Seasonal Pattern of Preterm Births in Korea for 2000-2012.
The aim of this study was to investigate a seasonal pattern of preterm births in Korea. Data were obtained from the national birth registry of the Korean Statistics Office and included all births in Korea during the period 2000-2012 (n = 6,310,800). Delivery dates were grouped by month of the year or by season (winter [December, January, February], spring [March, April, May], summer [June, July, August], and autumn [September, October, November]). The seasonal patterns of prevalence of preterm births were assessed. The rates of preterm births at 37 weeks were highest twice a year (once in winter and again in summer). The rates of preterm births increased by 13.9% in summer and 7.5% in winter, respectively, than in spring (OR, 1.139; 95% CI, 1.127-1.152, and OR, 1.075; 95% 1.064-1.087, respectively) after controlling for age, the educational level of the parents, maternal parity, and neonatal gender. The pattern for spontaneous preterm births < 34 weeks was similar. In Korea, a seasonal pattern of preterm births was observed, with peak prevalence in summer and winter. A seasonal pattern of preterm births may provide new insights for the pathophysiology of preterm births.


Annotating high-impact 5'untranslated region variants with the UTRannotator.
Current tools to annotate the predicted effect of genetic variants are heavily biased towards protein-coding sequence. Variants outside of these regions may have a large impact on protein expression and/or structure and can lead to disease, but this effect can be challenging to predict. Consequently, these variants are poorly annotated using standard tools. We have developed a plugin to the Ensembl Variant Effect Predictor, the UTRannotator, that annotates variants in 5'untranslated regions (5'UTR) that create or disrupt upstream open reading frames. We investigate the utility of this tool using the ClinVar database, providing an annotation for 31.9% of all 5'UTR (likely) pathogenic variants, and highlighting 31 variants of uncertain significance as candidates for further follow-up. We will continue to update the UTRannotator as we gain new knowledge on the impact of variants in UTRs. UTRannotator is freely available on Github: https://github.com/ImperialCardioGenetics/UTRannotator. Supplementary data are available at Bioinformatics online.


Feasibility of data linkage in the PARAMEDIC trial: a cluster randomised trial of mechanical chest compression in out-of-hospital cardiac arrest.
There is considerable interest in reducing the cost of clinical trials. Linkage of trial data to administrative datasets and disease-specific registries may improve trial efficiency, but it has not been reported in resuscitation trials conducted in the UK. To assess the feasibility of using national administrative and clinical datasets to follow up patients transported to hospital following attempted resuscitation in a cluster randomised trial of a mechanical chest compression device in out-of-hospital cardiac arrest. Hospital data on trial participants were requested from Hospital Episode Statistics (HES), the Intensive Care National Audit and Research Centre, and Myocardial Ischaemia National Audit Project and National Audit of Percutaneous Coronary Interventions, using unique patient identifiers. Linked data were received between June 2014 and June 2015. Of 4471 patients randomised in the pre-hospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial, 2398 (53.6%) were not known to be deceased at emergency department arrival and were eligible for linkage. We achieved an overall match rate of 86.7% in the combined HES accident and emergency, inpatient and critical care dataset, with variable match rates (4.2%-80.4%) in individual datasets. Patient demographics, cardiac arrest-related characteristics and major outcomes were predominantly similar between HES matched and unmatched groups, in the linkage apart from location, response time and return of spontaneous circulation (ROSC) at handover. This study shows that it is feasible to track patients from the prehospital setting through to hospital admission using routinely available administrative datasets with a moderate to high degree of success. This approach has the potential to complement the trial data with the demographic and clinical management information about the studied cohort, as well as to improve the efficiency and reduce the costs of follow-up in cardiac arrest trials. ISRCTN08233942; Post-results.


Acute social stress-induced immunomodulation in pigs high and low responders to ACTH.
Pig husbandry is known as an intensive breeding system, piglets being submitted to multiple stressful events such as early weaning, successive mixing, crowding and shipping. These stressors are thought to impair immune defences and might contribute, at least partly, to the prophylactic use of antibiotics. Robustness was recently defined as the ability of an individual to express a high-production potential in a wide variety of environmental conditions. Increasing robustness thus appears as a valuable option to improve resilience to stressors and could be obtained by selecting piglets upon their adrenocortical activity. In this study, we aimed at depicting the consequences of an acute social stress on the immune capacity of piglets genetically selected upon divergent hypothalamic-pituitary-adrenocortical (HPA) axis activity. For this purpose, we monitored neuroendocrine and immune parameters, in high- (HPAhi) and low- (HPAlo) responders to ACTH, just before and immediately after a one-hour mixing with unfamiliar conspecifics. As expected, stressed piglets displayed higher levels of circulating cortisol and norepinephrine. Blood cell count analysis combined to flow cytometry revealed a stress-induced leukocyte mobilization in the bloodstream with a specific recruitment of CD8α+ lymphocytes. Besides, one-hour mixing decreased LPS-induced IL-8 and TNFα secretions in whole-blood assays (WBA) and reduced mononuclear cell phagocytosis. Altogether, our data demonstrate that acute social stress alters immune competence of piglets from both groups, and bring new insights in favour of good farming practices. While for most parameters high- and low-responders to ACTH behaved similarly, HPAhi piglets displayed higher number of CD4+ CD8α- T cells, as well as increased cytokine production in WBA (LPS-induced TNFα and PIL-induced IL-8), which could confer them increased resistance to pathogens. Finally, a principal component analysis including all parameters highlighted that overall stress effects were less pronounced on piglets with a strong HPA axis. Thus, selection upon adrenocortical axis activity seems to reduce the magnitude of response to stress and appears as a good tool to increase piglet robustness.


Extracellular vesicles for liquid biopsy in prostate cancer: where are we and where are we headed?
Extracellular vesicles (EVs) are a heterogeneous class of lipid bound particles shed by any cell in the body in physiological and pathological conditions. EVs play critical functions in intercellular communication. EVs can actively travel in intercellular matrices and eventually reach the circulation. They can also be released directly in biological fluids where they appear to be stable. Because the molecular content of EVs reflects the composition of the cell of origin, they have recently emerged as a promising source of biomarkers in a number of diseases. EV analysis is particularly attractive in cancer patients that frequently present with increased numbers of circulating EVs. We sought to review the current literature on the molecular profile of prostate cancer-derived EVs in model systems and patient biological fluids in an attempt to draw some practical and universal conclusions on the use of EVs as a tool for liquid biopsy in clinical specimens. We discuss advantages and limitations of EV-based liquid biopsy approaches summarizing salient studies on protein, DNA and RNA. Several candidate biomarkers have been identified so far but these results are difficult to apply to the clinic. However, the field is rapidly moving toward the implementation of novel tools to isolate cancer-specific EVs that are free of benign EVs and extra-vesicular contaminants. This can be achieved by identifying markers that are exquisitely present in tumor cell-derived EVs. An important contribution might also derive from a better understanding of EV types that may play specific functions in tumor progression and that may be a source of cancer-specific markers. EV analysis holds strong promises for the development of non-invasive biomarkers in patients with prostate cancer. Implementation of modern methods for EV isolation and characterization will enable to interrogate circulating EVs in vivo.


Assay and functional properties of Rabkinesin-6/Rab6-KIFL/MKlp2 in cytokinesis.
Here we describe methods for the characterization of the kinesin-9 family motor protein Rabkinesin-6/Rab6-KIFL/MKlp2 in cytokinesis. Here we outline biochemical assays for studying the interaction of Rabkinesin-6/Rab6-KIFL/MKlp2 with microtubules, and its regulation and interaction with the mitotic polo-like kinase 1 using recombinant proteins expressed in and purified from insect cells. Protocols for the in vivo functional analysis of Rabkinesin-6/Rab6-KIFL/MKlp2 using depletion with small interfering RNA duplexes are described.


Integrating mouse anatomy and pathology ontologies into a phenotyping database: tools for data capture and training.
The Mouse Disease Information System (MoDIS) is a data capture system for pathology data from laboratory mice designed to support phenotyping studies. The system integrates the mouse anatomy (MA) and mouse pathology (MPATH) ontologies into a Microsoft Access database facilitating the coding of organ, tissue, and disease process to recognized semantic standards. Grading of disease severity provides scores for all lesions that can then be used for quantitative trait locus (QTL) analyses and haplotype association gene mapping. Direct linkage to the Pathbase online database provides reference definitions for disease terms and access to photomicrographic images of similar diagnoses in other mutant mice. MoDIS is an open source and freely available program (http://research.jax.org/faculty/sundberg/index.html). This provides a valuable tool for setting up a mouse pathology phenotyping program.


Rasch modeling and confirmatory factor analysis of the systemizing quotient-revised (SQ-R) scale.
This study assessed the dimensionality of the Systemizing Quotient-Revised (SQ-R), a measure of how strong a person's interest is in systems, using two statistical approaches: Rasch modeling and Confirmatory Factor Analysis (CFA). Participants included N = 675 with an autism spectrum condition (ASC), N = 1369 family members of people with ASC, and N = 2014 typical controls. Data were applied to the Rasch model (Rating Scale) using WINSTEPS. The data fit the Rasch model quite well lending support to the idea that systemizing could be seen as unidimensional. Reliability estimates were .99 for items and .92 for persons. A CFA parceling approach confirmed that a unidimensional model fit the data. There was, however, differential functioning by sex in some of these items. An abbreviated 44-item version of the scale, consisting of items without differential item functioning by sex was developed. This shorter scale also was tested from a Rasch perspective and confirmed through CFA. All measures showed differences on total scale scores between those participants with and without ASC (d = 0.71, p < .005), and between sexes (d = 0.53, p < .005). We conclude that the SQ-R is an appropriate measure of systemizing which can be measured along a single dimension.


