Quantification of opportunities for early-stage paramedicine students to practice clinical skills during clinical placements compared with an equal dose of simulation-based workshops.
A reported advantage of simulation-based learning environments (SLE) over clinical placements (CPs) is that the former can provide a greater number and breadth of opportunities to practice level-appropriate clinical skills compared with the random patient presentations provided during the latter. Although logical and widely accepted as fact, we find no published evidence to demonstrate the magnitude, nor indeed veracity, of this assumption. We therefore sought to quantify the clinical skills practiced by entry-level paramedicine students attending a well-selected CP compared with an equal dosage of SLE. N=37 first-year paramedicine students completed activity diaries during 3 days of CP and 3 days of SLE. Opportunities to practice clinical skills were quantified and coded as either: level-appropriate, beyond-level or of non-discipline relevance. During SLE, the average student was exposed 226 times to 11 level-appropriate clinical procedures. During CP the average student was exposed 48 times to 24 clinical procedures, the majority relevant to paramedicine (63%), but a minority level-appropriate (38%). Students' opportunities for supervised, 'hands on' practice represented only 10% of exposures in either SLE or CP but in terms of raw numbers of level-appropriate opportunities, SLE provided more than CP (n=23 vs 2). Our results confirm that SLE provides substantially more opportunities than CP for students to practice level-appropriate skills and is therefore more appropriate for repetitive practice. However, CP is likely to remain useful to students for practicing interpersonal skills and contextualisation of knowledge within the broader health system. Educators should therefore carefully articulate learning objectives before choosing between SLE and CP.


Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress.
Aquaporin 11 (AQP11) is a newly described member of the protein family of transport channels. AQP11 associates with the endoplasmic reticulum (ER) and is highly expressed in proximal tubular epithelial cells in the kidney. Previously, we identified and characterized a recessive mutation of the highly conserved Cys227 to Ser227 in mouse AQP11 that caused proximal tubule (PT) injury and kidney failure in mutant mice. The current study revealed induction of ER stress, unfolded protein response, and apoptosis as molecular mechanisms of this PT injury. Cys227Ser mutation interfered with maintenance of AQP11 oligomeric structure. AQP11 is abundantly expressed in the S1 PT segment, a site of major renal glucose flux, and Aqp11 mutant mice developed PT-specific mitochondrial injury. Glucose increased AQP11 protein expression in wild-type kidney and upregulation of AQP11 expression by glucose in vitro was prevented by phlorizin, an inhibitor of sodium-dependent glucose transport across PT. Total AQP11 levels in heterozygotes were higher than in wild-type mice but were not further increased in response to glucose. In Aqp11 insufficient PT cells, glucose potentiated increases in reactive oxygen species (ROS) production. ROS production was also elevated in Aqp11 mutation carriers. Phenotypically normal mice heterozygous for the Aqp11 mutation repeatedly treated with glucose showed increased blood urea nitrogen levels that were prevented by the antioxidant sulforaphane or by phlorizin. Our results indicate an important role for AQP11 to prevent glucose-induced oxidative stress in proximal tubules.


Use of ambulatory electrocardiography for detection of ventricular premature complexes in healthy dogs.
To evaluate the use of 24-hour ambulatory electrocardiography (AECG) for the detection of ventricular premature complexes (VPC) in healthy dogs. Case series. 50 healthy mature dogs. A 24-hour AECG was performed on each dog and evaluated for the presence of VPC. Fifty dogs weighing between 18.2 to 40.9 kg (40 and 90 lb) representing 13 breeds were evaluated; there were 4 sexually intact females, 21 spayed females, 4 sexually intact males, and 21 castrated males. Ages ranged from 1 to 12 years. Thirty-four dogs had no VPC; 16 dogs had between 1 and 24 VPC. The grade of arrhythmia ranged from 1 to 4, with 4 dogs having an arrhythmia with a grade > 1. Significant differences were not detected between the group of dogs with VPC and those without VPC with regard to sex, age, and minimum, maximum, or mean heart rate. We conclude that healthy mature dogs have infrequent VPC, as detected by use of 24-hour AECG. The presence of numerous or sequential VPC may be suggestive of cardiac or systemic disease and may indicate the need for thorough clinical evaluation.


Association of sleep and co-occurring psychological conditions at 1 year after traumatic brain injury.
To compare individuals' sleep 1 year after traumatic brain injury (TBI) with that of a healthy comparison group, and examine the relationship between sleep, co-occurring conditions, and functional status in those with TBI. Longitudinal assessment of a prospectively studied sample of individuals with moderate to severe TBI. Assessment of sleep occurred at 1 year after TBI. Inpatient acute rehabilitation for TBI and community follow-up at 1 year postinjury. Individuals with TBI (N=174) were recruited from consecutive admissions to an inpatient rehabilitation unit and enrolled into the TBI Model Systems study. Participant mean age was 38, and mean Glasgow Coma Scale score on admission was 9.3. Seventy-eight percent of the sample were men. None. Sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI). Depression, anxiety, and pain were measured with the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 Scale, and an analog pain rating scale, respectively. Participants with TBI reported significantly greater sleep difficulties than the healthy comparison group. Forty-four percent of participants with TBI reported significant sleep problems (PSQI>5). Participants with 1 or more co-occurring conditions (depression, pain, or anxiety) had significantly worse sleep than those without such a condition. The highest level of sleep problems was reported by participants with multiple co-occurring conditions. Sleep problems were also associated with poor functional status. Sleep difficulties are a frequent problem at 1 year after TBI, and often co-occur with depression, anxiety, and pain. Assessment and treatment of sleep difficulties should be included in clinical practice. Future research on the potential causal relationship among co-occurring conditions may assist in additional intervention planning.


Conservation and Diversification of Circadian Rhythmicity Between a Model Crassulacean Acid Metabolism Plant Kalanchoë fedtschenkoi and a Model C3 Photosynthesis Plant Arabidopsis thaliana.
Crassulacean acid metabolism (CAM) improves photosynthetic efficiency under limited water availability relative to C3 photosynthesis. It is widely accepted that CAM plants have evolved from C3 plants and it is hypothesized that CAM is under the control of the internal circadian clock. However, the role that the circadian clock plays in the evolution of CAM is not well understood. To identify the molecular basis of circadian control over CAM evolution, rhythmic gene sets were identified in a CAM model plant species (Kalanchoë fedtschenkoi) and a C3 model plant species (Arabidopsis thaliana) through analysis of diel time-course gene expression data using multiple periodicity detection algorithms. Based on protein sequences, ortholog groups were constructed containing genes from each of these two species. The ortholog groups were categorized into five gene sets based on conservation and diversification of rhythmic gene expression. Interestingly, minimal functional overlap was observed when comparing the rhythmic gene sets of each species. Specifcally, metabolic processes were enriched in the gene set under circadian control in K. fedtschenkoi and numerous genes were found to have retained or gained rhythmic expression in K. fedtsechenkoi. Additonally, several rhythmic orthologs, including CAM-related orthologs, displayed phase shifts between species. Results of this analysis point to several mechanisms by which the circadian clock plays a role in the evolution of CAM. These genes provide a set of testable hypotheses for future experiments.


Rice SNP-seek database update: new SNPs, indels, and queries.
We describe updates to the Rice SNP-Seek Database since its first release. We ran a new SNP-calling pipeline followed by filtering that resulted in complete, base, filtered and core SNP datasets. Besides the Nipponbare reference genome, the pipeline was run on genome assemblies of IR 64, 93-11, DJ 123 and Kasalath. New genotype query and display features are added for reference assemblies, SNP datasets and indels. JBrowse now displays BAM, VCF and other annotation tracks, the additional genome assemblies and an embedded VISTA genome comparison viewer. Middleware is redesigned for improved performance by using a hybrid of HDF5 and RDMS for genotype storage. Query modules for genotypes, varieties and genes are improved to handle various constraints. An integrated list manager allows the user to pass query parameters for further analysis. The SNP Annotator adds traits, ontology terms, effects and interactions to markers in a list. Web-service calls were implemented to access most data. These features enable seamless querying of SNP-Seek across various biological entities, a step toward semi-automated gene-trait association discovery. URL: http://snp-seek.irri.org.


A simple and fast method for tissue cryohomogenization enabling multifarious molecular extraction.
Research in molecular biology often relies on parallel analysis of nucleic acids, protein and other molecules from a given tissue. When extracted from a single sample however, the quality and quantity of these products can be compromised. One solution is to obtain near-identical samples from multiple animals and dedicate each to a given molecular component, but this approach is not optimal from both an operational and ethical perspective. Thus, we refined the methods for cryohomogenization to allow efficient use of a single experimental sample so that it can easily be divided into fractions for extraction of different molecular components, immediately or after storage. Using western blot, nanodrop UV/V spectrometry, and a bioanalyzer, we show that cryohomogenized hippocampus samples provide high-quality RNA and protein without significant loss in abundance. The method may be particularly advantageous for parallel molecular extraction from brain structures with known hemispheric lateralization, such as the hippocampus, parietal cortex, suprachiasmatic nucleus, and amygdala.


