Improving the provision of language services at an academic medical center: ensuring high-quality health communication for limited-English-proficient patients.
To evaluate and improve the provision of language services at an academic medicine center caring for a diverse population including many limited-English-proficient (LEP) patients. The authors performed a prospective observational study between November 2006 and December 2008 evaluating the provision of language services at the University of Michigan Health System. The primary performance measures were (1) screening patients for their preferred language for health care, (2) assessing the proportion of LEP patients receiving language services from a qualified language services provider, and (3) assessing whether there were any disparities in diabetes care for LEP patients compared with English-speaking patients. The proportion of patients screened for preferred language increased from 59% to 96% with targeted inventions, such as training staff to capture preferred language for health care and correcting prior inaccurate primary language data entry. The proportion of LEP outpatients with a qualified language services provider increased from 19% to 83% through the use of staff and contract interpreters, over-the-phone interpreting and bilingual providers. There were no systematic differences in diabetes quality performance measures between LEP and English-proficient patients. Academic medical centers should measure their provision of language services and compare quality and safety data (e.g., performance measures and adverse events) between LEP and English-speaking patients to identify disparities in care. Leadership support and ongoing training are needed to ensure language-specific services are embedded into clinical care to meet the needs of our diverse patient populations.


DC-SIGN promotes exogenous MHC-I-restricted HIV-1 antigen presentation.
Dendritic cells (DCs) facilitate HIV-1 spread in the host by capturing virions and transferring them to permissive lymphocytes in lymphoid organs. Lectins such as DC-specific ICAM-grabbing non-integrin (DC-SIGN) are involved in HIV-1 uptake by DCs, through high-affinity binding to viral envelope glycoproteins. We examined the role of DC-SIGN on the fate of incoming virions and on major histocompatibility complex class I (MHC-I)-restricted HIV-1 antigen presentation. We show that DC-SIGN expression in B-cell lines dramatically enhances viral internalization. In these cells, and also in primary DCs, most of the captured virions are rapidly degraded, likely in a lysosomal compartment. In addition, a fraction of incoming viral material is processed by the proteasome, leading to activation of anti-HIV-specific cytotoxic T lymphocytes (CTLs) by DC-SIGN-expressing cells. In DCs, DC-SIGN is not the only receptor involved, and redundant pathways of virus capture leading to antigen presentation likely coexist. Altogether, our results highlight new aspects of DC-SIGN interactions with HIV-1. The lectin does not significantly protect captured virions against degradation and promotes MHC-I exogenous presentation of HIV-1 antigens.


A prospective comparative evaluation of persistent respiratory morbidity in esophageal atresia and congenital diaphragmatic hernia survivors.
The aim of the study was to compare long-term respiratory morbidity in children after repair of esophageal atresia (EA) or congenital diaphragmatic hernia (CDH). Children were seen at 6, 12, and 24 months and 5 years within a prospective longitudinal follow-up program in a tertiary children's hospital. Respiratory morbidity and physical condition were evaluated at all moments. At age 5 years, pulmonary function and maximal exercise performance were tested. In 3 of 23 atresia patients and 10 of 20 hernia patients, bronchopulmonary dysplasia was developed. Seventeen atresia and 11 hernia patients had recurrent respiratory tract infections mainly in the first years of life. At age 5, 25% of EA and CDH patients measured showed reduced forced expiratory volume in 1 second (z-score < -2). Both atresia and hernia patients showed impaired growth, with catch-up growth at 5 years in patients with EA but not in those with hernia. Maximal exercise performance was significantly below normal for both groups. Esophageal atresia and CDH are associated with equal risk of long-term respiratory morbidity, growth impairment, and disturbed maximal exercise performance. Prospective follow-up of EA patients aimed at identifying respiratory problems other than tracheomalacia should be an integral part of interdisciplinary follow-up programs.


The sensitivity of 38 heart rate variability measures to the addition of artifact in human and artificial 24-hr cardiac recordings.
Artifact is common in cardiac RR interval data derived from 24-hr recordings and has a significant impact on heart rate variability (HRV) measures. However, the relative impact of progressively added artifact on a large group of commonly used HRV measures has not been assessed. This study compared the relative sensitivity of 38 commonly used HRV measures to artifact to determine which measures show the most change with increasing increments of artifact. A secondary aim was to ascertain whether short-term and long-term HRV measures, as groups, share similarities in their sensitivity to artifact. Up to 10% of artifact was added to 20 artificial RR (ARR) files and 20 human cardiac recordings, which had been assessed for artifact by a cardiac technician. The added artifact simulated deletion of RR intervals and insertion of individual short RR intervals. Thirty-eight HRV measures were calculated for each file. Regression analysis was used to rank the HRV measures according to their sensitivity to artifact as determined by the magnitude of slope. RMSSD, SDANN, SDNN, RR triangular index and TINN, normalized power and relative power linear measures, and most nonlinear methods examined are most robust to artifact. Short-term time domain HRV measures are more sensitive to added artifact than long-term measures. Absolute power frequency domain measures across all frequency bands are more sensitive than normalized and relative frequency domain measures. Most nonlinear HRV measures assessed were relatively robust to added artifact, with Poincare plot SD1 being most sensitive.


Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein.
Death is a vital developmental cell fate. In Caenorhabditis elegans, programmed death of the linker cell, which leads gonadal elongation, proceeds independently of caspases and apoptotic effectors. To identify genes promoting linker-cell death, we performed a genome-wide RNA interference screen. We show that linker-cell death requires the gene pqn-41, encoding an endogenous polyglutamine-repeat protein. pqn-41 functions cell-autonomously and is expressed at the onset of linker-cell death. pqn-41 expression is controlled by the mitogen-activated protein kinase kinase SEK-1, which functions in parallel to the zinc-finger protein LIN-29 to promote cellular demise. Linker-cell death is morphologically similar to cell death associated with normal vertebrate development and polyglutamine-induced neurodegeneration. Our results may therefore provide molecular inroads to understanding nonapoptotic cell death in metazoan development and disease.


The "calcium antagonist" TMB-8 [3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester] is a potent, non-competitive, functional antagonist at diverse nicotinic acetylcholine receptor subtypes.
[3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester] (TMB-8) has seen wide use as an "intracellular Ca2+ antagonist." However, this study shows that TMB-8 acts as a noncompetitive, functional antagonist at diverse nicotinic acetylcholine receptor (nAChR) subtypes with potencies that exceed those for other reported effects of TMB-8, including inhibition of intracellular Ca2+ mobilization. TMB-8 is a potent inhibitor (IC50 approximately 400 nM) of agonist-stimulated ion flux mediated by functional human muscle nAChR or ganglionic alpha 3 beta 4-nAChR subtypes expressed by TE671/RD or SH-SY5Y cells. TMB-8 is also a potent inhibitor (IC50 approximately 500 nM) of a functional, central nervous system nAChR subtype that mediates nicotinic agonist-stimulated [3H]dopamine release from rat brain synaptosomes. TMB-8 is much less potent (IC50 approximately 30-200 microM) as an inhibitor of high-affinity 3H-labeled acetylcholine or 125I-labeled alpha-bungarotoxin binding to human muscle nAChR, ganglionic alpha 3 beta 4-nAChR, or ganglionic alpha 7-nAChR subtypes. Moreover, functional inhibition by TMB-8 of muscle-type nAChR is due to a reduction in agonist efficacy, but not potency, and is proportionately stronger with increasing agonist concentration, thereby suggesting that TMB-8 acts as a noncompetitive inhibitor. Similar effects are observed for local anesthetics such as tetracaine and procaine (functional IC50 values of approximately 5 and approximately 50 microM, respectively), although TMB-8 is the most potent of these agents. Studies with TMB-8 or BAPTA [1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid] analogues indicate that the amino group of TMB-8 is essential and that Ca2+ chelation is not required for inhibition of nAChR function.(ABSTRACT TRUNCATED AT 250 WORDS)


The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea.
Germline mutations in E-cadherin (CDH1) have been reported in families with early onset, diffuse gastric cancer. More recently, mutations in CDH1 have been described in colorectal cancer cell lines. We have investigated if germline mutations in CDH1 occur among different groups of Korean gastric and colorectal cancer patients, with and without a positive family history. We studied 131 patients and 168 normal controls (88 Korean and 80 non-Korean). Patients were divided into five groups: group I, 20 gastric cancer patients with a family history; group II, 26 colorectal cancer patients with a family history of gastric cancer (those from familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) kindred were excluded); group III, 16 HNPCC patients without identified germline mutations in hMLH1 and hMSH2; group IV, 35 gastric cancer patients without a family history; and group V, 34 colorectal cancer patients without a family history. Polymerase chain reaction, single strand conformational polymorphism analysis, direct sequencing, and genotyping for identified variants were performed. Several germline changes in CDH1 were found. In addition to previously described polymorphisms, we found three novel changes, two of which were missense changes (T340A and L599V). T340A was present in one patient in group III and one in group V. L599V was present in one patient in group II, in two in group III, and in one in group IV. T340A was not found in normal controls while L599V was present in two of 88 Korean controls. Patients with these variants may appear to have a tendency to early onset cancer with a positive family history, although differences in frequencies did not reach statistical significance. Genotyping results suggest that these variants might have a common origin, particularly T340A. We have described two new missense germline variants in CDH1 in various groups of Korean gastrointestinal cancer patients. Further work is required to assess if these variants increase the risk of gastrointestinal cancer.


