Hairstyle as an adaptive means of displaying phenotypic quality.
Although facial features that are considered beautiful have been investigated across cultures using the framework of sexual selection theory, the effects of head hair on esthetic evaluations have rarely been examined from an evolutionary perspective. In the present study the effects of six hair-styles (short, medium-length, long, disheveled, knot [hair bun], unkempt) on female facial attractiveness were examined in four dimensions (femininity, youth, health, sexiness) relative to faces without visible head hair ("basic face"). Three evolutionary hypotheses were tested (covering hypothesis, healthy mate theory, and good genes model); only the good genes model was supported by our data. According to this theory, individuals who can afford the high costs of long hair are those who have good phenotypic and genetic quality. In accordance with this hypothesis, we found that only long and medium-length hair had a significant positive effect on ratings of women's attractiveness; the other hairstyles did not influence the evaluation of their physical beauty. Furthermore, these two hairstyles caused a much larger change in the dimension of health than in the rest of the dimensions. Finally, male raters considered the longer-haired female subjects' health status better, especially if the subjects were less attractive women. The possible relationships between facial attractiveness and hair are discussed, and alternative explanations are presented.


Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy.
The last two decades have seen a revival of interest in the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA) as an adjunct to psychotherapy, particularly for the treatment of post-traumatic stress disorder. While clinical results are highly promising, and MDMA is expected to be approved as a treatment in the near future, it is currently the only compound in its class of action that is being actively investigated as a medicine. This lack of alternatives to MDMA may prove detrimental to patients who do not respond well to the particular mechanism of action of MDMA or whose treatment calls for a modification of MDMA's effects. For instance, patients with existing cardiovascular conditions or with a prolonged history of stimulant drug use may not fit into the current model of MDMA-assisted psychotherapy, and could benefit from alternative drugs. This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives in the future, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action and entactogenic commonalities with MDMA. The substances examined derive from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole and amphetamine classes. Several compounds from these classes are identified as potential alternatives to MDMA.


An evaluation of the species and subspecies of the genus Salmonella with whole genome sequence data: Proposal of type strains and epithets for novel S. enterica subspecies VII, VIII, IX, X and XI.
Species and subspecies within the Salmonella genus have been defined for public health purposes by biochemical properties; however, reference laboratories have increasingly adopted sequence-based, and especially whole genome sequence (WGS), methods for surveillance and routine identification. This leads to potential disparities in subspecies definitions, routine typing, and the ability to detect novel subspecies. A large-scale analysis of WGS data from the routine sequencing of clinical isolates was employed to define and characterise Salmonella subspecies population structure, demonstrating that the Salmonella species and subspecies were genetically distinct, including those previously identified through phylogenetic approaches, namely: S. enterica subspecies londinensis (VII), subspecies brasiliensis (VIII), subspecies hibernicus (IX) and subspecies essexiensis (X). The analysis also identified an additional novel subspecies, reptilium (XI). Further, these analyses indicated that S. enterica subspecies arizonae (IIIa) isolates were divergent from the other S. enterica subspecies, which clustered together and, on the basis of ANI analysis, subspecies IIIa was sufficiently distinct to be classified as a separate species, S. arizonae. Multiple phylogenetic and statistical approaches generated congruent results, suggesting that the proposed species and subspecies structure was sufficiently biologically robust for routine application. Biochemical analyses demonstrated that not all subspecies were distinguishable by these means and that biochemical approaches did not capture the genomic diversity of the genus. We recommend the adoption of standardised genomic definitions of species and subspecies and a genome sequence-based approach to routine typing for the identification and definition of novel subspecies.


Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner.
Caspase activation in target cells is a major function of granzyme B (grB) during cytotoxic lymphocyte granule-induced apoptosis. grB-mediated cell death can occur in the absence of active caspases, and the molecular targets responsible for this additional pathway remain poorly defined. Apoptotic plasma membrane blebbing is caspase independent during granule exocytosis-mediated cell death, whereas in other instances, this event is a consequence of the cleavage by caspases of the Rho effector, Rho-associated coiled coil-containing protein kinase (ROCK) I. We show here that grB directly cleaves ROCK II, a ROCK family member encoded by a separate gene and closely related to ROCK I, and this causes constitutive kinase activity and bleb formation. For the first time, two proteins of the same family are found to be specifically cleaved by either a caspase or grB, thus defining two independent pathways with similar phenotypic consequences in the cells. During granule-induced cell death, ROCK II cleavage by grB would overcome, for this apoptotic feature, the consequences of deficient caspase activation that may occur in virus-infected or malignant target cells.


Response of cluster headache to psilocybin and LSD.
The authors interviewed 53 cluster headache patients who had used psilocybin or lysergic acid diethylamide (LSD) to treat their condition. Twenty-two of 26 psilocybin users reported that psilocybin aborted attacks; 25 of 48 psilocybin users and 7 of 8 LSD users reported cluster period termination; 18 of 19 psilocybin users and 4 of 5 LSD users reported remission period extension. Research on the effects of psilocybin and LSD on cluster headache may be warranted.


Predictors of post-recurrence survival in patients with non-small-cell lung cancer initially completely resected.
Despite recent progress in diagnostic technology and therapeutic approaches to non-small-cell lung cancer (NSCLC), 30-75% of patients develop tumour recurrence after resection. However, the details of post-recurrence survival (PRS) are not well understood. We aimed to investigate the predictors of PRS in patients with NSCLC initially completely resected. A series of 568 NSCLC patients who had undergone complete resection between 2000 and 2009 were evaluated retrospectively. Patients who had developed recurrent NSCLC after complete resection were subjected to the current analysis. We examined PRS using the Kaplan-Meier method and multivariate Cox regression analyses. Of the 568 patients, 138 (24.3%) were identified as having disease recurrence. The 2-year and 5-year PRS rates were 44.6 and 25.9%, respectively, while the median PRS time was 22.5 months. Non-adenocarcinoma histology [hazard ratio (HR) = 2.825, 95% confidence interval (CI): 1.825-4.367, P < 0.001], serum carcinoembryonic antigen (CEA) at recurrence ≥5.0 mg/dl (HR = 2.205, 95% CI: 1.453-3.344, P < 0.001) and no systemic chemotherapy (HR = 2.137, 95% CI: 1.304-3.247, P = 0.002) were independent prognostic factors for PRS. The current results showed that non-adenocarcinoma histology, elevated serum CEA at recurrence and no systemic chemotherapy were independent unfavourable post-recurrence prognostic factors. The current data can be informative for patient follow-up after complete resection and further clinical investigation may give us more information about PRS and accurate treatment strategy for recurrent NSCLC after initial complete resection.


The relationship of endotoxaemia to peripheral and central nervous system inflammatory responses in Human African Trypanosomiasis.
Endotoxaemia has been described in cases of Human African trypanosomiasis (HAT), but it is unclear if this phenomenon influences inflammatory pathology either in the periphery or central nervous system (CNS). We studied endotoxin concentrations in the plasma and cerebrospinal fluid (CSF) of Trypanosoma brucei rhodesiense patients using the chromogenic Limulus Amoebocyte lysate assay. The relationship of endotoxin concentration to the presentation of gross signs of inflammation and the inflammatory/counter-inflammatory cytokine profile of the relevant compartments were analysed. We demonstrate that HAT patients exhibit parasitaemia-independent plasma endotoxaemia, and that this is associated with splenomegaly and lymphadenopathy. Endotoxin concentrations normalize rapidly after treatment. There was no evidence of endotoxin release in the CNS. A rapid normalization of endotoxin levels after treatment and lack of association with parasitaemia suggest that gut leakage is the main source of endotoxin in the circulation. Low CSF endotoxin concentrations and a lack of any association with neuroinflammatory markers or neurological sequelae suggest that endotoxin does not play a role in the pathogenesis of the disease in the CNS.


Waddlia, Parachlamydia and Chlamydiaceae in bovine abortion.
The etiology remains unknown in many cases of bovine abortion in Switzerland. Bacteria of the Chlamydiales order are known abortive agents, therefore cases of bovine abortion from three representative regions of Switzerland were investigated in this study. Particularly Chlamydiaceae as well as the Chlamydia-like organisms Waddlia and Parachlamydia were of interest, especially because of their possible zoonotic potential. Placenta samples (n=343) were tested for these bacteria by different PCR-methods, immunohistochemistry and serology for Chlamydia abortus. Additionally an attempt for the isolation of Waddlia and Parachlamydia was made by co-cultivation in amoebae. In 67.3% of the 343 cases a necrotizing and/or purulent placentitis was found histologically. By real-time PCR, 0.9% (3/343) of the cases were positive for Waddlia, 13.4% (46/343) positive for Parachlamydia and 14.6% (50/343) positive or questionable positive for Chlamydiaceae. Of these samples, confirmation by immunohistochemistry was possible in 2/3 cases for Waddlia, 25/46 for Parachlamydia and 4/50 for Chlamydiaceae. Of the 50 cases positive or questionable positive for Chlamydiaceae, species-identification by ArrayTube Microarray or 16S rRNA PCR resulted in 41 cases positive for C. abortus whereas the presence of Chlamydia suis was confirmed in four and Chlamydia pecorum in one case. This study brought evidence for the importance of different members of Chlamydiales in different regions of Switzerland although Waddlia is not occurring in a high prevalence. On the other hand mixed infections with different Chlamydiales as well as with other abortigenic agents could be found.


Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.


Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation.
In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-d-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-d-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG-sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor.


