Proteomic identification of CIB1 as a potential diagnostic factor in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC), among the most common malignancies worldwide, remains a major threat to public health, and there is an urgent need to identify novel biomarkers for diagnosis, prognosis and targets for anti-cancer treatment. In this study, two-dimensional polyacrylamide gel electrophoresis coupled with ESI-Q-TOF MS/MS analysis was used to identify differentially expressed proteins among the HCC tumour centre, tumour margin and nontumourous liver tissues. In total, 52 spots with significant alteration were positively identified byMS/MSanalysis. Altered expression of representative proteins, including CIB1, was validated by Western blotting. Immunostaining suggested an increase tendency of CIB1 expression from nontumourous liver tissue to tumour centre. Knockdown of CIB1 expression by RNA interference led to the significant suppression of the cell growth in hepatoma HepG2 cells. These data suggest that CIB1 may be used as a novel prognostic factor and possibly an attractive therapeutic target for HCC.


Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.
Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells.


Microwave stabilization enhances immunocytochemical detection of estrogen receptor in frozen sections of macaque oviduct.
We have found that microwave (MW) stabilization greatly improves detection of the estrogen receptor (ER) in frozen sections of rhesus monkey oviduct by immunocytochemistry (ICC). Fresh samples of fimbriae were MW-irradiated, frozen, and then cryosectioned. The frozen sections were also MW-treated and then fixed in a paraformaldehyde-based fixative before ICC processing. A parallel set of samples from each monkey were frozen, sectioned and processed for ICC without any MW treatment. MW stabilization clearly increased immunostaining intensity with either of two ER-specific monoclonal antibodies, namely, H222 and 1D5. The greatest increase was noted in tissues collected from spayed or progesterone-treated animals. An antibody dilution series indicated that MW stabilization increased the sensitivity approximately 20- to 40-fold. In addition, we incubated spayed macaque fimbriae at 4 C in the presence of 10 nM [3H]Moxestrol and then either froze the tissues immediately (non-MW) or treated them with MW. Slide-mounted cryosections of non-MW and MW-treated tissue were then incubated with either a Tris-EDTA buffer (low salt) or the same buffer containing 4 M KCl (high salt). The quantity of [3H]Moxestrol-occupied ER extracted from the frozen sections by each buffer was determined by a sucrose gradient shift assay. The low salt buffer extracted significantly more radiolabeled ER from non-MW sections than from MW-treated sections (P < 0.01), whereas the high salt buffer extracted equal amounts of ER from both the MW-treated and non-MW sections. MW-irradiation enhanced ICC detectability of ER in frozen sections by greatly reducing the amount of ER extracted during the various washes used during normal ICC processing.


Prevalence and abundance of selected genes conferring macrolide resistance genes in COPD patients during maintenance treatment with azithromycin.
Maintenance treatment with macrolide antibiotics has shown to be effective in reducing exacerbations in COPD patients. A major concern with prolonged treatment with antibiotics is the development of bacterial resistance. In this study we determined the effect of azithromycin on the development and acquisition of resistance to macrolides in the nasopharyngeal flora in COPD patients. This study was part of the COLUMBUS trial, a randomised, double-blind, placebo-controlled trial to measure the effect of maintenance treatment with azithromycin in 92 COPD patients on the exacerbation rates during a 12-month period. In order to determine resistance to macrolides, we used a targeted metagenomic approach to measure the presence and relative abundance of specific macrolide resistance genes ermB, ermF and mefA in throat samples collected at different time-points during this 12-month period. There was no increased risk for acquisition of macrolide resistance genes in the azithromycin group compared to the placebo group in COPD patients. However, loss of the macrolide resistance gene ermB was increased overtime in the placebo treated group compared to the azithromycin group (n = 5 for the placebo group versus n = 0 for the azithromycin group at 12 months; p = 0.012). The change in relative abundance of the three macrolide-resistance genes showed that all but one (ermF) increased during treatment with azithromycin. The acquisition rate of macrolide resistance genes in COPD patients treated with azithromycin maintenance therapy was limited, but the relative abundance of macrolide resistance genes increased significantly over time compared to placebo. This study was part of the COLUMBUS trial ( Clinicaltrials.gov , NCT00985244 ).


The structure and organization of lanceolate mechanosensory complexes at mouse hair follicles.
In mouse hairy skin, lanceolate complexes associated with three types of hair follicles, guard, awl/auchene and zigzag, serve as mechanosensory end organs. These structures are formed by unique combinations of low-threshold mechanoreceptors (LTMRs), Aβ RA-LTMRs, Aδ-LTMRs, and C-LTMRs, and their associated terminal Schwann cells (TSCs). In this study, we investigated the organization, ultrastructure, and maintenance of longitudinal lanceolate complexes at each hair follicle subtype. We found that TSC processes at hair follicles are tiled and that individual TSCs host axonal endings of more than one LTMR subtype. Electron microscopic analyses revealed unique ultrastructural features of lanceolate complexes that are proposed to underlie mechanotransduction. Moreover, Schwann cell ablation leads to loss of LTMR terminals at hair follicles while, in contrast, TSCs remain associated with hair follicles following skin denervation in adult mice and, remarkably, become re-associated with newly formed axons, indicating a TSC-dependence of lanceolate complex maintenance and regeneration in adults. DOI: http://dx.doi.org/10.7554/eLife.01901.001.


School Victimization, Immigration, Dropping Out, and Gender Disparities.
The children of immigrants face a number of educational hurdles, such as disparate rates of victimization and increased risk of dropping out of high school. Few studies have explored how school victimization can explain the relationship between immigrant generation status and the likelihood of dropping out. The current study explores if, and how, the associations between school victimization, feeling unsafe at school, and dropping out vary across immigration generations andgender. Data are drawn from the Educational Longitudinal Study of 2002. The sample for this study consists of 9,870 first (N = 1,170, 12%), second (N = 1,540, 16%), and third-plus (N = 7,160, 73%) generation, female (N = 5,050; 51%), and male (4,820; 49%) students in 580 public schools. Results indicate partial support for segmented assimilation and highlight important nuances related to immigrant generation status.in relation to key variables. For both males and females, generational status, victimization, and feeling unsafe at school significantly influence the likelihood (positively and negatively) of dropping out. In regard to school victimization, first generation females are less likely to drop out than third-plus generation females. For males, victimization at school generally decreases their likelihood of dropping out, except for second generation males who have an increased likelihood of dropping out. Females who feel unsafe are generally more likely to drop out, with no significant differences across generations. For males, feeling unsafe at school generally increases the likelihood of dropping out, except for second generation males who have a decreased likelihood of dropping out.


Oxidative stress in Cyprinus carpio to analyze microcystin impact in eutrophic shallow lakes: a preliminary study.
Microcystins (MCYSTs) are toxins produced by cyanobacteria in aquatic environment and are of high potential risk to aquatic organisms. The physiological responses and pathobiological developments that they elicit in fish have been extensively studied, mainly through acute toxicity experiments. This study was designed to examine the seasonal fluctuation of biochemical markers of oxidative stress in different tissues of a natural population of Cyprinus carpio inhabiting a shallow Mediterranean lake, along with the respective MCYSTs concentrations in blood and tissues at environmentally relevant MCYSTs values. MCYSTs content was assessed in liver, kidney, intestine, brain and muscle along with the MCYSTs in lake water and scum applying ELISA technique. Catalase activity, GSH/GSSH relative concentrations and lipid peroxidation were used as biochemical markers. Our results suggest that common carp of Lake Pamvotis exposed to naturally fluctuating concentrations of MCYST in water and scum contained stably high MCYST concentrations in all tissues that might pose a threat to public health. Liver and kidney were the primary target organs. Tissue concentrations did not correlate with the response of any of the elements of the antioxidant defence system. Hepatic catalase, GSH content and TBARS in all tissues tested followed the fluctuations of major limnological parameters, i.e. water temperature and oxygen concentration, chlorophyll-a, MCYST in water and scum, suggesting that they should be cautiously used to monitor exposure to MCYSTS in natural freshwater ecosystems.


Long term prospective of the Seine River system: confronting climatic and direct anthropogenic changes.
To explore the evolution of a human impacted river, the Seine (France), over the 21st century, three driving factors were examined: climate, agriculture, and point source inputs of domestic and industrial origin. Three future scenarios were constructed, by modification of a baseline representative of recent conditions. A climate change scenario, based on simulations by a general circulation model driven by the SRES-A2 scenario of radiative forcing, accounts for an average warming of +3.3 degrees C over the watershed and marked winter increase and summer decrease in precipitation. To illustrate a possible reduction in nitrate pollution from agricultural origin, a scenario of good agricultural practices was considered, introducing catch crops and a 20% decrease in nitrogen fertilisation. Future point source pollution was estimated following the assumptions embedded in scenario SRES-A2 regarding demographic, economic and technologic changes, leading to reductions of 30 to 75% compared to 2000, depending on the pollutants. Four models, addressing separate components of the river system (agronomical model, hydrogeological model, land surface model and water quality model), were used to analyse the relative impact of these scenarios on water quality, in light of their impact on hydrology and crop production. The first-order driving factor of water quality over the 21st century is the projected reduction of point source pollution, inducing a noticeable decrease in eutrophication and oxygen deficits downstream from Paris. The impact of climate change on these terms is driven by the warming of the water column. It enhances algal growth in spring and the loss factors responsible for phytoplankton mortality in late summer (grazers and viruses). In contrast, increased seasonal contrasts in river discharge have a negligible impact on river water quality, as do the changes in riverine nitrate concentration, which never gets limiting. The latter changes have a similar magnitude under the three scenarios. Under climate change, riverine and groundwater nitrate concentrations increase and crop production is advantaged with reduced growing cycles and increased yields. In contrast, nitrate concentrations decrease under the good agricultural practices scenario, with a limited decrease in crop production. When these two scenarios are combined, the changes in nitrate concentrations balance each other and crop yields increase. The results of this numerical exercise indicate that the potential changes to the Seine River system during the 21st century will not lead to severely degraded water quality.


