Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif.
Deletion of Gly-720 and Tyr-721 from a highly conserved GYxxØ trafficking signal in the SIVmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed ΔGY, leads to a striking perturbation in pathogenesis in rhesus macaques (Macaca mulatta). Infected macaques develop immune activation and progress to AIDS, but with only limited and transient infection of intestinal CD4(+) T cells and an absence of microbial translocation. Here we evaluated ΔGY in pig-tailed macaques (Macaca nemestrina), a species in which SIVmac239 infection typically leads to increased immune activation and more rapid progression to AIDS than in rhesus macaques. In pig-tailed macaques, ΔGY also replicated acutely to high peak plasma RNA levels identical to those for SIVmac239 and caused only transient infection of CD4(+) T cells in the gut lamina propria and no microbial translocation. However, in marked contrast to rhesus macaques, 19 of 21 pig-tailed macaques controlled ΔGY replication with plasma viral loads of <15 to 50 RNA copies/ml. CD4(+) T cells were preserved in blood and gut for up to 100 weeks with no immune activation or disease progression. Robust antiviral CD4(+) T cell responses were seen, particularly in the gut. Anti-CD8 antibody depletion demonstrated CD8(+) cellular control of viral replication. Two pig-tailed macaques progressed to disease with persisting viremia and possible compensatory mutations in the cytoplasmic tail. These studies demonstrate a marked perturbation in pathogenesis caused by ΔGY's ablation of the GYxxØ trafficking motif and reveal, paradoxically, that viral control is enhanced in a macaque species typically predisposed to more pathogenic manifestations of simian immunodeficiency virus (SIV) infection. The pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) reflects a balance between viral replication, host innate and adaptive antiviral immune responses, and sustained immune activation that in humans and Asian macaques is associated with persistent viremia, immune escape, and AIDS. Among nonhuman primates, pig-tailed macaques following SIV infection are predisposed to more rapid disease progression than are rhesus macaques. Here, we show that disruption of a conserved tyrosine-based cellular trafficking motif in the viral transmembrane envelope glycoprotein cytoplasmic tail leads in pig-tailed macaques to a unique phenotype in which high levels of acute viral replication are followed by elite control, robust cellular responses in mucosal tissues, and no disease. Paradoxically, control of this virus in rhesus macaques is only partial, and progression to AIDS occurs. This novel model should provide a powerful tool to help identify host-specific determinants for viral control with potential relevance for vaccine development.


Prevalence and genetic diversity of Salmonella spp. in a river in a tropical environment in Mexico.
The capability of Salmonella to survive outside a host is especially relevant in tropical regions, where the environmental conditions could be more suitable for its long-term persistence. This study investigated the prevalence and genetic diversity of salmonellae within rivers of the Culiacan Valley in the northwestern region of Mexico. From July 2008 to June 2009, a total of 138 water samples were evaluated for the presence of Salmonella spp.; additionally, its association with environmental parameters was determined using Generalized Additive Models (GAMs). Salmonella spp. were isolated from 111 (80.4%) samples without any statistical influence on the environmental parameters investigated, according to the GAM analysis. Twenty-four serotypes were identified; the most frequently isolated serotypes were Salmonella Oranienburg (25%), Salmonella Saintpaul (9%) and Salmonella Minnesota (6%). Diverse genetic variants of Salmonella Oranienburg were found distributed across the valley with no distinctive geographical or temporal patterns. The high persistence of Salmonella spp. and the lack of differentiation of types found along the river basins suggest the existence of non-point source contamination. Furthermore, the discrepancy between the prevailing serotypes in human infections and those identified in this study denotes a limited influence of these aquatic environments in bacterial dissemination and disease transmission.


Objects of consciousness.
Current models of visual perception typically assume that human vision estimates true properties of physical objects, properties that exist even if unperceived. However, recent studies of perceptual evolution, using evolutionary games and genetic algorithms, reveal that natural selection often drives true perceptions to extinction when they compete with perceptions tuned to fitness rather than truth: Perception guides adaptive behavior; it does not estimate a preexisting physical truth. Moreover, shifting from evolutionary biology to quantum physics, there is reason to disbelieve in preexisting physical truths: Certain interpretations of quantum theory deny that dynamical properties of physical objects have definite values when unobserved. In some of these interpretations the observer is fundamental, and wave functions are compendia of subjective probabilities, not preexisting elements of physical reality. These two considerations, from evolutionary biology and quantum physics, suggest that current models of object perception require fundamental reformulation. Here we begin such a reformulation, starting with a formal model of consciousness that we call a "conscious agent." We develop the dynamics of interacting conscious agents, and study how the perception of objects and space-time can emerge from such dynamics. We show that one particular object, the quantum free particle, has a wave function that is identical in form to the harmonic functions that characterize the asymptotic dynamics of conscious agents; particles are vibrations not of strings but of interacting conscious agents. This allows us to reinterpret physical properties such as position, momentum, and energy as properties of interacting conscious agents, rather than as preexisting physical truths. We sketch how this approach might extend to the perception of relativistic quantum objects, and to classical objects of macroscopic scale.


Role of TLR4 in Persistent Leptospira interrogans Infection: A Comparative In Vivo Study in Mice.
Toll-Like Receptor (TLR) 4, the LPS receptor, plays a central role in the control of leptospirosis and absence of TLR4 results in lethal infection in mice. Because human TLR4 does not sense the atypical leptospiral-LPS, we hypothesized that TLR4/MD-2 humanized transgenic mice (huTLR4) may be more susceptible to leptospirosis than wild-type mice, and thus may constitute a model of acute human leptospirosis. We infected huTLR4 mice, which express human TLR4 but not murine TLR4, with a high dose of L. interrogans serovar Copenhageni FioCruz (Leptospira) in comparison to C57BL/6J wild-type (WT) and, as a control, a congenic strain in which the tlr4 coding sequences are deleted (muTLR4Lps-del). We show that the huTLR4 gene is fully functional in the murine background. We found that dissemination of Leptospira in blood, shedding in urine, colonization of the kidney and overall kinetics of leptospirosis progression is equivalent between WT and huTLR4 C57BL/6J mice. Furthermore, inflammation of the kidney appeared to be subdued in huTLR4 compared to WT mice in that we observed less infiltrates of mononuclear lymphocytes, less innate immune markers and no relevant differences in fibrosis markers. Thus, huTLR4 mice showed less inflammation and kidney pathology, and are not more susceptible to leptospirosis than WT mice. This study is significant as it indicates that one intact TLR4 gene, be it mouse or human, is necessary to control acute leptospirosis.


Selection and validation of reference genes for quantitative gene expression analyses in persimmon (Diospyros kaki Thunb.) using real-time quantitative PCR.
Persimmon (Diospyros kaki) is an economically important fruit tree species with complex flowering characteristics. To obtain accurate expression pattern analysis results, it is vital to select a reliable gene for the normalization of real-time quantitative polymerase chain reaction data. The aim of this study was to identify the optimal internal control gene among six candidate genes for gene expression analysis in different persimmon organs and developmental stages. This analysis was conducted using geNorm and NormFinder software to show differences in the stability of the six reference genes among tissues and floral developmental stages of the same plant. Although genes that exhibited moderate expression in NormFinder revealed slightly different expression stabilities than those obtained by geNorm, both sets of results showed that GAPDH was the best reference gene in different organs and floral buds at different developmental stages, whereas 18SrRNA was the least stable gene. Based on the overall ranking, GAPDH is the most suitable reference gene and is highly recommended for gene expression studies in different organs and different developmental stages of persimmon. This study provides useful reference data for future gene expression studies and will contribute to improving the accuracy of gene expression results in persimmon.


Characterisation of Arabidopsis calnexin 1 and calnexin 2 in the endoplasmic reticulum and at plasmodesmata.
Calnexin (CNX) is a highly conserved endoplasmic reticulum (ER) chaperone protein. Both calnexin and the homologous ER-lumenal protein, calreticulin, bind calcium ions and participate in protein folding. There are two calnexins in Arabidopsis thaliana, CNX1 and CNX2. GUS expression demonstrated that these are expressed in most Arabidopsis tissues throughout development. Calnexin transfer DNA (T-DNA) mutant lines exhibited increased transcript abundances of a number of other ER chaperones, including calreticulins, suggesting a degree of redundancy. CNX1 and CNX2 localised to the ER membrane including that within plasmodesmata, the intercellular channels connecting plant cells. This is comparable with the previous localisations of calreticulin in the ER lumen and at plasmodesmata. However, from green fluorescent protein (GFP) diffusion studies in single and double T-DNA insertion mutant lines, as well as overexpression lines, we found no evidence that CNX1 or CNX2 play a role in intercellular transport through plasmodesmata. In addition, calnexin T-DNA mutant lines showed no change in transcript abundance of a number of plasmodesmata-related proteins. CNX1 and CNX2 do not appear to have a specific localisation or function at plasmodesmata-rather the association of calnexin with the ER is simply maintained as the ER passes through plasmodesmata.


