RNA interference screen for human genes associated with West Nile virus infection.
West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.


Understanding and estimating effective population size for practical application in marine species management.
Effective population size (N(e)) determines the strength of genetic drift in a population and has long been recognized as an important parameter for evaluating conservation status and threats to genetic health of populations. Specifically, an estimate of N(e) is crucial to management because it integrates genetic effects with the life history of the species, allowing for predictions of a population's current and future viability. Nevertheless, compared with ecological and demographic parameters, N(e) has had limited influence on species management, beyond its application in very small populations. Recent developments have substantially improved N(e) estimation; however, some obstacles remain for the practical application of N(e) estimates. For example, the need to define the spatial and temporal scale of measurement makes the concept complex and sometimes difficult to interpret. We reviewed approaches to estimation of N(e) over both long-term and contemporary time frames, clarifying their interpretations with respect to local populations and the global metapopulation. We describe multiple experimental factors affecting robustness of contemporary N(e) estimates and suggest that different sampling designs can be combined to compare largely independent measures of N(e) for improved confidence in the result. Large populations with moderate gene flow pose the greatest challenges to robust estimation of contemporary N(e) and require careful consideration of sampling and analysis to minimize estimator bias. We emphasize the practical utility of estimating N(e) by highlighting its relevance to the adaptive potential of a population and describing applications in management of marine populations, where the focus is not always on critically endangered populations. Two cases discussed include the mechanisms generating N(e) estimates many orders of magnitude lower than census N in harvested marine fishes and the predicted reduction in N(e) from hatchery-based population supplementation.


Macrophages and dendritic cells: the usual suspects in atherogenesis.
Atherosclerosis, the major risk factor for cardiovascular disease (CVD) and the leading cause of death worldwide, is a multifactorial chronic inflammatory disease, which, clinically manifests from early lipid-rich lesions to plaque rupture and/or thrombosis in the arterial wall. The myeloid cell compartment, including macrophages and dendritic cells (DCs), is long known to contribute to the initiation and progression of atherosclerosis. However their complex phenotypic heterogeneity hampers our full understanding of their role. Here, we review the biological and functional versatility of the myeloid cells in atherosclerosis. Several distinct subsets of macrophages and myeloid cells have been identified in atherosclerotic plaques, including subsets that are specific to atherosclerosis itself. Our ability to target them therapeutically is still limited. The challenge for the future will be the definition of treatments that target specific myeloid subsets to prevent the activation of pro-atherogenic myeloid cell subsets while preserving the anti-atherogenic and repairable function of myeloid cells.


ITI-007 demonstrates brain occupancy at serotonin 5-HT₂A and dopamine D₂ receptors and serotonin transporters using positron emission tomography in healthy volunteers.
Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r (2) = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.


Mouse strain differences in phencyclidine-induced behavioural changes.
Administration of phencyclidine (PCP) is acknowledged to generate a model of psychosis in animals. With the identification of genetic susceptibility factors for schizophrenia and bipolar disorder, great efforts have been made to generate genetic animal models for major mental illnesses. As these disorders are multifactorial, comparisons among drug-induced (non-genetic) and genetic models are becoming an important issue in biological psychiatry. A major barrier is that the standard mouse strain used in the generation of genetic models is C57BL/6, whereas almost all studies with PCP-induced models have utilized other strains. To fill this technical gap, we systematically compared the behavioural changes upon PCP administration in different mouse strains, including C57BL/6N, C57BL/6J, ddY, and ICR. We observed strain differences in PCP-induced hyperlocomotion and enhanced immobility in the forced swim test (ddY>>C57BL/6N and 6J>ICR). In contrast, there was no strain difference in the impairment of recognition memory in the novel object recognition memory test after withdrawal of chronic PCP administration. This study provides practical guidance for comparing genetic with PCP-induced models of psychosis in C57BL/6. Furthermore, such strain differences may provide a clue to the biological mechanisms underlying PCP-induced endophenotypes possibly relevant to major mental illnesses.


Memory enhancing effect of Nigella Sativa hydro-alcoholic extract on lipopolysaccharide-induced memory impairment in rats.
In this study, the effects of Nigella Sativa (NS) hydro-alcoholic extract on lipopolysaccharide (LPS)-induced learning and memory impairments, hippocampal cytokine levels, and brain tissues oxidative damage were investigated in rats. The rats were grouped and treated: (1) control (saline), (2) LPS (1 mg/kg i.p.), and (3-5) 100, 200, or 400 mg/kg NS hydro-alcoholic extract 30 min before LPS injection. The treatment was started since 6 days before the behavioral experiments and continued during the behavioral tests (LPS injection 2 h before each behavioral experiment). Finally, the brains were removed for biochemical assessments. In Morris water maze (MWM) test, LPS increased the escape latency and traveled path compared to control group, whereas all doses of NS hydro-alcoholic extract decreased them compared to LPS group. In passive avoidance (PA) test, the latency to enter the dark compartment in LPS group was shorter than control group while in all treated groups it was longer than LPS group. LPS increased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), and nitric oxide (NO) metabolites, and decreased thiol content, superoxide dismutase (SOD), and catalase (CAT) in the hippocampal tissues compared to control group while NS hydro-alcoholic extract decreased MDA and NO metabolites and increased thiol content, SOD, and CAT compared to LPS group. Findings of the current study indicated that the hydro-alcoholic extract of NS improved the LPS-induced learning and memory impairments induced by LPS in rats by improving hippocampal cytokine levels and brain tissues oxidative damage.


Specific hemosiderin deposition in spleen induced by a low dose of cisplatin: altered iron metabolism and its implication as an acute hemosiderin formation model.
Cisplatin is one of the commonly-used chemotherapeutic drugs to efficiently treat malignant tumors in clinic, however, the adverse effects of cisplatin such as nephrotoxicity, neurotoxicity, and hemolytic uremic syndrome are often observed at its clinical doses (approximately 60 mg/m(2)), which limit its broader application. In earlier studies, little attention was paid to the subtle changes in the architecture of lymphatic organs after low doses of cisplatin treatment. This paper reviews current understanding of cisplatin-induced erythrocyte injury, and presents our latest finding that a low dose of cisplatin (3.6 mg/m(2)/day, 14 days) could induce specific hemosiderin deposition in spleen of both normal and hepatoma-22 (H22) inoculated Balb/C mice. This dose of cisplatin significantly inhibited H22-induced acute ascites development. No significant toxicity was induced by this dose of cisplatin to tissues except for hemosiderin accumulation in the spleen of both normal and H22 tumor-bearing mice. Increased splenic iron content and erythrocyte injury were observed after treatment with the low dose of cisplatin. The mRNA levels of ferroportin (FPN1) and ferritin were upregulated by 25 and 5-fold in spleen, respectively. Overexpression of FPN1 and ferritin protein were also been observed at protein levels by Western blotting analysis. In addition, the mRNA expression of hepcidin was also increased, suggesting blockage of iron recycling through FPN1 in spleen with cisplatin treatment. In conclusion, cisplatin treatment damages the erythrocytes which accumulate in the red pulp of spleen with defective recycling of FPN1 and ferritin protein. Hepcidin inhibits the function of FPN1 as iron-exporter leading to iron overloaded inside ferritins of splenic cells, which are stained with abnormal hemosiderin accumulation. These results demonstrate that cisplatin-caused hemosiderin deposition in spleen provides a valuable clue for understanding the molecular basis of toxicity of cisplatin and hemosiderin accumulation and iron metabolism in vivo.


A common genomic framework for a diverse assembly of plasmids in the symbiotic nitrogen fixing bacteria.
This work centres on the genomic comparisons of two closely-related nitrogen-fixing symbiotic bacteria, Rhizobium leguminosarum biovar viciae 3841 and Rhizobium etli CFN42. These strains maintain a stable genomic core that is also common to other rhizobia species plus a very variable and significant accessory component. The chromosomes are highly syntenic, whereas plasmids are related by fewer syntenic blocks and have mosaic structures. The pairs of plasmids p42f-pRL12, p42e-pRL11 and p42b-pRL9 as well large parts of p42c with pRL10 are shown to be similar, whereas the symbiotic plasmids (p42d and pRL10) are structurally unrelated and seem to follow distinct evolutionary paths. Even though purifying selection is acting on the whole genome, the accessory component is evolving more rapidly. This component is constituted largely for proteins for transport of diverse metabolites and elements of external origin. The present analysis allows us to conclude that a heterogeneous and quickly diversifying group of plasmids co-exists in a common genomic framework.


Nephrologists' perspectives on dialysis treatment: results of an international survey.
In-centre haemodialysis (ICHD) is the most common dialysis method used by patients worldwide. However, quality of life and clinical outcomes in patients treated via ICHD have not improved for some time. 'High-dose' haemodialysis (HD) regimens--which are longer and/or more frequent than conventional regimens and are particularly suitable to delivery in the home--may offer a route to improved outcomes and quality of life. This survey aimed to determine nephrologists' views on the validity of alternatives to ICHD, particularly home HD and high-dose HD. A total of 1,500 nephrologists from Europe, Canada and the United States were asked to respond to an online questionnaire that was designed following previous qualitative research. Certified nephrologists in practice for 2-35 years who managed >25 adult dialysis patients were eligible to take part. A total of 324 nephrologists completed the survey. ICHD was the most common type of dialysis used by respondents' current patients (90%), followed by peritoneal dialysis (8%) and home HD (2%). The majority of respondents believed that: home HD provides better quality of life; increasing the frequency of dialysis beyond three times per week significantly improves clinical outcomes; and longer dialysis sessions performed nocturnally would result in significantly better clinical outcomes than traditional ICHD. Survey results indicated that many nephrologists believe that home HD and high-dose HD are better for the patient. However, the majority of their patients were using ICHD. Education, training and support on alternative dialysis regimens are needed.


Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group pilot study.
A phase II study of ifosfamide, carboplatin, and prolonged oral administration of etoposide (ICE) in patients with untreated extensive-disease (ED) small-cell lung cancer (SCLC) was conducted to assess toxicities, response, and median survival. Between July 1990 and August 1992, 35 patients were treated. ICE doses were ifosfamide 5 g/m2 by 24-hour continuous intravenous (CIV) infusion with mesna on day 1, carboplatin 300 mg/m2 intravenously (IV) on day 1, and etoposide 50 mg/m2 orally on days 1 to 21 every 4 weeks for up to six to eight cycles (schedule I). Because of severe hematologic toxicity in the first 18 patients, the last 17 patients received ifosfamide 3.75 mg/m2 IV on day 1, carboplatin 300 mg/m2 IV on day 1, and etoposide 50 mg orally on days 1 to 14 (schedule II). Nine of 18 patients (50%) on schedule I had 13 episodes of severe hematologic toxicity (one death), and only two (11%) received full doses on cycle 2. However, with schedule II, only four of 17 patients (24%) developed severe hematologic toxicity, and eight (47%) received full doses on cycle 2. Objective responses were observed in 29 of 35 patients (83%) (schedule 1, 16 of 18 patients [89%]; schedule II, 13 of 17 patients [76%]). There were eight (23%) complete responses (CRs) and 21 (60%) partial responses (PRs). The median survival duration was 8.3 months, and 1- and 2-year survival rates were 37% and 14%, respectively. ICE with oral etoposide has comparable activity with other regimens in ED SCLC. However, the 2-year survival rate may be higher and ICE with the lower doses of schedule II could be given safely with acceptable toxicity. Further studies of ICE compared with standard two-drug regimens are warranted.


Synaptic interactions between GABA-immunoreactive profiles and the terminals of functionally defined myelinated nociceptors in the monkey and cat spinal cord.
This study analyzes the synaptic interactions between the central terminals of A delta high threshold mechanoreceptors (A delta HTMs) and GABA-immunoreactive profiles. A delta HTM primary afferents from three monkeys and one cat were electrophysiologically identified and intracellularly labeled with HRP, and their terminal arborizations in laminae I and II of the sacrocaudal spinal cord were studied at the ultrastructural level. GABA-immunoreactive profiles in relation to A delta HTM terminals were demonstrated using postembedding colloidal gold techniques. Monkey A delta HTM terminals (n = 131) usually constituted the central element of synaptic glomeruli; they established large asymmetric synaptic contacts with 1-13 dendrites (modal value 2-4) and were surrounded by 0-6 peripheral axon terminals (modal value 2-3). The large majority (around 85%) of the peripheral axon terminals were GABA immunoreactive. They were found presynaptic to the A delta HTM terminal and/or to dendrites postsynaptic to the primary afferent terminal. Furthermore, all peripheral axon terminals found presynaptic to the A delta HTM terminals showed GABA immunoreactivity. Within a single A delta HTM fiber, this synaptic arrangement was found in 20-60% of its boutons. In addition, 28% of the postsynaptic dendritic profiles displayed weak GABA immunoreactivity. Some of them contained vesicles; however, only in a few cases did we observe synapses between a GABA-immunoreactive vesicle-containing dendrite and a dendritic profile postsynaptic to an A delta HTM terminal. Similar synaptology and interactions with GABA-immunoreactive profiles were displayed by the terminals of the single cat A delta HTM fiber studied. Our data support the hypothesis that GABA-containing neurons use both presynaptic and/or postsynaptic mechanisms to exert a powerful control, presumably inhibitory, over the transmission of nociceptive information between A delta HTM afferents and second-order neurons in monkey and cat spinal cord. Our results also imply that GABA may be released within the synaptic glomeruli formed by A delta HTM terminals either by local dendrites or by axon terminals. We discuss the possibility that these GABAergic synapses can be driven by inputs from both primary afferents and/or descending systems to modulate the transmission of nociceptive sensory information.


Agreement Between Self-Reported and Confirmed Cancer Diagnoses in New York City Firefighters and EMS Workers, 2001-2011.
Because of the delay in availability of cancer diagnoses from state cancer registries, self-reported diagnoses may be valuable in assessing the current cancer burden in many populations. We evaluated agreement between self-reported cancer diagnoses and state cancer registry-confirmed diagnoses among 21,437 firefighters and emergency medical service workers from the Fire Department of the City of New York. We also investigated the association between World Trade Center (WTC) exposure and other characteristics in relation to accurate reporting of cancer diagnoses. Participants self-reported cancer status in questionnaires from October 2, 2001, to December 31, 2011. We obtained data on confirmed cancer diagnoses from nine state cancer registries, which we used as our gold standard. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), comparing self-reported cancer diagnoses with confirmed cancer diagnoses. We used multivariable logistic regression models to assess the association between WTC exposure and correct self-report of cancer status, false-positive cancer reports, and false-negative cancer reports. Sensitivity and specificity for all cancers combined were 90.3% and 98.7%, respectively. Specificities and NPVs remained high in different cancer types, while sensitivities and PPVs varied considerably. WTC exposure was not associated with accurate reporting. We found high specificities, NPVs, and general concordance between self-reported cancer diagnoses and registry-confirmed diagnoses. Given the low population prevalence of cancer, self-reported cancer diagnoses may be useful for determining non-cancer cases. Because of the low sensitivities and PPVs for some individual cancers, however, case confirmation with state cancer registries or medical records remains critically important.


Phylodynamics on local sexual contact networks.
Phylodynamic models are widely used in infectious disease epidemiology to infer the dynamics and structure of pathogen populations. However, these models generally assume that individual hosts contact one another at random, ignoring the fact that many pathogens spread through highly structured contact networks. We present a new framework for phylodynamics on local contact networks based on pairwise epidemiological models that track the status of pairs of nodes in the network rather than just individuals. Shifting our focus from individuals to pairs leads naturally to coalescent models that describe how lineages move through networks and the rate at which lineages coalesce. These pairwise coalescent models not only consider how network structure directly shapes pathogen phylogenies, but also how the relationship between phylogenies and contact networks changes depending on epidemic dynamics and the fraction of infected hosts sampled. By considering pathogen phylogenies in a probabilistic framework, these coalescent models can also be used to estimate the statistical properties of contact networks directly from phylogenies using likelihood-based inference. We use this framework to explore how much information phylogenies retain about the underlying structure of contact networks and to infer the structure of a sexual contact network underlying a large HIV-1 sub-epidemic in Switzerland.


Application of Cinematic Rendering in Clinical Routine CT Examination of Ankle Sprains.
Cinematic rendering technique is used to generate almost photorealistic 3D reconstructions of volumetric data. The purpose of this study was to evaluate the feasibility of cinematically rendered reconstructions in routine CT examinations of ankle sprains. Cinematic rendering technique may be primarily used to deliver visual information to patients, physicians, and virtual anatomy classes. Postprocessing requires more time than traditional methods do, which can be a hindrance in clinical work.


Sowerby's beaked whale biosonar and movement strategy indicate deep-sea foraging niche differentiation in mesoplodont whales.
Closely related species are expected to diverge in foraging strategy, reflecting the evolutionary drive to optimize foraging performance. The most speciose cetacean genus, Mesoplodon, comprises beaked whales with little diversity in external morphology or diet, and overlapping distributions. Moreover, the few studied species of beaked whales (Ziphiidae) show very similar foraging styles with slow, energy-conserving movement during long, deep foraging dives. This raises the question of what factors drive their speciation. Using data from animal-attached tags and aerial imagery, we tested the hypothesis that two similar-sized mesoplodonts, Sowerby's (Mesoplodon bidens) and Blainville's (Mesoplodon densirostris) beaked whales, exploit a similar low-energy niche. We show that, compared with the low-energy strategist Blainville's beaked whale, Sowerby's beaked whale lives in the fast lane. While targeting a similar mesopelagic/bathypelagic foraging zone, they consistently swim and hunt faster, perform shorter deep dives, and echolocate at a faster rate with higher frequency clicks. Further, extensive near-surface travel between deep dives challenges the interpretation of beaked whale shallow inter-foraging dives as a management strategy for decompression sickness. The distinctively higher frequency echolocation clicks do not hold apparent foraging benefits. Instead, we argue that a high-speed foraging style influences dive duration and echolocation behaviour, enabling access to a distinct prey population. Our results demonstrate that beaked whales exploit a broader diversity of deep-sea foraging and energetic niches than hitherto suspected. The marked deviation of Sowerby's beaked whales from the typical ziphiid foraging strategy has potential implications for their response to anthropogenic sounds, which appears to be strongly behaviourally driven in other ziphiids.


EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing: a NICE medical technology guidance.
A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC's findings, and the final NICE guidance issued.


