Purple Corn Extract as Anti-allodynic Treatment for Trigeminal Pain: Role of Microglia.
Natural products have attracted interest in the search for new and effective analgesics and coadjuvant approaches to several types of pain. It is in fact well known that many of their active ingredients, such as anthocyanins (ACNs) and polyphenols, can exert potent anti-inflammatory actions. Nevertheless, their potential beneficial effects in orofacial painful syndromes have not been assessed yet. Here, we have evaluated the preventive effect of an ACN-enriched purple corn extract against the development of orofacial allodynia, in comparison with isogenic yellow corn extract containing only polyphenols. Orofacial allodynia developed following induction of temporomandibular joint (TMJ) inflammation in male rats, due to the injection of Complete Freund's Adjuvant (CFA), and was evaluated by von Frey filaments. Animals drank purple or yellow corn extracts or water starting from 11 days before induction of inflammation and up to the end of the experiment 3 days later. To highlight possible additive and/or synergic actions, some animals also received the anti-inflammatory drug acetyl salicylic acid (ASA). In parallel with the evaluation of allodynia, we have focused our attention on the activation of microglia cells in the central nervous system (CNS), as it is well-known that they significantly contribute to neuronal sensitization and pain. Our data demonstrate that purple corn extract is as effective as ASA in preventing the development of orofacial allodynia, and only partial additive effect is observed when the two agents are co-administered. Yellow corn exerted no effect. Multiple mechanisms are possibly involved in the action of purple corn, including reduction of trigeminal macrophage infiltration and the shift of microglia cell polarization to an anti-inflammatory phenotype. In fact, in rats receiving yellow corn or water microglia cells show thick, short cell processes typical of activated cells. Conversely, thinner and longer microglia cell processes are observed in the brainstem of animals drinking purple corn extract; shape changes are accompanied by a reduction in the expression of pro-inflammatory molecules and increased production of anti-inflammatory mediators. Administration of purple corn extracts therefore represents a possible low-cost and easy way to reduce trigeminal-associated pain in various pathological conditions also thanks to the modulation of microglia reactivity.


Sustained response of recombinant human C1 esterase inhibitor for acute treatment of hereditary angioedema attacks.
Symptoms of hereditary angioedema (HAE) attacks can recur soon after initial treatment; the durability of response for recombinant human C1 esterase inhibitor (rhC1INH) treatment is unknown. To examine the efficacy and durability of rhC1INH for acute HAE attacks. In this pooled post hoc analysis of 2 trials, patients with type I or II HAE (functional C1INH levels <50% of normal) and a baseline visual analog scale score of at least 50 mm were included if they had received at least 1 intravenous dose of 50 IU/kg of rhC1INH. Response was defined as symptom relief within 4 hours after treatment with persistence (≥20-mm decrease in visual analog scale scores [0 mm {"no symptoms at all"} to 100 mm {"extremely disabling"}] at 2 consecutive time points) during the 4 hours. Durability was the response without an increase of at least 20 mm in the minimum post-treatment visual analog scale score up to 24 hours. Recurrence and new attack symptoms were determined for patients with 72-hour post-treatment data. Data were analyzed for 127 patients treated with 50 IU/kg of rhC1INH in 2 studies. Most attacks (90.7%) responded within 4 hours, with differences in response rates among attack locations (61.5%-94.4%). The median time to the beginning of symptom relief was 75.0 minutes (95% confidence interval 65.0-80.0). No relapse occurred during 24 hours for attacks that initially responded. Only 7.1% of attacks were associated with symptom recurrence within 72 hours of initial rhC1INH treatment. This integrated analysis supports the efficacy of rhC1INH for treatment of acute HAE across multiple attacks, with a sustained response for at least 3 days. ClinicalTrials.gov Identifiers: NCT00225147 and NCT00262301.


Egg consumption and risk of type 2 diabetes: a meta-analysis of prospective studies.
Observational data on the association between egg consumption and risk of type 2 diabetes mellitus (DM) have been inconsistent. Because eggs are a good source of protein and micronutrients and are inexpensive, it is important to clarify their role in the risk of developing DM. We conducted a meta-analysis of published prospective cohort studies to evaluate the relation of egg consumption with the risk of DM. We searched PubMed, Ovid, Cochrane, and Google Scholar (up to October 2015) to retrieve published studies. We used RRs from extreme categories of egg consumption for the main analysis but also evaluated dose response by using cubic splines and generalized least squares regression. We identified 12 cohorts for a total of 219,979 subjects and 8911 cases of DM. When comparing the highest with the lowest category of egg intake, pooled multivariate RRs of DM were 1.09 (95% CI: 0.99, 1.20) using the fixed-effect model and 1.06 (95% CI: 0.86, 1.30) using the random-effect model. There was evidence for heterogeneity (I(2) = 73.6%, P < 0.001). When stratified by geographic area, there was a 39% higher risk of DM (95% CI: 21%, 60%) comparing highest with lowest egg consumption in US studies (I(2) = 45.4%, P = 0.089) and no elevated risk of DM with egg intake in non-US studies (RR = 0.89; 95% CI: 0.79, 1.02 using the fixed-effect model, P < 0.001 comparing US with non-US studies). In a dose-response assessment using cubic splines, elevated risk of DM was observed in US studies among people consuming ≥3 eggs/wk but not in non-US studies. Our meta-analysis shows no relation between infrequent egg consumption and DM risk but suggests a modest elevated risk of DM with ≥3 eggs/wk that is restricted to US studies.


Competitive interactions between forest trees are driven by species' trait hierarchy, not phylogenetic or functional similarity: implications for forest community assembly.
The relative importance of competition vs. environmental filtering in the assembly of communities is commonly inferred from their functional and phylogenetic structure, on the grounds that similar species compete most strongly for resources and are therefore less likely to coexist locally. This approach ignores the possibility that competitive effects can be determined by relative positions of species on a hierarchy of competitive ability. Using growth data, we estimated 275 interaction coefficients between tree species in the French mountains. We show that interaction strengths are mainly driven by trait hierarchy and not by functional or phylogenetic similarity. On the basis of this result, we thus propose that functional and phylogenetic convergence in local tree community might be due to competition-sorting species with different competitive abilities and not only environmental filtering as commonly assumed. We then show a functional and phylogenetic convergence of forest structure with increasing plot age, which supports this view.


Australian general practitioner attitudes to residential aged care facility visiting.
Demographic trends suggest that the sustainability of the general practitioner (GP) Residential Aged Care Facility (RACF) workforce, worldwide and in Australia, is under threat, compromising the ongoing care of chronically ill RACF residents. It is therefore important to ascertain current GP attitudes towards this work, to better understand and hypothesise means of reversing this trend. To this end, during 2014 the views of 26 GPs and GP Registrars working in rural and regional New South Wales, Australia, were captured during focus group discussions and one-on-one interviews. Analysis of the qualitative date revealed that GP attitudes towards RACF visiting fell into five key themes: pleasure, duty, remuneration and logistics, hesitation, and frustration. The data also revealed that the overriding emotion GPs felt about RACF visitation was frustration with the avoidable delays and inefficiencies associated with the work. Despite the pleasure GPs derived from their work in RACFs and their sense of obligation to be involved, their hesitation and frustration was compounded by the work's perceived poor remuneration. This research suggests that the barriers to GP participation in RACF visiting were managerial rather than attitudinal, and that a strategic focus upon improving administrative and logistical support is needed.


Signaling Interaction between Facial and Meningeal Inputs of the Trigeminal System Mediates Peripheral Neurostimulation Analgesia in a Rat Model of Migraine.
Peripheral neurostimulation within the trigeminal nerve territory has been used for pain alleviation during migraine attacks, but the mechanistic basis of this non-invasive intervention is still poorly understood. In this study, we investigated the therapeutic role of peripheral stimulation of the trigeminal nerve, which provides homosegmental innervation to intracranial structures, by assessing analgesic effects in a nitroglycerin (NTG)-induced rat model of migraine. As a result of neurogenic inflammatory responses in the trigeminal nervous system, plasma protein extravasation was induced in facial skin by applying noxious stimulation to the dura mater. Noxious chemical stimulation of the dura mater led to protein extravasation in facial cutaneous tissues and caused mechanical sensitivity. Trigeminal ganglion (TG) neurons were double-labeled via retrograde tracing to detect bifurcated axons. Extracellular recordings of wide dynamic range (WDR) neurons in the spinal trigeminal nucleus caudalis (Sp5C) demonstrated the convergence and interaction of inputs from facial tissues and the dura mater. Peripheral neurostimulation of homotopic facial tissues represented segmental pain inhibition on cephalic cutaneous allodynia in the migraine model. The results indicated that facial territories and intracranial structures were directly connected with each other through bifurcated double-labeled neurons in the TG and through second-order WDR neurons. Homotopic stimulation at the C-fiber intensity threshold resulted in much stronger inhibition of analgesia than the same intensity of heterotopic stimulation. These results provide novel evidence for the neurological bases through which peripheral neurostimulation may be effective in treating migraine in clinical practice.


