A volatile biomarker in breath predicts lung cancer and pulmonary nodules.
previous studies have reported volatile organic compounds (VOCs) in the breath as apparent biomarkers of lung cancer. We tested the hypothesis that a robust breath VOC biomarker of lung cancer should also predict pulmonary nodules in chest CT images. Biomarker discovery study (unblinded): 301 subjects were screened for lung cancer with low dose chest CT (LDCT), and donated duplicate samples of alveolar breath for analysis with gas chromatography mass spectrometry (GC MS). Monte Carlo analysis of breath chromatograms revealed a mass ion as a biomarker that identified biopsy-proven lung cancer as well as suspicious pulmonary nodules on LDCT. The biomarker was termed Mass Abnormalities in Gaseous Ions with Imaging Correlates (MAGIIC). The chemical structure of MAGIIC was tentatively identified from the NIST library of mass spectra; the best-fit compounds included C4 and C5 alkane derivatives that were consistent with metabolic products of oxidative stress. Blinded validation of MAGIIC: the abundance of the MAGIIC biomarker was determined in a different group of 161 subjects undergoing screening with LDCT. They donated duplicate alveolar breath VOC samples that were analyzed at two independent laboratories. The study was blinded and monitored with Good Clinical Practice. The abundance of MAGIIC in breath predicted biopsy-proven lung cancer with 84% accuracy, sensitivity = 75.4% and specificity = 85.0%. MAGIIC also predicted pulmonary nodules in LDCT with 80.5% accuracy, sensitivity = 80.1% and specificity = 75.0%. Breath MAGIIC abundance was not significantly affected by tobacco smoking history. in a blinded study, breath VOC MAGIIC accurately predicted lung cancer confirmed on a tissue biopsy, as well as suspicious pulmonary nodules observed on LDCT. MAGIIC may have been a product of oxidative stress and it could potentially be employed as an ancillary to LDCT to predict the likelihood that a pulmonary nodule is malignant.


[Plasma fractionation in the world: current status].
From 22 to 25 million liters of plasma are fractionated yearly in about 70 fractionation plants, either private or government-owned, mainly located in industrialized countries, and with a capacity ranging from 50000 to three million liters. In an increasingly global environment, the plasma industry has recently gone through a major consolidation phase that has seen mergers and acquisitions, and has led to the closure of a number of small plants in Europe. Currently, some fifteen countries are involved into contract plasma fractionation programs to ensure a supply of plasma-derived medicinal products. The majority of the plasma for fractionation is obtained by automated plasmapheresis, the remaining (recovered plasma) being prepared from whole blood as a by-product of red cell production. Plasma for fractionation should be produced, and controlled following well established procedures to meet the strict quality requirements set by regulatory authorities and fractionators. The plasma fractionation technology still relies heavily on the cold ethanol fractionation process, but has been improved by the introduction of modern chromatographic purification methods, and efficient viral inactivation and removal treatments, ensuring quality and safety to a large portfolio of fractionated plasma products. The safety of these products with regards to the risk of transmission of variant Creutzfeldt-Jakob disease seems to be provided, based on current scientific data, by extensive removal of the infectious agent during certain fractionation steps. The leading plasma product is now the intravenous immunoglobulin G, which has replaced factor VIII and albumin in this role. The supply of plasma products (most specifically coagulation products and immunoglobulin) at an affordable price and in sufficient quantity remains an issue; the problem is particularly acute in developing countries, as the switch to recombinant factor VIII in rich countries has not solved the supply issue and has even led to an increase of the mean price of plasma-derived factor VIII to the developing world. In the last few years, the plasma fractionation industry has improved greatly, and should remain essential in the years to come for the procurement of many essential medicines.


A descriptive study of hand injuries presenting to the adult emergency department of a tertiary care center in urban India.
Despite having a dedicated Plastic Surgery Unit, emergency physicians (EPs) manage many of the acute, traumatic hand injuries. Further very minimal information exists about the extent to which tetanus recommendations as per Advisory Committee on Immunization Practices are followed in emergency departments (EDs). Furthermore, the management of pain is often neglected. To provide a clinical description of hand injuries with etiology and mechanism; and describe the trends of ED management, including analgesia and tetanus prophylaxis. Records of eighty patients with hand injuries were reviewed. SPSS version 18 was used for statistical analysis. Wilcoxon signed rank test, and Pearson Chi-square test were used to compare left with right-hand injuries and validate associations, respectively. The mean age of the patients was 27.41 years and median delay in presentation was 2 h. Occupational injury was the predominant mode of injury (74%) most patients (59 of the 86) received intravenous analgesia; while very few (6) received local anesthesia and (24) received no analgesia at all. A majority of patients (56) received tetanus toxoid prophylaxis, while only four patients (4.6%) also received tetanus immunoglobulin intramuscular. Most patients (71%) were admitted, while only a small number of patients (14%) were discharged from the ED. Proper training and sensitization towards the need and technique of anesthesia (particularly local anesthesia) would improve the quality of patient care. Printed guidelines and periodic review of the charts would help to overcome poor adherence to tetanus prophylaxis. Hand injuries could be managed better by the EP, with training through rotations to the Plastic Surgery Unit.


Versatile toolbox for high throughput biochemical and functional studies with fluorescent fusion proteins.
Fluorescent fusion proteins are widely used to study protein localization and interaction dynamics in living cells. However, to fully characterize proteins and to understand their function it is crucial to determine biochemical characteristics such as enzymatic activity and binding specificity. Here we demonstrate an easy, reliable and versatile medium/high-throughput method to study biochemical and functional characteristics of fluorescent fusion proteins. Using a new system based on 96-well micro plates comprising an immobilized GFP-binding protein (GFP-mulitTrap), we performed fast and efficient one-step purification of different GFP- and YFP-fusion proteins from crude cell lysate. After immobilization we determined highly reproducible binding ratios of cellular expressed GFP-fusion proteins to histone-tail peptides, DNA or selected RFP-fusion proteins. In particular, we found Cbx1 preferentially binding to di-and trimethylated H3K9 that is abolished by phosphorylation of the adjacent serine. DNA binding assays showed, that the MBD domain of MeCP2 discriminates between fully methylated over unmethylated DNA and protein-protein interactions studies demonstrate, that the PBD domain of Dnmt1 is essential for binding to PCNA. Moreover, using an ELISA-based approach, we detected endogenous PCNA and histone H3 bound at GFP-fusions. In addition, we quantified the level of H3K4me2 on nucleosomes containing different histone variants. In summary, we present an innovative medium/high-throughput approach to analyse binding specificities of fluroescently labeled fusion proteins and to detect endogenous interacting factors in a fast and reliable manner in vitro.


The importance of the development of the intestinal microbiota in infancy.
The development of the intestinal microbiota occurs primarily during infancy, and a distortion could potentially contribute to a wide range of diseases. This review summarizes the current understanding of the intestinal microbiota in infants. The potential consequences of different colonization patterns on child health and possible preventive interventions are discussed. Recent studies and the use of culture-independent techniques have shown that Bifidobacterium is only a minor component of the infant gut microbiota. These techniques have also introduced the concept of a core microbiome in which metabolic function is more important than the presence of a particular bacterial species. A less diverse gut microbiota with high counts of Bacteroides, Clostridium, Enterobacteriaceae and Staphylococcus early in life has been associated with an increased risk for atopic disease. Changes in infant gut colonization were also found in relation to childhood obesity. Probiotics have no proven preventive effect on the development of asthma and an unconfirmed effect on atopic dermatitis. A prebiotic trial could show a preventive effect on the development of both atopic diseases. Molecular techniques have improved our understanding of the infant gut ecosystem. The available probiotics for prevention of atopic disease are disappointing, and the results with prebiotics need further confirmation. New studies on the relation between gut microbiota and disease should consider asthma and atopic dermatitis separately. Future trials should focus on high-risk groups, determine their long-term effect and also investigate the effect on Bacteroides and Clostridium.


Status of Serum Prolactin Levels among Male Cohort in Infertile Couples.
Abnormalities of serum prolactin adversely impact the reproductive functions among infertile men. Hence, this study was aimed to determine the influence of prolactin abnormalities on gonadal functions of male cohorts of infertile unions in Port Harcourt, Nigeria. This was a retrospective survey of 1845 males of infertile unions who presented in a health-care facility for reproductive endocrine evaluation following abnormal semen parameters between 2007 and 2018. The demographic, clinical, and laboratory variables were evaluated among study cohorts. Hyperprolactinemia was observed in 16.7% of the study cohorts with 9.6%, 5.0%, and 2.1% of mild, moderate, and severe grades, respectively. The hyperprolactinemic cohorts had depressed levels of follicle-stimulating hormone (FSH), luteinizing hormones (LH), and total testosterone (TT) which worsened further with worsening grades of hyperprolactinemia. Inverse relationship of prolactin levels existed with FSH (crude β: -0.651; P < 0.001; adjusted β: -0.666; P < 0.001), LH (crude β: -0.481; P < 0.001; adjusted β: -0.536; P < 0.001), and TT (crude β: -0.525; P < 0.001; adjusted β: -0.546; P < 0.001) in crude analysis and amplified on age and body mass index (BMI) adjustment. The greatest risk of depressive impact of hyperprolactinemia was on serum TT (crude hazard ratio [HR]: 35.185; P < 0.001; age and BMI-adjusted HR: 35.086; P < 0.001). Erectile dysfunction (ED) was the single most isolated sexual abnormality (n = 111; 35.6%) recorded among the general hyperprolactinemics; however, the ED was specifically more prevalent (n = 15; 38.5%) among the severely hyperprolactinemics. The present study revealed a high frequency of hyperprolactinemia among studied participants. Since the hyperprolactinemia was associated with a large number of cases with other endocrine and sexual dysfunctions, diagnostic and treatment protocols should include prolactin measurement and management during infertility evaluation in males.