[Clinical features of acute hepatitis A in recent two years].
The purpose of this study was to characterize the clinical features of acute hepatitis A in Seoul and Gyeonggi province during the recent 2 years. We reviewed the medical records of 222 patients who were diagnosed as acute hepatitis A between August 2005 and March 2007 at the Konkuk University Hospital and Korea University, Ansan Hospital. The clinical manifestation, serological tests, and image findings were analyzed. Median age of the patients was 28.1 years and the age groups of highest incidence were the second and third decade. The frequent symptoms were anorexia (66.4%), fatigue (49.2%), fever (47.7%), and abdominal discomfort (42.5%). Fourteen cases (6.3%) showed renal insufficiency, and hemodialysis was performed in one. Cholestatic hepatitis in 2 cases, relapsing hepatitis in 4 cases and prolonged hepatitis in 13 cases were observed. However, there was no case of fulminant hepatitis or death. The underlying diseases including chronic hepatitis B, diabetes mellitus and thyroid disorder did not affect the disease severity of hepatitis A. IgM anti-HAV was not detected initially in 6.7% of the patients. Anti-HEV (IgM) was detected simultaneously in 3 of 150 patients. The age of patients with acute hepatitis A has been increased in the recent years. Most patients recovered uneventfully. However, unusual patterns of severe hepatitis and renal insufficiency occurred in considerable number of cases. Follow-up serologic test for IgM anti-HAV is needed in seronegative cases with hepatitis A.


New surgical instrumentation reduces the revision rate of unicompartmental knee replacement: A propensity score matched comparison of 15,906 knees from the National Joint Registry.
Unicompartmental knee replacement (UKR) offers advantages over total knee replacement but has higher revision rates. New instrumentation known as Microplasty was introduced to address this. The aim was to compare the revision rates of UKRs implanted with Microplasty and traditional instrumentation (Non-Microplasty). National Joint Registry (NJR) data was used to propensity score match 15,906 UKRs (7953 Microplasty and 7953 Non-Microplasty) for important patient, implant and surgical factors. Implant survival rates were determined using the Kaplan-Meier method and compared using Cox regression models in a multilevel model. The five-year implant survival for Microplasty and Non-Microplasty UKRs were 96.7% (95% CI: 96.0%-97.2%) and 94.5% (CI: 93.8-95.1%), respectively. The revision rate for Microplasty UKR was significantly lower than that of Non-Microplasty UKRs (hazard ratio [HR] = 0.77, p = 0.008). Compared with Non-Microplasty UKRs, the revision rate of Microplasty UKRs implanted during the year after the introduction of Microplasty was lower, but the difference was not significant (HR: 0.86, CI: 0.67-1.10, p = 0.23), whereas for those implanted more than a year after introduction, the difference was significant (HR: 0.69, CI: 0.54-0.89, p = 0.004). The use of Microplasty instrumentation has resulted in an improved five-year UKR survival. Microplasty UKR implanted during the first year after introduction had a small, non-significant decrease in revision rate. As the revision rate did not increase, this suggests that there is no adverse learning curve effect. Microplasty UKRs implanted after this transition period had a revision rate 31% lower than the Non-Microplasty group. II.


Uncemented cups with and without screw holes in primary THA: a Swedish Hip Arthroplasty Register study with 22,725 hips.
Background and purpose - Uncemented cups in total hip arthroplasty (THA) are often augmented with additional screws to enhance their primary stability. We investigated whether there is a difference in the risk for revision between cups with screw holes and cups without screw holes. Patients and methods - We analyzed the risk for cup revision of uncemented cups registered in the Swedish Hip Arthroplasty Register (SHAR) between 2000 and 2017 with respe ct to the presence of screw holes. Only patients with primary osteoarthritis (OA) were included. 22,725 cups, including 12,354 without screw holes and 10,371 with screw holes, were evaluated. Revision rates at 2 and 10 years after the primary operation were analyzed. Results - At a median follow-up time of 3.4 years (0-18), 459 cup revisions were reported. The main reasons for cup revision during the whole observation time were infection, 52% of all cup revisions, and dislocation, 26% of all cup revisions. The survival rate with cup revision due to aseptic loosening as endpoint was 99.9% (95% CI 99.8-99.9) at 2 years for both cups with and cups without screw holes, and the survival rates at 10 years were 99.5% (CI 99.3-99.7) and 99.1% (CI 98.6-99.5), respectively. Cups without screw holes showed a decreased risk of revision due to any reason at both 2 years (adjusted hazard ratio [HR] 0.6, CI 0.5-0.8) and 10 years (HR 0.7, CI 0.5-0.9). Interpretation - We found a very low revision rate for aseptic loosening with modern, uncemented cup designs. Cups with screw holes had an increased risk of revision due to any reason in patients with primary OA.


Evaluation of the clinical profile, laboratory parameters and outcome of two hundred COVID-19 patients from a tertiary centre in India.
COVID-19 is a pandemic with over 5 million cases worldwide. The disease has imposed a huge burden on health resources. Evaluation of clinical and epidemiological profiles of such patients can help in understanding and managing the outbreak more efficiently. This study was a prospective observational analysis of 200 diagnosed COVID-19 patients admitted to a tertiary care center from 20th march to 8th May 2020. All these patients were positive for COVID-19 by an oro-nasopharyngeal swab-rtPCR based testing. Analyses of demographic factors, clinical characteristics, comorbidities, laboratory parameters, and the outcomes were performed. The mean age of the population was 40 years with a slight male predominance (116 patients out of 200, 58%). A majority of the patients (147, 73.5 %) were symptomatic, with fever being the most common symptom (109, 54.5%), followed by cough (91, 45.5%). An older age, presence of symptoms and their duration, leukocytosis, a high quick SOFA score, a high modified SOFA score, need for ventilator support, an AST level more than 3 times the upper limit of normal (ULN), and a serum creatinine level of 2 mg/dl or greater were at a significantly higher risk of ICU admission and mortality. Presence of diabetes mellitus, AST > three times ULN, serum creatinine 2 mg/dl or higher, and a qSOFA score of 1 or higher were all associated with significantly greater odds of critical care requirement. Triage and severity assessment helps in deciding the requirement for a hospital stay and ICU admission for COVID-19 which can easily be done using clinical and laboratory parameters. A mild, moderate and severe category approach with defined criteria and treatment guidelines will help in judicious utilization of health-care resources, especially for developing countries like India. *Other members of the Safdarjung Hospital COVID-19 working group: Balvinder Singh (Microbiology), MK Sen (Pulmonary Medicine), Shibdas Chakrabarti (Pulmonary Medicine), NK Gupta (Pulmonary medicine), AJ Mahendran (Pulmonary Medicine), Ramesh Meena (Medicine), G Usha (Anaesthesiology), Santvana Kohli (Anaesthesiology), Sahil Diwan (Anaesthesiology), Rushika Saksena (Microbiology), Vikramjeet Dutta (Microbiology), Anupam Kr Anveshi (Microbiology).


Design of multishell sampling schemes with uniform coverage in diffusion MRI.
In diffusion MRI, a technique known as diffusion spectrum imaging reconstructs the propagator with a discrete Fourier transform, from a Cartesian sampling of the diffusion signal. Alternatively, it is possible to directly reconstruct the orientation distribution function in q-ball imaging, providing so-called high angular resolution diffusion imaging. In between these two techniques, acquisitions on several spheres in q-space offer an interesting trade-off between the angular resolution and the radial information gathered in diffusion MRI. A careful design is central in the success of multishell acquisition and reconstruction techniques. The design of acquisition in multishell is still an open and active field of research, however. In this work, we provide a general method to design multishell acquisition with uniform angular coverage. This method is based on a generalization of electrostatic repulsion to multishell. We evaluate the impact of our method using simulations, on the angular resolution in one and two bundles of fiber configurations. Compared to more commonly used radial sampling, we show that our method improves the angular resolution, as well as fiber crossing discrimination. We propose a novel method to design sampling schemes with optimal angular coverage and show the positive impact on angular resolution in diffusion MRI.


Isolation of oviposition pheromone from the eggs of the sandfly Lutzomyia longipalpis.
Semiochemical components of eggs of the sandfly Lutzomyia longipalpis (Diptera: Psychodidae) were separated by high performance liquid chromatography. HPLC fractions were examined quantitatively and qualitatively by gas chromatography (GC). A bioassay was used to determine the oviposition attraction of gravid L. longipalpis to each of the fractions separately and a peak responsible for the semiochemical activity was identified. Gravid flies were placed in individual oviposition tubes to determine if the peak of interest was an oviposition stimulant. The active semiochemical fraction attracted gravid flies for oviposition. Furthermore, egg laying was enhanced: gravid flies exposed to the pheromone oviposited earlier and laid more eggs than control flies. GC analysis indicated that 1200 eggs (2 days old) gave a yield of 12.75 micrograms of active pheromone. This fraction had similar HPLC and GC retention times to caryophyllene oxide, suggesting comparable polarity and molecular weight.


