Microbes Attaching to Endoparasitic Phytonematodes in Soil Trigger Plant Defense Upon Root Penetration by the Nematode.
Root-knot nematodes (Meloidogyne spp.) are among the most aggressive phytonematodes. While moving through soil to reach the roots of their host, specific microbes attach to the cuticle of the infective second-stage juveniles (J2). Reportedly, the attached microorganisms affect nematodes and reduce their performance on the host plants. We have previously shown that some non-parasitic bacterial strains isolated from the cuticle of Meloidogyne hapla in different soils affected J2 mortality, motility, hatching, and root invasion. Here we tested whether cuticle-attached microbes trigger plant defenses upon penetration of J2. In in vitro assays, M. hapla J2-attached microbes from a suppressive soil induced pathogen-associated molecular pattern-triggered immunity (PTI) in tomato roots. All tested PTI-responsive defense genes were upregulated after root invasion of J2 with attached microbes, compared to surface-sterilized J2, particularly the jasmonic acid-mediated PTI marker genes TFT1 and GRAS4.1. The strain Microbacterium sp. K6, that was isolated from the cuticle, significantly reduced root invasion when attached to the J2. Attached K6 cells supported plant defense and counteracted suppression of plant basal defense in roots by invaded J2. The plant response to the J2-attached K6 cells was stronger in leaves than in roots, and it increased from 1 to 3 days post inoculation (dpi). At 1 dpi, the plant responded to J2-attached K6 cells by ameliorating the J2-triggered down-regulation of defense genes mostly in roots, while at 3 dpi this response was systemic and more pronounced in leaves. In a reactive oxygen species (ROS) assay, the compounds released from J2 with attached K6 cells triggered a stronger ROS burst in tomato roots than the compounds from nematodes without K6, or the metabolites released from strain K6 alone. Leaves showed a 100 times more sensitive response than roots, and the metabolites of K6 with or without J2 induced strong ROS bursts. In conclusion, our results suggest the importance of microorganisms that attach to M. hapla in suppressive soil, inducing early basal defenses in plants and suppressing nematode performance in roots.


Preterm Birth and Renin-Angiotensin-Aldosterone System: Evidences of Activation and Impact on Chronic Cardiovascular Disease Risks.
Preterm birth (< 37 gestational weeks) reaches 10% of total births worldwide. Early exposure to an ex utero environment can alter organogenesis and maturation in the newborn. This early onset of events can further promote long-term developmental alterations and cardiovascular disease risks. Mechanisms activated during preterm birth and promoting such cardiovascular alterations have just recently been investigated. As a major candidate, the renin angiotensin aldosterone system (RAAS) can be acutely altered during preterm birth and persistently activated in later life. Further, RAAS alterations may occur as consequence of kidney and heart immaturity to promote adaptive responses, suggesting a dual role of this system on fetal and neonatal organogenesis. Furthermore, fetal or neonatal exposure to deleterious stress conditions can significantly impact on this dual RAAS role, contributing to the establishment of hemodynamic and structural alterations. In this review, clinical and experimental findings describing RAAS components and activation in relationship with preterm birth are discussed. Further clinical and experimental investigations on RAAS activation in the context of preterm birth are needed to better understand this dual role of RAAS on early development and on programming of risks to cardiovascular diseases.


Structural characterization of a prolyl aminodipeptidase (PepX) from Lactobacillus helveticus.
Prolyl aminodipeptidase (PepX) is an enzyme that hydrolyzes peptide bonds from the N-terminus of substrates when the penultimate amino-acid residue is a proline. Prolyl peptidases are of particular interest owing to their ability to hydrolyze food allergens that contain a high percentage of proline residues. PepX from Lactobacillus helveticus was cloned and expressed in Escherichia coli as an N-terminally His-tagged recombinant construct and was crystallized by hanging-drop vapor diffusion in a phosphate buffer using PEG 3350 as a precipitant. The structure was determined at 2.0 Å resolution by molecular replacement using the structure of PepX from Lactococcus lactis (PDB entry 1lns) as the starting model. Notable differences between the L. helveticus PepX structure and PDB entry 1lns include a cysteine instead of a phenylalanine at the substrate-binding site in the position which confers exopeptidase activity and the presence of a calcium ion coordinated by a calcium-binding motif with the consensus sequence DX(DN)XDG.


