Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with polycystic ovary syndrome.
We evaluated the hypothesis that metformin would improve signs and symptoms of polycystic ovary syndrome (PCOS) in adolescents as compared to oral contraceptive pills (OCP) and have a favorable effect on obesity. Thirty-five obese, post-menarchal, non-sexually active adolescents aged 12-21 years with PCOS and hyperinsulinism were randomly assigned to receive either OCP or metformin for 6 months. There was a significant decrease in BMI in the two groups over time, from 40.1 to 38.6 in the OCP group, and 37.3 to 36.3 in the metformin group, p = 0.0026, but no significant difference in the degree of change between the two groups. Both groups had decreased free testosterone (OCP: 1.8 pg/ml to 0.96 pg/ml; metformin: 2.1 pg/ml to 1.6 pg/ml), p < 0.0001, and improvements in insulin resistance as evidenced by increased glucose/insulin (G/I) ratio (p < 0.005) and increased QUICK1 scores (p < 0.0005). No significant differences in response to treatment were found between the metformin and OCP groups in outcome variables. Adolescents with PCOS treated with metformin or OCP experienced similar beneficial outcomes including reduction in androgen levels, weight loss, and increased insulin sensitivity. The choice of a treatment agent for long-term use will depend on safety profiles, therapeutic goals and patient adherence.


Effects of wood bark and fertilizer amendment on trace element mobility in mine soils, Broken Hill, Australia: implications for mined land reclamation.
Soil amendments can immobilize metals in soils, reducing the risks of metal exposure and associated impacts to flora, fauna and human health. In this study, soil amendments were compared, based on "closed system" water extracts, for reducing metal mobility in metal-contaminated soil from the Broken Hill mining center, Australia. Phosphatefertilizer (bovine bone meal, superphosphate, triple superphosphate, potassium orthophosphate) and pine bark (Pinus radiata) were applied to two soils (BH1, BH2) contaminated with mining waste. Both soils had near neutral to alkaline pH values, were sulfide- or sulfate-rich, and contained metal and metalloid at concentrations that pose high environmental risks (e.g., Pb = 1.25 wt% and 0.55 wt%, Zn = 0.71 wt% and 0.47 wt% for BH1 and BH2, respectively). The addition of fertilizers and/or pine bark to both soil types increased water extractable metals and metalloids concentrations (As, Cd, Cu, Fe, Mn, Pb, Sb, Zn) compared with nonamended soils. One or more of the elements As, Cd, Cu, Mn, Pb, and Zn increased significantly in extracts of a range of different soil+pine bark and soil+fertilizer+piner+pine bark tests in response to increased pine bark doses. By contrast, Fe and Sb concentrations in extracts did not change significantly with pine bark addition. Solution pH was decreased by phosphate fertilizers (except for bovine bone meal) and pine bark, and pine bark enhanced dissolved organic carbon. At least in the short-term, the application of phosphate fertilizers and pine bark proved to be an ineffective method for controlling metal and metalloid mobility in soils that contain admixtures of polymetallic, polymineralic mine wastes.


Mitochondrial sequence variation in ancient horses from the Carpathian Basin and possible modern relatives.
Movements of human populations leave their traces in the genetic makeup of the areas affected; the same applies to the horses that move with their owners This study is concerned with the mitochondrial control region genotypes of 31 archaeological horse remains, excavated from pre-conquest Avar and post-conquest Hungarian burial sites in the Carpathian Basin dating from the sixth to the tenth century. To investigate relationships to other ancient and recent breeds, modern Hucul and Akhal Teke samples were also collected, and mtDNA control region (CR) sequences from 76 breeds representing 921 individual specimens were combined with our sequence data. Phylogenetic relationships among horse mtDNA CR haplotypes were estimated using both genetic distance and the non-dichotomous network method. Both methods indicated a separation between horses of the Avars and the Hungarians. Our results show that the ethnic changes induced by the Hungarian Conquest were accompanied by a corresponding change in the stables of the Carpathian Basin.


[18F]Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin's lymphoma.
Currently, a routine bone marrow biopsy (BMB) is performed to detect bone marrow (BM) involvement in pediatric Hodgkin's lymphoma (HL) stage greater than IIA. [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is increasingly used for the initial staging of HL. The value of using FDG-PET to detect BM involvement has not been sufficiently defined. We compared the results of BMBs and FDG-PET for the diagnosis of BM involvement in a large pediatric group with HL. The initial staging of 175 pediatric patients with newly diagnosed classical HL stage greater than IIA was determined by using BMB, FDG-PET, chest computed tomography (CT), and magnetic resonance imaging (MRI) or CT of the neck, abdomen, and pelvis. Staging images were prospectively evaluated by a central review board. Skeletal regions that were suggestive of BM involvement by either method were re-evaluated by using different imaging modalities. In suspicious cases, bone scintigraphy was performed. If follow-up FDG-PET scans were available, the remission of skeletal lesions during treatment was evaluated. BMB results were positive in seven of 175 patients and were identified by FDG-PET. FDG-PET scans showed BM involvement in 45 patients. In addition, the lesions of 32 of these 45 patients had a typical multifocal pattern. In 38 of 39 follow-up positron emission tomography scans, most of the skeletal lesions disappeared after chemotherapy. There was no patient with skeletal findings suggestive of BM involvement by MRI or CT with a negative FDG-PET. FDG-PET is a sensitive and specific method for the detection of BM involvement in pediatric HL. The sensitivity of a BMB appears compromised by the focal pattern of BM involvement. Thus, FDG-PET may safely be substituted for a BMB in routine staging procedures.


Allergies, atopy, immune-related factors and childhood rhabdomyosarcoma: a report from the Children's Oncology Group.
Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case-control study of 322 childhood RMS cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex and age. The following atopic conditions were assessed: allergies, asthma, eczema and hives; in addition, we examined other immune-related factors: birth order, day-care attendance and breastfeeding. Conditional logistic-regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income and parental education. As the two most common histologic types of RMS are embryonal (n=215) and alveolar (n=66), we evaluated effect heterogeneity of these exposures. Allergies (OR=0.60, 95% CI: 0.41-0.87), hives (OR = 0.61, 95% CI: 0.38-0.97), day-care attendance (OR=0.48, 95% CI: 0.32-0.71) and breastfeeding for ≥ 12 months (OR=0.36, 95% CI: 0.18-0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p>0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system's role in the development of this tumor.


Natural and orthogonal interaction framework for modeling gene-environment interactions with application to lung cancer.
We aimed at extending the Natural and Orthogonal Interaction (NOIA) framework, developed for modeling gene-gene interactions in the analysis of quantitative traits, to allow for reduced genetic models, dichotomous traits, and gene-environment interactions. We evaluate the performance of the NOIA statistical models using simulated data and lung cancer data. The NOIA statistical models are developed for additive, dominant, and recessive genetic models as well as for a binary environmental exposure. Using the Kronecker product rule, a NOIA statistical model is built to model gene-environment interactions. By treating the genotypic values as the logarithm of odds, the NOIA statistical models are extended to the analysis of case-control data. Our simulations showed that power for testing associations while allowing for interaction using the NOIA statistical model is much higher than using functional models for most of the scenarios we simulated. When applied to lung cancer data, much smaller p values were obtained using the NOIA statistical model for either the main effects or the SNP-smoking interactions for some of the SNPs tested. The NOIA statistical models are usually more powerful than the functional models in detecting main effects and interaction effects for both quantitative traits and binary traits.


Mean level of positive affect moderates associations between volatility in positive affect, mental health, and alcohol consumption among mothers.
Affective volatility (i.e., variability) is typically conceptualized as a marker of poor mental and behavioral health. The current research challenges this notion. Among individuals who typically experience low positive affect (PA), vacillation between bouts of joy and marked anhedonia may be associated with better behavioral health relative to a restricted range of PA experience. We therefore tested the hypothesis that mean levels of PA captured via an 8-day intensive repeated Ecological Momentary Assessment (EMA) would moderate the association of EMA-measured PA variability with behavioral health measured at intake among working mothers (N = 202) with young children-a population at risk for experiencing repeated stress- and reward-induced PA changes. Mixed-effects location scale modeling parsed variance in PA mean and variability, which were used in subject-level regression models of associations with depressive symptoms, anxiety, and alcohol use. PA mean moderated the associations of PA variability with depressive symptoms (Interaction: β = .20, p = .02) and alcohol consumption frequency (Interaction: β = .22, p = .02). PA variability and depressive symptom and alcohol consumption levels were positively associated at higher PA mean levels, whereas PA variability was inversely associated with depressive symptom and alcohol consumption at low mean PA. PA Mean × Variability Interactions were not significant for anxiety and binge drinking. We conclude that (a) intensive longitudinal modeling of Affect Mean × Variability Interaction effects may provide incremental information in psychopathology research; (b) PA volatility does not unilaterally indicate poor behavioral health; and (c) a nuanced perspective on the role of PA volatility may benefit clinical services for working mothers. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Cytokinetic basis for the impaired activation of lymphocytes from patients with primary intracranial tumors.
Patients with malignant brain tumors have a variety of immunologic abnormalities, including the impaired responsiveness of peripheral blood lymphocytes (PBL) to mitogens and alloantigens. We further investigated this impairment of lymphocyte reactivity by employing the techniques of limiting dilution analysis and cytokinetic analysis. PBL preparations from patients have approximately six times fewer phytohemagglutinin (PHA)-responsive cells than PBL from normal subjects. Similar results were obtained with purified T cell preparations. Cytokinetic analysis of PHA-induced [3H]thymidine incorporation employing colchicine blocking of mitosis demonstrated that the number of first generation cells entering the S-phase of mitosis for each 24-hr period was less for PBL from patients than for PBL from normal individuals. First generation responding cells from patients and normal subjects entered DNA synthesis at the same time (48 to 72 hr). Cytokinetic analysis over a period of 168 hr demonstrated that whereas PBL from normal individuals demonstrated second generation responding cells, PBL from the majority of patients did not, thus indicating a defect in their ability to undergo clonal expansion. Measurement of interleukin 2 (IL 2) activity in culture fluids from PHA-activated PBL from normal subjects and patients revealed significantly lower IL 2 levels in culture fluids from PBL from patients. The addition of various concentrations of lectin-free IL 2 to PBL from patients stimulated with PHA did not restore responsiveness to normal values. There was no difference between the levels of interleukin 1 (IL 1) produced by lipopolysaccharide-activated monocytes from normal subjects and patients. Overall, these results suggest that an intrinsic defect exists in T cells obtained from brain tumor patients that renders them unable to enter into normal mitogen-induced blastogenesis.