The Middle Pleistocene (MIS 12) human dental remains from Fontana Ranuccio (Latium) and Visogliano (Friuli-Venezia Giulia), Italy. A comparative high resolution endostructural assessment.
The penecontemporaneous Middle Pleistocene sites of Fontana Ranuccio (Latium) and Visogliano (Friuli-Venezia Giulia), set c. 450 km apart in central and northeastern Italy, respectively, have yielded some among the oldest human fossil remains testifying to a peopling phase of the Italian Peninsula broadly during the glacial MIS 12, a stage associated with one among the harshest climatic conditions in the Northern hemisphere during the entire Quaternary period. Together with the large samples from Atapuerca Sima de los Huesos, Spain, and Caune de l'Arago at Tautavel, France, the remains from Fontana Ranuccio and Visogliano are among the few mid-Middle Pleistocene dental assemblages from Western Europe available for investigating the presence of an early Neanderthal signature in their inner structure. We applied two- three-dimensional techniques of virtual imaging and geometric morphometrics to the high-resolution X-ray microtomography record of the dental remains from these two Italian sites and compared the results to the evidence from a selected number of Pleistocene and extant human specimens/samples from Europe and North Africa. Depending on their preservation quality and on the degree of occlusal wear, we comparatively assessed: (i) the crown enamel and radicular dentine thickness topographic variation of a uniquely represented lower incisor; (ii) the lateral crown tissue proportions of premolars and molars; (iii) the enamel-dentine junction, and (iv) the pulp cavity morphology of all available specimens. Our analyses reveal in both samples a Neanderthal-like inner structural signal, for some aspects also resembling the condition shown by the contemporary assemblage from Atapuerca SH, and clearly distinct from the recent human figures. This study provides additional evidence indicating that an overall Neanderthal morphological dental template was preconfigured in Western Europe at least 430 to 450 ka ago.


Value of Apparent Diffusion Coefficient Values in Differentiating Malignant and Benign Breast Lesions.
Magnetic resonance imaging (MRI) has become a diagnostic and problem solving method for the breast examinations in addition to conventional breast examination methods. Diffusion-weighted imaging (DWI) adds valuable information to conventional MRI. Our aim was to show the impact of apparent diffusion coefficient (ADC) values acquired with DWI to differentiate benign and malignant breast lesions. Diagnostic accuracy study. Forty-six women with 58 breast masses (35 malignant, 23 benign) were examined on a 1.5 T clinical MRI scanner. The morphologic characteristics of the lesions on conventional MRI sequences and contrast uptake pattern were assessed. ADC values of both lesions and normal breast parenchyma were measured. The ADC values obtained were statistically compared with the histopathologic results using Paired Samples t-Test. Multiple lesions were detected in 12 (26%) of the patients, while only one lesion was detected in 34 (74%). Overall, 35 lesions out of 58 were histopathologically proven to be malignant. In the dynamic contrast-enhanced series, 5 of the malignant lesions were type 1, while 8 benign lesions revealed either type 2 or 3 time signal intensity curves (85% sensitivity, 56% spesifity). Mean ADC values were significantly different in malignant vs. benign lesions. (1.04±0.29×10(-3) cm(2)/sec vs. 1.61±0.50×10(-3) cm(2)/sec for the malignant and benign lesions, respectively, p=0.03). A cut-off value of 1.30×10(-3) mm(2)/sec for ADC detected with receiver operating characteristic analysis yielded 89.1% sensitivity and 100% specificity for the differentiation between benign and malignant lesions. ADC values improve the diagnostic accuracy of solid breast lesions when evaluated with the conventional MRI sequences. Therefore, DWI should be incorporated to routine breast MRI protocol.


Molecular cloning of an apolipoprotein B messenger RNA editing protein.
Mammalian apolipoprotein B (apo B) exists in two forms, each the product of a single gene. The shorter form, apo B48, arises by posttranscriptional RNA editing whereby cytidine deamination produces a UAA termination codon. A full-length complementary DNA clone encoding an apo B messenger RNA editing protein (REPR) was isolated from rat small intestine. The 229-residue protein contains consensus phosphorylation sites and leucine zipper domains. HepG2 cell extracts acquire editing activity when mixed with REPR from oocyte extracts. REPR is essential for apo B messenger RNA editing, and the isolation and characterization of REPR may lead to the identification of other eukaryotic RNA editing proteins.


Spectroscopic method for measuring refractive index.
A method for routine, but precise measurements of refractive index is described. The method is fast and accurate. It is based on the analysis of interference fringes, and uses positions of the fringe maxima and/or minima and a precise measurement of sample thickness to extract refractive index. An extremely dense dataset of refractive index values over the entire spectral range of interest can be routinely obtained.


Gene expression profile of glioblastoma peritumoral tissue: an ex vivo study.
The gene expression pattern of glioblastoma (GBM) is well documented but the expression profile of brain adjacent to tumor is not yet analysed. This may help to understand the oncogenic pathway of GBM development. We have established the genome-wide expression profiles of samples isolated from GBM tumor mass, white matter adjacent to tumor (apparently free of tumor cells), and white matter controls by using the Affymetrix HG-U133 arrays. Array-CGH (aCGH) was also performed to detect genomic alterations. Among genes dysregulated in peritumoral white matter, 15 were over-expressed, while 42 were down-regulated when compared to white matter controls. A similar expression profile was detected in GBM cells. Growth, proliferation and cell motility/adhesion-associated genes were up-regulated while genes involved in neurogenesis were down-regulated. Furthermore, several tumor suppressor genes along with the KLRC1 (a member of natural killer receptor) were also down-regulated in the peritumoral brain tissue. Several mosaic genomic lesions were detected by aCGH, mostly in tumor samples and several GBM-associated mosaic genomic lesions were also present in the peritumoral brain tissue, with a similar mosaicism pattern. Our data could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumour tissue. Alternatively, these findings could be substained by a relevant amount of "apparently normal" cells presenting a gene profile compatible with a precancerous state or even "quiescent" cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and from an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.


Plasma membrane Ca(2+) -ATPase associates with CLP36, alpha-actinin and actin in human platelets.
The plasma membrane Ca(2+)-ATPase (PMCA) plays an essential role in maintaining low cytosolic Ca(2+) in resting platelets. Earlier studies demonstrated that the 4b isoform of PMCA interacts via its C-terminal end with the PDZ domains of membrane-associated guanylate kinase proteins. Activation of saponin-permeabilized platelets in the presence of a peptide composed of the last ten residues of the PMCA4b C-terminus leads to a significant decrease of PMCA associated with the cytoskeleton, suggesting that PDZ domain interactions play a role in tethering the pump to the cytoskeleton. Here we present experiments conducted to evaluate the mechanism of this association. Co-immunoprecipitation assays coupled with liquid chromatography/tandem mass spectrometry analysis and immunoblotting were used to identify proteins that interact with PMCA in the resting platelet. Our results indicate that the only PDZ domain-containing protein associated with PMCA is the LIM family protein, CLP36. Glutathione-S-transferase pull-down from a platelet extract using a fusion protein containing the C-terminal PDZ domain binding motif of PMCA confirmed binding of CLP36 to PMCA. Gel filtration chromatography of detergent-solubilized platelets demonstrated the existence of a 1,000-kDa complex containing PMCA and CLP36, and in addition, alpha-actinin and actin. Immunoflourescence microscopy confirmed the co-localization of PMCA with CLP36 in resting and activated platelets. Taken together these results suggest that PMCA is localized in non-filamentous actin complexes in resting platelets by means of PDZ domain interactions and then associates with the actin cytoskeleton during cytoskeletal rearrangement upon platelet activation. Thus, in addition to the reversible serine/threonine and tyrosine phosphorylation events previously described in human platelets, PMCA function may be regulated by interactions with anchoring and cytoskeletal proteins.


Transcriptome analysis reveals candidate genes involved in splay leg syndrome in piglets.
Splay leg is frequently observed in newborn piglets and leads to economic loss as well as welfare concerns. However, the etiology and pathogenesis of splay leg syndrome in piglets are still poorly understood. The aims of this paper were to characterize changes in the transcriptome of splay leg piglets and identify candidate genes responsible for this disease. We chose three splay leg piglets and their healthy full sibs, and constructed six RNA libraries using skeletal muscle samples from both groups and identified the differentially expressed genes between the two groups using RNA-seq. A total of 555 differentially expressed genes were identified, of which 216 were up-regulated and 339 genes were down-regulated in the splay leg group relative to the healthy group. In addition, 321 significantly enriched GO terms and 12 significantly enriched KEGG pathways were identified. FBXO32 is one of the ten most differentially expressed genes in our experiment, and it is regulated by the significantly enriched pathway (PI3K-Akt). The overexpression of FBXO32 which leads to the process of muscle atrophy might be responsible for congenital splay leg in piglets. The result of this study could help improve understanding of the molecular mechanism of congenital splay leg syndrome.


Cognitive Behavioral Therapy and Acceptance and Commitment Therapy for the Discontinuation of Long-Term Benzodiazepine Use in Insomnia and Anxiety Disorders.
Benzodiazepines have proven to be highly effective for treating insomnia and anxiety. Although considered safe when taken for a short period of time, a major risk-benefit dilemma arises in the context of long-term use, relating to addiction, withdrawal symptoms, and potential side effects. For these reasons, benzodiazepines are not recommended for treating chronic sleep disorders, anxiety disorders, nor for people over the age of 65, and withdrawal among long-term users is a public health issue. Indeed, only 5% of patients manage to discontinue using these drugs on their own. Even with the help of a general practitioner, this rate does not exceed 25 to 30% of patients, of which approximately 7% manage to remain drug-free in the long term. Cognitive Behavioral Therapies (CBT) offer a crucial solution to this problem, having been shown to increase abstinence success to 70-80%. This article examines traditional and novel CBT techniques in this regard, such as Acceptance and Commitment Therapy, which address both the underlying condition (insomnia/anxiety) and the substance-related disorder. The theoretical framework and evidence supporting the use of these approaches are reviewed. Finally, current research gaps are discussed, and key research perspectives are proposed.