Comparative Study of Teicoplanin vs Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteraemia.
Forty patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia were randomised to receive either teicoplanin or vancomycin therapy to compare the clinical efficacy and safety of these glycopeptides. Treatment was successful in 17 (85%) of 20 patients who were randomised to the teicoplanin group, with 6 cures and 11 improvements, and in 15 (75%) of 20 patients randomised to the vancomycin group, with 8 cures and 7 improvements (p = 0.69). Microbiologically, all MRSA pathogens isolated were susceptible to both glycopeptides by the disc diffusion test. The mean zone of inhibition for teicoplanin was 18 ± 2mm (range 16 to 20mm) and 20 ± 2mm (range 16 to 24mm) for vancomycin. The minimum inhibitory concentration required to inhibit the growth of 90% of organisms in culture (MIC90) for all MRSA isolates was 2.0 mg/L (range 0.5 to 4 mg/L) for teicoplanin and 2.0 mg/L (range 0.5 to 2 mg/L) for vancomycin. The microbiological eradication rate was 85% (17 of 20 isolates) for teicoplanin and 75% (15 of 20 isolates) for vancomycin. None of the failures were due to the emergence of resistant pathogens. Adverse reactions occurred in 19% of patients treated with teicoplanin and 60% of patients treated with vancomycin. There was no significant difference in the occurrence of skin rash (p = 0.60) or in elevation of aminotransferase (p = 0.18). However, nephrotoxicity was significantly greater in the vancomycin group than in the teicoplanin group (50 vs 9.5%, p < 0.05).In conclusion, the results of this study demonstrate that teicoplanin appears to be a valuable alternative to vancomycin because it is as efficacious as vancomycin, has fewer adverse reactions, and is conveniently administered.


[Mania induced by antibiotic therapy].
We report two cases of adults who developed mania after taking the antibiotic clarithromycin. Clarithromycin is a frequently used antibiotic, but it can lead to a rare but significant psychiatric complication in the form of a manic episode. Mania is commonly associated with bipolar disorder, but the causes can be pharmacological, metabolic or neurologic, particularly when it occurs in patients who themselves or whose families have no past history of psychiatric illness. New-onset mania calls for detailed clinical and laboratory testing and neuro-imaging so that somatic causes can be ruled out. It is important that the currently used medication is included in the differential diagnosis of mania. The first step in treatment is to discontinue the antibiotic therapy. The pharmacological treatment for mania caused by antibiotic therapy is largely the same as for mania in bipolar disorder; this means starting with anti-manic and anti-psychotic medication and providing a structured and calming environment. Most cases of pharmacologically induced mania are resolved if the aetiology is determined and treated. Mania that has pharmacological causes generally does not require prophylactic mood-stabilising treatment. Nevertheless, a psychiatric follow-up is advisable. If these steps are taken, the prognosis is favourable.


Physical environmental designs in residential care to improve quality of life of older people.
The demand for residential aged care is increasing due to the ageing population. Optimising the design or adapting the physical environment of residential aged care facilities has the potential to influence quality of life, mood and function. To assess the effects of changes to the physical environment, which include alternative models of residential aged care such as a 'home-like' model of care (where residents live in small living units) on quality of life, behaviour, mood and depression and function in older people living in residential aged care. CENTRAL, MEDLINE, Embase, six other databases and two trial registries were searched on 11 February 2021. Reference lists and grey literature sources were also searched. Non-randomised trials, repeated measures or interrupted time series studies and controlled before-after studies with a comparison group were included. Interventions which had modified the physical design of a care home or built a care home with an alternative model of residential aged care (including design alterations) in order to enhance the environment to promote independence and well-being were included. Studies which examined quality of life or outcomes related to quality of life were included. Two reviewers independently assessed the abstracts identified in the search and the full texts of all retrieved studies. Two reviewers independently extracted data, assessed the risk of bias in each included study and evaluated the certainty of evidence according to GRADE criteria. Where possible, data were represented in forest plots and pooled. Twenty studies were included with 77,265 participants, although one large study included the majority of participants (n = 74,449). The main comparison was home-like models of care incorporating changes to the scale of the building which limit the capacity of the living units to smaller numbers of residents and encourage the participation of residents with domestic activities and a person-centred care approach, compared to traditional designs which may include larger-scale buildings with a larger number of residents, hospital-like features such as nurses' stations, traditional hierarchical organisational structures and design which prioritises safety. Six controlled before-after studies compared the home-like model and the traditional environment (75,074 participants), but one controlled before-after study included 74,449 of the participants (estimated on weighting). It is uncertain whether home-like models improve health-related quality of life, behaviour, mood and depression, function or serious adverse effects compared to traditional designs because the certainty of the evidence is very low. The certainty of the evidence was downgraded from low-certainty to very low-certainty for all outcomes due to very serious concerns due to risk of bias, and also serious concerns due to imprecision for outcomes with more than 400 participants. One controlled before-after study examined the effect of home-like models on quality of life. The author stated "No statistically significant differences were observed between the intervention and control groups." Three studies reported on global behaviour (N = 257). One study found little or no difference in global behaviour change at six months using the Neuropsychiatric Inventory where lower scores indicate fewer behavioural symptoms (mean difference (MD) -0.04 (95% confidence interval (CI) -0.13 to 0.04, n = 164)), and two additional studies (N = 93) examined global behaviour, but these were unsuitable for determining a summary effect estimate. Two controlled before-after studies examined the effect of home-like models of care compared to traditional design on depression. After 18 months, one study (n = 242) reported an increase in the rate of depressive symptoms (rate ratio 1.15 (95% CI 1.02 to 1.29)), but the effect of home-like models of care on the probability of no depressive symptoms was uncertain (odds ratio 0.36 (95% CI 0.12 to 1.07)). One study (n = 164) reported little or no difference in depressive symptoms at six months using the Revised Memory and Behaviour Problems Checklist where lower scores indicate fewer depressive symptoms (MD 0.01 (95% CI -0.12 to 0.14)). Four controlled before-after studies examined function. One study (n = 242) reported little or no difference in function over 18 months using the Activities of Daily Living long-form scale where lower scores indicate better function (MD -0.09 (95% CI -0.46 to 0.28)), and one study (n = 164) reported better function scores at six months using the Interview for the Deterioration of Daily Living activities in Dementia where lower scores indicate better function (MD -4.37 (95% CI -7.06 to -1.69)). Two additional studies measured function but could not be included in the quantitative analysis. One study examined serious adverse effects (physical restraints), and reported a slight reduction in the important outcome of physical restraint use in a home-like model of care compared to a traditional design (MD between the home-like model of care and traditional design -0.3% (95% CI -0.5% to -0.1%), estimate weighted n = 74,449 participants at enrolment). The remaining studies examined smaller design interventions including refurbishment without changes to the scale of the building, special care units for people with dementia, group living corridors compared to a non-corridor design, lighting interventions, dining area redesign and a garden vignette. There is currently insufficient evidence on which to draw conclusions about the impact of physical environment design changes for older people living in residential aged care. Outcomes directly associated with the design of the built environment in a supported setting are difficult to isolate from other influences such as health changes of the residents, changes to care practices over time or different staff providing care across shifts. Cluster-randomised trials may be feasible for studies of refurbishment or specific design components within residential aged care. Studies which use a non-randomised design or cluster-randomised trials should consider approaches to reduce risk of bias to improve the certainty of evidence.


Thunderstorm-associated asthma: the effect on GP consultations.
Evidence shows that asthma attacks can be brought on by adverse weather conditions such as those experienced during a thunderstorm; a prime example of such an occasion being a thunderstorm episode on 24 June 1994, which resulted in a well-documented increase in medical attendances made by those suffering with asthma and respiratory disorders. However, most of these studies have concerned admissions to accident and emergency departments. The aim of this paper was to ascertain whether a similar increase in consultations was observed in the primary care setting.


Involvement of enhanced sensitivity of N-methyl-D-aspartate receptors in vulnerability of developing cortical neurons to methylmercury neurotoxicity.
The developing cortical neurons have been well documented to be extremely vulnerable to the toxic effect of methylmercury (MeHg). In the present study, a possible involvement of N-methyl-D-aspartate (NMDA) receptors in MeHg neurotoxicity was examined because the sensitivity of cortical neurons to NMDA neurotoxicity has a similar developmental profile. Rats on postnatal day 2 (P2), P16, and P60 were orally administered MeHg (10 mg/kg) for 7 consecutive days. The most severe neuronal damage was observed in the occipital cortex of P16 rats. When MK-801 (0.1 mg/kg), a non-competitive antagonist of NMDA, was administered intraperitoneally with MeHg, MeHg-induced neurodegeneration was markedly ameliorated. Furthermore, there was a marked accumulation of nitrotyrosine, a reaction product of peroxynitrite and L-tyrosine, after chronic treatment of MeHg in the occipital cortex of P16 rats. The accumulation of nitrotyrosine was also significantly suppressed by MK-801. In the present electrophysiological study, the amplitude of synaptic responses mediated by NMDA receptors recorded in cortical neurons of P16 rats was significantly larger than those from P2 and P60 rats. These observations strongly suggest that a generation of peroxynitrite through activation of NMDA receptors is a major causal factor for MeHg neurotoxicity in the developing cortical neurons. Furthermore, enhanced sensitivity of NMDA receptors may make the cortical neurons of P16 rats most susceptible to MeHg neurotoxicity.


Stability of multiple antigen receptor gene rearrangements and immunophenotype in Hodgkin's disease-derived cell line L428 and variant subline L428KSA.
The Hodgkin's disease (HD) derived cell line L428 and a phorbol ester-selected subline L428KSA, which have been independently passaged in tissue culture for several years, were studied for possible antigen receptor gene and immunophenotypic differences. Multiple but identical alterations of these genes were found, including: the deletion of one and rearrangement of the other immunoglobulin (Ig) heavy chain allele; the rearrangement of one kappa and one lambda light chain allele; and the rearrangement of one T cell receptor (TCR) beta allele. Restriction mapping of the Ig heavy chain locus indicated that rearrangement of the retained allele produced a JH-C gamma 4 fusion product by an isotype switch mechanism. The 14q+ chromosome [t(14q32;?)] present in both cell cultures derived either from translocation 5' (telomeric) to the rearranged JH allele or 3' (centromeric) to the deleted Ig heavy chain allele and did not involve detectable rearrangement of the c-myc, bcl 1, or bcl 2 oncogenes. No differences in the immunophenotype were found between the L428 and L428KSA cells: both expressed leukocyte activation antigens and some determinants associated with myelomonocytic cells but no lymphoid markers. It is postulated that these phenotypic characteristics derived from secondary genetic events/differentiative reprogramming which produced extinction of primary lymphoid characters, including terminal deoxynucleotidyl transferase (TdT) essential to generation of the Ig and TCR gene rearrangements, and expression of an incomplete set of myelomonocytic markers.