Spatial appraisal of flood risk assessment and evaluation using integrated hydro-probabilistic approach in Panjkora River Basin, Pakistan.
Globally, flood is one of the devastating hydrometeorological disasters, causing human losses and damages to properties and infrastructure. There is a need to determine and geo-visualize flood risk to assist decision-making process for flood risk reduction. The current study is a local level pioneering attempt regarding the spatial appraisal of flood risk assessment and evaluation in Panjkora River Basin, eastern Hindu Kush. An integrated hydro-probabilistic approach is implemented by clubbing the results of Hydrologic Engineering Centre's River Analysis System (HEC-RAS) and Hydrologic Engineering Centre's Geographic River Analysis System (HEC-Geo-RAS) in geographic information system (GIS) environment. An Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) Global Digital Elevation Model (GDEM) is used as input data to delineate the target basin and generation of river geometry. Hydraulic and hydrological data were used to estimate and geo-visualize vertical profile and spatial extent of various floods in the active floodplain of Panjkora River. Gumbel's frequency distribution model is applied in analyzing daily peak discharge recorded during the past 32 years, and 200-year flood magnitude (1392m3/sec), probable inundation (45.5 km2), and vertical profile (19 m) are modeled. Analysis revealed that likelihood of such flood has increased the risk of potential damages to roads (46 km), retaining walls (49 km), bridges (16), and culverts (46). The analysis further revealed that built-up area (10.4 km2) and agricultural land (20.2 km2) will also come under flood with life loss. The resultant flood risk zones and spatial appraisal will definitely help in bringing down the probable flood damages. Similarly, current study has potential to assist disaster managers, hydraulic engineers, and policy makers to understand the flood risk and implement location-specific effective flood risk reduction strategies.


Langevin Dynamics Simulations of the Exchange of Complex Coacervate Core Micelles: The Role of Nonelectrostatic Attraction and Polyelectrolyte Length.
Complex coacervate core micelles (C3Ms) are promising encapsulators for a wide variety of (bio)molecules. To protect and stabilize their cargo, it is essential to control their exchange dynamics. Yet, to date, little is known about the kinetic stability of C3Ms and the dynamic equilibrium of molecular building blocks with micellar species. Here we study the C3M exchange during the initial micellization by using Langevin dynamics simulations. In this way, we show that charge neutral heterocomplexes consisting of multiple building blocks are the primary mediator for exchange. In addition, we show that the kinetic stability of the C3Ms can be tuned not only by the electrostatic interaction but also by the nonelectrostatic attraction between the polyelectrolytes, the polyelectrolyte length ratio, and the overall polyelectrolyte length. These insights offer new rational design guides to aid the development of new C3M encapsulation strategies.


Consequences of waiting for cataract surgery.
PURPOSE OR REVIEW: To conduct a concise review of primary research articles over the preceding year on the subject of the consequences of waiting for cataract surgery. Waiting for cataract surgery beyond 6 months may result in increasing vision loss, decrease in quality life, loss of driver's license, depression and adverse events including falls and fractures. The consequences of waiting for cataract surgery not only affect patients, families and surgeons, but also health ministries and public health policy makers. Consequences are both quantitative and qualitative in nature, ranging from progressive vision loss to patients' decrease in quality of life from factors other than vision loss. Cataract wait lists are not unique to North America, and numerous international articles have described a broad variety of consequences. Consequences of waiting for cataract surgery are multivariate in nature and easily extend beyond the clinical setting into sociodemographic realms and public health costs and policy arenas.


The expression and functions of toll-like receptors in atherosclerosis.
Inflammation drives atherosclerosis. Both immune and resident vascular cell types are involved in the development of atherosclerotic lesions. The phenotype and function of these cells are key in determining the development of lesions. Toll-like receptors are the most characterised innate immune receptors and are responsible for the recognition of exogenous conserved motifs on pathogens, and, potentially, some endogenous molecules. Both endogenous and exogenous TLR agonists may be present in atherosclerotic plaques. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system. In this paper, we will describe the expression of TLRs on immune and resident vascular cells, highlight the TLR ligands that may act through TLRs on these cells, and discuss the consequences of TLR activation in atherosclerosis.


Rhinovirus induction of the CXC chemokine epithelial-neutrophil activating peptide-78 in bronchial epithelium.
Epithelial-neutrophil activating peptide-78 (ENA-78) induces neutrophil migration, an early response to viral infection. Rhinovirus serotype 16 (RV16) was used to infect primary bronchial epithelial cells and a cell line (BEAS-2B). Release of ENA-78 protein was measured by enzyme-linked immunosorbent assay, ENA-78 mRNA production was quantified by reverse-transcription polymerase chain reaction, and ENA-78 promoter activity was assessed by use of a promoter construct. After infection with RV16, ENA-78 protein and mRNA increased significantly, and RV16 induced 3-fold increases in ENA-78 gene transcription. Nasal ENA-78 measured in patients with asthma with and without RV infection was more elevated in patients with RV infection present. Our study demonstrates that ENA-78 is produced in bronchial epithelial cells in response to RV16 infection. With other chemokines, it may be an important initiator of neutrophil airway inflammation during RV common colds and thus may play a role in the development of virus-associated airway pathologies.


Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.
Over 1000 different mutants of the tumor suppressor protein p53 with one amino acid change in the core domain have been reported in human cancers. In mouse knock-in models, two frequent mutants displayed loss of wild-type (wt) p53 function, inhibition of wt p53 and wt p53-independent gain of function. The remaining mutants have been systematically characterized for loss of wt p53 function, but not other phenotypes. We report the concomitant assessment of loss of function and interference with wt p53 using URA3-based p53 yeast and confirmatory mammalian assays. We studied 76 mutants representing 54% of over 15 000 reported missense core domain mutations. The majority showed the expected complete loss of wt p53 function and dominant p53 inhibition. A few infrequent p53 mutants had wt p53-like activity. Remarkably, one-third showed no interference with wt p53 despite loss of wt p53 function at 37 degrees C. Half of this group consisted of temperature-sensitive p53 mutants, but the other half was surprisingly made up of mutants with complete loss of wt p53 function. Our findings illustrate the diverse behavior of p53 mutants and mechanisms of malignant transformation by p53 mutants. The identification of full-length p53 mutants without dominant inhibition of wt p53 highlights the importance of determining the status of the wt p53 allele in human cancers, in particular in the context of clinical studies. In the case of p53 mutants with no or weak dominant p53 inhibition, presence of the wt allele may indicate a good prognosis cancer, whereas loss of heterozygosity may spell an aggressive, therapy-resistant cancer.


Impacts of ocean acidification on sediment processes in shallow waters of the Arctic Ocean.
Despite the important roles of shallow-water sediments in global biogeochemical cycling, the effects of ocean acidification on sedimentary processes have received relatively little attention. As high-latitude cold waters can absorb more CO2 and usually have a lower buffering capacity than warmer waters, acidification rates in these areas are faster than those in sub-tropical regions. The present study investigates the effects of ocean acidification on sediment composition, processes and sediment-water fluxes in an Arctic coastal system. Undisturbed sediment cores, exempt of large dwelling organisms, were collected, incubated for a period of 14 days, and subject to a gradient of pCO2 covering the range of values projected for the end of the century. On five occasions during the experimental period, the sediment cores were isolated for flux measurements (oxygen, alkalinity, dissolved inorganic carbon, ammonium, nitrate, nitrite, phosphate and silicate). At the end of the experimental period, denitrification rates were measured and sediment samples were taken at several depth intervals for solid-phase analyses. Most of the parameters and processes (i.e. mineralization, denitrification) investigated showed no relationship with the overlying seawater pH, suggesting that ocean acidification will have limited impacts on the microbial activity and associated sediment-water fluxes on Arctic shelves, in the absence of active bio-irrigating organisms. Only following a pH decrease of 1 pH unit, not foreseen in the coming 300 years, significant enhancements of calcium carbonate dissolution and anammox rates were observed. Longer-term experiments on different sediment types are still required to confirm the limited impact of ocean acidification on shallow Arctic sediment processes as observed in this study.


Colorectal cancer and nonfermented milk, solid cheese, and fermented milk consumption: a systematic review and meta-analysis of prospective studies.
Colorectal cancer is the second most prevalent cancer worldwide. A systematic review and meta-analysis of prospective studies was conducted to examine the association between intake of different types of dairy foods during adulthood and the development of colorectal cancer, specifically comparing nonfermented milk, solid cheese, and fermented milk. Seven databases were systematically searched and 15 cohort studies selected for inclusion, involving over 900,000 subjects and over 5200 colorectal cancer cases. Meta-analysis resulted in an overall relative risk of colon cancer of 0.74 (95% confidence interval 0.60-0.91) in men consuming nonfermented milk (highest intake category averaging 525 g/day). No association was found between consumption of nonfermented milk and rectal cancer in men or nonfermented milk and colon or rectal cancer in women. No protective association was found between consumption of solid cheese or fermented milk and colorectal cancer. Reasons for the differences in the impact of nonfermented milk, solid cheese, and fermented milk in the colon are discussed. This meta-analysis supports the inverse association between nonfermented milk consumption and risk of colon cancer in men, and provides an evidence base to assist in the formulation of dietary guidelines involving dairy foods.


Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro.
Bone regeneration is required for fracture healing. Various procedures have been used to promote osteogenesis with bone morphogenetic proteins (BMPs). We assessed the effects of BMP-2, BMP-5, and BMP-6 in isolated and combined use on the generation of osteoblasts and osteoclasts by comparing the osteoclastic potency of each on osteoclasts of primary murine bone marrow cells. Subsequently, cells were stained for tartrate-resistant acid phosphatase, and real time PCR analysis of receptor activator of NKκB ligand and osteoprotegerin was conducted. The same combination of BMPs was used to assess their potential to enhance osteoblasts, employing a mineralization assay and real-time PCR analysis of collagen type-1, runx2, and osterix. While BMP-2 alone and the combination of BMP-2 and BMP-5 significantly enhanced osteoclastogenesis, BMP-2, BMP-5, and BMP-6 in combination did not have additional effects. However, the combined use of BMP-2, BMP-5, and BMP-6 had an additive effect on matrix mineralization and osterix expression in osteoblasts. Our study shows that the combination of BMP-2, BMP-5, and BMP-6 stimulates osteoblasts but not osteoclastogenesis. Thus, the synergistic use of various BMPs might improve effective bone regeneration in the clinical setting.