Gastric carcinogenesis: 2-chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled Sanma hiraki fish, or similarly treated methionine.
The customary salting and pickling of fish in high risk gastric cancer regions were modeled to explore the relevant causative chemicals. The fish Sanma hiraki was treated with sodium chloride and sodium nitrite at pH 3. Previously, it had been found that an extract of the treated fish was mutagenic in Salmonella typhimurium TA 1535 without S9 and also that it induced glandular stomach cancer upon gavage to rats. We now demonstrate that the mutagenicity was enhanced by preincubation of the raw meat for several days before salt-nitrite treatment. HPLC techniques showed that three mutagens were present in the fish extract. One of the mutagens was found to be stable over the pH range of 1.0-9.0. This mutagen was purified by silica gel solid phase extraction, followed by a series of reverse phase HPLC steps, and was characterized by low and high resolution MS, NMR, and FT-IR. While N-nitroso compounds were generally believed to be associated with gastric carcinogenesis, it was unexpectedly found that the mutagen has the novel structure 2-chloro-4-methylthiobutanoic acid (CMBA). Based on the structure, it seemed likely that methionine might be the precursor, and this was, indeed, proven. Both salt and nitrite are essential factors for forming this mutagen. The yield of CMBA was linear for chloride concentrations from 0 to 800 mM NaCl. Of 20 amino acids reacted with nitrite and chloride at pH 3, only methionine generated a mutagen for S. typhimurium TA 1535. Tryptophan gave a product mutagenic in S. typhimurium TA 100 and TA 98, but not TA 1535, and in the case of tyrosine, the mutagen was active only for TA 100. These results suggest an important role for salt in gastric carcinogenesis and provide new approaches for exploring the formation of mutagens/carcinogens for specific target organs.


Ribosome crystallization in chicken embryos. I. Isolation, characterization, and in vitro activity of ribosome tetramers.
Isolated tetrameric particles (166S) derived from the crystalline lattices known to appear in hypothermic chicken embryos consist of mature 80S ribosomes which contain all species of ribosomal RNA and a complete set of ribosomal proteins. Ribosome tetramers are not a special type of polysomes since in solutions of high ionic strengths (500 mM KCl and 50 nM triethanolamine-HCl buffer) containing 5 mM MgCl(2) they dissociate into 40S and 60S ribosomal subunits, without the need of puromycin, and at a concentration of Mg(++) higher than 3 mM they are not disassembled by mild RNase treatment. Tetramers spontaneously disassemble into 80S monomers when the Mg(++) concentration is lowered to 1 mM at relatively low ionic strength. Tetramers failed to couple in vitro puromycin-(3)H into an acid-insoluble product, indicating the lack of nascent polypeptide chains. Although tetramers have no endogenous messenger RNA activity, they can be programmed in vitro with polyuridylic acid (poly U) to synthesize polyphenylalanine. All ribosomes within a tetramer can accept poly U, without the need of disassembly of the tetramers into monomers or subunits.


The mechanical basis of impaired esophageal emptying postfundoplication.
Fundoplication (FP) efficacy is a trade-off between protection against reflux and postoperative dysphagia from the surgically altered mechanical balance within the esophagogastric segment. The purpose of the study was to contrast quantitatively the mechanical balance between normal and post-FP esophageal emptying. Physiological data were combined with mathematical models based on the laws of mechanics. Seven normal controls (NC) and seven post-FP patients underwent concurrent manometry and fluoroscopy. Temporal changes in geometry of the distal bolus cavity and hiatal canal, and cavity-driving pressure were quantified during emptying. Mathematical models were developed to couple cavity pressure to hiatal geometry and esophageal emptying and to determine cavity muscle tone. We found that the average length of the hiatal canal post-FP was twice that of NC; reduction of hiatal radius was not significant. All esophageal emptying events post-FP were incomplete (51% retention); there was no significant difference in the period of emptying between NC and post-FP, and average emptying rates were 40% lower post-FP. The model predicted three distinct phases during esophageal emptying: hiatal opening (phase I), a quasi-steady period (phase II), and final emptying (phase III). A rapid increase in muscle tone and driving pressure forced normal hiatal opening. Post-FP there was a severe impairment of cavity muscle tone causing deficient hiatal opening and flow and bolus retention. We conclude that impaired esophageal emptying post-FP follows from the inability of distal esophageal muscle to generate necessary tone rapidly. Immobilization of the intrinsic sphincter by the surgical procedure may contribute to this deficiency, impaired emptying, and possibly, dysphagia.


Selection of men for investigation of possible testicular cancer in primary care: a large case-control study using electronic patient records.
Testicular cancer incidence has risen over the last two decades and is expected to continue to rise. There are no primary care studies on the clinical features of testicular cancer, with recent National Institute for Health and Care Excellence (NICE) guidance based solely upon clinical consensus. To identify clinical features of testicular cancer and to quantify their risk in primary care patients, with the aim of improving the selection of patients for investigation. A matched case-control study in males aged ≥17 years, using Clinical Practice Research Datalink records. Putative clinical features of testicular cancer were identified and analysed using conditional logistic regression. Positive predictive values (PPVs) were calculated for those aged <50 years. In all, 1398 cases were available, diagnosed between 2000 and 2012, with 4956 age-, sex-, and practice-matched controls. Nine features were independently associated with testicular cancer, the top three being testicular swelling (odds ratio [OR] 280, 95% confidence interval [CI] = 110 to 690), testicular lump (OR 270, 95% CI = 100 to 740), and scrotal swelling (OR 170, 95% CI = 35 to 800). The highest PPV for 17-49-year-olds was testicular lump, at 2.5% (95% CI = 1.1 to 5.6). Combining testicular lump with testicular swelling or testicular pain produced PPVs of 17% and 10%, respectively. Testicular enlargement carries a risk of cancer of 2.5% - close to the current 3% threshold in UK referral guidance. Contrary to traditional teaching, painful testicular enlargement may signify cancer. Some initial hydrocele diagnoses appear to be wrong, with missed cancers, suggesting an ultrasound may be useful when a hydrocele diagnosis is uncertain. These results support the existing NICE guidelines, and help to characterise when an ultrasound should be considered in symptomatic men.


Factors Associated With Osteopathic Primary Care Residency Choice Decisions.
The osteopathic medical profession traditionally emphasized the education of primary care physicians. A common thread for both osteopathic and allopathic residency matches, however, has been an increase in the interest in specialties outside of primary care. To determine whether there are critical points in medical school associated with residency selection decision-making, what factors affect residency selection decisions, and whether any identifiable shifts or trends exist. This mixed-methods study sequentially used qualitative and quantitative research approaches. The study population was a convenience sample of osteopathic medical students, interns and residents, and practicing physicians from partner medical schools, associated hospitals, and a regional association of osteopathic physicians. In the first phase, interviews and focus group discussions were analyzed for codes, categories, and themes relating to factors that influence residency selection. In the second phase, a survey was created from the results of the first phase and administered to study participants. Of the 3450 potential participants, 282 completed the survey. Ninety-one of 209 participants (43.5%) indicated that the third year of medical school was the time they will or did decide what type of residency program to pursue. There were no significant differences in the mean scores between the respondent groups (ie, students, residents, and physicians) when ranking the importance of the 10 influential factors associated with residency selection decision-making (P>.05 for all). The highest percentage of participants indicated the third year of medical school was the time that they made residency selection decisions regarding what specialty they were interested in entering. No shifts regarding the importance of specific primary care residency choice factors were found between training status of respondents.