Autologous hematopoietic cell transplantation for acute myeloid leukemia in adults: 25 years of experience in Japan.
Autologous hematopoietic cell transplantation (HCT) has not gained universal popularity in the treatment of acute myeloid leukemia (AML), and its status remains unclear. To determine the implementation status and outcomes of autologous HCT for adults with AML in Japan, we analyzed data from 1,174 patients (including 446 with acute promyelocytic leukemia [APL]) who underwent autologous HCT between 1992 and 2016 consecutively reported to the Japanese nationwide transplantation registry. The annual number of transplantations peaked at 82 cases in 1997, and has recently remained at around 40 cases. The percentage of APL has increased sharply since 2004, and currently exceeds 70%. While most non-APL patients underwent autologous HCT during first complete remission (CR), transplantation during second CR has become mainstream for APL patients since the early 2000s. The 5-year survival, relapse, and non-relapse mortality rates were 55.3%, 42.1%, and 8.6% for non-APL patients, and 87.6%, 12.9%, and 3.4% for APL patients, respectively. Patients transplanted in the later period showed better survival than those transplanted in the earlier period, both for non-APL (P < 0.001) and APL (P = 0.036). These results clearly show the various changes in transplantation practice and post-transplant outcomes in Japan over the past 25 years.


Lateral elbow tendinopathy: correlation of ultrasound findings with pain and functional disability.
Lateral elbow tendinopathy is a common condition often diagnosed by ultrasound. Debate exists regarding which ultrasound findings correlate with disease severity and prognosis. Sonographic predictors for tendon healing in patients with lateral elbow tendinopathy can be found by correlating initial ultrasound findings with subsequent changes in pain and functional disability scores after a period of nonoperative management. Cohort study (prognosis); Level of evidence, 2. Sixty-two elbows (34 right, 28 left) in 62 patients (30 male, 32 female) with a clinical diagnosis of lateral elbow tendinopathy underwent sonographic evaluation of the common extensor origin after assessment with a validated outcome measure, the Patient-Rated Tennis Elbow Evaluation (PRTEE). After 6 months of nonoperative standardized treatment (physiotherapy with eccentric loading), the PRTEE questionnaire was repeated. The mean pretreatment PRTEE was 78 (range, 51-97) and posttreatment score was 29 (range, 0-91). This difference in means was found to be significant (P < .0001). A positive correlation was identified between the presence of a lateral collateral ligament tear (P < .0001) and the size of the largest intrasubstance tear (P < .0001) and poor outcome. A negative correlation was identified with amount of hypoechogenicity (P = .0009). No correlation was found with age, sex, side, duration of symptoms, thickness of tendon, or amount of neovascularity. The size of intrasubstance tears and presence of a lateral collateral ligament tear on ultrasound can be used to assess lateral elbow tendinopathy severity, indicate those who may not respond to nonoperative therapy, and potentially guide more invasive treatment. Those patients with a large intrasubstance tear or tears identified on ultrasound are less likely to respond to nonoperative treatment. Presence of neovascularity has little correlation with change in pain severity or functional disability and may be a poor predictor of prognosis.


48-hours administration of fenoterol in spontaneous preterm labor - does it affect fetal preload?
to investigate whether any changes in the preload index (PLI) occur within the first 48 hours of fenoterol intravenous tocolysis. Doppler evaluation of placental and fetal circulation was performed in 36 pregnant women prior to fenoterol administration and after 24/48 hours. Measurements were obtained from a longitudinal section of the inferior vena cava (IVC) and preload index was calculated. To determine changes over time, an all study variable analysis of variance (ANOVA) for repeated measurements, followed by Tukey-Kramer's multiple comparison test was used. The effects of additional clinical covariates were checked. The maternal heart rate values were significantly increased after 24 hours and 48 hours in comparison to pre-treatment values. No significant changes in fetal heart rate were observed during treatment. The fetal IVC PLI values were significantly reduced after 24 hours and 48 hours of treatment. The increase in PLI values when comparing 24 and 48 hours results were not statistically significant. These observations were consistent with ANOVA post-hoc analysis. 48 hours intravenous administration of fenoterol appears not to alter inferior vena cava blood flow by itself. The reduction in PLI values may reflect lower fetal preload conditions during the course of successful tocolytic treatment. Therefore, Doppler IVC PLI measurement should be considered as a possible additional assessment method of effectiveness of treatment. However, other Doppler venous blood flow parameters should be assessed to confirm the results and clarify whether maternal corticosteroids administration may be interfering with the results.


Comparison of musculoskeletal disorder health claims between construction floor layers and a general working population.
Compare rates of medical insurance claims for musculoskeletal disorders (MSD) between workers in a construction trade and a general worker population to determine if higher physical exposures in construction lead to higher rates of claims on personal medical insurance. Health insurance claims between 2006 and 2010 from floor layers were frequency matched by age, gender, eligibility time and geographic location to claims from insured workers in general industry obtained from MarketScan. We extracted MSD claims and dates of service from six regions of the body: neck, low back, knee, lower extremity, shoulder and distal arm, and evaluated differences in claim rates. Fifty-one per cent of floor layers (n=1475) experienced musculoskeletal claims compared with 39% of MarketScan members (p<0.001). Claim rates were higher for floor layers across all body regions with nearly double the rate ratios for the knee and neck regions (RR 2.10 and 2.07). The excess risk was greatest for the neck and low back regions; younger workers had disproportionately higher rates in the knee, neck, low back and distal arm. A larger proportion of floor layers (22%) filed MSD claims in more than one body region compared with general workers (10%; p<0.001). Floor layers have markedly higher rates of MSD claims compared with a general worker population, suggesting a shifting of medical costs for work-related MSD to personal health insurance. The occurrence of disorders in multiple body regions and among the youngest workers highlights the need for improved work methods and tools for construction workers.


The dream-lag effect: Selective processing of personally significant events during Rapid Eye Movement sleep, but not during Slow Wave Sleep.
Incorporation of details from waking life events into Rapid Eye Movement (REM) sleep dreams has been found to be highest on the night after, and then 5-7 nights after events (termed, respectively, the day-residue and dream-lag effects). In experiment 1, 44 participants kept a daily log for 10 days, reporting major daily activities (MDAs), personally significant events (PSEs), and major concerns (MCs). Dream reports were collected from REM and Slow Wave Sleep (SWS) in the laboratory, or from REM sleep at home. The dream-lag effect was found for the incorporation of PSEs into REM dreams collected at home, but not for MDAs or MCs. No dream-lag effect was found for SWS dreams, or for REM dreams collected in the lab after SWS awakenings earlier in the night. In experiment 2, the 44 participants recorded reports of their spontaneously recalled home dreams over the 10 nights following the instrumental awakenings night, which thus acted as a controlled stimulus with two salience levels, high (sleep lab) and low (home awakenings). The dream-lag effect was found for the incorporation into home dreams of references to the experience of being in the sleep laboratory, but only for participants who had reported concerns beforehand about being in the sleep laboratory. The delayed incorporation of events from daily life into dreams has been proposed to reflect REM sleep-dependent memory consolidation. However, an alternative emotion processing or emotional impact of events account, distinct from memory consolidation, is supported by the finding that SWS dreams do not evidence the dream-lag effect.


Efficient homogenization procedure for the calculation of optical properties of 3D nanostructured composites.
We present a very efficient recursive method to calculate the effective optical response of metamaterials made up of arbitrarily shaped inclusions arranged in periodic 3D arrays. We apply it to dielectric particles embedded in a metal matrix with a lattice constant much smaller than the wavelength of the incident field, so that we may neglect retardation and factor the geometrical properties from the properties of the materials. If the conducting phase is continuous the low frequency behavior is metallic, and if the conducting paths are thin, the high frequency behavior is dielectric. Thus, extraordinary-transparency bands may develop at intermediate frequencies, whose properties may be tuned by geometrical manipulation.


The impact of pistachio intake alone or in combination with high-carbohydrate foods on post-prandial glycemia.
Dietary strategies that reduce post-prandial glycemia are important in the prevention and treatment of diabetes and coronary heart disease (CHD). This may be achieved by addition of high-quality protein and fat contained in pistachio nuts, to carbohydrate-containing foods or meals. A total of 10 healthy volunteers (3 males, 7 females); aged 48.3±6.4 years; Body mass index (BMI) 28.0±4.8 kg/m(2) participated in two studies. Study 1 assessed the dose-response effect of 28, 56 and 84 g pistachios consumed alone or co-ingested with white bread (50 g available carbohydrate); Study 2 assessed the effective dose (56 g) of pistachios on post-prandial glycemia consumed with different commonly consumed carbohydrate foods (50 g available carbohydrate). Relative glycemic responses (RGRs) of study meals compared with white bread, were assessed over the 2 h post-prandial period. The RGRs of pistachios consumed alone expressed as a percentage of white bread (100%) were: 28 g (5.7±1.8%); 56 g (3.8±1.8%); 84 g (9.3±3.2%), P<0.001. Adding pistachios to white bread resulted in a dose-dependent reduction in the RGR of the composite meal; 28 g (89.1±6.0, P=0.100); 56 g (67.3±9.8, P=0.009); 84 g (51.5±7.5, P<0.001). Addition of 56 g pistachios to carbohydrate foods significantly reduced the RGR: parboiled rice (72.5±6.0) versus rice and pistachios (58.7±5.1) (P=0.031); pasta (94.8±11.4) versus pasta and pistachios (56.4±5.0) (P=0.025); whereas for mashed potatoes (109.0±6.6) versus potatoes and pistachios, (87.4±8.0) (P=0.063) the results approached significance. Pistachios consumed alone had a minimal effect on post-prandial glycemia and when taken with a carbohydrate meal attenuated the RGR. The beneficial effects of pistachios on post-prandial glycemia could, therefore, be part of the mechanism by which nuts reduce the risk of diabetes and CHD.