Psychometric properties of the DISABKIDS Chronic Generic Module (DCGM-37) when used in children undergoing treatment for cancer.
The aim was to evaluate data quality and psychometric properties of an instrument for measurement of health-related quality of life: DISABKIDS Chronic Generic Module (DCGM-37) used in school-aged children with cancer. All school-children diagnosed with cancer in Sweden during a two-and-a-half year period were invited to participate in the study. Analysis was performed on combined data from two assessments, two and-a-half and five months after start of cancer treatment (n = 170). The instrument was examined with respect to feasibility, data quality, reliability and construct and criterion-based validity. Missing items per dimension ranged from 0 to 5.3 percent, with a majority below three percent. Cronbach's alpha values exceeded 0.70 for all dimensions. There was support for the suggested groupings of items into dimensions for all but six of the 36 items of the DCGM-37 included in this study. The instrument discriminated satisfactorily between diagnoses reflecting treatment burden. The results indicate satisfactory data quality and reliability of the DCGM-37 when used in children undergoing treatment for cancer. Evaluation of construct validity showed generally acceptable results, although not entirely supporting the suggested dimensionality. Continued psychometric evaluation in a larger sample of children during and after treatment for cancer is recommended.


Nematicidal activity of 'major royal jelly protein'-containing glycoproteins from Acacia honey.
Parasitic nematodes infect more than two billion people worldwide particularly in developing countries. We previously reported nematicidal activity of natural honey using model nematode Caenorhabditis elegans. In this study, characterization of nematicidal effects of natural honey and its glycoproteins has been carried out. Chromatographically separated honey glycoproteins showed potent anti-C. elegans activity (LD50 = 100 ng proteins/μL). Honey glycoproteins with molecular masses of ∼260 kD and ∼160 kD comprised of 'major royal jelly protein-1'-containing complexes. In these complexes, MRJP1 was present in different glycosylation forms. Quantitative PCR based gene expression assays described molecular functions of C. elegans affected by honey and honey glycoproteins. Expression of 14 gene transcripts associated with key cellular and molecular functions including energy metabolism, cytoskeleton, cell division, transcription and translation was analyzed. Acacia honey exerted a concentration-dependent alteration of gene transcripts involved in the citric acid cycle (mdh-1 and idhg-1) and cytoskeleton (act-1, act-2, and arp6). Likewise, MRJP1-containing glycoproteins caused down-regulation of arp-6 and idhg-1; and up-regulation of act-1 and mdh-1 gene transcripts. Consistent down-regulation of isocitrate dehydrogenase encoding idhg-1 gene which is among the rate-controlling enzymes of the citric acid cycle was considered as main biochemical factor involved in the nematicidal activity of honey and MRJP-containing glycoproteins. Acacia honey suppressed the expression of gene transcripts encoding actin-2, while honey glycoproteins did not. Hence, honey partly exerted anti-C. elegans activity by decreasing the transcription of actin-2 gene transcripts, demonstrated by a defect in the movement and egg laying. Moreover, arp-6 gene transcripts encoding actin-related protein 6 was significantly and constantly down-regulated by honey and honey proteins.


Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside.
We investigated treatment with gemtuzumab ozogamicin (GO) in 51 patients aged 65 years or older with newly diagnosed acute myeloid leukemia (AML), refectory anemia (RA) with excess of blasts in transformation, or RA with excess blasts. GO was given in doses of 9 mg/m(2) of body-surface area on days 1 and 8 or, therapeutically equivalently, on days 1 and 15, with or without interleukin 11 (IL-11; 15 microg/kg per day on days 3 to 28), with assignment to IL-11 treatment made randomly. Complete remission (CR) rates were 2 of 26 (8%) for GO without IL-11 and 9 of 25 (36%) for GO with IL-11. Regression analyses indicated that IL-11 was independently predictive of CR but not survival. We compared GO with or without IL-11 with idarubicin plus cytosine arabinoside (IA), as previously administered, in similar patients. The CR rate with IA was 15 of 31 (48%), and survival was superior with IA compared with GO with or without IL-11 (P =.03). Besides accounting for possible covariate effects on outcome, we also accounted for possible trial effects (TEs) arising because IA and GO with or without IL-11 were not arms of a randomized trial. Bayesian posterior probabilities that GO with or without IL-11 produced longer survival than IA, after accounting for covariates and TEs, were less than 0.01 in patients with abnormal cytogenetic findings (AC) and less than 0.15 in patients with normal cytogenetic findings (NC). Regarding CR, the analogous probabilities were less than 0.02 for GO without IL-11 (all cytogenetic groups), and for GO with IL-11, less than 0.25 for AC groups and about 0.50 for NC groups. TEs 2 to 5 times the magnitude of those previously observed would be needed to conclude that survival with GO with or without IL-11 is likely longer than with IA. Thus, there is little evidence to suggest that GO with or without IL-11 should be used instead of IA in older patients with newly diagnosed AML or myelodysplastic syndrome.


A systematic review of the safety and efficacy of aerobic exercise during cytotoxic chemotherapy treatment.
Aerobic exercise improves prognosis and quality of life (QoL) following completion of chemotherapy. However, the safety and efficacy of aerobic exercise during chemotherapy is less certain. A systematic review was performed of randomised trials of adult patients undergoing chemotherapy, comparing an exercise intervention with standard care. From 253 abstracts screened, 33 unique trials were appraised in accordance with PRISMA guidance, including 3257 patients. Interventions included walking, jogging or cycling, and 23 were of moderate intensity (50-80% maximum heart rate). Aerobic exercise improved, or at least maintained fitness during chemotherapy. Moderately intense exercise, up to 70-80% of maximum heart rate, was safe. Any reported adverse effects of exercise were mild and self-limiting, but reporting was inconsistent. Adherence was good (median 72%). Exercise improved QoL and physical functioning, with earlier return to work. Two out of four studies reported improved chemotherapy completion rates. Four out of six studies reported reduced chemotherapy toxicity. There was no evidence that exercise reduced myelosuppression or improved response rate or survival. Exercise during chemotherapy is safe and should be encouraged because of beneficial effects on QoL and physical functioning. More research is required to determine the impact on chemotherapy completion rates and prognosis.


Public open spaces and walking for recreation: moderation by attributes of pedestrian environments.
This study examined whether attributes of pedestrian environments moderate the relationships between access to public open spaces (POS) and adults' recreational walking. Data were collected from participants of the North West Adelaide Health Study in 2007. Recreational walking was determined using self-reported walking frequency. Measures of POS access (presence, count, and distance to the nearest POS) were assessed using a Geographic Information System. Pedestrian environmental attributes included aesthetics, walking infrastructure, barrier/traffic, crime concern, intersection density, and access to walking trails. Regression analyses examined whether associations between POS access and recreational walking were moderated by pedestrian environmental attributes. The sample included 1574 participants (45% men, mean age: 55). POS access measures were not associated with recreational walking. However, aesthetics, walking infrastructure, and access to walking trail were found to moderate the POS-walking relationships. The presence of POS was associated with walking among participants with aesthetically pleasing pedestrian environments. Counter-intuitively, better access to POS was associated with recreational walking for those with poorer walking infrastructure or no access to walking trails. Local pedestrian environments moderate the relationships between access to POS and recreational walking. Our findings suggest the presence of complex relationships between POS availability and pedestrian environments.


Measurement of an Excess in the Yield of J/ψ at Very Low p_{T} in Pb-Pb Collisions at sqrt[s]_{NN}=2.76 TeV.
We report on the first measurement of an excess in the yield of J/ψ at very low transverse momentum (p_{T}<0.3 GeV/c) in peripheral hadronic Pb-Pb collisions at sqrt[s_{NN}]=2.76 TeV, performed by ALICE at the CERN LHC. Remarkably, the measured nuclear modification factor of J/ψ in the rapidity range 2.5<y<4 reaches about 7 (2) in the p_{T} range 0-0.3 GeV/c in the 70%-90% (50%-70%) centrality class. The J/ψ production cross section associated with the observed excess is obtained under the hypothesis that coherent photoproduction of J/ψ is the underlying physics mechanism. If confirmed, the observation of J/ψ coherent photoproduction in Pb-Pb collisions at impact parameters smaller than twice the nuclear radius opens new theoretical and experimental challenges and opportunities. In particular, coherent photoproduction accompanying hadronic collisions may provide insight into the dynamics of photoproduction and nuclear reactions, as well as become a novel probe of the quark-gluon plasma.


A Japanese Encephalitis Virus Vaccine Inducing Antibodies Strongly Enhancing In Vitro Infection Is Protective in Pigs.
The Japanese encephalitis virus (JEV) is responsible for zoonotic severe viral encephalitis transmitted by Culex mosquitoes. Although birds are reservoirs, pigs play a role as amplifying hosts, and are affected in particular through reproductive failure. Here, we show that a lentiviral JEV vector, expressing JEV prM and E proteins (TRIP/JEV.prME), but not JEV infection induces strong antibody-dependent enhancement (ADE) activities for infection of macrophages. Such antibodies strongly promoted infection via Fc receptors. ADE was found at both neutralizing and non-neutralizing serum dilutions. Nevertheless, in vivo JEV challenge of pigs demonstrated comparable protection induced by the TRIP/JEV.prME vaccine or heterologous JEV infection. Thus, either ADE antibodies cause no harm in the presence of neutralizing antibodies or may even have protective effects in vivo in pigs. Additionally, we found that both pre-infected and vaccinated pigs were not fully protected as low levels of viral RNA were found in lymphoid and nervous system tissue in some animals. Strikingly, the virus from the pre-infection persisted in the tonsils throughout the experiment. Finally, despite the vaccination challenge, viral RNA was detected in the oronasal swabs in all vaccinated pigs. These latter data are relevant when JEV vaccination is employed in pigs.