Spatio-temporal correlations can drastically change the response of a MAPK pathway.
Multisite covalent modification of proteins is omnipresent in eukaryotic cells. A well-known example is the mitogen-activated protein kinase (MAPK) cascade where, in each layer of the cascade, a protein is phosphorylated at two sites. It has long been known that the response of a MAPK pathway strongly depends on whether the enzymes that modify the protein act processively or distributively. A distributive mechanism, in which the enzyme molecules have to release the substrate molecules in between the modification of the two sites, can generate an ultrasensitive response and lead to hysteresis and bistability. We study by Green's Function Reaction Dynamics (GFRD), a stochastic scheme that makes it possible to simulate biochemical networks at the particle level in time and space, a dual phosphorylation cycle in which the enzymes act according to a distributive mechanism. We find that the response of this network can differ dramatically from that predicted by a mean-field analysis based on the chemical rate equations. In particular, rapid rebindings of the enzyme molecules to the substrate molecules after modification of the first site can markedly speed up the response and lead to loss of ultrasensitivity and bistability. In essence, rapid enzyme-substrate rebindings can turn a distributive mechanism into a processive mechanism. We argue that slow ADP release by the enzymes can protect the system against these rapid rebindings, thus enabling ultrasensitivity and bistability.


Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after alpha-galactosylceramide administration.
Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the alpha-galactosylceramide [alpha-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified alpha-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)-dependent natural killer (NK)- and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC-NK-cell interaction and raise concern for the use of alpha-GalCer therapeutically to modulate GVHD and GVL effects.


Macroporous interpenetrating cryogel network of poly(acrylonitrile) and gelatin for biomedical applications.
Cryogels are supermacroporous gel network formed by cryogelation of appropriate monomers or polymeric precursors at subzero temperature. The beneficial feature of this system is a unique combination of high porosity with adequate mechanical strength and osmotic stability, due to which they are being envisaged as potential scaffold material for various biomedical applications. One of the important aspect of cryogel is simple approach by which they can be synthesized and use of aqueous solvent for their synthesis which make them suitable for different biological applications. Various modifications of the cryogels have been sought which involves coupling of various ligands to its surfaces, grafting of polymer chain to cryogel surface or interpenetrating networks of two or more polymers to form a cryogel which provides diversity of its applications. In the following work we have synthesized full interpenetrating network of polyacrylonitrile (PAN)-gelatin with varied gelatin concentration. The PAN-gelatin cryogel interpenetrating network is macroporous in nature and has high percentage swelling equilibrium in the range of 862-1,200 with a flow rate greater than 10 ml/min, which characterizes the interconnectivity of pores and convective flow within the network. PAN-gelatin interpenetrating cryogel network has good mechanical stability as determined by Young's modulus which varies from 123 kPa to 819 kPa depending upon the polymer concentration. Moreover they are shown to be biocompatible and support cell growth within the scaffolds.


A wood-strand material for wind erosion control: effects on total sediment loss, PM10 vertical flux, and PM10 loss.
Fugitive dust from eroding land poses risks to environmental quality and human health, and thus, is regulated nationally based on ambient air quality standards for particulate matter with mean aerodynamic diameter < or = 10 microm (PM10) established in the Clean Air Act. Agricultural straw has been widely used for rainfall-induced erosion control; however, its performance for wind erosion mitigation has been less studied, in part because straw is mobile at moderate wind velocities. A wood-based long-strand material has been developed for rainfall-induced erosion control and has shown operational promise for control of wind-induced erosion and dust emissions from disturbed sites. The purpose of this study was to evaluate the efficacy of both agricultural straw and wood-strand materials in controlling wind erosion and fugitive dust emissions under laboratory conditions. Wind tunnel tests were conducted to compare wood strands of several geometries to agricultural wheat straw and bare soil in terms of total sediment loss, PM10 vertical flux, and PM10 loss. Results indicate that the types of wood strands tested are stable at wind speeds of up to 18 m s(-1), while wheat straw is only stable at speeds of up to 6.5 m s(-1). Wood strands reduced total sediment loss and PM10 emissions by 90% as compared to bare soil across the range of wind speeds tested. Wheat straw did not reduce total sediment loss for the range of speeds tested, but did reduce PM10 emissions by 75% compared to a bare soil at wind speeds of up to 11 m s(-1).


Blood metallothionein, neuron specific enolase, and protein S100B in patients with traumatic brain injury.
The aim of this study was to evaluate the correlation of neuron specific enolase (NSE), protein S100B and time-profile of Glasgow Coma Score (GCS) development with metallothionein (MT) blood levels in patients with traumatic brain injury (TBI) during 10 days of hospitalization. Patients were divided into 2 groups with respect to NSE and S100B levels - with (group I) and without (group II) GCS improvement. Serum NSE and S100B concentrations were measured by immunochemical methods; serum metallothionein concentration by electrochemical technique. Cortical biopsies were investigated immunohistochemically and by electron microscope. A cDNA microarray containing 700 gene probes was used to study the changes in gene expression in the ipsilateral cortex. Values of MT in the blood of group I showed a non-significant decrease compared to group II during 1-3 days after admission. There was an increase of MT during 4-8 days in comparison with values of 1-3 days. The highest value of MT during hospitalization was found in a patient with diffuse axonal injury (group II). The data of cDNA microarray suggested an increase in expression of gene transcripts for oxygen free radical scavenger proteins corresponding with the increase of MT during 4-8 days in both groups. The experimental data indicate that monitoring the content of MT in patients with trauma brain injury would be a suitable approach to evaluate the degree of injury or duration of prolonging unconsciousness, particularly in diagnosis of diffuse axonal injury.


Automated measurement of anteroposterior diameter and foraminal widths in MRI images for lumbar spinal stenosis diagnosis.
Lumbar Spinal Stenosis causes low back pain through pressures exerted on the spinal nerves. This can be verified by measuring the anteroposterior diameter and foraminal widths of the patient's lumbar spine. Our goal is to develop a novel strategy for assessing the extent of Lumbar Spinal Stenosis by automatically calculating these distances from the patient's lumbar spine MRI. Our method starts with a semantic segmentation of T1- and T2-weighted composite axial MRI images using SegNet that partitions the image into six regions of interest. They consist of three main regions-of-interest, namely the Intervertebral Disc, Posterior Element, and Thecal Sac, and three auxiliary regions-of-interest that includes the Area between Anterior and Posterior elements. A novel contour evolution algorithm is then applied to improve the accuracy of the segmentation results along important region boundaries. Nine anatomical landmarks on the image are located by delineating the region boundaries found in the segmented image before the anteroposterior diameter and foraminal widths can be measured. The performance of the proposed algorithm was evaluated through a set of experiments on the Lumbar Spine MRI dataset containing MRI studies of 515 patients. These experiments compare the performance of our contour evolution algorithm with the Geodesic Active Contour and Chan-Vese methods over 22 different setups. We found that our method works best when our contour evolution algorithm is applied to improve the accuracy of both the label images used to train the SegNet model and the automatically segmented image. The average error of the calculated right and left foraminal distances relative to their expert-measured distances are 0.28 mm (p = 0.92) and 0.29 mm (p = 0.97), respectively. The average error of the calculated anteroposterior diameter relative to their expert-measured diameter is 0.90 mm (p = 0.92). The method also achieves 96.7% agreement with an expert opinion on determining the severity of the Intervertebral Disc herniations.


The role of MRI as a surrogate outcome measure in multiple sclerosis.
The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sderosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on dinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.


Notch signaling represses p63 expression in the developing surface ectoderm.
The development of the mature epidermis requires a coordinated sequence of signaling events and transcriptional changes to specify surface ectodermal progenitor cells to the keratinocyte lineage. The initial events that specify epidermal keratinocytes from ectodermal progenitor cells are not well understood. Here, we use both developing mouse embryos and human embryonic stem cells (hESCs) to explore the mechanisms that direct keratinocyte fate from ectodermal progenitor cells. We show that both hESCs and murine embryos express p63 before keratin 14. Furthermore, we find that Notch signaling is activated before p63 expression in ectodermal progenitor cells. Inhibition of Notch signaling pharmacologically or genetically reveals a negative regulatory role for Notch signaling in p63 expression during ectodermal specification in hESCs or mouse embryos, respectively. Taken together, these data reveal a role for Notch signaling in the molecular control of ectodermal progenitor cell specification to the epidermal keratinocyte lineage.


UR-1505, a new salicylate, blocks T cell activation through nuclear factor of activated T cells.
2-Hydroxy-4(-2,2,3,3,3-pentafluoropropoxy)-benzoic acid (UR-1505), a new molecule chemically related to salicylic acid, has immunomodulator properties and is currently under clinical development for treatment of atopic dermatitis. The present work describes the immunomodulatory profile of UR-1505. UR-1505 targets T cells, inhibiting their proliferation and cytokine production by blocking nuclear factor of activated T cells (NF-AT) DNA-binding activity. The effects of UR-1505 (100-300 microM) on T cell proliferation seems to be dependent on the stimulus, because UR-1505 inhibited CD3/CD28-induced T-cell proliferation, increased p27(KIP) levels, and induced G1/S cell arrest but, interestingly, did not inhibit the Janus tyrosine kinase/signal transducer and activator of transcription-induced T-cell proliferation. These data suggest that UR-1505 acts by means of a specific mechanism inhibiting T cell activation depending on T cell receptor signaling pathway. Furthermore, the antiproliferative effects of UR-1505 are not a consequence of decreased cell viability. In addition to the inhibition of T-cell proliferation, UR-1505 decreased, in a dose-dependent manner, the production of interleukin (IL)-5 and interferon (IFN)-gamma in activated T cells, and this effect was produced at the transcriptional level. Because T-cell proliferation and cytokine production were regulated through NF-AT, we examined the effect of UR-1505 on this transcription factor. According to its effect on IL-5 and IFN-gamma mRNA expression, UR-1505 specifically inhibited NF-AT DNA binding without effect on nuclear factor-kappaB and activator protein-1 activities. The effect of UR-1505 on NF-AT is not attributable to a blockade of nuclear import. In conclusion, UR-1505 is a new immunomodulator agent that specifically inhibits NF-AT activation. Because NF-AT regulates the transcription of most genes involved in lymphocyte activation, its selective inactivation results in both decreased T-cell proliferation and cytokine production.