Valorisation of xylose to renewable fuels and chemicals, an essential step in augmenting the commercial viability of lignocellulosic biorefineries.
Biologists and engineers are making tremendous efforts in contributing to a sustainable and green society. To that end, there is growing interest in waste management and valorisation. Lignocellulosic biomass (LCB) is the most abundant material on the earth and an inevitable waste predominantly originating from agricultural residues, forest biomass and municipal solid waste streams. LCB serves as the renewable feedstock for clean and sustainable processes and products with low carbon emission. Cellulose and hemicellulose constitute the polymeric structure of LCB, which on depolymerisation liberates oligomeric or monomeric glucose and xylose, respectively. The preferential utilization of glucose and/or absence of the xylose metabolic pathway in microbial systems cause xylose valorization to be alienated and abandoned, a major bottleneck in the commercial viability of LCB-based biorefineries. Xylose is the second most abundant sugar in LCB, but a non-conventional industrial substrate unlike glucose. The current review seeks to summarize the recent developments in the biological conversion of xylose into a myriad of sustainable products and associated challenges. The review discusses the microbiology, genetics, and biochemistry of xylose metabolism with hurdles requiring debottlenecking for efficient xylose assimilation. It further describes the product formation by microbial cell factories which can assimilate xylose naturally and rewiring of metabolic networks to ameliorate xylose-based bioproduction in native as well as non-native strains. The review also includes a case study that provides an argument on a suitable pathway for optimal cell growth and succinic acid (SA) production from xylose through elementary flux mode analysis. Finally, a product portfolio from xylose bioconversion has been evaluated along with significant developments made through enzyme, metabolic and process engineering approaches, to maximize the product titers and yield, eventually empowering LCB-based biorefineries. Towards the end, the review is wrapped up with current challenges, concluding remarks, and prospects with an argument for intense future research into xylose-based biorefineries.


Epidermal growth factor receptor blockers for the treatment of ovarian cancer.
This is an update of a previously published version of the review (Issue 10, 2011).Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer death among women worldwide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy. Between 55% and 75% of women who respond to first-line therapy experience relapse within two years. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Improved understanding about the molecular basis of EOC has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anti-EGFR antibodies. To compare the effectiveness and harmful effects of interventions that target the epidermal growth factor receptor in the treatment of epithelial ovarian cancer (EOC). We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2010, Issue 4), MEDLINE, and Embase up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field. This update includes further searches up to September 2017. Randomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven EOC. Two review authors independently abstracted data, assessed risk of bias, and performed GRADE assessment. From 6105 references obtained through the literature search and an additional 15 references derived from grey literature searches, we identified seven RCTs that met our inclusion criteria and included 1725 participants. Trial results show that after first-line chemotherapy is provided, maintenance treatment with erlotinib (EGFR tyrosine kinase inhibitor (TKI)) probably makes little or no difference in overall survival (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.81 to 1.20; one study; 835 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 1.05, 95% CI 0.90 to 1.23; one study; 835 participants; very low-certainty evidence). Less than 50% of participants provided quality of life data, and study authors reported these results incompletely. The certainty of evidence is very low, but treatment may reduce quality of life compared to observation.Treatment with an EGFR TKI (vandetanib) for women with relapsed EOC may make little or no difference in overall survival (HR 1.25, 95% CI 0.80 to 1.95; one study; 129 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 0.99, 95% CI 0.69 to 1.42; one study; 129 participants; very low-certainty evidence). In treating patients with relapse, giving EGFR TKI may slightly increase some toxicities, such as severe rash (risk ratio (RR) 13.63, 95% CI 0.78 to 236.87; one study; 125 participants; very low-certainty evidence). Quality of life data were not available for meta-analysis.Anti-EGFR antibody treatment in relapsed EOC may or may not make a difference to overall survival (HR 0.93, 95% CI 0.74 to 1.18; four studies; 658 participants; moderate-certainty evidence) and may or may not have any effect on progression-free survival (HR 0.90, 95% CI 0.70 to 1.16; four studies; 658 participants; low-certainty evidence). Anti-EGFR antibody treatment may or may not increase side effects, including severe nausea and/or vomiting (RR 1.27, 95% CI 0.56 to 2.89; three studies; 503 participants; low-certainty evidence), severe fatigue (RR 1.06, 95% CI 0.66 to 1.73; I² = 0%; four studies; 652 participants; low-certainty evidence), and hypokalaemia (RR 2.01, 95% CI 0.80 to 5.06; I² = 0%; three studies; 522 participants; low-certainty evidence). Severe diarrhoea rates were heterogeneous across studies (RR 2.87, 95% CI 0.59 to 13.89; four studies; 652 participants; low-certainty evidence), and subgroup analysis revealed that severe diarrhoea was more likely with pertuzumab (RR 6.37, 95% CI 1.89 to 21.45; I² = 0%; three studies; 432 participants; low-certainty evidence) than with seribantumab treatment (RR 0.38, 95% CI 0.07 to 2.23; I² = 0%; one study; 220 participants; very low-certainty evidence). Quality of life data were incompletely reported, and we were unable to combine them in a meta-analysis. Current evidence suggests that an anti-EGFR single-agent biological treatment (EGFR TKI or anti-EGFR antibody) makes little or no difference to survival, either as maintenance treatment after first-line chemotherapy or in association with chemotherapy in recurrent cancer. Anti-EGFR therapy may increase some side effects and may or may not reduce quality of life.


Characterization of a laboratory model of computer mouse use - applications for studying risk factors for musculoskeletal disorders.
In the present study, we assessed the wrist kinetics (range of motion, mean position, velocity and mean power frequency in radial/ulnar deviation, flexion/extension, and pronation/supination) associated with performing a mouse-operated computerized task involving painting rectangles on a computer screen. Furthermore, we evaluated the effects of the painting task on subjective perception of fatigue and wrist position sense. The results showed that the painting task required constrained wrist movements, and repetitive movements of about the same magnitude as those performed in mouse-operated design tasks. In addition, the painting task induced a perception of muscle fatigue in the upper extremity (Borg CR-scale: 3.5, p<0.001) and caused a reduction in the position sense accuracy of the wrist (error before: 4.6 degrees , error after: 5.6 degrees , p<0.05). This standardized painting task appears suitable for studying relevant risk factors, and therefore it offers a potential for investigating the pathophysiological mechanisms behind musculoskeletal disorders related to computer mouse use.


[Average life expectancy in Switzerland--historic and international background and thoughts on future development].
Age-specific mortality rates are a sensitive measure for the conditions of life in a population. Life tables--in Switzerland calculated approximately all ten years since 1876/80--indicate for any age and any observation period the mean life expectancy as well as the probabilities of death and survival, respectively. In the past centuries survival curves developed more and more a rectangular shape, but mortality rates didn't decrease uniformly in all age groups: until the first part of the twentieth century, increases in mean life expectancy were predominantly due to a rapid decline of infant and children's mortality; since the 1930s decreasing adults' mortality gained more importance, and not until the 1960s lower death rates in the population aged over 60 became a major component of prolonging the mean span of life. The nowadays favourable mortality situation of Switzerland within Europe started to emerge in the 1950s, predominantly due to declining mortality rates in the uppermost age groups. For the decades to come, experts predict a further substantial increase of mean life expectancy, in spite of actually rather unfavourable trends in the mortality rates of young adults. Consequently, the number of those aged over 65 and particularly those over 80 years will considerably increase till 2020, even if the scenarios of 1995 would prove to be too optimistic.


Feasibility and Preliminary Efficacy of an Occupational Therapy Intervention for Older Adults With Chronic Conditions in a Primary Care Clinic.
Occupational therapy can play a role in primary care management of chronic diseases among older adults. To assess the feasibility of delivering a primary care occupation-focused intervention (Integrated PRimary care and Occupational therapy for Aging and Chronic disease Treatment to preserve Independence and Functioning, or i-PROACTIF) for older adults with chronic disease. Feasibility study comparing i-PROACTIF with complex care management using a two-group randomized controlled trial design with data gathered at baseline and during and after the 8-wk intervention. Family medicine clinic serving an urban, low-income, working-class community. Feasibility indicators were recruitment, retention, utility of clinical assessments, and acceptability of interventions assessed through feedback surveys completed by patients and primary care providers (PCPs). Patient outcomes, including perspectives on chronic illness care, occupational performance, and overall well-being, were collected using standardized, validated measures and analyzed descriptively. Eighteen adult volunteers, ages ≥50 yr, with heart disease, arthritis, and uncontrolled diabetes completed the study. Ten PCPs completed feedback surveys. i-PROACTIF focuses on preserving functional independence, is based on the Person-Environment-Occupation framework, and consists of two assessment sessions and six weekly treatment sessions. Recruitment goals were achieved, with an 86% retention rate. Clinical measures unearthed deficits in areas that were unreported or underreported by patients. Participants reported being extremely satisfied with the intervention. Physicians and nurses also supported the intervention. Both groups showed improved scores on most outcomes. Delivering and evaluating i-PROACTIF was feasible and acceptable. Future efficacy trials are needed before it can be used in clinical settings. The results of this study can inform future occupational therapy interventions and clinical trials in primary care for older adults with chronic conditions.


Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40.
The RNA-binding protein Roquin is required to prevent autoimmunity. Roquin controls T-helper cell activation and differentiation by limiting the induced expression of costimulatory receptors such as tumor necrosis factor receptor superfamily 4 (Tnfrs4 or Ox40). A constitutive decay element (CDE) with a characteristic triloop hairpin was previously shown to be recognized by Roquin. Here we use SELEX assays to identify a novel U-rich hexaloop motif, representing an alternative decay element (ADE). Crystal structures and NMR data show that the Roquin-1 ROQ domain recognizes hexaloops in the SELEX-derived ADE and in an ADE-like variant present in the Ox40 3'-UTR with identical binding modes. In cells, ADE-like and CDE-like motifs cooperate in the repression of Ox40 by Roquin. Our data reveal an unexpected recognition of hexaloop cis elements for the posttranscriptional regulation of target messenger RNAs by Roquin.


A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1.
Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by the insulin receptor permits this docking protein to interact with signaling proteins that promote insulin action. Serine phosphorylation uncouples IRS-1 from the insulin receptor, thereby inhibiting its tyrosine phosphorylation and insulin signaling. For this reason, there is great interest in identifying serine/threonine kinases for which IRS-1 is a substrate. Tumor necrosis factor (TNF) inhibited insulin-promoted tyrosine phosphorylation of IRS-1 and activated the Akt/protein kinase B serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase (PI 3-kinase). The effect of TNF on insulin-promoted tyrosine phosphorylation of IRS-1 was blocked by inhibition of PI 3-kinase and the PTEN tumor suppressor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Akt impaired insulin-promoted IRS-1 tyrosine phosphorylation. Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt. Inhibition of IRS-1 tyrosine phosphorylation by TNF was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), a downstream target of Akt. mTOR induced the serine phosphorylation of IRS-1 (Ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that TNF impairs insulin signaling through IRS-1 by activation of a PI 3-kinase/Akt/mTOR pathway, which is antagonized by PTEN.


Treatment and outcome of traumatic endophthalmitis in open globe injury with retained intraocular foreign body.
Our aim was to evaluate the incidence, risk factors, pathogens, use of systemic and intravitreal antibiotics, and outcome of traumatic endophthalmitis after open globe injury with retained intraocular foreign body (RIOFB). Patients with open globe injury and RIOFB complicated by endophthalmitis were enrolled and retrospectively studied in Taiwan over a 20-year-period from 1981 to 2002. There were 125 patients, who sustained open globe injury and RIOFB, which required surgical management. In 15 patients (12%) traumatic endophthalmitis was identified. Thirteen (87%) of these 15 cases had signs of endophthalmitis at their initial presentation. The patients' mean age was 41 years; all of them were male. Invading micro-organisms were isolated in 8 patients, and the positive culture rate was 53%. Gram-negative bacteria were the most commonly isolated organisms in 6 patients and 1 eye with multiple organisms. One eye with culture-proven Bacillus cereus had a very fulminant course and ended with phthisis bulbi. All 15 patients received topical and systemic intravenous antibiotic treatment; 9 eyes (60%) were given intravitreal antibiotic injection with broad-spectrum combined vancomycin and ceftazidime in 5 eyes. Pars plana vitrectomy was performed in 9 patients, with successful removal of RIOFB. The final visual acuity improved in 8 patients (53.5%), was unchanged in 1 (6.7%) and worse in 6 (40.0%). Five patients (33%) got a visual outcome of 6/60 or better. There were also 5 patients (33%) with a poor outcome of no light perception. Eleven (73%) of 15 patients had treatment delayed for >24 h after injury, and 5 out of these 11 patients had a very poor visual outcome (1 hand motion, 4 no light perception). Delay of presentation for >24 h after injury was associated with a tendency to increased risk of endophthalmitis [11/71 (15.5%) vs. 4/54 (7.4%)]. Early intravitreal antibiotics and prompt vitrectomy to remove the contaminating IOFB may salvage useful vision in some patients with traumatic endophthalmitis with RIOFB. Delay of treatment for >24 h was associated with increased risk of traumatic endophthalmitis.


An evaluation of the effectiveness of oral iron therapy in hemodialysis patients receiving recombinant human erythropoietin.
Iron balance is critical for adequate erythropoiesis in hemodialysis patients treated with recombinant human erythropoietin (EPO). The role of oral iron therapy in maintaining or replenishing iron stores has not yet been well defined in such patients. We undertook a double-blind, placebo-controlled study to evaluate the efficacy of oral iron in 49 hemodialysis patients, divided into two groups, based on adequate or deficient iron stores. These groups were treated for 3 months with 150 mg elemental iron (Polysaccharide complex, Central Pharmaceuticals) or placebo, twice daily. Laboratory parameters were followed for five months. These parameters included: hematocrit (Hct), ferritin, transferrin saturation (Tsat), and zinc protoporphyrin (ZPP). A side-effects questionnaire was recorded monthly. Our results indicate that iron replete patients show evidence of falling iron stores during the study period; this observation was identical in both oral iron and placebo subgroups. Iron deficient patients had a significantly greater drop-out rate due to side effects when compared to iron replete patients (33% vs. 8%), despite equivalent responses to the side-effect questionnaire. We conclude: 1) Oral iron fails to maintain iron stores in iron replete patients; 2) Iron deficiency observed in this study may be due to poor medication compliance rather than side-effects.


Antihyperlipidemic and anti-hyperglycemic effects of Cymbopogon jwarancusa in high-fat high-sugar diet model.
Hyperlipidemia is the root cause for development of atherosclerosis, coronary heart disease, diabetes mellitus, obesity, hypertension and cerebral palsy. Cymbopogon jwarancusa is an aromatic grass (Rusha grass, khavi grass) belonging to family Poaceaea. C. jwarancusa essential oil is famous for its use in perfumery, soaps cosmetics, detergents, medicine and pharmaceuticals. The anti-pyretic, anti-fungal, antibacterial, anti-oxidant and cytotoxic activities of C. jwarancusa have been reported in literature. In the present study different doses of C. jwarancusa extract have been investigated for anti-hyperlipidemic and anti-hyperglycemic activities in high-fat high sugar diet model in rats. Hyperlipidemia and hyperglycemia were assessed by measuring body weight, serum lipid profile and fasting blood glucose levels. Administration of ethanol leaves extract of C. jwarancusa exhibited significant dose-dependent reduction in body weight, lipid parameters and blood sugar levels. Hence it may be concluded that C. jwarancusa aids in ameliorating hyperlipidemic, hyperglycemic conditions and has potential to reduce the risk of cardiovascular problems.


Distinct mechanisms of neurodegeneration induced by chronic complex I inhibition in dopaminergic and non-dopaminergic cells.
Chronic mitochondrial dysfunction, in particular of complex I, has been strongly implicated in the dopaminergic neurodegeneration in Parkinson's disease. To elucidate the mechanisms of chronic complex I disruption-induced neurodegeneration, we induced differentiation of immortalized midbrain dopaminergic (MN9D) and non-dopaminergic (MN9X) neuronal cells, to maintain them in culture without significant cell proliferation and compared their survivals following chronic exposure to nanomolar rotenone, an irreversible complex I inhibitor. Rotenone killed more dopaminergic MN9D cells than non-dopaminergic MN9X cells. Oxidative stress played an important role in rotenone-induced neurodegeneration of MN9X cells, but not MN9D cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and antioxidants decreased rotenone toxicity only in MN9X cells. MN9X cells were also more sensitive to exogenous oxidants than MN9D cells. In contrast, disruption of bioenergetics played a more important role in MN9D cells: rotenone decreased mitochondrial membrane protential and ATP levels in MN9D cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-beta-hydroxybutyrate, decreased rotenone toxicity in MN9D cells, but not in MN9X cells. MN9D cells were also more susceptible to disruption of oxidative phosphorylation or glycolysis than MN9X cells. These findings indicate that, during chronic rotenone exposure, MN9D cells die primarily through mitochondrial energy disruption, whereas MN9X cells die primarily via oxidative stress. Thus, intrinsic properties of individual cell types play important roles in determining the predominant mechanism of complex I inhibition-induced neurodegeneration.


Doctors' and nurses' explanations for racial disparities in medical treatment.
Racial inequality in medical treatment is a problem whose sources are not fully understood. To gain better insight into how race may affect treatment, semi-structured interviews were conducted with 26 doctors and nurses. Using an open coding scheme, the explanations of racial inequality in treatment were coded by two people. Four major categories of responses emerged to explain why Black patients are less likely to receive the same levels of medical care as Whites: access to care, physician bias, Black patients' perceived shortcomings, and White patients' demands. Interviewees commonly cited access and patient factors before naming physician bias. The majority questioned the validity of studies reporting disparities. Educational campaigns should emphasize evidence that racial disparities persist even after controlling for factors such as insurance and patient characteristics. Educational programs should also address subconscious racial bias and how it may operate in a clinical setting.


Dual-Task Effect on Gait in Healthy Adolescents: Association between Health-Related Indicators and DT Performance.
The purpose of this study was to determine how dual-task (DT) effect on gait differs among adolescents with different fitness and health profiles. The gait performances of 365 adolescents aged 13-14 years were assessed at single and DT walking. The proportional changes in gait parameters from single to dual were regressed against gender, body mass index (BMIz), three components of MABC-2 (balance, aiming &catching and manual dexterity), group (high vs low motor competence), body strength, physical fitness level using multiple regression analyses; and gender and four items of balance subtest of MABC-2 in the secondary analysis. The analyses showed that being female was associated with greater reduction in gait speed and stride length and an increase in double support time and step time; and having lower score in balance was related to greater reduction in gait speed, and cadence, and an increase in step time. Only zig-zag hopping item of the balance subtest was associated with DT effect on gait speed and stride length. No significant relationships were found between DT effect on gait and the rest of the predictors. Females and adolescents with lower level of balance function may be at higher risk of having DT deficit during walking.