Evaluation of recombinant chitinase and SXP1 antigens as antimicrofilarial vaccines.
Prior studies indicate that a microfilarial stage-specific chitinase is a possible candidate antigen for a transmission-blocking vaccine against Brugian filariasis. The antigen is a functional enzyme that progressively appears as microfilariae mature and become able to infect and develop in a susceptible mosquito vector. It is recognized by a monoclonal antibody that reduces microfilaremia in infected animals and by a subset of sera from infected persons who remain amicrofilaremic. Immunization of jirds with recombinant chitinase induced partial protection against microfilaremia resulting from subsequent infection with Brugia malayi, but did not reduce adult worm burdens. Vaccination was much less effective when administered during the prepatent stage of infection and was ineffective when given to microfilaremic jirds. The protective epitope appears to be located close to the carboxy terminus of the chitinase molecule. Immunization of jirds with SXP1, an antigen present in multiple worm stages, also reduced microfilaremia and, in some experiments, adult worm burdens, but hyperimmunization with a recombinant filarial myosin was not protective. These observations indicate that the relative timing of immunization and infection is an important factor in the efficacy of antimicrofilarial vaccines.


Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave.
A link is found between T wave alternans and vulnerability to ventricular fibrillation, and a new approach is provided for quantification of susceptibility to malignant arrhythmias. Complex demodulation reveals that alternation of the electrocardiogram is concentrated during the first half of the T wave, coinciding with the vulnerable period of the cardiac cycle. During myocardial ischemia and reperfusion, there are marked increases in the degree of T wave alternans that parallel the established time course of changes in vulnerability. The influence of the sympathetic nervous system in arrhythmogenesis is also accurately detected. Ultimately, complex demodulation of the electrocardiogram could provide a technique for identification and management of individuals at risk for sudden cardiac death.


Photodynamic properties of aza-analogues of phthalocyanines.
The replacement of benzene rings in phthalocyanines with various N-heterocycles produces a number of aza-analogues, azaphthalocyanines. This review summarizes their properties important for photodynamic therapy with a focus on (but not limited to) the most studied derivatives, i.e. tetrapyrazinoporphyrazines, tetra(2,3-pyrido)porphyrazines and tetra(3,4-pyrido)porphyrazines. Specifically, the spectral properties in both organic and aqueous solutions are discussed, with an emphasis on the prevention of undesirable aggregation, which typically leads to a loss of the photodynamic effects. Photophysical properties, such as the quantum yield of singlet oxygen production, may provide insights into the potential of azaphthalocyanines to cause cell death, whereas fluorescence quantum yields may refer to their role in cancer visualization. The main part of this review summarizes published results on the in vitro evaluation of these aza-analogues for anticancer, antifungal, and antimicrobial treatments as well as their interactions with biological materials.


Austrian recommendations for the management of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis: an expert statement.
The entity "myelofibrosis" represents a subgroup of the Philadelphia chromosome-negative myeloproliferative neoplasms. It comprises primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. This heterogeneous disease is characterized by clonal myeloproliferation, dysregulated kinase signalling and the abnormal expression of several proinflammatory cytokines. Clinically, patients present with symptoms related to thrombocytosis/leukocytosis, anemia and/or progressive splenomegaly. Mutations in Janus kinase 2, an enzyme that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 60% of patients with primary myelofibrosis. Recent molecular advances have not only elucidated critical pathways in the pathogenesis of the disease, but also contributed to a more precise assessment of a patient's individual risk. While allogeneic stem cell transplantation remains the only curative treatment, the natural course of the disease and the patient's survival and quality of life may be improved by new treatments, notably ruxolitinib, the first Janus kinase 1/2 inhibitor approved for the management of myelofibrosis. Additional treatment options are being explored.


Lead exposure effect on angiotensin II renal vasoconstriction.
Low levels of chronic lead exposure can produce hypertension and endothelial dysfunction, which could be associated with oxidative stress, changes in vascular tone and an imbalance of endothelial-derived vasoconstriction and vasodilator factors. The aim was to investigate the effect of chronic lead-exposure on angiotensin II-induced vasoconstriction in isolated perfused kidney and microvessels. Male Wistar rats (230-250 g) were treated for 12 weeks with lead acetate (100 ppm, Pbgroup) or pure water (control group). We evaluated the vascular reactivity in the kidneys and renal microvessels in the presence and absence of N(omega)-nitro-L-arginine methyl ester (L-NAME) in both groups. The nitrite concentration in renal perfusate was measured as an index of NO released, renal abundance of 3-nitrotyrosine was measured as well as endothelial NO synthase (eNOS) expression. Oxidative stress was measured by using the oxidative fluorescence dye dihydroethidium (DHE) to evaluate in situ production of superoxide and identified by confocal microscopy. Lead-exposure significantly increased blood pressure, eNOS protein expression, oxidative stress and vascular reactivity to angiotensin II. L-NAME potentiated vascular response to angiotensin II in control group but had no effect on the Pb-group. Nitrites released from the kidney of lead-group was lower compared to the control group while 3-nitrotyrosine was higher. This data suggest that lead-induced hypertension could be caused partially by an altered NOsystem.


Relative electromyographic activity in trunk, hip, and knee muscles during unilateral weight bearing exercises: Implications for rehabilitation.
Clinicians routinely prescribe unilateral weight bearing exercises to strengthen the lower extremity. Researchers have primarily examined thigh muscle activation with minimal attention to the hip and trunk muscles. The purpose of this study was to quantify trunk, hip, and thigh muscle activation during these types of exercises. Electromyographic (EMG) activity was collected for the abdominal obliques (AO), lumbar extensors (LE), gluteus maximus (GMX), gluteus medius (GM), and vastus medialis (VM) as subjects performed four unilateral weight bearing exercises. Data were expressed as 100% of a maximum voluntary isometric contraction (% MVIC). Separate analyses of variance with repeated measures were used to identify muscle activity differences across exercise. The sequentially-rejective Bonferroni test was used for all post-hoc analyses. EMG activity for the AO, LE, and GMX was low (5.7-18.9% MVIC) during all the exercises. The GM activity was moderate (21.4-26.5% MVIC) while VM activity was high (40.0-45.2% MVIC). Lower AO and LE activation most likely resulted from subjects maintaining a vertical trunk position over the stance limb during each exercise. The fact that the exercises required greater frontal plane control (from balancing on a single limb) most likely accounted for lower GMX activity. The exercises would provide little, if any, benefit for individuals with AO, LE, or GMX weakness. The unilateral weight bearing exercises would be beneficial for GM neuromuscular re-education and endurance and VM strengthening.


Clinical pathways: effects on professional practice, patient outcomes, length of stay and hospital costs.
Clinical pathways are structured multidisciplinary care plans used by health services to detail essential steps in the care of patients with a specific clinical problem. They aim to link evidence to practice and optimise clinical outcomes whilst maximising clinical efficiency. To assess the effect of clinical pathways on professional practice, patient outcomes, length of stay and hospital costs. We searched the Database of Abstracts of Reviews of Effectiveness (DARE), the Effective Practice and Organisation of Care (EPOC) Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and bibliographic databases including MEDLINE, EMBASE, CINAHL, NHS EED and Global Health. We also searched the reference lists of relevant articles and contacted relevant professional organisations. Randomised controlled trials, controlled clinical trials, controlled before and after studies and interrupted time series studies comparing stand alone clinical pathways with usual care as well as clinical pathways as part of a multifaceted intervention with usual care. Two review authors independently screened all titles to assess eligibility and methodological quality. Studies were grouped into those comparing clinical pathways with usual care and those comparing clinical pathways as part of a multifaceted intervention with usual care. Twenty-seven studies involving 11,398 participants met the eligibility and study quality criteria for inclusion. Twenty studies compared stand alone clinical pathways with usual care. These studies indicated a reduction in in-hospital complications (odds ratio (OR) 0.58; 95% confidence interval (CI) 0.36 to 0.94) and improved documentation (OR 13.65: 95%CI 5.38 to 34.64). There was no evidence of differences in readmission to hospital or in-hospital mortality. Length of stay was the most commonly employed outcome measure with most studies reporting significant reductions. A decrease in hospital costs/ charges was also observed, ranging from WMD +261 US$ favouring usual care to WMD -4919 US$ favouring clinical pathways (in US$ dollar standardized to the year 2000). Considerable heterogeneity prevented meta-analysis of length of stay and hospital cost results. An assessment of whether lower hospital costs contributed to cost shifting to another health sector was not undertaken.Seven studies compared clinical pathways as part of a multifaceted intervention with usual care. No evidence of differences were found between intervention and control groups. Clinical pathways are associated with reduced in-hospital complications and improved documentation without negatively impacting on length of stay and hospital costs.


Diffraction-enhanced beam-focusing for X-rays in curved multi-plate crystal cavity.
Unusual x-ray focusing effect is reported for parabolic curved multi-plate x-ray crystal cavities of silicon consisting of compound refractive lenses (CRL). The transmitted beam of the (12 4 0) back reflection near 14.4388 keV from these monolithic silicon crystal devices exhibits extraordinary focusing enhancement, such that the focal length is reduced by as much as 18% for 2-beam and 56% for 24-beam diffraction from the curved crystal cavity. This effect is attributed to the presence of the involved Bragg diffractions, in which the wavevector of the transmitted beam is bent further when traversing several curved crystal surfaces.


Percentage of Body Fat and Fat Mass Index as a Screening Tool for Metabolic Syndrome Prediction in Colombian University Students.
High body fat is related to metabolic syndrome (MetS) in all ethnic groups. Based on the International Diabetes Federation (IDF) definition of MetS, the aim of this study was to explore thresholds of body fat percentage (BF%) and fat mass index (FMI) for the prediction of MetS among Colombian University students. A cross-sectional study was conducted on 1687 volunteers (63.4% women, mean age = 20.6 years). Weight, waist circumference, serum lipids indices, blood pressure, and fasting plasma glucose were measured. Body composition was measured by bioelectrical impedance analysis (BIA) and FMI was calculated. MetS was defined as including more than or equal to three of the metabolic abnormalities according to the IDF definition. Receiver operating curve (ROC) analysis was used to determine optimal cut-off points for BF% and FMI in relation to the area under the curve (AUC), sensitivity, and specificity in both sexes. The overall prevalence of MetS was found to be 7.7%, higher in men than women (11.1% vs. 5.3%; p < 0.001). BF% and FMI were positively correlated to MetS components (p < 0.05). ROC analysis indicated that BF% and FMI can be used with moderate accuracy to identify MetS in university-aged students. BF% and FMI thresholds of 25.55% and 6.97 kg/m² in men, and 38.95% and 11.86 kg/m² in women, were found to be indicative of high MetS risk. Based on the IDF criteria, both indexes' thresholds seem to be good tools to identify university students with unfavorable metabolic profiles.