CLPFFD-PEG functionalized NIR-absorbing hollow gold nanospheres and gold nanorods inhibit β-amyloid aggregation.
Gold nanoparticles with specific optical properties in combination with the CLPFFD peptide that exhibits selectivity for β-amyloid (Aβ) aggregates are promising photothermal absorbers for application in Alzheimer's disease therapy. We report on hollow gold nanospheres (HAuNS) and gold nanorods (AuNR), which exhibit strong plasmonic near infrared (NIR) absorbance in the optical window of biological tissue and which are functionalized with CLPFFD in two different ways. Therefore the peptide was either directly bound to the particle surface or indirectly to a particle-protecting polyethylene glycol (PEG) ligand shell, thereby reducing the CLPFFD density on the surfaces of both types of particles. Fully PEGylated particles were used for comparison. The effects on cell viability and the fundamental suitability of the HAuNS and AuNR conjugates as photothermal absorbers to inhibit Aβ-fibrillation are analysed in vitro. The positive influence of the use of PEG ligands on the reduced cytotoxicity of the conjugates and on the Aβ-disaggregation is discussed.


Physiological and genetic analysis of the carbon regulation of the NAD-dependent glutamate dehydrogenase of Saccharomyces cerevisiae.
We found that cells of Saccharomyces cerevisiae have an elevated level of the NAD-dependent glutamate dehydrogenase (NAD-GDH; encoded by the GDH2 gene) when grown with a nonfermentable carbon source or with limiting amounts of glucose, even in the presence of the repressing nitrogen source glutamine. This regulation was found to be transcriptional, and an upstream activation site (GDH2 UASc) sufficient for activation of transcription during respiratory growth conditions was identified. This UAS was found to be separable from a neighboring element which is necessary for the nitrogen source regulation of the gene, and strains deficient for the GLN3 gene product, required for expression of NAD-GDH during growth with the activating nitrogen source glutamate, were unaffected for the expression of NAD-GDH during growth with activating carbon sources. Two classes of mutations which prevented the normal activation of NAD-GDH in response to growth with nonfermentable carbon sources, but which did not affect the nitrogen-regulated expression of NAD-GDH, were found and characterized. Carbon regulation of GDH2 was found to be normal in hxk2, hap3, and hap4 strains and to be only slightly altered in a ssn6 strain; thus, in comparison with the regulation of previously identified glucose-repressed genes, a new pathway appears to be involved in the regulation of GDH2.


Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 1.
Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases-related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response.


Surgical fixation methods for tibial plateau fractures.
Fractures of the tibial plateau, which are intra-articular injuries of the knee joint, are often difficult to treat and have a high complication rate, including early-onset osteoarthritis. Surgical fixation is usually used for more complex tibial plateau fractures. Additionally, bone void fillers are often used to address bone defects caused by the injury. Currently there is no consensus on either the best method of fixation or bone void filler. To assess the effects (benefits and harms) of different surgical interventions, and the use of bone void fillers, for treating tibial plateau fractures. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (12 September 2014), the Cochrane Central Register of Controlled Trials (2014 Issue 8), MEDLINE (1946 to September Week 1 2014), EMBASE (1974 to 2014 Week 36), trial registries (4 July 2014), conference proceedings and grey literature (4 July 2014). We included randomised and quasi-randomised controlled clinical trials comparing surgical interventions for treating tibial plateau fractures and the different types of filler for filling bone defects. Two review authors independently screened search results, selected studies, extracted data and assessed risk of bias. We calculated risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). Only very limited pooling, using the fixed-effect model, was possible. Our primary outcomes were quality of life measures, patient-reported outcome measures of lower limb function and serious adverse events. We included six trials in the review, with a total of 429 adult participants, the majority of whom were male (63%). Three trials evaluated different types of fixation and three analysed different types of bone graft substitutes. All six trials were small and at substantial risk of bias. We judged the quality of most of the available evidence to be very low, meaning that we are very uncertain about these results.One trial compared the use of a circular fixator combined with insertion of percutaneous screws (hybrid fixation) versus standard open reduction and internal fixation (ORIF) in people with open or closed Schatzker types V or VI tibial plateau fractures. Results (66 participants) for quality of life scores using the 36-item Short Form Health Survey (SF-36)), Hospital for Special Surgery (HSS) scores and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function scores tended to favour hybrid fixation, but a benefit of ORIF could not be ruled out. Participants in the hybrid fixation group had a lower risk for an unplanned reoperation (351 per 1000 people compared with 450 in the ORIF group; 95% CI 197 fewer to 144 more) and were more likely to have returned to their pre-injury activity level (303 per 1000 people, compared with 121 in the ORIF group; 95% CI 15 fewer to 748 more). Results of the two groups were comparable for the WOMAC pain subscale and stiffness scores, but mean knee range of motion values were higher in the hybrid group.Another trial compared the use of a minimally invasive plate (LISS system) versus double-plating ORIF in 84 people who had open or closed bicondylar tibial plateau fractures. Nearly twice as many participants (22 versus 12) in the ORIF group had a bone graft. Quality of life, pain, knee range of motion and return to pre-injury activity were not reported. The trial provided no evidence of differences in HSS knee scores, complications or reoperation entailing implant removal or revision fixation. A quasi-randomised trial comparing arthroscopically-assisted percutaneous reduction and internal fixation versus standard ORIF reported results at 14 months in 58 people with closed Schatzker types II or III tibial plateau fracture. Quality of life, pain and return to pre-injury activity were not reported. There was very low quality evidence of higher HSS knee scores and higher knee range of motion values in the arthroscopically assisted group. No reoperations were reported.Three trials compared different types of bone substitute versus autologous bone graft (autograft) for managing bone defects. Quality of life, pain and return to pre-injury activity were not reported. Only one trial (25 participants) reported on lower limb function, finding good or excellent results in both groups for walking, climbing stairs, squatting and jumping at 12 months. The incidences of individual complications were similar between groups in all three trials. One trial found no cases of inflammatory response in the 20 participants receiving bone substitute, and two found no complications associated with the donor site in the autograft group (58 participants). However, all 38 participants in the autologous iliac bone graft group of one trial reported prolonged pain from the harvest site. Two trials reported similar range of motion results in the two groups, whereas the third trial favoured the bone substitute group. Currently, there is insufficient evidence to ascertain the best method of fixation or the best method of addressing bone defects during surgery. However, the evidence does not contradict approaches aiming to limit soft-tissue dissection and damage or to avoid autograft donor site complications through using bone substitutes. Further well-designed, larger randomised trials are warranted.


Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene.
Sexual differentiation of the brain in rodents is achieved by estrogens, which are converted from androgens in the brain, during the perinatal period. We have identified the progranulin (PGRN) gene as one of the sex steroid-inducible genes that may be involved in masculinization of the rat brain. In the present study, we generated a line of mice with targeted disruption of the PGRN gene, and investigated male sexual behaviour, aggression and anxiety. PGRN-deficient mice exhibited a decrease in ejaculation incidence, while the latency and frequency of both mount and intromission were unchanged. For the aggressive behaviour test, the resident-intruder paradigm was used, and PGRN-deficient mice exhibited enhanced aggressiveness. In wild-type mice, males exhibited lower levels of anxiety than females by the open field test, while male PGRN-deficient mice exhibited an elevated level of anxiety and sex difference in anxiety was not observed. In addition, mRNA expression of the serotonergic receptor 5-HT1A, which could be related to the inhibition of aggression and anxiety, was significantly reduced in the hippocampus of PGRN-deficient mice after aggressive encounters. On the other hand, deficiency of the PGRN gene did not affect serum testosterone concentrations. These results suggest that PGRN gene plays a role in establishing sexual dimorphic behaviours at least partially by modulating the brain serotonergic system.


Dosed myofascial release in three-dimensional bioengineered tendons: effects on human fibroblast hyperplasia, hypertrophy, and cytokine secretion.
The purpose of this study was to investigate potential differences of magnitudes and durations associated with dosed myofascial release (MFR) on human fibroblast proliferation, hypertrophy, and cytokine secretions. Bioengineered tendons (BETs) attached to nylon mesh anchors were strained uniaxially using a vacuum pressure designed to model MFR varying in magnitudes (0%, 3%, 6%, 9%, and 12% elongation) and durations (0.5 and 1-5 minutes). Conditioned media were analyzed for cytokine secretion via protein microarray (n = 2). Bioengineered tendons were weighted and fibroblasts extracted from the BET were assessed for total cell protein and proliferation via double-stranded DNA quantification (n = 5). All data were compared by a 1-way analysis of variance with post hoc Dunnett test and Student t test. Changing MFR magnitude and duration did not have an effect on total fibroblast cellular protein or DNA accumulation. However, we observed a stepwise increase in BET weight with higher-magnitude MFR treatments. Longer durations of MFR resulted in progressive increase in the secretions of angiogenin, interleukin (IL)-3, IL-8, growth colony-stimulating factor, and thymus activation-regulated chemokine. Alternatively, increasing strain magnitude induced secretions of IL-1β, monocyte chemoattractant cytokine, and regulated and normal T cell expressed and secreted chemotactic cytokine. Cellular proliferation and hypertrophy were not significantly changed by any treatment. However, the change in total BET dry weight suggests that production of extracellular matrix protein may be up-regulated. Different MFR parameters induce secretions of a unique subset of cytokines and growth factors that can be further enhanced by increasing the magnitude and duration of treatment. If clinically translatable, these results suggest that variations to manual therapy biomechanical parameters may differentially affect physiological responses in vivo.


The roles of cortical oscillations in sustained attention.
We rely on sustained attention to protect task performance against fatigue and distraction. Time-related variations in attention correlate with amplitude changes of specific cortical oscillations. However, the ways in which these oscillations might support sustained attention, how these oscillations are controlled, and the extent to which they influence one another remain unclear. We address this issue by proposing an oscillatory model of sustained attention. Within this framework, sustained attention relies on frontomedial theta oscillations, inter-areal communication via low-frequency phase synchronisation, and selective excitation and inhibition of cognitive processing through gamma and alpha oscillations, respectively. Sustained attention also relies on interactions between these oscillations across attention-related brain networks.