Identification and characterization of genes controlled by the sporulation-regulatory gene spo0H in Bacillus subtilis.
We describe a general strategy for the identification of genes that are controlled by a specific regulatory factor in vivo and the use of this strategy to identify genes in Bacillus subtilis that are controlled by spo0H, a regulatory gene required for the initiation of sporulation. The general strategy makes use of a cloned regulatory gene fused to an inducible promoter to control expression of the regulatory gene and random gene fusions to a reporter gene to monitor expression in the presence and absence of the regulatory gene product. spo0H encodes a sigma factor of RNA polymerase, sigma H, and is required for the extensive reprograming of gene expression during the transition from growth to stationary phase and during the initiation of sporulation. We identified 18 genes that are controlled by sigma H (csh genes) in vivo by monitoring expression of random gene fusions to lacZ, made by insertion mutagenesis with the transposon Tn917lac, in the presence and absence of sigma H. These genes had lower levels of expression in the absence of sigma H than in the presence of sigma H. Patterns of expression of the csh genes during growth and sporulation in wild-type and spo0H mutant cells indicated that other regulatory factors are probably involved in controlling expression of some of these genes. Three of the csh::Tn917lac insertion mutations caused noticeable phenotypes. One caused a defect in vegetative growth, but only in combination with a spo0H mutation. Two others caused a partial defect in sporulation. One of these also caused a defect in the development of genetic competence. Detailed characterization of some of the csh genes and their regulatory regions should help define the role of spo0H in the regulation of gene expression during the transition from growth to stationary phase and during the initiation of sporulation.


Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology.
Clinical adoption of normothermic machine perfusion (NMP) may be facilitated by simplifying logistics and reducing costs. This can be achieved by cold storage of livers for transportation to recipient centers before commencing NMP. The purpose of this study was to assess the safety and feasibility of post-static cold storage normothermic machine perfusion (pSCS-NMP) in liver transplantation. In this multicenter prospective study, 31 livers were transplanted. The primary endpoint was 30-day graft survival. Secondary endpoints included the following: peak posttransplant aspartate aminotransferase (AST), early allograft dysfunction (EAD), postreperfusion syndrome (PRS), adverse events, critical care and hospital stay, biliary complications, and 12-month graft survival. The 30-day graft survival rate was 94%. Livers were preserved for a total of 14 hours 10 minutes ± 4 hours 46 minutes, which included 6 hours 1 minute ± 1 hour 19 minutes of static cold storage before 8 hours 24 minutes ± 4 hours 4 minutes of NMP. Median peak serum AST in the first 7 days postoperatively was 457 U/L (92-8669 U/L), and 4 (13%) patients developed EAD. PRS was observed in 3 (10%) livers. The median duration of initial critical care stay was 3 days (1-20 days), and median hospital stay was 13 days (7-31 days). There were 7 (23%) patients who developed complications of grade 3b severity or above, and 2 (6%) patients developed biliary complications: 1 bile leak and 1 anastomotic stricture with no cases of ischemic cholangiopathy. The 12-month overall graft survival rate (including death with a functioning graft) was 84%. In conclusion, this study demonstrates that pSCS-NMP was feasible and safe, which may facilitate clinical adoption.


Modulation of synaptic plasticity by stress and antidepressants.
Recent preclinical and clinical studies have shown that mechanisms underlying neuronal plasticity and survival are involved in both the outcome of stressful experiences and the action of antidepressants. Whereas most antidepressants predominantly affect the brain levels of monoamine neurotransmitters, it is increasingly appreciated that they also modulate neurotransmission at synapses using the neurotransmitter glutamate (the most abundant in the brain). In the hippocampus, a main area of the limbic system involved in cognitive functions as well as attention and affect, specific molecules enriched at glutamatergic synapses mediate major changes in synaptic plasticity induced by stress paradigms or antidepressant treatments. We analyze here the modifications induced by stress or antidepressants in the strength of synaptic transmission in hippocampus, and the molecular modifications induced by antidepressants in two main mediators of synaptic plasticity: the N-methyl-D-aspartate (NMDA) receptor complex for glutamate and the Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Both stress and antidepressants induce alterations in long-term potentiation of hippocampal glutamatergic synapses, which may be partly accounted for by the influence of environmental or drug-induced stimulation of monoaminergic pathways projecting to the hippocampus. In the course of antidepressant treatments significant changes have been described in both the NMDA receptor and CaM kinase II, which may account for the physiological changes observed. A central role in these synaptic changes is exerted by brain-derived neurotrophic factor (BDNF), which modulates both synaptic plasticity and its molecular mediators, as well as inducing morphological synaptic changes. The role of these molecular effectors in synaptic plasticity is discussed in relation to the action of antidepressants and the search for new molecular targets of drug action in the therapy of mood disorders.


Ten years of REACH - An animal protection perspective.
It has now been 11 years since the EU's new chemicals legislation (Regulation No. 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals [REACH]) came into force. Two important statements in the REACH Regulation in relation to animal testing and alternatives are: Article 1(1), which states that one of its purposes is to promote alternative methods; and Article 25(1), which states that animal testing should be used as a last resort. This review looks at the mechanisms that were put in place within REACH to achieve these aims and asks, not only if they are being implemented properly, but also if they have been sufficient. Whilst the chemical industry has heavily used data-sharing and read-across, this review concludes that nevertheless over 2.2 million animals have already been used in new tests for REACH registrations. This equates to an annual average of 275,000 animals; 58,000 more per year than the best-case estimate made by the European Commission in 2004. The use of in vitro and (Q)SAR approaches as standalone replacements for animal tests has been relatively low. The levels of funding for research into alternative methods remain low, and there are concerns over the speed of formal adoption of those that have been validated. In addition, there have been issues with the recognition that testing as a last resort and the promotion of alternative methods applies to all parties, including the Commission, Member States and the agency responsible, the European Chemicals Agency. This review provides ten recommendations for better implementation of these two key aspirations, as well as lessons to be learned for future similar legislation.


Aging-dependent reduction in glyoxalase 1 delays wound healing.
Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (≤12 weeks) and old (≥52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 ± 2.2 vs. 55.4 ± 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 ± 1.6 vs. 77.2 ± 3.1%; p < 0.05) and 64% (40.4 ± 7.9 vs. 66.4 ± 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice.


Universal Oriented van der Waals Epitaxy of 1D Cyanide Chains on Hexagonal 2D Crystals.
The atomic or molecular assembly on 2D materials through the relatively weak van der Waals interaction is quite different from the conventional heteroepitaxy and may result in unique growth behaviors. Here, it is shown that straight 1D cyanide chains display universal epitaxy on hexagonal 2D materials. A universal oriented assembly of cyanide crystals (AgCN, AuCN, and Cu0.5Au0.5CN) is observed, where the chains are aligned along the three zigzag lattice directions of various 2D hexagonal crystals (graphene, h-BN, WS2, MoS2, WSe2, MoSe2, and MoTe2). The potential energy landscape of the hexagonal lattice induces this preferred alignment of 1D chains along the zigzag lattice directions, regardless of the lattice parameter and surface elements as demonstrated by first-principles calculations and parameterized surface potential calculations. Furthermore, the oriented microwires can serve as crystal orientation markers, and stacking-angle-controlled vertical 2D heterostructures are successfully fabricated by using them as markers. The oriented van der Waals epitaxy can be generalized to any hexagonal 2D crystals and will serve as a unique growth process to form crystals with orientations along the zigzag directions by epitaxy.


Near-field optical storage system using a solid immersion lens with a left-handed material slab.
A new near-field optical storage system utilizing a left-handed material (LHM) is introduced by attaching an LHM slab to the lower surface of a conventional solid immersion lens (SIL). The performance of the present storage system is compared with a conventional SIL system through numerical simulation. The LHM slab in the present storage system can image very well the focused spot at the lower surface of the SIL to the surface of a disc. It allows a large air-gap for the mechanical convenience while keeping a large signal contrast and a high storage density. The tolerance of the air-gap is also improved.


Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3.
Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1-/- mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK's effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.


Evolving views of DNA replication (in)fidelity.
"It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material" (Watson and Crick 1953). In the years since this remarkable understatement, we have come to realize the enormous complexity of the cellular machinery devoted to replicating DNA with the accuracy needed to maintain genetic information over many generations, balanced by the emergence of mutations on which selection can act. This complexity is partly based on the need to remove or tolerate cytotoxic and mutagenic lesions in DNA generated by environmental stress. Considered here is the fidelity with which undamaged and damaged DNA is replicated by the many DNA polymerases now known to exist. Some of these seriously violate Watson-Crick base-pairing rules such that, depending on the polymerase, the composition and location of the error, and the ability to correct errors (or not), DNA synthesis error rates can vary by more than a millionfold. This offers the potential to modulate rates of point mutations over a wide range, with consequences that can be either deleterious or beneficial.


Production and characterization of two monoclonal antibodies to bovine tumour necrosis factor alpha (TNF-alpha) and their cross-reactivity with ovine TNF-alpha.
Tumour necrosis factor alpha (TNF-alpha) is an innate pro-inflammatory cytokine involved in protection against intracellular pathogens. Existing methods for measuring TNF-alpha production and function in ruminants are limited to ELISA and many rely on polyclonal antisera. With a view to developing improved detection methods for bovine (bov) TNF-alpha, monoclonal antibodies (mAb) were produced by immunising mice with a plasmid encoding bov TNF-alpha. Two of the resulting mAb, termed CC327 and CC328, were used to develop a sandwich ELISA capable of detecting both native and recombinant bov TNF-alpha. This ELISA did not detect recombinant ovine (ov) TNF-alpha. A luminometric method was applied to the ELISA to improve sensitivity for detection of native bov TNF-alpha in culture supernatants derived from bovine monocyte-derived dendritic cells (DC) infected with Mycobacterium bovis. Both CC327 and CC328 detected intracytoplasmic expression of TNF-alpha in mitogen-activated bovine T lymphocytes. However, only CC328 detected intracytoplasmic ovine TNF-alpha in transfected cells, explaining the failure of the sandwich ELISA to detect recombinant ov TNF-alpha. These mAbs have generated the capability to study the role of TNF-alpha in host immune protection and disease pathogenesis in ruminants.