Electric fields around and within single cells during electroporation-a model study.
One of the key issues in electric field-mediated molecular delivery into cells is how the intracellular field is altered by electroporation. Therefore, we simulated the electric field in both the extracellular and intracellular domains of spherical cells during electroporation. The electroporated membrane was modeled macroscopically by assuming that its electric resistivity was smaller than that of the intact membrane. The size of the electroporated region on the membrane varied from zero to the entire surface of the cell. We observed that for a range of values of model constants, the intracellular current could vary several orders of magnitude whereas the maximum variations in the extracellular and total currents were less than 8% and 4%, respectively. A similar difference in the variations was observed when comparing the electric fields near the center of the cell and across the permeabilized membrane, respectively. Electroporation also caused redirection of the extracellular field that was significant only within a small volume in the vicinity of the permeabilized regions, suggesting that the electric field can only facilitate passive cellular uptake of charged molecules near the pores. Within the cell, the field was directed radially from the permeabilized regions, which may be important for improving intracellular distribution of charged molecules.


Long-term Survival for Patients Undergoing Volatile versus IV Anesthesia for Cancer Surgery: A Retrospective Analysis.
Surgical resection remains the best option for long-term survival in many solid tumors. Surgery can, however, lead to tumor cell release into the circulation. Data have suggested differential effects of anesthetic agents on cancer cell growth. This retrospective analysis investigated the association of anesthetic technique with long-term survival in patients presenting for elective surgery in a comprehensive cancer center over 3 yr. All patients undergoing elective surgery between June 2010 and May 2013 were included. Patients were grouped according to whether they had received volatile inhalational (INHA) or total IV anesthesia (TIVA). After excluding those who received both forms of anesthesia during the study period, Kaplan-Meier survival curves were constructed from the date of surgery to death. After propensity matching, univariate and multivariable regression models were used to compare hazard ratios for death. A total of 11,395 anesthetics using INHA or TIVA were delivered in the study period. After exclusions, 3,316 patients (796 deaths, 24%) remained in the INHA group and 3,714 (504 deaths, 13.5%) in the TIVA group. After propensity matching, 2,607 patients remained in each group (597 deaths, 22.8%, in INHA group vs. 407, 15.6%, in TIVA group). Volatile inhalational anesthesia was associated with a hazard ratio of 1.59 (1.30 to 1.95) for death on univariate analysis and 1.46 (1.29 to 1.66) after multivariable analysis of known confounders in the matched group. This retrospective analysis demonstrates an association between type of anesthetic delivered and survival. This analysis alongside biological plausibility should lead to urgent prospective work exploring the effect of anesthetic technique on survival.


Components for integral evaluation in quantum chemistry.
Sharing low-level functionality between software packages enables more rapid development of new capabilities and reduces the duplication of work among development groups. Using the component approach advocated by the Common Component Architecture Forum, we have designed a flexible interface for sharing integrals between quantum chemistry codes. Implementation of these interfaces has been undertaken within the Massively Parallel Quantum Chemistry package, exposing both the IntV3 and Cints/Libint integrals packages to component applications. Benchmark timings for Hartree-Fock calculations demonstrate that the overhead due to the added interface code varies significantly, from less than 1% for small molecules with large basis sets to nearly 10% for larger molecules with smaller basis sets. Correlated calculations and density functional approaches encounter less severe performance overheads of less than 5%. While these overheads are acceptable, additional performance losses occur when arbitrary implementation details, such as integral ordering within buffers, must be handled. Integral reordering is observed to add an additional overhead as large as 12%; hence, a common standard for such implementation details is desired for optimal performance.


Evidence for loss of a partial flagellar glycolytic pathway during trypanosomatid evolution.
Classically viewed as a cytosolic pathway, glycolysis is increasingly recognized as a metabolic pathway exhibiting surprisingly wide-ranging variations in compartmentalization within eukaryotic cells. Trypanosomatid parasites provide an extreme view of glycolytic enzyme compartmentalization as several glycolytic enzymes are found exclusively in peroxisomes. Here, we characterize Trypanosoma brucei flagellar proteins resembling glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoglycerate kinase (PGK): we show the latter associates with the axoneme and the former is a novel paraflagellar rod component. The paraflagellar rod is an essential extra-axonemal structure in trypanosomes and related protists, providing a platform into which metabolic activities can be built. Yet, bioinformatics interrogation and structural modelling indicate neither the trypanosome PGK-like nor the GAPDH-like protein is catalytically active. Orthologs are present in a free-living ancestor of the trypanosomatids, Bodo saltans: the PGK-like protein from B. saltans also lacks key catalytic residues, but its GAPDH-like protein is predicted to be catalytically competent. We discuss the likelihood that the trypanosome GAPDH-like and PGK-like proteins constitute molecular evidence for evolutionary loss of a flagellar glycolytic pathway, either as a consequence of niche adaptation or the re-localization of glycolytic enzymes to peroxisomes and the extensive changes to glycolytic flux regulation that accompanied this re-localization. Evidence indicating loss of localized ATP provision via glycolytic enzymes therefore provides a novel contribution to an emerging theme of hidden diversity with respect to compartmentalization of the ubiquitous glycolytic pathway in eukaryotes. A possibility that trypanosome GAPDH-like protein additionally represents a degenerate example of a moonlighting protein is also discussed.


Predictive value of actin-free Gc-globulin in acute liver failure.
Serum concentrations of the actin scavenger Gc-globulin may provide prognostic information in acute liver failure (ALF). The fraction of Gc-globulin not bound to actin is postulated to represent a better marker than total Gc-globulin but has been difficult to measure. We tested a new rapid assay for actin-free Gc-globulin to determine its prognostic value when compared with the King's College Hospital (KCH) criteria in a large number of patients with ALF. A total of 252 patients with varying etiologies from the U.S. ALF Study Group registry were included; the first 178 patients constituted the learning set, and the last 74 patients served as the validation set. Actin-free Gc-globulin was determined with a commercial enzyme-linked immunosorbent assay kit. The median (range) actin-free Gc-globulin level at admission for the learning set was significantly reduced compared with controls (47 [0-183] mg/L vs. 204 [101-365] mg/L, respectively, P < 0.001). Gc-globulin levels were significantly higher in spontaneous survivors than in patients who died or were transplanted (53 [0-129] mg/L vs. 37 [0-183] mg/L, P = 0.002). A receiver operating characteristic curve analysis showed that a 40 mg/L cutoff level carried the best prognostic information, yielding positive and negative predictive values of 68% and 67%, respectively, in the validation set. The corresponding figures for the KCH criteria were 72% and 64%. A new enzyme-linked immunosorbent assay for actin-free Gc-globulin provides the same (but not optimal) prognostic information as KCH criteria in a single measurement at admission.


Sanitary justice in scarcity.
Justice in health care and the allocation of scarce medical resources must be analyzed differently in affluent as compared to economically weaker societies. The protective functions of the state must be extended to cover basic needs for those too poor to meet them on their own. Medical needs are a high priority, since poor health hampers the ability to secure other basic needs. The state may operate as either a health care provider or supervisor, guaranteeing that citizens be treated fairly by nongovernmental institutions. Two-tiered systems with a vigorous private heath care sector are compatible with the explicit right to health care, provided the private tier operates without directly or indirectly draining public funds.


Functional expression of Rat Nav1.6 voltage-gated sodium channels in HEK293 cells: modulation by the auxiliary β1 subunit.
The Nav1.6 voltage-gated sodium channel α subunit isoform is abundantly expressed in the adult rat brain. To assess the functional modulation of Nav1.6 channels by the auxiliary β1 subunit we expressed the rat Nav1.6 sodium channel α subunit by stable transformation in HEK293 cells either alone or in combination with the rat β1 subunit and assessed the properties of the reconstituted channels by recording sodium currents using the whole-cell patch clamp technique. Coexpression with the β1 subunit accelerated the inactivation of sodium currents and shifted the voltage dependence of channel activation and steady-state fast inactivation by approximately 5-7 mV in the direction of depolarization. By contrast the β1 subunit had no effect on the stability of sodium currents following repeated depolarizations at high frequencies. Our results define modulatory effects of the β1 subunit on the properties of rat Nav1.6-mediated sodium currents reconstituted in HEK293 cells that differ from effects measured previously in the Xenopus oocyte expression system. We also identify differences in the kinetic and gating properties of the rat Nav1.6 channel expressed in the absence of the β1 subunit compared to the properties of the orthologous mouse and human channels expressed in this system.