The structure of a chondroitin sulfate-binding domain important in placental malaria.
Adhesive PfEMP1 proteins are displayed on the surface of malaria-infected red blood cells. They play a critical role in the disease, tethering infected cells away from destruction by the spleen and causing many severe symptoms. A molecular understanding of how these domains maintain their binding properties while evading immune detection will be important in developing therapeutics. In malaria of pregnancy, domains from the var2csa-encoded PfEMP1 protein interact with chondroitin sulfate on the placenta surface. This causes accumulation of infected red blood cells, leading to placental inflammation and block of blood flow to the developing fetus. This is associated with maternal anemia, low birth weight, and premature delivery and can lead to the death of mother and child. Here I present the structure of the chondroitin sulfate-binding DBL3X domain from a var2csa-encoded PfEMP1 protein. The domain adopts a fold similar to malarial invasion proteins, with extensive loop insertions. One loop is flexible in the unliganded structure but observed in the presence of sulfate or disaccharide, where it completes a sulfate-binding site. This loop, and others surrounding this putative carbohydrate-binding site, are flexible and polymorphic, perhaps protecting the binding site from immune detection. This suggests a model for how the domain maintains ligand binding while evading the immune response and will guide future drug and vaccine development.


A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease.
Recent clinical studies of Crohn's disease patients demonstrated dramatic clinical responses following one i.v. infusion of a chimeric mAb to TNF-alpha (cA2). To assess the role of TNF-alpha in mucosal cytokine regulation, the effects of TNF-alpha on lamina propria mononuclear cell (LPMC) Th1 production were determined. Increased IFN-gamma production was demonstrated in anti-CD2-stimulated LPMC cultured in TNF-alpha. To determine the effects of cA2 on cytokine production, TNF-alpha- and IFN-gamma-producing cells were quantitated in LPMC from five Crohn's disease patients treated with cA2. In all four patients who demonstrated clinical and endoscopic improvement, decreased numbers of LPMC producing IFN-gamma and TNF-alpha following CD2/CD28 activation paralleled improvement in disease activity over 8 wk. In one patient who did not improve, increased numbers of TNF-alpha- and IFN-gamma-secreting LPMC were observed. In three of four responding patients, CD2/CD28-activated PBMC demonstrated increased IFN-gamma production over 8 wk. These observations suggest that TNF-alpha may be a cofactor for mucosal Th1 responses, and improvement in clinical parameters and intestinal inflammation induced by cA2 in Crohn's disease may be mediated by down-regulation of mucosal Th1 cytokines.


A method to extract fishers' knowledge (FK) to generate evidence for sustainable management of fishing gears.
The dangerous effects of Abandoned, Lost or Discarded Fishing Gears (ALDFG) is documented in the literature. However, there exists an overall lack of understanding in quantifying the pollution loads of fishing gears (FG) in territorial waters or on the beaches. The lack of data on FG life cycle results in mismanagement of one of the troublesome resources across the globe. In the remote and data-less situations, local stakeholders' knowledge remains the only source of information. Therefore, in this article, we propose: •A methodology to extract fishers' knowledge (FK) for generating evidence on FG handling and management practices in Norway.•The stepwise approach includes mapping of relevant stakeholders, drafting and finalizing a structured questionnaire using the Delphi method among experts to build the consensus and finally, statistically analyzing the recorded responses from the fishers.•The questions are designed to extract both qualitative and quantitative information on purchase, repair, gear loss and disposal rates of commercial FGs. The responses from 114 Norwegian fishers are recorded, analyzed and presented as a part of method validation. The evidence from the survey is then used as an input to coin the regional FG handling and management strategies in Norway. The presented method is proven a robust strategy to retrieve scientific information from the local stakeholders' and can easily be replicated elsewhere to build global evidence around the ALDFG problematic.


Early events in the thymus affect the balance of effector and regulatory T cells.
In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3, a transcription factor required for a major subset of regulatory T (Tr) cells. Thus, many studies have focused on the developmental origin of Tr cells, with the prevailing view that they emerge in the thymus from late-stage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands. This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse gammabeta T cells into potent cytolytic and interferon-gamma-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4+CD8+ T-cell progenitors to influence in trans early gammabeta cell progenitors. Unexpectedly, we found that the propensity of early TCR-alphabeta+ progenitors to differentiate into Foxp3+ Tr cells is also regulated in trans by CD4+CD8+ T-cell progenitor cells, before agonist selection.


Biodiversity and health: Lessons and recommendations from an interdisciplinary conference to advise Southeast Asian research, society and policy.
Southeast Asia is an economic, biodiverse, cultural and disease hotspot. Due to rapid socio-economic and environmental changes, the role of biodiversity and ecosystems for human health ought to be examined and communicated to decision-makers and the public. We therefore summarized the lessons and recommendations from an interdisciplinary conference convened in Cambodia in 2014 to advise Southeast Asian societies on current research efforts, future research needs, and to provide suggestions for improved education, training and science-policy interactions. First, we reviewed several examples of the important role of ecosystems as 'sentinels' in the sense that potentially harmful developments for human health become first apparent in ecosystem components. Other ecosystem services which also benefit human well-being are briefly summarized. Second, we summarized the recommendations of the conference's roundtable discussions and added recent developments in the science-policy interface. The recommendations were organized along five themes: Ethical and legal considerations; implementation of the One Health approach; education, training, and capacity building; future research priorities; and potential science-policy interactions. While the role of biodiversity for human health needs further research, especially for zoonoses and emerging diseases, many direct and indirect benefits to human health are already apparent, but have yet to filter down to the science-policy interface in order to influence legislation and enforcement. Therefore, efforts to strengthen the interface in Southeast Asia should become a high priority in order to strengthen the health and resilience of Southeast Asian societies.


The influence of hospice use on nursing home and hospital use in assisted living among dual-eligible enrollees.
This study examined the impact of hospice enrollment on the probabilities of hospital and nursing home admissions among a sample of frail dual-eligible assisted living (AL) residents. The study used a retrospective cohort design. We estimated bivariate probit models with 2 binary outcome variables: any hospital admissions and any nursing home admissions after assisted living enrollment. A total of 328 licensed AL communities accepting Medicaid waivers in Florida. We identified all newly admitted dual-eligible AL residents in Florida between January and June of 2003 who had complete state assessment data (n = 658) and followed them for 6 to 12 months. Using the Andersen behavioral model, predisposing (age, gender, race), enabling (marital status, available caregiver, hospice use), and need (ADL/IADL, comorbidity conditions, and incontinence) characteristics were included as predictors of 2 binary outcomes (hospital and nursing home admission). Demographics, functional status, and caregiver availability were obtained from the state client assessment database. Data on diagnosis and hospital, nursing home, and hospice use were obtained from Medicare and Medicaid claims. Death dates were obtained from the state vital statistics death certificate data. The mean age of the study sample was 81.5 years. Three-fourths were female and 63% were White. The average resident had a combined ADL/IADL dependency score of 11.49. Fifty-eight percent of the sample had dementia. During the average 8.9-month follow-up period, 6.8% were enrolled in hospice and 10.2% died. Approximately 33% of the sample had been admitted into a hospital and 20% had been admitted into a nursing home. Bivariate probit models simultaneously predicting the likelihood of hospital and nursing home admissions showed that hospice enrollment was associated with lower likelihood of hospital (OR = 0.24, P < .01) and nursing home admissions (OR = 0.56, P < .05). Significant predictors of hospital admissions included higher Charlson Comorbidity Index score and incontinence. Predictors of nursing home admissions included higher Charlson Comorbidity Index score, the absence of available informal caregiver, and incontinence. Hospice enrollment was associated with a lower likelihood of hospital and nursing home admissions, and, thus, may have allowed AL residents in need of palliative care to remain in the AL community. AL providers should support and facilitate hospice care among older frail dual-eligible AL residents. More research is needed to examine the impact of hospice care on resident quality of life and total health care expenditures among AL residents.


Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.


Universal precautions are not universally followed.
Adherence to universal blood and body fluid precautions was studied in surgical patient care areas of a university hospital in an effort to identify potentially hazardous health care personnel practices. Surgical teams of an 18-unit operating room, three surgical ward patient care teams, and patient care personnel in a 16-bed surgical intensive care unit were observed during routine patient care activities before (study 1) and after (study 2) specific educational programs were held to improve universal precaution compliance. Overall, infractions occurred in 57% of 549 observed procedures in study 1 and in 58% of 616 observed procedures in study 2. In study 1, infractions occurred in 75% of operating room procedures, 30% of surgical ward procedures, and 75% of surgical intensive care unit procedures. Study 2 procedure infraction rates were 81%, 32%, and 40%, respectively. Only surgical intensive care unit compliance significantly improved. Noncompliance with universal precautions occurs frequently during the care of patients who have undergone surgery, with the type of infraction and specific offender varying according to patient locale. These violations appear unamenable to one-time educational efforts. Substantial overall improvement may arise from ongoing educational programs directed at specific personnel who care for patients who have undergone surgery.


RNA virus population diversity, an optimum for maximal fitness and virulence.
The ability of an RNA virus to exist as a population of genetically distinct variants permits the virus to overcome events during infections that would otherwise limit virus multiplication or drive the population to extinction. Viral genetic diversity is created by the ribonucleotide misincorporation frequency of the viral RNA-dependent RNA polymerase (RdRp). We have identified a poliovirus (PV) RdRp derivative (H273R) possessing a mutator phenotype. GMP misincorporation efficiency for H273R RdRp in vitro was increased by 2-3-fold that manifested in a 2-3-fold increase in the diversity of the H273R PV population in cells. Circular sequencing analysis indicated that some mutations were RdRp-independent. Consistent with the population genetics theory, H273R PV was driven to extinction more easily than WT in cell culture. Furthermore, we observed a substantial reduction in H273R PV virulence, measured as the ability to cause paralysis in the cPVR mouse model. Reduced virulence correlated with the inability of H273R PV to sustain replication in tissues/organs in which WT persists. Despite the attenuated phenotype, H273R PV was capable of replicating in mice to levels sufficient to induce a protective immune response, even when the infecting dose used was insufficient to elicit any visual signs of infection. We conclude that optimal RdRp fidelity is a virulence determinant that can be targeted for viral attenuation or antiviral therapies, and we suggest that the RdRp may not be the only source of mutations in a RNA virus genome.