Both conventional and interferon killer dendritic cells have antigen-presenting capacity during influenza virus infection.
Natural killer cells are innate effector cells known for their potential to produce interferon-gamma and kill tumour and virus-infected cells. Recently, B220(+)CD11c(int)NK1.1(+) NK cells were found to also have antigen-presenting capacity like dendritic cells (DC), hence their name interferon-producing killer DC (IKDC). Shortly after discovery, it has already been questioned if IKDC really represent a separate subset of NK cells or merely represent a state of activation. Despite similarities with DCs, in vivo evidence that they behave as bona fide APCs is lacking. Here, using a model of influenza infection, we found recruitment of both conventional B220(-) NK cells and IKDCs to the lung. To study antigen-presenting capacity of NK cell subsets and compare it to cDCs, all cell subsets were sorted from lungs of infected mice and co-cultured ex vivo with antigen specific T cells. Both IKDCs and conventional NK cells as well as cDCs presented virus-encoded antigen to CD8 T cells, whereas only cDCs presented to CD4 T cells. The absence of CD4 responses was predominantly due to a deficiency in MHCII processing, as preprocessed peptide antigen was presented equally well by cDCs and IKDCs. In vivo, the depletion of NK1.1-positive NK cells and IKDCs reduced the expansion of viral nucleoprotein-specific CD8 T cells in the lung and spleen, but did finally not affect viral clearance from the lung. In conclusion, we found evidence for APC function of lung NK cells during influenza infection, but this is a feature not exclusive to the IKDC subset.


Reappraisal of Vipera aspis venom neurotoxicity.
The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2) neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2) composition of the snakes captured in the same areas. We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2)s. We used SELDI technology to study the diversity of PLA(2) in various venom samples. Neurological signs (mainly cranial nerve disturbances) were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrénées and Provence-Alpes-Côte d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom neurotoxic PLA(2)s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2) venom composition confirmed the existence of population of neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. The association of epidemiological studies to genetic, biochemical and immunochemical analyses of snake venoms allowed a good evaluation of the potential neurotoxicity of snake bites. A correlation was found between the expression of neurological symptoms in humans and the intensity of the cross-reaction of venoms with anti-ammodytoxin antibodies, which is correlated with the level of neurotoxin (vaspin and/or ammodytoxin) expression in the venom. The origin of the two recently identified neurotoxic snake populations is discussed according to venom PLA(2) genome and transcriptome data.


Rupture of the internal elastic lamina and vascular fragility in stroke-prone spontaneously hypertensive rats.
We studied a possible relation between stroke and an enhanced susceptibility to rupture of the arterial internal elastic lamina by comparing stroke-prone spontaneously hypertensive rats with spontaneously hypertensive rats, which have a very low incidence of stroke. We quantified interruptions in the internal elastic lamina in certain arteries and studied the effect of beta-aminopropionitrile, an inhibitor of cross-link formation in collagen and elastic fibers, on rupture of the internal elastic lamina and on mortality in these two substrains. To eliminate any influence of higher blood pressure in the stroke-prone rats on the parameters studied, we used antihypertensive treatment to obtain equivalent blood pressures in the two substrains. Results showed that stroke sensitivity was associated with an enhanced early spontaneous rupture of the internal elastic lamina in the caudal artery, an increased susceptibility to beta-aminopropionitrile-induced rupture of the internal elastic lamina, and earlier mortality, mainly from aortic rupture, under beta-aminopropionitrile treatment. These findings suggest that stroke-prone rats have an enhanced minor connective tissue defect that is expressed by rupture of the internal elastic lamina and may be related, at least in part, to their greater vascular fragility and increased susceptibility to stroke.


A Comparative Study on the Faecal Bacterial Community and Potential Zoonotic Bacteria of Muskoxen (Ovibos moschatus) in Northeast Greenland, Northwest Greenland and Norway.
Muskoxen (Ovibos moschatus) are ruminants adapted to a high-fibre diet. There is increasing interest in the role that gut microbes play in the digestion and utilization of these specialized diets but only limited data available on the gut microbiome of high-Arctic animals. In this study, we metabarcoded the 16S rRNA region of faecal samples from muskoxen of Northeast Greenland, Northwest Greenland and Norway, and quantified the effects of physiological and temporal factors on bacterial composition. We found significant effects of body mass, year of sampling and location on the gut bacterial communities of North East Greenland muskoxen. These effects were however dwarfed by the effects of location, emphasizing the importance of the local ecology on the gut bacterial community. Habitat alterations and rising temperatures may therefore have a considerable impact on muskoxen health and reproductive success. Moreover, muskoxen are hunted and consumed in Greenland, Canada and Alaska; therefore, this study also screened for potential zoonoses of food safety interest. A total of 13 potentially zoonotic genera were identified, including the genera Erysipelothrix and Yersinia implicated in recent mass die-offs of the muskoxen themselves.


Effects of fatigue on golf performance.
The purpose of this study was to determine if body position, weight transfer, and/or pelvis/trunk rotations changed as a result of a golf specific fatiguing protocol and whether these changes affected resultant club head velocity at impact and shot consistency. Six male golfers and one female golfer participated in the study, who had a mean age, height, and body mass of 23.9 +/- 3.9 years, 177.4 +/- 4.9 cm, and 75.3 +/- 9.9 kg, respectively. Path analysis was used to determine the relationships between fatigue, biomechanical variables, and resultant club head velocity at impact and shot consistency. In the statistical models representing the effects of biomechanical variables calculated at the top of the swing and ball contact, golf specific fatigue was associated with a 2.0% and 2.5% reduction in the club head velocity and a 7.1% and 9.4% improvement in the shot consistency, respectively. These data suggest that golf specific fatigue was not related to the initial lower body sagittal plane angles at address nor was simulated golf specific fatigue related to peak transverse plane pelvis and trunk rotational velocities (or their timings) in a manner that indicates a relationship to resultant club head velocity and shot consistency.


Tailoring bilberry powder functionality through processing: Effects of drying and fractionation on the stability of total polyphenols and anthocyanins.
Bilberries are a rich natural source of phenolic compounds, especially anthocyanins. The press cake obtained during the processing of bilberry juice is a potential source of phytochemicals. The objective of this study was to evaluate different drying techniques and the fractionation of bilberry press cake powder toward obtaining phenolic-rich ingredients for incorporation into value-added food products. The derived powders were dispersed in water and dairy cream, to investigate the effects of drying and fractionation on the dispersibility and solubility of phenolic compounds. The drying techniques, hot air drying and microwave drying, applied on bilberry press cake reduced the content of total phenolics and anthocyanins. The degradation was, however, consistently small and similar for both techniques. The major anthocyanins detected in the samples were stable during drying and fractionation treatments. Fractionation of the press cake powder affected the total apparent phenolic content and composition of the different fractions. The highest phenolic content (55.33 ± 0.06 mg g-1 DW) and highest anthocyanin content (28.15 ± 0.47 mg g-1 DW) were found in the fractions with the smallest particle size (<500 μm), with delphinidin-3-O-galactoside being the most abundant anthocyanin. Dispersibility of all dried powder samples was higher in dairy cream than water, and the highest level of anthocyanins was measured in samples from the powder with the smallest particle size (<500 μm), dispersed in cream. The application of drying, milling and fractionation was found to be a promising approach to transform bilberry press cake into stable and deliverable ingredients that can be used for fortification of food products with high levels of phenolic compounds.


Current impact and future directions of high throughput sequencing in plant virus diagnostics.
The ability to provide a fast, inexpensive and reliable diagnostic for any given viral infection is a key parameter in efforts to fight and control these ubiquitous pathogens. The recent developments of high-throughput sequencing (also called Next Generation Sequencing - NGS) technologies and bioinformatics have drastically changed the research on viral pathogens. It is now raising a growing interest for virus diagnostics. This review provides a snapshot vision on the current use and impact of high throughput sequencing approaches in plant virus characterization. More specifically, this review highlights the potential of these new technologies and their interplay with current protocols in the future of molecular diagnostic of plant viruses. The current limitations that will need to be addressed for a wider adoption of high-throughput sequencing in plant virus diagnostics are thoroughly discussed.


Support for the involvement of large copy number variants in the pathogenesis of schizophrenia.
We investigated the involvement of rare (<1%) copy number variants (CNVs) in 471 cases of schizophrenia and 2792 controls that had been genotyped using the Affymetrix GeneChip 500K Mapping Array. Large CNVs >1 Mb were 2.26 times more common in cases (P = 0.00027), with the effect coming mostly from deletions (odds ratio, OR = 4.53, P = 0.00013) although duplications were also more common (OR = 1.71, P = 0.04). Two large deletions were found in two cases each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia and a deletion on 17p12, at 14.0-15.4 Mb. The latter is known to cause hereditary neuropathy with liability to pressure palsies. The same deletion was found in 6 of 4618 (0.13%) cases and 6 of 36 092 (0.017%) controls in the re-analysed data of two recent large CNV studies of schizophrenia (OR = 7.82, P = 0.001), with the combined significance level for all three studies achieving P = 5 x 10(-5). One large duplication on 16p13.1, which has been previously implicated as a susceptibility factor for autism, was found in three cases and six controls (0.6% versus 0.2%, OR = 2.98, P = 0.13). We also provide the first support for a recently reported association between deletions at 15q11.2 and schizophrenia (P = 0.026). This study confirms the involvement of rare CNVs in the pathogenesis of schizophrenia and contributes to the growing list of specific CNVs that are implicated.