Long-term viability of carbon sequestration in deep-sea sediments.
Sequestration of carbon dioxide in deep-sea sediments has been proposed for the long-term storage of anthropogenic CO2 that can take advantage of the current offshore infrastructure. It benefits from the negative buoyancy effect and hydrate formation under conditions of high pressure and low temperature. However, the multiphysics process of injection and postinjection fate of CO2 and the feasibility of subseabed disposal of CO2 under different geological and operational conditions have not been well studied. With a detailed study of the coupled processes, we investigate whether storing CO2 into deep-sea sediments is viable, efficient, and secure over the long term. We also study the evolution of multiphase and multicomponent flow and the impact of hydrate formation on storage efficiency. The results show that low buoyancy and high viscosity slow down the ascending plume and the forming of the hydrate cap effectively reduces permeability and finally becomes an impermeable seal, thus limiting the movement of CO2 toward the seafloor. We identify different flow patterns at varied time scales by analyzing the mass distribution of CO2 in different phases over time. We observe the formation of a fluid inclusion, which mainly consists of liquid CO2 and is encapsulated by an impermeable hydrate film in the diffusion-dominated stage. The trapped liquid CO2 and CO2 hydrate finally dissolve into the pore water through diffusion of the CO2 component, resulting in permanent storage. We perform sensitivity analyses on storage efficiency under variable geological and operational conditions. We find that under a deep-sea setting, CO2 sequestration in intact marine sediments is generally safe and permanent.


First principles description of the giant dipole resonance in 16O.
We present a calculation of the giant dipole resonance in (16)O based on a nucleon-nucleon (NN) interaction from chiral effective field theory that reproduces NN scattering data with high accuracy. By merging the Lorentz integral transform and the coupled-cluster methods, we extend the previous theoretical limits for breakup observables in light nuclei with mass numbers (A ≤ 7) and address the collective giant dipole resonance of (16)O. We successfully benchmark the new approach against virtually exact results from the hyperspherical harmonics method in (4)He. Our results for (16)O reproduce the position and the total strength (bremsstrahlung sum rule) of the dipole response very well. When compared to the cross section from photoabsorption experiments, the theoretical curve exhibits a smeared form of the peak. The tail region between 40 and 100 MeV is reproduced within uncertainties.


A riboswitch-regulated antisense RNA in Listeria monocytogenes.
Riboswitches are ligand-binding elements located in 5' untranslated regions of messenger RNAs, which regulate expression of downstream genes. In Listeria monocytogenes, a vitamin B12-binding (B12) riboswitch was identified, not upstream of a gene but downstream, and antisense to the adjacent gene, pocR, suggesting it might regulate pocR in a nonclassical manner. In Salmonella enterica, PocR is a transcription factor that is activated by 1,2-propanediol, and subsequently activates expression of the pdu genes. The pdu genes mediate propanediol catabolism and are implicated in pathogenesis. As enzymes involved in propanediol catabolism require B12 as a cofactor, we hypothesized that the Listeria B12 riboswitch might be involved in pocR regulation. Here we demonstrate that the B12 riboswitch is transcribed as part of a noncoding antisense RNA, herein named AspocR. In the presence of B12, the riboswitch induces transcriptional termination, causing aspocR to be transcribed as a short transcript. In contrast, in the absence of B12, aspocR is transcribed as a long antisense RNA, which inhibits pocR expression. Regulation by AspocR ensures that pocR, and consequently the pdu genes, are maximally expressed only when both propanediol and B12 are present. Strikingly, AspocR can inhibit pocR expression in trans, suggesting it acts through a direct interaction with pocR mRNA. Together, this study demonstrates how pocR and the pdu genes can be regulated by B12 in bacteria and extends the classical definition of riboswitches from elements governing solely the expression of mRNAs to a wider role in controlling transcription of noncoding RNAs.


Cleavage of ST6Gal I by radiation-induced BACE1 inhibits golgi-anchored ST6Gal I-mediated sialylation of integrin β1 and migration in colon cancer cells.
Previously, we found that β-galactoside α2,6-sialyltransferase (ST6Gal I), an enzyme that adds sialic acids to N-linked oligosaccharides of glycoproteins and is frequently overexpressed in cancer cells, is up-regulated by ionizing radiation (IR) and cleaved to a form possessing catalytic activity comparable to that of the Golgi-localized enzyme. Moreover, this soluble form is secreted into the culture media. Induction of ST6Gal I significantly increased the migration of colon cancer cells via sialylation of integrin β1. Here, we further investigated the mechanisms underlying ST6Gal I cleavage, solubilization and release from cells, and addressed its functions, focusing primarily on cancer cell migration. We performed immunoblotting and lectin affinity assay to analyze the expression of ST6 Gal I and level of sialylated integrin β1. After ionizing radiation, migration of cells was measured by in vitro migration assay. α2, 6 sialylation level of cell surface was analyzed by flow cytometry. Cell culture media were concentrated and then analyzed for soluble ST6Gal I levels using an α2, 6 sialyltransferase sandwich ELISA. We found that ST6Gal I was cleaved by BACE1 (β-site amyloid precursor protein-cleaving enzyme), which was specifically overexpressed in response to IR. The soluble form of ST6Gal I, which also has sialyltransferase enzymatic activity, was cleaved from the Golgi membrane and then released into the culture media. Both non-cleaved and cleaved forms of ST6Gal I significantly increased colon cancer cell migration in a sialylation-dependent manner. The pro-migratory effect of the non-cleaved form of ST6Gal I was dependent on integrin β1 sialylation, whereas that of the cleaved form of ST6Gal I was not, suggesting that other intracellular sialylated molecules apart from cell surface molecules such as integrin β1 might be involved in mediating the pro-migratory effects of the soluble form of ST6Gal I. Moreover, production of soluble form ST6Gal I by BACE 1 inhibited integrin β1 sialylation and migration by Golgi-anchored form of ST6Gal I. Our results suggest that soluble ST6Gal I, possibly in cooperation with the Golgi-bound form, may participate in cancer progression and metastasis prior to being secreted from cancer cells.


Thick Prelaminar Tissue Decreases Lamina Cribrosa Visibility.
Evaluation of the effect of prelaminar tissue thickness on visualization of the lamina cribrosa (LC) using optical coherence tomography (OCT). The optic nerve head (ONH) region was scanned using OCT. The quality of visible LC microstructure was assessed subjectively using a grading system and objectively by analyzing the signal intensity of each scan's superpixel components. Manual delineations were made separately and in 3-dimensions quantifying prelaminar tissue thickness, analyzable regions of LC microstructure, and regions with a visible anterior LC (ALC) boundary. A linear mixed effect model quantified the association between tissue thickness and LC visualization. A total of 17 healthy, 27 glaucoma suspect, and 47 glaucomatous eyes were included. Scans with thicker average prelaminar tissue measurements received worse grading scores (P = 0.007), and superpixels with low signal intensity were associated significantly with regions beneath thick prelaminar tissue (P < 0.05). The average prelaminar tissue thickness in regions of scans where the LC was analyzable (214 μm) was significantly thinner than in regions where the LC was not analyzable (569 μm; P < 0.001). Healthy eyes had significantly thicker average prelaminar tissue measurements than glaucoma or glaucoma suspect eyes (both P < 0.001), and glaucoma suspect eyes had significantly thicker average prelaminar tissue measurements than glaucoma eyes (P = 0.008). Significantly more of the ALC boundary was visible in glaucoma eyes (63% of ONH) than in healthy eyes (41%; P = 0.005). Thick prelaminar tissue was associated with impaired visualization of the LC. Healthy subjects generally had thicker prelaminar tissue, which potentially could create a selection bias against healthy eyes when comparing LC structures.


A mathematical model to study the dynamics of epithelial cellular networks.
Epithelia are sheets of connected cells that are essential across the animal kingdom. Experimental observations suggest that the dynamical behavior of many single-layered epithelial tissues has strong analogies with that of specific mechanical systems, namely large networks consisting of point masses connected through spring-damper elements and undergoing the influence of active and dissipating forces. Based on this analogy, this work develops a modeling framework to enable the study of the mechanical properties and of the dynamic behavior of large epithelial cellular networks. The model is built first by creating a network topology that is extracted from the actual cellular geometry as obtained from experiments, then by associating a mechanical structure and dynamics to the network via spring-damper elements. This scalable approach enables running simulations of large network dynamics: the derived modeling framework in particular is predisposed to be tailored to study general dynamics (for example, morphogenesis) of various classes of single-layered epithelial cellular networks. In this contribution, we test the model on a case study of the dorsal epithelium of the Drosophila melanogaster embryo during early dorsal closure (and, less conspicuously, germband retraction).


Outcomes of Patients With Coronary Arterial Bifurcation Narrowings Undergoing Provisional 1-Stent Treatment (from the BIONICS Trial).
Treatment of bifurcation lesions is technically challenging and has been associated with an increased risk of adverse events. We sought to evaluate the clinical and angiographic outcomes of patients who underwent bifurcation lesion provisional treatment in the BioNIR Ridaforolimus Eluting Coronary Stent System in Coronary Stenosis trial. A prospective, multicenter, 1:1 randomized trial was conducted to evaluate the safety and efficacy of ridaforolimus-eluting stents (RES) versus zotarolimus-eluting stents (ZES). Enrollment of bifurcation lesions treated with a provisional 1-stent technique was allowed. Bifurcation lesions were analyzed by an angiographic core laboratory. Outcomes were analyzed according to the presence of a bifurcation lesion treatment. Study population included 686 (35.8%) patients with and 1,228 (64.2%) patients without bifurcation lesion treatment. Procedural success was high and similar between groups. In 2 years, there was no difference in the rate of target lesion failure between the bifurcation and nonbifurcation groups (7.6% vs 7.3%, respectively, p = 0.81) regardless of the presence of side branch stenosis ≥50%. In 159 patients with angiographic follow-up, there was no difference in the rate of binary restenosis between groups (9.0% vs 9.2%, p = 0.96). Rates of target lesion failure at 1-year were similar with ZES and RES, and consistent in patients with and without bifurcation lesions (pinteraction = 0.61). In conclusion, patients with bifurcation lesions treated and a provisional strategy experienced similar outcomes as those with nonbifurcation lesions. RES performed as well as ZES in bifurcation and nonbifurcation lesions.