Genotoxicity of chromium in human gastric mucosa cells and peripheral blood lymphocytes evaluated by the single cell gel electrophoresis (comet assay).
Hexavalent chromium compounds are well-recognized carcinogens. They easily penetrate the cell membrane and are reduced inside the cell to their trivalent form, which is supposed to react directly with DNA. Chromium is present in some workplaces as well as in water resources and food chain, so it can interact with the mucosa of the gastrointestinal tract. In order to elucidate the genotoxic potency of chromium in human gastric mucosa (GM) cells, the DNA-damaging effect of potassium dichromate (K2Cr2O7) was investigated using alkaline single cell gel electrophoresis (comet assay). Biopsy samples were obtained during gastroscopy from macroscopically healthy tissue of the stomach. Parallel test with human peripheral blood lymphocytes was also performed. Both types of cells were incubated at 37 degrees C with 1.6 mM of K2Cr2O7 for 1 h and after washing, were placed in a chromium-free medium to examine DNA repair. Alkaline single cell gel electrophoresis (comet assay) was used to assess DNA damage and repair. Chromium introduced a damage to DNA both in the GM cells and lymphocytes. The effect induced by K2Cr2O7 in GM cells was comparable with that caused in the lymphocytes. Treated cells were able to recover within a 60-min incubation in a chromium-free medium at 37 degrees C. The results obtained indicate that hexavalent chromium compounds, which may be found in the diet, can interact directly with DNA of the mucosa of the stomach.


Communication of direction by the honey bee.
In the presence of controls for site- and path-specific odors, observer and food-source scents, Nasanov gland and alarm odors, visual cues, wind, and general site taxis, recruited bees were able to locate the food source indicated by the dances of returning foragers in preference to a food source located at an equal distance in the opposite direction. This was true even when foragers were simultaneously dancing to indicate two different stations. Recruitment in the absence of dancing was very low, while in the absence of foraging it was virtually zero. Thus, under the experimental conditions used, the directional information contained in the dance appears to have been communicated from forager to recruit and subsequently used by the recruit.


To live or let die - complexity within the E2F1 pathway.
The E2F1 transcription factor is a recognized regulator of the cell cycle as well as a potent mediator of DNA damage-induced apoptosis and the checkpoint response. Understanding the diverse and seemingly dichotomous functions of E2F1 activity has been the focus of extensive ongoing research. Although the E2F pathway is frequently deregulated in cancer, the contributions of E2F1 itself to tumorigenesis, as a promoter of proliferation or cell death, are far from understood. In this review we aim to provide an update on our current understanding of E2F1, with particular insight into its novel interaction partners and post-translational modifications, as a means to explaining its diverse functional complexity.


Optical manipulation of animal behavior using a ruthenium-based phototrigger.
A visible-light activatable caged compound based on a ruthenium-polypyridine complex was used to elicit the feeding response of the freshwater cnidarian Hydra vulgaris. The phototrigger delivers l-arginine in a clean reaction under irradiation with blue or green light. The synthesis, characterization and application mode of this caged arginine are described. A combination of fiber-optics setup and a high absorbance medium allows the precise control of uncaging in the submillimetric range, needed to address the zone where activation takes place.


Targeting senescence-like fibroblasts radiosensitizes non-small cell lung cancer and reduces radiation-induced pulmonary fibrosis.
Cancer cell radioresistance is the primary cause of the decreased curability of non-small cell lung cancer (NSCLC) observed in patients receiving definitive radiotherapy (RT). Following RT, a set of microenvironmental stress responses is triggered, including cell senescence. However, cell senescence is often ignored in designing effective strategies to resolve cancer cell radioresistance. Herein, we identify the senescence-like characteristics of cancer-associated fibroblasts (CAFs) after RT and clarify the formidable ability of senescence-like CAFs in promoting NSCLC cell proliferation and radioresistance through the JAK/STAT pathway. Specific induction of senescence-like CAF apoptosis using FOXO4-DRI, a FOXO4-p53-interfering peptide, resulted in remarkable effects on radiosensitizing NSCLC cells in vitro and in vivo. In addition, in this study, we also uncovered an obvious therapeutic effect of FOXO4-DRI on alleviating radiation-induced pulmonary fibrosis (RIPF) by targeting senescence-like fibroblasts in vivo. In conclusion, by targeting senescence, we offer a strategy that simultaneously decreases radioresistance of NSCLC and the incidence of RIPF.


No maternal or direct effects of ocean acidification on egg hatching in the Arctic copepod Calanus glacialis.
Widespread ocean acidification (OA) is transforming the chemistry of the global ocean and the Arctic is recognised as the region where this transformation will occur at the fastest rate. Moreover, many Arctic species are considered less capable of tolerating OA due to their lower capacity for acid-base regulation. This inability may put severe restraints on many fundamental functions, such as growth and reproductive investments, which ultimately may result in reduced fitness. However, maternal effects may alleviate severe effects on the offspring rendering them more tolerant to OA. In a highly replicated experiment we studied maternal and direct effects of OA predicted for the Arctic shelf seas on egg hatching time and success in the keystone copepod species Calanus glacialis. We incubated females at present day conditions (pHT 8.0) and year 2100 extreme conditions (pHT 7.5) during oogenesis and subsequently reciprocally transplanted laid eggs between these two conditions. Statistical tests showed no effects of maternal or direct exposure to OA at this level. We hypothesise that C. glacialis may be physiologically adapted to egg production at low pH since oogenesis can also take place at conditions of potentially low haemolymph pH of the mother during hibernation in the deep.


Admitting international graduate nursing students: what faculty need to know.
The number of international applicants to US nursing graduate programs is increasing. Modifying standard admission criteria, such as RN licensure, graduate record examination, validation of BSN degree, criminal background check, letters of recommendation, and personal statements, is necessary because of unique complexities. Addressing admission requirements unique to international students, such as English proficiency, visas, and proof of financial resources, is critical. Managing complexities of admitting international students is necessary to facilitate their success.


Congenital central hypoventilation syndrome from past to future: model for translational and transitional autonomic medicine.
The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24-33 alanines (genotypes 20/24-20/33). The remaining approximately 10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day.


Low-dose idebenone treatment in Friedreich's ataxia with and without cardiac hypertrophy.
Left ventricular hypertrophy (LVH) is a frequent finding in Friedreich's ataxia (FRDA). In previous studies treatment with idebenone, a synthetic analogue of coenzyme Q10, has been associated with a substantial decrease in myocardial hypertrophy, despite great variability in cardiac responsiveness among patients. Here we present the results of a retrospective analysis of a cohort of 35 patients (20 with LVH, 15 without LVH) with confirmed molecular diagnosis of FRDA, treated with idebenone 5 mg/kg/day for up to five years. At the end of the study, we found an increase of interventricular septum and posterior wall thickness in the group without LVH before treatment and no change in the group with LVH before treatment. The neurological picture of the disease significantly deteriorated with time in both groups.


Nonlinear excitation power dependence of surface enhanced fluorescence from a nanostructured Ag film.
We investigate the excitation power dependence of fluorescent emission from Cy3-tagged molecules separated from an Ag film prepatterned with arrays of nanostructures by a thin spacer. While the fluorescent intensities from both the patterned area and the flat Ag surfaces increase monotonically with the power of excitation light, the fluorescent contrast between them decreases with excitation power in a nonlinear fashion. We propose a simple theoretical model which includes basic properties of molecular fluorescence, the effect of near field enhancement from surface plasmon excited on the patterned structure, and the effect of enhancement of fluorescent emission rate and non-radiative decay rate. Our results agree qualitatively with the prediction of a model for which there is a larger enhancement of the excitation rate than that of the total decay rate of the excited molecule.


Regional changes in adipose tissue blood flow and metabolism in rats after a meal.
Adipose tissue blood flow was measured in five depots, and plasma concentrations of glucose, insulin, and triglyceride were measured at 0, 15, 30, and 45 min after the start of a meal in unanesthetized, freely moving rats. In addition, adipose tissue lipoprotein lipase activity was measured in four depots before and 45 min after the start of a meal. Plasma glucose was significantly elevated only at the 15-min time point, and while plasma triglyceride increased these changes did not reach significance. Plasma insulin was significantly elevated at all time points after a meal. Feeding resulted in a consistent decrease of adipose tissue blood flow expressed per gram wet weight of tissue. This decrease was maximal at 30 min after the start of feeding. The decrease in adipose tissue blood flow averaged 45% at 45 min after the start of feeding for the five depots evaluated. Lipoprotein lipase activity significantly increased in the retroperitoneal and mesenteric fat depots at 45 min after the meal start, but did not change in the epididymal or dorsal subcutaneous fat depots. These results suggest that a decrease in adipose tissue blood flow is a normal result of a meal in the rat. The regional specificity of changes in adipose tissue lipoprotein lipase activity supports the concept of regional specificity of function for adipose tissue and suggests that the mesenteric and retroperitoneal depots are particularly important for the storage of triglycerides immediately after a meal.