An assessment of a double-isotope method for the detection of transferrin accumulation in the lungs of patients with widespread pulmonary infiltrates.
1. The accumulation in the lung of the plasma protein transferrin was determined in 44 patients with widespread pulmonary infiltrates of various causes and in 11 healthy volunteers using a double-isotope method based on labelling in vivo of circulating transferrin with indium and erythrocytes with technetium. 2. In 22 patients meeting criteria for the adult respiratory distress syndrome (ARDS) the mean transferrin accumulation rate was threefold greater (P less than 0.005) than in 22 patients not meeting these criteria, although most possessed an appropriate risk factor for ARDS, in addition to extensive radiographic changes. 3. The double-isotope method did not completely separate patients with ARDS from those not meeting the criteria or from control subjects and cannot be considered a diagnostic test for the condition. Statistically significant rates of transferrin accumulation, however, occurred more frequently in patients with ARDS (82%) than in controls (64%) or in those without ARDS (59%).


Brain morphology in normal and dyslexic children: the influence of sex and age.
Morphometric magnetic resonance imaging techniques were used to compare the convolutional surface area of the planum temporale, temporal lobe volume and superior surface area, and an estimate of overall brain volume in a homogeneous sample of 17 dyslexic children (7 girls) and 14 nonimpaired children (7 girls). Substantial sex differences were apparent for all measured regions, with all the measurements in boys being significantly larger. Age, even within the narrow range employed here (7.5-9.7 years), was positively correlated with the size of each brain region. While initial analyses suggested smaller left hemisphere structures in dyslexics compared to control subjects, subsequent analyses controlling for age and overall brain size revealed no significant differences between dyslexics and nonimpaired children on a variety of measures, in particular surface area and symmetry of the planum temporale. We suggest that differences in subject characteristics (i.e., sex, age, handedness, and definition of dyslexia) as well as procedural variations in the methods used to acquire images and to define and measure anatomical regions of interest such as the planum temporale all may play an important role in explaining apparent discrepant results in the neuroimaging literature on dyslexia.


Complicating decisions: The work ethic heuristic and the construction of effortful decisions.
The notion that effort and hard work yield desired outcomes is ingrained in many cultures and affects our thinking and behavior. However, could valuing effort complicate our lives? In the present article, the authors demonstrate that individuals with a stronger tendency to link effort with positive outcomes end up complicating what should be easy decisions. People distort their preferences and the information they search and recall in a manner that intensifies the choice conflict and decisional effort they experience before finalizing their choice. Six experiments identify the effort-outcome link as the underlying mechanism for such conflict-increasing behavior. Individuals with a stronger tendency to link effort with positive outcomes (e.g., individuals who subscribe to a Protestant Work Ethic) are shown to complicate decisions by: (a) distorting evaluations of alternatives (Study 1); (b) distorting information recalled about the alternatives (Studies 2a and 2b); and (3) distorting interpretations of information about the alternatives (Study 3). Further, individuals conduct a superfluous search for information and spend more time than needed on what should have been an easy decision (Studies 4a and 4b). (PsycINFO Database Record


The Healthy Migrant Families Initiative: development of a culturally competent obesity prevention intervention for African migrants.
Although obesity among immigrants remains an important area of study given the increasing migrant population in Australia and other developed countries, research on factors amenable to intervention is sparse. The aim of the study was to develop a culturally-competent obesity prevention program for sub-Saharan African (SSA) families with children aged 12-17 years using a community-partnered participatory approach. A community-partnered participatory approach that allowed the intervention to be developed in collaborative partnership with communities was used. Three pilot studies were carried out in 2008 and 2009 which included focus groups, interviews, and workshops with SSA parents, teenagers and health professionals, and emerging themes were used to inform the intervention content. A cultural competence framework containing 10 strategies was developed to inform the development of the program. Using findings from our scoping research, together with community consultations through the African Review Panel, a draft program outline (skeleton) was developed and presented in two separate community forums with SSA community members and health professionals working with SSA communities in Melbourne. The 'Healthy Migrant Families Initiative (HMFI): Challenges and Choices' program was developed and designed to assist African families in their transition to life in a new country. The program consists of nine sessions, each approximately 1 1/2 hours in length, which are divided into two modules based on the topic. The first module 'Healthy lifestyles in a new culture' (5 sessions) focuses on healthy eating, active living and healthy body weight. The second module 'Healthy families in a new culture' (4 sessions) focuses on parenting, communication and problem solving. The sessions are designed for a group setting (6-12 people per group), as many of the program activities are discussion-based, supported by session materials and program resources. Strong partnerships and participation by SSA migrant communities enabled the design of a culturally competent and evidence-based intervention that addresses obesity prevention through a focus on healthy lifestyles and healthy families. Program implementation and evaluation will further inform obesity prevention interventions for ethnic minorities and disadvantaged communities.


High tuberculosis exposure among neonates in a high tuberculosis and human immunodeficiency virus burden setting.
Maternal and neonatal tuberculosis (TB) are under-recognised, particularly in settings with a high burden of human immunodeficiency virus (HIV) infection. Retrospective audit of neonates routinely screened for TB in a South African hospital during 2009. Surveillance sources reviewed included routine clinical, laboratory and pharmacy records. Among 70 neonates (60% HIV-exposed) screened for TB, the median gestational age was 35.5 weeks (IQR 33-38), and the median birth weight was 2000 g (IQR 1530-2484). The neonates were grouped according to a history of documented TB exposure: maternal TB in 41/70 (59%), suspected maternal TB in 9/70 (13%), other documented household TB exposure in 5/70 (7%), and no known TB exposure 15/70 (21%). Of the 50 neonates exposed to confirmed or suspected maternal TB, 36 (72%) were initiated on TB chemoprophylaxis, 5 (10%) received TB treatment and 9 (18%) received no intervention. Eight (8/50, 16%) were diagnosed with TB, all of whom were born to mothers with suspected or proven TB. Maternal TB, primarily among HIV-infected women, was the main indication for TB screening of neonates. Routine TB screening of pregnant women and TB care in mothers and infants should be improved in settings with a high burden of TB and HIV.


Calcium signaling mediates five types of cell morphological changes to form neural rosettes.
Neural rosette formation is a critical morphogenetic process during neural development, whereby neural stem cells are enclosed in rosette niches to equipoise proliferation and differentiation. How neural rosettes form and provide a regulatory micro-environment remains to be elucidated. We employed the human embryonic stem cell-based neural rosette system to investigate the structural development and function of neural rosettes. Our study shows that neural rosette formation consists of five types of morphological change: intercalation, constriction, polarization, elongation and lumen formation. Ca2+ signaling plays a pivotal role in the five steps by regulating the actions of the cytoskeletal complexes, actin, myosin II and tubulin during intercalation, constriction and elongation. These, in turn, control the polarizing elements, ZO-1, PARD3 and β-catenin during polarization and lumen production for neural rosette formation. We further demonstrate that the dismantlement of neural rosettes, mediated by the destruction of cytoskeletal elements, promotes neurogenesis and astrogenesis prematurely, indicating that an intact rosette structure is essential for orderly neural development.


Metformin is Associated with Decreased 30-Day Mortality Among Nursing Home Residents Infected with SARS-CoV2.
The COVID-19 pandemic presents an urgent need to investigate whether existing drugs can enhance or even worsen prognosis; metformin, a known mammalian target of rapamycin (m-TOR) inhibitor, has been identified as a potential agent. We sought to evaluate mortality benefit among older persons infected with SARS-CoV-2 who were taking metformin as compared to those who were not. Retrospective cohort study. 775 nursing home residents infected with SARS-CoV-2 who resided in one of the 134 Community Living Centers (CLCs) of the Veterans Health Administration (VHA) during March 1, 2020, to May 13, 2020, were included. Using a window of 14 days prior to SARS-CoV-2 testing, bar-coded medication administration records were examined for dispensing of medications for diabetes. The COVID-19-infected residents were divided into 4 groups: (1) residents administered metformin alone or in combination with other medications, (2) residents who used long-acting or daily insulin, (3) residents administered other diabetes medications, and (4) residents not administered diabetes medication, including individuals without diabetes and patients with untreated diabetes. Proportional hazard models adjusted for demographics, hemoglobin A1c, body mass index, and renal function. Relative to those not receiving diabetes medications, residents taking metformin were at significantly reduced hazard of death [adjusted hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.28, 0.84] over the subsequent 30 days from COVID-19 diagnosis. There was no association with insulin (adjusted HR 0.99, 95% CI 0.60, 1.64) or other diabetes medications (adjusted HR 0.71, 95% CI 0.38, 1.32). Our data suggest a reduction in 30-day mortality following SARS-CoV-2 infection in residents who were on metformin-containing diabetes regimens. These findings suggest a relative survival benefit in nursing home residents on metformin, potentially through its mTOR inhibition effects. A prospective study should investigate the therapeutic benefits of metformin among persons with COVID-19.


