. VE estimates from both models were similarly low overall (Cox PH: 20%, 95% confidence interval: -57, 59; TH: 27%, 95% credible interval: -23, 58) and highest for children <9 years of age (Cox PH: 40%, 95% confidence interval: -49, 76; TH: 52%, 95% credible interval: 7, 75). VE estimates were robust to model choice, although the ability of the TH model to accurately describe transmission of influenza presents continued opportunity for analyses.


Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient.
Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by computer-assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2-45), correlating with Ishak stage (stage 6 range, 13%-45%), and with HVPG (r = 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more [odds ratio, 1.206; 95% confidence interval (CI), 1.094-1.331; P < 0.001], or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026-1.191; P = 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis.


Protective effect of Sharbat-e-Deenar against acetaminophen-induced hepatotoxicity in experimental animals.
To investigate the effect of Sharbat-e-Deenar (SD) on acetaminophen (APAP)-induced hepatotoxicity in rat model. Albino rats were treated with SD at the doses of 1, 2 and 4 mL/kg, p.o. against hepatotoxicity after APAP (2 g/kg, p.o. once only) intoxication. The blood, tissue biochemical parameters and histopathological observation were performed. APAP exposure in rats significantly increased the level of biochemical parameters such as aspartate aminotransaminase, alanine aminotransaminase, lactate dehydrogenase, serum alkaline phosphatase, bilirubin, urea and creatinine into blood circulation which were reversed towards normal by SD therapy at all doses. The tissue biochemical parameters such as lipid peroxidation, reduced glutathione, adenosine tri-phosphatase and glucose-6-phosphatase were significantly restored after SD treatment against hepatotoxity. Histological analysis confirmed that SD-treated rats significantly alleviated of liver damage and reduced lesions caused by APAP intoxication. The biochemical changes are in good correlation with the histopathological observations. On the basis of these results, it can be concluded that SD exerts hepatoprotective activity against APAP-induced liver injury.


Stressors and Resources Related to Medication Management: Associations With Spousal Caregivers' Role Overload.
Managing medications can be stressful for spousal caregivers, but little is known about particular aspects of medication management that are most consequential for caregiving outcomes. We examined care stressors and resources related to medication management, their associations with role overload among spousal caregivers, and whether these links vary by care recipients' number of chronic health conditions and dementia status. This cross-sectional study included 377 spousal caregivers of adults aged 65 and older from the 2011 National Health and Aging Trends Study and National Study of Caregiving. Linear regressions were estimated to evaluate how medication-related stressors (ordering medication, keeping track of medications, giving injections) and resources (medication reminder systems, shared medication management within the spousal dyad) are associated with caregivers' role overload. Care recipients' number of chronic health conditions and dementia status were considered as moderators. Models controlled for caregivers' sociodemographic characteristics, chronic health conditions, and other care tasks. Caregivers who administered injections reported more role overload, whereas those who worked with care recipients to jointly manage medications reported less role overload. Keeping track of medications was linked to caregivers' greater role overload when care recipients had 5 or more chronic health conditions. Finally, care recipients' use of medication reminder systems was linked to less role overload for caregivers of a partner with dementia. Devising strategies to assist spousal caregivers in the more onerous components of medication management and promote resources that mitigate medication-related stress may improve caregiver well-being.


Palliative care for prison inmates: "don't let me die in prison".
The number of older inmates in US correctional facilities is increasing and with it the need for quality palliative health care services. Morbidity and mortality are high in this population. Palliative care in the correctional setting includes most of the challenges faced in the free-living community and several unique barriers to inmate care. Successful models of hospice care in prisons have been established and should be disseminated and evaluated. This article highlights why the changing demographics of prison populations necessitates hospice in this setting and highlights many of the barriers that correctional and consulting physicians face while providing palliative care. Issues specific to palliative care and hospice in prison include palliative care standards, inmate-physician and inmate-family relationships, confidentiality, interdisciplinary care, do-not-resuscitate orders and advance medical directives, medical parole, and the use of inmate volunteers in prison hospice programs. We also include practical recommendations to community-based physicians working with incarcerated or recently released prisoners and describe solutions that can be implemented on an individual and systems basis.


EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.