Hypnotic Tactile Anesthesia: Psychophysical and Signal-Detection Analyses.
Two experiments that studied the effects of hypnotic suggestions on tactile sensitivity are reported. Experiment 1 found that suggestions for anesthesia, as measured by both traditional psychophysical methods and signal-detection procedures, were linearly related to hypnotizability. Experiment 2 employed the same methodologies in an application of the real-simulator paradigm to examine the effects of suggestions for both anesthesia and hyperesthesia. Significant effects of hypnotic suggestion on both sensitivity and bias were found in the anesthesia condition but not for the hyperesthesia condition. A new bias parameter, C', indicated that much of the bias found in the initial analyses was artifactual, a function of changes in sensitivity across conditions. There were no behavioral differences between reals and simulators in any of the conditions, though analyses of postexperimental interviews suggested the 2 groups had very different phenomenal experiences.


Kv1.3 lymphocyte potassium channel inhibition as a potential novel therapeutic target in acute ischemic stroke.
Stroke-induced immunosuppression (SIIS) leads to severe complications in stroke patients, including an increased risk of infections. However, functional alterations of T lymphocytes during SIIS are poorly described in acute ischemic stroke (AIS). We aimed to characterize Ca(2+) influx kinetics in major lymphocyte subsets (CD4, Th1, Th2, CD8) in AIS patients without infection 6 hours and one week after the CNS insult. We also assessed the sensitivity of the above subsets to specific inhibition of the Kv1.3 and IKCa1 lymphocyte K(+) channels. We took peripheral blood samples from 12 non-stroke individuals and 12 AIS patients. We used an innovative flow cytometry approach to determine Ca(2+) influx kinetics and the surface expression of Kv1.3 channels. Our results indicate that Ca(2+) influx kinetics is altered in the Th2 and CD8 subsets in AIS which may play a role in the development of SIIS. Specific inhibition of Kv1.3 channels selectively decreased Ca(2+) influx in the CD8 and Th2 subsets of AIS patients. The surface expression of Kv1.3 channels is also altered compared to non-stroke individuals. Kv1.3 channel inhibition might have beneficial therapeutic consequences in AIS, selectively targeting two distinct T cell subsets at two different time points following the CNS insult. Within hours after the insult, it might prevent excessive tissue injury through the inhibition of CD8 cells, while at one week after the insult, it may improve the inflammatory response through the inhibition of Th2 cells, thus reducing the unwanted clinical consequences of SIIS.


Direct Aqueous-Phase Synthesis of Sub-10 nm "Luminous Pearls" with Enhanced in Vivo Renewable Near-Infrared Persistent Luminescence.
Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs), possessing unique NIR PL properties, have recently emerged as important materials for a wide variety of applications in chemistry and biology, for which they must endure high-temperature solid-state annealing reactions and subsequent complicated physical post-treatments. Herein, we report on a first direct aqueous-phase chemical synthesis route to NIR PLNPs and present their enhanced in vivo renewable NIR PL. Our method leads to monodisperse PLNPs as small as ca. 8 nm. Such sub-10 nm nanocrystals are readily dispersed and functionalized, and can form stable colloidal solutions in aqueous solution and cell culture medium for biological applications. Under biotissue-penetrable red-light excitation, we found that such nanocrystals possess superior renewable PL photoluminescence in vitro and in vivo compared to their larger counterparts currently made by existing methods. We believe that this solid-state-reaction-free chemical approach overcomes the current key roadblock in regard to PLNP development, and thus will pave the way to broad use of these advanced miniature "luminous pearls" in photonics and biophotonics.


Thermal behavior of Pd@SiO2 nanostructures in various gas environments: a combined 3D and in situ TEM approach.
The thermal stability of core-shell Pd@SiO2 nanostructures was for the first time monitored by using in situ Environmental Transmission Electron Microscopy (E-TEM) at atmospheric pressure coupled with Electron Tomography (ET) on the same particles. The core Pd particles, with octahedral or icosahedral original shapes, were followed during thermal heating under gas at atmospheric pressure. In the first step, their morphology/faceting evolution was investigated in a reductive H2 environment up to 400 °C by electron tomography performed on the same particles before and after the in situ treatment. As a result, we observed the formation of small Pd particles inside the silica shell due to the thermally activated diffusion from the core particle. A strong dependence of the shape and faceting transformations on the initial structure of the particles was evidenced. The octahedral monocrystalline NPs were found to be less stable than the icosahedral ones; in the first case, the Pd diffusion from the core towards the silica external surface led to a progressive decrease of the particle size. The icosahedral polycrystalline NPs do not exhibit a morphology/faceting change, as in this case the atom diffusion within the particle is favored against diffusion towards the silica shell, due to a high amount of crystallographic defects in the particles. In the second part, the Pd@SiO2 NPs behavior at high temperatures (up to 1000 °C) was investigated under reductive or oxidative conditions; it was found to be strongly related to the thermal evolution of the silica shell: (1) under H2, the silica is densified and loses its porous structure leading to a final state with Pd core NPs encapsulated in the shell; (2) under air, the silica porosity is maintained and the increase of the temperature leads to an enhancement of the diffusion mechanism from the core towards the external surface of the silica; as a result, at 850 °C all the Pd atoms are expelled outside the silica shell.


Orientation, scale, and discontinuity as emergent properties of illusory contour shape.
A recent neural model of illusory contour formation is based on a distribution of natural shapes traced by particles moving with constant speed in directions given by Brownian motions. The input to that model consists of pairs of position and direction constraints, and the output consists of the distribution of contours joining all such pairs. In general, these contours will not be closed, and their distribution will not be scale-invariant. In this article, we show how to compute a scale-invariant distribution of closed contours given position constraints alone and use this result to explain a well-known illusory contour effect.


Pancreatic cancer susceptibility loci and their role in survival.
Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.


Acyl-ghrelin Is Permissive for the Normal Counterregulatory Response to Insulin-Induced Hypoglycemia.
Insulin-induced hypoglycemia leads to far-ranging negative consequences in patients with diabetes. Components of the counterregulatory response (CRR) system that help minimize and reverse hypoglycemia and coordination between those components are well studied but not yet fully characterized. Here, we tested the hypothesis that acyl-ghrelin, a hormone that defends against hypoglycemia in a preclinical starvation model, is permissive for the normal CRR to insulin-induced hypoglycemia. Ghrelin knockout (KO) mice and wild-type (WT) littermates underwent an insulin bolus-induced hypoglycemia test and a low-dose hyperinsulinemic-hypoglycemic clamp procedure. Clamps also were performed in ghrelin-KO mice and C57BL/6N mice administered the growth hormone secretagogue receptor agonist HM01 or vehicle. Results show that hypoglycemia, as induced by an insulin bolus, was more pronounced and prolonged in ghrelin-KO mice, supporting previous studies suggesting increased insulin sensitivity upon ghrelin deletion. Furthermore, during hyperinsulinemic-hypoglycemic clamps, ghrelin-KO mice required a 10-fold higher glucose infusion rate (GIR) and exhibited less robust corticosterone and growth hormone responses. Conversely, HM01 administration, which reduced the GIR required by ghrelin-KO mice during the clamps, increased plasma corticosterone and growth hormone. Thus, our data suggest that endogenously produced acyl-ghrelin not only influences insulin sensitivity but also is permissive for the normal CRR to insulin-induced hypoglycemia.


Preoperative protective stenting of the internal carotid artery in the management of complex head and neck paragangliomas: long-term results.
To investigate the long-term results of preoperative stenting of the internal carotid artery (ICA) in complex head and neck paragangliomas (HNP) as well as to report on indications and technical details of the procedure. A comprehensive retrospective review of patients affected by HNP, consecutively operated on and preoperatively treated with stenting of the ICA in a quaternary referral skull base center, was performed. Nineteen patients affected by complex HNP were identified, on whom 21 preoperative stenting procedures were performed. The mean follow-up period after stent insertion was 53.8 months; the patients' age ranged from 33 to 56 years. Fourteen patients were affected by tympanojugular paragangliomas, 4 by vagal paragangliomas and 1 by bilateral carotid body tumors. Five patients presented with recurrent tumors, while 7 presented with multiple or bilateral HNP. There were no complications associated with endovascular procedures. Total tumor removal was accomplished in 52.4% of the cases with 1 recurrence. An advanced stage was the main factor conditioning total removal. Clinical control was obtained in 80% of the patients with residual disease. Total tumor removal from and around the ICA was obtained in 95.2% of the cases. Long-term stent patency was evident in 20 of 21 cases. Preoperative stenting of the ICA represents a safe and effective procedure in selected cases, obviating the need for balloon occlusion or bypass procedures and reducing the risk of intraoperative vascular injury.


THE CHEMISTRY OF THE LIVER IN ACUTE YELLOW ATROPHY.
From the liver of a young man who died of typical, " idiopathic" acute yellow atrophy of the liver, after an illness of six weeks, there were isolated and identified the following amino acids: Histidin, lysin, tyrosin, leucin, glycocoll, alanin, prolin, glutaminic acid, aspartic acid. These were found free in extracts of the liver, and presumably represent products of the autolysis of liver cells, although the amount of soluble non-protein nitrogen present in the extracts was so large as to suggest that there must be some other source for these substances. Small quantities of free proteoses and peptones, and of xanthin and hypoxanthin, were also found in the extracts. In the insoluble proteins of the liver the proportion of diamino acids was decreased slightly as compared with normal livers. The proportion of protein phosphorus was increased, probably because of active regenerative proliferation, while the sulphur was normal in amount. Iron was increased because of the large quantity of blood in the liver and the hematogenous pigmentation of the liver cells. Gelatigenous material was increased both absolutely and relatively, because of the loss of parenchyma and the proliferation of the stroma. The proportion of water to solids was much increased, there having been a loss of over two-thirds of the entire parenchymatous elements of the liver. The amount of fat, lecithin and cholesterin was not far from that normal for the liver.