A Review and Critique of Teledermatology in the South African Public Health Sector.
Nearly 80% of the world's population live in developing countries in Asia, Africa, and Latin America. Many of these countries must face a triple or quadruple burden of disease with severely limited resources and health systems. South Africa (SA) is one such country, and recognises the potential for e-health to moderate these limitations. Dermatological issues remain a concern in SA and globally. Indeed, the World Health Organisation (WHO) has recognised that a number of diseases are most likely to manifest themselves through a dermatological problem before becoming full-blown. However, there is an acute shortage of dermatologists in SA. Teledermatology has promise as a service delivery intervention. This study reports on the current status of teledermatology services in the public health sector of SA. The study adopted a qualitative, inductive research approach based on a structured literature review of teledermatology in SA. A modified Momentum-Treat tool was used to critique identified teledermatology services. 159 resources were identified, of which 68 were excluded. The remaining 91 resources revealed a history of ad hoc teledermatology services, of which few remained active. Requests for teledermatology service confirmations provided some feedback, together with follow-up meetings and interviews. No evidence of scaling of teledermatology services and integration into routine healthcare was found. Of eight services, 4 remain active. Review and modified Momentum-Treat critique showed opportunities for improved readiness assessment, programme governance, and alignment to government policy direction, in order to improve scaling and sustainability. Full-scale teledermatology integration is possible, but stronger programme development is needed. Findings will inform development of a teledermatology scale-up framework to assist with future integration of teledermatology into routine healthcare.


Clinical and functional characteristics of patients two years after being affected by the soybean asthma epidemic in Barcelona.
Patients affected during the asthma outbreaks caused by soybean dust inhalation in Barcelona presented with sudden onset of severe asthma followed by the rapid relief of symptoms after treatment. Two years after the epidemics ended, a case-control study was conducted in which the clinical, functional, and immunological characteristics of these asthma patients (a randomised sample of asthmatic patients admitted as emergency cases on epidemic days, n = 213) were compared with those of a control group (a random sample of asthmatic patients admitted as emergency cases for attacks of asthma on non-epidemic days, n = 170). The study included the administration of the ATS-DLD78 standardised respiratory questionnaire, the measurement of atopy, and performance of spirometric tests and a methacholine inhalation test. Patients with epidemic asthma reported fewer symptoms of asthma, had attended emergency departments less frequently during the previous year for acute attacks of asthma, were taking fewer inhaled corticosteroids at the time of the study, and attended medical follow up less frequently than did the patients with non-epidemic asthma. However, the cases and controls showed no differences in ventilatory capacity or reactivity to the methacholine bronchoprovocation test. Two years after the end of the soybean epidemics, people affected by epidemic asthma had a favourable prognosis. This finding contrasts with a higher risk of life threatening asthma and death during the epidemics. This paradox could be the result of a complex interaction between host and conditions of exposure.


A rare cause of acute abdomen in the ED: Chemotherapy-induced pneumatosis intestinalis.
Pneumatosis intestinalis (PI) and portomesenteric venous gas (PVG) refers to the presence of air within the intestinal wall and portomesenteric vessels. Most of the time, it is associated with mesenteric ischemia that requires immediate surgical intervention as it has high mortality rate. It may also be seen secondary to various conditions, including infections, surgeries, and some chemotherapeutic drugs. A 61-year old-male was admitted to our emergency department complaining of abdominal pain after chemotherapy. Radiological evaluation of the patient demonstrated massive PVG and PI. Patient underwent urgent surgery due to the possibility of intestinal ischemia and infarction, but no necrosis was identified Chemotherapeutic drug-induced PI and PVG was the final diagnosis. Although PI and PVG are signs of mesenteric ischemia and intestinal necrosis most the of time, chemotherapeutic drugs may also cause PI and PVG rarely. Recent history of chemotheraphy and absence of any mesenteric vascular occlusion may be the diagnostic clue.


High-throughput flow alignment of barcoded hydrogel microparticles.
Suspension (particle-based) arrays offer several advantages over conventional planar arrays in the detection and quantification of biomolecules, including the use of smaller sample volumes, more favorable probe-target binding kinetics, and rapid probe-set modification. We present a microfluidic system for the rapid alignment of multifunctional hydrogel microparticles designed to bear one or several biomolecule probe regions, as well as a graphical code to identify the embedded probes. Using high-speed imaging, we have developed and optimized a flow-through system that (1) allows for a high particle throughput, (2) ensures proper particle alignment for decoding and target quantification, and (3) can be reliably operated continuously without clogging. A tapered channel flanked by side focusing streams is used to orient the flexible, tablet-shaped particles into a well-ordered flow in the center of the channel. The effects of channel geometry, particle geometry, particle composition, particle loading density, and barcode design are explored to determine the best combination for eventual use in biological assays. Particles in the optimized system move at velocities of approximately 50 cm s(-1) and with throughputs of approximately 40 particles s(-1). Simple physical models and CFD simulations have been used to investigate flow behavior in the device.


Requirement for CDK6 in MLL-rearranged acute myeloid leukemia.
Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts.


Characteristics of phantom upper limb mobility encourage phantom-mobility-based prosthesis control.
There is an increasing need to extend the control possibilities of upper limb amputees over their prosthetics, especially given the development of devices with numerous active joints. One way of feeding pattern recognition myoelectric control is to rely on the myoelectric activities of the residual limb associated with phantom limb movements (PLM). This study aimed to describe the types, characteristics, potential influencing factors and trainability of upper limb PLM. Seventy-six below- and above-elbow amputees with major amputation underwent a semi-directed interview about their phantom limb. Amputation level, elapsed time since amputation, chronic pain and use of prostheses of upper limb PLM were extracted from the interviews. Thirteen different PLM were found involving the hand, wrist and elbow. Seventy-six percent of the patients were able to produce at least one type of PLM; most of them could execute several. Amputation level, elapsed time since amputation, chronic pain and use of myoelectric prostheses were not found to influence PLM. Five above-elbow amputees participated in a PLM training program and consequently increased both endurance and speed of their PLM. These results clearly encourage further research on PLM-associated muscle activation patterns for future PLM-based modes of prostheses control.


Induction of a strong HIV-specific CD8+ T cell response in mice using a fowlpox virus vector expressing an HIV-1 multi-CTL-epitope polypeptide.
Recombinant avipoxvirus vectors are attractive candidates for use in vaccination strategies for infections such as human immunodeficiency virus type 1 (HIV-1), where induction of a CD8+ T cell response is thought to be an important component of protective immunity. Here, we report the expression of a multiepitope polypeptide (TAB9) composed of the central 15 amino acids of the V3 loop from six different isolates of HIV-1 in a fowlpox virus (FWPV) vector, and the use of this vector (FPTAB9LZ) to induce strong HIV-specific CD8+ T cell responses in mice. In animals immunized twice intravenously with FPTAB9LZ, almost 2% of the CD8+ T cells in the spleen were shown to produce IFN-gamma in response to stimulation with HIV-1 peptides 1 week after the second immunization. The most dominant response was to the HIV-1 IIIB peptide. A strong HIV-specific response was also induced by intraperitoneal immunization of mice with FPTAB9LZ, whilst subcutaneous immunization elicited a weaker response. Intraperitoneal immunization with FPTAB9LZ was also shown to provide protection against challenge with a recombinant vaccinia virus expressing antigens, including those in TAB9. These results confirm the potential of FWPV vectors for use in HIV vaccination strategies.


Effects of ultrapure hemodialysis and low molecular weight heparin on the endothelial surface layer.
Chronic kidney disease patients show changes in the endothelial surface layer (ESL). Whether hemodialysis (HD) itself or low molecular weight heparins (LMWH) induce ESL alterations is unknown. We studied the ESL in 20 HD patients with Sidestream Dark Field Imaging [measuring perfused boundary region (PBR)] and measurement of ESL constituents in plasma during HD in 2 studies. LMWH was administered at the start of HD in study A, and 120 min after the start of HD in study B. Mean platelet volume (MPV) and platelet large cell ratio (P-LCR) were also measured. Syndecan-1 increased significantly 30 min after LMWH administration. sP-Selectin increased 120 min after HD start, and MPV and P-LCR decreased significantly during HD. No significant changes of PBR, sE-Selectin, sICAM-1, or sVCAM-1 were perceived. HD caused a significant increase in Syndecan-1 without a change in PBR. The administration of LMWH appeared to precede the rise in Syndecan-1.


Impaired Feedback Processing for Symbolic Reward in Individuals with Internet Game Overuse.
Reward processing, which plays a critical role in adaptive behavior, is impaired in addiction disorders, which are accompanied by functional abnormalities in brain reward circuits. Internet gaming disorder, like substance addiction, is thought to be associated with impaired reward processing, but little is known about how it affects learning, especially when feedback is conveyed by less-salient motivational events. Here, using both monetary (±500 KRW) and symbolic (Chinese characters "right" or "wrong") rewards and penalties, we investigated whether behavioral performance and feedback-related neural responses are altered in Internet game overuse (IGO) group. Using functional MRI, brain responses for these two types of reward/penalty feedback were compared between young males with problems of IGO (IGOs, n = 18, mean age = 22.2 ± 2.0 years) and age-matched control subjects (Controls, n = 20, mean age = 21.2 ± 2.1) during a visuomotor association task where associations were learned between English letters and one of four responses. No group difference was found in adjustment of error responses following the penalty or in brain responses to penalty, for either monetary or symbolic penalties. The IGO individuals, however, were more likely to fail to choose the response previously reinforced by symbolic (but not monetary) reward. A whole brain two-way ANOVA analysis for reward revealed reduced activations in the IGO group in the rostral anterior cingulate cortex/ventromedial prefrontal cortex (vmPFC) in response to both reward types, suggesting impaired reward processing. However, the responses to reward in the inferior parietal region and medial orbitofrontal cortex/vmPFC were affected by the types of reward in the IGO group. Unlike the control group, in the IGO group the reward response was reduced only for symbolic reward, suggesting lower attentional and value processing specific to symbolic reward. Furthermore, the more severe the Internet gaming overuse symptoms in the IGO group, the greater the activations of the ventral striatum for monetary relative to symbolic reward. These findings suggest that IGO is associated with bias toward motivationally salient reward, which would lead to poor goal-directed behavior in everyday life.