Overexpression of the ASN1 gene enhances nitrogen status in seeds of Arabidopsis.
In wild-type Arabidopsis, levels of ASN1 mRNA and asparagine (Asn) are tightly regulated by environmental factors and metabolites. Because Asn serves as an important nitrogen storage and transport compound used to allocate nitrogen resources between source and sink organs, we tested whether overexpression of the major expressed gene for Asn synthetase, ASN1, would lead to changes in nitrogen status in the ultimate storage organ for metabolites-seeds. Transgenic Arabidopsis constitutively overexpressing ASN1 under the cauliflower mosaic virus 35S promoter were constructed (35S-ASN1). In seeds of the 35S-ASN1 lines, three observations support the notion that the nitrogen status was enhanced: (a) elevations of soluble seed protein contents, (b) elevations of total protein contents from acid-hydrolyzed seeds, and (c) higher tolerance of young seedlings when grown on nitrogen-limiting media. Besides quantitative differences, changes in the relative composition of the seed amino acid were also observed. The change in seed nitrogen status was accompanied by an increase of total free amino acids (mainly Asn) allocated to flowers and developing siliques. In 35S-ASN1 lines, sink tissues such as flowers and developing siliques exhibit a higher level of free Asn than source tissues such as leaves and stems, despite significantly higher levels of ASN1 mRNA observed in the source tissues. This was at least partially due to an enhanced transport of Asn from source to sink via the phloem, as demonstrated by the increased levels of Asn in phloem exudates of the 35S-ASN1 plants.


The violence prevention climate of mental health wards: a cross-sectional study of staff and patient views.
Ward climate can shape the behaviour of both staff and patients. A subset of the ward climate is the violence prevention climate, the unique characteristics that are perceived by the people within the environment as contributing towards the prevention of violence. The aim of this study was to explore differences between and within staff and patient groups in terms of their perceptions of the violence prevention climate. A cross-sectional survey was conducted with staff (n = 326) and patients (n = 95) in mental health care pathways within one charitable trust. All participants completed the VPC-14 to measure perceptions of the violence prevention climate, a validated 14-item two-factor scale (staff actions and patient actions). Staff demographic information was collected on the VPC-14 front sheet; patient demographic, clinical and violence data were collected from electronic case records. Bivariate analyses were conducted to compare within- and between-group variables. Significant staff and patient variables were entered into multiple hierarchical regression analyses to assess their relationship with VPC-14 factors. Staff had a more positive view than patients of staff actions and patients had a more positive view of patient actions than did staff; staff- or patient-group membership was the best predictor of staff action scores. Individual staff characteristics accounted for a small amount of the variance in staff and patient action scores; individual patient characteristics explained more variance, but this was still below 20%. Staff perceive their violence prevention-related contributions more positively than patients and vice versa. This has implications for staff; they may need to better articulate their role in violence prevention to patients, as well as recognise the role that patients play. However, within staff and patient groups, individual variables only make up a small amount of variance of perceptions of the violence prevention climate. This suggests that the violence prevention climate is a valid construct, i.e. that despite differences in individual variables, individuals within the patient group have similar perceptions of the VPC, as do those within the staff group.


When should one adjust for measurement error in baseline variables in observational studies?
Previously, we showed that in randomised experiments, correction for measurement error in a baseline variable induces bias in the estimated treatment effect, and conversely that ignoring measurement error avoids bias. In observational studies, non-zero baseline covariate differences between treatment groups may be anticipated. Using a graphical approach, we argue intuitively that if baseline differences are large, failing to correct for measurement error leads to a biased estimate of the treatment effect. In contrast, correction eliminates bias if the true and observed baseline differences are equal. If this equality is not satisfied, the corrected estimator is also biased, but typically less so than the uncorrected estimator. Contrasting these findings, we conclude that there must be a threshold for the true baseline difference, above which correction is worthwhile. We derive expressions for the bias of the corrected and uncorrected estimators, as functions of the correlation of the baseline variable with the study outcome, its reliability, the true baseline difference, and the sample sizes. Comparison of these expressions defines a theoretical decision threshold about whether to correct for measurement error. The results show that correction is usually preferred in large studies, and also in small studies with moderate baseline differences. If the group sample sizes are very disparate, correction is less advantageous. If the equivalent balanced sample size is less than about 25 per group, one should correct for measurement error if the true baseline difference is expected to exceed 0.2-0.3 standard deviation units. These results are illustrated with data from a cohort study of atherosclerosis.


Functional and network analyses of human exposure to long-term evolution signal.
Human exposure to the electromagnetic field emitted by wireless communication systems has raised public concerns. There were claims of the potential association of some neurophysiological disorders with the exposure, but the mechanism is yet to be established. The wireless networks, recently, experience a transition from the 4th generation (4G) to 5th generation (5G), while 4G long-term evolution (LTE) is still the frequently used signal in wireless communication. In the study, exposure experiments were conducted using the LTE signal. The subjects were divided into sham and real exposure groups. Before and after the exposure experiments, they underwent functional magnetic resonance imaging. Within-session and between-session comparisons have been executed for functional connectivity and network properties. Individual specific absorption rate (SAR) was also calculated. The results indicated that acute LTE exposure beneath the safety limits modulated both the functional connection and graph-based properties. To characterize the effect of functional activity, SAR averaged over a certain tissue mass was not an appropriate metric. The potential neurophysiological effect of 5G exposure has also been discussed in the study.


Molecular dynamics simulations on pars intercerebralis major peptide-C (PMP-C) reveal the role of glycosylation and disulfide bonds in its enhanced structural stability and function.
Fucosylation of Thr 9 in pars intercerebralis major peptide-C (PMP-C) enhances its structural stability and functional ability as a serine protease inhibitor. In order to understand the role of disulfide bonds and glycosylation on the structure and function of PMP-C, we have carried out multiple explicit solvent molecular dynamics (MD) simulations on fucosylated and non-fucosylated forms of PMP-C, both in the presence and absence of the disulfide bonds. Our simulations revealed that there were no significant structural changes in the native disulfide bonded forms of PMP-C due to fucosylation. On the other hand, the non-fucosylated form of PMP-C without disulfide bonds showed larger deviations from the starting structure than the fucosylated form. However, the structural deviations were restricted to the terminal regions while core β-sheet retained its hydrogen bonded structure even in absence of disulfide bonds as well as fucosylation. Interestingly, fucosylation of disulfide bonded native PMP-C led to a decreased thermal flexibility in the residue stretch 29-32 which is known to interact with the active site of the target proteases. Our analysis revealed that disulfide bonds covalently connect the residue stretch 29-32 to the central β-sheet of PMP-C and using a novel network of side chain interactions and disulfide bonds fucosylation at Thr 9 is altering the flexibility of the stretch 29-32 located at a distal site. Thus, our simulations explain for the first time, how presence of disulfide bonds between conserved cysteines and fucosylation enhance the function of PMP-C as a protease inhibitor.


Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass.
Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.


Lactobacillus paracasei reduces intestinal inflammation in adoptive transfer mouse model of experimental colitis.
Studies showed that specific probiotics provide therapeutic benefits in inflammatory bowel disease. In vitro evidence suggested that Lactobacillus paracasei also called ST11 (CNCM I-2116) is a potent strain with immune modulation properties. However, little is known about its capacity to alleviate inflammatory symptoms in vivo In this context, the main objective of this study was to investigate the role of ST11 on intestinal inflammation using the adoptive transfer mouse model of experimental colitis. Rag2(-/-) recipient mice were fed with ST11 (10(9) CFU/day)a month prior toinduce colitis by adoptive transfer of naive T cells. One month later, in clear contrast to nonfed mice, weight loss was significantly reduced by 50% in ST11-fed mice. Further analysis of colon specimens revealed a significant reduction neutrophil infiltration and mucosal expression of IL1β, IL-6, and IL12 proinflammatory cytokines, whereas no consistent differences in expression of antibacterial peptides or tight junction proteins were observed between PBS and ST11-fed mice. All together, our results demonstrate that oral administration of ST11 was safe and had a significant preventive effect on colitis. We conclude that probiotics such as Lactobacillus paracasei harbor worthwhile in vivo immunomodulatory properties to prevent intestinal inflammation by nutritional approaches.


Robust Normalization of Luciferase Reporter Data.
Transient Luciferase reporter assays are widely used in the study of gene regulation and intracellular cell signaling. In order to control for sample-to-sample variation in luminescence arising from variability in transfection efficiency and other sources, an internal control reporter is co-transfected with the experimental reporter. The luminescence of the experimental reporter is normalized against the control by taking the ratio of the two. Here we show that this method of normalization, "ratiometric", performs poorly when the transfection efficiency is low and leads to biased estimates of relative activity. We propose an alternative methodology based on linear regression that is much better suited for the normalization of reporter data, especially when transfection efficiency is low. We compare the ratiometric method against three regression methods on both simulated and empirical data. Our results suggest that robust errors-in-variables (REIV) regression performs the best in normalizing Luciferase reporter data. We have made the R code for Luciferase data normalization using REIV available on GitHub.


Do Breast Cancer Survivorship Care Plans Improve Health Outcomes?
Although they have been widely studied, important questions remain about the impact of breast cancer survivorship care plans on improving health outcomes. The goal of this article was to review published studies on the impact of cancer survivorship care plans on health outcomes and health care delivery among breast cancer survivors. A total of 111 article citations were identified in PubMed and non-duplicates in CINAHL. After screening the abstracts or full texts of these articles and reviewing the references of previous review articles, 7 studies met the eligibility criteria. All of the studies had a randomized controlled design. Early trials of the efficacy of breast cancer survivorship care plans generally showed little or no improvement in health outcomes. The positive findings of recent studies suggest that survivorship care interventions that empower and activate patients to self-manage their follow-up care and improve patient-provider communication may be especially promising.