A genomewide survey of developmentally relevant genes in Ciona intestinalis. II. Genes for homeobox transcription factors.
Homeobox-containing genes play crucial roles in various developmental processes, including body-plan specification, pattern formation and cell-type specification. The present study searched the draft genome sequence and cDNA/EST database of the basal chordate Ciona intestinalis to identify 83 homeobox-containing genes in this animal. This number of homeobox genes in the Ciona genome is smaller than that in the Caenorhabditis elegans, Drosophila melanogaster, human and mouse genomes. Of the 83 genes, 76 have possible human orthologues and 7 may be unique to Ciona. The ascidian homeobox genes were classified into 11 classes, including Hox class, NK class, Paired class, POU class, LIM class, TALE class, SIX class, Prox class, Cut class, ZFH class and HNF1 class, according to the classification scheme devised for known homeobox genes. As to the Hox cluster, the Ciona genome contains single copies of each of the paralogous groups, suggesting that there is a single Hox cluster, if any, but genes orthologous to Hox7, 8, 9 and 11 were not found in the genome. In addition, loss of genes had occurred independently in the Ciona lineage and was noticed in Gbx of the EHGbox subclass, Sax, NK3, Vax and vent of the NK class, Cart, Og9, Anf and Mix of the Paired class, POU-I, III, V and VI of the POU class, Lhx6/7 of the LIM class, TGIF of the TALE class, Cux and SATB of the Cut class, and ZFH1 of the ZFH class, which might have reduced the number of Ciona homeobox genes. Interestingly, one of the newly identified Ciona intestinalis genes and its vertebrate counterparts constitute a novel subclass of HNF1 class homeobox genes. Furthermore, evidence for the gene structures and expression of 54 of the 83 homeobox genes was provided by analysis of ESTs, suggesting that cDNAs for these 54 genes are available. The present data thus reveal the repertoire of homeodomain-containing transcription factors in the Ciona genome, which will be useful for future research on the development and evolution of chordates.


Sexual risk behavior among HIV-infected women in South Africa at 12-months postpartum.
The postnatal period is a time of increased susceptibility to HIV infection and superinfection for postpartum women, sexual partners, and infants. This study examined the effect of a prevention to mother-to-child transmission of HIV intervention compared to standard care, and factors associated with unprotected last sex and inconsistent condom use at 12-months postpartum. Participants were N = 1399 HIV-infected women 6-30 weeks pregnant (M = 18 weeks (SD = 5.75)) assessed during pregnancy and 12-months postpartum. Women were aged an average of 28 (SD = 5.82); 48% reported 10-11 years of education. Older age (adjusted odds ratio [AOR] = 1.00) and being employed (AOR = 1.51) were associated with greater odds of unprotected sex at 12-month postpartum. Disclosure of HIV status (AOR = 0.64) and greater male involvement during pregnancy (AOR = 0.92) were associated with lower odds of unprotected sex at 12-month postpartum. HIV negative or unknown partner status (AOR = 0.45) and greater depressive symptoms (AOR = 0.97) were associated with lower odds of inconsistent condom use at 12-months postpartum. The intervention was not associated with reduced sexual risk behavior. Future studies should address male involvement and consider measurement of culturally tailored male involvement constructs for men South Africa. Perinatal women may require support for sexual communication and gender equity to reduce sexual risk.


Foam-driven fracture.
In hydraulic fracturing, water is injected at high pressure to crack shale formations. More sustainable techniques use aqueous foams as injection fluids to reduce the water use and wastewater treatment of conventional hydrofractures. However, the physical mechanism of foam fracturing remains poorly understood, and this lack of understanding extends to other applications of compressible foams such as fire-fighting, energy storage, and enhanced oil recovery. Here we show that the injection of foam is much different from the injection of incompressible fluids and results in striking dynamics of fracture propagation that are tied to the compressibility of the foam. An understanding of bubble-scale dynamics is used to develop a model for macroscopic, compressible flow of the foam, from which a scaling law for the fracture length as a function of time is identified and exhibits excellent agreement with our experimental results.


Hofbauer-Buchner eyelet affects circadian photosensitivity and coordinates TIM and PER expression in Drosophila clock neurons.
Extraretinal photoreception is a common input route for light resetting signals into the circadian clock of animals. In Drosophila melanogaster, substantial circadian light inputs are mediated via the blue light photoreceptor CRYPTOCHROME (CRY) expressed in clock neurons within the brain. The current model predicts that, upon light activation, CRY interacts with the clock proteins TIMELESS (TIM) and PERIOD (PER), thereby inducing their degradation, which in turn leads to a resetting of the molecular oscillations within the circadian clock. Here the authors investigate the function of another putative extraretinal circadian photoreceptor, the Hofbauer-Buchner eyelet (H-B eyelet), located between the retina and the medulla in the fly optic lobes. Blocking synaptic transmission between the H-B eyelet and its potential target cells, the ventral circadian pacemaker neurons, impaired the flies' ability to resynchronize their behavior under jet-lag conditions in the context of nonfunctional retinal photoreception and a mutation in the CRY-encoding gene. The same manipulation also affected synchronized expression of the clock proteins TIM and PER in different subsets of the clock neurons. This shows that synaptic communication between the H-B eyelet and clock neurons contributes to synchronization of molecular and behavioral rhythms and confirms that the H-B eyelet functions as a circadian photoreceptor. Blockage of synaptic transmission from the H-B eyelet in the presence of functional compound eyes and the absence of CRY also results in increased numbers of flies that are unable to synchronize to extreme photoperiods, supplying independent proof for the role of the H-B eyelet as a circadian photoreceptor.


FUNCTIONAL ANALYSIS OF SWIM-BLADDER MUSCLES ENGAGED IN SOUND PRODUCTION OF THE TOADFISH.
A functional analysis of the striated swim-bladder muscles engaged in the sound production of the toadfish has been performed by simultaneous recording of muscle action potentials, mechanical effects, and sound. Experiments with electrical nerve stimulation were made on excised bladder, while decerebrate preparations were used for studies of reflex activation of bladders in situ. The muscle twitch in response to a single maximal nerve volley was found to be very fast. The average contraction time was 5 msec. with a range from 3 to 8 msec., the relaxation being somewhat slower. The analysis of muscle action potentials with surface electrodes showed that the activity of the muscle fibers running transversely to the long axis of the muscle was well synchronized both during artificial and reflex activation. With inserted metal microelectrodes monophasic potentials of 0.4 msec. rise time and 1.2 to 1.5 msec. total duration were recorded. The interval between peak of action potential and onset of contraction was only 0.5 msec. Microphonic recordings of the characteristic sound effect accompanying each contraction showed a high amplitude diphasic deflection during the early part of the contraction. During relaxation a similar but smaller deflection of opposite phase could sometimes be distinguished above the noise level. The output from the microphone was interpreted as a higher order derivative function of the muscle displacement. This interpretation was supported by complementary experiments on muscle sound in mammalian muscle. The dependence of the sound effects on the rate of muscle contraction was demonstrated by changing the temperature of the preparation and, in addition, by a special series of experiments with repeated stimulation at short intervals. Results obtained by varying the pressure within the bladder provided further evidence for the view that the sound initiated in the muscle is reinforced by bladder resonance. Analysis of spontaneous grunts confirmed the finding of a predominant sound frequency of about 100 per second, which was also found in reflexly evoked grunts. During these, muscle action potentials of the same rate as the dominant sound frequency were recorded, the activity being synchronous in the muscles on both sides. Some factors possibly contributing to rapid contraction are discussed.


Granulysin delivered by cytotoxic cells damages endoplasmic reticulum and activates caspase-7 in target cells.
Granulysin is a human cytolytic molecule present in cytotoxic granules with perforin and granzymes. Recombinant 9-kDa granulysin kills a variety of microbes, including bacteria, yeast, fungi, and parasites, and induces apoptosis in tumor cells by causing intracellular calcium overload, mitochondrial damage, and activation of downstream caspases. Reasoning that granulysin delivered by cytotoxic cells may work in concert with other molecules, we crossed granulysin transgenic (GNLY(+/-)) mice onto perforin (perf)- or granzyme B (gzmb)-deficient mice to examine granulysin-mediated killing in a more physiologic whole-cell system. Splenocytes from these animals were activated in vitro with IL-15 to generate cytolytic T cells and NK cells. Cytotoxic cells expressing granulysin require perforin, but not granzyme B, to cause apoptosis of targets. Whereas granzyme B induces mitochondrial damage and activates caspases-3 and -9 in targets, cytotoxic cell-delivered granulysin induces endoplasmic reticulum stress and activates caspase-7 with no effect on mitochondria or caspases-3 and -9. In addition, recombinant granulysin and cell-delivered granulysin activate distinct apoptotic pathways in target cells. These findings suggest that cytotoxic cells have evolved multiple nonredundant cell death pathways, enabling host defense to counteract escape mechanisms employed by pathogens or tumor cells.