Repression of Irs2 by let-7 miRNAs is essential for homeostasis of the telencephalic neuroepithelium.
Structural integrity and cellular homeostasis of the embryonic stem cell niche are critical for normal tissue development. In the telencephalic neuroepithelium, this is controlled in part by cell adhesion molecules and regulators of progenitor cell lineage, but the specific orchestration of these processes remains unknown. Here, we studied the role of microRNAs in the embryonic telencephalon as key regulators of gene expression. By using the early recombiner Rx-Cre mouse, we identify novel and critical roles of miRNAs in early brain development, demonstrating they are essential to preserve the cellular homeostasis and structural integrity of the telencephalic neuroepithelium. We show that Rx-Cre;DicerF/F mouse embryos have a severe disruption of the telencephalic apical junction belt, followed by invagination of the ventricular surface and formation of hyperproliferative rosettes. Transcriptome analyses and functional experiments in vivo show that these defects result from upregulation of Irs2 upon loss of let-7 miRNAs in an apoptosis-independent manner. Our results reveal an unprecedented relevance of miRNAs in early forebrain development, with potential mechanistic implications in pediatric brain cancer.


A meta-analysis of responses of canopy photosynthetic conversion efficiency to environmental factors reveals major causes of yield gap.
Improving plant energy conversion efficiency (εc) is crucial for increasing food and bioenergy crop production and yields. Using a meta-analysis, the effects of greenhouse gases, weather-related stresses projected to intensify due to climate change, and management practices including inputs, shading, and intercropping on εc were statistically quantified from 140 published studies to identify where improvements would have the largest impact on closing yield gaps. Variation in the response of εc to treatment type and dosage, plant characteristics, and growth conditions were also examined. Significant mean increases in εc were caused by elevated [CO2] (20%), shade (18%), and intercropping (15%). εc increased curvilinearly up to 55% with nitrogen additions whereas phosphorus application was most beneficial at low levels. Significant decreases in εc of -8.4% due to elevated [O3], -16.8% due to water stress, and -6.5% due to foliar damage were found. A non-significant decrease in εc of -17.3% was caused by temperature stress. These results identify the need to engineer greater stress tolerance and enhanced responses to positive factors such as [CO2] and nitrogen to improve average yields and yield potential. Optimizing management strategies will also enhance the benefits possible with intercropping, shade, and pest resilience. To determine optimal practices for εc improvement, further studies should be conducted in the field since several responses were exaggerated by non-field experimental conditions.


Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8.
A correct alignment is an essential requirement in homology modeling. Yet in order to bridge the structural gap between template and target, which may not only involve loop rearrangements, but also shifts of secondary structure elements and repacking of core residues, high-resolution refinement methods with full atomic details are needed. Here, we describe four approaches that address this "last mile of the protein folding problem" and have performed well during CASP8, yielding physically realistic models: YASARA, which runs molecular dynamics simulations of models in explicit solvent, using a new partly knowledge-based all atom force field derived from Amber, whose parameters have been optimized to minimize the damage done to protein crystal structures. The LEE-SERVER, which makes extensive use of conformational space annealing to create alignments, to help Modeller build physically realistic models while satisfying input restraints from templates and CHARMM stereochemistry, and to remodel the side-chains. ROSETTA, whose high resolution refinement protocol combines a physically realistic all atom force field with Monte Carlo minimization to allow the large conformational space to be sampled quickly. And finally UNDERTAKER, which creates a pool of candidate models from various templates and then optimizes them with an adaptive genetic algorithm, using a primarily empirical cost function that does not include bond angle, bond length, or other physics-like terms.


A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Aβ25-35-impaired mouse cognitive function.
The mechanism involved in AD is complex, which has prompted to develop compounds that could simultaneously interact with several potential targets. Here, we report a new synthesized compound SCR-1693 which is designed to target both AChE and calcium channels that are potential for AD therapy. We investigated the effects of SCR-1693 on AChE and calcium channels, the effects of neuroprotection and anti-amnesia in icv-Aβ25-35-injected mice, and the potential mechanisms. AChE activity assay, intracellular Ca(2+) content and calcium currents measurement, and Aβ25-35-induced cellular death determine were performed for validation of designed targets and neuroprotection of SCR-1693. Mice were orally administrated with SCR-1693 once daily after an Aβ25-35 injection. The Morris water maze and Y-maze test, and hippocampal protein detection were conducted on days 5-10, day 11, and day 8. The pyramidal neuron number, hippocampal AChE activity, and synaptic transmission were measured on day 12. SCR-1693 acted as a selective, reversible, and noncompetitive inhibitor of AChE, and a nonselective voltage-gated calcium channel blocker. SCR-1693 also inhibited the increase of AChE activity in the mouse hippocampus. SCR-1693 was more effective than donepezil and memantine in preventing Aβ25-35-induced long-term and short-term memory impairment, maintaining the basal transmission of Schaffer collateral-CA1 synapses, and sustaining LTP in mouse hippocampus. SCR-1693 attenuated Aβ25-35-induced death of SH-SY5Y cell and the loss of hippocampal pyramidal neurons, and regulated Aβ25-35-induced signal cascade in neurons. All these findings indicated that SCR-1693, as a double-target-direction agent, is a considerable candidate for AD therapy.


Recent Advances in Pathophysiology of Traumatic Brain Injury.
Traumatic brain injury (TBI) constitutes the primary reason for mortality and morbidity in persons worldwide below 45 years of age. 1.7 million Traumatic events occur yearly in the United States alone, considering for 50,000 deaths. In severe traumatic brain injury sufferers, a considerable achievement attained in treating short-term consequences; but till date, huge failures are occurring in researcher's capability to render severe traumatic brain injury sufferers to an elevated degree of performing. Initial damage force results in Primary brain injury, causing tissue destruction and distortion in the early post-injury period. These secondary injuries from TBI cause changes in cell performance and dissemination of trauma via activities like free-radical generation, depolarization, and formation of edema, excitotoxicity, and disruption of blood brain barrier, calcium homeostasis, and intracranial hematoma. The expectation for developing effect in TBI sufferers is the best knowledge of these activities and enhancement of remedies that restrict secondary brain damage. The focal point of this study is on knowing the complex outburst of secondary impairments and studying the pathophysiology of TBI which provides alternative treatment benefits. While injured persons demonstrate dissimilar levels of harm and every case is novel with specific recovery profiles, this article strengthens the recent pathophysiological sight of TBI mainly attention on oxidative stress, excitotoxicity, cerebral oxygenation and cerebral blood flow (CBF), development of edema, and inflammatory activities. For initial research acknowledgment of these recurring factors could permit clarification of possible beneficial targets.


Response to Heethoff, Norton, and Raspotnig: Ant and Mite Diversity Drives Toxin Variation in the Little Devil Poison Frog and Erratum.
Our recent publication titled "Ant and Mite Diversity Drives Toxin Variation in the Little Devil Poison Frog" aimed to describe how variation in diet contributes to population differences in toxin profiles of poison frogs. Some poison frogs (Family Dendrobatidae) sequester alkaloid toxins from their arthropod diet, which is composed mainly of ants and mites. Our publication demonstrated that arthropods from the stomach contents of three different frog populations were diverse in both chemistry and species composition. To make progress towards understanding this trophic relationship, our main goal was to identify alkaloids that are found in either ants or mites. With the remaining samples that were not used for chemical analysis, we attempted to identify the arthropods using DNA barcoding of cytochrome oxidase 1 (CO1). The critique of Heethoff, Norton, and Raspotnig refers to the genetic analysis of a small number of mites. Here, we respond to the general argument of the critique as well as other minor issues detailed by Heethoff, Norton, and Raspotnig.


A novel strain sensor based on the campaniform sensillum of insects.
The functional design of the campaniform sensillum was modelled as a hole in a plate using two- and three-dimensional finite-element modelling. Different shapes of opening in a fibrous composite plate amplify differently the global strains imposed on the plate, and different configurations of reinforcement also have an effect. In this paper, the main objective is to study the strain and displacement fields associated with circular or elliptical openings in laminated plates in order to investigate their potential for integrated strain sensors. Since we are therefore primarily interested with the detection of displacement, the detailed stress concentration levels associated with these openings are not of primary concern. However, strain energy density levels associated with different hole and fibre configurations have been used to assess the relative likely strength reduction effect of the openings. To compare the relative strain amplification effect of drilled and formed holes of the same size in loaded plates, we have used the relative change in length of diameters (circular) or semi-axes (elliptical) in directions parallel and normal to the load. Various techniques which could sense this deformation were investigated, in particular, the coupling mechanism of a campaniform sensillum of Calliphora vicina. This mechanism was resolved into discrete components: a cap surrounded by a collar, a joint membrane and an annulus-shaped socket septum with a spongy compliant zone. The coupling mechanism is a mechanical linkage which transforms the stimulus into two deformations in different directions: monoaxial transverse compression of the dendritic tip and vertical displacement of the cap. The mechanism is insensitive to change of the material properties of the socket septum, the cuticular cap and the spongy cuticle. The joint membrane may serve as a gap filler. The material properties of the collar have a substantial influence on the coupling mechanism's output. A 30% change of stiffness of the collar causes 45% change in the output of the coupling mechanism. The collar may be able to tune the sensitivity of the sensillum by changing its elastic properties.