Mutual influences between partners' hormones shape conflict dialog and relationship duration at the initiation of romantic love.
Early-stage romantic love involves reorganization of neurohormonal systems and behavioral patterns marked by mutual influences between the partners' physiology and behavior. Guided by the biobehavioral synchrony conceptual frame, we tested bidirectional influences between the partners' hormones and conflict behavior at the initiation of romantic love. Participants included 120 new lovers (60 couples) and 40 singles. Plasma levels of five affiliation and stress-related hormones were assessed: oxytocin (OT), prolactin (PRL), testosterone (T), cortisol (CT), and dehydroepiandrosterone sulfate (DHEAS). Couples were observed in conflict interaction coded for empathy and hostility. CT and DHEAS showed direct actor effects: higher CT and DHEAS predicted greater hostility. OT showed direct partner effects: individuals whose partners had higher OT showed greater empathy. T and CT showed combined actor-partner effects. High T predicted greater hostility only when partner also had high T, but lower hostility when partner had low T. Similarly, CT predicted low empathy only in the context of high partner's CT. Mediational analysis indicated that combined high CT in both partners was associated with relationship breakup as mediated by decrease in empathy. Findings demonstrate the mutual influences between hormones and behavior within an attachment bond and underscore the dynamic, co-regulated, and systemic nature of pair-bond formation in humans.


Improvement in insulin resistance and the restoration of reduced phosphodiesterase 3B gene expression by pioglitazone in adipose tissue of obese diabetic KKAy mice.
Phosphodiesterase (PDE) 3B is a key enzyme in the mediation of the antilipolytic action of insulin in adipocytes, and activation of this molecule results in a reduced output of free fatty acids (FFAs). An elevation of serum FFAs is known to cause insulin resistance in skeletal muscle and liver, which could be the primary cause of type 2 diabetes. To elucidate whether PDE3B is involved in this disease, we examined the PDE3B gene expression in epididymal fat tissues of obese insulin-resistant diabetic KKAy mice. We also examined the effect of an insulin-sensitizing drug, pioglitazone, on this gene expression. In adipose tissue of KKAy mice, PDE3B mRNA and its corresponding protein were reduced to 48 and 43% of those in C57BL/6J control mice. Basal and insulin-stimulated membrane-bound PDE activities were also decreased to 50 and 36% of those in the controls, respectively. Pioglitazone increased both PDE3B mRNA and protein levels by 1.8-fold of those in untreated KKAy mice. Basal and insulin-induced membrane-bound PDE activities were also increased by 1.6- and 2.0-fold, respectively. Pioglitazone reduced the elevated levels of serum insulin, glucose, FFAs, and triglyceride in KKAy mice. Thus, the reduced PDE3B gene expression in adipose tissues could be the primary event in the development of insulin resistance in KKAy mice, which was improved by pioglitazone possibly because of the restoration of the reduced PDE3B gene expression.


ACE I/D polymorphism associated with abnormal atrial and atrioventricular conduction in lone atrial fibrillation and structural heart disease: implications for electrical remodeling.
The angiotensin-converting enzyme (ACE) gene contains a common polymorphism based on the insertion (I) or deletion (D) of a 287-bp intronic DNA fragment. The D allele is associated with higher ACE activity and thus higher angiotensin II levels. Angiotensin II stimulates cardiac fibrosis and conduction heterogeneity. The purpose of this study was to determine whether the ACE I/D polymorphism modulates cardiac electrophysiology. Three different cohorts of patients were studied: 69 patients with paroxysmal lone atrial fibrillation (AF), 151 patients with structural heart disease and no history of AF, and 161 healthy subjects without cardiovascular disease or AF. Patients taking drugs that affect cardiac conduction were excluded from the study. ECG parameters during sinus rhythm were compared among the ACE I/D genotypes. The ACE I/D polymorphism was associated with the PR interval and heart block in the lone AF cohort. In multivariable linear regression models, the D allele was associated with longer PR interval in the lone AF and heart disease cohorts (12.0-ms and 7.1-ms increase per D allele, respectively). P-wave duration showed a similar trend, with increase in PR interval across ACE I/D genotypes in the lone AF and heart disease cohorts. The ACE D allele is associated with electrical remodeling in patients with lone AF and in those with heart disease, but not in control subjects. ACE activity may play a role in cardiac remodeling after the development of AF and heart disease.


Assessment of left ventricular function by two-dimensional speckle-tracking echocardiography in small breed dogs with hyperadrenocorticism.
Hyperadrenocorticism (HAC) is associated with an increased prevalence of hypertension. This study investigated the left ventricular function using two-dimensional speckle-tracking echocardiography (2D-STE) in small breed dogs affected with spontaneous HAC. Age-matched healthy controls (n = 9), dogs with pituitary-dependent hyperadrenocorticism (PDH, n = 10), and dogs with adrenal-dependent hyperadrenocorticism (ADH, n = 9) were included in this study. Conventional echocardiography, global longitudinal and circumferential strain, and strain rate were assessed. On group-wise comparison, left ventricular free wall (LVFWd) and interventricular septal thickness in diastole (IVSd) were thickest in the ADH group, followed by the PDH and controls (P = 0.014 and P = 0.001, respectively). Neither LVFWd nor IVSd was correlated with systemic blood pressure (P = 0.238 and P = 0.113, respectively). The values of all variables derived from the global strain and strain rate in longitudinal and circumferential directions followed the same pattern: highest in the controls, followed by PDH and then ADH (all P < 0.05, respectively). On multiple regression analyses, global longitudinal strain, global longitudinal strain rate in systole and early diastole, and global circumferential strain all decreased linearly with increased IVSd (all P < 0.05). Left ventricular hypertrophy (LVH) was more prevalent in the HAC group compared to the control group. Association between hypertension and development of LVH was not identified. Decreased global longitudinal and circumferential strains were associated with increased IVSd. 2D-STE revealed significant decreases in systolic functions that were undetected using conventional echocardiography in the ADH and PDH groups.


Natural-focal diseases: mapping experience in Russia.
Natural-focal diseases constitute a serious hazard for human health. Agents and vectors of such diseases belong to natural landscapes. The aim of this study is to identify the diversity and geography of natural-focal diseases in Russia and to develop cartographic approaches for their mapping, including mathematical-cartographical modeling. Russian medico-geographical mapping of natural-focal diseases is highly developed regionally and locally but extremely limited at the national level. To solve this problem, a scientific team of the Faculty of Geography at Lomonosov Moscow State University has developed and implemented a project of a medico-geographical Atlas of Russia "Natural-Focal Diseases". The mapping is based on medical statistics data. The Atlas contains a series of maps on disease incidence, long-term dynamics of disease morbidity, etc. In addition, other materials available to the authors were used: mapping of the natural environment, field data, archival materials, analyzed satellite images, etc. The maps are processed using ArcGIS (ESRI) software application. Different methods of rendering of mapped phenomena are used (geographical ranges, diagrams, choropleth maps etc.). A series of analytical, integrated, and synthetic maps shows disease incidence in the population at both the national and regional levels for the last 15 years. Maps of the mean annual morbidity of certain infections and maps of morbidity dynamics and nosological profiles allow for a detailed analysis of the situation for each of 83 administrative units of the Russian Federation. The degree of epidemic hazard in Russia by natural-focal diseases is reflected in a synthetic medico-geographical map that shows the degree of epidemic risks due to such diseases in Russia and allows one to estimate the risk of disease manifestation in a given region. This is the first attempt at aggregation and public presentation of diverse and multifaceted information about natural-focal diseases in Russia. Taken in entirety, the maps that have been prepared for the Atlas will enable researchers to evaluate the stability of epidemic manifestation of individual diseases and the susceptibility of a given territory to disease transmission. The results can be used for sanitary monitoring and disease prevention.


The relationship between an inflammation-based prognostic score (Glasgow Prognostic Score) and changes in serum biochemical variables in patients with advanced lung and gastrointestinal cancer.
The Glasgow Prognostic Score (GPS), an inflammation-based prognostic score formed from standard thresholds of C reactive protein (CRP) and albumin, has prognostic value in patients with advanced cancer. Little is known about the general biochemical disturbance associated with the systemic inflammatory response in cancer. To examine the relationship between the GPS and blood biochemistry in patients with advanced lung and gastrointestinal cancer. The GPS (albumin <35 g/l = 1 and CRP >10 mg/l = 1 combined to form a prognostic score of 0 (normal) and 1 or 2 (abnormal)) and a variety of biochemical variables were examined in patients (n = 50) with advanced lung or gastrointestinal cancer and in a healthy control group (n = 13). The GPS was normal in all the controls, but abnormal in 78% of the cancer group. Serum levels of sodium, chloride, creatine kinase, zinc and vitamin D were lower in the cancer group (all p<0.01), whereas levels of calcium, copper (both p<0.05), alkaline phosphatase, gamma-glutamyl transferase (both p<0.001) and lactate dehydrogenase (p<0.10) were raised. In the patient group, with increasing GPS, there was a median reduction in Karnofsky Performance Status (25%), haemoglobin (22%), sodium (3%), zinc (15%) and survival (93%, all p<0.05) and a median increase in white cell count (129%), alkaline phosphatase (217%), gamma-glutamyl transferase (371%) and lactate dehydrogenase (130%, all p<0.05). CRP levels were strongly and similarly correlated with alkaline phosphatase and gamma-glutamyl transferase, accounting for more than 25% of the variation in their activities. Several correlations were seen between biochemical variables and increasing GPS. In particular, chronic activation of the systemic inflammatory response in cancer was associated with increase in gamma-glutamyl transferase and alkaline phosphatase activity in patients with advanced lung and gastrointestinal cancer.