Physicians' opinions about medications to treat alcoholism.
Medications play a limited role in the treatment of alcoholism. This paper examines physicians' opinions about and use of two alcoholism medications currently approved in the US--disulfiram and naltrexone--and one alcoholism medication--acamprosate--that might be approved. A total of 1388 substance abuse specialist physicians who were members of the American Academy of Addiction Psychiatry or the American Society of Addiction Medicine completed a questionnaire in 2001 (65% response rate). The average percentages of physicians' patients with alcoholism who were prescribed the following medications were: 13% (naltrexone), 9% (disulfiram), 46% (antidepressants) and 11% (benzodiazepines). Almost all physicians had heard of naltrexone and disulfiram, but their self-reported level of knowledge about these medications was lower than for antidepressants. Physicians estimated that naltrexone had a small-to-medium effect size, which was similar in magnitude to the effect size reported in recent meta-analyses of randomized clinical trials. Physicians identified the following three courses of action as the most likely to result in greater use of medications to treat alcohol dependence: more research to develop new medications (33%), more education of physicians about existing medications (17%), and increased involvement of physicians in alcoholism treatment (17%). Physicians' low rate of use of naltrexone may reflect its small-to-medium effect size.


Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.
In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.


Quantification and aging of the post-blast residue of TNT landmines.
Post-blast residues are potential interferents to chemical detection of landmines. To assess the potential problem related to 2,4,6-trinitrotoluene (TNT), its post-blast residue was identified and quantified. In the first part of this study laboratory-scale samples of TNT (2 g) were detonated in a small-scale explosivity device (SSED) to evaluate the explosive power and collect post-blast residue for chemical analysis. Initiator size was large relative to the TNT charge; thus, issues arose regarding choice of initiator, residue from the initiator, and afterburning of TNT. The second part of this study detonated 75 to 150 g of military-grade TNT (typical of antipersonnel mines) in 55-gal barrels containing various witness materials (metal plates, sand, barrel walls, the atmosphere). The witness materials were analyzed for explosive residue. In a third set of tests, 75-g samples of TNT were detonated over soil (from Fort Leonard Wood or Sandia National Laboratory) in an indoor firing chamber (100 by 4.6 by 2.7 m high). Targeted in these studies were TNT and four explosive-related compounds (ERC): 2,4-dinitrotoluene (DNT), 1,3-dinitrobenzene (DNB), 2- and 4-aminodinitrotoluene (2-ADNT and 4-ADNT). The latter two are microbial degradation products of TNT. Post-blast residue was allowed to age in the soils as a function of moisture contents (5 and 10%) in order to quantify the rate of degradation of the principal residues (TNT, DNT, and DNB) and formation of the TNT microbial degradation products (2-ADNT and 4-ADNT). The major distinction between landmine leakage and post-blast residue was not the identity of the species but relative ratios of amounts. In landmine leakage the DNT/TNT ratio was usually greater than 1. In post-blast residue it was on the order of 1 to 1/100th of a percent, and the total amount of pre-blast residue (landmine leakage) was a factor of 1/100 to 1/1000 less than post-blast. In addition, landmine leakage resulted in low DNT/ADNT ratios, usually less than 1, whereas pre-blast residues started with ratios above 20. Because with time DNT decreased and ADNT increased, over a month the ratio decreased by a factor of 2. The rate of TNT degradation in soil observed in this study was much slower than that reported when initial concentrations of TNT were lower. Degradation rates yielded half-lives of 40 and 100 days for 2,4-DNT and TNT, respectively.


Effectiveness of Short-Term Health Coaching on Diabetes Control and Self-Management Efficacy: A Quasi-Experimental Trial.
Introduction: The aim of this study was to explore the effectiveness in HbA1c lowering and self-efficacy of diabetes self-management of a 6 months coaching intervention. Methods: This paper was a two-armed coaching intervention study in which 116 participants who presented type 2 diabetes were recruited at a medical center. The intervention group had health coaching and usual care for 6 months, whereas the control had usual care only. The main outcome variables were HbA1c level and self-efficacy of diabetes self-management, in followed-up measure at 3 and 6 months. Results: We found that an approximate 0.68% (CI = 0.40 to 0.96) reduction in HbA1c was achieved after a 6-month health coaching. Both physical activity and self-efficacy of diabetes self-management were shown to benefit by health coaching. Conclusions: Health coaching might be an effective strategy to enhance self-management for diabetes patients in Taiwan where "Diabetes Shared Care Network" had been implemented for over 20 years. Consider limitations of this study, more studies with designs that yield higher quality evidence for the role of health coaching in diabetic patients are needed. Clinical Trial Registration: www.isrctn.com (ID number: ISRCTN52454940, date: 10 May, 2018, retrospectively registered).


Safety assessment of the substance (triethanolamine-perchlorate, sodium salt) dimer, for use in food contact materials.
The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the substance (triethanolamine-perchlorate, sodium salt) dimer, FCM substance No 1080, intended to be used as a thermal stabiliser at up to 0.15% w/w in rigid poly(vinyl chloride) (PVC) for repeated use bottles in contact with water. No thermal degradation of the substance is expected during the manufacture of the PVC articles. In water, the substance fully dissociates into triethanolamine, sodium (cations) and perchlorate. Therefore, migration would lead to exposure to triethanolamine and perchlorate and not to the substance itself. Specific migration of perchlorate, ethanolamine, diethanolamine and triethanolamine was tested under repeated use conditions covering the requested uses. After the second and third contacts, perchlorate was detected at ca. 0.3 μg/kg food. Ethanolamine, diethanolamine and triethanolamine were not detected in any of the three contacts at an estimated limit of detection of 0.03 mg/kg food. The available in vitro studies on the substance confirmed the lack of concern for genotoxicity, as anticipated by the dissociation of the substance into authorised non-genotoxic substances. Therefore, the CEP Panel concluded that the substance is not of safety concern for the consumer if used, under the condition requested by the applicant, as an additive at up to 0.15% w/w in rigid PVC for repeated use bottles intended for contact with water. Additionally, the migration of triethanolamine and perchlorate should not exceed the specific migration limits (SMLs) of 50 μg/kg food and 2 μg/kg food, respectively, set in the Regulation (EU) 10/2011. This evaluation also covers acidic foods such as fruit juices that can reasonably be foreseen to be in contact.


Design of the PEDS-C trial: pegylated interferon +/- ribavirin for children with chronic hepatitis C viral infection.
PEDS-C is the first multicenter placebo-controlled trial for the treatment of chronic hepatitis C (HCV) in childhood that has ever been conducted in the United States (USA). Establishment of the research team, protocol, administrative infrastructure, and ancillary contributors for the pediatric trial took years of planning. To study the safety and efficacy of pegylated-interferon alpha (PEG-2a) plus ribavirin (RV) with PEG-2a monotherapy in children aged 5 years through 18 years. To assess the health-related quality of life and growth and body composition in children with chronic hepatitis C infection, before, during, and after treatment. Eleven centers of pediatric hepatobiliary clinical research were united in a National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) funded grant with financial support from the Food and Drug Administration (FDA) and a corporate sponsor to conduct the treatment trial. The most important initial limitation in the design of this complex study was securing the financial support and infrastructural organization, a process that took several years. Challenges faced by the study group included identifying the optimal study design given the limited study population, and determining what ancillary studies could be incorporated into the treatment trial. In this article the process taken to design the study and administrative infrastructure, the lessons learned, and the controversial issues deliberated during the planning process are discussed. The evolution of the study and the considerations taken in the development of the protocol are valuable tools which can be applied to pediatric clinical trials in general.


Phantom breast and other syndromes after mastectomy: eight breast cancer patients describe their experiences over time: a 2-year follow-up study.
Patients often experience hard-to-treat neuropathic pain and other sensations after surgery; consequently, they could develop chronic pain conditions. The phantom limb phenomenon is a well-documented postoperative pain condition. However, phantom phenomena after mastectomies are less documented. The reviews report several views on the prevalence of breast phantoms and coexisting distress. Researchers observed that new methodological approaches might facilitate further research of these issues. This prospective, qualitative study used semistructured interviews to acquire knowledge of if and how phantom breast phenomena appear within the range of other postmastectomy symptoms and sensations. The study revealed that a phantom breast could be difficult to describe and position spatially. The phantom breast phenomenon varied from classic phantom extremity phenomenon and did not seem to cause much distress. However, it proved to be a phenomenon so unknown and different that there is urgent need for more knowledge. This study highlights the importance of further investigation regarding how information and communication related to a phantom breast might be developed. The phantom breast is only one piece of a complicated puzzle. Because it was relatively unknown for the women in the study, it is important that analyses of this phenomenon, as a part of a postmastectomy syndrome, be conducted in a dialogue with the patients, by scientifically using qualitative methods.