Marine vs freshwater microalgae exopolymers as biosolutions to microplastics pollution.
Microalgae can excrete exopolymer substances (EPS) with a potential to form hetero-aggregates with microplastic particles. In this work, two freshwater (Microcystis panniformis and Scenedesmus sp.) and two marine (Tetraselmis sp. and Gloeocapsa sp.) EPS producing microalgae were exposed to different microplastics. In this study, the influence of the microplastic particles type, size and density in the production of EPS and hetero-aggregates potential was studied. Most microalgae contaminated with microplastics displayed a cell abundance decrease (of up to 42%) in the cultures. The results showed that the formed aggregates were composed of microalgae and EPS (homo-aggregates) or a combination of microalgae, EPS and microplastics (hetero-aggregates). The hetero-aggregation was dependent on the size and yield production of EPS, which was species specific. Microcystis panniformis and Scenedesmus sp. exhibited small EPS, with a higher propension to disaggregate, and consequently lower capabilities to aggregate microplastics. Tetraselmis sp. displayed a higher ability to aggregate both low and high-density microplastics, being partially limited by the size of the microplastics. Gloeocapsa sp. had an outstanding EPS production and presented excellent microplastic aggregation capabilities (adhered onto the surface and also incorporated into the EPS). The results highlight the potential of microalgae to produce EPS and flocculate microplastics, contributing to their vertical transport and consequent deposition. Thus, this work shows the potential of microalgae as biocompatible solutions to water microplastics treatment.


Generation of calves persistently infected with HoBi-like pestivirus and comparison of methods for detection of these persistent infections.
The identification and elimination of persistently infected (PI) cattle are the most effective measures for controlling bovine pestiviruses, including bovine viral diarrhea virus (BVDV) and the emerging HoBi-like viruses. Here, colostrum-deprived calves persistently infected with HoBi-like pestivirus (HoBi-like PI calves) were generated and sampled (serum, buffy coat, and ear notches) on the day of birth (DOB) and weekly for 5 consecutive weeks. The samples were subjected to diagnostic tests for BVDV--two reverse transcriptase PCR (RT-PCR) assays, two commercial real-time RT quantitative PCR (RT-qPCR), two antigen capture enzyme-linked immunosorbent assays (ACE), and immunohistochemistry (IHC)--and to HoBi-like virus-specific RT-PCR and RT-qPCR assays. The rate of false negatives varied among the calves. The HoBi-like virus-specific RT-PCR detected HoBi-like virus in 83%, 75%, and 87% of the serum, buffy coat, and ear notch samples, respectively, while the HoBi-like RT-qPCR detected the virus in 83%, 96%, and 62%, respectively. In comparison, the BVDV RT-PCR test had a higher rate of false negatives in all tissue types, especially for the ear notch samples (missing detection in at least 68% of the samples). The commercial BVDV RT-qPCRs and IHC detected 100% of the ear notch samples as positive. While ACE based on the BVDV glycoprotein E(rns) detected infection in at least 87% of ear notches, no infections were detected using NS3-based ACE. The BVDV RT-qPCR, ACE, and IHC yielded higher levels of detection than the HoBi-like virus-specific assays, although the lack of differentiation between BVDV and HoBi-like viruses would make these tests of limited use for the control and/or surveillance of persistent HoBi-like virus infection. An improvement in HoBi-like virus tests is required before a reliable HoBi-like PI surveillance program can be designed.


Fluoride and Oral Health.
The discovery during the first half of the 20th century of the link between natural fluoride, adjusted fluoride levels in drinking water and reduced dental caries prevalence proved to be a stimulus for worldwide on-going research into the role of fluoride in improving oral health. Epidemiological studies of fluoridation programmes have confirmed their safety and their effectiveness in controlling dental caries. Major advances in our knowledge of how fluoride impacts the caries process have led to the development, assessment of effectiveness and promotion of other fluoride vehicles including salt, milk, tablets, toothpaste, gels and varnishes. In 1993, the World Health Organization convened an Expert Committee to provide authoritative information on the role of fluorides in the promotion of oral health throughout the world (WHO TRS 846, 1994). This present publication is a revision of the original 1994 document, again using the expertise of researchers from the extensive fields of knowledge required to successfully implement complex interventions such as the use of fluorides to improve dental and oral health. Financial support for research into the development of these new fluoride strategies has come from many sources including government health departments as well as international and national grant agencies. In addition, the unique role which industry has played in the development, formulation, assessment of effectiveness and promotion of the various fluoride vehicles and strategies is noteworthy. This updated version of 'Fluoride and Oral Health' has adopted an evidence-based approach to its commentary on the different fluoride vehicles and strategies and also to its recommendations. In this regard, full account is taken of the many recent systematic reviews published in peer reviewed literature.


Perinatal mental disorders in Switzerland: prevalence estimates and use of mental-health services.
Perinatal mental disorders (PMDs) are the most common complication of pregnancy and the first postpartum year. Since PMD prevalence and use of mental-health services by perinatal women in Switzerland are unknown, we analysed existing health statistics. We used statistics from a large health insurance company, hospitals and freelance midwives. We assessed the annual rates of mental-healthcare use in perinatal women (n = 13 969). We ascertained the annual rates of PMD treatment in obstetric inpatients (n = 89 699), and annual rates of PMD records by freelance midwives (n = 57 951). In 15 104 women who gave birth in 2012 or 2013, we assessed use of mental healthcare before and during pregnancy, and in the postpartum year. For the same sample, we determined proportions of medication and consultation treatments. We used multiple regression analysis to estimate the influence of PMD on overall healthcare costs of mandatory health insurance. The annual rate of mental-healthcare use by perinatal women was 16.7%. The annual rate of PMD treatment in obstetric inpatients was 1.1%. The annual rate of PMD records in the midwifery care setting was 2.9%. Women with PMD use mental health services mainly in non-obstetric outpatient settings. Medication was the most frequent treatment. Primary care providers and mental health specialists contributed almost equally to consultation treatments. PMD during pregnancy raised overall costs of healthcare in the postpartum year by 1214 Swiss francs. Health-system research and perinatal healthcare should take into consideration the high prevalence of PMD. Real PMD prevalence may be even higher than our data suggest and could be assessed with a survey using our model of PMD prevalence.


Isolation of Alcaligenes sp. strain L6 at low oxygen concentrations and degradation of 3-chlorobenzoate via a pathway not involving (chloro)catechols.
Isolations of 3-chlorobenzoate (3CBA)-degrading aerobic bacteria under reduced O2 partial pressures yielded organisms which metabolized 3CBA via the gentisate or the protocatechuate pathway rather than via the catechol route. The 3CBA metabolism of one of these isolates, L6, which was identified as an Alcaligenes species, was studied in more detail. Resting-cell suspensions of L6 pregrown on 3CBA oxidized all known aromatic intermediates of both the gentisate and the protocatechuate pathways. Neither growth on nor respiration of catechol could be detected. Chloride production from 3CBA by L6 was strictly oxygen dependent. Cell-free extracts of 3CBA-grown L6 cells exhibited no catechol dioxygenase activity but possessed protocatechuate 3,4-dioxygenase, gentisate dioxygenase, and maleylpyruvate isomerase activities instead. In continuous culture with 3CBA as the sole growth substrate, strain L6 demonstrated an increased oxygen affinity with decreasing steady-state oxygen concentrations.


Lack of DNA polymerase theta (POLQ) radiosensitizes bone marrow stromal cells in vitro and increases reticulocyte micronuclei after total-body irradiation.
Abstract Mammalian POLQ (pol theta) is a specialized DNA polymerase with an unknown function in vivo. Roles have been proposed in chromosome stability, as a backup enzyme in DNA base excision repair, and in somatic hypermutation of immunoglobulin genes. The purified enzyme can bypass AP sites and thymine glycol. Mice defective in POLQ are viable and have been reported to have elevated spontaneous and radiation-induced frequencies of micronuclei in circulating red blood cells. To examine the potential roles of POLQ in hematopoiesis and in responses to oxidative stress responses, including ionizing radiation, bone marrow cultures and marrow stromal cell lines were established from Polq(+/+) and Polq(-/-) mice. Aging of bone marrow cultures was not altered, but Polq(-/-) cells were more sensitive to gamma radiation than were Polq(+/+) cells. The D(0) was 1.38 +/- 0.06 Gy for Polq(+/+) cells compared to 1.27 +/- 0.16 and 0.98 +/- 0.10 Gy (P = 0.032) for two Polq(-/-) clones. Polq(-/-) cells were moderately more sensitive to bleomycin than Polq(+/+) cells and were not hypersensitive to paraquat or hydrogen peroxide. ATM kinase activation appeared to be normal in gamma-irradiated Polq(-/-) cells. Inhibition of ATM kinase activity increased the radiosensitivity of Polq(+/+) cells slightly but did not affect Polq(-/-) cells. Polq(-/-) mice had more spontaneous and radiation-induced micronucleated reticulocytes than Polq+/+ and (+/-) mice. The sensitivity of POLQ-defective bone marrow stromal cells to ionizing radiation and bleomycin and the increase in micronuclei in red blood cells support a role for this DNA polymerase in cellular tolerance of DNA damage that can lead to double-strand DNA breaks.


Printing sub-micron structures using Talbot mask-aligner lithography with a 193 nm CW laser light source.
A continuous improvement of resolution in mask-aligner lithography is sought after to meet the requirements of an ever decreasing minimum feature size in back-end processes. For periodic structures, utilizing the Talbot effect for lithography has emerged as a viable path. Here, by combining the Talbot effect with a continuous wave laser source emitting at 193 nm, we demonstrate successfully the fabrication of periodic arrays in silicon substrates with sub-micron feature sizes. The excellent coherence and the superior brilliance of this light source, compared to more traditional mercury lamps and excimer lasers as light source, enables the efficient beam shaping and a reduced minimum feature size at a fixed gap of 20 µm. We present a comprehensive study of proximity printing with this system, including simulations and selected experimental results of prints in up to the fourth Talbot plane. This printing technology can be used to manufacture optical metasurfaces, bio-sensor arrays, membranes, or microchannel plates.