Khipu accounting in ancient Peru.
Khipu are knotted-string devices that were used for bureaucratic recording and communication in the Inka Empire. We recently undertook a computer analysis of 21 khipu from the Inka administrative center of Puruchuco, on the central coast of Peru. Results indicate that this khipu archive exemplifies the way in which census and tribute data were synthesized, manipulated, and transferred between different accounting levels in the Inka administrative system.


A statistical shape model of the human second cervical vertebra.
Statistical shape and appearance models play an important role in reducing the segmentation processing time of a vertebra and in improving results for 3D model development. Here, we describe the different steps in generating a statistical shape model (SSM) of the second cervical vertebra (C2) and provide the shape model for general use by the scientific community. The main difficulties in its construction are the morphological complexity of the C2 and its variability in the population. The input dataset is composed of manually segmented anonymized patient computerized tomography (CT) scans. The alignment of the different datasets is done with the procrustes alignment on surface models, and then, the registration is cast as a model-fitting problem using a Gaussian process. A principal component analysis (PCA)-based model is generated which includes the variability of the C2. The SSM was generated using 92 CT scans. The resulting SSM was evaluated for specificity, compactness and generalization ability. The SSM of the C2 is freely available to the scientific community in Slicer (an open source software for image analysis and scientific visualization) with a module created to visualize the SSM using Statismo, a framework for statistical shape modeling. The SSM of the vertebra allows the shape variability of the C2 to be represented. Moreover, the SSM will enable semi-automatic segmentation and 3D model generation of the vertebra, which would greatly benefit surgery planning.


Association between ambulance diversion and survival among patients with acute myocardial infarction.
Ambulance diversion, a practice in which emergency departments (EDs) are temporarily closed to ambulance traffic, might be problematic for patients experiencing time-sensitive conditions, such as acute myocardial infarction (AMI). However, there is little empirical evidence to show whether diversion is associated with worse patient outcomes. To analyze whether temporary ED closure on the day a patient experiences AMI, as measured by ambulance diversion hours of the nearest ED, is associated with increased mortality rates among patients with AMI. DESIGN, STUDY, AND PARTICIPANTS: A case-crossover design of 13,860 Medicare patients with AMI from 508 zip codes within 4 California counties (Los Angeles, San Francisco, San Mateo, and Santa Clara) whose admission date was between 2000 and 2005. Data included 100% Medicare claims data that covered admissions between 2000 and 2005, linked with date of death until 2006, and daily ambulance diversion logs from the same 4 counties. Among the hospital universe, 149 EDs were identified as the nearest ED to these patients. The percentage of patients with AMI who died within 7 days, 30 days, 90 days, 9 months, and 1 year from admission (when their nearest ED was not on diversion and when that same ED was exposed to <6, 6 to <12, and ≥12 hours of diversion out of 24 hours on the day of admission). Between 2000 and 2006, the mean (SD) daily diversion duration was 7.9 (6.1) hours. Based on analysis of 11,625 patients admitted to the ED between 2000 and 2005, and whose nearest ED had at least 3 diversion exposure levels (3541, 3357, 2667, and 2060 patients for no exposure, exposure to <6, 6 to <12, and ≥12 hours of diversion, respectively), there were no statistically significant differences in mortality rates between no diversion and exposure to less than 12 hours of diversion. Exposure to 12 or more hours of diversion was associated with higher 30-day mortality vs no diversion status (unadjusted mortality rate, 392 patients [19%] vs 545 patients [15%]; regression adjusted difference, 3.24 percentage points; 95% confidence interval [CI], 0.60-5.88); higher 90-day mortality (537 patients [26%] vs 762 patients [22%]; 2.89 percentage points; 95% CI, 0.13-5.64); higher 9-month mortality (680 patients [33%] vs 980 patients [28%]; 2.93 percentage points; 95% CI, 0.15-5.71); and higher 1-year mortality (731 patients [35%] vs 1034 patients [29%]; 3.04 percentage points; 95% CI, 0.33-5.75). Among Medicare patients with AMI in 4 populous California counties, exposure to at least 12 hours of diversion by the nearest ED was associated with increased 30-day, 90-day, 9-month, and 1-year mortality.


Safety, efficiency, and cost-effectiveness of a multidisciplinary percutaneous tracheostomy program.
The frequency of bedside percutaneous tracheostomies is increasing in intensive care medicine, and both safety and efficiency of care are critical elements in continuing success of this procedure. Prioritizing patient safety, a tracheostomy team was created at our institution to provide bedside expertise in surgery, anesthesiology, respiratory, and technical support. This study was performed to evaluate the metrics of patient outcome, efficiency of care, and cost-benefit analysis of the multidisciplinary Johns Hopkins Percutaneous Tracheostomy Program. A review was performed for patients who received tracheostomies in 2004, the year before the Johns Hopkins Percutaneous Tracheostomy Program was established, and those who received tracheostomies in 2008, the year following the program's establishment. Comparative outcomes were evaluated, including the efficiency of procedure and intensive care unit length of stay, complication rate including bleeding, hypoxia, loss of airway, and a financial cost-benefit analysis. Single-center, major university hospital. The sample consisted of 363 patients who received a tracheostomy in the years 2004 and 2008. The number of percutaneous procedures increased from 59 of 126 tracheostomy patients in 2004, to 183 of 237 in 2008. There were significant decreases in the prevalence of procedural complications, particularly in the realm of airway injuries and physiologic disturbances. Regarding efficiency, the structured program reduced the time to tracheostomy and overall procedural time. The intensive care unit length of stay in nonpulmonary patients and improvement in intensive care unit and operating room back-fill efficiency contributed to an overall institutional financial benefit. An institutionally subsidized, multi-disciplinary percutaneous tracheostomy program can improve the quality of care in a cost-effective manner by decreasing the incidence of tracheostomy complications and improving both the time to tracheostomy, duration of procedure, and postprocedural intensive care unit stay.


The role of the biochemical and biophysical environment in chondrogenic stem cell differentiation assays and cartilage tissue engineering.
The field of regenerative medicine offers hope for the development of a cell-based therapy for the repair of articular cartilage (AC). Yet, the greatest challenge in the use of stem cells for tissue repair, is understanding how the cells respond to stimuli and using that knowledge to direct cell fate. Novel methods that utilize stem cells in cartilage regeneration will require specific spatio-temporal controls of the biochemical and biophysical signaling environments. Current chondrogenic differentiation research focuses on the roles of biochemical stimuli like growth factors, hormones, and small molecules, and the role of the physical environment and mechanical stimuli, such as compression and shear stress, which likely act through mechanical receptors. Numerous signals are associated with chondrogenic-like activity of cells in different systems, however many variables for a controlled method still need to be optimized; e.g., spatial and temporal application of the stimuli, and time of transplantation of an engineered construct. Understanding the necessary microenvironmental signals for cell differentiation will advance cell therapy for cartilage repair.


N-tuple network, CART and bagging.
Similarities between bootstrap aggregation (bagging) and N-tuple sampling are explored to propose a retina-free data-driven version of the N-tuple network, whose close analogies to aggregated regression trees, such as classification and regression trees (CART), lead to further architectural enhancements. Performance of the proposed algorithms is compared with the traditional versions of the N-tuple and CART networks on a number of regression problems. The architecture significantly outperforms conventional N-tuple networks while leading to more compact solutions and avoiding certain implementational pitfalls of the latter.


Anti-diabetic effect of sorghum extract on hepatic gluconeogenesis of streptozotocin-induced diabetic rats.
It has been suggested that Sorghum, a rich source of phytochemicals, has a hypoglycemic effect, but the mechanism is unknown. We investigated the effects of oral administration of sorghum extract (SE) on hepatic gluconeogenesis and the glucose uptake of muscle in streptozotocin-induced diabetic rats for six weeks. Male Wistar rats were divided in five groups (n=5 per group): normal control (NC), rats with STZ-induced diabetic mellitus (DM), diabetic rats administrated 0.4 g/kg body weight of SE (DM-SE 0.4) and 0.6 g/kg body weight of SE (DM-SE 0.6), and diabetic rats administrated 0.7 mg/kg body weight of glibenclamide (DM-G). Administration of SE and G reduced the concentration of triglycerides, total and LDL-cholesterol and glucose, and the area under the curve of glucose during intraperitoneal glucose tolerance tests down to the levels observed in non-diabetic rats. In addition, administration of 0.4 and 0.6 g/kg SE and 0.7 mg/kg glibenclamide (G) significantly reduced the expression of phosphoenolpyruvate carboxykinase and the phosphor-p38/p38 ratio, while increased phosphor adenosine monophosphate activated protein kinase (AMPK)/AMPK ratio, but the glucose transporter 4 translocation and the phosphor-Akt/Akt ratio was significantly increased only by administration of G. These results indicate that the hypoglycemic effect of SE was related to hepatic gluconeogenesis but not the glucose uptake of skeletal muscle, and the effect was similar to that of anti-diabetic medication.


Discovery of a novel activator of KCNQ1-KCNE1 K channel complexes.
KCNQ1 voltage-gated K(+) channels (Kv7.1) associate with the family of five KCNE peptides to form complexes with diverse gating properties and pharmacological sensitivities. The varied gating properties of the different KCNQ1-KCNE complexes enables the same K(+) channel to function in both excitable and non excitable tissues. Small molecule activators would be valuable tools for dissecting the gating mechanisms of KCNQ1-KCNE complexes; however, there are very few known activators of KCNQ1 channels and most are ineffective on the physiologically relevant KCNQ1-KCNE complexes. Here we show that a simple boronic acid, phenylboronic acid (PBA), activates KCNQ1/KCNE1 complexes co-expressed in Xenopus oocytes at millimolar concentrations. PBA shifts the voltage sensitivity of KCNQ1 channel complexes to favor the open state at negative potentials. Analysis of different-sized charge carriers revealed that PBA also targets the permeation pathway of KCNQ1 channels. Activation by the boronic acid moiety has some specificity for the Kv7 family members (KCNQ1, KCNQ2/3, and KCNQ4) since PBA does not activate Shaker or hERG channels. Furthermore, the commercial availability of numerous PBA derivatives provides a large class of compounds to investigate the gating mechanisms of KCNQ1-KCNE complexes.