PathMiner: a Web-based tool for computer-assisted diagnostics in pathology.
Large-scale, multisite collaboration has become indispensable for a wide range of research and clinical activities that rely on the capacity of individuals to dynamically acquire, share, and assess images and correlated data. In this paper, we report the development of a Web-based system, PathMiner , for interactive telemedicine, intelligent archiving, and automated decision support in pathology. The PathMiner system supports network-based submission of queries and can automatically locate and retrieve digitized pathology specimens along with correlated molecular studies of cases from "ground-truth" databases that exhibit spectral and spatial profiles consistent with a given query image. The statistically most probable diagnosis is provided to the individual who is seeking decision support. To test the system under real-case scenarios, a pipeline infrastructure was developed and a network-based test laboratory was established at strategic sites at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Robert Wood Johnson University Hospital, the University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, The Cancer Institute of New Jersey, and Rutgers University. The average five-class classification accuracy of the system was 93.18% based on a tenfold cross validation on a close dataset containing 3691 imaged specimens. We also conducted prospective performance studies with the PathMiner system in real applications in which the specimens exhibited large variations in staining characters compared with the training data. The average five-class classification accuracy in this open-set experiment was 87.22%. We also provide the comparative results with the previous literature and the PathMiner system shows superior performance.


PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.
Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment1,2. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma3,4. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model of glioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members of the glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment.


Specification of subunit assembly by the hydrophilic amino-terminal domain of the Shaker potassium channel.
The functional heterogeneity of potassium channels in eukaryotic cells arises not only from the multiple potassium channel genes and splice variants but also from the combinatorial mixing of different potassium channel polypeptides to form heteromultimeric channels with distinct properties. One structural element that determines the compatibility of different potassium channel polypeptides in subunit assembly has now been localized to the hydrophilic amino-terminal domain. A Drosophila Shaker B (ShB) potassium channel truncated polypeptide that contains only the hydrophilic amino-terminal domain can form a homomultimer; the minimal requirement for the homophilic interaction has been localized to a fragment of 114 amino acids. Substitution of the amino-terminal domain of a distantly related mammalian potassium channel polypeptide (DRK1) with that of ShB permits the chimeric DRK1 polypeptide to coassemble with ShB.


Healthy lifestyle behaviors are major predictors of mental wellbeing during COVID-19 pandemic confinement: A study on adult Arabs in higher educational institutions.
In the past infectious diseases affected the quality of lifestyle during home confinement. The study conducted examines the influence of home confinement during the COVID-19 pandemic outbreak on lifestyle, mental wellbeing, nutritional status, and sleeping pattern. An online multicategorical questionnaire was distributed to collect demographic information combined with the following tools: Food Frequency Questionnaire (FFQ), International Physical Activity Questionnaire (IPAQ), WHO-5 wellbeing score, and Pittsburgh Sleep Quality Index (PSQI). A snowball non-discriminate sampling procedure was conducted to collect data from people attending or working at higher institutions from March 1, 2020 to April 24, 2020. A total of 1723 completed responses (917 males, 37.4 ±13.4 years old and 806 females 32.2 ± 11.5 years old) were collected. The female participants had significantly lower mental health scores than males (53.9% vs. 46.1%). The mental wellbeing scores were higher among participants with medium and high physical activity (PA) levels (p < 0.00). Additionally, the mental wellbeing scores were significantly improved by dietary quality and it's sleeping score (p < 0.001). However, PA was by far the major determinant of the mental health scores. Factors such as PA, diet, and sleeping patterns were associated with mental wellbeing during the COVID-19 confinement among Arab participants.


Short-Term Medical Costs of a VHA Health Information Exchange: A CHEERS-Compliant Article.
The Virtual Lifetime Electronic Record (VLER) Health program provides the Veterans Health Administration (VHA) a framework whereby VHA providers can access the veterans' electronic health record information to coordinate healthcare across multiple sites of care. As an early adopter of VLER, the Indianapolis VHA and Regenstrief Institute implemented a regional demonstration program involving bi-directional health information exchange (HIE) between VHA and non-VHA providers.The aim of the study is to determine whether implementation of VLER HIE reduces 1 year VHA medical costs.A cohort evaluation with a concurrent control group compared VHA healthcare costs using propensity score adjustment. A CHEERs compliant checklist was used to conduct the cost evaluation.Patients were enrolled in the VLER program onsite at the Indianapolis VHA in outpatient clinics or through the release-of-information office.VHA cost data (in 2014 dollars) were obtained for both enrolled and nonenrolled (control) patients for 1 year prior to, and 1 year after, the index date of patient enrollment.There were 6104 patients enrolled in VLER and 45,700 patients in the control group. The annual adjusted total cost difference per patient was associated with a higher cost for VLER enrollees $1152 (95% CI: $807-1433) (P < 0.01) (in 2014 dollars) than VLER nonenrollees.Short-term evaluation of this demonstration project did not show immediate reductions in healthcare cost as might be expected if HIE decreased redundant medical tests and treatments. Cost reductions from shared health information may be realized with longer time horizons.


Hodgkin disease-an ever-evolving therapy.
Therapy of Hodgkin lymphoma (HL) is a rapidly changing field due to plenty of currently emerging data. Treatment approaches are currently based on tailoring of therapy in order to achieve a maximal response with minimal toxicity. Since the median age of HL patients is 33 years and their prospective life expectancy of another half a century, a major emphasis needs to be put on dramatic reduction of later toxicity. The assessment of the treatment effect should be based not only on progression-free survival, but should include evaluation of cardiac toxicity, secondary neoplasms, and fertility in the long-term follow-up. The ancient principle "first do no harm" should be central in HL therapy. Completion of ongoing and currently initiated trials could elucidate multiple issues related to the management of HL patients.


Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury.
Hypoxic-ischemic (HI) brain injury in newborn infants represents a major cause of cerebral palsy, development delay, and epilepsy. Stem cell-based therapy has the potential to rescue and replace the ischemic tissue caused by HI and to restore function. However, the mechanisms by which stem cell transplants induce functional recovery are yet to be elucidated. In the present study, we sought to investigate the efficacy of human neural stem cells derived from human embryonic stem cells in a rat model of neonatal HI and the mechanisms enhancing brain repair. The human neural stem cells were genetically engineered for in vivo molecular imaging and for postmortem histological tracking. Twenty-four hours after the induction of HI, animals were grafted with human neural stem cells into the forebrain. Motor behavioral tests were performed the fourth week after transplantation. We used immunocytochemistry and neuroanatomical tracing to analyze neural differentiation, axonal sprouting, and microglia response. Treatment-induced changes in gene expression were investigated by microarray and quantitative polymerase chain reaction. Bioluminescence imaging permitted real time longitudinal tracking of grafted human neural stem cells. HI transplanted animals significantly improved in their use of the contralateral impeded forelimb and in the Rotorod test. The grafts showed good survival, dispersion, and differentiation. We observed an increase of uniformly distributed microglia cells in the grafted side. Anterograde neuroanatomical tracing demonstrated significant contralesional sprouting. Microarray analysis revealed upregulation of genes involved in neurogenesis, gliogenesis, and neurotrophic support. These results suggest that human neural stem cell transplants enhance endogenous brain repair through multiple modalities in response to HI.


The Geographic Concentration of Enterprise in Developing Countries.
A nation's economic geography can have an enormous impact on its development. In Thailand, we show that a high concentration of enterprise in an area predicts high subsequent growth in and around that area. We also find spatially contiguous convergence of enterprise with stagnant areas left behind. Exogenous physiographic conditions are correlated with enterprise location and growth. We fit a structural, micro-founded model of occupation transitions with fine-tuned geographic capabilities to village data and replicate these salient facts. Key elements of the model include costs, credit constraints on occupation choice, and spatially varying expansion of financial service providers.


Plasma n-3 Polyunsaturated Fatty Acids are negatively associated with obesity.
The objective of the present study was to investigate the relationship between plasma n-3 PUFA composition and weight status. A total of 124 adults, stratified by weight status: healthy weight (n 21), overweight (n 40) and obese (n 63) were recruited. Fasting blood samples, anthropometric measures and body composition were collected. Plasma fatty acid composition was determined by GC. BMI, waist circumference and hip circumference were inversely correlated with n-3 PUFA, EPA and DHA (P < 0.05 for all) in the obese group. Obese individuals had significantly lower plasma concentrations of total n-3 PUFA, compared with healthy-weight individuals (4.53 (SD 1.11) v. 5.25 (SD 1.43) %). When subjects were pooled and stratified into quartiles of total n-3 PUFA, a significant inverse trend was found for BMI (P = 0.002), waist circumference and hip circumference (P = 0.01 and P < 0.001 respectively). Higher plasma levels of total n-3 PUFA are associated with a healthier BMI, waist circumference and hip circumference. Our findings suggest that n-3 PUFA may play an important role in weight status and abdominal adiposity.


Progressive and accelerated disability onset by race/ethnicity and education among late midlife and older adults.
This study explores the pace of severe disability onset with an emphasis on the role of race/ethnicity and education. More specifically, this research examines whether race/ethnicity and educational attainment are independent predictors of progressive and accelerated disability onset. Using the Health and Retirement Study (HRS) Waves 2 to 10 (1994-2010), a series of discrete-time Cox proportional hazards models with multiple competing events were created to ascertain whether respondents developed progressive or accelerated disability in subsequent waves. Black and Hispanic respondents were at an increased risk of developing progressive disability. Respondents without a high school degree were more likely to experience progressive or accelerated disability. Low educational attainment was a particularly strong predictor of accelerated disability onset and may represent an acute lack of resources over the life course. Race and ethnicity were important predictors of progressive disability onset, which may reflect racial/ethnic variations in the disabling process.