A Nucleus-Localized Long Non-Coding RNA Enhances Drought and Salt Stress Tolerance.
Long noncoding RNAs (lncRNAs) affect gene expression through a wide range of mechanisms and are considered as important regulators in many essential biological processes. A large number of lncRNA transcripts have been predicted or identified in plants in recent years. However, the biological functions for most of them are still unknown. In this study, we identified an Arabidopsis (Arabidopsis thaliana) lncRNA, DROUGHT INDUCED lncRNA (DRIR), as a novel positive regulator of the plant response to drought and salt stress. DRIR was expressed at a low level under nonstress conditions but can be significantly activated by drought and salt stress as well as by abscisic acid (ABA) treatment. We identified a T-DNA insertion mutant, drirD , which had higher expression of the DRIR gene than the wild-type plants. The drirD mutant exhibits increased tolerance to drought and salt stress. Overexpressing DRIR in Arabidopsis also increased tolerance to drought and salt stress of the transgenic plants. The drirD mutant and the overexpressing seedlings are more sensitive to ABA than the wild type in stomata closure and seedling growth. Genome-wide transcriptome analysis demonstrated that the expression of a large number of genes was altered in drirD and the overexpressing plants. These include genes involved in ABA signaling, water transport, and other stress-relief processes. Our study reveals a mechanism whereby DRIR regulates the plant response to abiotic stress by modulating the expression of a series of genes involved in the stress response.


Recognition of depression in people of different cultures: a qualitative study.
Many minority group patients who attend primary health care are depressed. To identify a depressive state when GPs see patients from other cultures than their own can be difficult because of cultural and gender differences in expressions and problems of communication. The aim of this study was to explore and analyse how GPs think and deliberate when seeing and treating patients from foreign countries who display potential depressive features. The data were collected in focus groups and through individual interviews with GPs in northern Sweden and analysed by qualitative content analysis. In the analysis three themes, based on various categories, emerged; "Realizing the background", "Struggling for clarity" and "Optimizing management". Patients' early life events of importance were often unknown which blurred the accuracy. Reactions to trauma, cultural frictions and conflicts between the new and old gender norms made the diagnostic process difficult. The patient-doctor encounter comprised misconceptions, and social roles in the meetings were sometimes confused. GPs based their judgement mainly on clinical intuition and the established classification of depressive disorders was discussed. Tools for management and adequate action were diffuse. Dialogue about patients' illness narratives and social context are crucial. There is a need for tools for multicultural, general practice care in the depressive spectrum. It is also essential to be aware of GPs' own conceptions in order to avoid stereotypes and not to under- or overestimate the occurrence of depressive symptoms.


Two-year cost effectiveness between two gradual tapering strategies in rheumatoid arthritis: cost-utility analysis of the TARA trial.
The aim of the current study was to evaluate the 2-year cost-utility ratio between tapering conventional synthetic disease-modifying antirheumatic drugs (csDMARD) first followed by the tumour necrosis factor (TNF)-inhibitor, or vice versa, in patients with rheumatoid arthritis (RA). Two-year data of the Tapering strategies in Rheumatoid Arthritis trial were used. Patients with RA, who used both a csDMARD and a TNF-inhibitor and had a well-controlled disease (disease activity score ≤2.4 and swollen joint count≤1) for at least 3 months, were randomised into gradual tapering the csDMARD first followed by the TNF-inhibitor, or vice versa. Quality-adjusted life years (QALYs) were derived from the European Quality of life questionnaire with 5 dimensions. Healthcare and productivity costs were calculated with data from patient records and questionnaires. The incremental cost-effectiveness ratio and the incremental net monetary benefit were used to assess cost effectiveness between both tapering strategies. 94 patients started tapering their TNF-inhibitor first, while the other 95 tapered their csDMARD first. QALYs (SD) were, respectively, 1.64 (0.22) and 1.65 (0.22). Medication costs were significantly lower in the patients who tapered the TNF-inhibitor first, while indirect cost were higher due to more productivity loss (p=0.10). Therefore, total costs (SD) were €38 833 (€39 616) for tapering csDMARDs first, and €39 442 (€47 271) for tapering the TNF-inhibitor (p=0.88). For willingness-to-pay (WTP) levels <€83 800 tapering, the csDMARD first has the highest probability of being cost effective, while for WTP levels >€83 800 tapering the TNF-inhibitor first has the highest probability. Our economic evaluation shows that costs are similar for both tapering strategies. Regardless of the WTP, tapering either the TNF-inhibitor or the csDMARD first is equally cost effective. NTR2754.


Predictors of depression, stress, and anxiety among non-tenure track faculty.
Nationwide in the United States, 70% of faculty members in higher education are employed off the tenure-track. Nearly all of these non-tenure-track (NTT) appointments share a quality that may produce stress for those who hold them: contingency. Most NTT appointments are contingent on budget, enrollment, or both, and the majority of contingent faculty members are hired for one quarter or semester at a time. Significant research has investigated the effects of contingency on teaching, students, departments, colleges, and universities; however, little research has focused on the psychological experiences of NTT faculty. The current study examined perceptions of workplace stressors and harm, organizational commitment, common coping mechanisms, and depression, anxiety and stress among NTT faculty using a longitudinal design that spanned 2-4 months. Results indicate that NTT faculty perceive unique stressors at work that are related to their contingent positions. Specific demographic characteristics and coping strategies, inability to find a permanent faculty position, and commitment to one's organization predispose NTT faculty to perceive greater harm and more sources of stress in their workplaces. Demographic characteristics, lower income, inability to find a permanent faculty position, disengagement coping mechanisms (e.g., giving up, denial), and organizational commitment were associated with the potential for negative outcomes, particularly depression, anxiety, and stress. Our findings suggest possibilities for institutional intervention. Overall, we argue that universities would be well-served by attending to the needs of NTT faculty on campus in order to mitigate negative outcomes for institutions, students, and faculty.


Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys.
Small pediatric recipients of an adult-sized kidney have insufficient renal blood flow early after transplantation, with secondary chronic hypoperfusion and irreversible histological damage of the tubulo-interstitial compartment. It is unknown whether this is reflected by renal resistive indices. We measured renal graft resistive indices and volumes of 47 healthy pediatric kidney transplant recipients of an adult-sized kidney in a prospective study for six months post-transplant. A total of 205 measurements were performed. The smallest recipients (BSA <or=0.75 m(2)) had higher resistive indices compared to recipients with a BSA between 0.75 and 1.5 m(2) (p < 0.0001) and to recipients with a BSA >or= 1.5 m(2) (p < 0.0001). Resistive indices increased during the first six months in the smallest recipients (p = 0.02), but not in the two larger recipient groups (BSA 0.75-1.5 m(2) and >or=1.5 m(2)). All three BSA groups showed a reduction in renal volume after transplantation, with the greatest reduction occurring in the smallest recipients. In conclusion, renal transplant resistive indices reflect pediatric recipient BSA dependency. The higher resistance to intra-renal vascular flow and significant decrease in renal volume in the smallest group likely reflect accommodation of the size discrepant transplanted adult-sized kidney to the smaller pediatric recipient vasculature with associated lower renal artery flow.


Volatiles from the fungal microbiome of the marine sponge Callyspongia cf. flammea.
The volatiles emitted by five fungal strains previously isolated from the marine sponge Callyspongia cf. flammea were captured with a closed-loop stripping apparatus (CLSA) and analyzed by GC-MS. Besides several widespread compounds, a series of metabolites with interesting bioactivities were found, including the quorum sensing inhibitor protoanemonin, the fungal phytotoxin 3,4-dimethylpentan-4-olide, and the insect attractant 1,2,4-trimethoxybenzene. In addition, the aromatic polyketides isotorquatone and chartabomone that are both known from Eucalyptus and a new O-desmethyl derivative were identified. The biosynthesis of isotorquatone was studied by feeding experiments with isotopically labeled precursors and its absolute configuration was determined by enantioselective synthesis of a reference compound. Bioactivity testings showed algicidal activity for some of the identified compounds, suggesting a potential ecological function in sponge defence.


Protein synthesis and protein phosphorylation during heat stress, recovery, and adaptation.
Incubating cells at elevated temperatures causes an inhibition of protein synthesis. Mild heat stress at 41-42 degrees C inhibits the fraction of active, polysomal ribosomes from greater than 60% (preheating) to less than 30%. A return to 37 degrees C leads to an increase in protein synthesis, termed "recovery." Continuous incubation at 41-42 degrees C also leads to a gradual restoration of protein synthesis (greater than 70% of ribosomes reactivated by 2-4 h), termed "adaptation". Protein synthesis inhibition and reactivation is prestressed, recovered cells that contain elevated levels of the heat stress proteins occur to the same extent and at the same rate as in "naive" cells. The adaptation response requires transcription of new RNA whereas recovery does not. A large number of phosphorylation changes are induced by severe heat stress and occur with kinetics similar to the inhibition of protein synthesis. These include phosphorylation of eukaryotic protein synthesis initiation factor (eIF)-2 alpha and dephosphorylation of eIF-4B and eIF-4Fp25 (eIF-4E). However, the extent to which the modification occurs is proportional to the severity of the stress, and, under mild (41-42 degrees C) heat stress conditions, these initiation factor phosphorylation changes do not occur. Similarly, under conditions of severe heat stress eIF-2 alpha and eIF-4B frequently recover to their prestress phosphorylation state before the recovery of protein synthesis. eIF-4E dephosphorylation likewise does not occur under mild heat stress conditions. Therefore, these changes in phosphorylation states, which are thought to be sufficient cause, are not necessary for the inhibition of protein synthesis observed.