Israeli acute paralysis virus: epidemiology, pathogenesis and implications for honey bee health.
Israeli acute paralysis virus (IAPV) is a widespread RNA virus of honey bees that has been linked with colony losses. Here we describe the transmission, prevalence, and genetic traits of this virus, along with host transcriptional responses to infections. Further, we present RNAi-based strategies for limiting an important mechanism used by IAPV to subvert host defenses. Our study shows that IAPV is established as a persistent infection in honey bee populations, likely enabled by both horizontal and vertical transmission pathways. The phenotypic differences in pathology among different strains of IAPV found globally may be due to high levels of standing genetic variation. Microarray profiles of host responses to IAPV infection revealed that mitochondrial function is the most significantly affected biological process, suggesting that viral infection causes significant disturbance in energy-related host processes. The expression of genes involved in immune pathways in adult bees indicates that IAPV infection triggers active immune responses. The evidence that silencing an IAPV-encoded putative suppressor of RNAi reduces IAPV replication suggests a functional assignment for a particular genomic region of IAPV and closely related viruses from the Family Dicistroviridae, and indicates a novel therapeutic strategy for limiting multiple honey bee viruses simultaneously and reducing colony losses due to viral diseases. We believe that the knowledge and insights gained from this study will provide a new platform for continuing studies of the IAPV-host interactions and have positive implications for disease management that will lead to mitigation of escalating honey bee colony losses worldwide.


Role of Extensive Lymphadenectomy in Early-Stage Cervical Cancer Patients With Radical Hysterectomy Followed by Adjuvant Radiotherapy.
The objective of this study was to assess the effect of extensive lymphadenectomy on survival of early-stage cervical cancer patients with radical hysterectomy followed by adjuvant radiotherapy (RT). A retrospective analysis was performed on early-stage patients with high-risk factors who received radical hysterectomy with lymphadenectomy followed by adjuvant RT. All patients were divided into the less than or equal to 40 dissected pelvic lymph nodes (DPLN ≤40) and greater than 40 dissected pelvic lymph nodes (DPLN >40) groups to assess the effect of extensive lymphadenectomy. Distributions of disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Significance of survival was assessed by the log-rank test. Cox proportional hazards models were applied to assess the effects of the factors on survival by univariate and multivariate analyses. After a median follow-up of 76 months for a total of 178 patients, 5-year DFS of the DPLN >40 group was significantly higher than that of the DPLN ≤40 group (86% vs 74%, P = 0.045). Five-year OS was comparable between the 2 groups (85% vs 78%, P = 0.49). The multivariate analysis showed that the DPLN ≤40 group was at a significantly higher risk of recurrence (hazard ratio, 2.3; 95% confidence interval (CI), 1.1-4.8; P = 0.020), whereas OS was not affected by the DPLN group (P = 0.26). Positive pelvic lymph node, parametrial invasion, histological type, and the absence of RT-combined chemotherapy remained significant prognostic factors for lower DFS and OS by the multivariate analysis. Adjusted hazard ratio of DPLN ≤40 for DFS was 1.2 (95% CI, 0.11-12; P = 0.91) in patients with negative pelvic lymph node (PLN) whereas it was 2.6 (95% CI, 1.1-5.8; P = 0.024) in patients with positive PLN. These results suggest that more extensive lymphadenectomy significantly improve the outcomes of patients with positive PLN even followed by adjuvant RT.


Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire.
The Primary Care Evaluation of Mental Disorders (PRIME-MD) was developed as a screening instrument but its administration time has limited its clinical usefulness. To determine if the self-administered PRIME-MD Patient Health Questionnaire (PHQ) has validity and utility for diagnosing mental disorders in primary care comparable to the original clinician-administered PRIME-MD. Criterion standard study undertaken between May 1997 and November 1998. Eight primary care clinics in the United States. Of a total of 3000 adult patients (selected by site-specific methods to avoid sampling bias) assessed by 62 primary care physicians (21 general internal medicine, 41 family practice), 585 patients had an interview with a mental health professional within 48 hours of completing the PHQ. Patient Health Questionnaire diagnoses compared with independent diagnoses made by mental health professionals; functional status measures; disability days; health care use; and treatment/referral decisions. A total of 825 (28%) of the 3000 individuals and 170 (29%) of the 585 had a PHQ diagnosis. There was good agreement between PHQ diagnoses and those of independent mental health professionals (for the diagnosis of any 1 or more PHQ disorder, kappa = 0.65; overall accuracy, 85%; sensitivity, 75%; specificity, 90%), similar to the original PRIME-MD. Patients with PHQ diagnoses had more functional impairment, disability days, and health care use than did patients without PHQ diagnoses (for all group main effects, P<.001). The average time required of the physician to review the PHQ was far less than to administer the original PRIME-MD (<3 minutes for 85% vs 16% of the cases). Although 80% of the physicians reported that routine use of the PHQ would be useful, new management actions were initiated or planned for only 117 (32%) of the 363 patients with 1 or more PHQ diagnoses not previously recognized. Our study suggests that the PHQ has diagnostic validity comparable to the original clinician-administered PRIME-MD, and is more efficient to use.


Facing biology's open questions: Rupert Sheldrake's "heretical" hypothesis turns 40.
Despite the triumphant rhetoric of mechanistic materialism, current biology has no shortage of unsolved fundamental problems. In 1981, seeking a way forward, Rupert Sheldrake proposed the hypothesis of "formative causation" as a unifying organizing principle of life. Expanding the concept of morphogenetic fields, Sheldrake posited a spatio-temporal connection termed "morphic resonance" whereby the more often a self-organizing process takes place, the easier it will be for it to take place in the future. After initial acclaim, his project was quickly met with dogmatic skepticism, dismissed as scientific heresy, and ultimately ignored. Forty years later, the experimental implications of his ideas remain largely untested. Visionary or not, Sheldrake's case illustrates the conceptual resistance of the scientific enterprise to revise its own deepest theoretical commitments. Beyond career-building selection pressures, young researchers need to be presented with the major questions in their field and encouraged to entertain radically alternative points of view. Science is what scientists make of it.


The archaeal DNA primase: biochemical characterization of the p41-p46 complex from Pyrococcus furiosus.
We characterized the primase complex of the hyperthermophilic archaeon, Pyrococcus furiosus. The two proteins, Pfup41 and Pfup46, have similar sequences to the p48 and p58 subunits, respectively, of the eukaryotic DNA polymerase alpha-primase complex. Unlike previously reported primases, the Pfup41 preferentially utilizes deoxyribonucleotides for its de novo synthesis, and moreover, it synthesizes up to several kilobases in length in a template-dependent manner (Bocquier, A., Liu, L., Cann, I., Komori, K., Kohda, D., and Ishino, Y. (2001) Curr. Biol. 11, 452-456). The p41-p46 complex showed higher DNA binding activity than the catalytic p41 subunit alone. In addition, the amount of DNA synthesized by the p41-p46 complex was much more abundant and shorter in length than that by Pfup41 alone. The activity for RNA primer synthesis, which was not detected with Pfup41, was observed from the reaction using the p41-p46 complex in vitro. The in vitro replication of M13 single-stranded DNA by the P. furiosus proteins was stimulated by ATP. Observation of the labeled primers by using [gamma-(32)P]ATP in the substrates suggests ATP as the preferable initiating nucleotide for the p41-p46 complex. These results show that the primer synthesis activity of Pfup41 is regulated by Pfup46, and the p41-p46 complex may function as the primase in the DNA replication machinery of P. furiosus, in a similar fashion to the eukaryotic polymerase alpha-primase complex.


Canadian Thoracic Society 2011 guideline update: diagnosis and treatment of sleep disordered breathing.
The Canadian Thoracic Society (CTS) published an executive summary of guidelines for the diagnosis and treatment of sleep disordered breathing in 2006⁄2007. These guidelines were developed during several meetings by a group of experts with evidence grading based on committee consensus. These guidelines were well received and the majority of the recommendations remain unchanged. The CTS embarked on a more rigorous process for the 2011 guideline update, and addressed eight areas that were believed to be controversial or in which new data emerged. The CTS Sleep Disordered Breathing Committee posed specific questions for each area. The recommendations regarding maximum assessment wait times, portable monitoring, treatment of asymptomatic adult obstructive sleep apnea patients, treatment with conventional continuous positive airway pressure compared with automatic continuous positive airway pressure, and treatment of central sleep apnea syndrome in heart failure patients replace the recommendations in the 2006⁄2007 guidelines. The recommendations on bariatric surgery, complex sleep apnea and optimum positive airway pressure technologies are new topics, which were not covered in the 2006⁄2007 guidelines.


Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent.
Prostate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case-control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African-Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83-0.97 and OR 0.88, 95% CI: 0.82-0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01-1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46-0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene-environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent.


Functionalization of nanostructured cerium oxide films with histidine.
The surfaces of polycrystalline cerium oxide films were modified by histidine adsorption under vacuum and characterized by the synchrotron based techniques of core and valence level photoemission, resonant photoemission and near edge X-ray absorption spectroscopy, as well as atomic force microscopy. Histidine is strongly bound to the oxide surface in the anionic form through the deprotonated carboxylate group, and forms a disordered molecular adlayer. The imidazole ring and the amino side group do not form bonds with the substrate but are involved in the intermolecular hydrogen bonding which stabilizes the molecular adlayer. The surface reaction with histidine results in water desorption accompanied by oxide reduction, which is propagated into the bulk of the film. Previously studied, well-characterized surfaces are a guide to the chemistry of the present polycrystalline surface and histidine bonds via the carboxylate group in both cases. In contrast, bonding via the imidazole group occurs on the well-ordered surface but not in the present case. The morphology and structure of the cerium oxide are decisive factors which define the adsorption geometry of the histidine adlayer.