Children's Reactions to Flood Disaster in Kashmir.
The flood disaster of 9th-10th September 2014 wreaked havoc in the Jammu and Kashmir region of India. Incessant rains and deluge claimed 283 lives and damaged 2.53 lakh houses. This article presents the findings of the psychosocial care team from the National Institute of Mental Health and Neuro Sciences, Bengaluru, India, during the early phase of disaster. The team assessed posttraumatic stress symptoms of 64 child survivors from six villages of two districts struck by floods using Children's Revised Impact of Event Scale (CRIES)-8 and qualitative narrations. Children showed high levels of intrusion and avoidance in the aftermath of floods. Both boys and girls showed moderate to severe level of psychological impact on the domains of CRIES-8. The narrations by the children centred on the theme of "water" and "enjoyment in seeing lots of water;" followed by "fearing of the parent's life," later on "fear of their own life," and subsequently to avoidance to go near the river and nightmares like "floating in the water." Disasters immensely impact children because of their particular stage of psychological and social development. This highlights the need for psychosocial interventions to minimize the impact of disasters on children at the earliest using simple psychosocial care techniques by employing available community-based manpower.


Improving patient-centredness in partnership with female patients: a cluster RCT in fertility care.
What is the effect of a multifaceted intervention with participation of patients on improvement of patient-centredness in fertility care? A multifaceted intervention with participation of patients did not improve total patient-centredness scores provided by women in fertility care. We should provide care that takes into account the preferences and needs of patients, i.e. patient-centred care. Especially infertile patients who suffer from a high emotional burden of treatment could benefit from a more patient-centred approach in healthcare. However, the improvement of patient-centred care is still needed, because effective strategies to come to improvement are lacking. A cluster RCT was performed within 32 Dutch fertility clinics, covering about one-third of all Dutch hospitals. After randomization, 16 clinics in the intervention group were exposed to a multifaceted improvement strategy for patient-centred fertility care for 1 year. This strategy comprised audit and feedback, educational outreach visits and patient-mediated interventions. The remaining 16 clinics in the control group performed care as usual. The clinics' levels of patient-centredness were measured, using the validated Patient-centredness Questionnaire-Infertility (PCQ-Infertility). At baseline measurement, a total of 1620 women in couples undergoing fertility care (this included both male, female, mixed infertility and infertility of unknown cause) in one of the participating clinics were randomly selected to participate in the study and complete the questionnaire. For the after measurement, we randomly selected a comparable sample of 1565 women in infertile couples. Both women who had already started their treatment before the start of the study (67%) and women who started their treatment after the start of this study (33%) were included. To avoid bias, we only included the responses of non-pregnant respondents. The final analysis involved 30 clinics. A total of 946 women (response 58.4%) completed their questionnaire at baseline measurement and also a total of 946 women (response 60.4%) at after measurement. After excluding the pregnant patients, respectively 696 and 730 questionnaires were eligible for analysis at baseline and after measurement. The total score of case-mix adjusted PCQ-Infertility at after measurement did not differ significantly between the intervention and control group (B = 0.06; 95% confidence interval (CI) = -0.04-0.15; P = 0.25). However, scores on the continuity of care subscale were significantly higher in the intervention group compared with the control group (B = 0.20; 95% CI = 0.00-0.40; P < 0.05). The addition of three interaction terms to the model had a significant impact: (i) being younger than 36 years, (ii) beginning treatment after the study had started and (iii) using complementary and alternative medicine. If women met all three conditions, the scores in the intervention group were on average 0.31 points higher compared with the control group (95% CI = 0.14-0.48; P = <0.001). Our response rates are sufficient, but the responses of many women are still lacking which might have biased our results. Furthermore, the PCQ-Infertility scores at baseline measurement were already reasonably high, which could have limited the effect of the multifaceted improvement strategy. Because we only included women in infertile couples in our study, we cannot draw conclusions on the effect of an improvement strategy for patient-centred fertility care for partners. A multifaceted intervention with participation of patients did not improve total patient-centredness scores, although some effect could be observed in specific groups of women and in specific dimensions of patient-centredness. These results can guide future research, in which we should focus more on personalized strategies and outcome measures. This work was supported by Merck Sharp & Dohme (MSD), The Netherlands. There are no competing interests. Clinical Trials NCT01481064.


The relationship between depression and diabetes mellitus: findings from the Hertfordshire Cohort Study.
To assess the relationship between depression scores and diabetes, glucose and insulin in a cross-sectional population-based study. One thousand, five hundred and seventy-nine men and 1418 women from the Hertfordshire Cohort Study were assessed for diabetes. Plasma glucose and insulin concentrations were measured at 0, 30 and 120 min during a standard 75-g oral glucose tolerance test. Depressive and anxiety symptoms were measured using the Hospital Anxiety and Depression Scale (HADS). Overall, 431 (14.6%) were diagnosed with diabetes [232 men (14.9%) and 199 women (14.3%)]. One hundred and eight (47%) men and 74 (37%) women had known diabetes. The remainder were previously undiagnosed. Fifty-nine (3.7%) men and 65 (4.6%) women had possible depression (HAD-D scores 8-10) and 17 (1.1%) men and 20 (1.4%) women had probable depression (HAD-D scores > or = 11). Probable depression was associated with an adjusted odds ratio for diabetes of 3.89 [95% confidence interval (CI) 1.28-11.88] in men and 1.51 (95% CI 0.47-4.84) in women. In men without previously diagnosed diabetes, fasting insulin (P = 0.035), 2-h glucose concentrations (P = 0.028) and insulin resistance (P = 0.032) were significantly associated with HAD-D scores. With the exception of 2-h glucose concentrations (P = 0.034), the associations were not significant in women. These data support the hypothesis that depression may increase the risk for diabetes. The relationship between depression score and metabolic variables extends across the whole population and is not confined to those with either diagnosed depression or diabetes. This relationship should lead clinicians to consider screening for diabetes in those with depression and vice versa.


A comparison of strategies for estimation of ultrafine particle number concentrations in urban air pollution monitoring networks.
We propose three estimation strategies (local, remote and mixed) for ultrafine particles (UFP) at three sites in an urban air pollution monitoring network. Estimates are obtained through Gaussian process regression based on concentrations of gaseous pollutants (NOx, O3, CO) and UFP. As local strategy, we use local measurements of gaseous pollutants (local covariates) to estimate UFP at the same site. As remote strategy, we use measurements of gaseous pollutants and UFP from two independent sites (remote covariates) to estimate UFP at a third site. As mixed strategy, we use local and remote covariates to estimate UFP. The results suggest: UFP can be estimated with good accuracy based on NOx measurements at the same location; it is possible to estimate UFP at one location based on measurements of NOx or UFP at two remote locations; the addition of remote UFP to local NOx, O3 or CO measurements improves models' performance.


Analysis of novel domain-specific mutations in the zebrafish ndr2/cyclops gene generated using CRISPR-Cas9 RNPs.
Nodal-related protein (ndr2) is amember of the transforming growth factor type β superfamily of factors and is required for ventral midline patterning of the embryonic central nervous system in zebrafish. In humans, mutations in the gene encoding nodal cause holoprosencephaly and heterotaxy. Mutations in the ndr2 gene in the zebrafish (Danio rerio) lead to similar phenotypes, including loss of the medial floor plate, severe deficits in ventral forebrain development and cyclopia. Alleles of the ndr2 gene have been useful in studying patterning of ventral structures of the central nervous system. Fifteen different ndr2 alleles have been reported in zebrafish, of which eight were generated using chemical mutagenesis, four were radiation-induced and the remaining alleles were obtained via random insertion, gene targeting (TALEN) or unknown methods. Therefore, most mutation sites were random and could not be predicted a priori. Using the CRISPR-Cas9 system from Streptococcus pyogenes, we targeted distinct regions in all three exons of zebrafish ndr2 and observed cyclopia in the injected (G0) embryos.We show that the use of sgRNA-Cas9 ribonucleoprotein (RNP) complexes can cause penetrant cyclopic phenotypes in injected (G0) embryos. Targeted polymerase chain reaction amplicon analysis using Sanger sequencing showed that most of the alleles had small indels resulting in frameshifts. The sequence information correlates with the loss of ndr2 activity. In this study, we validate multiple CRISPR targets using an in vitro nuclease assay and in vivo analysis using embryos. We describe one specific mutant allele resulting in the loss of conserved terminal cysteine-coding sequences. This study is another demonstration of the utility of the CRISPR-Cas9 system in generating domain-specific mutations and provides further insights into the structure-function of the ndr2 gene.