Bridging the regeneration gap: genetic insights from diverse animal models.
Significant progress has recently been made in our understanding of animal regenerative biology, spurred on by the use of a wider range of model organisms and an increasing ability to use genetic tools in traditional models of regeneration. This progress has begun to delineate differences and similarities in the regenerative capabilities and mechanisms among diverse animal species, and to address some of the key questions about the molecular and cell biology of regeneration. Our expanding knowledge in these areas not only provides insights into animal biology in general, but also has important implications for regenerative medicine and stem-cell biology.


Basal but not luminal mammary epithelial cells require PI3K/mTOR signaling for Ras-driven overgrowth.
The mammary ducts of humans and mice are comprised of two main mammary epithelial cell (MEC) subtypes: a surrounding layer of basal MECs and an inner layer of luminal MECs. Breast cancer subtypes show divergent clinical behavior that may reflect properties inherent in their MEC compartment of origin. How the response to a cancer-initiating genetic event is shaped by MEC subtype remains largely unexplored. Using the mouse mammary gland, we designed organotypic three-dimensional culture models that permit challenge of discrete MEC compartments with the same oncogenic insult. Mammary organoids were prepared from mice engineered for compartment-restricted coexpression of oncogenic H-RAS(G12V) together with a nuclear fluorescent reporter. Monitoring of H-RAS(G12V)-expressing MECs during extended live cell imaging permitted visualization of Ras-driven phenotypes via video microscopy. Challenging either basal or luminal MECs with H-RAS(G12V) drove MEC proliferation and survival, culminating in aberrant organoid overgrowth. In each compartment, Ras activation triggered modes of collective MEC migration and invasion that contrasted with physiologic modes used during growth factor-initiated branching morphogenesis. Although basal and luminal Ras activation produced similar overgrowth phenotypes, inhibitor studies revealed divergent use of Ras effector pathways. Blocking either the phosphoinositide 3-kinase or the mammalian target of rapamycin pathway completely suppressed Ras-driven invasion and overgrowth of basal MECs, but only modestly attenuated Ras-driven phenotypes in luminal MECs. We show that MEC subtype defines signaling pathway dependencies downstream of Ras. Thus, cells-of-origin may critically determine the drug sensitivity profiles of mammary neoplasia.


US and MDCT findings in a caudal blind ending bifid ureter with calculi.
Herein we present a rare ureteric duplication anomaly; blind ending bifid ureter with calculi which is asymptomatic unless complicated by infection, reflux, calculi or malignancy. The diagnosis is often missed at intravenous urography (IVU) and US because the ipsilateral ureter and kidney are grossly normal. In this case the diagnosis was established with ultrasound (US) and mainly with multidetector computerized tomography (MDCT) imaging using multiplanar reformats and 3-D reconstructions which were unique to this case. MDCT scans not only revealed the exact diagnosis and anatomic relationships but also ruled out other pathologies included in the differential diagnosis as well, such as ureter and bladder diverticula.


Psychotic disorders and comorbidity: somatic illness vs. side effect.
Schizophrenia often co-occurs with chronic medical illnesses. Beside comorbid somatic illness, somatic symptoms appear as a result of side effects of antipsychotics during treatment of psychotic disorders, which may lead to certain diagnostic problems in deciding regarding the origin of such symptoms (somatic illness vs. side effects). The aim of this article is to review literature regarding comorbidity of psychotic disorders and somatic disorders and to point at possible diagnostic problems in differentiating comorbid somatic illness from side effects of antipsychotics. Literature research included structured searches of Medline and other publications on the subject of comorbidity of psychotic disorders and somatic disorders and possible diagnostic problems in differentiating comorbid somatic illnesses from side effects of antipsychotics. Co-occurrence of schizophrenia and somatic illnesses is frequent. Genetic factors, sedentary life style, poor diet, risk behaviors and smoking are some important factors that contribute to such comorbidity. Side effects of antipsychotics may cause diagnostic problems in deciding regarding the origin of such symptoms (somatic illness vs. side effects) during treatment of psychotic disorders. Bearing in mind frequent comorbidity between of psychotic and somatic disorders, early recognition of such comorbidity is important, as well as the selection of antipsychotics. It is important to recognize psychotic symptoms in patients with somatic illnesses, as well as somatic illness in patients primarily treated because of psychotic disorder.


Assessment of dysglycemia risk in the Kitikmeot region of Nunavut: using the CANRISK tool.
The Public Health Agency of Canada adapted a Finnish diabetes screening tool (FINDRISC) to create a tool (CANRISK) tailored to Canada's multi-ethnic population. CANRISK was developed using data collected in seven Canadian provinces. In an effort to extend the applicability of CANRISK to northern territorial populations, we completed a study with the mainly Inuit population in the Kitikmeot region of Nunavut. We obtained CANRISK questionnaires, physical measures and blood samples from participants in five Nunavut communities in Kitikmeot. We used logistic regression to test model fit using the original CANRISK risk factors for dysglycemia (prediabetes and diabetes). Dysglycemia was assessed using fasting plasma glucose (FPG) alone and/or oral glucose tolerance test. We generated participants' CANRISK scores to test the functioning of this tool in the Inuit population. A total of 303 individuals participated in the study. Half were aged less than 45 years, two-thirds were female and 84% were Inuit. A total of 18% had prediabetes, and an additional 4% had undiagnosed diabetes. The odds of having dysglycemia rose exponentially with age, while the relationship with BMI was U-shaped. Compared with lab test results, using a cut-off point of 32 the CANRISK tool achieved a sensitivity of 61%, a specificity of 66%, a positive predictive value of 34% and an accuracy rate of 65%. The CANRISK tool achieved a similar accuracy in detecting dysglycemia in this mainly Inuit population as it did in a multi-ethnic sample of Canadians. We found the CANRISK tool to be adaptable to the Kitikmeot region, and more generally to Nunavut.


Viral-based nanomaterials for plasmonic and photonic materials and devices.
Over the last decade, viruses have established themselves as a powerful tool in nanotechnology. Their proteinaceous capsids benefit from biocompatibility, chemical addressability, and a variety of sizes and geometries, while their ability to encapsulate, scaffold, and self-assemble enables their use for a wide array of purposes. Moreover, the scaling up of viral-based nanotechnologies is facilitated by high capsid production yield and speed, which is particularly advantageous when compared with slower and costlier lithographic techniques. These features enable the bottom-up fabrication of photonic and plasmonic materials, which relies on the precise arrangement of photoactive material at the nanoscale to control phenomena such as electromagnetic wave propagation and energy transfer. The interdisciplinary approach required for the fabrication of such materials combines techniques from the life sciences and device engineering, thus promoting innovative research. Materials with applications spanning the fields of sensing (biological, chemical, and physical sensors), nanomedicine (cellular imaging, drug delivery, phototherapy), energy transfer and conversion (solar cells, light harvesting, photocatalysis), metamaterials (negative refraction, artificial magnetism, near-field amplification), and nanoparticle synthesis are considered with exclusive emphasis on viral capsids and protein cages. This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.


Global signatures and dynamical origins of the Little Ice Age and Medieval Climate Anomaly.
Global temperatures are known to have varied over the past 1500 years, but the spatial patterns have remained poorly defined. We used a global climate proxy network to reconstruct surface temperature patterns over this interval. The Medieval period is found to display warmth that matches or exceeds that of the past decade in some regions, but which falls well below recent levels globally. This period is marked by a tendency for La Niña-like conditions in the tropical Pacific. The coldest temperatures of the Little Ice Age are observed over the interval 1400 to 1700 C.E., with greatest cooling over the extratropical Northern Hemisphere continents. The patterns of temperature change imply dynamical responses of climate to natural radiative forcing changes involving El Niño and the North Atlantic Oscillation-Arctic Oscillation.


Dynorphin A-induced rat spinal cord injury: evidence for excitatory amino acid involvement in a pharmacological model of ischemic spinal cord injury.
Dynorphin A reduced lumbosacral blood flow, elevated cerebrospinal fluid lactic acid concentrations and caused flaccid hindlimb paralysis and striking neuropathological changes after its injection into the spinal subarachnoid space in rats. Coadministration of the vasodilator hydralazine substantially eliminated the paralytic, anaerobic metabolic and neuropathological responses to dynorphin A. In contrast, in concentrations up to 1 mM, dynorphin A did not alter the viability of cultured rat spinal cord neurons. Thus, it appears that this peptide lacks direct neurotoxic effects and that neuronal injuries in vivo result primarily from ischemia associated with dynorphin A-induced blood flow reductions. NMDA receptor antagonists significantly improved recovery from dynorphin A-induced hindlimb paralysis, and substantially eliminated neuropathological changes without attenuating the acute blood flow reductions or lactic acid elevations. Additionally, glutamate and aspartate concentrations were increased significantly in spinal cord cerebrospinal fluid samples removed during the time that peptide-induced spinal cord blood flow reductions were observed. In contrast, neither amino acid concentration was elevated in media removed after 1-hr exposure of spinal cord neuronal cell cultures to 100 microM concentrations of dynorphin A. These results indicate that the paralysis and spinal cord injuries produced in rats after spinal subarachnoid injection of dynorphin A result predominantly from spinal cord ischemia, and further identify excitatory amino acids and N-methyl-D-aspartate receptor mechanisms as important mediators in this injury model.


Incidences of Hypothyroidism Associated With Surgical Procedures for Thyroid Disorders: A Nationwide Population-Based Study.
Background and Aim: Limited information available about different types of thyroid surgeries with risk for postoperative hypothyroidism. This study aimed to investigate the risk of developing early and late-onset postoperative hypothyroidism in patients with thyroid disorders. Methods: We used a large cohort data from the Taiwan National Health Insurance Research Data Base (NHIRDB) and identified 9,693 (9, 348) patients from January 1998 to December 2010, admitted for thyroid disorder surgeries. We used the surgical procedures time as the index date. Our observational retrospective cohort study excluded the subjects diagnosed with hypoparathyroidism and hypothyroidism before any surgeries. We analyzed the data using the Cox regression model to calculate the hazard ratio. Result: Postoperative hypothyroidism associated with bilateral-total (HR, 4.27; 95% CI, 3.32-5.50), one-side total and another subtotal (HR, 3.16; 95% CI, 2.59-3.86), bilateral-subtotal (HR, 1.65; 95% CI, 1.37-1.98), and unilateral-total (HR, 1.17; 95% CI, 0.95-1.44) surgical procedures. The time intervals for thyroid disorders were 320 cases developed postoperative hypoparathyroidism in eight weeks, 480 cases the second month, and 1000 cases in the first year after surgery. Conclusion: Findings suggest that thyroidectomy was associated with transient postoperative hypothyroidism in thyroid disorder patients. The bilateral-total surgical procedure was strongly associated with temporary postoperative hypothyroidism.