Distribution and habitat attributes associated with the Himalayan red panda in the westernmost distribution range.
The Himalayan red panda (Ailurus fulgens), a recently confirmed distinct species in the red panda genus, is distributed in Nepal, India, Bhutan, and south Tibet. Nepal represents the westernmost distribution of the Himalayan red panda. This study aims to determine important habitat features influencing the distribution of red panda and recommend possible habitat corridors. This manuscript described current potential habitat of 3,222 km2 with the relative abundance of 3.34 signs/km in Nepal. Aspect, canopy cover, bamboo cover, and distance to water were the important habitat attributes. It suggested five potential corridors in western Nepal. Overall, the study has important implications for conservation of the Himalayan red panda in western distribution range.


Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy.
: Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13-23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction.


Image reconstruction in optoacoustic tomography for dispersive acoustic media.
Conventional image reconstruction methods for optoacoustic tomography (OAT) assume an idealized, non-dispersive acoustic medium. However, the linear attenuation coefficient and the phase velocity of acoustic waves propagating in soft tissue depend on temporal frequency and satisfy a known dispersion law. These frequency-dependent effects are incorporated into an optoacoustic wave equation, and a corresponding reconstruction method for OAT is developed. The improvement in image fidelity that can be achieved over conventional reconstruction methods is demonstrated by use of computer-simulation studies.


Evaluation of an automated enzyme-linked fluorescent assay for thyroxine measurement in cat and dog sera.
Measurement of total thyroxine (T4) is the first testing step in the work-up of thyroid disease in small animals. We evaluated an enzyme-linked fluorescent assay (ELFA) as an in-house method to measure T4 in cats and dogs. We compared the T4 concentration in sera of 122 cats and 176 dogs measured by the ELFA with an enzyme immunoassay (EIA) to assess the concordance of the 2 methods. Bias of the ELFA in cats was -11.4% and in dogs 1.4%. Using Bland-Altman plots, limits of agreement were -81.5 to 58.7% in cats and -71.4 to 74.4% in dogs. Imprecision was calculated for both methods. Intra- and interassay coefficients of variation (CVs) of the ELFA in feline sera were 0.7 and 3.4% and of the EIA 7.6 and 15.7%, respectively. Intra- and interassay CVs of both ELFA and EIA in canine sera were <9.5%. Reference intervals for the ELFA method were established and were 13.3-49.5 nmol/L for cats and 10.1-42.9 nmol/L for dogs. Accuracy of the EIA and ELFA was scored by assessing if the measured T4 value would identify the expected T4 range (low, normal, or elevated) of patients, based on history, clinical presentation, other diagnostic means, and response to therapy. This was possible for 75 cats and 50 dogs. Both methods yielded acceptable results, but the EIA was more accurate compared to the ELFA (percentage of true-positives in cats and dogs: EIA: 97% and 100%; ELFA: 92% and 94%).


The ArsD As(III) metallochaperone.
Arsenic, a toxic metalloid widely existing in the environment, causes a variety of health problems. The ars operon encoded by Escherichia coli plasmid R773 has arsD and arsA genes, where ArsA is an ATPase that is the catalytic subunit of the ArsAB As(III) extrusion pump, and ArsD is an arsenic chaperone for ArsA. ArsD transfers As(III) to ArsA and increases the affinity of ArsA for As(III), allowing resistance to environmental concentrations of arsenic. Cys12, Cys13 and Cys18 in ArsD form a three sulfur-coordinated As(III) binding site that is essential for metallochaperone activity. ATP hydrolysis by ArsA is required for transfer of As(III) from ArsD to ArsA, suggesting that transfer occurs with a conformation of ArsA that transiently forms during the catalytic cycle. The 1.4 Å x-ray crystal structure of ArsD shows a core of four β-strands flanked by four α-helices in a thioredoxin fold. Docking of ArsD with ArsA was modeled in silico. Independently ArsD mutants exhibiting either weaker or stronger interaction with ArsA were selected. The locations of the mutations mapped on the surface of ArsD are consistent with the docking model. The results suggest that the interface with ArsA involves one surface of α1 helix and metalloid binding site of ArsD.


Health workforce and governance: the crisis in Nigeria.
In Nigeria, several challenges have been reported within the health sector, especially in training, funding, employment, and deployment of the health workforce. We aimed to review recent health workforce crises in the Nigerian health sector to identify key underlying causes and provide recommendations toward preventing and/or managing potential future crises in Nigeria. We conducted a scoping literature search of PubMed to identify studies on health workforce and health governance in Nigeria. A critical analysis, with extended commentary, on recent health workforce crises (2010-2016) and the health system in Nigeria was conducted. The Nigerian health system is relatively weak, and there is yet a coordinated response across the country. A number of health workforce crises have been reported in recent times due to several months' salaries owed, poor welfare, lack of appropriate health facilities and emerging factions among health workers. Poor administration and response across different levels of government have played contributory roles to further internal crises among health workers, with different factions engaged in protracted supremacy challenge. These crises have consequently prevented optimal healthcare delivery to the Nigerian population. An encompassing stakeholders' forum in the Nigerian health sector remain essential. The national health system needs a solid administrative policy foundation that allows coordination of priorities and partnerships in the health workforce and among various stakeholders. It is hoped that this paper may prompt relevant reforms in health workforce and governance in Nigeria toward better health service delivery in the country.


Illustrating the Applicability of IRT to Implementation Science: Examining an Instrument of Therapist Attitudes.
Pragmatic instruments with psychometric support are important to advance dissemination and implementation (D&I) research, but few well-researched D&I instruments exist. Item response theory (IRT), an approach that is underutilized in D&I, can help with the development of actionable and brief instruments. This paper provides an overview of IRT for D&I researchers and examines an instrument of therapist attitudes using IRT measurement models. Eight items of the Attitudes Towards Individualized Assessment-Monitoring and Feedback (AIA-MF) Clinical Utility scale were fit to the Graded Response Model in a national sample of master's level therapists. Various IRT model characteristics including item threshold and discrimination parameters, information, and item and person fit were examined. Discrimination and thresholds parameters showed significant variability across the eight items. Item information curves also showed that each item contributed variably to the total test information, suggesting that items 4 and 5 reliably measure therapist attitudes across the latent continuum and items 3 and 6 warrant further investigation. Results suggest that IRT models can help D&I researchers examine existing instruments with greater specificity than traditional measurement methods, thus increasing measurement precision while lowering response burden, both important considerations for the field.


Threatened and endangered subspecies with vulnerable ecological traits also have high susceptibility to sea level rise and habitat fragmentation.
The presence of multiple interacting threats to biodiversity and the increasing rate of species extinction make it critical to prioritize management efforts on species and communities that maximize conservation success. We implemented a multi-step approach that coupled vulnerability assessments evaluating threats to Florida taxa such as climate change, sea-level rise, and habitat fragmentation with in-depth literature surveys of taxon-specific ecological traits. The vulnerability, adaptive capacity, and ecological traits of 12 threatened and endangered subspecies were compared to non-listed subspecies of the same parent species. Overall, the threatened and endangered subspecies showed high vulnerability and low adaptive capacity, in particular to sea level rise and habitat fragmentation. They also exhibited larger home ranges and greater dispersal limitation compared to non-endangered subspecies, which may inhibit their ability to track changing climate in fragmented landscapes. There was evidence for lower reproductive capacity in some of the threatened or endangered taxa, but not for most. Taxa located in the Florida Keys or in other low coastal areas were most vulnerable to sea level rise, and also showed low levels of adaptive capacity, indicating they may have a lower probability of conservation success. Our analysis of at-risk subspecies and closely related non-endangered subspecies demonstrates that ecological traits help to explain observed differences in vulnerability and adaptive capacity. This study points to the importance of assessing the relative contributions of multiple threats and evaluating conservation value at the species (or subspecies) level when resources are limited and several factors affect conservation success.


Nociceptors: the sensors of the pain pathway.
Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.


Supplemental L-arginine enhances wound healing in diabetic rats.
L-arginine has been shown to enhance wound strength and collagen deposition in rodents and humans. Diabetes mellitus, which impairs wound healing, is accompanied by a reduction in nitric oxide at the wound site. The amino acid L-arginine is the only substrate for nitric oxide synthesis. We sought to determine whether supplemental L-arginine can restore the impaired wound healing of diabetic rats. Fifty-six male Lewis rats were used in this study, of which twenty-nine rats were rendered diabetic 7 days prior to surgery with intraperitoneal streptozotocin. Twenty-seven untreated rats served as controls. Animals underwent a dorsal skin incision with implantation of polyvinyl-alcohol sponges. Sixteen diabetic and 14 normal rats received 1 g/kg/day of L-arginine by injection, while the remainder received saline injections only. Animals were euthanized 10 days postwounding, and their wounds were analyzed for breaking strength. The wound sponges were assayed for total hydroxyproline and nitrite/nitrate content. Plasma and wound fluid concentrations of L-arginine, ornithine, and citrulline were determined. Wound sponge RNA was extracted and subjected to Northern blot analysis for procollagen I and III. Diabetic wounds had greatly decreased breaking strengths compared with controls. L-arginine significantly enhanced wound breaking strengths in both control (+23%) and diabetic animals (+44%), and also increased wound hydroxyproline levels in both diabetic (+40%) and control animals (+24%) as compared to their saline-treated counterparts. mRNA for procollagen I and III were elevated by L-arginine treatment in both diabetic rats and controls. Treatment with L-arginine significantly increased wound fluid nitrite/nitrate levels in diabetic animals. The data show that the impaired healing of diabetic wounds can be partially corrected by L-arginine supplementation, and that this effect is accompanied by enhanced wound nitric oxide synthesis.