Pyogenic liver abscess caused by Burkholderia pseudomallei in Taiwan.
Pyogenic liver abscess in Taiwan is a well-known disease entity, commonly associated with a single pathogen, Klebsiella pneumoniae. Melioidosis is an endemic disease in Taiwan that can manifest as multiple abscesses in sites including the liver. We report three cases of liver abscesses caused by Burkholderia pseudomallei. The first patient was a 54-year-old diabetic woman, who presented with liver abscess and a left subphrenic abscess resulting from a ruptured splenic abscess, co-infected with K. pneumoniae and B. pseudomallei. The second patient, a 58-year-old diabetic man, developed bacteremic pneumonia over the left lower lung due to B. pseudomallei with acute respiratory distress syndrome, and relapsed 5 months later with bacteremic abscesses of the liver, spleen, prostate and osteomyelitis, due to lack of compliance with prescribed antibiotic therapy. The third patient was a 61-year-old diabetic man with a history of travel to Thailand, who presented with jaundice and fever of unknown origin. Liver and splenic abscesses due to B. pseudomallei were diagnosed. A high clinical alertness to patients' travel history, underlying diseases, and the presence of concomitant splenic abscess is essential to early detection of the great mimicker, melioidosis. The treatment of choice is intravenous ceftazidime for at least 14 days or more. An adequate duration of maintenance oral therapy, with amoxicillin-clavulanate or trimethoprim-sulfamethoxazole for 12-20 weeks, is necessary to prevent relapse. Liver abscess in Taiwan is most commonly due to K. pneumoniae, but clinicians should keep in mind that this may be a presenting feature of melioidosis.


Mountain biodiversity, its causes and function.
The personal safety and well-being of one fifth, and water supply for almost half of all people depend directly or indirectly on the functional integrity of mountain ecosystems, the key component of which is a robust vegetation cover. The green 'coat' of the world's mountains is composed of specialized plants, animals and microbes, all nested in a great variety of microhabitats. Because a single mountain may host a series of climatically different life zones over short elevational distances, mountains are hot spots of biodiversity and priority regions for conservation. With their diverse root systems, plants anchor soils on slopes and prevent erosion. Both landuse and atmospheric changes such as elevated CO2 and climatic warming affect mountain biodiversity. Sustained catchment value depends on sustained soil integrity, which in turn depends on a diverse plant cover. Whether landuse in mountains is sustainable is a question of its consequences for water yield and biodiversity. Given their dependence on mountains, lowlanders should show concern for the highlands beyond their recreational value.


Effects of an acute bout of exercise on memory in 6th grade children.
Research supports the positive effects of exercise on cognitive performance by children. However, a limited number of studies have explored the effects specifically on memory. The purpose of this study was to compare the effects of an acute bout of exercise on learning, short-term memory, and long-term memory in a sample of children. Children were randomly assigned to an exercise condition or to a no-treatment control condition and then performed repeated trials on an auditory verbal learning task. In the exercise condition, participants performed the PACER task, an aerobic fitness assessment, in their physical education class before performing the memory task. In the control condition, participants performed the memory task at the beginning of their physical education class. Results showed that participants in the exercise condition demonstrated significantly better learning of the word lists and significantly better recall of the words after a brief delay. There were not significant differences in recognition of the words after an approximately 24-hr delay. These results provide evidence in a school setting that an acute bout of exercise provides benefits for verbal learning and long-term memory. Future research should be designed to identify the extent to which these findings translate to academic measures.


Depressive deficits in forgetting.
The aim of this study was to investigate whether difficulties in forgetting (like difficulties in remembering) are associated with depressive states. First, dysphoric and nondysphoric students learned 40 word pairs, each consisting of a positive or negative adjective and a neutral noun (target). Next, the students practiced responding with some targets and suppressing others, when given the adjective as cue, for a varied number of repetitions. On the final test, they were told to disregard the prior instruction to suppress and to recall the target associated with every cue. Compared with nondysphoric students, dysphoric students recalled similar percentages of targets from sets assigned for response practice but higher percentages from sets assigned for suppression practice. The degree of forgetting showed some mood-congruent tendencies and was significantly correlated with self-report measures of rumination and unwanted thoughts.


Tight Glycemic Control in Critically Ill Children.
In multicenter studies, tight glycemic control targeting a normal blood glucose level has not been shown to improve outcomes in critically ill adults or children after cardiac surgery. Studies involving critically ill children who have not undergone cardiac surgery are lacking. In a 35-center trial, we randomly assigned critically ill children with confirmed hyperglycemia (excluding patients who had undergone cardiac surgery) to one of two ranges of glycemic control: 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter; lower-target group) or 150 to 180 mg per deciliter (8.3 to 10.0 mmol per liter; higher-target group). Clinicians were guided by continuous glucose monitoring and explicit methods for insulin adjustment. The primary outcome was the number of intensive care unit (ICU)-free days to day 28. The trial was stopped early, on the recommendation of the data and safety monitoring board, owing to a low likelihood of benefit and evidence of the possibility of harm. Of 713 patients, 360 were randomly assigned to the lower-target group and 353 to the higher-target group. In the intention-to-treat analysis, the median number of ICU-free days did not differ significantly between the lower-target group and the higher-target group (19.4 days [interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P=0.58). In per-protocol analyses, the median time-weighted average glucose level was significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1 mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter [IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P<0.001). Patients in the lower-target group also had higher rates of health care-associated infections than those in the higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P=0.04), as well as higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant differences were observed in mortality, severity of organ dysfunction, or the number of ventilator-free days. Critically ill children with hyperglycemia did not benefit from tight glycemic control targeted to a blood glucose level of 80 to 110 mg per deciliter, as compared with a level of 150 to 180 mg per deciliter. (Funded by the National Heart, Lung, and Blood Institute and others; HALF-PINT ClinicalTrials.gov number, NCT01565941 .).


Diverse Hormone Response Networks in 41 Independent Drosophila Cell Lines.
Steroid hormones induce cascades of gene activation and repression with transformative effects on cell fate . Steroid transduction plays a major role in the development and physiology of nearly all metazoan species, and in the progression of the most common forms of cancer. Despite the paramount importance of steroids in developmental and translational biology, a complete map of transcriptional response has not been developed for any hormone . In the case of 20-hydroxyecdysone (ecdysone) in Drosophila melanogaster, these trajectories range from apoptosis to immortalization. We mapped the ecdysone transduction network in a cohort of 41 cell lines, the largest such atlas yet assembled. We found that the early transcriptional response mirrors the distinctiveness of physiological origins: genes respond in restricted patterns, conditional on the expression levels of dozens of transcription factors. Only a small cohort of genes is constitutively modulated independent of initial cell state. Ecdysone-responsive genes tend to organize into directional same-stranded units, with consecutive genes induced from the same strand. Here, we identify half of the ecdysone receptor heterodimer as the primary rate-limiting step in the response, and find that initial receptor isoform levels modulate the activated cohort of target transcription factors. This atlas of steroid response reveals organizing principles of gene regulation by a model type II nuclear receptor and lays the foundation for comprehensive and predictive understanding of the ecdysone transduction network in the fruit fly.


The influence of chemical sympathectomy on oxygen uptake during development of rat brain cortical tissue.
In this study the influence of 6-hydroxydopamine (6-OHDA), in vitro and in vivo, on the oxygen consumption in the rat brain cortical slices was examined. The treatment with 6-OHDA increased the oxygen uptake of brain cortical tissue of young rats. The maximum increase was observed 7 and 14 days after treatment with 6-OHDA. On the contrary, 6-OHDA added in vitro produced very marked depression of oxygen uptake in slices of brain cortical tissue of the tested animals. The addition of isoprenaline in vitro stimulated the respiratory activity in the cerebral tissue of control young rats in all the periods of examination. Thus, 18 days after the birth, the isoprenaline-stimulation of oxygen uptake in brain tissue was 44.3% as compared to the control values. The same degree of stimulation was noted in the cerebral tissue of older animals (25, 32 and 45 days after birth). However, addition of isoprenaline did not influence the respiration of cerebral tissue stimulated by 6-OHDA.


Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.
Background Many rare, potentially pathogenic, RYR2 variants identified in individuals with clinically definite catecholaminergic polymorphic ventricular tachycardia are classified ambiguously as variants of uncertain significance (VUS). We aimed to determine if a phenotype-enhanced variant classification approach could reduce the burden of RYR2 VUS encountered during clinical genetic testing. Methods This retrospective study was conducted in 84 RYR2-positive individuals from the Mayo Clinic (Rochester, MN) and validated in 149 RYR2-positive individuals from Amsterdam University Medical Center (Amsterdam, NL). Using a newly developed diagnostic scorecard, the pretest clinical probability of catecholaminergic polymorphic ventricular tachycardia was determined for all RYR2-positive individuals. Each RYR2 variant was then readjudicated using a phenotype-enhanced American College of Medical Genetics approach that incorporates new criteria that reflect the phenotypic strength associated with each individual RYR2 variant. Results Overall, 72 distinct RYR2 variants were identified among the 84 Mayo Clinic (39 unique) and 149 Amsterdam University Medical Center (30 unique) cases. Three variants were present in both cohorts. American College of Medical Genetics guidelines classified 47% of all RYR2 variants as VUS. In the Mayo Clinic cohort, readjudication using amended phenotype-enhanced American College of Medical Genetics standards dropped the VUS rate significantly (20/42 [48%] versus 3/42 [7%]; P<0.001) with 13/20 (65%) RYR2 VUS promoted to likely pathogenic and 4/20 (20%) demoted to likely benign. A similar drop in VUS rate (14/33 [42%] versus 3/33 [9%]; P=0.001) was observed in the Amsterdam University Medical Center validation cohort with 10/14 (71%) RYR2 VUS promoted to likely pathogenic and 1/14 (7%) demoted to likely benign. Conclusions This multicenter study illustrates the potential utility of phenotype-enhanced variant classification in catecholaminergic polymorphic ventricular tachycardia.