From particle attachment to space-filling coral skeletons.
Reef-building corals and their aragonite (CaCO3) skeletons support entire reef ecosystems, yet their formation mechanism is poorly understood. Here we used synchrotron spectromicroscopy to observe the nanoscale mineralogy of fresh, forming skeletons from six species spanning all reef-forming coral morphologies: Branching, encrusting, massive, and table. In all species, hydrated and anhydrous amorphous calcium carbonate nanoparticles were precursors for skeletal growth, as previously observed in a single species. The amorphous precursors here were observed in tissue, between tissue and skeleton, and at growth fronts of the skeleton, within a low-density nano- or microporous layer varying in thickness from 7 to 20 µm. Brunauer-Emmett-Teller measurements, however, indicated that the mature skeletons at the microscale were space-filling, comparable to single crystals of geologic aragonite. Nanoparticles alone can never fill space completely, thus ion-by-ion filling must be invoked to fill interstitial pores. Such ion-by-ion diffusion and attachment may occur from the supersaturated calcifying fluid known to exist in corals, or from a dense liquid precursor, observed in synthetic systems but never in biogenic ones. Concomitant particle attachment and ion-by-ion filling was previously observed in synthetic calcite rhombohedra, but never in aragonite pseudohexagonal prisms, synthetic or biogenic, as observed here. Models for biomineral growth, isotope incorporation, and coral skeletons' resilience to ocean warming and acidification must take into account the dual formation mechanism, including particle attachment and ion-by-ion space filling.


New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum.
Leukoencephalopathies of unknown origin constitute a considerable problem in child neurology. The purpose of our ongoing study of the subject was to define new disease entities among them by using primarily MR imaging pattern recognition. We identified seven unrelated patients with a distinct MR imaging pattern consisting of hypomyelination and atrophy of the basal ganglia (neostriatum) and cerebellum (H-ABC). We reviewed the clinical, MR imaging, MR spectroscopic, and laboratory data. Clinically, the patients' diseases were characterized by variably disturbed early development followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacity was variably affected, but it appeared to be relatively preserved. Parents were not related, and none of their siblings were affected. No metabolic defect was found. Follow-up MR imaging demonstrated atrophy of the cerebral white matter, neostriatum, and cerebellum, which was most pronounced in the most clinically severe cases. Single-voxel proton MR spectroscopic results were normal in the parietal cortex. In the cerebral white matter, myo-inositol and creatine levels were elevated; this finding was compatible with gliosis. N-acetylaspartate and choline levels were normal, suggesting that neither axonal loss nor active demyelination occurred. Proton MR spectroscopic imaging revealed relatively decreased N-acetylaspartate levels in the frontal region. The uniform and highly characteristic MR imaging findings, in combination with the similarities in the clinical findings, provide evidence of a distinct nosologic entity. The acronym H-ABC is offered to indicate patients sharing these clinical and MR imaging features.


Open Waste Canals as Potential Sources of Antimicrobial Resistance Genes in Aerosols in Urban Kanpur, India.
Understanding the movement of antimicrobial resistance genes (ARGs) in the environment is critical to managing their spread. To assess potential ARG transport through the air via urban bioaerosols in cities with poor sanitation, we quantified ARGs and a mobile integron (MI) in ambient air over periods spanning rainy and dry seasons in Kanpur, India (n = 53), where open wastewater canals (OWCs) are prevalent. Gene targets represented major antibiotic groups-tetracyclines (tetA), fluoroquinolines (qnrB), and beta-lactams (blaTEM)-and a class 1 mobile integron (intI1). Over half of air samples located near, and up to 1 km from OWCs with fecal contamination (n = 45) in Kanpur had detectable targets above the experimentally determined limits of detection (LOD): most commonly intI1 and tetA (56% and 51% of samples, respectively), followed by blaTEM (8.9%) and qnrB (0%). ARG and MI densities in these positive air samples ranged from 6.9 × 101 to 5.2 × 103 gene copies/m3 air. Most (7/8) control samples collected 1 km away from OWCs were negative for any targets. In comparing experimental samples with control samples, we found that intI1 and tetA densities in air are significantly higher (P = 0.04 and P = 0.01, respectively, alpha = 0.05) near laboratory-confirmed fecal contaminated waters than at the control site. These data suggest increased densities of ARGs and MIs in bioaerosols in urban environments with inadequate sanitation. In such settings, aerosols may play a role in the spread of AR.


Triadin binding to the C-terminal luminal loop of the ryanodine receptor is important for skeletal muscle excitation contraction coupling.
Ca(2+) release from intracellular stores is controlled by complex interactions between multiple proteins. Triadin is a transmembrane glycoprotein of the junctional sarcoplasmic reticulum of striated muscle that interacts with both calsequestrin and the type 1 ryanodine receptor (RyR1) to communicate changes in luminal Ca(2+) to the release machinery. However, the potential impact of the triadin association with RyR1 in skeletal muscle excitation-contraction coupling remains elusive. Here we show that triadin binding to RyR1 is critically important for rapid Ca(2+) release during excitation-contraction coupling. To assess the functional impact of the triadin-RyR1 interaction, we expressed RyR1 mutants in which one or more of three negatively charged residues (D4878, D4907, and E4908) in the terminal RyR1 intraluminal loop were mutated to alanines in RyR1-null (dyspedic) myotubes. Coimmunoprecipitation revealed that triadin, but not junctin, binding to RyR1 was abolished in the triple (D4878A/D4907A/E4908A) mutant and one of the double (D4907A/E4908A) mutants, partially reduced in the D4878A/D4907A double mutant, but not affected by either individual (D4878A, D4907A, E4908A) mutations or the D4878A/E4908A double mutation. Functional studies revealed that the rate of voltage- and ligand-gated SR Ca(2+) release were reduced in proportion to the degree of interruption in triadin binding. Ryanodine binding, single channel recording, and calcium release experiments conducted on WT and triple mutant channels in the absence of triadin demonstrated that the luminal loop mutations do not directly alter RyR1 function. These findings demonstrate that junctin and triadin bind to different sites on RyR1 and that triadin plays an important role in ensuring rapid Ca(2+) release during excitation-contraction coupling in skeletal muscle.


The first case of Horn Kolb Syndrome in Turkey, diagnosed prenatally at the 23(rd) week of a pregnancy: A very rare and unusual case far from the original geography.
The aim of this report was to evaluate and announce the first documented appearance of Horn Kolb syndrome in Turkey. Acheiropodia (Horn Kolb Syndrome) is the bilateral congenital amputation of the distal parts of the 4 extremities. It is an autosomal recessive developmental disorder. The characteristic features are amputation of the upper and lower extremities with aplasia of the hands and feet. The disorder affects only the extremities without other systemic manifestations. In this report, we present the first known case of Horn Kolb syndrome in Turkey, along with the diagnostic features. Severe dysmorphic skeletal anomalies should be excluded as soon as the earlier gestational weeks in every pregnancy by visualizing all 4 limbs of the fetus in routine prenatal ultrasound screening.


IL-2 gene delivery within an established murine tumor causes its regression without proliferation of preexisting antitumor-specific CTL.
Regression of P815 tumors established on naive syngeneic mice can be obtained by the intratumoral injection of a single dose of an adenoviral vector expressing the IL-2 gene (Ad.IL2). Injection triggers local IL-2 production for at least 10 days. We measured a number of immunologic parameters in situ following intratumoral Ad.IL2 treatment. We also analyzed the situation of regression obtained upon challenge with P815 cells of mice previously immunized against the tumor and compared both systems. While IFN-gamma messenger RNA expression was found to be elevated in both situations of tumor regression, the level of infiltration by tumor-specific CTL was different. A small amount of tumor-specific CD8+ T cells were present in growing, untreated tumors. Such cells are found in much larger numbers in tumors rejected upon challenge, consistent with a CTL-mediated rejection. In contrast, they were found not to proliferate following Ad.IL2 injection. The latter caused an increased infiltration of a polyclonal, presumably nonspecific, T cell population. These results suggest that the initial regression of established P815 tumors following Ad.IL2 treatment in vivo is mostly due to nonspecific effectors.


Universal behaviour of gel formation from acrylamide-carrageenan mixture around the gel point: a fluorescence study.
The steady state fluorescence (SSF) technique was used to study the sol-gel transition, for the solution free radical crosslinking copolymerization of acrylamide (AAm) with various carrageenan content. N, N'- methylenebis (acrylamide) (BIS) and ammonium persulfate (APS) are used as crosslinker and an initiator, respectively. Pyranine (8-hydroxypyrene-1, 3,6-trisulfonic acid, trisodium salt, HPTS) was added as a floroprobe for monitoring the polymerization. Pyranine molecules start to bind to acrylamide polymer chains upon the initiation of the polymerization; thus, the spectra of the bonded pyranines shift to the shorter wavelengths. Fluorescence spectra from the bonded pyranines allows one to monitor the sol-gel transition, without disturbing the system mechanically, and to test the universality of the sol-gel transition as a function of some kinetic parameters like polymer concentration. Observations around the critical point show that the gel fraction exponent beta obeyed the percolation result for low carrageenan concentrations (< 2.0%) however classical results were produced at higher carrageenan concentration (> 2.0%).