Enabling Posthumous Medical Data Donation: An Appeal for the Ethical Utilisation of Personal Health Data.
This article argues that personal medical data should be made available for scientific research, by enabling and encouraging individuals to donate their medical records once deceased, similar to the way in which they can already donate organs or bodies. This research is part of a project on posthumous medical data donation developed by the Digital Ethics Lab at the Oxford Internet Institute at the University of Oxford. Ten arguments are provided to support the need to foster posthumous medical data donation. Two major risks are also identified-harm to others, and lack of control over the use of data-which could follow from unregulated donation of medical data. The argument that record-based medical research should proceed without the need to secure informed consent is rejected, and instead a voluntary and participatory approach to using personal medical data should be followed. The analysis concludes by stressing the need to develop an ethical code for data donation to minimise the risks, and offers five foundational principles for ethical medical data donation suggested as a draft code.


Regional-scale scenario modeling for coral reefs: a decision support tool to inform management of a complex system.
The worldwide decline of coral reefs threatens the livelihoods of coastal communities and puts at risk valuable ecosystem services provided by reefs. There is a pressing need for robust predictions of potential futures of coral reef and associated human systems under alternative management scenarios. Understanding and predicting the dynamics of coral reef systems at regional scales of tens to hundreds of kilometers is imperative, because reef systems are connected by physical and socioeconomic processes across regions and often across international boundaries. We present a spatially explicit regional-scale model of ecological dynamics for a general coral reef system. In designing our model as a tool for decision support, we gave precedence to portability and accessibility; the model can be parameterized for dissimilar coral reef systems in different parts of the world, and the model components and outputs are understandable for nonexperts. The model simulates local-scale dynamics, which are coupled across regions through larval connectivity between reefs. We validate our model using an instantiation for the Meso-American Reef system. The model realistically captures local and regional ecological dynamics and responds to external forcings in the form of harvesting, pollution, and physical damage (e.g., hurricanes, coral bleaching) to produce trajectories that largely fall within limits observed in the real system. Moreover, the model demonstrates behaviors that have relevance for management considerations. In particular, differences in larval supply between reef localities drive spatial variability in modeled reef community structure. Reef tracts for which recruitment is low are more vulnerable to natural disturbance and synergistic effects of anthropogenic stressors. Our approach provides a framework for projecting the likelihood of different reef futures at local to regional scales, with important applications for the management of complex coral reef systems.


RNA polymerase II binding patterns reveal genomic regions involved in microRNA gene regulation.
MicroRNAs are small non-coding RNAs involved in post-transcriptional regulation of gene expression. Due to the poor annotation of primary microRNA (pri-microRNA) transcripts, the precise location of promoter regions driving expression of many microRNA genes is enigmatic. This deficiency hinders our understanding of microRNA-mediated regulatory networks. In this study, we develop a computational approach to identify the promoter region and transcription start site (TSS) of pri-microRNAs actively transcribed using genome-wide RNA Polymerase II (RPol II) binding patterns derived from ChIP-seq data. Based upon the assumption that the distribution of RPol II binding patterns around the TSS of microRNA and protein coding genes are similar, we designed a statistical model to mimic RPol II binding patterns around the TSS of highly expressed, well-annotated promoter regions of protein coding genes. We used this model to systematically scan the regions upstream of all intergenic microRNAs for RPol II binding patterns similar to those of TSS from protein coding genes. We validated our findings by examining the conservation, CpG content, and activating histone marks in the identified promoter regions. We applied our model to assess changes in microRNA transcription in steroid hormone-treated breast cancer cells. The results demonstrate many microRNA genes have lost hormone-dependent regulation in tamoxifen-resistant breast cancer cells. MicroRNA promoter identification based upon RPol II binding patterns provides important temporal and spatial measurements regarding the initiation of transcription, and therefore allows comparison of transcription activities between different conditions, such as normal and disease states.


Distribution of the Beijing family genotypes of Mycobacterium tuberculosis in Taiwan.
To investigate the distribution of the Beijing family genotypes of Mycobacterium tuberculosis in Taiwan, we collected 421 M. tuberculosis complex clinical isolates at random from four geographic regions of Taiwan and analyzed them by spacer oligonucleotide typing (spoligotyping) in 2003. We found 113 resolved spoligotypes, among which we identified 28 (24.8%) clusters. One hundred eighty-seven (44.4%) isolates were Beijing family genotypes and consisted of 172 (40.9%) characteristic Beijing genotypes and 15 (3.6%) Beijing-like ones. We also found that substantially larger proportions of tuberculosis patients were infected with Beijing family genotypes in the northern (51.6%) and eastern (46.2%) regions of Taiwan, while 31.6 and 28.0% of the tuberculosis patients in the central and southern regions, respectively, were infected with these genotypes. The proportion of Beijing genotype isolates was the highest in patients below the age of 24 years (61.5%), the second highest in elderly patients over age 65 years (46.8%), and the lowest in middle-age patients between the ages of 45 and 54 years (34.0%). Geographic location and age were found by multivariate analysis to be associated with Beijing family genotypes. Antituberculosis drug resistance was found more often in Beijing family genotype strains (46.4%) than in non-Beijing family genotype strains (34.3%), with more Beijing family genotype strains being resistant to ethambutol and isoniazid. These findings suggest that M. tuberculosis Beijing family genotypes have been dominant for several decades and that they are the cause of a significant proportion of the recent transmissions of tuberculosis in Taiwan.


Recurrent and metastatic breast cancer PET, PET/CT, PET/MRI: FDG and new biomarkers.
Primary breast cancer often displays only moderately increased glucose metabolism resulting in a low sensitivity of positron emission tomography (PET) using [F-18]fluorodeoxyglucose (FDG) in detecting small breast carcinomas, locoregional micrometastases and non-enlarged tumor infiltrated lymphnodes. In contrast, distant breast cancer metastases are generally characterized by significantly increased metabolic activity compared to normal tissue. Therefore, FDG-PET provides accurate diagnostic information as a whole body imaging modality in staging of breast cancer patients. The metabolic information from FDG-PET/CT is often more sensitive than conventional imaging for the detection of distant metastases, particularly in the recurrent setting. FDG-PET is superior in detecting tumor-involved distant lymphnodes, particularly those which are normal in size, as well as in characterizing enlarged lymphnodes as positive or negative for malignancy. Of note, CT is superior in detecting small lung metastases. Although the overall sensitivity for bone scintigraphy and FDG-PET are comparable, bone scintigraphy seems to be superior in the detection of osteoblastic disease whereas FDG-PET is superior for osteolytic metastases, suggesting a complementary role for both imaging procedures. FDG-PET/MR has an evolving role in breast cancer management, for example in the detection of liver metastases and in the research setting for treatment monitoring. The utilization of PET for prediction of treatment response to primary chemotherapy is an area of active research, using FDG as well as other PET biomarkers including [F-18]Fluoroestradiol, [F-18]Fluorothymidine and integrin targeting tracer for monitoring anti-angiogenic therapy.


Brokering for the primary healthcare needs of recent immigrant families in Atlantic, Canada.
This case study describes how broker organizations supported a network of community-based services to work together to address the primary healthcare needs of recent immigrant families with young children. In parts of Canada with low levels of immigration compared with large urban centres, service providers may need to collaborate more closely with one another so that cultural competencies and resources are shared. Providers within Atlantic Canada, with its relatively small immigrant population, were faced with such a challenge. Social network analysis and qualitative inquiry were the methods used within this case study. Twenty-seven organizations and four proxy organizations representing other organization types were identified as part of the network serving a geographically bounded neighbourhood within a mid-sized urban centre in Atlantic Canada in 2009. Twenty-one of the 27 organizations participated in the network survey and 14 key informants from the service community were interviewed. Findings Broker organizations were identified as pivotal for ensuring connections among network members, for supporting immigrant family access to services through their involvement with multiple providers, and for developing cultural competence capacities in the system overall. Network cohesiveness differed depending on the type of need being addressed, as did the organizations playing the role of broker. Service providers were able to extend their reach through the co-location of services in local centres and schools attended by immigrant families and their children. The study demonstrates the value of ties across service sectors facilitated by broker organizations to ensure the delivery of comprehensive services to young immigrant families challenged by an unfamiliar system of care.


Selection of Potential Pharmacological Targets in ALS Based on Whole- Genome Expression Profiling.
Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by the gradual degeneration and death of upper and lower motor neurons. Despite continue efforts, the etiology and pathogenesis of ALS are not well understood yet. The lack of knowledge about molecular and cellular players involved in the neurodegenerative progression of ALS hinders effective therapy development. Several genomicbased studies have been conducted to identify genetic contributors to sporadic ALS (SALS) and new potential pharmacological targets, but these have resulted in short and non-overlapping lists of candidates. In the last few years, our research group has developed the largest whole-genome expression profile database of SALS human samples. We have identified several genes deregulated in the motor cortex of SALS patients and analyzed the role of these genes within deregulated pathways, providing a full molecular portrait of ALS pathogenesis. Some of deregulated genes encode for proteins that are direct or indirect targets of experimental or therapeutic drugs already applied to unrelated diseases. In this review, we focus on the potential role of candidate targets in ALS pathophysiology, highlighting their possible contribution to ALS therapy. The rational selection of the most promising drug targets and related modulatory drugs may provide a starting point for their preclinical or clinical validation and, hopefully, the development of more effective treatments for ALS patients.


Nonlinear equation of the modes in circular slab waveguides and its application.
In this paper, circularly curved inhomogeneous waveguides are transformed into straight inhomogeneous waveguides first by a conformal mapping. Then, the differential transfer matrix method is introduced and adopted to deduce the exact dispersion relation for modes. This relation itself is complex and difficult to solve, but it can be approximated by a simpler nonlinear equation in practical applications, which is close to the exact relation and quite easy to analyze. Afterward, optimized asymptotic solutions are obtained and act as initial guesses for the following Newton's iteration. Finally, very accurate solutions are achieved in the numerical experiment.