Fracture structure and thermoelectric enhancement of Cu2Se with substitution of nanostructured Ag2Se.
Recently, copper chalcogenides have attracted great attention due to their potential application for mid- to high-temperature thermoelectric power generation. In this work, we report the thermoelectric properties of Cu2Se compounds with different sample preparation processes and the inclusion of a nanoscale Ag2Se powder synthesized with a unique wet chemistry procedure. The Cu2Se compounds were prepared by solid state reaction (SSR), fast quenching (FQ) and mechanically alloyed with nanostructured Ag2Se (NM) followed by hot pressing. High temperature transport properties were assessed by the Seebeck coefficient, electrical conductivity and thermal conductivity measurements. Structural characterization demonstrates that the nano-Ag2Se included sample is multi-phase with several nanoscale features not seen in the Cu2Se samples prepared in the standard method. As a result, the Cu2Se-NM sample possesses a miniscule thermal conductivity, with values as low as 0.5 W m-1 K-1. Fortunately, the nano-inclusions present in the Cu2Se-NM sample do not significantly disrupt electronic transport, preserving the power factor at a consistently high value over a broad range of temperatures. Consequently, the nano-Ag2Se included sample exhibits large average ZT values and a maximum of 1.85 at 800 K that rivals some of the best thermoelectrics currently available. Here, we present microstructural and transport evidence that the wet chemistry technique implemented in our study enables the optimization of thermoelectric performance in superionic conductor Cu2Se.


Modular subdivisions of dolphin insular cortex: does evolutionary history repeat itself?
The structural organization of the insular cortex in the bottlenose dolphin was investigated by examining Nissl- and myelin-stained tissue that was sectioned coronally and tangentially. An uneven distribution of cell clusters that coincided with myelin-light zones was observed in layer II. When the present observations were compared to descriptions of modules in other animals, we found that the range of module size is restricted, while the size of the brain, particularly the neocortex, varies dramatically. Indeed, despite the tremendous expansion of the cetacean neocortex, the size of the modules in the insular cortex is similar to that described for small-brained mammals like the mouse, suggesting that module size is evolutionarily stable across species. Selection for optimal-size processing units, in terms of the lengths of connections within and between them, is a likely source of this stability.


How Urban Storm- and Wastewater Management Prepares for Emerging Opportunities and Threats: Digital Transformation, Ubiquitous Sensing, New Data Sources, and Beyond - A Horizon Scan.
Ubiquitous sensing will create many opportunities and threats for urban water management, which are only poorly understood today. To identify the most relevant trends, we conducted a horizon scan regarding how ubiquitous sensing will shape the future of urban drainage and wastewater management. Our survey of the international urban water community received an active response from both the academics and the professionals from the water industry. The analysis of the responses demonstrates that emerging topics for urban water will often involve experts from different communities, including aquatic ecologists, urban water system engineers and managers, as well as information and communications technology professionals and computer scientists. Activities in topics that are identified as novel will either require (i) cross-disciplinary training, such as importing new developments from the IT sector, or (ii) research in new areas for urban water specialists, for example, to help solve open questions in aquatic ecology. These results are, therefore, a call for interdisciplinary research beyond our own discipline. They also demonstrate that the water management community is not yet prepared for the digital transformation, where we will experience a data demand, i.e. a "pull" of urban water data into external services. The results suggest that a lot remains to be done to harvest the upcoming opportunities. Horizon scanning should be repeated on a routine basis, under the umbrella of an experienced polling organization.


Analysis of a vascular screening program in a rural community.
Implementation and adaptation of a vascular screening program in a rural community. A vascular screening program was offered free to the general population aged 55 years and older. It comprised of ultrasound screening of the carotid arteries, abdominal aorta, and the lower extremity segmental Doppler with ankle brachial index measurements. The program was initially developed in Annapolis, MD, and adapted to rural Warren, PA. Between March 2008 and June 2009, a total of 758 screenings were completed. Mild disease was detected in 12.7% of the population, moderate disease in 2.5% of the population, and severe disease in 1.3% of the population; 61.7% of all the participants had atherosclerotic plaques without stenosis and 45.9% of the participants had a history of smoking, 12.1% diabetes, 81.4% dyslipidemia, 58.3% hypertension, and 9.8% heart disease. This model of vascular screening program is an important tool for the detection of vascular disease and preventive health counseling. It detects not only vascular disease but its associated risk factors. Adequate treatment decreases cardiovascular disease mortality. This program, through local sponsorship, is adaptable to the rural community.


Results From the Mozambique 2016 Report Card on Physical Activity for Children and Adolescents.
This article describes the procedures and development of the 2016 Mozambican Report Card on Physical Activity for Children and Adolescents. Following the procedures adopted in 2014 for that year's report card, comprehensive searches on new data related to indicators of physical activity (PA) were done. A committee composed of physical activity and sports specialists graded each indicator consistent with the process and methodology outlined by the Active Healthy Kids Canada Report Card model. Nine indicators of PA were graded. Compared with 2014 there were several differences which were caused by changes in the country as well as a more effective evaluation from the committee. The following grades were assigned: Overall Physical Activity Levels, C; Organized Sport Participation, F; Active Play, D; Active Transportation, C; Schools, D; Community and the Built Environment, F; and Government, F. Sedentary Behaviors and Family and Peers were graded Incomplete due to the lack of available information. The decline of the PA habits in urban centers reported in 2014 are accentuated and is influencing the rural areas in several ways. At present, there is no strategy or effective action from authorities to reverse this negative trend.