The Effect of Chemerin on Cardiac Parameters and Gene Expressions in Isolated Perfused Rat Heart
Chemerin is a novel chemoattractant adipokine expressed in cardiovascular system, and its receptor has been detected in the epicardial adipose tissue. To determine the effects of chemerin on the cardiac parameters and gene expressions in the isolated perfused rat heart. Animal experiment. The hearts were retrogradely perfused with Langendorff technique to measure the cardiac parameters. The experimental groups were acutely treated with 10, 100, and 1000 nM doses of chemerin. Another group was given 10 μM L-nitric oxide synthase inhibitor for 5 min before 1000 nM chemerin administration. The real-time polymerase chain reaction was performed for detecting the expression of target genes. All doses of chemerin significantly decreased the left ventricular developed pressure (max 35.33 Δ%, p<0.001), and +dP/dtmax (max 31.3 Δ%, p<0.001), which are the indexes of cardiac contractile force. In addition, 1000 nM chemerin reduced the coronary flow (max 31 Δ%, p<0.001). N(W)-nitro-L-arginine methyl ester antagonized the negative inotropic effect of chemerin on contractility. Chemerin induced a 2.16-fold increase in endothelial nitric oxide synthase mRNA and increased the cyclic guanosine monophosphate levels (p<0.001) but decreased the PI3Kγ gene expression (1.8-fold, p<0.001). Furthermore, all doses of chemerin decreased the CaV1.2 gene expression (1.69-fold, p<0.001). Acute chemerin treatment induces a negative inotropic action with the involvement of nitric oxide pathway, CaV1.2, and PI3Kγ on isolated rat heart.


FAST Conformational Searches by Balancing Exploration/Exploitation Trade-Offs.
Molecular dynamics simulations are a powerful means of understanding conformational changes. However, it is still difficult to simulate biologically relevant time scales without the use of specialized supercomputers. Here, we introduce a goal-oriented sampling method, called fluctuation amplification of specific traits (FAST), for extending the capabilities of commodity hardware. This algorithm rapidly searches conformational space for structures with desired properties by balancing trade-offs between focused searches around promising solutions (exploitation) and trying novel solutions (exploration). FAST was inspired by the hypothesis that many physical properties have an overall gradient in conformational space, akin to the energetic gradients that are known to guide proteins to their folded states. For example, we expect that transitioning from a conformation with a small solvent-accessible surface area to one with a large surface area will require passing through a series of conformations with steadily increasing surface areas. We demonstrate that such gradients are common through retrospective analysis of existing Markov state models (MSMs). Then we design the FAST algorithm to exploit these gradients to find structures with desired properties by (1) recognizing and amplifying structural fluctuations along gradients that optimize a selected physical property whenever possible, (2) overcoming barriers that interrupt these overall gradients, and (3) rerouting to discover alternative paths when faced with insurmountable barriers. To test FAST, we compare its performance to other methods for three common types of problems: (1) identifying unexpected binding pockets, (2) discovering the preferred paths between specific structures, and (3) folding proteins. Our conservative estimate is that FAST outperforms conventional simulations and an adaptive sampling algorithm by at least an order of magnitude. Furthermore, FAST yields both the proper thermodynamics and kinetics, allowing for a direct connection with kinetic experiments that is impossible with many other advanced sampling algorithms because they provide only thermodynamic information. Therefore, we expect FAST to be of great utility for a wide range of applications.


Chrono-nutrition: From molecular and neuronal mechanisms to human epidemiology and timed feeding patterns.
The circadian timing system governs daily biological rhythms, synchronising physiology and behaviour to the temporal world. External time cues, including the light-dark cycle and timing of food intake, provide daily signals for entrainment of the central, master circadian clock in the hypothalamic suprachiasmatic nuclei (SCN), and of metabolic rhythms in peripheral tissues, respectively. Chrono-nutrition is an emerging field building on the relationship between temporal eating patterns, circadian rhythms, and metabolic health. Evidence from both animal and human research demonstrates adverse metabolic consequences of circadian disruption. Conversely, a growing body of evidence indicates that aligning food intake to periods of the day when circadian rhythms in metabolic processes are optimised for nutrition may be effective for improving metabolic health. Circadian rhythms in glucose and lipid homeostasis, insulin responsiveness and sensitivity, energy expenditure, and postprandial metabolism, may favour eating patterns characterised by earlier temporal distribution of energy. This review details the molecular basis for metabolic clocks, the regulation of feeding behaviour, and the evidence for meal timing as an entraining signal for the circadian system in animal models. The epidemiology of temporal eating patterns in humans is examined, together with evidence from human intervention studies investigating the metabolic effects of morning compared to evening energy intake, and emerging chrono-nutrition interventions such as time-restricted feeding. Chrono-nutrition may have therapeutic application for individuals with and at-risk of metabolic disease and convey health benefits within the general population.


Distribution of influenza vaccine to high-risk groups.
Vaccine distribution programs have historically targeted individuals at high risk of complications due to influenza. Despite recommendations from the Advisory Committee on Immunization Practices, vaccination coverage among high-risk populations has been generally low. This review systematically summarizes the recent literature evaluating programs in different settings, from within medical settings to venue-based and community-based approaches, in an effort to identify successful program components. The published literature was identified by using the MEDLINE database from 1990 to 2006 covering studies that reported on interventions or programs aimed at vaccinating high-risk populations. The authors reviewed 56 studies. In the United States, the Healthy People 2010 goals included 90% vaccination coverage for adults aged > or = 65 years and 60% for high-risk adults aged 18-64 years. Only a handful of the studies reviewed managed to meet those goals. Interventions that increased vaccination coverage to Healthy People 2010 goals included advertising, provider and patient mailings, registry-based telephone calls, patient and staff education, standing orders coupled with standardized forms, targeting of syringe exchange customers, and visiting nurses. Few studies evaluated the impact of vaccination programs by race/ethnicity and socioeconomic status. Few studies targeted individuals outside of the health-care and social services sectors. Given the growing disparities in health and health-care access, understanding the way in which interventions can remedy disparities is crucial.


Dopamine blocks stress-mediated ovarian carcinoma growth.
Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth. Expression of dopamine receptors (DR1-DR5) was analyzed by reverse transcriptase-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis, and migration were examined. For in vivo therapy, murine and human DR2-siRNAs were incorporated into chitosan nanoparticles (CH-NP). In this model of chronic stress, tumoral norepinephrine levels remained elevated whereas dopamine levels were significantly decreased compared with nonstressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density as well as the stimulatory effect on apoptosis, as the DR2 antagonist eticlopride reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cyclic AMP levels and inhibited norepinephrine and vascular permeability factor/VEGF-induced Src kinase activation. Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement.


Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review.
Neonatal interventions are largely focused on reduction of mortality and progression towards Millennium Development Goal 4 (child survival). However, little is known about the global burden of long-term consequences of intrauterine and neonatal insults. We did a systematic review to estimate risks of long-term neurocognitive and other sequelae after intrauterine and neonatal insults, especially in low-income and middle-income countries. We searched Medline, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, and Embase for studies published between Jan 1, 1966, and June 30, 2011, that reported neurodevelopmental sequelae after preterm or neonatal insult. For unpublished studies and grey literature, we searched Dissertation Abstracts International and the WHO library. We reviewed publications that had data for long-term outcome after defined neonatal insults. We summarised the results with medians and IQRs, and calculated the risk of at least one sequela after insult. Of 28,212 studies identified by our search, 153 studies were suitable for inclusion, documenting 22,161 survivors of intrauterine or neonatal insults. The overall median risk of at least one sequela in any domain was 39·4% (IQR 20·0-54·8), with a risk of at least one severe impairment in any insult domain of 18·5% (7·7-33·3), of at least one moderate impairment of 5·0% (0·0-13·3%), and of at least one mild impairment of 10·0% (1·4-17·9%). The pooled risk estimate of at least one sequela (weighted mean) associated with one or more of the insults studied (excluding HIV) was 37·0% (95% CI 27·0-48·0%) and this risk was not significantly affected by region, duration of the follow-up, study design, or period of data collection. The most common sequelae were learning difficulties, cognition, or developmental delay (n=4032; 59%); cerebral palsy (n=1472; 21%); hearing impairment (n=1340; 20%); and visual impairment (n=1228; 18%). Only 40 (26%) studies included data for multidomain impairments. These studies included 2815 individuals, of whom 1048 (37%) had impairments, with 334 (32%) having multiple impairments. Intrauterine and neonatal insults have a high risk of causing substantial long-term neurological morbidity. Comparable cohort studies in resource-poor regions should be done to properly assess the burden of these conditions, and long-term outcomes, such as chronic disease, and to inform policy and programme investments. The Bill & Melinda Gates Foundation, Saving Newborn Lives, and the Wellcome Trust.


Conceptual Framework for Optimised Proxy Value Set Selection Through Supra-National Value Set Development for the EQ-5D Instruments.
Preference differences between countries and populations justify the use of country-specific value sets for the EQ-5D instruments. There are no clear criteria based on which the selection of value sets for countries without a national value set should be made. As part of the European PECUNIA project, this study aimed to identify factors contributing to differences in preference-based valuations and develop supra-national value sets for homogenous country clusters in Europe. A literature review was conducted to identify factors relevant to variations in the EQ-5D-3L/5L health state valuations across countries. Factors fulfilling the pre-specified criteria of validity, reliability, international feasibility and comparability were used to group 27 European Union member states, the European Free Trade Association countries and the UK. Clusters of countries were developed based on the frequency of their appearance in the same grouping. The supra-national value sets were estimated for these clusters from the coefficients of existing published valuation studies using the ordinary least-squares model. Ten factors were identified from 69 studies. From these, five grouping variables: (1) culture and religion; (2) linguistics; (3) healthcare system typology; (4) healthcare system financing; and (5) sociodemographic aspects were derived to define the groups of homogenous countries. Frequency-based grouping revealed five cohesive clusters: English-speaking, Nordic, Central-Western, Southern and Eastern European. European countries were clustered considering variables that may relate to differences in health state valuations. Supra-national value sets provide optimised proxy value set selection in the lack of a national value set and/or for regional decision making.