Chemical magnetoreception in birds: the radical pair mechanism.
Migratory birds travel vast distances each year, finding their way by various means, including a remarkable ability to perceive the Earth's magnetic field. Although it has been known for 40 years that birds possess a magnetic compass, avian magnetoreception is poorly understood at all levels from the primary biophysical detection events, signal transduction pathways and neurophysiology, to the processing of information in the brain. It has been proposed that the primary detector is a specialized ocular photoreceptor that plays host to magnetically sensitive photochemical reactions having radical pairs as fleeting intermediates. Here, we present a physical chemist's perspective on the "radical pair mechanism" of compass magnetoreception in birds. We outline the essential chemical requirements for detecting the direction of an Earth-strength approximately 50 microT magnetic field and comment on the likelihood that these might be satisfied in a biologically plausible receptor. Our survey concludes with a discussion of cryptochrome, the photoactive protein that has been put forward as the magnetoreceptor molecule.


Association of Antipsychotic Treatment With Risk of Unexpected Death Among Children and Youths.
Children and youths who are prescribed antipsychotic medications have multiple, potentially fatal, dose-related cardiovascular, metabolic, and other adverse events, but whether or not these medications are associated with an increased risk of death is unknown. To compare the risk of unexpected death among children and youths who are beginning treatment with antipsychotic or control medications. This retrospective cohort study was conducted from 1999 through 2014 and included Medicaid enrollees aged 5 to 24 years in Tennessee who had no diagnosis of severe somatic illness, schizophrenia or related psychoses, or Tourette syndrome or chronic tic disorder. Data analysis was performed from January 1, 2017, to August 15, 2018. Current, new antipsychotic medication use at doses higher than 50 mg (higher-dose group) or 50 mg or lower chlorpromazine equivalents (lower-dose group) as well as control medications (ie, attention-deficit/hyperactivity disorder medications, antidepressants, or mood stabilizers) (control group). Deaths during study follow-up while out of hospital or within 7 days after hospital admission, classified as either deaths due to injury or suicide or unexpected deaths. Secondary outcomes were unexpected deaths not due to overdose and death due to cardiovascular or metabolic causes. This study included 189 361 children and youths in the control group (mean [SD] age, 12.0 [5.1] years; 43.4% female), 28 377 in the lower-dose group (mean [SD] age, 11.7 [4.4] years; 32.3% female), and 30 120 in the higher-dose group (mean [SD] age, 14.5 [4.8] years; 39.2% female). The unadjusted incidence of death in the higher-dose group was 146.2 per 100 000 person-years (40 deaths per 27 354 person-years), which was significantly greater than that in the control group (54.5 per 100 000 population; 67 deaths per 123 005 person-years) (P < .001). The difference was primarily attributable to the increased incidence of unexpected deaths in the higher-dose group (21 deaths; 76.8 per 100 000 population) compared with the control group (22 deaths; 17.9 per 100 000 population). The propensity score-adjusted hazard ratios were as follows: all deaths (1.80; 95% CI, 1.06-3.07), deaths due to unintentional injury or suicide (1.03; 95% CI, 0.53-2.01), and unexpected deaths (3.51; 95% CI, 1.54-7.96). The hazard ratio was 3.50 (95% CI, 1.35-9.11) for unexpected deaths not due to overdose and 4.29 (95% CI, 1.33-13.89) for deaths due to cardiovascular or metabolic causes. Neither the unadjusted nor adjusted incidence of death in the lower-dose group differed significantly from that in the control group. The findings suggest that antipsychotic use is associated with increased risk of unexpected death and appear to reinforce recommendations for careful prescribing and monitoring of antipsychotic treatment for children and youths and to underscore the need for larger antipsychotic treatment safety studies in this population.


Helminth-induced interleukin-4 abrogates invariant natural killer T cell activation-associated clearance of bacterial infection.
Helminth infections affect 1 billion people worldwide and render these individuals susceptible to bacterial coinfection through incompletely understood mechanisms. This includes urinary tract coinfection by bacteria and Schistosoma haematobium worms, the etiologic agent of urogenital schistosomiasis. To study the mechanisms of S. haematobium-bacterial urinary tract coinfections, we combined the first tractable model of urogenital schistosomiasis with an established mouse model of bacterial urinary tract infection (UTI). A single bladder exposure to S. haematobium eggs triggers interleukin-4 (IL-4) production and makes BALB/c mice susceptible to bacterial UTI when they are otherwise resistant. Ablation of IL-4 receptor alpha (IL-4Rα) signaling restored the baseline resistance of BALB/c mice to bacterial UTI despite prior exposure to S. haematobium eggs. Interestingly, numbers of NKT cells were decreased in coexposed versus bacterially monoinfected bladders. Given that schistosome-induced, non-natural killer T (NKT) cell leukocyte infiltration may dilute NKT cell numbers in the bladders of coexposed mice without exerting a specific functional effect on these cells, we next examined NKT cell biology on a per-cell basis. Invariant NKT (iNKT) cells from coexposed mice expressed less gamma interferon (IFN-γ) per cell than did those from mice with UTI alone. Moreover, coexposure resulted in lower CD1d expression in bladder antigen-presenting cells (APC) than did bacterial UTI alone in an IL-4Rα-dependent fashion. Finally, coexposed mice were protected from prolonged bacterial infection by administration of α-galactosylceramide, an iNKT cell agonist. Our findings point to a previously unappreciated role for helminth-induced IL-4 in impairment of iNKT cell-mediated clearance of bacterial coexposure.


Glyceollin-elicited soy protein consumption induces distinct transcriptional effects as compared to standard soy protein.
Glyceollins are stress-induced compounds in soybeans with bioactive properties distinct from parent soy isoflavones. The goals of this study were to evaluate the effects of dietary glyceollin-enriched and standard soy protein isolates and identify candidate target pathways of glyceollins on transcriptional profiles within mammary gland tissue. Thirty female postmenopausal cynomolgus monkeys were randomized to diets containing one of three protein sources for 3 weeks: (1) control casein/lactalbumin (C/L), (2) standard soy protein containing 194 mg/day isoflavones (SOY), and (3) glyceollin-enriched soy protein containing 189 mg/day isoflavones + 134 mg/day glyceollins (GLY). All diets contained a physiologic dose of estradiol (E2) (1 mg/day). All doses are expressed in human equivalents scaled by caloric intake. Relative to the control C/L diet, the GLY diet resulted in greater numbers of differentially regulated genes, which showed minimal overlap with those of SOY. Effects of GLY related primarily to pathways involved in lipid and carbohydrate metabolism, including peroxisome proliferator-activated receptor (PPAR)-γ and AMP-activated protein kinase (AMPK) signaling, adipocytokine expression, triglyceride synthesis, and lipase activity. Notable genes upregulated by the GLY diet included PPAR-γ, adiponectin, leptin, lipin 1, and lipoprotein lipase. The GLY diet also resulted in lower serum total cholesterol, specifically nonhigh-density lipoprotein cholesterol, and increased serum triglycerides as compared to the C/L diet. No effects of GLY or SOY were seen on serum insulin, adipocytokines, or vascular and bone turnover markers. These preliminary findings suggest that glyceollin-enriched soy protein has divergent effects from standard soy with some specificity for adipocyte activity and nutrient metabolism.


Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide.
Members of the HCN channel family generate hyperpolarization-activated cation currents (Ih) that are directly regulated by cAMP and contribute to pacemaker activity in heart and brain. The four HCN isoforms show distinct but overlapping patterns of expression in different tissues. Here, we report that HCN1 and HCN2, isoforms coexpressed in neocortex and hippocampus that differ markedly in their biophysical properties, coassemble to generate heteromultimeric channels with novel properties. When expressed in Xenopus oocytes, HCN1 channels activate 5-10-fold more rapidly than HCN2 channels. HCN1 channels also activate at voltages that are 10-20 mV more positive than those required to activate HCN2. In cell-free patches, the steady-state activation curve of HCN1 channels shows a minimal shift in response to cAMP (+4 mV), whereas that of HCN2 channels shows a pronounced shift (+17 mV). Coexpression of HCN1 and HCN2 yields Ih currents that activate with kinetics and a voltage dependence that tend to be intermediate between those of HCN1 and HCN2 homomers, although the coexpressed channels do show a relatively large shift by cAMP (+14 mV). Neither the kinetics, steady-state voltage dependence, nor cAMP dose-response curve for the coexpressed Ih can be reproduced by the linear sum of independent populations of HCN1 and HCN2 homomers. These results are most simply explained by the formation of heteromeric channels with novel properties. The properties of these heteromeric channels closely resemble the properties of I(h) in hippocampal CA1 pyramidal neurons, cells that coexpress HCN1 and HCN2. Finally, differences in Ih channel properties recorded in cell-free patches versus intact oocytes are shown to be due, in part, to modulation of Ih by basal levels of cAMP in intact cells.


Profiling bacterial diversity and taxonomic composition on speleothem surfaces in Kartchner Caverns, AZ.
Caves are relatively accessible subterranean habitats ideal for the study of subsurface microbial dynamics and metabolisms under oligotrophic, non-photosynthetic conditions. A 454-pyrotag analysis of the V6 region of the 16S rRNA gene was used to systematically evaluate the bacterial diversity of ten cave surfaces within Kartchner Caverns, a limestone cave. Results showed an average of 1,994 operational taxonomic units (97 % cutoff) per speleothem and a broad taxonomic diversity that included 21 phyla and 12 candidate phyla. Comparative analysis of speleothems within a single room of the cave revealed three distinct bacterial taxonomic profiles dominated by either Actinobacteria, Proteobacteria, or Acidobacteria. A gradient in observed species richness along the sampling transect revealed that the communities with lower diversity corresponded to those dominated by Actinobacteria while the more diverse communities were those dominated by Proteobacteria. A 16S rRNA gene clone library from one of the Actinobacteria-dominated speleothems identified clones with 99 % identity to chemoautotrophs and previously characterized oligotrophs, providing insights into potential energy dynamics supporting these communities. The robust analysis conducted for this study demonstrated a rich bacterial diversity on speleothem surfaces. Further, it was shown that seemingly comparable speleothems supported divergent phylogenetic profiles suggesting that these communities are very sensitive to subtle variations in nutritional inputs and environmental factors typifying speleothem surfaces in Kartchner Caverns.