Pneumocystis jirovecii pneumonia in HIV-uninfected, rituximab treated non-Hodgkin lymphoma patients.
Rituximab is associated with a higher incidence of Pneumocystis jirovecii pneumonia infection. Pneumocystis prophylaxis is advised in many immunocompromised populations treated with rituximab. However, the beneficial effect of pneumocystis prophylaxis in HIV-uninfected, rituximab-treated non-Hodgkin lymphoma (NHL) patients has not been assessed. Thus, we conducted this retrospective study to explore pneumocystis infection in HIV-uninfected NHL patients who received at least three courses of chemotherapy without haematopoietic stem cell transplantation using the Taiwan National Health Insurance Research Database. Patients who had rituximab-based chemotherapy were included in the experimental (rituximab) group, while the rest of the patients who did not receive any rituximab-based chemotherapy throughout the study period formed the control group. The prevalence rate of pneumocystis infection in the rituximab group (N = 7,554) was significantly higher than that in the control group (N = 4,604) (2.95% vs. 1.32%). The onset of pneumocystis infection occurred between 6 and 16 weeks after chemotherapy. Patients who had pneumocystis prophylaxis, whether or not they had a pneumocystis infection later in their treatment course, had significantly better first-year survival rates (73% vs. 38%). Regular pneumocystis prophylaxis should be considered in this group of patients.


Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation.
Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions.


Individual and combined roles of the master regulators AphA and LuxR in control of the Vibrio harveyi quorum-sensing regulon.
Bacteria use a chemical communication process called quorum sensing to control transitions between individual and group behaviors. In the Vibrio harveyi quorum-sensing circuit, two master transcription factors, AphA and LuxR, coordinate the quorum-sensing response. Here we show that AphA regulates 167 genes, LuxR regulates 625 genes, and they coregulate 77 genes. LuxR strongly controls genes at both low cell density and high cell density, suggesting that it is the major quorum-sensing regulator. In contrast, AphA is absent at high cell density and acts to fine-tune quorum-sensing gene expression at low cell density. We examined two loci as case studies of coregulation by AphA and LuxR. First, AphA and LuxR directly regulate expression of the genes encoding the quorum-regulatory small RNAs Qrr2, Qrr3, and Qrr4, the consequence of which is a specifically timed transition between the individual and the group life-styles. Second, AphA and LuxR repress type III secretion system genes but at different times and to different extents. The consequence of this regulation is that type III secretion is restricted to a peak at mid-cell density. Thus, the asymmetric production of AphA and LuxR coupled with differences in their strengths and timing of target gene regulation generate a precise temporal pattern of gene expression.


Prevalence and Determinants of Severe Mental Disorders in Iran: Evidence from the National Survey of STEPs- 2016.
The determinants and correlates of severe mental disorders are less understood compared to the common mental disorders, both in the world and in Iran. In this study, we aimed to identify a wide range of determinants of severe stress, severe anger, and severe sadness among Iranian population. This study is part of a large nationwide cross-sectional survey entitled STEPs conducted using a comprehensive questionnaire to determine the prevalence of main preventable risk factors of non-communicable diseases (NCDs) in Iran by age and sex groups in 2016. In total, 30541 people aged 18+participated in this study. Univariate and multivariate logistic regression analyses were used to examine the associations between the dependent variable, which is severe mental disorders, and independent variables including socio-economic factors, lifestyle and selected NCDs. The prevalence of severe stress, severe anger and sever sadness in the Iranian society was 33%, 35%, and 25%, respectively. Of the investigated socio-economic factors, being men, older, never married and living in rural areas were associated with significantly lower experience of severe mental disorders compared to other groups. For education, income and wealth index, there was no linear and clear pattern. Among lifestyle factors, being nonsmoker, having low physical activities, and higher intake of fruits and vegetables were found to be preventive of severe mental disorders. Additionally, having NCDs including hypertension, high cholesterol, diabetes and heart attacks were also significantly correlated with severe mental disorders. determining factors associated with severe mental disorders in this study would help in raising people's awareness on avoiding harmful factors, and taking healthier lifestyle such as quitting smoke, and consuming enough vegetables and fruits. Screening high risk people in terms of mental health could contribute to the reduction of mental disorders in the Iranian community.