Tuberculosis knowledge, misconceptions/myths in adults: findings from Lesotho, Malawi, Namibia and Zambia Demographic Health Surveys (2013-2016).
To determine TB knowledge and misconceptions/myths amongst HIV positive and negative adults using Demographic Health Survey data from Lesotho, Malawi, Namibia and Zambia. Overall 97% (n = 58,107) of both male and female respondents irrespective of their HIV status had heard of tuberculosis out of whom 82.6% knew that it can be cured. Knowledge that TB is spread in air when coughing or sneezing was 73.8%. Significantly higher proportions of HIV positive men and women than their HIV negative counterparts, had ever heard about TB, knew that it is transmitted through air when coughing and sneezing and also that it can be cured. However interestingly, significantly higher proportions of HIV positive men and women, than their HIV negative counterparts, had the misconception that TB is spread through sharing utensils or would overall say they did not know how it is spread. TB knowledge was significantly higher among individuals who are less than 26 years of age compared to those who were older.


Workforce perceptions of hospital safety culture: development and validation of the patient safety climate in healthcare organizations survey.
To describe the development of an instrument for assessing workforce perceptions of hospital safety culture and to assess its reliability and validity. Primary data collected between March 2004 and May 2005. Personnel from 105 U.S. hospitals completed a 38-item paper and pencil survey. We received 21,496 completed questionnaires, representing a 51 percent response rate. Based on review of existing safety climate surveys, we developed a list of key topics pertinent to maintaining a culture of safety in high-reliability organizations. We developed a draft questionnaire to address these topics and pilot tested it in four preliminary studies of hospital personnel. We modified the questionnaire based on experience and respondent feedback, and distributed the revised version to 42,249 hospital workers. We randomly divided respondents into derivation and validation samples. We applied exploratory factor analysis to responses in the derivation sample. We used those results to create scales in the validation sample, which we subjected to multitrait analysis (MTA). We identified nine constructs, three organizational factors, two unit factors, three individual factors, and one additional factor. Constructs demonstrated substantial convergent and discriminant validity in the MTA. Cronbach's alpha coefficients ranged from 0.50 to 0.89. It is possible to measure key salient features of hospital safety climate using a valid and reliable 38-item survey and appropriate hospital sample sizes. This instrument may be used in further studies to better understand the impact of safety climate on patient safety outcomes.


Chemopreventive role of green tea in head and neck cancers.
In the era of personalized medicine, selecting the ideal treatment modality for head and neck cancer is becoming more complex. Also, despite the use of the newest agents, overall survival has not been improved notably over the past few decades. Currently, in accordance with the development of diagnostic tools, prevention and early detection of cancer are being emphasized more in obtaining better treatment outcomes. Among the various cancer preventative methods, the use of green tea is one of the most common approaches, and tea is known to be involved in multiple steps of carcinogenesis. Thus, in this short review, the protective roles of green tea components against the initiation, progression, and metastasis of head and neck malignancies will be discussed.


Synaptotagmin I functions as a calcium regulator of release probability.
In all synapses, Ca2+ triggers neurotransmitter release to initiate signal transmission. Ca2+ presumably acts by activating synaptic Ca2+ sensors, but the nature of these sensors--which are the gatekeepers to neurotransmission--remains unclear. One of the candidate Ca2+ sensors in release is the synaptic Ca2+-binding protein synaptotagmin I. Here we have studied a point mutation in synaptotagmin I that causes a twofold decrease in overall Ca2+ affinity without inducing structural or conformational changes. When introduced by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca2+ binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.


Severe hypomyelination of the murine CNS in the absence of myelin-associated glycoprotein and fyn tyrosine kinase.
The analysis of mice deficient in the myelin-associated glycoprotein (MAG) or Fyn, a nonreceptor-type tyrosine kinase proposed to act as a signaling molecule downstream of MAG, has revealed that both molecules are involved in the initiation of myelination. To obtain more insights into the role of the MAG-Fyn signaling pathway during initiation of myelination and formation of morphologically intact myelin sheaths, we have analyzed optic nerves of MAG-, Fyn- and MAG/Fyn-deficient mice. We observed a slight hypomyelination in optic nerves of MAG mutants that was significantly increased in Fyn mutants and massive in MAG/Fyn double mutants. The severe morphological phenotype of MAG/Fyn mutants, accompanied by behavioral deficits, substantiates the importance of both molecules for the initiation of myelination. The different severity of the phenotype of different genotypes indicates that the MAG-Fyn signaling pathway is complex and suggests the presence of compensatory mechanisms in the single mutants. However, data are also compatible with the possibility that MAG and Fyn act independently to initiate myelination. Hypomyelination of optic nerves was not related to a loss of oligodendrocytes, indicating that the phenotype results from impaired interactions between oligodendrocyte processes and axons and/or impaired morphological maturation of oligodendrocytes. Finally, we demonstrate that Fyn, unlike MAG, is not involved in the formation of ultrastructurally intact myelin sheaths.


Public injecting and the need for 'safer environment interventions' in the reduction of drug-related harm.
One key structural dimension in the distribution of drug-related harm associated with injecting drug use is the injecting environment. Epidemiological evidence associates elevated blood-borne viral risk with injecting in 'public' and 'semipublic' environments. Yet the quality of evidence on public injecting and related viral risk is variable, and is lacking in many countries such as the United Kingdom. This commentary considers the micro-injecting environment as a critical dimension of risk, exploring the need for 'safer injecting environment interventions'. We draw upon published research evidence and qualitative case examples. We note the limits in epidemiological evidence on public injecting and emphasize the need for ethnographic research to determine the 'social relations' of how drug users and risk practices interact with injecting environments. We identify three main forms of 'safer environment intervention': purpose-built drug consumption rooms; interventions within existing spatial relations; and spatial programming and urban design. While drug consumption rooms find evidence-based support, they are not a panacea. We emphasize the potential of interventions embedded within existing spatial and social relations. These include low-cost pragmatic interventions enhancing facilities and safety at public and semipublic injecting sites and, primarily, peer-based interventions, including peer-supervised injecting sites. We caution against spatial programming and urban design interventions which can cause the displacement of socially marginalized populations and the redistribution of harm. Public health interventions in the addictions field have in the past focused upon individual behavioural change at the cost of social interventions and environmental change. We wish to focus greater attention on reducing risks related to public injecting and encourage greater debate on 'safer environment interventions' in harm reduction.


Development and validation of reversed-phase high-performance liquid chromatography method for estimation of rizatriptan benzoate in oral strip formulations.
A simple, accurate, precise, and reproducible reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of rizatriptan benzoate in oral strip formulations. Separation was achieved under optimized chromatographic condition on a Hiper C18 column (250 mm × 4.6 mm, 5 m) using Shimadzu HPLC. The mobile phase consisted of phosphate buffer (20 mM pH adjusted to 3.2 ± 0.005 with ortho phosphoric acid): Methanol in the ratio of 70:30 v/v with isocratic elution at a flow rate of 1 ml/min at ambient temperature was performed. The detection was carried out at 225 nm using photodiode array detector. The method was validated as per Q1A (R2) guidelines and suitability of developed method was ascertained by using optimized oral strip formulation. The retention time of rizatriptan benzoate was found to be 5.17 min, and the calibration curve was linear in the concentration range of 0.20-20 mg/mL (r (2)= 0.9998). The limit of detection and the limit of quantitation were found to be 0.016 mg/mL and 0.0528 mg/mL, respectively. Method validation parameters were found to be within the specified limits. The percentage drug content of oral strips formulation was found to be 98.96 ± 1.37. The proposed HPLC method may be used efficiently for routine and quality control analysis of rizatriptan benzoate in pharmaceutical formulations.


Spectral sharpening with positivity
Spectral sharpening is a method for developing camera or other optical-device sensor functions that are more narrowband than those in hardware, by means of a linear transform of sensor functions. The utility of such a transform is that many computer vision and color-correction algorithms perform better in a sharpened space, and thus such a space can be used as an intermediate representation for carrying out calculations. In this paper we consider how one may sharpen sensor functions such that the transformed sensors are all positive. We show that constrained optimization can be used to produce positive sensors in two fundamentally different ways: by constraining the coefficients in the transform or by constraining the functions directly. In the former method, we prove that convexity can be used to constrain the solution exactly. In a sense, we are continuing the work of MacAdam and of Pearson and Yule, who formed positive combinations of the color-matching functions. However, the advantage of the spectral sharpening approach is that not only can we produce positive curves, but the process is "steerable" in that we can produce positive curves with as good or better properties for sharpening within a given set of sharpening intervals. At base, however, it is positive colors in the transformed space that are the prime objective. Therefore we also carry out sharpening of sensor curves governed not by positivity of the curves themselves but of colors resulting from them. Curves that result have negative lobes but generate positive colors. We find that this type of constrained sharpening generates the best results, which are almost as good as for unconstrained sharpening but without the penalty of negative colors. All methods discussed may be used with any number of sensors.