Deletion of the major GATA1 enhancer HS 1 does not affect eosinophil GATA1 expression and eosinophil differentiation.
Expression of the myeloid transcription factor GATA1 is required for early stages of eosinophil differentiation. Defining mechanisms regulating eosinophil GATA1 expression will be important to understand development of this lineage. However, the cis-elements required for eosinophil GATA1 expression are not fully characterized. Previous work identified HS 1 as a major GATA1 enhancer, but its role in eosinophil GATA1 expression is unclear. Here, we show that mouse HS 1 deletion leaves eosinophil GATA1 mRNA expression and eosinophil differentiation unaffected. Chromatin isolated from eosinophils and encompassing HS 1 is weakly enriched for acetylated histones H3/H4. HS 1 deletion does not alter eosinophil GATA1 locus histone acetylation. In eosinophils, GATA1 and CCAAT/enhancer binding protein epsilon (C/EBP epsilon) do not bind HS 1 but bind selectively a cis-element in the first GATA1 intron. Thus, HS 1 is not required for eosinophil GATA1 expression. Instead, this study suggests a previously unsuspected role for the GATA1 intron element for this function.


Twenty-year outcome for individuals with autism and average or near-average cognitive abilities.
Previous studies found substantial variability in adult outcome for people with autism whose cognitive functioning was within the near-average and average ranges. This study examined adult outcome for 41 such individuals (38 men and 3 women) originally identified through an epidemiological survey of autism in Utah. Mean age at the time of their previous cognitive assessment was 7.2 years (SD=4.1, range=3.1-25.9 years) and at follow-up was 32.5 years (SD=5.7 years, range=22.3-46.4 years). Outcome measures included standardized assessments of diagnostic status, cognitive ability, and adaptive behavior. Additional information collected concerned demographic variables, indicators of independence, social relationships, medical and psychiatric conditions, and social service use. Outcomes for this sample were better than outcomes described in previous work on individuals with similar cognitive functioning. For example, half of the participants were rated as "Very Good" or "Good" on a global outcome measure. As in previous studies, there was considerable variability in measured cognitive ability over time. Over half of the sample had large gains or losses of cognitive ability of greater than 1 standard deviation. Cognitive gain was associated with better outcome, as was better adaptive functioning. While all participants had baseline IQs in the nonimpaired range, there was limited evidence to support the use of other early childhood variables to predict adult outcome.


Influence of shift work on rest-activity rhythms, sleep quality, and fatigue of female nurses.
Female nurses working rotating shifts must change their daily routines often, which affects their biological circadian rhythms and could cause sleep disorders and fatigue. The objective of this study was to compare the sleep-wake rhythms, sleep quality, and fatigue of female nurses working rotating shifts and fixed day shifts and to analyze the factors that influence their fatigue. Participants comprised a shift worker group of 101 nurses and a day worker group of 76 nurses. Following the collection of basic information of the nurses and their scores in the various constructs of the Pittsburg Sleep Quality Index (PSQI) and the Checklist Individual Strength (CIS) questionnaire, each nurse wore an actigraph for seven consecutive days to collect for analysis the sleep-wake rhythm parameter dichotomy index (I < O) and durations of continuous sleep and wake. Multivariable linear regression was then used to determine whether the influence of various variables on fatigue differed between the two groups. Results revealed that the sleep-wake rhythm parameter I < O of the day worker group was significantly higher than that of the shift worker group (t = 5.08, p < .001). The shift worker group exhibited significantly higher PSQI global scores (t = -2.00, p = .047), longer total sleep time (t = 2.07, p = .040), poorer habitual sleep efficiency (t = -3.06, p = .003), and greater use of sleeping medication (t = -2.90, p = .004) than did the day worker group. Multivariable linear regression was performed to analyze the important predictors of the CIS score in the two groups with body mass index, age, work experience, marital status, educational background, department of employment, shift type at the time of recruitment, sleep-wake rhythm parameter I < O, and quality of sleep as independent variables. Results indicated that in the shift worker group, the overall explanatory power (R2) of the multivariable linear regression model was 22.9% (F = 3.01, p = .003), and only the PSQI global score (β = 0.33, p = .003) influenced the CIS score. In the day worker group, the various variables did not influence the CIS score in the multivariable linear regression model. Although the female nurses working rotating shifts spent more time in bed, their sleep-wake rhythms and sleep quality were poorer than those of the day worker group. Furthermore, the sleep quality of female nurses in the shift worker group had a significant impact on their fatigue. In other words, for female nurses who must work rotating shifts, sleep quality determines whether fatigue can be reduced. The shift-working nurses themselves should implement sleep management, such as avoiding disruptions to their sleep-wake rhythm and improving sleep quality, which should be effective strategies to reduce fatigue.


Neuropeptide metabolism on intact, regional brain slices: effect of dopaminergic agents on substance P, cholecystokinin and Met-enkephalin degradation.
Neuroleptic drugs have been shown to affect the level and messenger ribonucleic acid of specific neuropeptides. The effect of subchronically administered neuroleptics on neuropeptide metabolism, however, has not been systematically characterized. In the present study, the effect of neuroleptics and other dopaminergic compounds on substance P (SP), cholecystokinin and met-enkephalin degradation was determined on intact, regional, rat brain slices. After 7-day administration of haloperidol (1 mg/kg) or chlorpromazine (20 mg/kg), SP degradation was decreased in caudate-putamen and nucleus accumbens. After administration of the dopaminergic agonist apomorphine (5 mg/kg, b.i.d.), SP degradation was increased in the nucleus accumbens. The dopamine D2-receptor antagonist sulpiride (100 mg/kg, b.i.d.) produced no effect on SP degradation. Met-enkephalin degradation was decreased after haloperidol administration in both frontal cortex and caudate-putamen and unaffected by apomorphine administration. The metabolism of cholecystokinin was not affected by neuroleptic treatment. Studies performed with specific peptidase inhibitors suggested that neutral endopeptidase 24.11, metalloendopeptidase 24.15 and aminopeptidases degrade SP on caudate-putamen and nucleus accumbens slices. Therefore, alterations in these peptidases may be responsible for the change noted in SP degradation after dopaminergic compound administration. These metabolic changes noted after neuroleptic administration may therefore contribute to neuroleptic-induced alterations in regional peptide levels.


Microplasma Processed Ultrathin Boron Nitride Nanosheets for Polymer Nanocomposites with Enhanced Thermal Transport Performance.
This Research Article reports on the enhancement of the thermal transport properties of nanocomposite materials containing hexagonal boron nitride in poly(vinyl alcohol) through room-temperature atmospheric pressure direct-current microplasma processing. Results show that the microplasma treatment leads to exfoliation of the hexagonal boron nitride in isopropyl alcohol, reducing the number of stacks from >30 to a few or single layers. The thermal diffusivity of the resulting nanocomposites reaches 8.5 mm(2) s(-1), 50 times greater than blank poly(vinyl alcohol) and twice that of nanocomposites containing nonplasma treated boron nitride nanosheets. From TEM analysis, we observe much less aggregation of the nanosheets after plasma processing along with indications of an amorphous carbon interfacial layer, which may contribute to stable dispersion of boron nitride nanosheets in the resulting plasma treated colloids.


Terfenadine effect on the bronchoconstriction, dermal response, and leukopenia induced by platelet-activating factor.
We have investigated the protective effect of oral terfenadine, a H1 antagonist, on the dermal and pulmonary response, and changes of circulating WBCs to injected and inhaled platelet activating factor. Nine men with mild asthma participated in a double-blind, crossover study using terfenadine, 120 mg, or placebo. Three hours after administration of study drug, pulmonary function was measured, and a PAF challenge was performed. Skin test to histamine and PAF was performed prior to study drug, and 2.5 hours after drug. Circulating WBC count was determined prior to PAF inhalation and during the PAF challenge. There was a significant improvement in pulmonary function on terfenadine. Terfenadine significantly inhibited the wheal and flare response to histamine and the flare response to injected PAF. Terfenadine did not have an effect on the change in circulating WBC count or the change in pulmonary function to inhaled PAF. These results suggest a limited role for endogenous histamine for the effects of PAF.


RelB+ Steady-State Migratory Dendritic Cells Control the Peripheral Pool of the Natural Foxp3+ Regulatory T Cells.
Thymus-derived natural Foxp3+ CD4+ regulatory T cells (nTregs) play a key role in maintaining immune tolerance and preventing autoimmune disease. Several studies indicate that dendritic cells (DCs) are critically involved in the maintenance and proliferation of nTregs. However, the mechanisms how DCs manage to keep the peripheral pool at constant levels remain poorly understood. Here, we describe that the NF-κB/Rel family transcription factor RelB controls the frequencies of steady-state migratory DCs (ssmDCs) in peripheral lymph nodes and their numbers control peripheral nTreg homeostasis. DC-specific RelB depletion was investigated in CD11c-Cre × RelBfl/fl mice (RelBDCko), which showed normal frequencies of resident DCs in lymph nodes and spleen while the subsets of CD103- Langerin- dermal DCs (dDCs) and Langerhans cells but not CD103+ Langerin+ dDC of the ssmDCs in skin-draining lymph nodes were increased. Enhanced frequencies and proliferation rates were also observed for nTregs and a small population of CD4+ CD44high CD25low memory-like T cells (Tml). Interestingly, only the Tml but not DCs showed an increase in IL-2-producing capacity in lymph nodes of RelBDCko mice. Blocking of IL-2 in vivo reduced the frequency of nTregs but increased the Tml frequencies, followed by a recovery of nTregs. Taken together, by employing RelBDCko mice with increased frequencies of ssmDCs our data indicate a critical role for specific ssmDC subsets for the peripheral nTreg and IL-2+ Tml frequencies during homeostasis.