Twenty years of follow-up of survivors of childhood osteosarcoma: a report from the Childhood Cancer Survivor Study.
Osteosarcoma survivors have received significant chemotherapy and have undergone substantial surgeries. Their very long-term outcomes (20 year) are reported here. The authors assessed the long-term outcomes of 733 5-year survivors of childhood osteosarcoma diagnosed from 1970 to 1986 to provide a comprehensive evaluation of medical and psychosocial outcomes for survivors enrolled in the Childhood Cancer Survivor Study (CCSS). Outcomes evaluated included overall survival, second malignant neoplasms (SMNs), recurrent osteosarcoma, chronic health conditions, health status (general and mental health and functional limitations), and psychosocial factors. Outcomes of osteosarcoma survivors were compared with general-population statistics, other CCSS survivors, and CCSS siblings. Survivors had a mean follow-up of 21.6 years. The overall survival of children diagnosed with osteosarcoma who survived 5 years at 20 years from original diagnosis was 88.6% (95% confidence interval [CI], 86.6%-90.5%). The cumulative incidence of SMNs at 25 years was 5.4%, with a standardized incidence ratio of 4.79 (95% CI, 3.54-6.33; P<.01). Overall, 86.9% of osteosarcoma survivors experienced at least 1 chronic medical condition, and >50% experienced ≥2 conditions. Compared with survivors of other cancers, osteosarcoma survivors did not differ in their reported general health status (odds ratio [OR], 0.9; 95% CI, 0.7-1.2), but were more likely to report an adverse health status in at least 1 domain (OR, 1.9; 95% CI, 1.6-2.2), with activity limitations (29.1%) being the most common. Childhood osteosarcoma survivors in this cohort did relatively well, considering their extensive treatment, but are at risk of experiencing chronic medical conditions and adverse health status. Survivors warrant life-long follow-up.


Organization of actin, myosin, and intermediate filaments in the brush border of intestinal epithelial cells.
Terminal webs prepared from mouse intestinal epithelial cells were examined by the quick-freeze, deep-etch, and rotary-replication method. The microvilli of these cells contain actin filaments that extend into the terminal web in compact bundles. Within the terminal web these bundles remain compact; few filaments are separated from the bundles and fewer still bend towards the lateral margins of the cell. Decoration with subfragment 1 (S1) of myosin confirmed that relatively few actin filaments travel horizontally in the web. Instead, between actin bundles there are complicated networks of the fibrils. Here we present two lines of evidence which suggest that myosin is one of the major cross-linkers in the terminal web. First, when brush borders are exposed to 1 mM ATP in 0.3 M KCl, they lose their normal ability to bind antimyosin antibodies as judged by immunofluorescence, and they lose the thin fibrils normally found in deep-etch replicas. Correspondingly, myosin is released into the supernatant as judged by SDS gel electrophoresis. Second, electron microscope immunocytochemistry with antimyosin antibodies followed by ferritin-conjugated second antibodies leads to ferritin deposition mainly on the fibrils at the basal part of rootlets. Deep-etching also reveals that the actin filament bundles are connected to intermediate filaments by another population of cross-linkers that are not extracted by ATP in 0.3 M KCl. From these results we conclude that myosin in the intestinal cell may not only be involved in a short range sliding-filament type of motility, but may also play a purely structural role as a long range cross-linker between microvillar rootlets.


Synthesis and evaluation of nicotine alpha4beta2 receptor radioligand, 5-(3'-18F-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine, in rodents and PET in nonhuman primate.
Nicotine alpha(4)beta(2) receptor subtypes are implicated in the study of Alzheimer's disease, schizophrenia, substance abuse, lung cancer, and other disorders. We report the development and evaluation of a putative antagonist, 5-(3'-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (nifrolidine) as a PET agent for nicotine alpha(4)beta(2) receptors. In vitro binding affinity of nifrolidine was measured in rat brain slices labeled with (125)I-iodoepibatidine or (125)I-bungaratoxin. Selectivity of binding was measured in the presence of cytisine. (18)F radiolabeling was performed by reacting the tosylate precursor with (18)F-fluoride followed by deprotection. In vitro autoradiographic studies in rat brain slices with 5-(3'-(18)F-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine ((18)F-nifrolidine) were read on a phosphor imager. Rats were injected with (18)F-nifrolidine (3.7 MBq each), and brain regions were counted at various times (2-120 min). Blocking studies were performed by subcutaneous injection of nicotine (10 mg/kg). A PET study of (18)F-nifrolidine (approximately 148 MBq) was performed on an anesthetized rhesus monkey using a high-resolution scanner. In vitro binding affinity of nifrolidine exhibited an inhibition constant of 2.89 nmol/L for the alpha(4)beta(2) sites. Radiosynthesis and high-performance liquid chromatography purifications yielded the product in approximately 20%-40% decay-corrected radiochemical yield to provide (18)F-nifrolidine specific activities of approximately 111-185 GBq/mumol. In vitro autoradiography in rat brain slices revealed selective binding of (18)F-nifrolidine to the anteroventral thalamic nucleus, ventral posteriomedial thalamus, dorsolateral geniculate, and, to a lesser extent, cortex and striata, which are known to contain alpha(4)beta(2) sites. This specific binding was completely abolished by 300 mumol/L nicotine. Ex vivo rat brain distribution studies indicated selective binding in the thalamus with a maximal thalamus-to-cerebellum ratio of approximately 3. The PET study revealed selective maximal uptake (0.01% injected dose/mL) in regions of the thalamus (anteroventral and anteromedial thalamus, ventrolateral thalamus) and extrathalamic regions such as cingulate gyrus, lateral geniculate, temporal cortex, and frontal cortex. Binding of (18)F-nifrolidine to alpha(4)beta(2) receptor-rich regions in rats and monkeys indicates promise as a PET agent. Additionally, the thalamus-to-cerebellum ratio approached a plateau of 1.7 in 120 min, indicating relatively faster kinetics compared with previously reported imaging agents.


Combined modality therapy increasing local control of pancreatic cancer.
Twenty patients with inoperable locally advanced Stage II and III pancreatic cancer were treated with combined modality therapy. Radiotherapy consisted of split courses of 2000 cGy each and, as needed, an additional 1400 cGy, separated by 2-week intervals. Simultaneous multidrug regimen chemotherapy consisted of 5-fluorouracil, continuous infusion, 1 g/m2 days 1-5; streptozotocin, 300-500 mg/m2 days 1, 2, 3; and cisplatin, 100 mg/m2 day 3 of every 4-week radiotherapy course (RT-FSP). Primary tumors decreased more than 50% in volume in 11 of 20 patients. Computed tomography scans demonstrated apparent complete disappearance of the primary tumor in 7 patients. Only 3 patients had tumor regrowth within the radiotherapy field, all after the end of radiotherapy. Local control improved as measured by increased frequency of tumor shrinkage and decreased frequency of primary tumor growth, recognizing the limitations of a pilot study and comparisons to best historical results achieved with standard short 5-fluorouracil schedules and radiotherapy. Successful local control largely eliminates the most common cause of refractory pain and may decrease the need for some forms of early palliative surgical intervention. Tumor shrinkage sometimes downstages tumors, creating frequent investigational opportunities for either elective extirpative surgery or intraoperative radiotherapy. This pilot experience also supports testing of expanded eligibility staging criteria for combined modality treatment and testing of new drugs as part of 5-fluorouracil-radiotherapy-based regimens.


Multifrequency Analysis of Single Inductive Coil Measurements Across a Gel Phantom Simulation of Internal Bleeding in the Brain.
The present study is part of an ongoing effort to develop a simple diagnostic technology for detecting internal bleeding in the brain, which can be used in lieu or in support of medical imaging and thereby reduce the cost of diagnostics in general, and in particular, would make diagnostics accessible to economically disadvantaged populations. The study deals with a single coil inductive device to be used for detecting cerebral hemorrhage. It presents a first-order experimental study that examines the predictions of our recently published theoretical study. The experimental model employs a homogeneous cylindrical phantom in which internal head bleeding was simulated by way of a fluid inclusion. We measured the changes in amplitude and phase across the coil with a network vector analyzer as a function of frequency (100-1,000 MHz), volume of blood simulating fluid, and the site of the fluid injection. We have developed a new mathematical model to statistically analyze the complex data produced in this experiment. We determined that the resolution for the fluid volume increase following fluid injection is strongly dependent on frequency as well as the location of liquid accumulation. The experimental data obtained in this study supports the predictions of our previous theoretical study, and the statistical analysis shows that the simple single coil device is sensitive enough to detect changes due to fluid volume alteration of two milliliters. Bioelectromagnetics. 2020;41:21-33 © 2019 Bioelectromagnetics Society.


Synthetic control systems for high performance gene expression in mammalian cells.
Tunable induction of gene expression is an essential tool in biology and biotechnology. In spite of that, current induction systems often exhibit unpredictable behavior and performance shortcomings, including high sensitivity to transactivator dosage and plasmid take-up variation, and excessive consumption of cellular resources. To mitigate these limitations, we introduce here a novel family of gene expression control systems of varying complexity with significantly enhanced performance. These include: (i) an incoherent feedforward circuit that exhibits output tunability and robustness to plasmid take-up variation; (ii) a negative feedback circuit that reduces burden and provides robustness to transactivator dosage variability; and (iii) a new hybrid circuit integrating negative feedback and incoherent feedforward that combines the benefits of both. As with endogenous circuits, the complexity of our genetic controllers is not gratuitous, but is the necessary outcome of more stringent performance requirements. We demonstrate the benefits of these controllers in two applications. In a culture of CHO cells for protein manufacturing, the circuits result in up to a 2.6-fold yield improvement over a standard system. In human-induced pluripotent stem cells they enable precisely regulated expression of an otherwise poorly tolerated gene of interest, resulting in a significant increase in the viability of the transfected cells.