Cavity quantum electrodynamics: coherence in context.
Modern cavity quantum electrodynamics (cavity QED) illuminates the most fundamental aspects of coherence and decoherence in quantum mechanics. Experiments on atoms in cavities can be described by elementary models but reveal intriguing subtleties of the interplay of coherent dynamics with external couplings. Recent activity in this area has pioneered powerful new approaches to the study of quantum coherence and has fueled the growth of quantum information science. In years to come, the purview of cavity QED will continue to grow as researchers build on a rich infrastructure to attack some of the most pressing open questions in micro- and mesoscopic physics.


Modulation Z-scan technique for characterization of photorefractive crystals.
We propose a simple single-beam configuration for characterization of the amplitude, speed of growth, and polarization properties of the photoinduced refractive-index change that is due to a drift photorefractive mechanism of nonlinearity in crystals, namely, the modulation Z-scan technique, based on the modulation of an externally applied electric field. The results of a simple theoretical model developed for one-dimensional parabolic photorefractive lens formation in this configuration are illustrated by original experiments with a semi-insulating GaAs crystal at lambda -1.06 microm.


Studies on the subtype selectivity of CP-101,606: evidence for two classes of NR2B-selective NMDA receptor antagonists.
The subtype-selectivity of racemic [(3)H]CP-101,606, a novel high-affinity NMDA receptor radioligand was determined using defined recombinant NMDA receptor subunits expressed in HEK 293 cells. [(3)H]CP-101,606 binds to adult rodent forebrain and NR1/NR2B receptors expressed in HEK 293 cells with K(D)=4.2 nM and 6.0 nM, respectively. In contrast, no high affinity specific binding was detected to NR1, NR2A, NR2B subunits expressed alone or NR1/NR2A receptors. HEK 293 cells were transfected with NR1, NR2A and NR2B receptor subunits and complexes comprising all three subunits were isolated by anti-NR2A immunoaffinity chromatography. Based on immunoblotting with subunit-selective antibodies, the immunopurified material contained all three NMDA receptor subunit polypeptides. However, in contrast to parallel studies in which high affinity [(3)H]Ro-25,6981 binding activity was observed, no high affinity [(3)H]CP-101,606 binding sites were detected to the immunopurified material. This study provides further evidence for two distinct classes of NR2B-directed NMDA receptor antagonists, one which binds with high affinity irrespective whether another NR2 subunit type is present (Ro-25,6981) and a second class which is affected significantly by the presence of another NR2 subunit type within the receptor complex, exemplified by CP-101,606.


Quality of life in pediatric patients with atopic dermatitis.
To measure the impact of atopic dermatitis (AD) on the quality of life of pediatric patients and their families, establishing correlations with scores of disease severity. This was an observational study of the correlations between clinical indicators of severity and two questionnaires on quality of life: IDQOL and DFI. The study also included scoring of eczema severity EASI. Forty-two children with AD, fulfilling established diagnostic criteria, and 44 children with other dermatologic diseases were investigated for the effect of eczema on quality of life. Pearson's correlation was used for the correlation analysis and the comparison between the groups was carried out using the Mann-Whitney test. Data analysis demonstrated significant differences between the scores for the two groups. The mean score in the eczema group was 9.2 (range 1-19) for IDQOL and 8.5 (range 0-17) for DFI. The highest scoring questions for IDQOL referred to itching and scratching, mood changes and problems caused by treatment. For the FDI, the highest impact domains were treatment-related expenditure and sleep disturbance affecting family members. AD has a negative impact on the quality of life of pediatric patients and their families. Data obtained in studies of quality of life in AD should be used to guide clinical practice in order to identify individual treatment strategies and should lead to the adoption of measures to reduce the impact of the disease on patients and their families.


Wall structures of myocardial precapillary arterioles and postcapillary venules reexamined and reconstructed in vitro for studies on barrier functions.
The barrier functions of myocardial precapillary arteriolar and postcapillary venular walls (PCA or PCV, respectively) are of considerable scientific and clinical interest (regulation of blood flow and recruitment of immune defense). Using enzyme histochemistry combined with confocal microscopy, we reexamined the cell architecture of human PCA and PVC and reconstructed appropriate in vitro models for studies of their barrier functions. Contrary to current opinion, the PCA endothelial tube is encompassed not by smooth muscle cells but rather by a concentric layer of pericytes cocooned in a thick, microparticle-containing extracellular matrix (ECM) that contributes substantially to the tightness of the arteriolar wall. This core tube extends upstream into the larger arterioles, there additionally enwrapped by smooth muscle. PCV consist of an inner layer of large, contractile endothelial cells encompassed by a fragile, wide-meshed pericyte network with a weakly developed ECM. Pure pericyte and endothelial cell preparations were isolated from PCA and PCV and grown in sandwich cultures. These in vitro models of the PCA and PCV walls exhibited typical histological and functional features. In both plasma-like (PLM) and serum-containing (SCM) media, the PCA model (including ECM) maintained its low hydraulic conductivity (L(P) = 3.24 ± 0.52·10(-8)cm·s(-1)·cmH(2)O(-1)) and a high selectivity index for transmural passage of albumin (SI(Alb) = 0.95 ± 0.02). In contrast, L(P) and SI(Alb) in the PCV model (almost no ECM) were 2.55 ± 0.32·10(-7)cm·s(-1)·cmH(2)O(-1) and 0.88 ± 0.03, respectively, in PLM, and 1.39 ± 0.10·10(-6)cm·s(-1)·cmH(2)O(-1) and 0.49 ± 0.04 in SCM. With the use of these models, systematic, detailed studies on the regulation of microvascular barrier properties now appear to be feasible.


Skin care practices for newborns and infants: review of the clinical evidence for best practices.
In recent years, there have been continuing efforts to understand the effects of baby skin care routines and products on the healthy development of baby skin. Such efforts aim ultimately to determine the best infant skin care practices. The pediatric and dermatologic communities have not reached consensus on what constitutes an appropriate cleansing practice. In the United States, guidelines for neonatal skin care have been developed, propagated, and implemented. The accumulated knowledge has promoted evidence-based clinical practices and, therefore, may help to improve clinical outcomes, although these guidelines primarily cover the care of preterm newborns and the treatment of those with other health problems. High-level, long-term clinical evidence of the effective and safe cleansing of healthy, full-term newborns and infants is scarce. This review presents a comprehensive analysis of the scientific literature on baby skin development, cleansing practices, and related products (for healthy newborns and babies) since 1970. The evidence drawn from the reviewed literature can be summarized as follows: Bathing immersed in water seems generally superior to washing alone. Bathing or washing with synthetic detergents (syndets) or mild liquid baby cleansers seems comparable with or even superior to water alone. Nevertheless, larger randomized clinical trials with age-defined cohorts of babies as well as more-defined parameters are required to identify optimal practices and products for skin cleansing of healthy infants. These parameters may include standardized skin function parameters such as transepidermal water loss, stratum corneum hydration, skin surface pH, and sebum production. Clinical skin scores such as the Neonatal Skin Condition Score may be employed as outcome measures.


Cognitive-behavioural therapy (CBT) for renal fatigue (BReF): a feasibility randomised-controlled trial of CBT for the management of fatigue in haemodialysis (HD) patients.
Fatigue is one of the most common and disabling symptoms in end-stage kidney disease, particularly among in-centre haemodialysis patients. This two-arm parallel group feasibility randomised controlled trial will determine whether a fully powered efficacy trial is achievable by examining the feasibility of recruitment, acceptability and potential benefits of a cognitive-behavioural therapy (CBT)-based intervention for fatigue among in-centre haemodialysis patients. We aim to recruit 40 adult patients undergoing in-centre haemodialysis at secondary care outpatient dialysis units, who meet clinical levels of fatigue. Patients will be randomised individually (using a 1:1 ratio) to either a 4-6 weeks' CBT-based intervention (intervention arm) or to a waiting-list control (control arm). The primary feasibility outcomes include descriptive data on numbers within each recruiting centre meeting eligibility criteria, rates of recruitment, numbers retained postrandomisation and treatment adherence. To assess the potential benefits of the cognitive-behavioural therapy for renal fatigue intervention, secondary self-report outcomes include measures of fatigue severity (Chalder Fatigue Questionnaire), fatigue-related functional impairment (Work and Social Adjustment Scale), sleep quality (Pittsburgh Sleep Quality Index), depression (Patient Health Questionnaire-9) and anxiety (Generalised Anxiety Disorder-7). Changes in fatigue perceptions (Brief Illness Perception Questionnaire), cognitive and behavioural responses to fatigue (Cognitive and Behavioural Responses to Symptoms Questionnaire), sleep hygiene behaviours (Sleep Hygiene Index) and physical activity (International Physical Activity Questionnaire-short form) will also be explored. These self-report measures will be collected at baseline and 3 months postrandomisation. Nested qualitative interviews will be conducted postintervention to explore the acceptability of the intervention and identify any areas in need of improvement. The statistician and assessor will be blinded to treatment allocation. A National Health Service (NHS) Research Ethics Committee approved the study. Any amendments to the protocol will be submitted to the NHS Committee and study sponsor. ISRCTN91238019;Pre-results.