Dysfunctional reward circuitry in obsessive-compulsive disorder.
Obsessive-compulsive disorder (OCD) is primarily conceived as an anxiety disorder but has features resembling addictive behavior. Patients with OCD may develop dependency upon compulsive behaviors because of the rewarding effects following reduction of obsession-induced anxiety. Reward processing is critically dependent on ventral striatal-orbitofrontal circuitry and brain imaging studies in OCD have consistently shown abnormal activation within this circuitry. This is the first functional imaging study to investigate explicitly reward circuitry in OCD. Brain activity during reward anticipation and receipt was compared between 18 OCD patients and 19 healthy control subjects, using a monetary incentive delay task and functional magnetic resonance imaging. Reward processing was compared between OCD patients with predominantly contamination fear and patients with predominantly high-risk assessment. Obsessive-compulsive disorder patients showed attenuated reward anticipation activity in the nucleus accumbens compared with healthy control subjects. Reduced activity of the nucleus accumbens was more pronounced in OCD patients with contamination fear than in patients with high-risk assessment. Brain activity during reward receipt was similar between patients and control subjects. A hint toward more dysfunctional reward processing was found in treatment-resistant OCD patients who subsequently were successfully treated with deep brain stimulation of the nucleus accumbens. Obsessive-compulsive disorder patients may be less able to make beneficial choices because of altered nucleus accumbens activation when anticipating rewards. This finding supports the conceptualization of OCD as a disorder of reward processing and behavioral addiction.


Do clinical trials reflect reality? A systematic review of inclusion/exclusion criteria in trials of renal transplant immunosuppression.
Renal transplant recipients and donors are becoming increasingly more marginal, with more expanded criteria (ECD) and donation after circulatory death (DCD) donors and older recipients. Despite this, high-risk donors and recipients are often excluded from clinical trials, leading to uncertainty about the generalizability of findings. We extracted data regarding inclusion/exclusion criteria from 174 trials of immunosuppression in renal transplant recipients published over a 5-year period and compared criteria with those specified in published trial registries. Frequently reported donor exclusion criteria were age (16.1%), donor type and cold ischaemic time (22.4%). Common recipient exclusion criteria included upper age limit (38.5%), high panel reactive antibody (PRA) (42.5%) and previous transplantation (39.7%). Inclusion/exclusion criteria recorded in trial registries matched those reported in the manuscript in only 6 (7.8%) trials. Of registered trials, 51 (66.2%) trials included additional criteria in the manuscript, 51 (66.2%) were missing criteria in the manuscript specified in the protocol, and in 19 (24.7%) key criteria changed from the protocol to the manuscript. Our findings suggest many recent immunosuppression trials have restrictive inclusion criteria which may not be reflective of current renal transplant populations. Discrepancies between trial protocols and published reports raise the possibility of selection bias.


Development of role-differentiated bimanual manipulation during the infant's first year.
Role-differentiated bimanual manipulation (RDBM) is a complementary movement of both hands that requires differentiation between actions of the hands. Previous research showed that RDBM can be observed in infants as early as 7 months. However, RDBM could be considered a skill only when its frequency, duration, and use is appropriate for the type of manual task, and there is some evidence of intentionality in use. Twenty-four normally developing infants were studied longitudinally at 7, 9, 11, and 13 months to assess the frequency and duration of five clearly different types of RDBM with three "single-part" and three "two-part" toys as they emerge during development. Also, the sequences of actions that lead to RDBM were examined for evidence of "intentionality." The results show that although the each type of RDBM appears early in infancy, RDBM only begins to exhibit the characters of a skill by 13 months. Moreover, the type of toy influences not only the likelihood of eliciting role differentiation, but also the type of RDBM behavior and the organization of the sequence of actions that lead to RDBM. Some useful criteria for defining an infant sensorimotor skill are provided in discussion.


THAP11F80L cobalamin disorder-associated mutation reveals normal and pathogenic THAP11 functions in gene expression and cell proliferation.
Twelve human THAP proteins share the THAP domain, an evolutionary conserved zinc-finger DNA-binding domain. Studies of different THAP proteins have indicated roles in gene transcription, cell proliferation and development. We have analyzed this protein family, focusing on THAP7 and THAP11. We show that human THAP proteins possess differing homo- and heterodimer formation properties and interaction abilities with the transcriptional co-regulator HCF-1. HEK-293 cells lacking THAP7 were viable but proliferated more slowly. In contrast, HEK-293 cells were very sensitive to THAP11 alteration. Nevertheless, HEK-293 cells bearing a THAP11 mutation identified in a patient suffering from cobalamin disorder (THAP11F80L) were viable although proliferated more slowly. Cobalamin disorder is an inborn vitamin deficiency characterized by neurodevelopmental abnormalities, most often owing to biallelic mutations in the MMACHC gene, whose gene product MMACHC is a key enzyme in the cobalamin (vitamin B12) metabolic pathway. We show that THAP11F80L selectively affected promoter binding by THAP11, having more deleterious effects on a subset of THAP11 targets, and resulting in altered patterns of gene expression. In particular, THAP11F80L exhibited a strong effect on association with the MMACHC promoter and led to a decrease in MMACHC gene transcription, suggesting that the THAP11F80L mutation is directly responsible for the observed cobalamin disorder.


Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells.
Ovarian cancer is the most common cause of cancer related death from gynecologic tumors in the United States. The insidious nature of the disease precludes early diagnosis, therefore surgical debulking and chemotherapy are considered as standard treatment modalities for advanced stages. We investigated the effect of the LXR agonist, T0901317, on ovarian cancer cell proliferation and apoptosis as a potential therapeutic agent. T0901317 treatment resulted in a significant (P <0.001) inhibition of cell proliferation in a time- and dose-dependent manner in CaOV3, SKOV3 and A2780 cells. Western blot analysis demonstrated an induction of p21 and p27 with a concominant reduction in phospho-RB protein levels. Cell cycle analysis demonstrated a significant (P <0.001) arrest in the G1 cell cycle phase. Significant induction of Caspase-3 and BAX gene expression occurred with treatment. Induction of apoptosis was confirmed by significant (P < 0.001) elevation of caspase activity on FACS analysis, caspase-glo assay, BAX protein induction and decreased caspase 3 precursor protein expression on Western blot analysis. LXR alpha/beta knockdown experiments did not reverse the anti-proliferative and cytotoxic effects of T0901317. The LXR agonist, T0901317, significantly suppresses cell proliferation and induces programmed cell death in a dose- and time-dependent manner. Our results indicate that T0901317 induces its anti-proliferative and cytotoxic effects via an LXR-independent mechanism.


Effects of vinblastine, podophyllotoxin and nocodazole on mitotic spindles. Implications for the role of microtubule dynamics in mitosis.
Inhibition of mitosis by many drugs that bind to tubulin has been attributed to depolymerization of microtubules. However, we found previously that low concentrations of vinblastine and vincristine blocked mitosis in HeLa cells with little or no depolymerization of spindle microtubules, and spindles appeared morphologically normal or nearly normal. In the present study, we characterized the effects of vinblastine, podophyllotoxin and nocodazole over broad concentration ranges on mitotic spindle organization in HeLa cells. These three drugs are known to affect the dynamics of microtubule polymerization in vitro and to depolymerize microtubules in cells. We wanted to probe further whether mitotic inhibition by these drugs is brought about by a more subtle effect on the microtubules than net microtubule depolymerization. We compared the effects of vinblastine, podophyllotoxin and nocodazole on the organization of spindle microtubules, chromosomes and centrosomes, and on the total mass of microtubules. Spindle organization was examined by immunofluorescence microscopy, and microtubule polymer mass was assayed on isolated cytoskeletons by a quantitative enzyme-linked immunoadsorbence assay for tubulin. As the drug concentration was increased, the organization of mitotic spindles changed in the same way with all three drugs. The changes were associated with mitotic arrest, but were not necessarily accompanied by net microtubule depolymerization. With podophyllotoxin, mitotic arrest was accompanied by microtubule depolymerization. In contrast, with vinblastine and nocodazole, mitotic arrest occurred in the presence of a full complement of spindle microtubules. All three drugs induced a nearly identical rearrangement of spindle microtubules, an increasingly aberrant organization of metaphase chromosomes, and fragmentation of centrosomes. The data suggest that these anti-mitotic drugs block mitosis primarily by inhibiting the dynamics of spindle microtubules rather than by simply depolymerizing the microtubules.


Thrombocytopenia in malaria.
The relationship between platelet counts and platelet bound (direct) or platelet directed (indirect) serum antibody concentrations was studied in 17 patients with Plasmodium falciparum malaria and 12 patients with P. vivax malaria. Platelet counts rose with recovery from infection from 196 +/- 84 x 10(9)/l (mean +/- SD) and 195 +/- 34 x 10(9)/l to 319 +/- 99 and 283 +/- 62 x 10(9)/l respectively (p less than 0.002), but there was no relationship between either absolute platelet count or changes in counts and either indirect or direct platelet antibody levels. These findings suggest that a non-immunologically mediated mechanism is involved in the pathogenesis of thrombocytopenia in malaria.