Effect of volume loading on the Frank-Starling relation during reductions in central blood volume in heat-stressed humans.
During reductions in central blood volume while heat stressed, a greater decrease in stroke volume (SV) for a similar decrease in ventricular filling pressure, compared to normothermia, suggests that the heart is operating on a steeper portion of a Frank-Starling curve. If so, volume loading of heat-stressed individuals would shift the operating point to a flatter portion of the heat stress Frank-Starling curve thereby attenuating the reduction in SV during subsequent decreases in central blood volume. To investigate this hypothesis, right heart catheterization was performed in eight males from whom pulmonary capillary wedge pressure (PCWP), central venous pressure and SV (via thermodilution) were obtained while central blood volume was reduced via lower-body negative pressure (LBNP) during normothermia, whole-body heating (increase in blood temperature 1 degrees C), and during whole-body heating after intravascular volume expansion. Volume expansion was accomplished by administration of a combination of a synthetic colloid (HES 130/0.4, Voluven) and saline. Before LBNP, SV was not affected by heating (122 +/- 30 ml; mean +/- s.d.) compared to normothermia (110 +/- 20 ml; P = 0.06). However, subsequent volume loading increased SV to 143 +/- 29 ml (P = 0.003). LBNP provoked a larger decrease in SV relative to the decrease in PCWP during heating (8.6 +/- 1.9 ml mmHg(1)) compared to normothermia (4.5 +/- 3.0 ml mmHg(1), P = 0.02). After volume loading while heat stressed, the reduction in the SV to PCWP ratio during LBNP was comparable to that observed during normothermia (4.8 +/- 2.3 ml mmHg(1); P = 0.78). These data support the hypothesis that a Frank-Starling mechanism contributes to compromised blood pressure control during simulated haemorrhage in heat-stressed individuals, and extend those findings by showing that volume infusion corrects this deficit by shifting the operating point to a flatter portion of the heat stress Frank-Starling curve.


Innate Mucosal Immune System Response of BALB/c vs C57BL/6 Mice to Injury in the Setting of Enteral and Parenteral Feeding.
Outbred mice exhibit increased airway and intestinal immunoglobulin A (IgA) following injury when fed normal chow, consistent with humans. Parenteral nutrition (PN) eliminates IgA increases at both sites. Inbred mice are needed for detailed immunological studies; however, specific strains have not been evaluated for this purpose. BALB/c and C57BL/6 are common inbred mouse strains but demonstrate divergent immune responses to analogous stress. This study addressed which inbred mouse strain best replicates the outbred mouse and human immune response to injury. Intravenously cannulated mice received chow or PN for 5 days and then underwent sacrifice at 0 or 8 hours following controlled surgical injury (BALB/c: n = 16-21/group; C57BL/6: n = 12-15/group). Bronchoalveolar lavage (BAL) was analyzed by enzyme-linked immunosorbent assay for IgA, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, while small intestinal wash fluid (SIWF) was analyzed for IgA. No significant increase in BAL IgA occurred following injury in chow- or PN-fed BALB/c mice (chow: P = .1; PN: P = .7) despite significant increases in BAL TNF-α and SIWF IgA (chow: 264 ± 28 vs 548 ± 37, P < .0001; PN: 150 ± 12 vs 301 ± 17, P < .0001). Injury significantly increased mucosal IgA in chow-fed C57BL/6 mice (BAL: 149 ± 33 vs 342 ± 87, P = .01; SIWF: 236 ± 28 vs 335 ± 32, P = .006) and BAL cytokines. After injury, PN-fed C57BL/6 mice exhibited no difference in BAL IgA (P = .9), BAL cytokines, or SIWF IgA (P = .1). C57BL/6 mice exhibit similar airway responses to injury as outbred mice and humans, providing an appropriate model for studying mucosal responses to injury. The BALB/c mucosal immune system responds differently to injury and does not replicate the human injury response.


Factors associated with postpartum hemorrhage with vaginal birth.
A case-control study was performed to study risk factors for postpartum hemorrhage. Cases of hemorrhage were defined by a hematocrit decrease of 10 points or more between admission and post-delivery or by the need for red-cell transfusion. Patients with antenatal bleeding were excluded. Among 9598 vaginal deliveries, postpartum hemorrhage occurred in 374 cases (3.9%). Three controls were matched to each case and multiple logistic regression was used to control for covariance among predictor variables. Factors having a significant association with hemorrhage were prolonged third stage of labor (adjusted odds ratio 7.56), preeclampsia (odds ratio 5.02), mediolateral episiotomy (4.67), previous postpartum hemorrhage (3.55), twins (3.31), arrest of descent (2.91), soft-tissue lacerations (2.05), augmented labor (1.66), forceps or vacuum delivery (1.66), Asian (1.73) or Hispanic (1.66) ethnicity, midline episiotomy (1.58), and nulliparity (1.45). These data may help predict postpartum hemorrhage and may be useful in counseling patients about the advisability of home delivery, intravenous access in labor, or autologous blood donation.


A novel reductive graphene oxide-based magnetic molecularly imprinted poly(ethylene-co-vinyl alcohol) polymers for the enrichment and determination of polychlorinated biphenyls in fish samples.
The novel reductive graphene oxide-based magnetic molecularly imprinted poly(ethylene-co-vinyl alcohol) polymers (rGO@m-MIPs) were successfully synthesized as adsorbents for six kinds of polychlorinated biphenyls (PCBs) in fish samples. rGO@m-MIPs was prepared by surface molecular imprinting technique. Besides, Fe3 O4 nanoparticles (NPs) were employed as magnetic supporters, and rGO@Fe3 O4 was in situ synthesis. Different from functional monomer and cross-linker in traditional molecularly imprinted polymer, here, 3,4-dichlorobenzidine was employed as dummy molecular and poly(ethylene-co-vinyl alcohol) was adopted as the imprinted polymers. After morphology and inner structure of the magnetic adsorbent were characterized, the adsorbent was employed for disperse solid phase extraction toward PCBs and exhibited great selectivity and high adsorption efficiency. This material was verified by determination of PCBs in fish samples combined with gas chromatography-mass spectrometry (GC-MS) method. According to the detection, the low detection limits (LODs) of PCBs were 0.0035-0.0070 µg l(-1) and spiked recoveries ranged between 79.90 and 94.23%. The prepared adsorbent can be renewable for at least 16 times and expected to be a new material for the enrichment and determination of PCBs from contaminated fish samples.


Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways.
Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA's antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA's overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment.


Mechanical modelling quantifies the functional importance of outer tissue layers during root elongation and bending.
Root elongation and bending require the coordinated expansion of multiple cells of different types. These processes are regulated by the action of hormones that can target distinct cell layers. We use a mathematical model to characterise the influence of the biomechanical properties of individual cell walls on the properties of the whole tissue. Taking a simple constitutive model at the cell scale which characterises cell walls via yield and extensibility parameters, we derive the analogous tissue-level model to describe elongation and bending. To accurately parameterise the model, we take detailed measurements of cell turgor, cell geometries and wall thicknesses. The model demonstrates how cell properties and shapes contribute to tissue-level extensibility and yield. Exploiting the highly organised structure of the elongation zone (EZ) of the Arabidopsis root, we quantify the contributions of different cell layers, using the measured parameters. We show how distributions of material and geometric properties across the root cross-section contribute to the generation of curvature, and relate the angle of a gravitropic bend to the magnitude and duration of asymmetric wall softening. We quantify the geometric factors which lead to the predominant contribution of the outer cell files in driving root elongation and bending.


Efficacy of agonist-stimulated MEK activation determines the susceptibility of mitogen-activated protein (MAP) kinase to inhibition in rat aortic smooth muscle cells.
In rat aortic smooth muscle cells, platelet-derived growth factor (PDGF) stimulated a sustained activation of mitogen-activated protein kinase (MAP kinase) while the response to angiotensin II (AII) was transient. This was due to a relatively greater initial activation of MAP kinase kinase (MEK) and a correspondingly greater residual MEK activity at later time points. Pretreatment of cells with the novel MEK inhibitor PD 098059 reduced MEK activation at 5 min in response to each agonist by a similar proportion (70%); however, at this time point MAP kinase activation in response to PDGF was only marginally affected while the response to AII was substantially reduced. PD 098059 did, however, reduce PDGF-stimulated MEK activity after 30 min and this correlated with a loss in MAP kinase activity and DNA synthesis. Pretreatment with forskolin also caused a similar pattern of inhibition of agonist-stimulated MEK and MAP kinase activity. Only following protein kinase C down-regulation were both AII- and PDGF-stimulated MAP kinase activation substantially reduced and this correlated with the virtual loss of both MEK and c-Raf-1 activity in response to both agents. The differential inhibition of MAP kinase activation by forskolin was not due to specific activation of A-Raf by PDGF; both PDGF and AII stimulated A-Raf kinase and this activity was strongly inhibited by forskolin. These results suggest that the efficacy of MEK activation determines the duration of MAP kinase activation and the susceptibility of MAP kinase activation to inhibition by different agents. The results also argue against the selective activation of A-Raf by PDGF as a mechanism to explain the differences in the kinetics of MAP kinase activity stimulated by AII and PDGF.