Measurement error corrected sodium and potassium intake estimation using 24-hour urinary excretion.
Epidemiological studies of the association of sodium and potassium intake with cardiovascular disease risk have almost exclusively relied on self-reported dietary data. Here, 24-hour urinary excretion assessments are used to correct the dietary self-report data for measurement error under the assumption that 24-hour urine recovery provides a biomarker that differs from usual intake according to a classical measurement model. Under this assumption, dietary self-reports underestimate sodium by 0% to 15%, overestimate potassium by 8% to 15%, and underestimate sodium/potassium ratio by ≈20% using food frequency questionnaires, 4-day food records, or three 24-hour dietary recalls in Women's Health Initiative studies. Calibration equations are developed by linear regression of log-transformed 24-hour urine assessments on corresponding log-transformed self-report assessments and several study subject characteristics. For each self-report method, the calibration equations turned out to depend on race and age and strongly on body mass index. After adjustment for temporal variation, calibration equations using food records or recalls explained 45% to 50% of the variation in (log-transformed) 24-hour urine assessments for sodium, 60% to 70% of the variation for potassium, and 55% to 60% of the variation for sodium/potassium ratio. These equations may be suitable for use in epidemiological disease association studies among postmenopausal women. The corresponding signals from food frequency questionnaire data were weak, but calibration equations for the ratios of sodium and potassium/total energy explained ≈35%, 50%, and 45% of log-biomarker variation for sodium, potassium, and their ratio, respectively, after the adjustment for temporal biomarker variation and may be suitable for cautious use in epidemiological studies. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT00000611.


Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma.
Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC and its influence on the design of effective cancer immunotherapeutics. We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T-cell proliferation assays. In-depth interrogation of the immune landscapes showed that regulatory T cells (TREG) and CD8+ resident memory T cells (TRM) were enriched in HBV-related HCC, whereas Tim-3+CD8+ T cells and CD244+ natural killer cells were enriched in non-viral-related HCC. NGS of isolated TREG and TRM from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. TREG and TRM from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1+ TREG could be reversed with anti-PD-1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that TREG and TRM contributed to overall patient survival: TREG were associated with a poor prognosis and TRM were associated with a good prognosis in HCC. We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics.


Self-monitoring of blood glucose in type 2 diabetes: systematic review.
To examine whether or not self-monitoring of blood glucose (SMBG) is worthwhile, in terms of glycaemic control, hypoglycaemia, quality of life (QoL) and cost per quality-adjusted life-year (QALY), in people with type 2 diabetes (T2DM) who were not treated with insulin or who were on basal insulin in combination with oral agents. Literature searched included systematic reviews published since 1996, and a systematic review and meta-analyses of randomised controlled trials (RCTs) identified from the reviews, and from searches for more recent trials, along with review of qualitative and economic studies. Search strategies were limited to the English language and to articles published since 1996, and included: databases searched from 1996 to April 2009 - The Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science - limited to meeting abstracts; and websites. The intervention was self-testing of blood glucose with a meter and test strips. Studies included adult patients with T2DM on any oral treatment or combination of regimens, including lifestyle, oral agents or once-daily basal insulin. Existing systematic reviews of SMBG were summarised and results compared. Evidence synthesis of all of the studies meeting the inclusion criteria was carried out using a narrative review. Data were analysed by outcome and subgroups. HbA1c data from RCTs were summarised using a meta-analysis. Heterogeneity was calculated using the chi-squared and I2 methods. The following analyses were carried out: SMBG compared to self-monitoring of urine glucose, SMBG versus no SMBG, more intensive SMBG versus less intensive SMBG, and more intensive SMBG versus no SMBG. Available qualitative data gained from in-depth interview studies, repeated interviews, and questionnaire and survey data were summarised. The review identified 30 RCTs, although few were of high quality. Ten trials comparing SMBG with no SMBG showed statistically significant reduction in HbA1C of 0.21%, which may not be considered clinically significant. A similar, though not statistically significant difference, was shown where SMBG with education was compared to SMBG without education or feedback. RCTs showed no consistent effect on hypoglycaemic episodes and no impact on medication changes. Review of cost-effectiveness studies showed that costs of SMBG per annum vary considerably (10-259 pounds). Although some studies assert that SMBG may lead to savings in health-care costs which may offset the costs of testing, the best analysis to date (DiGEM - Diabetes Glycaemic Education and Monitoring) concluded that SMBG was not cost-effective. Qualitative studies revealed that there was a lack of education in how to interpret and use the data from SMBG, and that failure to act on the results was common. The evidence suggested that SMBG is of limited clinical effectiveness in improving glycaemic control in people with T2DM on oral agents, or diet alone, and is therefore unlikely to be cost-effective. SMBG may lead to improved glycaemic control only in the context of appropriate education - both for patients and health-care professionals - on how to respond to the data, in terms of lifestyle and treatment adjustment. Also, SMBG may be more effective if patients are able to self-adjust drug treatment. Further research is required on the type of education and feedback that are most helpful, characteristics of patients benefiting most from SMBG, optimal timing and frequency of SMBG, and the circumstances under which SMBG causes anxiety and/or depression.


Infra-slow EEG fluctuations are correlated with resting-state network dynamics in fMRI.
Ongoing neuronal activity in the CNS waxes and wanes continuously across widespread spatial and temporal scales. In the human brain, these spontaneous fluctuations are salient in blood oxygenation level-dependent (BOLD) signals and correlated within specific brain systems or "intrinsic-connectivity networks." In electrophysiological recordings, both the amplitude dynamics of fast (1-100 Hz) oscillations and the scalp potentials per se exhibit fluctuations in the same infra-slow (0.01-0.1 Hz) frequency range where the BOLD fluctuations are conspicuous. While several lines of evidence show that the BOLD fluctuations are correlated with fast-amplitude dynamics, it has remained unclear whether the infra-slow scalp potential fluctuations in full-band electroencephalography (fbEEG) are related to the resting-state BOLD signals. We used concurrent fbEEG and functional magnetic resonance imaging (fMRI) recordings to address the relationship of infra-slow fluctuations (ISFs) in scalp potentials and BOLD signals. We show here that independent components of fbEEG recordings are selectively correlated with subsets of cortical BOLD signals in specific task-positive and task-negative, fMRI-defined resting-state networks. This brain system-specific association indicates that infra-slow scalp potentials are directly associated with the endogenous fluctuations in neuronal activity levels. fbEEG thus yields a noninvasive, high-temporal resolution window into the dynamics of intrinsic connectivity networks. These results support the view that the slow potentials reflect changes in cortical excitability and shed light on neuronal substrates underlying both electrophysiological and behavioral ISFs.


WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse.
T-cell-receptor (TCR)-mediated integrin activation is required for T-cell-antigen-presenting cell conjugation and adhesion to extracellular matrix components. While it has been demonstrated that the actin cytoskeleton and its regulators play an essential role in this process, no mechanism has been established which directly links TCR-induced actin polymerization to the activation of integrins. Here, we demonstrate that TCR stimulation results in WAVE2-ARP2/3-dependent F-actin nucleation and the formation of a complex containing WAVE2, ARP2/3, vinculin, and talin. The verprolin-connecting-acidic (VCA) domain of WAVE2 mediates the formation of the ARP2/3-vinculin-talin signaling complex and talin recruitment to the immunological synapse (IS). Interestingly, although vinculin is not required for F-actin or integrin accumulation at the IS, it is required for the recruitment of talin. In addition, RNA interference of either WAVE2 or vinculin inhibits activation-dependent induction of high-affinity integrin binding to VCAM-1. Overall, these findings demonstrate a mechanism in which signals from the TCR produce WAVE2-ARP2/3-mediated de novo actin polymerization, leading to integrin clustering and high-affinity binding through the recruitment of vinculin and talin.


Endovascular repair of aortoiliac occlusive disease.
Occlusive disease of the aorta and iliac and femoral arteries may lead to limb-threatening ischemia when multiple levels of disease are present. The combined treatment of severe aortoiliac and infrainguinal disease using standard techniques may be hazardous or contraindicated in patients with multiple, previous reconstructions or severe co-morbid medical illnesses. This report summarizes the technical feasibility and early results of aortoiliac endovascular stented grafts (ESGs) in combination with conventional surgical reconstructions for the treatment of multilevel arterial occlusive disease. Forty-two patients with multilevel aortoiliofemoral limb-threatening occlusive disease had an ESG inserted to treat long-segment, multilevel, occlusive disease. ESGs originated from either the aorta or the common iliac artery and were inserted into one of the femoral arteries. ESG lengths ranged from 16 to 30 cm (mean 21 cm). Conventional surgical bypasses were constructed, when necessary, from polytetrafluoroethylene (PTFE) or saphenous vein and were extended using standard techniques to the popliteal, tibial, or contralateral femoral arteries. Technical success of graft insertion was achieved in 39 of 42 attempted ESG procedures (93%). The 18-month primary and secondary cumulative patency rates for ESGs were 89 +/- 9 (SE) and 100%, respectively. Limb salvage was achieved in 94% of patients at 24 months. Four patients had minor postprocedure complications (10%), and there was one death. Endovascular aortoiliac grafts, often in combination with conventional surgical infrainguinal bypasses, are a technically feasible, potentially safe option for the treatment of limb-threatening aortoiliofemoral occlusive disease and have demonstrated encouraging early patency. Long-term follow-up is necessary before widespread application of this technique is instituted.