Severe hypophosphataemia following ferric carboxymaltose infusion in paediatric patients with inflammatory bowel disease.
This case series describes the cases of three adolescent patients with established inflammatory bowel disease (IBD) who experienced significant hypophosphataemia following intravenous infusion of ferric carboxymaltose as treatment for iron deficiency anaemia. Hypophosphataemia may cause a diverse range of symptoms and may be difficult to diagnose clinically due to their non-specific nature. Checking a baseline phosphate (PO4) prior to intravenous iron infusion may identify patients at higher risk for significant hypophosphataemia and perhaps allow the selection of an alternative iron preparation. The routine monitoring of PO4 levels postinfusion presents a greater challenge; with cases of asymptomatic hypophosphataemia likely to be uncovered, as in case 3. Clinicians, patients and families should be aware of the symptoms of hypophosphataemia, and symptomatic patients should have bloods checked to allow prompt identification and correction of abnormalities where required. Review of guidelines surrounding intravenous iron infusion and management of hypophosphataemia in paediatric patients is now required.


Disengaged: a qualitative study of communication and collaboration between physicians and other professions on general internal medicine wards.
Poor interprofessional communication in hospital is deemed to cause significant patient harm. Although recognition of this issue is growing, protocols are being implemented to solve this problem without empirical research on the interprofessional communication interactions that directly underpin patient care. We report here the first large qualitative study of directly-observed talk amongst professions in general internal medicine wards, describing the content and usual conversation partners, with the aim of understanding the mechanisms by which current patterns of interprofessional communications may impact on patient care. Qualitative study with 155 hours of data-collection, including observation and one-on-one shadowing, ethnographic and semi-structured interviews with physicians, nurses, and allied health professionals in the General Internal Medicine (GIM) wards of two urban teaching hospitals in Canada. Data were coded and analysed thematically with a focus on collaborative interactions between health professionals in both interprofessional and intraprofessional contexts. Physicians in GIM wards communicated with other professions mainly in structured rounds. Physicians' communications were terse, consisting of reports, requests for information, or patient-related orders. Non-physician observations were often overlooked and interprofessional discussion was rare. Intraprofessional interactions among allied health professions, and between nursing, as well as interprofessional interactions between nursing and allied health were frequent and deliberative in character, but very few such discussions involved physicians, whose deliberative interactions were almost entirely with other physicians. Without interprofessional problem identification and discussion, physician decisions take place in isolation. While this might be suited to protocol-driven care for patients whose conditions were simple and courses predictable, it may fail complex patients in GIM who often need tailored, interprofessional decisions on their care.Interpersonal communication training to increase interprofessional deliberation may improve efficiency, patient-centredness and outcomes of care in hospitals. Also, electronic communications tools which reduce cognitive burden and facilitate the sharing of clinical observations and orders could help physicians to engage more in non-medical deliberation. Such interventions should take into account real-world power differentials between physicians and other health professions.


Longitudinal neurostimulation in older adults improves working memory.
An increasing concern affecting a growing aging population is working memory (WM) decline. Consequently, there is great interest in improving or stabilizing WM, which drives expanded use of brain training exercises. Such regimens generally result in temporary WM benefits to the trained tasks but minimal transfer of benefit to untrained tasks. Pairing training with neurostimulation may stabilize or improve WM performance by enhancing plasticity and strengthening WM-related cortical networks. We tested this possibility in healthy older adults. Participants received 10 sessions of sham (control) or active (anodal, 1.5 mA) tDCS to the right prefrontal, parietal, or prefrontal/parietal (alternating) cortices. After ten minutes of sham or active tDCS, participants performed verbal and visual WM training tasks. On the first, tenth, and follow-up sessions, participants performed transfer WM tasks including the spatial 2-back, Stroop, and digit span tasks. The results demonstrated that all groups benefited from WM training, as expected. However, at follow-up 1-month after training ended, only the participants in the active tDCS groups maintained significant improvement. Importantly, this pattern was observed for both trained and transfer tasks. These results demonstrate that tDCS-linked WM training can provide long-term benefits in maintaining cognitive training benefits and extending them to untrained tasks.


Squamous cervical lesions in women with human immunodeficiency virus: long-term follow-up.
To estimate the frequency of and trends in abnormal Pap test results in women with human immunodeficiency virus (HIV) and HIV-uninfected women. In a cohort study of HIV-infected and uninfected women, Pap tests were obtained every 6 months. Results of atypical squamous cells of undetermined significance (ASC-US) or worse were considered abnormal. Over a median of 8.4 years, 23,843 Pap tests were obtained from 1,931 HIV-positive women with 6,828 Pap tests from 533 HIV-negative women (13 women seroconverted during the study). Among women with HIV, Pap test results were ASC-US in 4,462 (19%), low-grade squamous intraepithelial lesion (LSIL) in 3,199 (13%), high-grade squamous intraepithelial lesion (HSIL) in 267 (1%), and cancer in 11 (0.05%). The incidence of abnormal Pap test results was 179 in 1,000 person-years for HIV-positive and 75 in 1,000 person-years for HIV-negative women (incidence rate ratio 2.4, 95% confidence interval 2.0-2.8). The incidence of HSIL or cancer was 4.4 in 1,000 person-years for HIV-positive and 1.3 in 1,000 person-years for HIV-negative women (incidence rate ratio 3.4, 95% confidence interval 1.2-9.5). Among women with HIV in a cervical cancer prevention program, Pap test abnormalities are common, but high-grade abnormalities are infrequent. II.


Studies of food hygiene and diarrhoeal disease.
Contamination of weaning foods and water with enteropathogenic micro-organisms has been recognised in the past, but its link with the development of diarrhoea by young children in developing countries is lacking. This may explain the unavailability of effective interventions to reduce the risk of diarrhoeal diseases from this contamination. The frequency of contamination of weaning foods with enteropathogens is high in developing countries, and is dependent on the food type, storage time and ambient temperature of storage, the method used, and the temperature reached on re-warming before re-feeding. Other considerations are the bacterial content of cooking and feeding utensils. Fruit and raw vegetables can become contaminated with enteropathogenic micro-organisms by sewage-containing irrigation water, by washing produce and fruits in contaminated water, and how they are processed at home. In most studies reviewed, the level of contamination is higher in weaning foods than in drinking water. Since there is a need to reach a critical level of contamination before illness can occur after the ingestion of an enteropathogen, it is postulated that weaning foods are probably more important than drinking water for transmission of diarrhoeal diseases in developing countries. Several potential interventions have been identified, which should be developed and tested in controlled trials in developing countries. These interventions are needed to reduce contamination of weaning foods in households from developing countries, while adequate facilities for the provision of clean water and sanitation to those communities are placed.


Planar photonic crystal cavities with far-field optimization for high coupling efficiency and quality factor.
Different types of planar photonic crystal cavities aimed at optimizing the far-field emission pattern are designed and experimentally assessed by resonant scattering measurements. We systematically investigate the interplay between achieving the highest possible quality (Q) factor and maximizing the in- and out-coupling efficiency into a narrow emission cone. Cavities operate at telecommunications wavelengths, i.e. around approximately 1.55 microm, and are realized in silicon membranes. A strong modification of the far-field emission pattern, and therefore a substantial increase of the coupling efficiency in the vertical direction, is obtained by properly modifying the holes around L3, L5 and L7 type PhC cavities, as we predict theoretically and show experimentally. An optimal compromise yielding simultaneously a high Q-factor and a large coupling to the fundamental cavity mode is found for a L7-type cavity with a measured Q congruent with 62000, whose resonant scattering efficiency is improved by about two orders of magnitude with respect to the unmodified structure. These results are especially useful for prospective applications in light emitting devices, such as nano-lasers or single-photon sources, in which vertical in- and out-coupling of the electromagnetic field is necessarily required.


Thiopental and midazolam do not seem to impede metabolism of glutamate in brain-injured patients.
Increased extracellular glutamate levels are related to glial and neuronal damage. Glutamate-mediated toxicity is limited by glial uptake and metabolic transformation of glutamate to glutamine and the energetic compounds alanine and lactate which are utilized by surrounding neurons. Under in vitro conditions, barbiturates have been shown to reduce glutamate uptake and its further metabolism, possibly impeding metabolic coupling between astrocytes and neurons. The aims were to investigate if under clinical conditions, the barbiturate thiopental reduces important detoxification of glutamate, resulting in lower CSF glutamine, alanine and lactate levels as opposed to patients receiving midazolam. During long-term administration of thiopental and midazolam, pathologically elevated ventricular CSF glutamate levels were associated with significantly increased glutamine and alanine levels up to 14 days after trauma. CSF lactate, however, remained normal. These data suggest that long-term administration of thiopental and midazolam under clinical conditions does not impede enzymatic activities responsible for detoxification and metabolism of glutamate.