House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program.
Children with asthma have a high prevalence of environmental allergies, especially to indoor allergens. The relationships of exposure to indoor allergens (dust mites, cat, dog, cockroach, and molds) and other host factors to allergy sensitization have not been evaluated simultaneously in a large cohort. We studied 1041 children aged 5 to 12 years with mild-to-moderate asthma to determine risk factors associated with having positive allergy skin test responses to indoor allergens. Also, we described, compared, and contrasted 6 allergens in the home environments of these children from 8 North American cities. Data were used from baseline visits of the Childhood Asthma Management Program. Patients' sensitivities to house dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus), cats, dogs, cockroaches, and molds were examined for relationships to demographic variables, home dust allergen exposures, number of other positive allergy skin test responses, total serum IgE levels, and smoking in the home. San Diego (78.5%) and Toronto (59.3%) had the topmost percentages of homes with moderate-to-high house dust mite levels. Boston (21.5%), St Louis (16.3%), and Baltimore (13.4%) had the highest percentages of homes with detectable levels of cockroach allergen. For house dust mites, the higher the level of allergen exposure, the more likely patients were to have positive allergy skin test responses, with relative odds of 9.0 (95% confidence interval, 5.4-15.1) for those exposed to high mite levels (>10.0 microg/g dust) relative to those unexposed. Even exposure to low levels of mite allergen (0.020-2.0 microg/g) was found to be a significant risk factor for sensitization. For cockroach allergen, those with detectable home exposure were more likely to have positive skin test responses (relative odds, 2.2; 95% confidence interval, 1.3-3.8) than those with undetectable exposure. In contrast, levels of exposure to cat, dog, and mold allergens were not related to sensitization rates. For cat allergen, this may reflect lower rates of cat ownership among highly sensitized subjects. Furthermore, the number of allergy skin test responses that were positive, excluding the test for the outcome of interest for each model, and total serum IgE levels were strong independent predictors of sensitization. Levels of exposure determined by house dust analysis are important determinants of sensitization for dust mite and cockroach allergen. This relationship was not demonstrable for cat, dog, or mold allergens, possibly because of confounding factors. For all allergens studied, the degree of atopy, determined by the total number of positive skin test responses or by total serum IgE levels, is an important contributing risk factor for sensitization.


Implementation of Enhanced Recovery After Surgery: a strategy to transform surgical care across a health system.
Enhanced Recovery After Surgery (ERAS) programs have been shown to have a positive impact on outcome. The ERAS care system includes an evidence-based guideline, an implementation program, and an interactive audit system to support practice change. The purpose of this study is to describe the use of the Theoretic Domains Framework (TDF) in changing surgical care and application of the Quality Enhancement Research Initiative (QUERI) model to analyze end-to-end implementation of ERAS in colorectal surgery across multiple sites within a single health system. The ultimate intent of this work is to allow for the development of a model for spread, scale, and sustainability of ERAS in Alberta Health Services (AHS). ERAS for colorectal surgery was implemented at two sites and then spread to four additional sites. The ERAS Interactive Audit System (EIAS) was used to assess compliance with the guidelines, length of stay, readmissions, and complications. Data sources informing knowledge translation included surveys, focus groups, interviews, and other qualitative data sources such as minutes and status updates. The QUERI model and TDF were used to thematically analyze 189 documents with 2188 quotes meeting the inclusion criteria. Data sources were analyzed for barriers or enablers, organized into a framework that included individual to organization impact, and areas of focus for guideline implementation. Compliance with the evidence-based guidelines for ERAS in colorectal surgery at baseline was 40%. Post implementation compliance, consistent with adoption of best practice, improved to 65%. Barriers and enablers were categorized as clinical practice (22%), individual provider (26%), organization (19%), external environment (7%), and patients (25%). In the Alberta context, 26% of barriers and enablers to ERAS implementation occurred at the site and unit levels, with a provider focus 26% of the time, a patient focus 26% of the time, and a system focus 22% of the time. Using the ERAS care system and applying the QUERI model and TDF allow for identification of strategies that can support diffusion and sustainment of innovation of Enhanced Recovery After Surgery across multiple sites within a health care system.


Social Influences on Drinking Trajectories From Adolescence to Young Adulthood in an Urban Minority Sample.
Research on the heterogeneity in drinking patterns of urban minorities within a socioecological framework is rare. The purpose of this study was to explore multiple, distinct patterns of drinking from adolescence to young adulthood in a sample of urban minority youth and to examine the influence of neighborhood, family, and peers on these trajectories. Data are from a longitudinal study of 584 (56% male) primarily Black (87%) youth who were first sampled in childhood based on their residence in low-income neighborhoods in Baltimore City and followed up annually through age 26. Data were analyzed using group-based trajectory modeling and multinomial logistic regression. Modeling revealed six trajectories from ages 14 to 26: abstainer, experimenter, adult increasing, young adult increasing, adolescent limited, and adolescent increasing. Neighborhood disadvantage was a risk factor for drinking regardless of the timing of onset. Perceptions of availability, peer drinking, and parental approval for drinking were risk factors for underage drinking trajectories, whereas parental supervision was a significant protective factor. Positive social activities in neighborhoods was protective against increased drinking, whereas a decline in perceptions of peer drinking was associated with adolescent-limited drinking. Our findings uniquely highlight the importance of developing interventions involving parents for urban minority youth for whom family is particularly relevant in deterring underage drinking. Perhaps most importantly, our data suggest that interventions that support positive social activities in disadvantaged neighborhoods are protective against adolescent drinking and altering perceptions of peer drinking may reduce adolescent drinking among low-income, urban minority youth.


Endovascular Therapy for Acute Mesenteric Ischemia: an NSQIP Analysis.
Acute mesenteric ischemia (AMI) continues to carry high morbidity and mortality. Endovascular strategies have been increasingly used in the management of AMI. The purpose of this study was to evaluate the impact of endovascular therapy on outcomes of patients with AMI. The National Surgical Quality Improvement Program database was queried to identify all patients requiring emergency surgical intervention for AMI. Demographics, clinical data, interventions, and outcomes were extracted. Patients were compared according to treatment (endovascular versus hybrid versus open revascularization). Over the six-year study period, a total of 439 patients were found to have AMI [27 (6.2%) endovascular, 23 (5.2%) hybrid, and 389 (88.6%) open revascularization]. A total of 16 (59.3%) patients in the endovascular group avoided laparotomy. There was a trend toward lower transfusion requirements (intraoperative transfusion: 3.7% for endovascular vs 17.4% for hybrid vs 19.3% for open, adjusted. P = 0.127) and complications in particular pneumonia (22.2% vs 39.1% vs 27.8%, respectively, Adj. P = 0.392) and sepsis (25.9% vs 21.7% vs 35.5%, adjusted P = 0.260). Endovascular therapy was associated with a 2.5-fold decrease in the risk of death [odds ratio, 95% confidence interval: 0.4 (0.2, 0.9), adjusted P = 0.018]. In this analysis of morbidity and mortality, endovascular therapy was associated with decreased need for laparotomy and a trend toward lower transfusion requirements and complications, in particular pneumonia and sepsis. Endovascular first therapy was associated with a 2.5-fold decrease in the risk of death. Further prospective evaluation of these results is warranted.


[Effects of SP-6 acupressure on dysmenorrhea, cortisol, epinephrine and norepinephrine in the college students].
The purpose of this study was to identify effects of the SP-6 acupressure on dysmenorrhea, and level of cortisol, epinephrine and norepinephrine in the college students. Data were collected from May 1 to August 31, 2002. A total of 58 students from two universities participated in the study. Both groups were pretested before the intervention for three variables, the intensity of dysmenorrhea, level of cortisol, epinephrine and norepinephrine. Then, SP-6 acupressure was provided for 20 minutes for students in the experimental group. The instruments used in this study included the Visual Analogue Scale developed by Johnson(1974), Menstrual Attitudes Questionnaire Scale developed by Brooks-Gunn & Ruble(1980), and Stress scale developed by Cheun and Kim(1990). There were statistically significant differences in the intensity of dysmenorrhea at the time immediately after, 30 minutes after, one hour after, and two hours after the intervention. The experimental group had a lower intensity than the control group. There was a statistically significant difference in level of norepinephrine at the time 30 minutes after the intervention with the experimental group. The SP-6 acupressure reduced the subjective perception of dysmenorrhea and the levels of norepinephrine. It was found out that the lasting period of 20 minutes of the SP-6 acupressure was two hours for college students.


Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity.
Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire(+) mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4(+) or CD8(+) thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4(+) thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. These interactions also involve the engagement of CD40 on mTECs by CD40L induced on the positively selected CD4(+) thymocytes. This antigen-specific TCR-MHC class II-mediated crosstalk between CD4(+) thymocytes and mTECs defines a unique checkpoint in thymic stromal development that is pivotal for generating a mature mTEC population competent for ensuring central T cell tolerance.


Reasons underlying failure to seek dental treatment among Nairobi University students.
A survey of 272 University of Nairobi undergraduate students was undertaken to assess their dental chairside experience and what reasons they gave for failing to seek dental treatment. Most respondents considered dental treatment uncomfortable and painful. The cost of treatment and fear arising from information given by other dental patients were important reasons that kept the respondents from visiting a dental clinic. This paper reveals the need for the dental profession to play a greater role in reducing costs of treatment and odontophobia.