Physical training considerations for optimizing performance in essential military tasks.
Physically demanding essential military tasks include load carriage, manual material handling and casualty evacuation. This narrative review characterizes the main physical attributes related to performance of these occupational tasks and reviews physical training intervention studies in military settings to improve performance in these military tasks. Load carriage performance requires both aerobic and neuromuscular fitness with greater emphasis on maximal strength and absolute maximal oxygen uptake, especially when carrying heavier loads. In manual material handling, maximal strength and power are strongly associated with discrete lifting, while muscular strength, muscular endurance and aerobic fitness are also associated with repetitive lifting performance. Maximal strength including grip strength, muscular endurance, absolute maximal oxygen uptake and anaerobic capacity are associated with casualty evacuation performance. The results of the present review particularly emphasize the role of muscular fitness in successful performance of the reviewed military occupational tasks. Training intervention studies indicate that load carriage performance can be effectively improved by combining strength, aerobic and specific load carriage training. Improvement in maximal lifting capacity can be achieved by strength training or combined strength and aerobic training, while strength and aerobic training alone, or their combination are effective in improving repetitive lifting, and carry tasks. Only a few studies are available for casualty evacuation and the results are inconclusive but may indicate benefits of strength or combined training. Moreover, emphasis on lower volume but higher intensity in combined training may be a feasible and effective mode to improve military occupational performance in recruits and active-duty soldiers.


Long-term programming effects on blood pressure following gestational exposure to the IKr blocker Dofetilide.
A slow embryonic heart rate in early-mid gestation is associated with increased risk of embryonic death and malformation, however, the long-term consequences remain unknown. We administered Dofetilide (Dof, 2.5 mg/kg), a drug that produces embryo-specific bradycardia, to pregnant rats from gestational days 11-14. Embryonic heart rate and rhythm were determined using embryo culture. Cardiovascular function was assessed in surviving adult offspring at rest, during acute psychological stress (air jet stress, AJS), and after 7 days of repeated AJS. Dof reduced embryonic HR by 40% for ~8 h on each of the treatment days. On postnatal day 3, Dof offspring were ~10% smaller. Blood pressure was elevated in adult Dof rats (systolic blood pressure, night: 103.8 ± 3.9 vs. 111.2 ± 3.0 mmHg, P = 0.01). While the pressor response to AJS was similar in both groups (control 17.7 ± 3.4; Dof 18.9 ± 0.9 mmHg, P = 0.74), after 7 days repeated AJS, clear habituation was present in control (P = 0.0001) but not Dof offspring (P = 0.48). Only Dof offspring showed a small increase in resting blood pressure after 7 days repeated stress (+3.9 ± 1.7 mmHg, P = 0.05). The results indicate that embryonic bradycardia programs hypertension and impaired stress adaptation, and have implications for the maternal use of cardioactive drugs during pregnancy.


Structural surface changes and inflammatory responses against alginate-based microcapsules after exposure to human peritoneal fluid.
Microencapsulation of cells is a promising approach to prevent rejection in the absence of immunosuppression. Clinical application, however, is hampered by insufficient insight in factors influencing biocompatibility of the capsules in humans. In the present study we exposed alginate-based capsules prepared of different types of alginate to human peritoneal fluid. Subsequently we studied the physicochemical changes of the capsule's surface by applying micro-Fourier Transform Infrared Spectroscopy. We did test alginate-beads and alginate-poly-L-lysine capsules prepared of different types of alginate. In all tested capsule formulations we found adsorption of components from human peritoneal fluid and clear physicochemical changes of the surface. These changes were alginate-dependent. The adsorption had no significant effects on the permselective properties of the capsule but we found a strong increase of TNFα production by human peripheral blood mononuclear cells when exposed to alginate-beads treated with human peritoneal fluid. This elevated responsiveness was not observed with alginate-PLL capsules. The results show that alginate-based capsule surfaces always undergo physicochemical changes of the surface when exposed to human peritoneal fluid. This adsorption may lead to enhancement of the inflammatory responses against the microcapsules. Our result implicate that biocompatibility measurements should not only been done with freshly prepared capsules but also with capsules that have been exposed to fluid from the implantation site in order to predict the in vivo responses.


Management of chronic tibial subluxation in the multiple-ligament injured knee.
Chronic tibial subluxation is a rare and complicated problem that requires careful evaluation and planning to achieve the desired outcome and patient satisfaction. Reconstruction of catastrophic knee injury requires obtaining a balance in 2 opposing goals: stability and range of motion. Complete understanding of the impact of each of the involved ligamentous structures on knee stability and motion is particularly important, given the absence of ligamentous restraints and landmarks in the multiligamentous knee injury. Three critical operative steps are necessary to produce a desired outcome: (1) complete release and excision of scar tissue, (2) recreation of the central knee axis through anterior cruciate ligament and posterior cruciate ligament allograft reconstruction, and (3) maintenance of postoperative stability and functional motion with an external hinge fixator or functional knee brace. Careful postoperative clinical and radiographic follow-up completes the process toward an excellent result in this difficult clinical scenario.


Perinatal exposure to bisphenol a increases adult mammary gland progesterone response and cell number.
Bisphenol A [BPA, 2,2,-bis (hydroxyphenyl) propane] is one of the highest-volume chemicals produced worldwide. It is detected in body fluids of more than 90% of the human population. Originally synthesized as an estrogenic compound, it is currently utilized to manufacture food and beverage containers resulting in uptake with food and drinks. There is concern that exposure to low doses of BPA, defined as less than or equal to 5 mg/kg body weight /d, may have developmental effects on various hormone-responsive organs including the mammary gland. Here, we asked whether perinatal exposure to a range of low doses of BPA is sufficient to alter mammary gland hormone response later on in life, with a possible impact on breast cancer risk. To mimic human exposure, we added BPA to the drinking water of C57/Bl6 breeding pairs. Analysis of the mammary glands of their daughters at puberty showed that estrogen-dependent transcriptional events were perturbed and the number of terminal end buds, estrogen-induced proliferative structures, was altered in a dose-dependent fashion. Importantly, adult females showed an increase in mammary epithelial cell numbers comparable to that seen in females exposed to diethylbestrol, a compound exposure to which was previously linked to increased breast cancer risk. Molecularly, the mRNAs encoding Wnt-4 and receptor activator of nuclear factor κB ligand, two key mediators of hormone function implicated in control of mammary stem cell proliferation and carcinogenesis, showed increased induction by progesterone in the mammary tissue of exposed mice. Thus, perinatal exposure to environmentally relevant doses of BPA alters long-term hormone response that may increase the propensity to develop breast cancer.


Purification and Characterization of Phosphoglycolate Phosphatase from the Cyanobacterium Coccochloris peniocystis.
The properties and role of the enzyme phosphoglycolate phosphatase in the cyanobacterium Coccochloris peniocystis have been investigated. Phosphoglycolate phosphatase was purified 92-fold and had a native molecular mass of approximately 56 kilodaltons. The enzyme demonstrated a broad pH optimum of pH 5.0 to 7.5 and showed a relatively low apparent affinity for substrate (K(m) = 222 micromolar) when compared to that from higher plants. The enzyme required both an anion and divalent cation for activity. Mn(2+) and Mg(2+) were effective divalent cations while Cl(-) was the most effective anion tested. The enzyme was specific for phosphoglycolate and did not show any activity toward a variety of organic phosphate esters. Growth of the cells on high CO(2) and transfer to air did not result in any significant change in phosphoglycolate phosphatase activity. Competitive inhibition of C. peniocystis triose phosphate isomerase by phosphoglycolate was demonstrated (K(i) = 12.9 micromolar). These results indicate the presence of a specific noninducible phosphoglycolate phosphatase whose sole function may be to hydrolyze phosphoglycolate and prevent phosphoglycolate inhibition of triose phosphate isomerase.


Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle.
Deaf-blindness in three distinct genetic forms of Usher type I syndrome (USH1) is caused by defects in myosin VIIa, harmonin and cadherin 23. Despite being critical for hearing, the functions of these proteins in the inner ear remain elusive. Here we show that harmonin, a PDZ domain-containing protein, and cadherin 23 are both present in the growing stereocilia and that they bind to each other. Moreover, we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments, thereby identifying a novel anchorage mode of the cadherins to the actin cytoskeleton. Moreover, harmonin b interacts directly with myosin VIIa, and is absent from the disorganized hair bundles of myosin VIIa mutant mice, suggesting that myosin VIIa conveys harmonin b along the actin core of the developing stereocilia. We propose that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia.


One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study.
Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab-ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab-ravulizumab, 64.5%; eculizumab-ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time. In adult, complement inhibitor-naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control. ClinicalTrials.gov identifier, NCT02946463.


The role of dietary fat throughout the prostate cancer trajectory.
Prostate cancer is the second most common cancer diagnosed world-wide; however, patients demonstrate exceptionally high survival rates. Many lifestyle factors, including obesity and diet, are considered risk factors for advanced prostate cancer. Dietary fat is a fundamental contributor to obesity and may be specifically important for prostate cancer patients. Prostate cancer treatment can result in changes in body composition, affecting quality of life for survivors by increasing the risk of co-morbidities, like cardiovascular disease and diabetes. We aim to examine dietary fat throughout the prostate cancer treatment trajectory, including risk, cancer development and survivorship. Focusing on one specific nutrient throughout the prostate cancer trajectory provides a unique perspective of dietary fat in prostate cancer and the mechanisms that may exacerbate prostate cancer risk, progression and recurrence. Through this approach, we noted that high intake of dietary fat, especially, high intake of animal and saturated fats, may be associated with increased prostate cancer risk. In contrast, a low-fat diet, specifically low in saturated fat, may be beneficial for prostate cancer survivors by reducing tumor angiogenesis and cancer recurrence. The insulin-like growth factor (IGF)/Akt signaling pathway appears to be the key pathway moderating dietary fat intake and prostate cancer development and progression.


Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner.
Somatostatin (SS) inhibits glucagon-like peptide-1 (GLP-1) secretion in a paracrine manner. We hypothesized that blocking somatostatin subtype receptor 2 (SSTR2) and 5 (SSTR5) would improve glycemia by enhancing GLP-1 secretion. In the perfused mouse small intestine, the selective SSTR5 antagonist (SSTR5a) stimulated glucose-induced GLP-1 secretion to a larger degree than the SSTR2 antagonist (SSTR2a). In parallel, mice lacking the SSTR5R showed increased glucose-induced GLP-1 secretion. Both antagonists improved glycemia in vivo in a GLP-1 receptor-dependent (GLP-1R-dependent) manner, as the glycemic improvements were absent in mice with impaired GLP-1R signaling and in mice treated with a GLP-1R-specific antagonist. SSTR5a had no direct effect on insulin secretion in the perfused pancreas, whereas SSTR2a increased insulin secretion in a GLP-1R-independent manner. Adding a dipeptidyl peptidase 4 inhibitor (DPP-4i) in vivo resulted in additive effects on glycemia. However, when glucose was administered intraperitoneally, the antagonist was incapable of lowering blood glucose. Oral administration of SSTR5a, but not SSTR2a, lowered blood glucose in diet-induced obese mice. In summary, we demonstrate that selective SSTR antagonists can improve glucose control primarily through the intestinal GLP-1 system in mice.


Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity.
This study was performed to determine whether the sisters of women with polycystic ovary syndrome (PCOS) have evidence for insulin resistance. Three hundred and thirty-six women with PCOS, 307 sisters of these probands, and 47 control women were studied. The sisters were grouped by phenotypes: PCOS [hyperandrogenemia (HA) with chronic oligo- or amenorrhea, n = 39], HA with regular menses (n = 36), unaffected (UA; n = 122), and unknown (n = 110). The analyses were adjusted for age and body mass index. PCOS and HA sisters of women with PCOS had similar and significantly elevated fasting insulin levels (P = 0.001) as well as similar and significantly decreased fasting glucose/insulin ratios (P < 0.001) suggestive of insulin resistance compared with UA sisters and control women. Markers of insulin resistance were associated with hyperandrogenemia and not with menstrual irregularity. PCOS sisters also had decreased levels of SHBG (P = 0.02) suggestive of higher ambient insulin levels. PCOS sisters had increased levels of proinsulin (P = 0.04) compared with control women, which suggested pancreatic beta-cell dysfunction in this group of sisters. The magnitude of obesity also differed significantly among the groups of sisters. The PCOS sisters were significantly more obese than all the other groups, and the HA sisters were more obese than the UA sisters. We conclude that markers of insulin resistance are associated with hyperandrogenemia rather than menstrual irregularity in the sisters of women with PCOS. Menstrual irregularity may be related to the magnitude of insulin sensitivity or insulin secretion or to other factors associated with obesity.


Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.
Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. EU Horizon 2020 programme.


Nocturnal Blood Pressure in Young Adults and Cognitive Function in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Nocturnal blood pressure (BP) is associated with risk for cardiovascular events. However, the relationship between nocturnal BP in young adults and cognitive function in midlife remains unclear. We used data from the ambulatory BP monitoring substudy of the Coronary Artery Risk Development in Young Adults Study, including 224 participants (mean age 30 years, 45% men, 63% African Americans). At the 20-year follow-up, the Stroop test (executive function), Digit Symbol Substitution Test (psychomotor speed), and Rey Auditory Verbal Learning Test (verbal memory) were assessed. Baseline mean office, daytime, and nocturnal BP were 109/73, 120/74, and 107/59 mm Hg, respectively. Nocturnal BP dipping, calculated as (nocturnal systolic BP [SBP]--daytime SBP) × 100/daytime SBP, was divided into quartiles (Q1: -39.3% to -16.9%; Q2: -16.8% to -13.2%, Q3 [reference]: -13.1% to -7.8%, and Q4: -7.7% to +56.4%). In multiple regression analyses, the least nocturnal SBP dipping (Q4 vs. reference) and higher nocturnal diastolic BP level were associated with worse Stroop scores, with adjustments for demographic and clinical characteristics, and cumulative exposure to office BP during follow-up (β [standard error]: 0.37 [0.18] and 0.19 [0.07], respectively; all P < 0.05). Digit Symbol Substitution Test and Rey Auditory Verbal Learning Test were not significantly associated with nocturnal SBP dipping or nocturnal SBP/diastolic BP levels. Among healthy young adults, less nocturnal SBP dipping and higher nocturnal diastolic BP levels were associated with lower executive function in midlife, independent of multiple measures of office BP during long-term follow-up.


The Role of Protective Behavioral Strategies, Social Environment, and Housing Type on Heavy Drinking among College Students.
Though research has examined heavy drinking by housing type, the link between type of college student housing and protective behavioral strategies (PBS) has rarely been examined comparing different college campuses. The purpose of this study is to examine the role of housing type, perceptions of peer drinking, and PBS with respondent heavy drinking among undergraduate college students from one Southeastern and one Midwestern university in the United States. 1,448 college students enrolled in undergraduate courses at two public universities completed a paper and pencil survey of attitudes and experiences about dating, sexuality, and substance use. Data were analyzed using multiple group path analysis. Students living in Greek housing perceived their close friends as engaging in more risky drinking, and had higher rates of heavy drinking compared to those living in other housing types. The effect of perceptions of peer drinking on PBS was significantly different between campuses as were several other indirect pathways to heavy drinking. Conclusion/Importance: Understanding more about the differing roles of college residential environments can help inform effective drinking interventions, and reduce heavy drinking among college students.


A comparison of the teratogenicity of methylmercury and selenomethionine injected into bird eggs.
Methylmercury chloride and seleno-L-methionine were injected separately or in combinations into the fertile eggs of mallards (Anas platyrhynchos), chickens (Gallus gallus), and double-crested cormorants (Phalacrocorax auritus), and the incidence and types of teratogenic effects were recorded. For all three species, selenomethionine alone caused more deformities than did methylmercury alone. When mallard eggs were injected with the lowest dose of selenium (Se) alone (0.1 μg/g), 28 of 44 embryos and hatchlings were deformed, whereas when eggs were injected with the lowest dose of mercury (Hg) alone (0.2 μg/g), only 1 of 56 embryos or hatchlings was deformed. Mallard embryos seemed to be more sensitive to the teratogenic effects of Se than chicken embryos: 0 of 15 chicken embryos or hatchlings from eggs injected with 0.1 μg/g Se exhibited deformities. Sample sizes were small with double-crested cormorant eggs, but they also seemed to be less sensitive to the teratogenic effects of Se than mallard eggs. There were no obvious differences among species regarding Hg-induced deformities. Overall, few interactions were apparent between methylmercury and selenomethionine with respect to the types of deformities observed. However, the deformities spina bifida and craniorachischisis were observed only when Hg and Se were injected in combination. One paradoxical finding was that some doses of methylmercury seemed to counteract the negative effect selenomethionine had on hatching of eggs while at the same time enhancing the negative effect selenomethionine had on creating deformities. When either methylmercury or selenomethionine is injected into avian eggs, deformities start to occur at much lower concentrations than when the Hg or Se is deposited naturally in the egg by the mother.


Pearl millet in layer diets enhances egg yolk n-3 fatty acids.
A study was conducted to determine whether substitution of pearl millet for corn in layer diets could enrich egg yolks with n-3 fatty acids. Seventy-two Single Comb White Leghorn hens of a commercial strain in their second cycle of production were fed isocaloric, isonitrogeneous diets (2,860 kcal AMEn/kg and 16% CP) formulated with corn, equal amounts of corn and pearl millet, or pearl millet as the grain source. Each of the three diets was fed to eight replicate groups of three hens for 6 wk. Dietary treatments had no effect on feed intake, BW, egg production, egg weight, and yolk weight. Feeding millet in place of corn significantly decreased yolk pigmentation. The ratio of n-6 fatty acids to n-3 fatty acids in eggs was 13.1, 10.1, and 8.3 for hens fed corn, corn+pearl millet, and pearl millet, respectively. Feeding pearl millet produces eggs significantly (P < 0.05) enriched in n-3 fatty acids.


Role of transfection in the priming of cytotoxic T-cells by DNA-mediated immunization.
DNA vaccination results in remarkably strong, broad-based immune responses to the encoded proteins and it is a simple and effective method of inducing cytotoxic T-lymphocyte (CTL) responses. Bone marrow-derived cells can take up and present exogenous antigenic protein liberated by transfected fibroblasts or myoblasts after the injection of such cells. In addition, dendritic cells can carry the injected plasmid DNA, supporting the hypothesis that dendritic cells can be directly transfected. It is, however, unclear from the current data what proportion of the cytotoxic immune response is initiated by the transfer of protein compared to that resulting from direct transfection of professional antigen presenting cells. This question is addressed here by using a matched series of plasmid DNA vectors expressing the wild-type or several mutant forms of HBsAg that are secretion-defective or severely truncated. The data indicate that neither HBsAg particle formation nor its secretion or liberation plays a significant role in the development of the cytotoxic immune response. The results argue that direct transfection of bone marrow-derived cells is the major, and possibly the only, mechanism used for priming of naive CTL precursors directed against the HBsAg.