The morphology and structure of the Hannibal Bank fisheries management zone, Pacific Panama using acoustic seabed mapping.
The Hannibal Bank sits within the Coiba UNESCO World Heritage Site in Pacific Panama and is also a fisheries management zone. Despite the protected status of the area and the importance of the Bank for commercial fish species such as snapper and tuna, the seamount has received no detailed survey except some collection of organisms. This study mapped the major topographic features and complexity of the Hannibal Bank seamount using acoustic remote sensing. A survey area of around 125 km2 was defined using existing charts and side-scan sonar data were collected during July 2008. A bathymetric output was imported to ArcGIS where a digital bathymetric model and slope map were created. The Benthic Terrain Modeler (BTM) extension for ArcGIS was used to calculate bathymetric position index and rugosity, and used to create a map of zones representing the various seabed morphology zones. The Hannibal bank is an elongated, triangular guyot (flat topped seamount), which ranges in depth from 53m to 416m, covers an area of 76 km2 and is 14.4 km long and 7.1 km wide. Hannibal bank is composed of steep slopes, more gentle slopes, top of the seamount, crests (elevated ridges at the top of the pinnacles), rugose areas (on crests, top of seamount and slope), gullies and pinnacles. The bank is asymmetric in nature with the Northerly side having a relatively gentle slope with gullies across the surface compared to the SouthWest side which is far steeper and more rugose. There are two pinnacles to the North and South East of the bank that range in depth from 180 to 333 m. Rocky substrate makes up 22.6 km2 of the bank and sediment 37.8 km2. The bank and its steeply sided, rugose areas and pinnacles provide upright structures which can disrupt and topographically enhance currents, increasing productivity. The rugose areas of Hannibal Bank should be primary targets for further research efforts as they may contain corals and their rugosity indicates that these should be some of the highest faunal diversity areas of the bank. Hannibal Bank is likely to come increasing pressure in the future through climate change and fishing and this study has produced valuable information to assist in the future mapping and management of habitats, associated species and fisheries.


MHC class I antigen cross-presentation mediated by PapMV nanoparticles in human antigen-presenting cells is dependent on autophagy.
Nanoparticles made of the coat protein of papaya mosaic virus (PapMV) and a single-strand RNA were previously shown to be an efficient antigen presentation system for the trigger of cellular immunity. Engineering of PapMV nano with a cytotoxic T lymphocyte epitope was previously shown activating specific T lymphocytes through a proteasome-independent major histocompatibility complex class I (MHC-I) cross-presentation. In this study, we provide new insights into the mechanism of the MHC-I cross-presentation mediated by PapMV nanoparticles. We demonstrate that PapMV nanoparticles do not require the transporter associated with antigen presentation (TAP), but rather depend on lysosome acidification and cathepsin S protease activity for presentation of the T cell epitope. We have also linked the induction of autophagy with this vacuolar MHC-I cross-presentation process. Interestingly, autophagy is induced in antigen-presenting cells after PapMV nanoparticles exposure and inhibition of autophagy reduce MHC-I cross-presentation. This study demonstrates that autophagy is associated with TAP- and proteasome-independent MHC-I cross-presentation. A deeper understanding of the autophagy-dependent MHC-I cross-presentation will be useful in designing vaccination platforms that aim to trigger an efficient cytotoxic T lymphocyte response.


Normal mouse peritoneum contains a large population of Ly-1+ (CD5) B cells that recognize phosphatidyl choline. Relationship to cells that secrete hemolytic antibody specific for autologous erythrocytes.
We have found that, in the peritoneums of normal adult mice, 5-15% of lymphocytes bind a fluorescent liposome probe. In ontogeny, cells with this specificity were shown to appear by 8 d after birth, and increase to the adult frequency by 2-3 wk. Some older mice contain an expanded population of these cells. We have shown that liposome binding occurs by cell surface IgM recognizing the common membrane phospholipid, phosphatidyl choline (PtC). Virtually all of these PtC-specific cells bear the cell surface marker Ly-1. Our results indicate that roughly 1 in 10 peritoneal Ly-1+ B cells has this single specificity. We have found that the precursors to all the cells that form plaques on protease-treated autologous erythrocytes (BrMRBC) are included in the PtC-specific population and can be isolated by FACS. We believe this is the first report of sorting large numbers of B cells with a single antigen specificity from normal, unimmunized animals. This method will allow for in vitro and in vivo studies of differentiative and proliferative properties of Ly-1+ B cells, which may help define their role in development and disease.


Entomologically famous, evolutionarily unexplored: the first phylogeny of the lanternfly family Fulgoridae (Insecta: Hemiptera: Fulgoroidea).
Lanternflies (Insecta: Hemiptera: Fulgoridae) are frequently used as examples of unusual morphological evolution, with some species (such as the peanut-headed bug, Fulgora laternaria Linnaeus) also ubiquitously cited as icons of tropical insect biodiversity. Despite that entomological notoriety, the phylogeny of this charismatic planthopper family has never before been studied. Presented here are the results of a phylogenetic investigation of Fulgoridae based on DNA nucleotide sequence data from five genetic loci (18S rDNA, 28S rDNA, histone 3, wingless, and cytochrome oxidase I). The resulting topologies are used to test the higher classification of Fulgoridae, which is based primarily on characters associated with the curious head morphology of many included species. Analyses include a taxonomic sample of 69 fulgorid species representing 46 (of 110) genera, 10 (of 11) tribes, and all 8 currently recognized subfamilies. Results of this study: (1) demonstrate the need for a revised classification of Fulgoridae, particularly at the higher taxonomic levels; (2) suggest that the genus Zanna is excluded from a monophyletic Fulgoridae; (3) indicate that there have been multiple losses of the extended head process across fulgorid evolution, with what appears to be convergence (in shape and/or loss) in distantly related lineages; and (4) suggest two alternative biogeographic hypotheses to explain the distribution of extant Fulgoridae, with either an Old World origin and a single subsequent colonization of the New World, or a contemporaneous diversification of Old and New World lineages.


Escherichia coli cyclophilin B binds a highly distorted form of trans-prolyl peptide isomer.
Cyclophilins facilitate the peptidyl-prolyl isomerization of a trans-isomer to a cis-isomer in the refolding process of unfolded proteins to recover the natural folding state with cis-proline conformation. To date, only short peptides with a cis-form proline have been observed in complexes of human and Escherichia coli proteins of cyclophilin A, which is present in cytoplasm. The crystal structures analyzed in this study show two complexes in which peptides having a trans-form proline, i.e. succinyl-Ala-trans-Pro-Ala-p-nitroanilide and acetyl-Ala-Ala-trans-Pro-Ala-amidomethylcoumarin, are bound on a K163T mutant of Escherichia coli cyclophilin B, the preprotein of which has a signal sequence. Comparison with cis-form peptides bound to cyclophilin A reveals that in any case the proline ring is inserted into the hydrophobic pocket and a hydrogen bond between CO of Pro and Neta2 of Arg is formed to fix the peptide. On the other hand, in the cis-isomer, the formation of two hydrogen bonds of NH and CO of Ala preceding Pro with the protein fixes the peptide, whereas in the trans-isomer formation of a hydrogen bond between CO preceding Ala-Pro and His47 Nepsilon2 via a mediating water molecule allows the large distortion in the orientation of Ala of Ala-Pro. Although loss of double bond character of the amide bond of Ala-Pro is essential to the isomerization pathway occurring by rotating around its bond, these peptides have forms impossible to undergo proton transfer from the guanidyl group of Arg to the prolyl N atom, which induces loss of double bond character.


Programmed Cell Death 1 (PD-1) Ligand (PD-L1) Expression in Solid Tumors As a Predictive Biomarker of Benefit From PD-1/PD-L1 Axis Inhibitors: A Systematic Review and Meta-Analysis.
Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway show significant clinical activity across several tumor types. However, a majority of patients do not respond to these agents. Use of biomarker assays to predict response to these agents is an active area of research; however, the predictive value of PD-L1 immunohistochemistry (IHC) assays is largely inconsistent across clinical trials. In this meta-analysis of clinical trials of PD-1/PD-L1-targeted agents, we evaluate the predictive value of a tumor and tumor-infiltrating immune cell PD-L1 IHC assay as a biomarker for objective response to PD-1/PD-L1 inhibitors. We searched databases (PubMed, Medline, ASCO abstracts, European Society for Medical Oncology abstracts, and Scopus) up until December 2016 for clinical trials using PD-1/PD-L1 inhibitors with reported PD-L1 biomarker data. Objective response rates (primary end point) from all phase I to III trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab in advanced solid tumors were collected. Odds ratios (ORs) for response in PD-L1-positive patients compared with PD-L1-negative patients were calculated using the DerSimonian-Laird random effects model to combine trials. We performed meta-analysis as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Forty-one distinct trials with 6,664 patients were identified. PD-L1 expression was predictive of favorable response across all tumor types (OR, 2.26; 95% CI, 1.85 to 2.75; P < .001), with the significantly largest effect observed in non-small-cell lung cancer (OR, 2.51; 95% CI, 1.99 to 3.17; P < .001). A subgroup analysis across all non-small-cell lung cancer trials using nivolumab and Dako clone 28-8 (Dako, Carpinteria, CA) IHC antibody assay yielded a significantly higher objective response rate in patients with tumor PD-L1 expression even at the minimum cutoff value of 1% (OR, 2.17; 95% CI, 1.03 to 4.57). Our meta-analysis shows that tumor and tumor-infiltrating immune cell PD-L1 overexpression based on IHC is associated with significantly higher response rates to PD-1/PD-L1 axis inhibitors across a range of malignant solid tumors.