Three-dimensional macroporous nanoelectronic networks as minimally invasive brain probes.
Direct electrical recording and stimulation of neural activity using micro-fabricated silicon and metal micro-wire probes have contributed extensively to basic neuroscience and therapeutic applications; however, the dimensional and mechanical mismatch of these probes with the brain tissue limits their stability in chronic implants and decreases the neuron-device contact. Here, we demonstrate the realization of a three-dimensional macroporous nanoelectronic brain probe that combines ultra-flexibility and subcellular feature sizes to overcome these limitations. Built-in strains controlling the local geometry of the macroporous devices are designed to optimize the neuron/probe interface and to promote integration with the brain tissue while introducing minimal mechanical perturbation. The ultra-flexible probes were implanted frozen into rodent brains and used to record multiplexed local field potentials and single-unit action potentials from the somatosensory cortex. Significantly, histology analysis revealed filling-in of neural tissue through the macroporous network and attractive neuron-probe interactions, consistent with long-term biocompatibility of the device.


Angiotensin receptor blockers improve insulin resistance in type 2 diabetic rats by modulating adipose tissue.
Adipose tissue is recognized as a pivotal organ in the development of insulin resistance. This study seeks to determine the effect of angiotensin receptor blockade (ARB) on insulin resistance of adipocytes in culture and in a rat model of type 2 diabetes. Treatment of Otsuka Long-Evans Tokushima Fatty rats with the ARB L158809 for six months significantly lowered fasting plasma glucose, cholesterol and triglyceride levels but led to higher plasma adiponectin levels. Insulin resistance, measured by an intraperitoneal glucose tolerance test, of the treated rats was significantly improved along with an increase in the number of small differentiated adipocytes; however, epididymal fat mass decreased. Treatment significantly lowered lipid peroxidation and MCP-1 expression while increasing adiponectin production by the adipose tissue. ARB treatment significantly improved insulin sensitivity and markedly suppressed AT2-induced oxidative stress, PAI-1 and MCP-1 levels and NF-kappaB activation of adipocytes in culture. Treatment increased adiponectin and PPARgamma expression along with intracellular triglyceride levels reflecting differentiation of the cultured adipocytes. Our study suggests that ARB treatment improves insulin resistance by modification of adipose tissue thereby blunting the development of diabetes.


Indicator Compounds Representative of Contaminants of Emerging Concern (CECs) Found in the Water Cycle in the United States.
The presence of contaminants of emerging concern (CECs) in the aquatic environment has recently become a global issue. The very large number of CECs reported in the literature makes it difficult to interpret potential risks as well as the removal efficiencies, especially for the more recalcitrant compounds. As such, there is a need for indicator compounds that are representative of CECs detected in systems worldwide. In an effort to develop such a list, five criteria were used to address the potential for applying indicator compounds; these criteria include usage, occurrence, resistance to treatment, persistence, and physicochemical properties that shed light on the potential degradability of a class of compounds. Additional constraints applied included the feasibility of procuring and analyzing compounds. In total, 22 CECs belonging to 13 groups were selected as indicator compounds. These compounds include acetaminophen and ibuprofen (analgesic); erythromycin, sulfamethoxazole, and trimethoprim (antibiotics); diazepam and fluoxetine (antidepressants); carbamazepine (antiepileptic); atenolol and propranolol (β-blockers); gemfibrozil (blood lipid regulator); tris(2-chloroethyl)phosphate (TCEP) (fire retardant); cotinine (nicotine metabolite); atrazine, metolachlor, and N,N-diethyl-meta-toluamide (DEET) (pesticides); 17β-estradiol and cholesterol (steroids); caffeine (psychomotor stimulant); perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) (surfactants); and iopromide (X-ray contrast agent). These thirteen groups of compounds represent CECs with the greatest resistance to treatment processes, most persistent in surface waters, and detected with significant frequency throughout the water cycle. Among the important implications of using indicator compounds are the ability to better understand the efficacy of treatment processes as well as the transport and fate of these compounds in the environment.


Ray aberrations analysis for phase plates illuminated by off-axis collimated beams.
Approximate expressions of the ray aberrations for off-axis collimated beams and free form phase plates with a small derivative magnitude are derived with the defocus aberration taken into account. The cubic phase plate, which is one of the most commonly used phase plates in wavefront coding imaging systems, is illustrated as an example. The approximate expressions for the upper and lower boundaries of ray map, and the spot size in the vicinity of the focal plane are derived. The sensitivity to the defocus aberration and the variation of the induced aberrations with respect to the field positions are analyzed with derived approximate expressions as well. Some characteristics unmentioned before are derived, showing a good agreement with the exact aberrations. Finally some useful guidelines are given for the design of imaging systems with phase plates.


Novel topological nodal lines and exotic drum-head-like surface states in synthesized CsCl-type binary alloy TiOs.
Very recently, searching for new topological nodal line semimetals (TNLSs) and drum-head-like (DHL) surface states has become a hot topic in the field of physical chemistry of materials. Via first principles, in this study, a synthesized CsCl type binary alloy, TiOs, was predicted to be a TNLS with three topological nodal lines (TNLs) centered at the X point in the kx/y/z = π plane, and these TNLs, which are protected by mirror, time reversal (T) and spatial inversion (P) symmetries, are perpendicular to one another. The exotic drum-head-like (DHL) surface states can be clearly observed inside and outside the crossing points (CPs) in the bulk system. The CPs, TNLs, and DHL surface states of TiOs are very robust under the influences of uniform strain, electron doping, and hole doping. Spin-orbit coupling (SOC)-induced gaps can be found in this TiOs system when the SOC is taken into consideration. When the SOC is involved, surface Dirac cones can be found in this system, indicating that the topological properties are still maintained. Similar to TiOs, ZrOs and HfOs alloys are TNLSs under the Perdew-Burke-Ernzerhof method. The CPs and the TNLs in both alloys disappear, however, under the Heyd-Scuseria-Ernzerhof method. It is hoped that the DHL surface property in TiOs can be detected by surface sensitive probes in the near future.


Identification of candidate genes of QTLs for seed weight in Brassica napus through comparative mapping among Arabidopsis and Brassica species.
Map-based cloning of quantitative trait loci (QTLs) in polyploidy crop species remains a challenge due to the complexity of their genome structures. QTLs for seed weight in B. napus have been identified, but information on candidate genes for identified QTLs of this important trait is still rare. In this study, a whole genome genetic linkage map for B. napus was constructed using simple sequence repeat (SSR) markers that covered a genetic distance of 2,126.4 cM with an average distance of 5.36 cM between markers. A procedure was developed to establish colinearity of SSR loci on B. napus with its two progenitor diploid species B. rapa and B. oleracea through extensive bioinformatics analysis. With the aid of B. rapa and B. oleracea genome sequences, the 421 homologous colinear loci deduced from the SSR loci of B. napus were shown to correspond to 398 homologous loci in Arabidopsis thaliana. Through comparative mapping of Arabidopsis and the three Brassica species, 227 homologous genes for seed size/weight were mapped on the B. napus genetic map, establishing the genetic bases for the important agronomic trait in this amphidiploid species. Furthermore, 12 candidate genes underlying 8 QTLs for seed weight were identified, and a gene-specific marker for BnAP2 was developed through molecular cloning using the seed weight/size gene distribution map in B. napus. Our study showed that it is feasible to identify candidate genes of QTLs using a SSR-based B. napus genetic map through comparative mapping among Arabidopsis and B. napus and its two progenitor species B. rapa and B. oleracea. Identification of candidate genes for seed weight in amphidiploid B. napus will accelerate the process of isolating the mapped QTLs for this important trait, and this approach may be useful for QTL identification of other traits of agronomic significance.


The importance of work conditions and health for voluntary job mobility: a two-year follow-up.
Changing jobs is part of modern working life. Within occupational health, job mobility has mainly been studied in terms of employees' intentions to leave their jobs. In contrast to actual turnover, turnover intentions are not definite and only reflect the probability that an individual will change job. The aim of this study was to determine what work conditions predict voluntary job mobility and to examine if good health or burnout predicts voluntary job mobility. The study was based on questionnaire data from 792 civil servants. The data were analysed using logistic regressions. Low variety and high autonomy were associated with increased voluntary job mobility. However, the associations between health and voluntary job mobility did not reach significance. Possible explanations for the null results may be that the population was homogeneous, and that the instruments for measuring global health are too coarse for a healthy, working population. Voluntary job mobility may be predicted by high autonomy and low variety. The former may reflect that individuals with high autonomy have stronger career development motives; the latter may reflect the fact that low variety leads to job dissatisfaction. In contrast to our results on job content, global health measurements are not strong predictors of voluntary job mobility. This may be because good health affects job mobility through several offsetting channels, involving the resources and ability to seek a new job. Future work should use more detailed measurements of health or examine other work settings so that we may learn more about which of the offsetting effects of health dominate in different contexts.


Mortality risk in children after renal allograft failure: a NAPRTCS study.
Studies have shown that adult dialysis patients with a failed renal allograft face a greater risk of mortality on dialysis compared with transplant-naïve patients. The outcome of children returning to dialysis after allograft failure has not been previously studied. Using the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry, we studied patients aged 2-21 years who initiated dialysis from 1 January 1992 to 31 December 2007. Of a total of 5,006 patients, 1,031 patients had a prior history of allograft failure and 3,975 did not (transplant-naïve). Demographic characteristics, including age at dialysis initiation, race, dialysis modality, primary renal disease, era of dialysis initiation, height Z score, and weight Z score were significantly different between the groups (p < 0.0001). Survival probability between the transplant-naïve and allograft failure groups was not significantly different (94.3% and 93.7% at 3 years respectively, log-rank p = 0.08). After covariate adjustment, allograft failure was not a significant factor contributing to increased mortality risk on dialysis (HR 0.98, CI 0.64-1.50, p = 0.94) based on Cox regression analysis. Children with failed allografts who return to dialysis are not at greater risk of mortality than their transplant-naïve dialysis counterparts.