The effect of body condition on postoperative recovery of dachshunds with intervertebral disc disease treated with postoperative physical rehabilitation.
To determine the impact of obesity on postoperative recovery from thoracolumbar hemilaminectomy in dachshunds treated with rehabilitation. Prospective observational trial. Thirty-two dachshunds with thoracolumbar intervertebral disk disease and pain perception. Dachshunds were entered into the study after unilateral thoracolumbar hemilaminectomy. Lean muscle and fat contents were measured with dual-energy x-ray absorptiometry (DEXA) at the beginning and at week 12 of the study. Aggressive rehabilitation was performed 1, 2, 4, and 6 weeks after surgery. Logistic regressions were used to determine the odds ratios between potential risk factors (age, duration of clinical signs, weight, body condition score, percentage body fat, percentage lean muscle mass, and disability index [DI] score at presentation) and return benchmarks of recovery. Body condition score, percentage body fat, percentage lean muscle mass, weight, and age did not influence the odds ratio for recovery. An increase in preoperative DI score was associated with increased risk of a slow postoperative recovery (P < .05). The odds ratios were 2.5, 4.8, and 1.8 for >7 days until standing, > 30 days until strong ambulation, and failure to return to normal within the study period, respectively. On average, dogs lost weight (2.2 kg) and body fat (2.4%) but gained muscle mass (3.0%) over the study period (P < .05). Preoperative disability but not body condition was a risk factor for a slow recovery after thoracolumbar hemilaminectomy in dachshunds with rehabilitation. A slower recovery is likely with increased preoperative disability, but body condition does not seem to affect the postoperative prognosis of dachshunds treated with rehabilitation.


Tissue invasion by Entamoeba histolytica: evidence of genetic selection and/or DNA reorganization events in organ tropism.
Entamoeba histolytica infection may have various clinical manifestations. Nine out of ten E. histolytica infections remain asymptomatic, while the remainder become invasive and cause disease. The most common form of invasive infection is amebic diarrhea and colitis, whereas the most common extra-intestinal disease is amebic liver abscess. The underlying reasons for the different outcomes are unclear, but a recent study has shown that the parasite genotype is a contributor. To investigate this link further we have examined the genotypes of E. histolytica in stool- and liver abscess-derived samples from the same patients. Analysis of all 18 paired samples (16 from Bangladesh, one from the United States of America, and one from Italy) revealed that the intestinal and liver abscess amebae are genetically distinct. The results suggest either that E. histolytica subpopulations in the same infection show varying organ tropism, or that a DNA reorganization event takes place prior to or during metastasis from intestine to liver.


Novel glycopolypeptide synthesis induced by gametic cell fusion in Chlamydomonas reinhardtii.
Within the first hour of zygote maturation, Chlamydomonas reinhardtii cells stop synthesizing certain polypeptides that characterize the vegetative and gametic stages of the life cycle and initiate the synthesis of novel, zygote-specific polypeptides. At least six of these polypeptides are secreted into the medium, and fine-structural studies indicate that they represent components of the cell wall that is synthesized and secreted early in zygote development. We conclude that a new program of protein synthesis, and possibly also gene transcription, is initiated shortly after gametic cells fuse, a program that appears highly suited to cell-differentiation studies.


Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor.
Transgenic mice were created with cardiac-specific overexpression of the beta 2-adrenergic receptor. This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; these parameters at baseline in the transgenic animals were equal to those observed in control animals maximally stimulated with isoproterenol. These results illustrate a useful approach for studying the effect of gene expression on cardiac contractility. Because chronic heart failure in humans is accompanied by a reduction in the number of myocardial beta-adrenergic receptors and in inotropic responsiveness, these results suggest a potential gene therapy approach to this disease state.


The prevalence and incidence of intimate partner violence in older women in primary care practices.
Identify the incidence and prevalence of intimate partner violence (IPV) in women over 55 years of age in primary care offices. Telephone survey conducted between March and June 2003 by trained female interviewers who gathered self-report information about health and abuse. A total of 3,636 women over 55 years of age had at least 1 visit in the past 12 months to primary care offices affiliated with an academic center in Southwestern Ohio were contacted by phone; 995 were deemed competent and completed the interview. INTERVENTION/INSTRUMENT: Thirty-eight page instrument that explored health, history of psychological (controlling behavior and threat of physical harm), physical, and sexual abuse since age 55 years. Interviews lasted 20 to 45 min. The mean age was 69 years (SD 8.35). Physical abuse in intimate relationships was reported by 1.52% since age 55 years (prevalence) and 0.41% in the past year (incidence). Prevalence and incidence rates for sexual abuse were 2.14% and 1.12%, threat of physical harm 2.63% and 1.62%, respectively. Less than half of the victims told someone else about the abuse. The mean number of health conditions was 3.84 for victims and 3.21 for nonvictims (P<.055) with significantly larger percentages of IPV victims reporting problems with chronic pain and depression. Physical and sexual abuse by an intimate partner does occur in women over 55 years, but rates are lower than those of younger women. Health care providers are reminded to think about IPV in older women and to ask about abuse as disclosure is rare.


Impairments in activities of daily living in older Japanese men in hawaii and Japan.
Introduction. Hypertension and cigarette smoking are dominant risk factors for cardiovascular disease in Japan while in westernized countries, broader effects encompass obesity, diabetes, and hypercholesterolemia. This paper examines whether different associations also appear important in the manifestation of activities of daily living (ADL) in older Japanese men in Hawaii and Japan. Methods. Measures of ADL (feeding, toileting, dressing, bathing, and walking around the house) were assessed from 1995 to 1999 in 1,893 men in Hawaii and 543 men in Japan. Concomitant risk factors were measured from 1990 to 1993. Results. In Hawaii, diabetes increased the odds of ≥1 ADL impairment nearly 1.5-fold (P = .020). A similar association was absent in Japan. In contrast, the odds of an ADL impairment in Japan was increased more than 5-fold in the presence of stroke (P < .001). The association in Hawaii was significantly weaker (P = .007). In both cohorts, past alcohol use was associated with a greater likelihood of ADL impairment. Conclusion. In this comparison of genetically similar samples, findings suggest that different strengths in risk factor associations with cardiovascular disease in Japan and westernized countries may also include different strengths in associations with impaired ADL.


Effect of thiophene linker addition to fluorene-benzotriazole polymers with the purpose of achieving white emission in OLEDs.
With the purpose of obtaining white emission from single layer organic light emitting diodes (OLEDs), fluorene benzotriazole based polymers with double bond subunits (namely TP2 and SP3 with and without thiophene linker, respectively) were synthesized by a Suzuki cross-coupling polymerization reaction. SP3 and TP2 were used as an emissive layer of the OLED devices due to their outstanding solubility in organic solvents, photoluminescence intensity and morphological suitability for fine thin film-forming capability. The optical, electrochemical, light emission and electroluminescence characteristics, Density Functional Theory (DFT) calculations and admittance spectroscopic analysis of OLEDs based on SP3 and TP2 were realized in detail to understand the effects of thiophene linker addition as a donor unit to the main chain of fluorene benzotriazole based polymers. As a result, TP2 emitted a bright yellow emission with a maximum brightness of 243 cd m-2 at 40 mA cm-2, and a maximum current efficiency of 1.38 cd A-1 with more broad electroluminescence characteristics than SP3 polymer without the thiophene linker. SP3 emitted a greenish yellow emission with a maximum brightness of 1001 cd m-2 at 845 mA cm-2, and a maximum current efficiency of 0.33 cd A-1. Carrier transport properties, charge carrier transit time and the equivalent circuit modelling studies were obtained through admittance spectroscopy. An equivalent circuit model with a combination of two resistors and one capacitor explained the charge conduction mechanism of SP3 and TP2 based OLEDs. SP3 and TP2 OLED devices represented typical p-type transporting characteristics with mobilities of 0.073 and 0.017 cm2 V-1 s-1, respectively with simplified device configuration. All the results indicate that thiophene addition to the main chain of fluorene benzotriazole based polymers with double bond subunits lead to a promising candidate for white emissive materials used in single layer white OLEDs.


Relating rheology and tribology of commercial dairy colloids to sensory perception.
This study aims to investigate the relationship between rheological and tribological properties of commercial full fat and fat-free/low fat versions of liquid and soft solid colloidal systems (milk, yoghurt, soft cream cheese) with their sensory properties. Oscillatory measurements (strain, frequency), flow curves and tribological measurements (lubrication behaviour using Stribeck analysis) were conducted. Oral condition was mimicked using artificial saliva at 37 ○C. Discrimination test was conducted by 63 untrained consumers, followed by a qualitative questionnaire. Consumers significantly discriminated the fat-free/low fat from the full fat versions (p < 0.01) in all product classes, with most common verbatim used being "creamy", "sweet" for the full fat versus "watery", "sour" for the fat-free samples. Flow behaviour of both versions of milk showed overlapping trends with no significant differences identified both in absence and presence of saliva (p > 0.05). Full fat and fat free yoghurts had similar yielding behaviour and elastic modulus (G'), even in simulated oral conditions. However, in case of soft cream cheese, the full fat version had a moderately higher G' than the low fat counterpart. Even in presence of artificial saliva, there was slight but significant difference in viscoelasticity between the cream cheese variants depending on fat content (p < 0.05). Stribeck curve analyses showed that at lower entrainment velocities (1-100 mm s-1), both full fat yoghurt and soft cream cheese exhibited a significantly lower traction coefficient when compared to fat-free/low fat versions (p < 0.05), which might be attributed to the lubricating effect of the coalesced fat droplets. Surprisingly, whole and skim milks showed no significant difference in traction coefficients irrespective of the entrainment speeds (p > 0.05). Results suggest that sensory distinction between fat-free and full fat versions, particularly in semi-solid systems could be better predicted by lubrication data as compared to bulk rheology.