The structure of the FnIII Tandem A77-A78 points to a periodically conserved architecture in the myosin-binding region of titin.
Titin is a large intrasarcomeric protein that, among its many roles in muscle, is thought to modulate the in vivo assembly of the myosin motor filament. This is achieved through the molecular template properties of its A-band region, which is composed of fibronectin type III (FnIII) and immunoglobulin (Ig) domains organized into characteristic 7-domain (D-zone) and 11-domain (C-zone) superrepeats. Currently, there is little knowledge on the structural details of this region of titin. Here we report the conformational characterization of three FnIII tandems, A77-A78, A80-A82, and A84-A86, which are components of the representative fourth C-zone superrepeat. The structure of A77-A78 has been elucidated by X-ray crystallography to 1.65 A resolution, while low-resolution models of A80-A82 and A84-A86 have been calculated using small-angle X-ray scattering. A77-A78 adopts an extended "up-down" domain arrangement, where domains are connected by a hydrophilic three-residue linker sequence. The linker is embedded in a rich network of polar contacts at the domain interface that results in a stiff molecular conformation. The models of A80-A82 and A84-A86, which contain hydrophobic six-residue-long interdomain linkers, equally showed elongated molecular shapes, but with slightly coiled or zigzagged conformations. Small-angle X-ray scattering data further suggested that the long linkers do not result in a noticeable increase in molecular flexibility but lead to semibent domain arrangements. Our findings indicate that the structural characteristics of FnIII tandems from A-band titin contrast markedly with those of poly-Ig tandems from the elastic I-band, which exhibit domain interfaces depleted of interactions and compliant conformations. Furthermore, the analysis of sequence conservation in FnIII domains from A-band titin points to the existence of conformationally defined interfaces at specific superrepeat positions, possibly leading to a periodic and locally ordered architecture supporting the molecular scaffold properties of this region of titin.


[Evaluating cytogenetic and hormonal state in female workers of dyeboard industry of fabric preparation].
The article covers data on oxidative activity in cellular DNA, on cytogenetic effects, on sexual hormones levels under exposure to chemical hazards in female workers of dyeboard fabric preparation industry. Findings are that in such occupations as bleacher, mercerization and glazing operator, chemical solutions and dyes. supplier, flushing equipment operator demonstrate the highest serum levels of manganese, lead, toluene and xylene vs. the reference group parameters (1.5-1.8 times) due to occupational hazards. Significant differences were seen between the groups of exposed and unexposed workers in parameters characterizing negative effects development: higher activity of DNA oxidation products formation (according to increased urinary level of 8-OHdG), higher prevalence and variability of chromosomal polymorphism characterizing genetic instability of somatic cells, disbalance of sexual hormones (according to increased serum prolactine and lower FSH). These processes can result in functional disorders of pelvic organs, with increased prevalence of hormone-dependent gynecologic diseases in the female workers and remote effects in the offspring.


Canadian Guidelines for the Assessment and Diagnosis of Patients with Schizophrenia Spectrum and Other Psychotic Disorders.
The objective of this article is to identify best practices in the diagnosis and assessment of patients with schizophrenia spectrum and other psychotic disorders. The diagnosis and assessment may occur in a range of situations from the emergency room to the outpatient clinic and at different stages of the disorder. The focus may be on acute exacerbations of illness, residual symptoms, levels of function, or changes in the response to treatment. A systematic search was conducted for guidelines published in the last 5 years for schizophrenia and schizophrenia spectrum disorders. The guidelines were rated by at least 2 raters, and recommendations adopted on the diagnosis and assessment were primarily drawn from the American Psychiatric Association practice guidelines for the psychiatric evaluation of adults and the National Institute for Health and Care Excellence guideline on psychosis and schizophrenia in adults. A number of de novo recommendations were also developed. Eleven recommendations were identified that cover a range of assessment situations from diagnosis to the involvement of families in assessments. An accurate assessment establishes the baseline for treatment planning based on clinical decision making for both pharmacotherapy and psychosocial treatments.