Effects of hypercapnia on membrane potential and intracellular calcium in rat carotid body type I cells.
1. An acid-induced rise in the intracellular calcium concentration ([Ca2+]i) of type I cells is thought to play a vital role in pH/PCO2 chemoreception by the carotid body. In this present study we have investigated the cause of this rise in [Ca2+]i in enzymatically isolated, neonatal rat type I cells. 2. The rise in [Ca2+]i induced by a hypercapnic acidosis was inhibited in Ca(2+)-free media, and by 2 mM Ni2+. Acidosis also increased Mn2+ permeability. The rise in [Ca2+]i is dependent, therefore, upon a Ca2+ influx from the external medium. 3. The acid-induced rise in [Ca2+]i was attenuated by both nicardipine and methoxyverapamil (D600), suggesting a role for L-type Ca2+ channels. 4. Acidosis depolarized type I cells and often (approximately 50% of cells) induced action potentials. These effects coincided with a rise in [Ca2+]i. When membrane depolarization was prevented by a voltage clamp, acidosis failed to evoke a rise in [Ca2+]i. The acid-induced rise in [Ca2+]i is a consequence, therefore, of membrane depolarization. 5. Acidosis decreased the resting membrane conductance of type I cells. The reversal potential of the acid-sensitive current was about -75 mV. 6. A depolarization (30 mM [K+]o)-induced rise in [Ca2+]i was blocked by either the removal of extracellular Ca2+ or the presence of 2 mM Ni2+, and was also substantially inhibited by nicardipine. Under voltage-clamp conditions, [Ca2+]i displayed a bell-shaped dependence on membrane potential. Depolarization raises [Ca2+]i, therefore, through voltage-operated Ca2+ channels. 7. Caffeine (10 mM) induced only a small rise in [Ca2+]i (< 10% of that induced by 30 mM extracellular K+). Ca(2+)-induced Ca2+ release is unlikely, therefore, to contribute greatly to the rise in [Ca2+]i induced by depolarization. 8. Although the replacement of extracellular Na+ with N-methyl-D-glucamine (NMG), but not Li+, inhibited the acid-induced rise in [Ca2+]i, this was due to membrane hyperpolarization and not to the inhibition of Na(+)-Ca2+ exchange or Na(+)-dependent action potentials. 9. The removal of extracellular Na+ (NMG substituted) did not have a significant effect upon the resting [Ca2+]i, and only slowed [Ca2+]i recovery slightly following repolarization from 0 to -60 mV. Therefore, if present, Na(+)-Ca2+ exchange plays only a minor role in [Ca2+]i homeostasis. 10. In summary, in the neonatal rat type I cell, hypercapnic acidosis raises [Ca2+]i through membrane depolarization and voltage-gated Ca2+ entry.


Patterns and trajectories of gestational weight gain: a prospective cohort study.
Gestational weight gain in excess of or below Health Canada's guidelines is known to increase the risk of adverse outcomes for both the woman and her baby. This study describes patterns and trajectories of total and rate of gestational weight gain in a large prospective cohort of pregnant women and adolescents in the Alberta Pregnancy Outcomes and Nutrition study. We collected weight and height data for 1541 pregnant adolescents and women (mean age 31 years, < 27 weeks' gestation) recruited through advertisements and physicians' offices in Calgary and Edmonton between May 2009 and November 2012. Data were collected once during each trimester following enrolment and once at about 3 months post partum. The participants were categorized according to their prepregnancy body mass index (BMI) as underweight, of normal weight, overweight or obese. We calculated distributions of total and weekly rates of weight gain and determined trajectories of weight gain for each prepregnancy BMI category. Of the 1541 participants, 761 (49.4%) exceeded Health Canada's guidelines for total gestational weight gain, and 272 (17.6%) gained less weight than recommended. A total of 63 (19.2%) and 38 (23.6%) participants categorized as overweight or obese, respectively, exceeded the recommended upper limit by 5 to less than 10 kg, and 53 (16.2%) and 27 (16.8%), respectively, exceeded the upper limit by at least 10 kg. Ninety-five participants (30.3%) in the overweight group and 59 (39.6%) of those in the obese group gained weight at more than double the recommended rate between the second and third trimesters. The median weight gain for participants in the normal, overweight and obese categories had exceeded recommended upper limits by about 30, 20 and 18 weeks' gestation, respectively. Adherence to Health Canada's guidelines for gestational weight gain was low. Excess gestational weight gain was most marked among those with a prepregnancy BMI in the overweight or obese category. The findings suggest that weight management in pregnancy is challenging and complex. Messages and supports that are tailored for women in different prepregnancy BMI categories may help to improve guideline-concordant gestational weight gain.


Low propensity for aerial dispersal in specialist spiders from fragmented landscapes.
Aerial dispersal by ballooning is a passive flight, by which wind drag generates an upward lift on a silk thread. It is likely to reflect an aerial lottery, in which the absence of flight direction control is a serious cost for long-distance dispersal in a fragmented landscape. For species occurring in one patchily distributed habitat type, dispersal should evolve in a different way from morphological traits, directly linked to active dispersal. Therefore, we expect that if the risk of landing in an unsuitable habitat is lower than the probability of reaching a suitable habitat, selection should benefit a well-developed ballooning behaviour. We investigated interspecific variation in the ballooning-initiating tiptoe behaviour as it is linked to spider dispersal performance. Our results indeed indicate that ballooning performance is negatively related to habitat specialization in spiders from patchy grey dunes, so habitat specialists are characterized by poorly developed dispersal behaviour. These findings are concordant with recent insights that dispersal is selected as risk spreading in generalists, while it is selected against in specialist species.


Obstructive sleep-disordered breathing, enuresis and combined disorders in children: chance or related association?
Nocturnal enuresis is usually diagnosed and treated by a primary paediatrician or family practitioner; if there is any doubt, the children may be referred to a paediatric urologist. Obstructive sleep-disordered breathing is a complex, multifactorial disorder. Adenotonsillar hypertrophy is considered an important factor associated with obstructive sleep apnoea syndrome. Enuresis and obstructive sleep-disordered breathing are both frequent problems of sleep in childhood. We conducted an electronic search in Medline, Scopus and the ISI Web of Science to look for published material and identify a putative link between nocturnal enuresis and obstructive sleep-disordered breathing. A total number of 98 documents were found, but 24 of these had to be excluded after an attentive reading of the title, abstract or full text because the information therein was not suitable for the aims of our search. Studies have found that children with obstructive sleep apnoea syndrome frequently also have nocturnal enuresis. Both disorders have an underlying sleep disturbance characterised by an altered arousal response and sleep fragmentation. The pathophysiology of enuretic events is seemingly linked to nocturnal obstructive events, causing increased intra-abdominal pressure and altered systemic blood pressure that induces natriuresis and polyuria by altering levels of antidiuretic hormone, and atrial and brain natriuretic peptides. We found 17 studies regarding the urological outcome of treatment for obstructive sleep-disordered breathing in children with enuresis. Although a vast amount of information is now available regarding the relationship between nocturnal enuresis and obstructive sleep-disordered breathing, many of the published studies were uncontrolled, retrospective or prospective cohort studies (grade C recommendation). Resolution of enuresis after medical or surgical treatment for obstructive sleep-disordered breathing has been emphasised. Consequently, symptoms such as snoring, sleep apnoeas and restless sleep should be sought for all children with enuresis. Confirmed obstructive sleep-disordered breathing should be treated promptly; subsequently, the persistence of enuresis requires treatment following the standard protocol.


Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance.
1. This study examined the effects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. 2. Repeated administration of intrathecal morphine (15 micrograms), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co-administration of ketorolac (30 and 45 micrograms) or S(+) ibuprofen (10 micrograms) with morphine (15 micrograms) prevented the decline of antinociceptive effect and increase in ED50 value. Similar treatment with L-NAME (100 micrograms) exerted weaker effects. Administration of S(+) but not R(-) ibuprofen (10 mg kg-1) had similar effects on systemic administration of morphine (15 mg kg-1). 3. Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. 4. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 micrograms) with morphine (15 micrograms) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L-NAME (100 micrograms) exerted a weaker effect. 5. These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance.


Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States, January-October 2003.
Myocarditis was reported after smallpox vaccination in Europe and Australia, but no association had been reported with the US vaccine. We conducted surveillance to describe and determine the frequency of myocarditis and/or pericarditis (myo/pericarditis) among civilians vaccinated during the US smallpox vaccination program between January and October 2003. We developed surveillance case definitions for myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination. We identified 21 myo/pericarditis cases among 37,901 vaccinees (5.5 per 10,000); 18 (86%) were revacinees, 14 (67%) were women, and the median age was 48 years (range, 25-70 years). The median time from vaccination to onset of symptoms was 11 days (range, 2-42 days). Myo/pericarditis severity was mild, with no fatalities, although 9 patients (43%) were hospitalized. Three additional vaccinees were found to have dilated cardiomyopathy, recognized within 3 months after vaccination. We describe an association between smallpox vaccination, using the US vaccinia strain, and myo/pericarditis among civilians.


Molecular relationship between two groups of the genus Leptospirillum and the finding that Leptospirillum ferriphilum sp. nov. dominates South African commercial biooxidation tanks that operate at 40 degrees C.
Iron-oxidizing bacteria belonging to the genus Leptospirillum are of great importance in continuous-flow commercial biooxidation reactors, used for extracting metals from minerals, that operate at 40 degrees C or less. They also form part of the microbial community responsible for the generation of acid mine drainage. More than 16 isolates of leptospirilla were included in this study, and they were clearly divisible into two major groups. Group I leptospirilla had G+C moles percent ratios within the range 49 to 52% and had three copies of rrn genes, and based on 16S rRNA sequence data, these isolates clustered together with the Leptospirillum ferrooxidans type strain (DSM2705 or L15). Group II leptospirilla had G+C moles percent ratios of 55 to 58% and had two copies of rrn genes, and based on 16S rRNA sequence data, they form a separate cluster. Genome DNA-DNA hybridization experiments indicated that three similarity subgroups were present among the leptospirilla tested, with two DNA-DNA hybridization similarity subgroups found within group I. The two groups could also be distinguished based on the sizes of their 16S-23S rRNA gene spacer regions. We propose that the group II leptospirilla should be recognized as a separate species with the name Leptospirillum ferriphilum sp. nov. Members of the two species can be rapidly distinguished from each other by amplification of their 16S rRNA genes and by carrying out restriction enzyme digests of the products. Several, but not all, isolates of the group II leptospirilla, but none from group I (L. ferrooxidans), were capable of growth at 45 degrees C. All the leptospirilla isolated from commercial biooxidation tanks in South Africa were from group II.