A practical guide to medical ethics for intensivists.
This series of articles provides a practical guide to dealing with the complex ethical and legal challenges we face in the provision of Intensive Care. They explain the implications of recent legal rulings and cases (such as "Montgomery" and the tragic case of Charlie Gard), and include discussion of clinical scenarios with which we are all familiar. Each article is written by those who are not only experts in their fields, but who also deal with these issues on a day-to-day basis.


Low-threshold supercontinuum generation in semiconductor nanoribbons by continuous-wave pumping.
We report the first observation of supercontinuum (SC) generation in single semiconductor nanoribbons (NRs). By launching a continuous wave (CW) 532-nm pump light along a 200-μm-length CdS NR for waveguiding excitation, SC generation is realized with a threshold down to sub-milliwatt level, which is ~3 orders lower compared with previous CW-pumped SC generated in glass fibers. The low threshold is benefitted from the favorable material properties and waveguide geometries including high Raman gains, strong light confinement, more optical guided modes and phonon modes. Our work paves the way to low-threshold nanoscale SC sources and may find widespread applications ranging from spectroscopic analysis and biological imaging to material research.


Excess of homozygosity in the major histocompatibility complex in schizophrenia.
Genome-wide association studies (GWAS) in schizophrenia have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904 schizophrenia cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in schizophrenia cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548 schizophrenia cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case-control recessive effects (P = 8.81 × 10(-8)) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes, TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class I MHC demonstrated clear additive effects on schizophrenia risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for schizophrenia, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease.


The social defeat hypothesis of schizophrenia: an update.
According to the social defeat (SD) hypothesis, published in 2005, long-term exposure to the experience of SD may lead to sensitization of the mesolimbic dopamine (DA) system and thereby increase the risk for schizophrenia. The hypothesis posits that SD (ie, the negative experience of being excluded from the majority group) is the common denominator of 5 major schizophrenia risk factors: urban upbringing, migration, childhood trauma, low intelligence, and drug abuse. The purpose of this update of the literature since 2005 is to answer 2 questions: (1) What is the evidence that SD explains the association between schizophrenia and these risk factors? (2) What is the evidence that SD leads to sensitization of the mesolimbic DA system? The evidence for SD as the mechanism underlying the increased risk was found to be strongest for migration and childhood trauma, while the evidence for urban upbringing, low intelligence, and drug abuse is suggestive, but insufficient. Some other findings that may support the hypothesis are the association between risk for schizophrenia and African American ethnicity, unemployment, single status, hearing impairment, autism, illiteracy, short stature, Klinefelter syndrome, and, possibly, sexual minority status. While the evidence that SD in humans leads to sensitization of the mesolimbic DA system is not sufficient, due to lack of studies, the evidence for this in animals is strong. The authors argue that the SD hypothesis provides a parsimonious and plausible explanation for a number of epidemiological findings that cannot be explained solely by genetic confounding.


A novel mitochondrial protein DIP mediates E2F1-induced apoptosis independently of p53.
The transcription factor E2F1 does not only induce cell proliferation but also shows the strongest proapoptotic effect of all E2F family members as part of an antitumor safeguard mechanism. We have recently identified KIAA0767 as a novel p53-independent target of E2F1. Here, we investigated the biological function of interaction. Overexpression studies of KIAA0767, termed D(eath)-I(nducing)-P(rotein), revealed its strong proapoptotic effect. DIP greatly reduced cell viability in several in vitro systems accompanied by typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase. Endogenous DIP levels increased following E2F1 activation. Yet, inhibition of endogenous DIP function by small interfering RNA rescued p53-negative cells from E2F1-induced apoptosis, indicating that DIP is an essential mediator of the p53-independent E2F1 death pathway. Localization studies showed that DIP localizes to the mitochondria, where endogenous DIP is upregulated following E2F1 induction. These results provide new insights to the incompletely understood regulatory mechanisms of E2F1-induced apoptosis.


The challenge of defining standards of prevention in HIV prevention trials.
As new HIV prevention tools are developed, researchers face a number of ethical and logistic questions about how and when to include novel HIV prevention strategies and tools in the standard prevention package of ongoing and future HIV prevention trials. Current Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO) guidance recommends that participants in prevention trials receive 'access to all state of the art HIV risk reduction methods', and that decisions about adding new tools to the prevention package be made in consultation with 'all relevant stakeholders'. The guidance, however, leaves open questions of both process and implementation. In March 2009, the Global Campaign for Microbicides, UNAIDS and the Centers for Disease Control and Prevention convened a consultation to develop practical answers to these questions. Fifty-nine diverse participants, including researchers, ethicists, advocates and policymakers, worked to develop consensus criteria on when to include new HIV prevention tools in future trials. Participants developed a set of questions to guide decision-making, including: whether the method has been recommended by international bodies or adopted at a national level; the size of the effect and weight of the evidence; relevance to the trial population; whether the tool has been approved or introduced in the trial country; whether adding the tool might lead to trial futility; outstanding safety issues and status of the trial. Further work is needed to develop, implement and evaluate approaches to facilitate meaningful stakeholder participation in this deliberative process.


Enhanced rotation sensing by nonlinear interactions in silicon microresonators.
We analyze the effect of the nonlinear Kerr index of refraction and two-photon absorption (TPA) in a rotating silicon microring resonator coupled to waveguides in an add-drop configuration. The nonlinear index of refraction leads to a bifurcation of the intensities of two counterpropagating modes in the nonrotating state. This bifurcation also significantly enhances the intensity difference between these modes due to the Sagnac-induced frequency splitting of the modes in the rotating resonator. Although silicon resonators have a very large Kerr index, they also suffer from large TPA at telecom wavelengths. It is shown that despite TPA, the Kerr nonlinear enhancement to the rotation sensitivity is still of the order of 104. An analysis of typical detector noise indicates that a detection limit of <1 deg/h in a 1.4 mm radius resonator is achievable.


Why do people believe in a "true self"? The role of essentialist reasoning about personal identity and the self.
Why do many people come to believe that they and others have a true self? We hypothesized that this belief emerges because people routinely rely on essentialist reasoning to understand personal identity and the self. Across eight studies, we found that (a) the features that participants attributed to the true self resembled the features typically attributed to essences (e.g., immutability, informativeness, inherence; Studies 1-4); (b) endorsement of belief in true selves correlated with endorsement of other essentialist beliefs (Study 5); and (c) experimental manipulations of essentialist beliefs in domains other than the self spilled over and affected participants' endorsement of belief in true selves (Studies 6-8). These findings advance theory on the origins and functions of beliefs about the true self, suggesting that these beliefs are, in part, a specific downstream consequence of the broader tendency to explain phenomena in the world in terms of underlying essences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


A review of the federal government's health activities in response to asbestos-contaminated ore found in Libby, Montana.
Vermiculite ore is a naturally occurring fibrous mineral widely used in various consumer products, such as attic insulation, lawn and garden products, and fireproofing material. While most vermiculite ore and products do not pose a health hazard, the vermiculite mined from Libby, MT was contaminated with naturally occurring asbestos. The federal Agency for Toxic Substances and Disease Registry (ATSDR) has documented a significant number of asbestos-related deaths among Libby residents. Additionally, as part of the ongoing investigation, ATSDR has learned that this contaminated ore was shipped to hundreds of locations around the United States for processing. While the Libby mine is now closed, studies from ATSDR and elsewhere show that people who worked in the Libby mine or vermiculite processing facilities may have been exposed to hazardous levels of asbestos while the facilities were in operation. People who lived or worked near these sites also may have been exposed to asbestos if they came into contact with contaminated vermiculite. Prolonged exposure to asbestos can cause serious and life-threatening health conditions, including asbestosis, lung cancer, and mesothelioma. In response, ATSDR has initiated 10 different activities to help evaluate the potential health effects among Libby residents and populations throughout the United States who might have been exposed to the asbestos-contaminated ore found in Montana. Some of these activities include conducting environmental exposure evaluations, health statistics reviews, community screenings, and disease-specific surveillance. This article presents the various follow-up activities that have been conducted to date by ATSDR and partnering state health departments.


How musical training affects cognitive development: rhythm, reward and other modulating variables.
Musical training has recently gained additional interest in education as increasing neuroscientific research demonstrates its positive effects on brain development. Neuroimaging revealed plastic changes in the brains of adult musicians but it is still unclear to what extent they are the product of intensive music training rather than of other factors, such as preexisting biological markers of musicality. In this review, we synthesize a large body of studies demonstrating that benefits of musical training extend beyond the skills it directly aims to train and last well into adulthood. For example, children who undergo musical training have better verbal memory, second language pronunciation accuracy, reading ability and executive functions. Learning to play an instrument as a child may even predict academic performance and IQ in young adulthood. The degree of observed structural and functional adaptation in the brain correlates with intensity and duration of practice. Importantly, the effects on cognitive development depend on the timing of musical initiation due to sensitive periods during development, as well as on several other modulating variables. Notably, we point to motivation, reward and social context of musical education, which are important yet neglected factors affecting the long-term benefits of musical training. Further, we introduce the notion of rhythmic entrainment and suggest that it may represent a mechanism supporting learning and development of executive functions. It also hones temporal processing and orienting of attention in time that may underlie enhancements observed in reading and verbal memory. We conclude that musical training uniquely engenders near and far transfer effects, preparing a foundation for a range of skills, and thus fostering cognitive development.