Effects of dance on gait and balance in Parkinson's disease: a comparison of partnered and nonpartnered dance movement.
Partnered tango dance can improve balance and gait in individuals with Parkinson's disease (PD). Partnered dance may allow these individuals to challenge balance more than nonpartnered dance. Alternatively, partnered practice could reduce balance gains because the participant may rely on the partner as a balance aid when challenged. The authors compared the effects of partnered and nonpartnered dance on balance and mobility in 39 people (11 women) with mild-moderate PD (Hoehn and Yahr stages I-III). Participants were randomly assigned to partnered or nonpartnered tango and attended 1-hour classes twice per week, completing 20 lessons within 10 weeks. Balance and gait were evaluated in the weeks immediately before, immediately after, and 1 month after the intervention. Both groups significantly improved on the Berg Balance Scale, comfortable and fast-as-possible walking velocity, and cadence. Improvements were maintained at the 1-month follow-up. The nonpartnered class improved as much as the partnered class; however, partnered participants expressed more enjoyment and interest in continuing.


Multiple generations of grain aggregation in different environments preceded solar system body formation.
The solar system formed from interstellar dust and gas in a molecular cloud. Astronomical observations show that typical interstellar dust consists of amorphous (a-) silicate and organic carbon. Bona fide physical samples for laboratory studies would yield unprecedented insight about solar system formation, but they were largely destroyed. The most likely repositories of surviving presolar dust are the least altered extraterrestrial materials, interplanetary dust particles (IDPs) with probable cometary origins. Cometary IDPs contain abundant submicron a-silicate grains called GEMS (glass with embedded metal and sulfides), believed to be carbon-free. Some have detectable isotopically anomalous a-silicate components from other stars, proving they are preserved dust inherited from the interstellar medium. However, it is debated whether the majority of GEMS predate the solar system or formed in the solar nebula by condensation of high-temperature (>1,300 K) gas. Here, we map IDP compositions with single nanometer-scale resolution and find that GEMS contain organic carbon. Mapping reveals two generations of grain aggregation, the key process in growth from dust grains to planetesimals, mediated by carbon. GEMS grains, some with a-silicate subgrains mantled by organic carbon, comprise the earliest generation of aggregates. These aggregates (and other grains) are encapsulated in lower-density organic carbon matrix, indicating a second generation of aggregation. Since this organic carbon thermally decomposes above ∼450 K, GEMS cannot have accreted in the hot solar nebula, and formed, instead, in the cold presolar molecular cloud and/or outer protoplanetary disk. We suggest that GEMS are consistent with surviving interstellar dust, condensed in situ, and cycled through multiple molecular clouds.


The impact of vitamin D supplement intake on vascular endothelial function; a systematic review and meta-analysis of randomized controlled trials.
Aim: to systematically review and conduct a meta-analysis of randomized controlled trials investigating the impact of vitamin D supplementation on endothelial function. Method: We searched PubMed-Medline, SCOPUS, Web of Science and Google Scholar (until June 2016) to detect prospective studies evaluating the impact of vitamin D supplementation on endothelial function indexes. We used random effects models (using DerSimonian-Laird method) and generic inverse variance methods to synthesize quantitative data. We used the leave-one-out method for sensitivity analysis. To quantitatively assess the heterogeneity we used the I2 index. Systematic review registration: CRD42016039329. Results: From a total of 213 entries identified, 12 studies were appropriate for inclusion into the final analysis. The meta-analysis indicated a significant enhancement in flow-mediated dilation (FMD) following D supplementation (vitamin D intervention group versus control group 1.27 %, (95% CI 0.20 to 2.34, N = 11 arms, heterogeneity p = 0.054; I2 51.2 %). These findings were robust in sensitivity analyses. Conclusions: This meta-analysis suggested that vitamin D supplementation may improve endothelial function. Randomized control trials with a longer-term follow-up are warranted to clarify the existing controversies and shed light on the potential underlying mechanisms.


Efficacy of Ozone and Selenium Therapy for Alcoholic Liver Injury: An Experimental Model.
Alcoholic liver disease is an important health problem which is reversible during early stages of liver damage, but becomes permanent with time. Nowadays, many studies focus on various agents that prevent, reduce or slow the progression of the toxic effects of alcohol. In our study, we investigated the efficiency of ozone and selenium against oxidative damage in a model of alcohol-induced liver damage. Forty-eight female Wistar Albino rats between 4 and 6 months of age and weighing 190-250 g were included in the study and were used as models of alcohol liver damage. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum and tissue total oxidant levels, serum and tissue total antioxidant levels, and the histopathological evaluation of the liver were performed in 8 groups. In the statistical analysis, it was observed that ozone and/or selenium therapies decreased the AST levels. Total oxidant and antioxidant serum levels were found to vary in serum and tissue. Ozone and/or selenium therapies decreased liver damage, according to histopathological findings. Through ozone and/or selenium therapies, less damage was observed histopathologically compared to the alcohol group. It is thought that the results of our study can be used in individual treatments following confirmation of liver damage in alcoholic patients.


Early expression of KCC2 in rat hippocampal cultures augments expression of functional GABA synapses.
The development of GABAergic synapses is associated with an excitatory to inhibitory shift of the actions of GABA because of a reduction of [Cl-]i. This is due to a delayed postnatal expression of the K+ -Cl- cotransporter KCC2, which has low levels at birth and peaks during the first few postnatal weeks. Whether the expression of the cotransporter and the excitatory to inhibitory shift have other consequences on the operation of GABA(A) receptors and synapses is not yet known. We have now expressed KCC2 in immature neurones at an early developmental stage and determined the consequences on the formation of GABA and glutamate synapses. We report that early expression of the cotransporter selectively enhances GABAergic synapses: there is a significant increase of the density of GABA(A) receptors and synapses and an increase of the frequency of GABAergic miniature postsynaptic currents. The density of glutamate synapses and frequency of AMPA miniature postsynaptic currents are not affected. We conclude that the expression of KCC2 and the reduction of [Cl-]i play a critical role in the construction of GABAergic networks that extends beyond the excitatory to inhibitory shift of the actions of GABA.


Cognitive Training for Adults With Bothersome Tinnitus: A Randomized Clinical Trial.
Individuals with tinnitus have poorer working memory, slower processing speeds and reaction times, and deficiencies in selective attention, all of which interfere with readiness and performance. Brain Fitness Program-Tinnitus (BFP-T) is a cognitive training program specially designed to exploit neuroplasticity for preservation and expansion of cognitive health in adults with tinnitus. To evaluate the effect of the BFP-T on tinnitus. This open-label, intention-to-treat randomized clinical trial prescreened 191 patients with tinnitus and 64 healthy controls (HCs) from June 1, 2012, through October 31, 2013. Participants were 40 adults with bothersome tinnitus for more than 6 months and 20 age-matched HCs. Patients with tinnitus were randomized to a BFP-T or non-BFP-T control group. The BFP-T was completed online, and assessments were completed at Washington University School of Medicine. Participants in the intervention group were required to complete the BFP-T online 1 hour per day 5 days per week for 8 weeks. Tinnitus assessment, neuroimaging, and cognitive testing were completed at baseline and 8 weeks later. The HCs underwent neuroimaging and cognitive assessments. The primary outcome measure was the change in Tinnitus Handicap Inventory (THI) score. Behavioral measures, neuroimaging, and cognitive tests were performed before and after the intervention. A total of 40 patients with tinnitus and 20 HCs participated in the study (median [range] age, 56 [35-64] years in the BFP-T group, 52 [24-64] years in the non-BFP-T group, and 50 [30-64] years in the HC group; 13 [65%] in the BFP-T group, 14 [70%] in the non-BFP-T group, and 13 [65%] in the HC group were males; and 16 [80%] in the BFP-T group, 16 [80%] in the non-BFP-T group, and 15 [75%] in the HC group were white). There was a reduction in the THI score in the BFP-T group (median, 7; range, -16 to 64) and non-BFP-T group (median, 11; range, -6 to 26), but this reduction was not significantly different between the 2 groups (median difference, 0; 95% CI, -10 to 8). There was no difference in cognitive test scores and other behavioral measures. There was a significant difference between baseline and follow-up in functional connectivity in cognitive control regions in the BFP-T group but not in HCs or individuals with untreated tinnitus. Of the 20 patients in the BFP-T group, 10 (50%) self-reported improvement attributable to the intervention, and 6 (30%) reported to be much improved in the domains of tinnitus, memory, attention, and concentration. These findings suggest that the computer-based cognitive training program is associated with self-reported changes in attention, memory, and perception of tinnitus. A possible mechanistic explanation for these changes could be neuroplastic changes in key brain systems involved in cognitive control. Cognitive training programs might have a role in the future treatment of patients with tinnitus. clinicaltrials.gov Identifier: NCT01458821.


Normal development following chromatin transfer correlates with donor cell initial epigenetic state.
If the full potential of chromatin transfer (CT) technology is to be realized for both animal production and biomedical applications it is imperative that the efficiency of the reprogramming process be improved, and the potential for deleterious development be eliminated. Generation of the first cloned animals from adult somatic cells demonstrated that development is substantially an epigenetic process (Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH, 1997. Viable offspring derived from fetal and adult mammalian cells. Nature. 385(6619): 810-813.). In this study, we provide preliminary evidence that the epigenetic state of the donor cell, may be valuable in assessing potential cloning success. We have measured key indicators of cellular epigenetic state in both serially derived cell populations of the same genetic origin, but differing in epigenomic status, and in a distinct cohort of donor cell populations with diverse genetic origins and epigenomic status. Specifically, the relative abundance of particular histone modifications in donor populations prior to manipulation has been correlated with the measurable variance in reprogramming efficiencies observed following CT, as defined by the number of resulting live births and healthy progeny, and the concomitant incidence of deleterious growth measures (notably the appearance of large offspring syndrome (LOS)). Thus, we suggest that the likely outcome and relative success of cloning may be predictable based on the expression of discriminating histone marks present in the donor cell population before CT. This approach may provide the basis of a prognostic signature for the future evaluation and risk assessment of putative donor cells prior to CT, and thus increase future cloning success and alleviate the incidence of abnormal development.