Fouling of Polymeric Hollow Fiber Heat Exchangers by Air Dust.
Currently, liquid-to-gas heat exchangers in buildings, domestic appliances and the automotive industry are mainly made of copper and aluminum. Using plastic instead of metal can be very beneficial from an economic and environmental point of view. However, it is required that a successful plastic design meets all the requirements of metal heat exchangers. The polymeric hollow fiber heat exchanger studied in this work is completive to common metal finned heat exchangers. Due to its unique design (the use of thousands of thin-walled microtubes connected in parallel), it achieves a high level of compactness and thermal performance, low pressure drops and high operation pressure. This paper focuses on an important aspect of heat exchanger operation-its fouling in conditions relevant to building and domestic application. In heating, ventilation and air conditioning (HVAC) and automotive and domestic appliances, outdoor and domestic dust are the main source of fouling. In this study, a heat exchanger made of polymeric hollow fibers was tested in conditions typical for indoor HVAC equipment, namely with the 20 °C room air flowing through the hot water coil (water inlet 50 °C) with air velocity of 1.5 m/s. ASHRAE test dust was used as a foulant to model domestic dust. A polymeric heat exchanger with fibers with an outer diameter of 0.6 mm (1960 fibers arranged into 14 layers in total) and a heat transfer area of 0.89 m2 was tested. It was proven that the smooth polypropylene surface of hollow fibers has a favorable antifouling characteristic. Fouling evolution on the metallic heat transfer surfaces of a similar surface density was about twice as quick as on the plastic one. The experimental results on the plastic heat exchanger showed a 38% decrease in the heat transfer rate and a 91% increase in pressure drops after eighteen days of the experiment when a total of 4000 g/m2 of the test dust had been injected into the air duct. The decrease in the heat transfer rate of the heat exchanger was influenced mainly by clogging in the frontal area because the first layers were fouled significantly more than the deeper layers.


A mathematical model predicts that calreticulin interacts with the endoplasmic reticulum Ca(2+)-ATPase.
A robust mathematical model developed from single cell calcium (Ca(2+)) dynamics has enabled us to predict the consequences of over-expression of endoplasmic reticulum-located chaperones. Model predictions concluded that calreticulin interacts with the lumenal domain of the sarcoplasmic and endoplasmic reticulum Ca(2+)-activated ATPase (SERCA) pump, altering pump affinity for Ca(2+) (K(1/2) switches from 247 to 431 nM) and hence generating Ca(2+) oscillations. Expression of calreticulin in the ER generated an average of six transient-decline oscillations during the Ca(2+) recovery phase, upon exposure to maximal levels of the agonist ATP. In contrast, normal cells produced a single Ca(2+) transient with few or no oscillations. By conditioning the model to experimental data, parameters for generation and decay of IP(3) and SERCA pump kinetics were determined. To elucidate the possible source of the oscillatory behavior three possible oscillators, 1) IP(3), 2) IP(3)R, and 3) SERCA pump, were investigated and parameters constrained by experimental data to produce the best candidate. Each of the three oscillators generated very good fits with experimental data. However, converting a normal exponential recovery to a transient-decline oscillator predicted that the SERCA pump is the most likely candidate for calreticulin-mediated Ca(2+) release, highlighting the role of this chaperone as a signal protein within the endoplasmic reticulum.


Nanoscale Mapping of Nonuniform Heterogeneous Nucleation Kinetics Mediated by Surface Chemistry.
Nucleation underlies the formation of many liquid-phase synthetic and natural materials with applications in materials chemistry, geochemistry, biophysics, and structural biology. Most liquid-phase nucleation processes are heterogeneous, occurring at specific nucleation sites at a solid-liquid interface; however, the chemical and topographical identity of these nucleation sites and how nucleation kinetics vary from site-to-site remain mysterious. Here we utilize in situ liquid cell electron microscopy to unveil counterintuitive nanoscale nonuniformities in heterogeneous nucleation kinetics on a macroscopically uniform solid-liquid interface. Time-resolved in situ electron microscopy imaging of silver nanoparticle nucleation at a water-silicon nitride interface showed apparently randomly located nucleation events at the interface. However, nanometric maps of local nucleation kinetics uncovered nanoscale interfacial domains with either slow or rapid nucleation. Interestingly, the interfacial domains vanished at high supersaturation ratio, giving way to rapid spatially uniform nucleation kinetics. Atomic force microscopy and nanoparticle labeling experiments revealed a topographically flat, chemically heterogeneous interface with nanoscale interfacial domains of functional groups similar in size to those observed in the nanometric nucleation maps. These results, along with a semiquantitative nucleation model, indicate that a chemically nonuniform interface presenting different free energy barriers to heterogeneous nucleation underlies our observations of nonuniform nucleation kinetics. Overall, our results introduce a new imaging modality, nanometric nucleation mapping, and provide important new insights into the impact of surface chemistry on microscopic spatial variations in heterogeneous nucleation kinetics that have not been previously observed.


Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions.
The human IgM B7-DC XAb protects mice from tumors in both therapeutic and prophylactic settings. Its mechanism of action is mediated by its binding to B7-DC/PD-L2 molecules on the surface of dendritic cells (DCs) to induce a multimolecular cap and subsequent activation of signaling cascades that determine a unique combination of DC phenotypes. One such phenotype, the B7-DC XAb-induced antigen accumulation in mTLR-matured DCs, has been linked to signaling through TREM-2, but the signals required for other DC phenotypes critical for the therapeutic effects in animal models remain unclear. Here, FRET and co-immunoprecipitation studies show that CD40 is recruited to the multi-molecular complex by B7-DC XAb. Signals emanating from CD40 are important, as CD40(-/-) DCs treated with B7-DC XAb (DC(XAb)) activated DAP12, but failed to activate NFkappaB, and were not protected from cell death upon cytokine withdrawal or treatment with Vitamin D(3). CD40(-/-) DC(XAb) also failed to secrete IL-6 and were unable to support the conversion of T regulatory cells into IL-17+ effector T cells in vitro. Importantly, the expression of CD40 was required for the overall ability of B7-DC XAb to induce anti-tumor CTL, to provide protection from a number of tumor types, and for DC(XAb) to be effective anti-tumor vaccines in vivo. These results indicate that B7-DC XAb modulation of DC phenotypes is through its ability to indirectly recruit common signaling molecules and elements of their endogenous signaling pathways through targeted binding to a cell-specific surface determinant.


Repetition of suicidal behaviour in elderly Europeans: a prospective longitudinal study.
The aim of this study was to assess any predictive factors for repeated attempted suicide and completed suicide in a 1-year follow-up on a sample of elderly European suicide attempters (60 years and over). From 1990 to 1993, 63 subjects completed the first interview and were recontacted after 1 year. At follow-up, eight subjects (12.7%) had taken their lives and seven (11.1%) had repeated at least one suicide attempt. On comparison of repeaters and non-repeaters, differences emerged in terms of death of the father in childhood and for mean Suicidal Intent Score. At the end of follow-up period, repeaters reported a more frequent desire to repeat suicidal behaviour and judged their mental health and social assistance received to be worse. Suicides and non-repeaters differed especially in relation to death of father during childhood and number of contacts with General Practitioner. Interpretation of the results must take into account the smallness of the test sample, the difficulties in obtaining complete data for the follow-up interview, the lack of a control group and a diagnosis formulated in a hospital consultation setting. The study confirms, however, the high risk of repetition of suicidal behaviour in the elderly. In old age suicidal ideation is often sustained over long periods of time and requests for help are addressed to relatives and GPs. An interesting finding is the more frequent death of the father during childhood among repeaters.


Increased dehydroepiandrosterone (DHEA) is associated with anxiety in adolescent girls.
The pubertal period is a time of rapid increase in the incidence of anxiety disorders, and thus, pubertal hormones may play a role in the precipitation of anxious psychopathology. DHEA, a steroid hormone that surges in adolescence, has been previously linked to anxiety, although the direction of this effect has been mixed. Using a cross-sectional design in a sample of 286 adolescent girls, the present study examined associations between salivary DHEA concentrations and self-report and interview-based measures of anxiety while controlling for pubertal status, menarche status, assessment time of day, and other hormones including testosterone, estradiol, and progesterone. Increased salivary DHEA concentrations were associated with more self-reported anxiety symptoms, increased anxiety symptom counts based on clinical interview, and increased probability of an anxiety disorder. Out of all anxiety symptom domains examined, generalized anxiety disorder symptoms were the best predictor of salivary DHEA concentrations after controlling for pubertal development. Collectively, our findings suggest relevance for DHEA in the development of anxiety in the pubertal period, as well as a robust relationship between DHEA and emerging symptoms of pathological worry during adolescence. The present study underscores the importance of examining associations between DHEA concentrations and anxiety in longitudinal designs.


Comparative Microbiome Analysis of a Fusarium Wilt Suppressive Soil and a Fusarium Wilt Conducive Soil From the Châteaurenard Region.
Disease-suppressive soils are soils in which specific soil-borne plant pathogens cause only limited disease although the pathogen and susceptible host plants are both present. Suppressiveness is in most cases of microbial origin. We conducted a comparative metabarcoding analysis of the taxonomic diversity of fungal and bacterial communities from suppressive and non-suppressive (conducive) soils as regards Fusarium wilts sampled from the Châteaurenard region (France). Bioassays based on Fusarium wilt of flax confirmed that disease incidence was significantly lower in the suppressive soil than in the conducive soil. Furthermore, we succeeded in partly transferring Fusarium wilt-suppressiveness to the conducive soil by mixing 10% (w/w) of the suppressive soil into the conducive soil. Fungal diversity differed significantly between the suppressive and conducive soils. Among dominant fungal operational taxonomic units (OTUs) affiliated to known genera, 17 OTUs were detected exclusively in the suppressive soil. These OTUs were assigned to the Acremonium, Chaetomium, Cladosporium, Clonostachys, Fusarium, Ceratobasidium, Mortierella, Penicillium, Scytalidium, and Verticillium genera. Additionally, the relative abundance of specific members of the bacterial community was significantly higher in the suppressive and mixed soils than in the conducive soil. OTUs found more abundant in Fusarium wilt-suppressive soils were affiliated to the bacterial genera Adhaeribacter, Massilia, Microvirga, Rhizobium, Rhizobacter, Arthrobacter, Amycolatopsis, Rubrobacter, Paenibacillus, Stenotrophomonas, and Geobacter. Several of the fungal and bacterial genera detected exclusively or more abundantly in the Fusarium wilt-suppressive soil included genera known for their activity against F. oxysporum. Overall, this study supports the potential role of known fungal and bacterial genera in Fusarium wilt suppressive soils from Châteaurenard and pinpoints new bacterial and fungal genera for their putative role in Fusarium wilt suppressiveness.