Widespread endoscopic mucosal resection of the esophagus with strategies for stricture prevention: a preclinical study.
Circumferential endoscopic mucosal resection of the esophagus is complicated by stricture formation. Prophylactic measures for avoiding such strictures have not been well studied. The aim of this preclinical study was to assess strategies for prevention of esophageal strictures in a porcine model following widespread endoscopic mucosal resection (EMR). A total of 18 60-kg pigs were included in the study. The roles of strip width (group 1), prophylactic steroids (group 2), and prophylactic stents (group 3) in the prevention of post-mucosectomy strictures were studied. Six animals were included in each group. Esophageal mucosal resection was achieved using a novel widespread EMR technique previously described by our group. Animals in group 1 underwent partial (50% circumference) mucosal resection without prophylactic measures, while animals in the other two groups underwent circumferential mucosal resection. Animals in group 2 received 80 mg of triamcinolone injected directly into the exposed submucosal tissue (20 mg injection in four quadrants). Animals in group 3 received esophageal metal stents coated with small-intestine submucosa (SIS) that were deployed immediately post-resection. Animals were kept alive for 1 month. Partial and circumferential widespread EMRs were achieved in all animals. There were no procedural complications. Repeat endoscopy at 1 month showed no strictures in group 1. Only four animals were studied in group 2, owing to the high complication rate (periesophageal abscess in all animals) with one early death. Three of the surviving animals developed mild to tight strictures. In group 3, all animals developed tight strictures; however, there was early stent migration in four animals and premature stent removal in two animals because of persistent vomiting. Partial widespread EMR of the esophagus heals without stricture formation and does not require prophylactic intervention. The use of deep mural steroid injection following a circumferential resection does not appear to prevent strictures and may result in serious adverse events. Short-term use of esophageal stents is inadequate for stricture prevention. However, better results may be anticipated with longer term (at least 6 weeks) stent use.


Liponucleoside thin films: the special behaviour of guanosine.
We performed a comparative study of self-assembling properties of liponucleoside materials containing different nucleobases in their hydrophilic headgroups, but possessing the same type of lipophilic moiety in their hydrophobic tails. Surface pressure versus area isotherms (π(A)) of monolayers formed at the air-water interface show that guanine-based materials form stable monolayer films exhibiting a profound first order phase transition from the liquid expanded to the condensed phase. Materials based on other nucleobases form less stable films exhibiting a liquid-like behaviour. Analysis of surface structures of Langmuir films with Brewster angle microscopy (BAM) and of Langmuir-Blodgett (LB) films deposited on mica surface by atomic force microscopy (AFM) confirms surface organization as resolved from the isotherms. The specific behaviour of molecules with a guanine head group is attributed to their optimal hydrophilic/hydrophobic balance, which is associated with the low water solubility of guanine derivatives.


Adsorbate-induced lattice deformation in IRMOF-74 series.
IRMOF-74 analogues are among the most widely studied metal-organic frameworks (MOFs) for adsorption applications because of their one-dimensional channels and high metal density. Most studies involving the IRMOF-74 series assume that the crystal lattice is rigid. This assumption guides the interpretation of experimental data, as changes in the crystal symmetry have so far been ignored as a possibility in the literature. Here, we report a deformation pattern, induced by the adsorption of argon, for IRMOF-74-V. This work has two main implications. First, we use molecular simulations to demonstrate that the IRMOF-74 series undergoes a deformation that is similar to the mechanism behind breathing MOFs, but is unique because the deformation pattern extends beyond a single unit cell of the original structure. Second, we provide an alternative interpretation of experimental small-angle X-ray scattering profiles of these systems, which changes how we view the fundamentals of adsorption in this MOF series.


Modifying the Intracerebral Hemorrhage Score to Suit the Needs of the Developing World.
Published literature on intracerebral haemorrhage (ICH) from the Indian subcontinent is very scarce. The study aims to assess the prognostic factors influencing outcome and validating the ICH score which is widely used to prognosticate the disease in this financially constraint population. Prognosticating the outcome at the time of admission is important to customize treatment in a cost-effective manner. We conducted a prospective study of all Spontaneous ICH patients admitted from February 2015 to May 2016. Data pertaining to patient demographics, clinical findings, biochemical parameters and cranial computed tomography (CT) findings were recorded. mRS (modified Rankin score) was used to assess outcome at discharge and at three month follow up. A total of 215 patients with hypertensive haemorrhage were analysed. The mean age of our cohort was 57.64 years and volume of bleed was 24.5ml. 73% pf patients with GCS<8, 46% with Intraventricular extension and 57% with hematoma volume >30 were died at the end of 3 months. Twenty eight patients succumbed during hospitalization while 38 died after their discharge. Mortality rates were 5%,16%, 33%, 54% and 93% for ICH Scores of 0, 1, 2, 3 and 4. The rICH score after modifying the age parameter in the ICH score to 70 years had mortality rates of 6%,15%,25%,51%,75% and 100%. ICH Score failed to accurately predict mortality in our cohort. ICH is predominately seen at a younger age group in our country and hence have better outcomes in comparison to the west. We propose a minor modification in the ICH score by reducing the age criteria by 10 years to prognosticate the disease better in our population.


Directed screen of Francisella novicida virulence determinants using Drosophila melanogaster.
Francisella tularensis is a highly virulent, facultative intracellular human pathogen whose virulence mechanisms are not well understood. Occasional outbreaks of tularemia and the potential use of F. tularensis as a bioterrorist agent warrant better knowledge about the pathogenicity of this bacterium. Thus far, genome-wide in vivo screens for virulence factors have been performed in mice, all however restricted by the necessity to apply competition-based, negative-selection assays. We wanted to individually evaluate putative virulence determinants suggested by such assays and performed directed screening of 249 F. novicida transposon insertion mutants by using survival of infected fruit flies as a measure of bacterial virulence. Some 20% of the genes tested were required for normal virulence in flies; most of these had not previously been investigated in detail in vitro or in vivo. We further characterized their involvement in bacterial proliferation and pathogenicity in flies and in mouse macrophages. Hierarchical cluster analysis of mutant phenotypes indicated a functional linkage between clustered genes. One cluster grouped all but four genes of the Francisella pathogenicity island and other loci required for intracellular survival. We also identified genes involved in adaptation to oxidative stress and genes which might induce host energy wasting. Several genes related to type IV pilus formation demonstrated hypervirulent mutant phenotypes. Collectively, the data demonstrate that the bacteria in part use similar virulence mechanisms in mammals as in Drosophila melanogaster but that a considerable proportion of the virulence factors active in mammals are dispensable for pathogenicity in the insect model.


The health needs and healthcare experiences of young people trafficked into the UK.
Young people who have been trafficked may have experienced significant trauma and violence but little is known about their health and healthcare needs. This UK study aimed to address that gap. It included a health survey and qualitative interviews with 29 young people aged 16-21 trafficked into the UK from other countries who were recruited through voluntary organisations and children's social services. These data were supplemented by interviews with relevant professionals. Over half the young people had been trafficked for sex work but sexual violence had also been experienced by those trafficked for domestic servitude and labour exploitation. Physical violence, threats, restrictions of liberty and deprivation were also widespread, as were experiences of physical and sexual violence prior to being trafficked. Five young women had become pregnant whilst trafficked; three were parents when interviewed. Two-thirds screened positive for high levels of psychological distress, including PTSD. Twelve reported suicidal thinking. Whilst some were keen for opportunities to talk to health professionals confidentially and wanted practitioners to treat their accounts as credible, others wanted to forget abusive experiences. Complex gatekeeping systems, language barriers and practitioners who failed to take them seriously limited access to healthcare. Support and advocacy were helpful in assisting these young people to navigate healthcare systems. Health professionals need to recognise and respond appropriately to trafficked young people's often complex mental health needs and refer them to relevant services, as well as facilitating care at later times when they might need support or be more ready to receive help.


Beam steering experiment with two cascaded ferroelectric liquid-crystal spatial light modulators.
The design, construction, and evaluation of a laser beam steerer that uses two binary ferroelectric liquid-crystal (FLC) spatial light modulators (SLMs) operated in conjunction are presented. The system is characterized by having few components and is in principle lossless. Experimentally, a throughput of approximately 20% was achieved. The simple system design was achieved because of the high tilt angle FLC material used in the SLMs, which were specifically designed and manufactured for this study. By coherently imaging the first SLM onto the second SLM, pixel by pixel, we obtained an effective four-level phase structure with a phase step of 90 degrees. An appropriate alignment procedure is presented. The beam steering performance of the system is reported and analyzed.


13. Decorporation of Chernobyl radionuclides.
Tens of thousands of Chernobyl children (mostly from Belarus) annually leave to receive treatment and health care in other countries. Doctors from many countries gratuitously work in the Chernobyl contaminated territories, helping to minimize the consequences of this most terrible technologic catastrophe in history. But the scale and spectrum of the consequences are so high, that no country in the world can cope alone with the long-term consequences of such a catastrophe as Chernobyl. The countries that have suffered the most, especially Ukraine and Belarus, extend gratitude for the help that has come through the United Nations and other international organizations, as well as from private funds and initiatives. Twenty-two years after the Chernobyl releases, the annual individual dose limit in heavily contaminated territories of Belarus, Ukraine, and European Russia exceed 1 mSv/year just because of the unavoidable consumption of locally contaminated products. The 11-year experience of the BELRAD Institute shows that for effective radiation protection it is necessary to establish the interference level for children at 30% of the official dangerous limit (i.e., 15-20 Bq/kg). The direct whole body counting measurements of Cs-137 accumulation in the bodies of inhabitants of the heavily contaminated Belarussian region shows that the official Dose Catalogue underestimates the annual dose burdens by three to eight times. For practical reasons the curative-like use of apple-pectin food additives might be especially helpful for effective decorporation of Cs-137. From 1996 to 2007 a total of more than 160,000 Belarussian children received pectin food additives during 18 to 25 days of treatment (5 g twice a day). As a result, levels of Cs-137 in children's organs decreased after each course of pectin additives by an average of 30 to 40%. Manufacture and application of various pectin-based food additives and drinks (using apples, currants, grapes, sea seaweed, etc.) is one of the most effective ways for individual radioprotection (through decorporation) under circumstances where consumption of radioactively contaminated food is unavoidable.


Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions.
Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.


A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter.
Type II NaPi cotransporters are expressed in the apical membrane of P(i)-(re)absorbing epithelia: the type IIa in renal proximal tubule and the type IIb in small intestine. Parathyroid hormone (PTH) leads to a retrieval from the apical membrane of the type IIa NaPi cotransporter. The type IIa cotransporter is also expressed in opossum kidney (OK) cells, and its expression is under the control of PTH. In the present study, we identified the molecular "domains" involved in the PTH-induced retrieval of the type IIa NaPi cotransporter. Wild-type mouse type IIa (mIIa) and type IIb (mIIb) as well as several mIIa-mIIb chimeras and site-directed mutants were fused to the enhanced green fluorescent protein and transfected into OK cells. We found that mIIa but not mIIb was internalized and degraded after incubation with 1-34 (or 3-34) PTH. Using chimeras, we found that the N and C termini were not required in this effect, whereas a "domain" located between residues 216 and 658 seemed to be necessary. This region contains two putative intracellular loops with highly conserved sequences between mIIa and mIIb; in the last intracellular loop, two charged amino acids of type IIa (K(503)R(504)) are replaced by uncharged residues in type IIb (N(520)I(521)). We generated two mutants in which these residues were interchanged: mIIaNI and mIIbKR. Similarly to mIIa, the mIIbKR mutant was endocytosed in response to 1-34 PTH; in contrast, mIIaNI behaved as mIIb and was not internalized. In conclusion, a dibasic amino acid motif (K(503)R(504)) located in the last intracellular loop of the type IIa NaPi cotransporter is essential for its PTH-induced retrieval.


Validity of reported retention in antiretroviral therapy after roll-out to peripheral facilities in Mozambique: Results of a retrospective national cohort analysis.
Retention in anti-retroviral therapy (ART) presents a challenge in sub-Saharan Africa. In Mozambique, after roll-out to peripheral facilities, the 12-month retention rate was reported mostly from sites with an electronic patient tracking system (EPTS), representing only 65% of patients. We conducted a nationally representative study, compared 12-month retention at EPTS and non-EPTS sites, and its predictors. Applying a proportionate to population size sampling strategy, we obtained a nationally representative sample of patients who initiated ART between January 2013 and June 2014. We calculated weighted proportions of the patients' status at 12 months after ART initiation, and 12-month incidence of lost to follow-up (LTFU) and death. We assessed determinants of LTFU and death by calculating adjusted hazard ratios (AHR) through multivariate cox-proportional hazard models. Among 19,297 patients sampled, 54.3% were still active, 33.1% LTFU, 2.0% dead, 2.6% transferred-out and 8.0% had unknown status, 12 months after ART initiation. Total attrition rate (LTFU or dead) was 45.5/100PY, higher at facilities without EPTS (51.8/100PY) than with EPTS (37.7/100PY). Clinical stage IV (AHR = 1.7), CD4 count ≤150 (AHR = 1.3) and being pregnant (AHR = 1.6) were significantly associated with LTFU. Clinical stage III or IV (AHR = 2.1 and 3.8), CD4 count ≤150 (AHR = 3.0), not being pregnant (AHR = 3.0), and ART regimens with stavudine (AHR = 4.28) were significantly associated with deaths. Patients enrolled in adherence support groups were 4.6 times less likely to be LTFU, but the number (n = 174) was too small to be significant (p = 0.273). Retention in ART was substantially lower at non-EPTS sites. EPTS should be expanded to all ART sites to facilitate comprehensive routine monitoring of retention in care. Retention in Mozambique is low and needs to be improved, especially among pregnant women and patients with advanced disease at ART initiation. The effect of ART adherence support groups needs to be further monitored.


HIF transcription factor expression and induction of hypoxic response genes in a retroperitoneal angiosarcoma.
Angiosarcoma is a rare and highly aggressive tumor of endothelial origin. The molecular mechanisms driving angiosarcoma growth have not been fully elucidated, although autocrine stimulation by vascular endothelial growth factor (VEGF) secretion may play a role in the pathogenesis of this tumor. We identified a patient with a very rare form of angiosarcoma arising from the retroperitoneum. Immunohistochemical analysis demonstrated widespread up-regulation of the hypoxic response pathway as a mechanism of enhanced VEGF expression. Disordered regulation of the hypoxic response pathway can result in the expression of factors such as VEGF and erythropoietin, which may promote autocrine tumor growth in angiosarcoma.


Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning.
Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.


Organosilicon modification to enhance the stability of black phosphorus nanosheets under ambient conditions.
Thanks to its tunable direct band gap, high charge-carrier mobility, and unique in-plane anisotropic structure, black phosphorus (BP) has become a rising star among post-graphene two-dimensional (2D) nanomaterials. However, BP is unstable under ambient conditions, which largely limits its application. In this paper, an organosilicon agent, TMSCl, was used for the surface coordination of BP nanosheets to generate TMSCl@BP, which could maintain its surface morphology and properties for 24 h under ambient conditions and has no cytotoxicity at a concentration of 200 ppm as per previous reports. Our study is the first evidence that bare BP can coordinate with organosilicon to generate the more stable TMSCl@BP. Notably, the photothermal effect of TMSCl@BP was maintained after exposure to ambient conditions for over 24 hours.


Sonic hedgehog shedding results in functional activation of the solubilized protein.
All Hedgehog (Hh) proteins are released from producing cells despite being synthesized as N- and C-terminally lipidated, membrane-tethered molecules. Thus, a cellular mechanism is needed for Hh solubilization. We previously suggested that a disintegrin and metalloprotease (ADAM)-mediated shedding of Sonic hedgehog (ShhNp) from its lipidated N and C termini results in protein solubilization. This finding, however, seemed at odds with the established role of N-terminal palmitoylation for ShhNp signaling activity. We now resolve this paradox by showing that N-palmitoylation of ShhNp N-terminal peptides is required for their proteolytic removal during solubilization. These peptides otherwise block ShhNp zinc coordination sites required for ShhNp binding to its receptor Patched (Ptc), explaining the essential yet indirect role of N-palmitoylation for ShhNp function. We suggest a functional model in which membrane-tethered multimeric ShhNp is at least partially autoinhibited in trans but is processed into fully active, soluble multimers upon palmitoylation-dependent cleavage of inhibitory N-terminal peptides.


Oxidation and reduction products of X irradiation at 10 K in sucrose single crystals: radical identification by EPR, ENDOR, and DFT.
Electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), and ENDOR-induced EPR (EIE) measurements on sucrose single crystals at 10 K after in situ X irradiation at this temperature reveal the presence of at least nine different radical species. Nine proton hyperfine coupling tensors were determined from ENDOR angular variations and assigned to six of these species (R1-R6) using EIE. Spectral simulations indicate that four of those (R1-R3 and R6) dominate the EPR absorption. Assisted by periodic density functional theory (DFT) calculations, R1 and R2 are identified as H-abstracted C1- and C5-centered radicals, R3 is tentatively assigned to an H-abstracted C6-centered radical, and R6 is identified as an alkoxy radical where the abstracted hydroxy proton has migrated to a neighboring OH group via intermolecular proton transfer. The latter radical had been characterized and identified in a previous study, but the present DFT calculations provide additional insight into its conformation and particular properties. This study provides the first step in unraveling the formation mechanism of the stable sucrose radicals detected after room-temperature irradiation and contributes to the understanding of the initial stages of radiation damage to solid-state carbohydrates.


Effects of introgression on the genetic population structure of two ecologically and economically important conifer species: lodgepole pine (Pinus contorta var. latifolia) and jack pine (Pinus banksiana).
Forest trees exhibit a remarkable range of adaptations to their environment, but as a result of frequent and long-distance gene flow, populations are often only weakly differentiated. Lodgepole and jack pine hybridize in western Canada, which adds the opportunity for introgression through hybridization to contribute to population structure and (or) adaptive variation. Access to large sample size, high density SNP datasets for these species would improve our ability to resolve population structure, parameterize introgression, and separate the influence of demography from adaptation. To accomplish this, 454 transcriptome reads for lodgepole and jack pine were assembled using Newbler and MIRA, the assemblies mined for SNPs, and 1536 SNPs were selected for typing on lodgepole pine, jack pine, and their hybrids (N = 536). We identified population structure using both Bayesian clustering and discriminate analysis of principle components. Introgressed SNP loci were identified and their influence on observed population structure was assessed. We found that introgressed loci resulted in increased differentiation both within lodgepole and jack pine populations. These findings are timely given the recent mountain pine beetle population expansion in the hybrid zone, and will facilitate future studies of adaptive traits in these ecologically important species.