The application of optical coherence tomography to image subsurface tissue structure of Antarctic krill Euphausia superba.
Many small open ocean animals, such as Antarctic krill, are an important part of marine ecosystems. To discover what will happen to animals such as krill in a changing ocean, experiments are run in aquaria where conditions can be controlled to simulate water characteristics predicted to occur in the future. The response of individual animals to changing water conditions can be hard to observe, and with current observation techniques it is very difficult to follow the progress of an individual animal through its life. Optical coherence tomography (OCT) is an optical imaging technique that allows images at high resolution to be obtained from depths up to a few millimeters inside biological specimens. It is compatible with in vivo imaging and can be used repeatedly on the same specimens. In this work, we show how OCT may be applied to post mortem krill samples and how important physiological data such as shell thickness and estimates of organ volume can be obtained. Using OCT we find an average value for the thickness of krill exoskeleton to be (30±4) µm along a 1 cm length of the animal body. We also show that the technique may be used to provide detailed imagery of the internal structure of a pleopod joint and provide an estimate for the heart volume of (0.73±0.03) mm3.


Structure and Function of the Left Atrium and Left Atrial Appendage: AF and Stroke Implications.
Atrial fibrillation (AF) and stroke are important major health problems that share common risk factors and frequently coexist. Left atrial (LA) remodeling is an important underlying substrate for AF and stroke. LA dilation and dysfunction form a prothrombotic milieu characterized by blood stasis and endothelial dysfunction. In addition, alterations of the atrial cardiomyocytes, increase of noncollagen deposits in the interstitial space and fibrosis, favor the occurrence of re-entry that predisposes to AF. Eventually, AF further impairs LA function and promotes LA remodeling, closing a self-perpetuating vicious circle. Multimodality imaging provides a comprehensive evaluation of several aspects of LA remodeling and offers several parameters to identify patients at risk of AF and stroke. How multimodality imaging can be integrated in clinical management of patients at risk of AF and stroke is the focus of the present review paper.


Anti-HHV-6 IgG titer significantly predicts subsequent relapse risk in multiple sclerosis.
Some of the strongest associations with MS onset are for human herpesviruses, particularly Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). Their role in MS clinical course is less clear, however. Prospective cohort of 198 persons with clinically definite MS, followed 2002-5, and serum samples obtained from all subjects at study entry to measure anti-HHV-6 and anti-EBV (Epstein-Barr nuclear antigen [EBNA] and viral capsid antigen [VCA]) IgG titers. Association with relapse evaluated using survival analysis; association with disability/progression evaluated using linear regression or multilevel mixed-effects linear regression. For the 145 persons with relapsing-remitting MS followed beyond one review, anti-HHV-6 IgG titer was positively associated with the hazard of relapse with a dose-dependent trend (p = 0.003), not affected by adjustment for anti-EBV IgG titers, neither of which were independently associated with relapse. There was no significant association between anti-human herpesvirus IgG titers and baseline-measured disability scores, or change in disability scores; however, anti-HHV-6 IgG titers were 2.8 times higher among progressive-course females than progressive-course males. These findings suggest that, in addition to a potential etiological role in MS, HHV-6 infection or the immune response to HHV-6 antigens may have an effect on the risk of MS relapses and possibly on progressive courses of MS. The observed effect was directly related to anti-HHV-6 IgG titers and may indicate that either HHV-6 infection or factors associated with an altered humoral immune response to HHV-6 may have an effect on MS clinical course. Anti-HHV-6 IgG titer may be a useful prognostic factor in relapsing-remitting MS clinical course.


In vivo formation of a proton-sensitive K+ channel by heteromeric subunit assembly of Kir5.1 with Kir4.1.
Kir5.1 is an inwardly rectifying K+ channel (Kir) subunit, whose physiological function is unknown. Human embryonic kidney HEK293T cells co-transfected with rat Kir5.1 and Kir4.1 cDNA expressed a functional K+ channel, whose properties were significantly different from those of the homomeric Kir4.1 channel. Formation of a Kir4. 1/Kir5.1 assembly in HEK293T was confirmed biochemically. We found that heteromeric Kir4.1/Kir5.1 channel activity was affected by internal pH levels between 6.0 and 8.0, when the homomeric Kir4.1 channel activity was relatively stable. Changing external pH in this range had no effect on either Kir channel. Western blot analysis using specific antibodies revealed that Kir4.1 and Kir5.1 proteins were expressed in kidney and brain, but co-immunoprecipitated only from kidney. These results indicate that the co-assembly of Kir5.1 with Kir4.1 occurs in vivo, at least in kidney. The heteromeric Kir4. 1/Kir5.1 channel may therefore sense intracellular pH in renal epithelium and be involved in the regulation of acid-base homeostasis.


Neuro2A differentiation by Galphai/o pathway.
Signaling from G(i/o)-coupled G protein-coupled receptors (GPCRs), such as the serotonin 1B, cannabinoid 1, and dopamine D2 receptors, inhibits cAMP production by adenylyl cyclases and activates protein kinases, such as Src, mitogen-activated protein kinases 1 and 2, and Akt. Activation of these protein kinases results in stimulation of neurite outgrowth in the central nervous system (CNS) and in neuronal cell lines. This Connections Map traces downstream signaling pathways from G(i/o)-coupled GPCRs to key protein kinases and key transcription factors involved in neuronal differentiation. Components in the Science Signaling Connections Map are linked to Nature Molecule Pages. This interoperability provides ready access to detail that includes information about specific states for the nodes.


Progabide treatment in severe epilepsy: a double-blind cross-over trial versus placebo.
Twenty therapy-resistant epileptic patients entered a double-blind, randomized, two-period, cross-over trial comparing progabide (19.3-36 mg/kg/day) and placebo as add-on drugs to standard therapy. Each period lasted 6 weeks with a gradual crossover during 4 days. Five patients were dropped because of reasons unrelated to treatment. Among the 15 patients who completed the study, seven had partial, six primary generalized, and two secondary generalized epilepsies. Preexisting antiepileptic drugs (AEDs) ranging from one to three per patient (mean 2.2 AEDs/patient) were maintained unchanged during the trial. Efficacy was assessed biweekly by means of total seizure counts, counts of each seizure type, and global clinical judgment. At the same time intervals, safety was assessed by means of reports of adverse events, clinical and neurological examination, laboratory tests, and measurement of plasma concentrations of progabide and associated AEDs. According to the clinical global judgment, eight patients were considered improved during progabide treatment. Seizures were reduced in 14 of 15 patients during the progabide as compared with the placebo period. During the progabide period, the reduction of the total seizure count was 45 and 58% in two patients and 88-97% in six patients. A significant reduction of the total seizure number was observed in the progabide period as compared with the placebo period, both in the whole patient group (p less than 0.01) and in the two subgroups of patients with generalized (p less than 0.01) and partial (p less than 0.05) epilepsies.(ABSTRACT TRUNCATED AT 250 WORDS)


The endogenous circadian temperature period length (tau) in delayed sleep phase disorder compared to good sleepers.
The currently assumed aetiology for delayed sleep phase disorder (DSPD) is a delay of the circadian system. Clinicians have sought to use bright light therapy, exogenous melatonin or chronotherapy to correct the disorder. However, these treatments have achieved unreliable outcomes for DSPD patients and, as such, one suggestion has been that the disorder may be caused by a longer than normal circadian rhythm period length (i.e. tau). The present study investigated this premise using a 78-h ultradian, ultra-short sleep-wake cycle. This constant bedrest routine was used to simulate a series of 1-h long 'days' by alternating 20-min sleep opportunities and 40 min of enforced wakefulness. Thirteen participants were recruited for the study including, six people diagnosed with DSPD according to the International Classification of Sleep Disorders-2 [mean age = 22.0, standard deviation (SD) = 3.3] and seven good sleepers (mean age = 23.1, SD = 3.9) with normal sleep timing. The DSPD participants' core temperature rhythm tau (mean = 24 h 54 min, SD = 23 min) was significantly longer (t = -2.33, P = 0.04, Cohen's d = 1.91) than the good sleepers' (mean 24 h 29 min, SD = 16 min). The temperature rhythm of the DSPD participants delayed more rapidly (i.e. >25 min day(-1) ) than the good sleepers'. These findings provide an explanation for the difficulty that DSPD patients have in phase advancing to a more conventional sleep time and their frequent relapse following treatment. The outcomes of this study support a vigorous and continued application of chronobiological and behavioural therapies to entrain DSPD patients to their desired earlier sleep times.


ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain.
Epidermal growth factor receptor (EGFR) vIII is a mutated EGFR that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors. In this study, we investigate the effect of ZD6474 (ZACTIMA, vandetanib), a dual inhibitor for vascular endothelial growth factor receptor 2 and EGFR on growth and angiogenesis of gliomas expressing EGFRvIII. We used two glioma xenograft models, U87MG cells overexpressing EGFRvIII and short-term cultured primary glioma GBM8 cells with EGFRvIII. ZD6474 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas. Moreover, significant inhibition of EGFRvIII-expressing U87MG and GBM8 gliomas was observed compared with their controls. Magnetic resonance imaging analysis using the apparent diffusion coefficient and three-dimensional T2*weighed measurements validated ZD6474 inhibition on tumor growth and angiogenesis in EGFRvIII-expressing GBM8 gliomas. Mechanistically, ZD6474 shows better inhibition of cell growth and survival of U87MG/EGFRvIII, GBM6, and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3, Akt, and Bcl-X(L) expression. Albeit in lesser extent, ZD6474 also displays suppressions of U87MG/EGFR and GBM12 cells that overexpress wild-type EGFR. Additionally, ZD6474 inhibits activation of extracellular signal-regulated kinase 1/2 in both types of cells, and expression of a constitutively active phosphoinositide 3-kinases partially rescued ZD6474 inhibition in U87MG/EGFRvIII cells. Taken together, these data show that ZD6474 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII-activated signaling mediators, suggesting a potential application of ZD6474 in treatments for glioblastomas that overexpress EGFRvIII. Mol Cancer Ther; 9(4); 929-41. (c)2010 AACR.


Quadratically convergent algorithm for orbital optimization in the orbital-optimized coupled-cluster doubles method and in orbital-optimized second-order Møller-Plesset perturbation theory.
Using a Lagrangian-based approach, we present a more elegant derivation of the equations necessary for the variational optimization of the molecular orbitals (MOs) for the coupled-cluster doubles (CCD) method and second-order Møller-Plesset perturbation theory (MP2). These orbital-optimized theories are referred to as OO-CCD and OO-MP2 (or simply "OD" and "OMP2" for short), respectively. We also present an improved algorithm for orbital optimization in these methods. Explicit equations for response density matrices, the MO gradient, and the MO Hessian are reported both in spin-orbital and closed-shell spin-adapted forms. The Newton-Raphson algorithm is used for the optimization procedure using the MO gradient and Hessian. Further, orbital stability analyses are also carried out at correlated levels. The OD and OMP2 approaches are compared with the standard MP2, CCD, CCSD, and CCSD(T) methods. All these methods are applied to H(2)O, three diatomics, and the O(4)(+) molecule. Results demonstrate that the CCSD and OD methods give nearly identical results for H(2)O and diatomics; however, in symmetry-breaking problems as exemplified by O(4)(+), the OD method provides better results for vibrational frequencies. The OD method has further advantages over CCSD: its analytic gradients are easier to compute since there is no need to solve the coupled-perturbed equations for the orbital response, the computation of one-electron properties are easier because there is no response contribution to the particle density matrices, the variational optimized orbitals can be readily extended to allow inactive orbitals, it avoids spurious second-order poles in its response function, and its transition dipole moments are gauge invariant. The OMP2 has these same advantages over canonical MP2, making it promising for excited state properties via linear response theory. The quadratically convergent orbital-optimization procedure converges quickly for OMP2, and provides molecular properties that are somewhat different than those of MP2 for most of the test cases considered (although they are similar for H(2)O). Bond lengths are somewhat longer, and vibrational frequencies somewhat smaller, for OMP2 compared to MP2. In the difficult case of O(4)(+), results for several vibrational frequencies are significantly improved in going from MP2 to OMP2.


Mesenchyme with fgf-10 expression is responsible for regenerative capacity in Xenopus limb buds.
A young tadpole of an anuran amphibian can completely regenerate an amputated limb, and it exhibits an ontogenetic decline in the ability to regenerate its limbs. However, whether mesenchymal or epidermal tissue is responsible for this decrease of the capacity remains unclear. Moreover, little is known about the molecular interactions between these two tissues during regeneration. The results of this study showed that fgf-10 expression in the limb mesenchymal cells clearly corresponds to the regenerative capacity and that fgf-10 and fgf-8 are synergistically reexpressed in regenerating blastemas. However, neither fgf-10 nor fgf-8 is reexpressed after amputation of a nonregenerative limb. Nevertheless, nonregenerative epidermal tissue can reexpress fgf-8 under the influence of regenerative mesenchyme, as was demonstrated by experiments using a recombinant limb composed of regenerative limb mesenchyme and nonregenerative limb epidermis. Taken together, our data demonstrate that the regenerative capacity depends on mesenchymal tissue and suggest that fgf-10 is likely to be involved in this capacity.


Prior exposure to organophosphorus and organochlorine pesticides increases the allergic potential of environmental chemical allergens in a local lymph node assay.
The dysregulation of immune functions by some pesticides leads to various immune disorders, including immunodeficiency, tumorigenesis, allergies, and autoimmunity. This study's primary objective was to examine the relationship between immune disorders and the immunosuppression induced by immunosuppressive pesticides. We focused on the modulation of allergic potential by the organophosphorus pesticide parathion, organochlorine pesticide methoxychlor, phenoxyacetic acid herbicide 2,4-d-butyl, and benzoic acid fungicide eugenol, as detected by a local lymph node assay (LLNA), which was developed initially for hazard identification of skin sensitization. Parathion and methoxychlor are immunosuppressive chemicals, and 2,4-d-butyl and eugenol are contact allergens. After the immunosuppressive characteristics of parathion and methoxychlor were confirmed in a pilot study, 4-week-old mice were orally administered parathion (0, 0.4, 1.2mg/kg) or methoxychlor (0, 100, 300 mg/kg). Four weeks after the last administration, an LLNA was conducted using 2,4-d-butyl (0%, 2.5%, 5%, and 10%) and eugenol (0%, 5%, 10%, and 25%). In addition, detailed analysis of their auricular lymph nodes for number of surface antigen expression of T cells and local cytokine production were performed using 5% 2,4-d-butyl and 5% eugenol treatment groups. EC3 values (estimated concentration to yield a stimulation index of 3) of 2,4-d-butyl and eugenol decreased markedly in parathion- and methoxychlor-pretreated groups. Parathion- and methoxychlor-pretreated groups induced marked increase in number of surface antigen expression of T cells and levels of Th1 cytokines (IFN-γ, TNF-α, and IL-17) produced by ex vivo restimulated lymph node cells. According to our results, the allergic potentials of 2,4-d-butyl and eugenol are increased by prior exposure to parathion and methoxychlor.


Genome-wide transcriptome analysis of two contrasting Brassica rapa doubled haploid lines under cold-stresses using Br135K oligomeric chip.
Genome wide transcription analysis in response to stresses is important to provide a basis of effective engineering strategies to improve stress tolerance in crop plants. We assembled a Brassica rapa oligomeric microarray (Br135K microarray) using sequence information from 41,173 unigenes and analyzed the transcription profiles of two contrasting doubled haploid (DH) lines, Chiifu and Kenshin, under cold-treatments. The two DH lines showed great differences in electrolyte leakage below -4°C, but similar patterns from 4°C to -2°C. Cold-treatments induced 885 and 858 genes in Chiifu and Kenshin, respectively. Overall, 134, and 56 genes showed an intrinsic difference in expression in Chiifu and Kenshin, respectively. Among 5,349 genes that showed no hit found (NHF) in public databases, 61 and 24 were specifically expressed in Chiifu and Kenshin, respectively. Many transcription factor genes (TFs) also showed various characteristics of expression. BrMYB12, BrMYBL2, BrbHLHs, BrbHLH038, a C2H2, a WRKY, BrDREB19 and a integrase-type TF were induced in a Chiifu-specific fashion, while a bHLH (Bra001826/AT3G21330), bHLH, cycling Dof factor and two Dof type TFs were Kenshin specific. Similar to previous studies, a large number of genes were differently induced or regulated among the two genotypes, but many genes, including NHFs, were specifically or intrinsically expressed with genotype specificity. Expression patterns of known-cold responsive genes in plants resulted in discrepancy to membrane leakage in the two DH lines, indicating that timing of gene expression is more important to conferring freezing tolerance rather than expression levels. Otherwise, the tolerance will be related to the levels of transcripts before cold-treatment or regulated by other mechanisms. Overall, these results indicate common signaling pathways and various transcriptional regulatory mechanisms are working together during cold-treatment of B. rapa. Our newly developed Br135K oligomeric microarray will be useful for transcriptome profiling, and will deliver valuable insight into cold stresses in B. rapa.


Colonization of the respiratory tract with Pseudomonas cepacia in cystic fibrosis. Risk factors and outcomes.
Between 1981 and 1983, some 85 patients with cystic fibrosis at Rainbow Babies and Childrens Hospital, Cleveland, developed colonization or infection of the respiratory tract with Pseudomonas cepacia. Twenty-nine (34 percent) of the colonized patients died; four were female patients with fulminant bacteremia with P cepacia prior to death. Case-control studies showed that increasing severity of underlying cystic fibrosis, increasing age, having a sibling with cystic fibrosis who was colonized with P cepacia, and previous hospitalizations were associated with increased risk of colonization. In patients with mild cystic fibrosis, no differences in clinical outcome were seen during the period of study; however, patients colonized with P cepacia who had moderate or advanced cystic fibrosis were hospitalized longer and died sooner after colonization, compared with control subjects with similar severity of cystic fibrosis. The excess mortality associated with such colonization varied in magnitude and trend according to the patient's sex and severity of underlying cystic fibrosis, reflecting the combined influence of colonization with P cepacia, sex, and severity of cystic fibrosis on the mortality of the patients. The source and mode of transmission of P cepacia were not determined, but the data suggest a possible nosocomial source. The results of this investigation showed that colonization with P cepacia most often affected patients with moderate or advanced cystic fibrosis and was associated with an adverse clinical outcome in these patients.