Creep and inverse stress relaxation behaviors of carbon nanotube yarns.
Creep, creep recovery and inverse stress relaxation behaviors of carbon nanotube yarns that consisted of 1-, 30-, and 100-yarn(s) were characterized. Primary and secondary creep stages were observed over the duration of 336 h. The primary creep stage lasted for about 4 h at an applied load equal to 75% of the ultimate tensile strength. The total strain in the primary stage was significantly larger in the carbon nanotube multi-yarn than in the carbon nanotube 1-yarn. In the secondary stage, 1-yarn also had a smaller steady state strain rate than the multi-yarn, and it was independent of number of yarns in multi-yarn. Strain response under cyclic creep loading condition was comparable to its counterpart in non-cyclic (i.e., standard) creep test except that strain response during the first cycle was slightly different from the subsequent cycles. Inverse creep (i.e., strain recovery) was observed in the 100-yarn during the cyclic creep tests after the first unloading cycle. Furthermore, inverse stress relaxation of the multi-yarns was characterized. Inverse stress relaxation was larger and for longer duration with the larger number of yarns.


Clustering through postinhibitory rebound in synaptically coupled neurons.
Postinhibitory rebound is a nonlinear phenomenon present in a variety of nerve cells. Following a period of hyperpolarization this effect allows a neuron to fire a spike or packet of spikes before returning to rest. It is an important mechanism underlying central pattern generation for heartbeat, swimming and other motor patterns in many neuronal systems. In this paper we consider how networks of neurons, which do not intrinsically oscillate, may make use of inhibitory synaptic connections to generate large scale coherent rhythms in the form of cluster states. We distinguish between two cases (i) where the rebound mechanism is due to anode break excitation and (ii) where rebound is due to a slow T-type calcium current. In the former case we use a geometric analysis of a McKean-type model to obtain expressions for the number of clusters in terms of the speed and strength of synaptic coupling. Results are found to be in good qualitative agreement with numerical simulations of the more detailed Hodgkin-Huxley model. In the second case we consider a particular firing rate model of a neuron with a slow calcium current that admits to an exact analysis. Once again existence regions for cluster states are explicitly calculated. Both mechanisms are shown to prefer globally synchronous states for slow synapses as long as the strength of coupling is sufficiently large. With a decrease in the duration of synaptic inhibition both systems are found to break into clusters. A major difference between the two mechanisms for cluster generation is that anode break excitation can support clusters with several groups, while slow T-type calcium currents predominantly give rise to clusters of just two (antisynchronous) populations.


Women's HIV disclosure to family and friends.
Previous researchers have documented rates of HIV disclosure to family at discrete time periods, yet none have taken a dynamic approach to this phenomenon. The purpose of this study is to take the next step and provide a retrospective comparison of rates of women's HIV disclosure to family and friends over a 15-year time span. Of particular interest are the possible influences of social network and relationship characteristics on the time-to-disclosure of serostatus. Time-to-disclosure was analyzed from data provided by 125 HIV-positive women. Participants were primarily married or dating (42%), unemployed (79.2%), African American (68%) women with a high school diploma or less (54.4%). Length of time since diagnosis ranged from 1 month to over 19 years (M=7.1 years). Results pointed to statistically significant differences in time-to-disclosure between family, friends, and sexual partners. Additionally, females and persons with whom the participant had more frequent contact were more likely to be disclosed to, regardless of the type of relationship. The results of this study underscore possible challenges with existing studies which have employed point prevalence designs, and point to new methods which could be helpful in family research.


Pharmacy student perceptions of public health service roles and responsibilities.
There is increasing emphasis on pharmacists' assuming responsibility for public health promotion and delivery with formal expansion of public health activities in their practice. A number of pharmacy school accreditation bodies now incorporate public health competencies within expected professional training outcomes. The objective of this study was to characterize pharmacy student perceptions towards pharmacist public health services roles and responsibilities. All undergraduate students at the College of Pharmacy at Qatar University were surveyed 1 week following a student-led breast cancer awareness event. A questionnaire was devised from a literature review and comprised of 10 questions assessing pharmacy student motivations, perceptions and anticipated comfort with various pharmacist-conducted public health activities. Ninety-four per cent of students responded, most having participated in the breast cancer awareness event. They generally felt pharmacist participation in such health promotions would enhance the profession's profile among patients (75.1%) and colleagues (89.6%), but recognized that other health professionals may be unfamiliar with certain pharmacist activities in this regard. Students considered knowledge of disease aetiology and diagnosis necessary for pharmacists (97.9%), as well as the obligation to offer non-pharmacological patient counselling (73.8%). Many (61.7%) anticipated comfort in communicating potentially culturally sensitive health matters both to patients in their own practice site or as a spokesperson to the general public. Undergraduate pharmacy students in our College of Pharmacy expressed favourable attitudes towards public health roles of pharmacists. Early enthusiasm for participation in public health activities is valuable for building communication skills, promoting leadership and potentially influencing practising pharmacists.


Dissemination of cephalosporin resistance genes between Escherichia coli strains from farm animals and humans by specific plasmid lineages.
Third-generation cephalosporins are a class of β-lactam antibiotics that are often used for the treatment of human infections caused by Gram-negative bacteria, especially Escherichia coli. Worryingly, the incidence of human infections caused by third-generation cephalosporin-resistant E. coli is increasing worldwide. Recent studies have suggested that these E. coli strains, and their antibiotic resistance genes, can spread from food-producing animals, via the food-chain, to humans. However, these studies used traditional typing methods, which may not have provided sufficient resolution to reliably assess the relatedness of these strains. We therefore used whole-genome sequencing (WGS) to study the relatedness of cephalosporin-resistant E. coli from humans, chicken meat, poultry and pigs. One strain collection included pairs of human and poultry-associated strains that had previously been considered to be identical based on Multi-Locus Sequence Typing, plasmid typing and antibiotic resistance gene sequencing. The second collection included isolates from farmers and their pigs. WGS analysis revealed considerable heterogeneity between human and poultry-associated isolates. The most closely related pairs of strains from both sources carried 1263 Single-Nucleotide Polymorphisms (SNPs) per Mbp core genome. In contrast, epidemiologically linked strains from humans and pigs differed by only 1.8 SNPs per Mbp core genome. WGS-based plasmid reconstructions revealed three distinct plasmid lineages (IncI1- and IncK-type) that carried cephalosporin resistance genes of the Extended-Spectrum Beta-Lactamase (ESBL)- and AmpC-types. The plasmid backbones within each lineage were virtually identical and were shared by genetically unrelated human and animal isolates. Plasmid reconstructions from short-read sequencing data were validated by long-read DNA sequencing for two strains. Our findings failed to demonstrate evidence for recent clonal transmission of cephalosporin-resistant E. coli strains from poultry to humans, as has been suggested based on traditional, low-resolution typing methods. Instead, our data suggest that cephalosporin resistance genes are mainly disseminated in animals and humans via distinct plasmids.


Histological and Behavioral Evaluation after Traumatic Brain Injury in Mice: A Ten Months Follow-Up Study.
Traumatic brain injury (TBI) is a chronic pathology, inducing long-term deficits that remain understudied in pre-clinical studies. In this context, exploration, anxiety-like behavior, cognitive flexibility, and motor coordination were assessed until 5 and 10 months after an experimental TBI in the adult mouse, using two cohorts. In order to differentiate age, surgery, and remote gray and white matter lesions, three groups (unoperated, sham-operated, and TBI) were studied. TBI induced delayed motor coordination deficits at the pole test, 4.5 months after injury, that could be explained by gray and white matter damages in ipsilateral nigrostriatal structures (striatum, internal capsule) that were spreading to new structures between cohorts, at 5 versus 10 months after the injury. Further, TBI induced an enhanced exploratory behavior during stressful situations (active phase during actimetry test, object exploration in an open field), risk-taking behaviors in the elevated plus maze 5 months after injury, and a cognitive inflexibility in the Barnes maze that persisted until 9 months after the injury. These behavioral modifications could be related to the white and gray matter lesions observed in ipsi- and contralateral limbic structures (amygdala, hilus/cornu ammonis 4, hypothalamus, external capsule, corpus callosum, and cingular cortex) that were spreading to new structures between cohorts, at 5 months versus 10 months after the injury. The present study corroborates clinical findings on TBI and provides a relevant rodent chronic model which could help in validating pharmacological strategies against the chronic consequences of TBI.


The impact of the heparin-induced thrombocytopenia (HIT) computerized alert on provider behaviors and patient outcomes.
The aim of this study was to measure the effect of an electronic heparin-induced thrombocytopenia (HIT) alert on provider ordering behaviors and on patient outcomes. A pop-up alert was created for providers when an individual's platelet values had decreased by 50% or to <100,000/mm(3) in the setting of recent heparin exposure. The authors retrospectively compared inpatients admitted between January 24, 2008 and August 24, 2008 to a control group admitted 1 year prior to the HIT alert. The primary outcome was a change in HIT antibody testing. Secondary outcomes included an assessment of incidence of HIT antibody positivity, percentage of patients started on a direct thrombin inhibitor (DTI), length of stay and overall mortality. There were 1006 and 1081 patients in the control and intervention groups, respectively. There was a 33% relative increase in HIT antibody test orders (p=0.01), and 33% more of these tests were ordered the first day after the criteria were met when a pop-up alert was given (p=0.03). Heparin was discontinued in 25% more patients in the alerted group (p=0.01), and more direct thrombin inhibitors were ordered for them (p=0.03). The number who tested HIT antibody-positive did not differ, however, between the two groups (p=0.99). The length of stay and mortality were similar in both groups. The HIT alert significantly impacted provider behaviors. However, the alert did not result in more cases of HIT being detected or an improvement in overall mortality. Our findings do not support implementation of a computerized HIT alert.