Comparing mortality in patients with atrial fibrillation who are receiving a direct-acting oral anticoagulant or warfarin: a meta-analysis of randomized trials.
In patients with non-valvular atrial fibrillation (AF), direct-acting oral anticoagulants (DOACs) are at least non-inferior to warfarin for the prevention of stroke and systemic embolism. The main objective of this study was to obtain reliable and precise estimates for all-cause mortality, vascular mortality and bleeding mortality in patients with AF receiving a DOAC or warfarin for stroke prevention. A meta-analysis was performed on phase 3 randomized trials that compared a DOAC with warfarin for stroke prevention in AF. Published data were pooled by use of the DerSimonian random-effect model, with revman 5.2 and comprehensive meta analysis software version 2. The results were presented as risk ratios (RRs), absolute risk reduction (ARR), and number-needed-to-treat (NNT). A total of 71 683 patients were included in this meta-analysis from four randomized controlled trials (median patient follow-up: 1.8-2.8 years) that compared a DOAC with warfarin for stroke prevention in AF. As compared with warfarin, DOACs significantly reduced all-cause mortality (RR 0.89, 95% confidence interval [CI] 0.85-0.94; ARR 0.76%, 95% CI 0.39-1.13%; NNT = 132), vascular mortality (RR 0.88, 95% CI 0.82-0.94; ARR 0.53%, 95% CI 0.23-0.83%; NNT = 189), and bleeding mortality (RR 0.54, 95% CI 0.44-0.67; ARR 0.32%, 95% CI 0.21-0.43%; NNT = 313). As compared with warfarin therapy for stroke prevention in patients with AF, DOACs significantly reduce all-cause mortality, vascular mortality, and bleeding mortality. This mortality benefit appears to be driven by the reduction in vascular-related and bleeding-related mortality, which, in turn, may be related to the reduction in intracranial bleeding.


Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations.
The global increase in the prevalence of obesity has heralded a rise in associated liver injury namely NAFLD (non-alcoholic fatty liver disease). It is estimated that 20-30% of adult populations in developed countries have NAFLD and, although high quality data is currently lacking, the condition is clearly increasing in children also. NAFLD should be suspected in those with commonly available simple clinical signs and biochemistry consistent with insulin resistance. A small number of individuals with NAFLD, often considered a relatively benign condition, will progress to more severe stages of liver disease including NASH (non-alcoholic steatohepatitis) with or without fibrosis, cirrhosis and occasionally hepatocellular carcinoma. NAFLD is also commonly associated with an increased risk of developing Type 2 diabetes and treatable features of insulin resistance such as dyslipidaemia and dysglycaemia. Histological examination of liver tissue remains the only proven method to distinguish between simple steatosis and NASH, a condition far more likely to progress to cirrhosis. Identification of an imaging technique or non-invasive marker to achieve this distinction is therefore much sought after and would allow larger clinical trials and better clinical assessment. Case series and pilot studies of lifestyle advice, insulin sensitizers and other medications have shown improvements in liver histology and serum liver enzymes but robust randomized controlled studies are needed. Furthermore, the cost/benefit ratio of any new therapies, and any potential harms, must be evaluated carefully before being clinically advocated.


Determination of orthotropic bone elastic constants using FEA and modal analysis.
Finite element models have been widely employed in an effort to quantify the stress and strain distribution around implanted prostheses and to explore the influence of these distributions on their long-term stability. In order to provide meaningful predictions, such models must contain an appropriate reflection of mechanical properties. Detailed geometrical and density information is now readily available from CT scanning. However, despite the use of phantoms, a method of determining mechanical properties (or elastic constants) from bone density has yet to be made available in a usable form. In this study, a cadaveric bone was CT scanned and its natural frequencies were measured using modal analysis. Using the geometry obtained from the CT scan data, a finite element mesh was created with the distribution of density established by matching the mass of the FE bone model with the mass of the cadaveric bone. The maximum values of the orthotropic elastic constants were then established by matching the predictions from FE modal analyses to the experimental natural frequencies, giving a maximum error of 7.8% over 4 modes of vibration. Finally, the elastic constants of the bone derived from the analyses were compared with those measured using ultrasound techniques. This produced a difference of <1% for both the maximum density and axial Young's Modulus. This study has thereby produced an orthotropic finite element model of a human femur. More importantly, however, is the implication that it is possible to create a valid FE model by simply comparing the FE results with the measured resonant frequency of the CT scanned bone.


Multipotent Mesenchymal Stem Cell Treatment for Discogenic Low Back Pain and Disc Degeneration.
Low back pain with resultant loss of function, decreased productivity, and high economic costs is burdensome for both the individual and the society. Evidence suggests that intervertebral disc pathology is a major contributor to spine-related pain and degeneration. When commonly used conservative therapies fail, traditional percutaneous or surgical options may be beneficial for pain relief but are suboptimal because of their inability to alter disc microenvironment catabolism, restore disc tissue, and/or preserve native spine biomechanics. Percutaneously injected Multipotent Mesenchymal Stem Cell (MSC) therapy has recently gained clinical interest for its potential to revolutionarily treat disc-generated (discogenic) pain and associated disc degeneration. Unlike previous therapies to date, MSCs may uniquely offer the ability to improve discogenic pain and provide more sustained improvement by reducing disc microenvironment catabolism and regenerating disc tissue. Consistent treatment success has the potential to create a paradigm shift with regards to the treatment of discogenic pain and disc degeneration.


A global and long-range picture of energy developments.
Most studies of energy supply and demand ignore either global inter-dependence or the long time spans necessary to adjust to new energy sources. The International Institute for Applied Systems Analysis has therefore studied on a global scale, for seven major world regions, the balance between energy supply and demand for the next 50 years. Reported here are the results for two benchmark scenarios. In the "low" scenario world energy consumption increases from today's 8.2 terawatt-year per year to 22 terawatt-year per year in 2030; in the "high" scenario, consumption increases to 35 terawatt-year per year. The study showed that time will be the limiting constraint in adapting the energy supply infrastructure to changing resource availability; resources will be available until the second half of the next century, but a strong shift will be required to low-grade fossil fuels such as shale oil and tar sands. Each scenario studied indicated increased environmental problems associated with increased use of fossil fuels, and potential geopolitical problems associated with the world distribution of resources.


Influence of the number of players and the relative pitch area per player on heart rate and physical demands in youth soccer.
The aim of this study was to analyze the influence of different large-sided games on the physical and physiological variables in under-13 soccer players. The effects on heart rate (HR) and physical demands of different number of players (NP) (7, 9, and 11) together with the relative pitch area (RPA) (100, 200, and 300 m) during two 12-minute repetitions were analyzed in this study. The variables analyzed were mean, maximum and different intensity zones of HR; total distance (TD); work:rest ratio (W:R); player load (PL); 5 absolute and 3 relative speed categories. The results support the hypothesis that a change in pitch dimensions affects locomotor activity more than the NP does but also refute the hypothesis that the change in the NP has a greater effect on HR. To be more specific, an increase in the RPA per player (300/200/100 m2) was associated with higher values of the following variables: TD (2,250-2,314/2,003-2,148/1,766-1,845 m), W:R (0.5-0.6/0.4-0.5/0.3 arbitrary unit [AU]), PL (271-306/246-285/229-267 AU), %HRmean (85-88/85-89/81-83%), %HRmax (95-100/97-100/95-98%), and affected the percentage of time spent in both absolute (above 8 km·h(-1)) and relative speed (above 40% Vmax) categories (p ≤ 0.05, effect size: 0.31-0.85). These results may help youth soccer coaches to plan the progressive introduction of large-sided games so that task demands are adapted to the physiological and physical development of participants.


Optical filtering to compensate for degradation of radiographic images produced by extended sources.
A method of optical filtering in order to provide for enhancement of x-ray images whose quality has been degraded because of the use of extended x-ray sources (penumbra effect) is considered. This method employs spatial filtering techniques in a coherent optical system. A description of the penumbra effect follows from the mathematical description of imaging in incoherent optical systems. With the use of this model the degradation can be described in terms of the effect of the extended source on the frequency content of the resulting image. This leads to a precise definition of the ideal filter in terms of the spatial intensity distribution of the source and a general description of the filtering operations which will be required in all cases, independent of the exact source distribution. It is shown that the form of the ideal filter is such that the same optical system used in the filtering process is ideally suited for generating filters with, approximately, the required transmission characteristics. Experi mental results are presented.


Albumin and collagen gene regulation in alcohol- and virus-induced human liver disease.
Common features of chronic alcoholic liver disease are progressive hypoalbuminemia and a spectrum of liver fibrosis. The molecular mechanisms that account for these effects are still the subject of controversy. Therefore, in the present study we evaluated albumin and collagen gene expression in livers of alcohol abusers and patients with virus-induced liver disease. Albumin and pro alpha 1(I) collagen messenger RNA levels were determined in 30 patients who underwent diagnostic liver biopsy. Of 14 alcoholics, 7 had alcoholic hepatitis alone and the other 7 had cirrhosis plus alcoholic hepatitis. Of 16 nonalcoholic patients with chronic viral infection, 6 had chronic active hepatitis and 10 had cirrhosis plus chronic active hepatitis. Total RNA was extracted from a portion of each biopsy specimen, hybridized with a human albumin or collagen complementary DNA clone, and compared with 2 normal surgical specimens, which served as controls. The Northern hybridization studies showed that (a) despite the presence of inflammation and fibrosis, the albumin messenger RNA levels of alcoholics were similar to those of the controls; (b) these alcoholics had significantly higher levels of albumin messenger RNA than did patients with similar histological levels of disease due to viral infection; and (c) all the categories of patients had markedly increased procollagen messenger RNA levels compared with controls. Given these results it is tempting to speculate that alcohol may actually increase albumin messenger RNA content in humans as it does in animals. Furthermore, the increased procollagen messenger RNA levels in fibrotic livers suggest that an increase in collagen syntheses may be a significant factor in the pathogenesis of hepatic fibrosis.