A transmembrane form of the prion protein in neurodegenerative disease.
At the endoplasmic reticulum membrane, the prion protein (PrP) can be synthesized in several topological forms. The role of these different forms was explored with transgenic mice expressing PrP mutations that alter the relative ratios of the topological forms. Expression of a particular transmembrane form (termed CtmPrP) produced neurodegenerative changes in mice similar to those of some genetic prion diseases. Brains from these mice contained CtmPrP but not PrPSc, the PrP isoform responsible for transmission of prion diseases. Furthermore, in one heritable prion disease of humans, brain tissue contained CtmPrP but not PrPSc. Thus, aberrant regulation of protein biogenesis and topology at the endoplasmic reticulum can result in neurodegeneration.


Behaviourally designed treatments that increase willingness to treatment from families with children suffering from autism spectrum disorder.
Autism spectrum disorder is a lifelong disability that is not well known by the general population and tends to be associated with social stigma; also, because it involves children, it may get highly emotionally charged. These stylised facts engender a number of possible heuristics and biases at the moment of deciding on following a treatment or looking for a diagnosis, which should be considered in the presentation of information. Using insights from Behavioural Economics, three treatments are designed to present the information regarding possible therapies. Between-subjects design with one level of variation. Interviews were performed with a convenience sample of 154 households from the metropolitan area of Bogotá (Colombia). The treatments include: use of default option, use of professional interviewer to illustrate the therapy and emotionally charged presentation. Kruskal-Wallis test of the intention to be treated rejects the null hypothesis (χ(2)=22.14, p=0.00). The cognitive processing of the information is not a determinant, supporting the claim that genuine framing effects shape the choice. The strongest effect of the treatment with a professional suggests a key role for asymmetry of the information, which is confirmed indirectly through the postexperiment questionnaire. Bad healthcare decisions are not necessarily driven by lack of information. Asymmetric information (eg, delegating the decision to a professional) improves choices, especially when social stigma is involved. Cognitive processing of information seems to be less relevant than the framing effect.


Controlled administration of dehydrochloromethyltestosterone in humans: Urinary excretion and long-term detection of metabolites for anti-doping purpose.
Dehydrochloromethyltestosterone (DHCMT) is an anabolic-androgenic steroid that was developed by Jenapharm in the 1960s and was marketed as Oral Turinabol®. It is prohibited in sports at all times; nevertheless, there are several findings by anti-doping laboratories every year. New long-term metabolites have been proposed in 2011/12, which resulted in adverse analytical findings in retests of the Olympic games of 2008 and 2012. However, no controlled administration trial monitoring these long-term metabolites was reported until now. In this study, DHCMT (5 mg, p.o.) was administered to five healthy male volunteers and their urine samples were collected for a total of 60 days. The unconjugated and the glucuronidated fraction were analyzed separately by gas chromatography coupled to tandem mass spectrometry. The formation of the described long-term metabolites was verified, and their excretion monitored in detail. Due to interindividual differences there were several varieties in the excretion profiles among the volunteers. The metabolite M3, which has a fully reduced A-ring and modified D-ring structure, was identified by comparison with reference material as 4α-chloro-17β-hydroxymethyl-17α-methyl-18-nor-5α-androstan-13-en-3α-ol. It was found to be suitable as long-term marker for the intake of DHCMT in four of the volunteers. In one of the volunteers, it was detectable for 45 days after single oral dose administration. However, in two of the volunteers M5 (already published as long-term metabolite in the 1990s) showed longer detection windows. In one volunteer M3 was undetectable but another metabolite, M2, was found as the longest detectable metabolite. The last sample clearly identified as positive was collected between 9.9 and 44.9 days. Furthermore, the metabolite epiM4 (partially reduced A-ring and a modified D-ring structure which is epimerized in position 17 compared to M3) was identified in the urine of all volunteers with the help of chemically synthesized reference as 4-chloro-17α-hydroxymethyl-17β-methyl-18-nor-androsta-4,13-dien-3β-ol. It may serve as additional confirmatory metabolite. It is highly recommended to screen for all known metabolites in both fractions, glucuronidated and unconjugated, to improve identification of cheating athletes. This study also offers some deeper insights into the metabolism of DHCMT and of 17α-methyl steroids in general.


Impact of a Shared Decision Making Intervention on Health Care Utilization: A Secondary Analysis of the Chest Pain Choice Multicenter Randomized Trial.
Patients at low risk for acute coronary syndrome are frequently admitted for observation and cardiac testing, resulting in substantial burden and cost to the patient and the health care system. The purpose of this investigation was to measure the effect of the Chest Pain Choice (CPC) decision aid on overall health care utilization as well as utilization of specific services both during the index emergency department (ED) visit and in the subsequent 45 days. This was a planned secondary analysis of data from a pragmatic multicenter randomized trial of shared decision making in adults presenting to the ED with chest pain who were being considered for observation unit admission for cardiac stress testing or coronary computed tomography angiography. The trial compared an intervention group engaged in shared decision making facilitated by the CPC decision aid to a control group receiving usual care. Hospital-level billing data were used to measure utilization for the index ED visit and during the following 45 days. Patients in both groups also were asked to keep a diary recording health care utilization over the same 45-day period. Outcomes assessed included length of time in the ED and observation, ED visits, office visits, hospitalizations, testing, imaging, and procedures. Of the 898 patients included in the original trial, we were able to contact 834 (92.9%) patients for 45-day health care diary review. There was no difference in patient-reported health care utilization between the study arms. Hospital-level billing data were obtained for all 898 (100%) patients. During the initial ED visit the length of stay (LOS) was similar, and there was no difference in the frequency of observation unit admission between study arms. However, the mean observation unit LOS was 95 minutes (95% confidence interval [CI] = 40.8-149.8) shorter in the CPC arm and the mean number of tests was lower in the CPC arm (decrease in 19.4 imaging studies per 100 patients, 95% CI = 15.5-23.3). When evaluating the entire encounter and follow-up period, the intervention arm underwent fewer tests (decrease in 125.6 tests per 100 patients, 95% CI = 29.3-221.6). More specifically, there were fewer advanced cardiac imaging tests completed (25.8 fewer per 100 patients, 95% CI = 3.74-47.9) in the intervention arm. Shared decision making in low-risk chest pain can lead to decreased diagnostic testing without worsening outcomes measured over 45 days.


Psychophysical and pupillometric study of spatial channels of visual processing in blindsight.
To date no systematic method has been used for characterising the residual capacity of blindsight subjects that would allow comparison and generalisation across all subjects. The detection of isoluminant gratings of varying spatial and temporal frequencies commends itself for detailed between-subject comparison, and for mapping results onto physiological properties in relation to neuronal circuitry. We report the ability of a blindsight subject (CS) to detect suprathreshold sine-wave gratings over a range of spatial and temporal frequencies using psychophysical techniques. A band-pass spatial channel with an upper cutoff below 3.5 cycles/deg is specified. The data also have been analysed to compare differences between two types of blindsight performances, type I and type II. Spatial gratings were also used to elicit a pupillary grating response, offering an objective method that is free of verbal nuances and response bias, and the resulting band-pass channel can be used both for clinical screening and for prediction and comparisons with psychophysical profiles. Finally, we have compared our results with those reported in studies of a well-known subject, GY, which demonstrate remarkable similarities. Implications are discussed in relation to blindsight research.


KAMEDO report no. 84: terrorist attacks against the World Trade Center, 11 September 2001.
On 11 September 2001, two hijacked airplanes collided with the World Trade Center in New York. Both towers collapsed, spreading smoke and debris for miles. Rescue personnel arrived rapidly, but the collapse of the towers made the scene too dangerous for these teams to rescue all those trapped inside. Although this collapse was impossible to predict, fires occurring in skyscrapers can cause the structures to collapse. When a fire erupts in the upper levels of the building, it is even more difficult for those trapped inside to escape. Communications systems were shut down. In future incidents with large numbers of injured victims, the injured should be transported to hospitals by non-traditional medical transport vehicles (taxis, cars, etc.). If future disasters occur in the vicinity of a hospital, the most severely injured victims should go to the hospital instead of congregating at assembly points. These victims often are already at hospitals before substantial aid arrives at the assembly points. On-scene care must be documented, and easy-to-read triage tags should be used. Reserve power supplies in major cities should be maintained in preparation for emergencies. Both victims and rescue personnel are susceptible to post-traumatic, psychosocial reactions.


Low risk despite high endemicity of methicillin-resistant Staphylococcus aureus infections following elective total joint arthroplasty: a 12-year experience.
Abstract Background. It is unknown if low rates of arthroplasty infections due to methicillin-resistant Staphylococcus aureus (MRSA) can be achieved in a setting with endemic MRSA (30%). Methods. We performed a 12-year prospective cohort study (1996-2008) of patients undergoing elective knee and hip joint arthroplasties with long-term follow-up. Retrospective MRSA surveillance was undertaken using electronic databases. Results. A total of 6,100 total joint arthroplasties (4001 hip; 2099 knee; 441 (7%) revisions) were monitored for a total of 34,281 person-years of follow-up (median 64 months). MRSA carriage was detected in 126 (2.1%) episodes before arthroplasty and in 147 (2.4%) after arthroplasty. Seven (0.11%) deep arthroplasty infections due to MRSA were retrieved for an overall incidence of 2 episodes per 10,000 person-years. Six were primary surgical site infections, while one infection resulted from endocarditis. MRSA colonization pressure was 11,411 MRSA-positive days for a total of 138,044 patient-days (8.3%) among all orthopedic patients. Conclusion. Institution-wide MRSA endemicity does not necessarily lead to a high MRSA infection risk after elective hip and knee arthroplasty.


Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils.
Anti-neutrophil cytoplasmic antibodies (ANCA) activate primed human polymorphonuclear neutrophils (PMN) in vitro, resulting in a respiratory burst and degranulation. In this study, the hypotheses that the initiation of this process requires engagement of the F(ab')2 portion of ANCA, and that crosslinking of ANCA target antigens is necessary to trigger superoxide (O2-) release, were explored. It is speculated that Fc gamma receptor engagement is a modulator of ANCA-mediated activation. Flow cytometry demonstrated that intact human ANCA immunoglobulin (Ig), their corresponding F(ab')2 and Fab fragments, as well as a murine monoclonal to human PR3 and its F(ab')2 fragment, bind to ANCA antigens on the surface of PMN primed with tumor necrosis factor (TNF) alpha. Intact Ig of patients with PR3-ANCA or with MPO-ANCA stimulate O2- release from TNF alpha-primed normal PMN (2.6 +/- 3.57 to 15.3 +/- 7.39 nmol O2-/2.5 x 10(6) PMN/30 min). Corresponding F(ab')2 fragments result in similar O2- production (10.2 +/- 4.34 to 36.9 nmol) in a dose-dependent manner. ANCA Fab fragments do not stimulate O2- generation until these fragments are crosslinked with F(ab')2 of goat anti-human Ig F(ab')2, or when fragments are biotinylated and crosslinked with avidin. In contrast with these human autoantibody data, a mouse monoclonal anti-human PR3 antibody (25.7 +/- 8.55 nmol O2-), but not its corresponding F(ab')2 fragment, activates TNF alpha-treated human PMN. When the Fc gamma IIa receptors were blocked, superoxide production was reduced by 33% using human PR3-ANCA Ig (P < 0.05). In conclusion, PMN activation by ANCA occurs when intact ANCA or ANCA F(ab')2 fragments crosslink target antigens on the neutrophil cell surface. ANCA F(ab') fragments result in PMN activation when crosslinked by secondary reagents.


Development of a multiomics database for personalized prognostic forecasting in head and neck cancer: The Big Data to Decide EU Project.
Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling. Stage III-IV HNSCC patients with locoregionally advanced HNSCC treated with curative intent (1537) were included. Whole transcriptomics and radiomics analyses were performed using pretreatment tumor samples and computed tomography/magnetic resonance imaging scans, respectively. The entire cohort was composed of 71% male (1097)and 29% female (440): oral cavity (429, 28%), oropharynx (624, 41%), larynx (314, 20%), and hypopharynx (170, 11%); median follow-up 50.5 months. Transcriptomics and imaging data were available for 1284 (83%) and 1239 (80%) cases, respectively; 1047 (68%) patients shared both. This annotated database represents the HNSCC largest available repository and will enable to develop/validate a decision support system integrating multiscale data to explore through classical and machine learning models their prognostic role.


Automatic montage of SD-OCT data sets.
This paper proposes an automatic algorithm for the montage of OCT data sets, which produces a composite 3D OCT image over a large field of view out of several separate, partially overlapping OCT data sets. First the OCT fundus images (OFIs) are registered, using blood vessel ridges as the feature of interest and a two step iterative procedure to minimize the distance between all matching point pairs over the set of OFIs. Then the OCT data sets are merged to form a full 3D montage using cross-correlation. The algorithm was tested using an imaging protocol consisting of 8 OCT images for each eye, overlapping to cover a total retinal region of approximately 50x35 degrees. The results for 3 normal eyes and 3 eyes with retinal degeneration are analyzed, showing registration errors of 1.5±0.3 and 2.0±0.8 pixels respectively.


Protein subcellular localization prediction using multiple kernel learning based support vector machine.
Predicting the subcellular locations of proteins can provide useful hints that reveal their functions, increase our understanding of the mechanisms of some diseases, and finally aid in the development of novel drugs. As the number of newly discovered proteins has been growing exponentially, which in turns, makes the subcellular localization prediction by purely laboratory tests prohibitively laborious and expensive. In this context, to tackle the challenges, computational methods are being developed as an alternative choice to aid biologists in selecting target proteins and designing related experiments. However, the success of protein subcellular localization prediction is still a complicated and challenging issue, particularly, when query proteins have multi-label characteristics, i.e., if they exist simultaneously in more than one subcellular location or if they move between two or more different subcellular locations. To date, to address this problem, several types of subcellular localization prediction methods with different levels of accuracy have been proposed. The support vector machine (SVM) has been employed to provide potential solutions to the protein subcellular localization prediction problem. However, the practicability of an SVM is affected by the challenges of selecting an appropriate kernel and selecting the parameters of the selected kernel. To address this difficulty, in this study, we aimed to develop an efficient multi-label protein subcellular localization prediction system, named as MKLoc, by introducing multiple kernel learning (MKL) based SVM. We evaluated MKLoc using a combined dataset containing 5447 single-localized proteins (originally published as part of the Höglund dataset) and 3056 multi-localized proteins (originally published as part of the DBMLoc set). Note that this dataset was used by Briesemeister et al. in their extensive comparison of multi-localization prediction systems. Finally, our experimental results indicate that MKLoc not only achieves higher accuracy than a single kernel based SVM system but also shows significantly better results than those obtained from other top systems (MDLoc, BNCs, YLoc+). Moreover, MKLoc requires less computation time to tune and train the system than that required for BNCs and single kernel based SVM.


[Long-term psychiatric and behavioural consequences of prenatal exposure to psychoactive drugs].
A growing body of evidence supports the hypothesis that exposure to prenatal environmental risk factors increases the vulnerability for a broad range of psychiatric disorders. Although the association between exposure to obstetric complications and increased vulnerability for psychiatric disorders is well documented, few studies have explored the putative deleterious impact of psychoactive substances and xenoestrogens on subsequent liability for psychological disturbances. Cohort studies suggest that prenatal exposure to nicotine is a risk factor for conduct disorders, and some case-control studies have reported an association between prenatal nicotine exposure and attention deficit hyperactivity disorder. Studies on the long-term behavioural consequences of prenatal exposure to other licit and illicit psychoactive substances are hampered by methodological flaws limiting the interpretation of the findings. Regarding prenatal exposure to hormones, sparse findings suggest that exposure to xenoestrogens such as diethylstilbestrol may be a risk factor for psychiatric disorders, mediated by a deleterious impact of these substances on the foetal neurodevelopment. However, this hypothesis is largely speculative due to the low number of studies and their methodological limitations. Further studies are required to explore the long-term cognitive and behavioural consequences of prenatal exposure to psychoactive drugs and xenoestrogens.


Transjugular intrahepatic portosystemic shunt creation for cirrhotic portal hypertension is well tolerated among patients with portal vein thrombosis.
Portal vein thrombosis (PVT) develops in cirrhotic patients because of stagnation of blood flow. Transjugular intrahepatic portosystemic shunt (TIPS) creates a low-resistance conduit that restores portal venous patency and blood flow. The effect of PVT on transplant-free survival in cirrhotic patients undergoing TIPS creation was evaluated. A multicenter, retrospective cohort study of patients who underwent TIPS creation for cirrhotic portal hypertension was carried out. A Cox model with propensity score adjustment was developed to evaluate the effect of PVT on 90-day and 3-year transplant-free survival. A subgroup analysis examining mortality of those with superior and inferior PVT was also carried out. A total of 252 consecutive TIPS creations were assessed, including 65 in patients with PVT. Survival of patients with high Model for End-stage Liver Disease scores (≥18) and PVT was not statistically different compared with patients with low Model for End-stage Liver Disease scores (<18) and no PVT at 90 days (P=0.46) and 3 years (P=0.42). Those with superior PVT had improved 90-day and 3-year survival both compared with patients with a inferior PVT and those without a PVT (P<0.01, all cases). The presence of PVT does not impair the prognosis of patients following TIPS creation, particularly in patients with superior portal occlusion.


Forensic analysis of tertiary-butyl alcohol (TBA) detections in a hydrocarbon-rich groundwater basin.
Tertiary-butyl alcohol (TBA), a high-production volume (HPV) chemical, was sporadically detected in groundwater and coalbed methane (CBM) wells in southeastern Colorado's hydrocarbon-rich Raton Basin. TBA concentrations in shallow water wells averaged 75.1 μg/L, while detections in deeper CBM wells averaged 14.4 μg/L. The detection of TBA prompted a forensic investigation to try to identify potential sources. Historic and recent data were reviewed to determine if there was a discernable pattern of TBA occurrence. Supplemental samples from domestic water wells, monitor wells, CBM wells, surface waters, and hydraulic fracturing (HF) fluids were analyzed for TBA in conjunction with methyl tertiary-butyl ether (MTBE) and ethyl tertiary-butyl ether (ETBE), proxies for evidence of contamination from reformulated gasoline or associated oxygenates. Exploratory microbiological sampling was conducted to determine if methanotrophic organisms co-occurred with TBA in individual wells. Meaningful comparisons of historic TBA data were limited due to widely varying reporting limits. Mapping of TBA occurrence did not reveal any spatial patterns or physical associations with CBM operations or contamination plumes. Additionally, TBA was not detected in HF fluids or surface water samples. Given the widespread use of TBA in industrial and consumer products, including water well completion materials, it is likely that multiple diffuse sources exist. Exploratory data on stable isotopes, dissolved gases, and microbial profiling provide preliminary evidence that methanotrophic activity may be producing TBA from naturally occurring isobutane. Reported TBA concentrations were significantly below a conservative risk-based drinking water screening level of 8000 μg/L derived from animal toxicity data.