Association between variant Y402H in age-related macular degeneration (AMD) susceptibility gene CFH and treatment response of AMD: a meta-analysis.
To investigate the association between polymorphism rs1061170 (T1277C, Y402H) in age-related macular degeneration (AMD) susceptibility gene Complement Factor H (CFH) and treatment response of neovascular AMD. We performed a literature-based meta-analysis including 10 published association studies involving 1,510 patients. Treatments included anti-VEGF (bevacizumab and ranibizumab) or photodynamic therapy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Q-statistic test was used to assess heterogeneity. Polymorphism rs1061170 showed a significant summary OR of 1.68 (95% CI, 1.09 to 2.60; P = 0.020; CC versus TT; random-effects) for treatment response of neovascular AMD with heterogeneity of 0.09. In subgroup analysis, rs1061170 was more likely to be a predictor of response to anti-VEGF therapy (P = 0.011). However, heterozygous TC genotype was not associated with altered treatment response (OR = 1.18, 95% CI, 0.95 to 1.47; P = 0.145; fixed-effects). Influence analysis indicated the robustness of our findings. rs1061170 might be associated with treatment response of neovascular AMD, especially for the anti-VEGF agents. It might be the first meta-analytically confirmed genetic marker predictive for AMD treatment response though a further validation in larger studies is needed.


Perceptions of social capital and the built environment and mental health.
There has been much speculation about a possible association between the social and built environment and health, but the empirical evidence is still elusive. The social and built environments are best seen as contextual concepts but they are usually estimated as an aggregation of individual compositional measures, such as perceptions on trust or the desirability to live in an area. If these aggregated compositional measures were valid measures, one would expect that they would evince correlations at higher levels of data collection (e.g., neighbourhood). The aims of this paper are: (1) to investigate the factor structure of a self-administered questionnaire measuring individual perceptions of trust, social participation, social cohesion, social control, and the built environment; (2) to investigate variation in these factors at higher than the individual level (households and postcodes) in order to assess if these constructs reflect some contextual effect; and (3) to study the association between mental health, as measured by the General Health Questionnaire-12 (GHQ-12), and these derived factors. A cross-sectional household survey was undertaken during May-August 2001 in a district of South Wales with a population of 140,000. We found that factor analysis grouped our questions in factors similar to the theoretical ones we had previously envisaged. We also found that approximately one-third of the variance for neighbourhood quality and 10% for social control was explained at postcode (neighbourhood) level after adjusting for individual variables, thus suggesting that some of our compositional measures capture contextual characteristics of the built and social environment. After adjusting for individual variables, trust and social cohesion, two key social capital components were the only factors to show statistically significant associations with GHQ-12 scores. However, these factors also showed little variation at postcode levels, suggesting a stronger individual determination. We conclude that our results provide some evidence in support of an association between mental health (GHQ-12 scores) and perceptions of social capital, but less support for the contextual nature of social capital.


Continuous fabrication of microcapsules with controllable metal covered nanoparticle arrays using droplet microfluidics for localized surface plasmon resonance.
The construction of ordered nanoparticle arrays is important for nanophotonics and sensing applications. We report a facile technology for continuous-flow fabrication of particle-laden plasmonic microcapsules (PLPMs) by combining droplet microfluidics, nanoparticle self-assembly and thin film deposition. The metallic hierarchical nanostructures on PLPMs are presented with high-density "hot-spot" scattering sites with the nanoarray pitch and gap distance being controlled by the deposited metal film thickness and nanoparticle size. The noble metal "hot-spots" show high, localized surface plasmon resonance according to the near-field electromagnetic field enhancement. Surface-enhanced Raman scattering (SERS) analytical enhancement factors of >107 can be obtained with good reproducibility using 4-methylbenzenethiol (4-MBT) as a probe molecule and Au or Ag as the metal layer. The droplet microfluidics platform enables continuous generation of homogeneous microcapsules with high frequency. This proposed strategy therefore combines advantages from both top-down (creation of microdroplets and deposition of the metal film) and bottom-up (self-assembly of nanoparticles) processes with flexibility in material selection (nanoparticles and polymer) and structure scaling (metal layer thickness, nanoparticle size and microcapsule size). Therefore, it provides a fast and reliable method of producing plasmonic microsensors.


International Association of Dental Traumatology guidelines for the management of traumatic dental injuries: 2. Avulsion of permanent teeth.
Avulsion of permanent teeth is one of the most serious dental injuries. Prompt and correct emergency management is essential for attaining the best outcome after this injury. The International Association of Dental Traumatology (IADT) has developed these Guidelines as a consensus statement after a comprehensive review of the dental literature and working group discussions. It represents the current best evidence and practice based on that literature search and expert opinions. Experienced researchers and clinicians from various specialties and the general dentistry community were included in the working group. In cases where the published data did not appear conclusive, recommendations were based on consensus opinions or majority decisions of the working group. They were then reviewed and approved by the members of the IADT Board of Directors. The purpose of these Guidelines is to provide clinicians with the most widely accepted and scientifically plausible approaches for the immediate or urgent care of avulsed permanent teeth. The IADT does not, and cannot, guarantee favorable outcomes from adherence to the Guidelines. However, the IADT believes that their application can maximize the probability of favorable outcomes.


Mode matching with a single thin lens.
From consideration of the physical mechanism of the matching of gaussian modes by means of a single thin lens, a straightforward method is developed for determining the position and the focal length of this lens, when the position and the size of the beam waists are given. The analytic results, although based on a quadratic equation, are unambiguous. An approximate solution is given for the case when the ratio of the beam waists approaches unity. The position of the matching lens may be determined graphically.


Social Media Use, School Connectedness, and Academic Performance Among Adolescents.
We examined the associations between social media use (SMU) and school connectedness and academic performance among middle and high school students, and tested whether age, gender, and school type (i.e., middle school vs. high school) moderated these relationships. We obtained study data from the 2013 cycle of the Ontario Student Drug Use and Health Survey, a representative province-wide cross-sectional survey of students in grades 7 through 12 (N = 10,076). We performed multiple linear regression analyses to examine the nature of the association between SMU and both school connectedness and academic performance. Because school type was a significant moderator of the relationships between social media use and school connectedness, all subsequent analyses were stratified by school type. After adjusting for age, gender, ethnicity, subjective socioeconomic status and substance use, results showed that SMU of 2 h or less per day was positively associated with high levels of school connectedness in high school students (β = 0.402; 95% CI 0.199, 0.605). However, an SMU of more than 2 h per day was negatively associated with school connectedness in middle school students (β = - 0.393; 95% CI - 0.649, - 0.137) and with academic performance in both middle school (β = - 0.153; 95% CI - 0.299, - 0.006) and high school (β = - 0.203; 95% CI - 0.323, - 0.083) students. Results further indicated that the relationship between SMU and school connectedness in high school students significantly varied by age, with stronger associations in older students. Gender was not a significant moderator of the observed relationships. In conclusion, heavy SMU is negatively associated with school connectedness and academic performance among middle and high school students. These results suggest that adolescents should limit their SMU to no more than 2 h per day.


A practical guide to basal and prandial insulin therapy.
Separating basal and meal-related insulin requirements allows a systematic approach to subcutaneous insulin therapy. Simple guidelines for both the doctor and patient can cater for the spectrum of severity of diabetes. A non-insulin-dependent diabetic who, despite dieting, continues to have moderate fasting hyperglycaemia (6-10 mmol/l) may need only a basal insulin supplement, whereas a totally insulin-dependent diabetic usually needs similar amounts of basal and meal-related insulin. The likely insulin requirements of individual diabetics can be predicted, including the increased amounts required by obese patients. The algorithms have been developed using ultralente to provide the basal insulin requirement, but the principles and doses probably apply to other similarly long-acting insulins or an insulin pump. The insulin doses can be easily altered for varying lifestyles, including night work, religious fasts or long distance aeroplane travel, and for temporary disturbances such as operations or intercurrent infections.


Contribution of elevated intracellular calcium to pulmonary arterial myocyte alkalinization during chronic hypoxia.
In the lung, exposure to chronic hypoxia (CH) causes pulmonary hypertension, a debilitating disease. Development of this condition arises from increased muscularity and contraction of pulmonary vessels, associated with increases in pulmonary arterial smooth muscle cell (PASMC) intracellular pH (pHi) and Ca(2+) concentration ([Ca(2+)]i). In this study, we explored the interaction between pHi and [Ca(2+)]i in PASMCs from rats exposed to normoxia or CH (3 weeks, 10% O2). PASMC pHi and [Ca(2+)]i were measured with fluorescent microscopy and the dyes BCECF and Fura-2. Both pHi and [Ca(2+)]i levels were elevated in PASMCs from hypoxic rats. Exposure to KCl increased [Ca(2+)]i and pHi to a similar extent in normoxic and hypoxic PASMCs. Conversely, removal of extracellular Ca(2+) or blockade of Ca(2+) entry with NiCl2 or SKF 96365 decreased [Ca(2+)]i and pHi only in hypoxic cells. Neither increasing pHi with NH4Cl nor decreasing pHi by removal of bicarbonate impacted PASMC [Ca(2+)]i. We also examined the roles of Na(+)/Ca(2+) exchange (NCX) and Na(+)/H(+) exchange (NHE) in mediating the elevated basal [Ca(2+)]i and Ca(2+)-dependent changes in PASMC pHi. Bepridil, dichlorobenzamil, and KB-R7943, which are NCX inhibitors, decreased resting [Ca(2+)]i and pHi only in hypoxic PASMCs and blocked the changes in pHi induced by altering [Ca(2+)]i. Exposure to ethyl isopropyl amiloride, an NHE inhibitor, decreased resting pHi and prevented changes in pHi due to changing [Ca(2+)]i. Our findings indicate that, during CH, the elevation in basal [Ca(2+)]i may contribute to the alkaline shift in pHi in PASMCs, likely via mechanisms involving reverse-mode NCX and NHE.