The Effect of Pregnancy on Disease Activity in Patients with Psoriatic Arthritis.
To evaluate the effect of pregnancy on disease activity in psoriatic arthritis (PsA). This is a retrospective case series. Review of the medical files of all female patients followed at the PsA clinic of 2 medical centers identified those with at least 1 pregnancy during followup and 1 visit during or soon after pregnancy. Twenty-five women with PsA (out of 107 women of reproductive age followed up in our PsA clinics) and 35 pregnancies were enrolled. Thirty-three pregnancies resulted in live healthy babies. In the whole group, there was no significant change in disease activity throughout pregnancy, while in 16 (48%) of pregnancies, patients worsened during the first postpartum year. In 15 out of 21 pregnancies, in which the women had been treated before conception with biologics, treatment was discontinued close to pregnancy or during the first trimester. Five of those 15 patients had been classified as having mild to severe PsA activity prior to pregnancy. That number increased to 8, 9, and 14 during the first and second trimesters and postpartum period, respectively. There was no significant change in degree of disease activity in 6 patients whose biologics were continued beyond the first trimester. Improvement in disease activity was observed during pregnancy among the nonbiologics-treated patients. Corticosteroids were initiated or the dosage was increased during 6 pregnancies, all involving patients whose biologics were stopped before pregnancy. Continuation of biologics therapy was associated with a low level of disease activity and a low probability of flare during pregnancy. Stopping treatment with biologics before pregnancy is associated with flare during pregnancy and the postpartum period.


Short communication: Rapid antibiotic screening tests detect antibiotic residues in powdered milk products.
Rapid antibiotic screening tests are widely used in the dairy industry to monitor milk for the presence of antibiotic residues above regulated levels. Given the persistent concern over contamination of milk products with antibiotic residues, we investigated the utility of IDEXX Snap test devices (IDEXX Laboratories Inc., Westbrook, ME) as tools for detecting antibiotic residues in powdered milk products. Five powdered milk products were reconstituted according to manufacturer specification with distilled water: Carnation (Nestlé USA Inc., Solon, OH), Nido youth and Nido adult (Nestlé Mexico Inc., Mexico City, Mexico), ELK (Campina, Eindhoven, the Netherlands), and Regilait (Saint-Martin-Belle-Roche, France). Positive samples were generated by spiking reconstituted milk with penicillin G, cephapirin, or tetracycline to either the European Union-regulated maximum residue limit or the FDA-regulated safe/tolerance level, whichever was lower. Control, unspiked negative milk samples and positive samples were tested with appropriate IDEXX Snap test kits (penicillin G and cephapirin with New Beta-Lactam, tetracycline with New Tetracycline). All samples yielded definitive results consistent with expectations, and there were no instances of false-positive or false-negative readings. These results suggest that both the New Beta-Lactam and New Tetracycline IDEXX Snap test kits effectively detect antibiotic residues in commercially available powdered milk samples and are useful tools for monitoring antibiotic residues in reconstituted powdered milk products.


Temporal and spatial expression patterns of Cdc25 phosphatase isoforms during early Xenopus development.
In early animal development, cell proliferation and differentiation are tightly linked and coordinated. It is important, therefore, to know how the cell cycle is controlled during early development. Cdc25 phosphatases activate cyclin-dependent kinases (Cdks) and thereby promote cell-cycle progression. In Xenopus laevis, three isoforms of cdc25 have been identified, viz. cdc25A, cdc25B and cdc25C. In this study, we isolated a cDNA encoding a novel Xenopus Cdc25 phosphatase (named cdc25D). We investigated the temporal and spatial expression patterns of the four cdc25 isoforms during early Xenopus development, using RT-PCR and whole-mount in situ hybridization. cdc25A and cdc25C were expressed both maternally and zygotically, whereas cdc25B and cdc25D were expressed zygotically. Both cdc25A and cdc25C were expressed mainly in prospective neural regions, whereas cdc25B was expressed preferentially in the central nervous system (CNS), such as the spinal cord and the brain. Interestingly, cdc25D was expressed in the epidermal ectoderm of the late-neurula embryo, and in the liver diverticulum endoderm of the mid-tailbud embryo. In agreement with the spatial expression patterns in whole embryos, inhibition of bone morphoge- netic protein (BMP), a crucial step for neural induction, induced an upregulation of cdc25B, but a downregulation of cdc25D in animal cap assays.These results indicate that different cdc25 isoforms are differently expressed and play different roles during early Xenopus development.


Perceptions of e-cigarettes: a comparison of adult smokers and non-smokers in a Mechanical Turk sample.
Given plans to extend its regulatory authority to e-cigarettes, the Food and Drug Administration (FDA) urgently needs to understand how e-cigarettes are perceived by the public. To examine how smoking status impacts adult perceptions and expectations of e-cigarettes. We used Mechanical Turk (MTurk), a "crowdsourcing" platform, to rapidly survey a large (n = 796; female = 381; male = 415), diverse sample of adult ever (44%) and never smokers (56%), including ever (28%) and never (72%) users of e-cigarettes. Smokers and non-smokers learned about e-cigarettes primarily through the internet and conversations with others. Ever smokers were more likely than never smokers, and female current smokers were more likely than female former smokers, to have learned about e-cigarettes from point of sale advertising (p's < 0.05) and to believe that e-cigarettes help smokers quit (ps < 0.05). Among never users of e-cigarettes, current smokers were more likely than never smokers and former smokers to report that they would try e-cigarettes in the future (ps < 0.01). Current smokers' top reason for wanting to try e-cigarettes was to quit or reduce smoking (56%), while never and former smokers listed curiosity. In contrast, female current smokers' top reason for not trying e-cigarettes was health and safety concerns (44%) while males were deterred by expense (44%). Adult smokers and non-smokers have different perceptions and expectations of e-cigarettes. Public health messages regarding e-cigarettes may need to be tailored separately for persons with and without a history of using conventional cigarettes. Tailoring messages by gender within smoker groups may also improve their impact.


Demonstration of 136 dB dynamic range capability for a simultaneous dual optical band CAOS camera.
For the first time, proposed and demonstrated is a simultaneous dual optical band coded access optical sensor (CAOS) camera design suited for extreme contrast multispectral bright target scenarios. Deploying a digital micromirror devices (DMDs)-based time-frequency agile pixels CAOS-mode within a two point detector spatially and spectrally isolating framework, this imager simultaneously and independently detects pixel selective image information for two different broad spectral bands that further undergo independent spectral image data extraction via finer-tuned wavelength filtering using all-optical or CAOS-mode electronic filters. A proof-of-concept visible-near infrared band CAOS imager is successfully demonstrated using a target scene containing LEDs and engaging narrowband optical filters. In addition, using the CAOS-mode, demonstrated is the RF domain simultaneous color content monitoring of a white light LED image pixel. Also proposed is the use of a higher bit count analog-to-digital converter (ADC) with both range and sampling duration parameter control along with a larger data set electronic DSP to extract higher DSP gain and realize additional noise suppression. Using a 16-bit ADC and 2,097,152 point fast Fourier transform (FFT) digital signal processing (DSP) for a 633 nm laser engaged test target scene that is subject to nearly 7 decades (107) of gradual optical attenuation, the experimental camera demonstrates an agile pixel extreme dynamic range of 136 dB, which is a 56 dB improvement over the previous CAOS-imaging demonstrations.


Effect of leak and breathing pattern on the accuracy of tidal volume estimation by commercial home ventilators: a bench study.
New home ventilators are able to provide clinicians data of interest through built-in software. Monitoring of tidal volume (VT) is a key point in the assessment of the efficacy of home mechanical ventilation. To assess the reliability of the VT provided by 5 ventilators in a bench test. Five commercial ventilators from 4 different manufacturers were tested in pressure support mode with the help of a breathing simulator under different conditions of mechanical respiratory pattern, inflation pressure, and intentional leakage. Values provided by the built-in software of each ventilator were compared breath to breath with the VT monitored through an external pneumotachograph. Ten breaths for each condition were compared for every tested situation. All tested ventilators underestimated VT (ranges of -21.7 mL to -83.5 mL, which corresponded to -3.6% to -14.7% of the externally measured VT). A direct relationship between leak and underestimation was found in 4 ventilators, with higher underestimations of the VT when the leakage increased, ranging between -2.27% and -5.42% for each 10 L/min increase in the leakage. A ventilator that included an algorithm that computes the pressure loss through the tube as a function of the flow exiting the ventilator had the minimal effect of leaks on the estimation of VT (0.3%). In 3 ventilators the underestimation was also influenced by mechanical pattern (lower underestimation with restrictive, and higher with obstructive). The inclusion of algorithms that calculate the pressure loss as a function of the flow exiting the ventilator in commercial models may increase the reliability of VT estimation.