Aspergillus flavus in Soils and Corncobs in South Texas: Implications for Management of Aflatoxins in Corn-Cotton Rotations.
Aspergillus flavus causes aflatoxin contamination in both cottonseed and corn. Corn-cotton rotations are common in South Texas, where reduced tillage frequently results in long-term residence of corncobs on soil surfaces. Corncobs are colonized by A. flavus either prior to harvest or while in the soil. This study sought to determine the potential of corncobs as sources of inoculum for cotton and corn in South Texas. A. flavus communities in corncob and soil samples were collected during the planting seasons of 2001 to 2003 from 29 fields extending from Calhoun and Victoria Counties in the north to the Rio Grande Valley. In order to assess persistence of A. flavus in corncobs, A. flavus communities in corncobs and soil were contrasted every 2 to 3 months in four fields throughout the 3-year study. To assess seasonal variation, similar contrasts were performed in two fields on a biweekly basis. The results indicate that corncobs are major sources of A. flavus inoculum. Corncobs from the previous season contained, on average, over 190 times more A. flavus propagules than soil from the same field, and 2-year-old corncobs still retained 45 times more propagules than soil. There was no significant difference in the incidence of A. flavus strain S on corncobs and soil. The quantity of A. flavus in corncobs decreased with corncob age (r 2 = 0.54; P = 0.002).


Prospective validation of a clinical decision rule to identify patients presenting to the emergency department with chest pain who can safely be removed from cardiac monitoring.
Most patients with chest pain in the emergency department are assigned to cardiac monitoring for several hours, blocking access for patients in greater need. We sought to validate a previously derived decision rule for safe removal of patients from cardiac monitoring after initial evaluation in the emergency department. We prospectively enrolled adults (age ≥ 18 yr) who presented with chest pain and were assigned to cardiac monitoring at 2 academic emergency departments over 18 months. We collected standardized baseline characteristics, findings from clinical evaluations and predictors for the Ottawa Chest Pain Cardiac Monitoring Rule: whether the patient is currently free of chest pain, and whether the electrocardiogram is normal or shows only nonspecific changes. The outcome was an arrhythmia requiring intervention in the emergency department or within 8 hours of presentation to the emergency department. We calculated diagnostic characteristics for the clinical prediction rule. We included 796 patients (mean age 63.8 yr, 55.8% male, 8.9% admitted to hospital). Fifteen patients (1.9%) had an arrhythmia, and the rule performed with the following characteristics: sensitivity 100% (95% confidence interval [CI] 78.2%-100%) and specificity 36.4% (95% CI 33.0%-39.6%). Application of the Ottawa Chest Pain Cardiac Monitoring Rule would have allowed 284 out of 796 patients (35.7%) to be safely removed from cardiac monitoring. We successfully validated the decision rule for safe removal of a large subset of patients with chest pain from cardiac monitoring after initial evaluation in the emergency department. Implementation of this simple yet highly sensitive rule will allow for improved use of health care resources.


Lack of the canonical pRB-binding domain in the E7 ORF of artiodactyl papillomaviruses is associated with the development of fibropapillomas.
The L-X-C-X-E pRB-binding motif of papillomavirus (PV) E7 proteins has been implicated in the immortalization and transformation of the host cell. However, sequencing of the complete genomes of bovine papillomavirus type 3 (BPV-3), bovine papillomavirus type 5 (BPV-5), equine papillomavirus (EQPV) and reindeer (Rangifer tarandus) papillomavirus (RPV) supports the notion that the pRB-binding motif is not ubiquitous among E7 proteins in the PV proteome. Key among the animal groups that lack the pRB-binding domain are the artiodactyl PVs, including European elk PV (EEPV), deer PV (DPV), reindeer PV (RPV), ovine PVs types 1 and 2 (OvPV-1 and -2) and bovine PVs 1, 2 and 5 (BPV-1, -2 and -5). Whereas the presence of the pRB-binding domain is normally associated with papillomas, the artiodactyl PVs are marked by the development of fibropapillomas on infection. Previous studies emphasized the role of E5 in the pathogenic mechanism of fibropapilloma development, but correlation between the lack of an E7 pRB-binding domain and the unique pathology of the artiodactyl PVs suggests a more complicated mechanism and an early evolutionary divergence from a pRB-binding ancestor.


Does the Fragrance of Essential Oils Alleviate the Fatigue Induced by Exercise? A Biochemical Indicator Test in Rats.
To study the effect of the essential oils of Citrus sinensis L., Mentha piperita L., Syzygium aromaticum L., and Rosmarinus officinalis L. on physical exhaustion in rats. Forty-eight male Wistar rats were randomly divided into a control group, a fatigue group, an essential oil mixture (EOM) group, and a peppermint essential oil (PEO) group. Loaded swimming to exhaustion was used as the rat fatigue model. Two groups were nebulized with EOM and PEO after swimming, and the others were nebulized with distilled water. After continuous inhalation for 3 days, the swimming time, blood glucose, blood lactic acid (BLA), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in blood were determined. While an increased time to exhaustion and SOD activity were apparent in both the EOM and PEO groups, the BLA and MDA were lower in both groups, in comparison with the fatigue group, and the changes in the EOM group were more dramatic. Additionally, the EOM group also showed marked changes of the rise of blood glucose and the decrease of BUN and GSH-PX. The results suggested that the inhalation of an essential oil mixture could powerfully relieve exercise-induced fatigue.


Setting research priorities to improve global newborn health and prevent stillbirths by 2025.
In 2013, an estimated 2.8 million newborns died and 2.7 million were stillborn. A much greater number suffer from long term impairment associated with preterm birth, intrauterine growth restriction, congenital anomalies, and perinatal or infectious causes. With the approaching deadline for the achievement of the Millennium Development Goals (MDGs) in 2015, there was a need to set the new research priorities on newborns and stillbirth with a focus not only on survival but also on health, growth and development. We therefore carried out a systematic exercise to set newborn health research priorities for 2013-2025. We used adapted Child Health and Nutrition Research Initiative (CHNRI) methods for this prioritization exercise. We identified and approached the 200 most productive researchers and 400 program experts, and 132 of them submitted research questions online. These were collated into a set of 205 research questions, sent for scoring to the 600 identified experts, and were assessed and scored by 91 experts. Nine out of top ten identified priorities were in the domain of research on improving delivery of known interventions, with simplified neonatal resuscitation program and clinical algorithms and improved skills of community health workers leading the list. The top 10 priorities in the domain of development were led by ideas on improved Kangaroo Mother Care at community level, how to improve the accuracy of diagnosis by community health workers, and perinatal audits. The 10 leading priorities for discovery research focused on stable surfactant with novel modes of administration for preterm babies, ability to diagnose fetal distress and novel tocolytic agents to delay or stop preterm labour. These findings will assist both donors and researchers in supporting and conducting research to close the knowledge gaps for reducing neonatal mortality, morbidity and long term impairment. WHO, SNL and other partners will work to generate interest among key national stakeholders, governments, NGOs, and research institutes in these priorities, while encouraging research funders to support them. We will track research funding, relevant requests for proposals and trial registers to monitor if the priorities identified by this exercise are being addressed.


Determination and characterization of a cannabinoid receptor in rat brain.
The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.


In vivo administration of bryostatin 1, a protein kinase C activator, decreases murine resistance to Salmonella typhimurium.
Bryostatin 1, a potent activator of protein kinase C, has antitumor activity against murine lymphoma, leukemia, and melanoma. In vitro, this compound stimulates the release of gamma-interferon, interleukins, and hematopoietic growth factors from accessory cells and activates both T- and B-cells. Bryostatin 1 is also able to stimulate neutrophils to undergo oxidative burst and degranulation. Because of the ability of this compound to stimulate the immune system, cause release of immune mediators, and activate neutrophils, we have examined its effect on bacterial infection by using the gram-negative bacterium Salmonella typhimurium in mice. We find that animals given injections i.v. of S. typhimurium have a shortened life span if they are also given injections i.p. of nonlethal doses of bryostatin 1. There is a dose-response relationship with 100 micrograms/kg bryostatin 1 having a greater effect on survival than 40 micrograms/kg. Below 40 micrograms/kg there are no effects on survival. Analysis of the first 4 h of Salmonella infection demonstrates that bryostatin 1 does not affect the blood clearance of the bacterium. However, by day 2 of infection greater numbers of bacteria are found in the livers and spleens of mice given injections of bryostatin 1. By day 5, 10-fold more S. typhimurium bacteria are found in the livers and spleens of mice receiving 40 micrograms/kg of bryostatin 1. To determine whether bryostatin 1 was affecting growth or causing the death of bacteria, we used a Salmonella carrying a plasmid which has a temperature-sensitive origin of replication and is unable to replicate when the bacteria are in mice. This experiment demonstrates that bryostatin 1 represses bacterial killing but does not affect bacterial growth. Bryostatin 1 given i.p. stimulates a transient syndrome of weight loss and diarrhea from which the mice recover and regain weight, suggesting that bryostatin 1 may release a number of important humoral mediators in vivo. The weight loss is exacerbated by Salmonella infection with mice receiving bryostatin 1 and S. typhimurium, in that they lose approximately 33% of body weight prior to death. Thus, at doses used to treat murine tumors, bryostatin 1 treatment does not affect the clearance of S. typhimurium from the blood but does decrease the killing of bacteria in the liver and spleen, leading to early animal death. Such potential effects of bryostatin 1 on the outcome of bacterial infections should be evaluated in ongoing human trials of this agent.


Proposal for identification methodology for urban agglomerations according to directive 91/271/EEC on wastewater treatment.
This paper discusses the problem of the identification and definition of the urban agglomerations in accordance with Directive 91/271/EC. The aim of this identification is to guarantee a satisfactory level of treatment for urban wastewaters and the achievement of the quality objectives for water bodies. The methodology employed, taking into account the existing planning tools in the water service sector, has been based on official national census data, on the Water Protection Plan, on the predictions of Water Service Plans prepared by each Water Authority and on detailed indications provided by the Authorities themselves. The proposed approach, obtained with geographic information systems applications and the calculation of pollution loads, is described and tested in the Veneto region, Italy. In the final part of the paper some considerations on the results obtained are presented and discussed.