The box H + ACA snoRNAs carry Cbf5p, the putative rRNA pseudouridine synthase.
Many or all of the sites of pseudouridine (Psi) formation in eukaryotic rRNA are selected by site-specific base-pairing with members of the box H + ACA class of small nucleolar RNAs (snoRNAs). Database searches previously identified strong homology between the rat nucleolar protein Nap57p, its yeast homolog Cbf5p, and the Escherichia coli Psi synthase truB/P35. We therefore tested whether Cbf5p is required for synthesis of Psi in the yeast rRNA. After genetic depletion of Cbf5p, formation of Psi in the pre-rRNA is dramatically inhibited, resulting in accumulation of the unmodified rRNA. Protein A-tagged Cbf5p coprecipitates all tested members of the box H + ACA snoRNAs but not box C + D snoRNAs or other RNA species. Genetic depletion of Cbf5p leads to depletion of all box H + ACA snoRNAs. These include snR30, which is required for pre-rRNA processing. Depletion of Cbf5p also results in a pre-rRNA processing defect similar to that seen on depletion of snR30. We conclude that Cbf5p is likely to be the rRNA Psi synthase and is an integral component of the box H + ACA class of snoRNPs, which function to target the enzyme to its site of action.


Efficacy and Safety of Long-Term Baricitinib With and Without Methotrexate for the Treatment of Rheumatoid Arthritis: Experience With Baricitinib Monotherapy Continuation or After Switching From Methotrexate Monotherapy or Baricitinib Plus Methotrexate.
To evaluate the long-term efficacy and safety of maintaining baricitinib monotherapy in patients with active rheumatoid arthritis (RA) originally treated with baricitinib monotherapy or switched from methotrexate (MTX) or the combination of baricitinib plus MTX to baricitinib monotherapy. This is a post hoc analysis of patients from the RA-BEGIN study who entered a long-term extension, RA-BEYOND, and were assessed for up to 24 weeks. In RA-BEGIN, MTX-naive patients with early active RA were randomized to MTX monotherapy, baricitinib 4 mg monotherapy, or baricitinib 4 mg plus MTX. At week 52, all patients entering RA-BEYOND received baricitinib 4 mg monotherapy. MTX could be prescribed during RA-BEYOND at the investigator's discretion. Patients in RA-BEYOND who were not rescued in RA-BEGIN (n = 423) were evaluated. Of these, 47% continued baricitinib monotherapy and 53% added MTX, with similar proportions from the 3 original arms. Patients with lower disease activity at the RA-BEYOND baseline generally continued to do well with baricitinib monotherapy as assessed by the Simplified Disease Activity Index, the Clinical Disease Activity Index, and the Health Assessment Questionnaire disability index scores. Patients prescribed MTX had higher disease activity at the RA-BEYOND baseline and had improved disease activity after the addition of MTX. Safety outcomes were similar across treatment groups. Many patients responded well to continued baricitinib monotherapy or to switching to baricitinib monotherapy from MTX monotherapy or baricitinib plus MTX, showing sustained or improved disease control. The groups of patients who had less disease control on their original therapies showed sustained or improved disease control with the addition of MTX to baricitinib.


How does early decompressive craniectomy influence the intracranial volume relationship in traumatic brain injury (TBI) patients?
Decompressive craniectomy (DC) is a common neurosurgical procedure involving the removal of part of the skull vault combined with subsequent duroplasty. The goal of DC is to produce extra space for the swollen brain and/or to reduce intracranial pressure. In the present study, DC was performed in order to create space for the swollen brain. to compare the volume alteration of selected intracranial fluid spaces before and after DC, to evaluate the volume of post-decompressive brain displacement (PDBD) and the largest dimension of oval craniectomy (LDOC), and to assess the early clinical effects of DC. The study group consisted of 45 patients with traumatic brain injury (four females and 41 males, mean age 54.5 years) who underwent DC (not later than five hours after admission to hospital) due to subdural haematomas and/or haemorrhagic brain contusions localised supratentorially and diagnosed by computed tomography (CT). The mortality rate in the study group was 40%. Study calculations were performed using Praezis Plus software by Med Tatra, Zeppelin and Pax Station by Compart Medical Systems. For statistical analysis, IBM SPSS Statistics software was used. The DC-related additional space was responsible for a statistically significant increase in the volume of preoperatively compressed intracranial fluid spaces. The mean volume of extra space filled by the swollen brain was 42.2 ml ± 40.7. The best early treatment results were achieved in patients under the age of 55. DC has limited effectiveness in patients aged over 70 years. In every patient with clamped basal cisterns, a skin incision enabling appropriate LDOC should be planned before surgery. DC should be as large as possible, and the limits of its dimensions should be the limits of anatomical safety.


African crop yield reductions due to increasingly unbalanced Nitrogen and Phosphorus consumption.
The impact of soil nutrient depletion on crop production has been known for decades, but robust assessments of the impact of increasingly unbalanced nitrogen (N) and phosphorus (P) application rates on crop production are lacking. Here, we use crop response functions based on 741 FAO maize crop trials and EPIC crop modeling across Africa to examine maize yield deficits resulting from unbalanced N : P applications under low, medium, and high input scenarios, for past (1975), current, and future N : P mass ratios of respectively, 1 : 0.29, 1 : 0.15, and 1 : 0.05. At low N inputs (10 kg ha(-1)), current yield deficits amount to 10% but will increase up to 27% under the assumed future N : P ratio, while at medium N inputs (50 kg N ha(-1)), future yield losses could amount to over 40%. The EPIC crop model was then used to simulate maize yields across Africa. The model results showed relative median future yield reductions at low N inputs of 40%, and 50% at medium and high inputs, albeit with large spatial variability. Dominant low-quality soils such as Ferralsols, which are strongly adsorbing P, and Arenosols with a low nutrient retention capacity, are associated with a strong yield decline, although Arenosols show very variable crop yield losses at low inputs. Optimal N : P ratios, i.e. those where the lowest amount of applied P produces the highest yield (given N input) where calculated with EPIC to be as low as 1 : 0.5. Finally, we estimated the additional P required given current N inputs, and given N inputs that would allow Africa to close yield gaps (ca. 70%). At current N inputs, P consumption would have to increase 2.3-fold to be optimal, and to increase 11.7-fold to close yield gaps. The P demand to overcome these yield deficits would provide a significant additional pressure on current global extraction of P resources.


Transient disturbance in physeal morphology is associated with long-term effects of nitrogen-containing bisphosphonates in growing rabbits.
Bisphosphonates have clinical benefit in children with severe osteogenesis imperfecta or osteoporosis and potential benefit in children with Perthes disease or undergoing distraction osteogenesis. However, there is concern about the effects of bisphosphonates on the physis and bone length. In 44 growing rabbits, zoledronic acid caused a transient disruption of physeal morphology, retention of cartilaginous matrix in trabeculae and cortical bone of the metaphysis, and a minor decrement in tibial bone length at maturity. Data from growing animal models suggest that bisphosphonates cause retention of longitudinal cartilaginous septa at the chondro-osseous junction, extension of trabeculae to the metaphyseal-diaphyseal junction, and varying dose-dependent effects on longitudinal growth. However, there is a lack of data regarding effects of intermittent use of nitrogen-containing bisphosphonates on the physis and on tibial length in models reaching maturity. Contralateral tibias of juvenile rabbits were examined after right tibial distraction osteogenesis from two previous studies. Animals were randomized to receive 0.1 mg/kg zoledronic acid (ZA) IV at 8 weeks of age (ZA*1) or 8 and 10 weeks of age (ZA*2) or saline. Body mass was analyzed from 5 to 44 weeks of age; tibial length and proximal physeal-metaphyseal histology and histomorphometry were analyzed at 8-52 weeks of age. Tibial length was 3% less at 14 weeks of age in the ZA*2-treated versus saline group (p<0.05) in both studies, and this difference persisted at maturity in the long-term study group (26 weeks of age, p<0.05). Total body mass gain from 5 to 26 weeks of age was 14% less in ZA*2-treated than saline animals (p<0.05). Rate of weight gain from 8 to 10 weeks of age was 76% less in ZA*2 compared with saline animals (p<0.05). Radiographs showed radiodense lines in the metaphyses of ZA-treated bones, corresponding to the number of doses. Histologically, lines resulting from the first dose of ZA contained longitudinal cartilaginous matrix cores surrounded by bone, whereas those from the second dose contained spherical cores of matrix caused by transient disruption of physeal morphology after the first dose of ZA. Resorption of these lines at later times was radiographically and histologically evident, but remnants of cartilaginous matrix remained in the cortical bone of ZA-treated animals. ZA treatment within the final 13.5% of the rabbit tibial growth period caused a transient disruption in physeal morphology and resorption associated with retention of cartilaginous matrix and coinciding with a persistent 3% decrement in tibial length. Disruption of physeal morphology and potential loss of bone length should be considered when administering nitrogen-containing bisphosphonates to children before closure of the major physes.


Imaging of near-field interference patterns by aperture-type SNOM - influence of illumination wavelength and polarization state.
Scanning near-field optical microscopy (SNOM) in combination with interference structures is a powerful tool for imaging and analysis of surface plasmon polaritons (SPPs). However, the correct interpretation of SNOM images requires profound understanding of principles behind their formation. To study fundamental principles of SNOM imaging in detail, we performed spectroscopic measurements by an aperture-type SNOM setup equipped with a supercontinuum laser and a polarizer, which gave us all the degrees of freedom necessary for our investigation. The series of wavelength- and polarization-resolved measurements, together with results of numerical simulations, then allowed us to identify the role of individual near-field components in formation of SNOM images, and to show that the out-of-plane component generally dominates within a broad range of parameters explored in our study. Our results challenge the widespread notion that this component does not couple to the aperture-type SNOM probe and indicate that the issue of SNOM probe sensitivity towards the in-plane and out-of-plane near-field components - one of the most challenging tasks of near field interference SNOM measurements - is not yet fully resolved.