Bottom-up data integration in polymer models of chromatin organisation.
Cellular functions crucially depend on the precise execution of complex biochemical reactions taking place on the chromatin fiber in the tightly packed environment of the cell nucleus. Despite the availability of large data sets probing this process from multiple angles, bottom-up frameworks which allow the incorporation of the sequence-specific nature of biochemistry in a unified model of 3D chromatin structure remain scarce. Here we propose SEMPER (Sequence Enhanced Magnetic PolymER), a novel stochastic polymer model which naturally incorporates observational data about sequence-driven biochemical processes, such as binding of transcription factor proteins, in a 3D model of chromatin structure. We introduce a novel approximate Bayesian algorithm to quantify a posteriori the relative importance of various factors, including the polymeric nature of DNA, in determining chromatin epigenetic state, thus providing a transparent way to generate biological hypotheses. While accurate prediction of contact frequencies (a problem already extensively studied in the literature) is not our main aim, as a byproduct of the inference procedure and without additional input from the genome 3D structure, our model can predict with reasonable accuracy some notable and nontrivial conformational features of chromatin folding within the nucleus. Our work highlights the importance of introducing physically realistic statistical models for predicting chromatin states from epigenetic data and opens the way to a new class of more systematic approaches to interpreting epigenomic data.


Efficacy of different 8 h time-restricted eating schedules on visceral adipose tissue and cardiometabolic health: A study protocol.
To investigate the efficacy and feasibility of three different 8 h time-restricted eating (TRE) schedules (i.e., early, late, and self-selected) compared to each other and to a usual-care (UC) intervention on visceral adipose tissue (VAT) and cardiometabolic health in men and women. Anticipated 208 adults (50% women) aged 30-60 years, with overweight/obesity (25 ≤ BMI<40 kg/m2) and with mild metabolic impairments will be recruited for this parallel-group, multicenter randomized controlled trial. Participants will be randomly allocated (1:1:1:1) to one of four groups for 12 weeks: UC, early TRE, late TRE or self-selected TRE. The UC group will maintain their habitual eating window and receive, as well as the TRE groups, healthy lifestyle education for weight management. The early TRE group will start eating not later than 10:00, and the late TRE group not before 13:00. The self-selected TRE group will select an 8 h eating window before the intervention and maintain it over the intervention. The primary outcome is changes in VAT, whereas secondary outcomes include body composition and cardiometabolic risk factors. This study will determine whether the timing of the eating window during TRE impacts its efficacy on VAT, body composition and cardiometabolic risk factors and provide insights about its feasibility.


Human CD47 expression permits survival of porcine cells in immunodeficient mice that express SIRPα capable of binding to human CD47.
Signal regulatory protein α (SIRPα) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47 prevents autologous phagocytosis. We have previously shown that pig CD47 does not interact with human SIRPα, and that human CD47 expression inhibits phagocytosis of porcine cells by human macrophages in vitro. In this study, we have investigated the potential of human CD47 expression to promote porcine cell survival in vivo. Human CD47-expressing and control porcine B-lymphoma cells were transplanted into T- and B-cell-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice that express SIRPα capable of interacting with human CD47. Only the human CD47-expressing porcine lymphoma cells survived and were able to form tumors in NOD/SCID mice; however, both the control and human CD47-expressing porcine cells survived in macrophage-depleted NOD/SCID mice. These results indicate that transgenic expression of human CD47 may provide an effective approach to inhibiting macrophage-mediated xenograft rejection in clinical xenotransplantation.


Effects of 1.23% acidulated phosphate fluoride gel and drinkable yogurt on human enamel erosion, in vitro.
In this in vitro study, the authors sought to determine the effects of 1.23% acidulated phosphate fluoride gel (APF) or drinkable yogurt on human enamel after exposure to an acidic drink. Sixteen surgically removed, caries-free, human third molars were cut into four portions: mesial, distal, buccal, and lingual. Each portion was distributed into one of four groups, with each specimen embedded in acrylic resin and its enamel center lightly ground and polished. Three groups of specimens were immersed in orange juice for 2 minutes. One group received no other treatment (OR), one group was subsequently immersed in drinkable yogurt for 5 minutes (OR:YO), while another group had 1.23% APF applied for 4 minutes (OR:APF). The final group was immersed in only drinkable yogurt for 5 minutes (YO). Each exposure was performed twice daily for 60 days; between exposures, the samples were stored in artificial saliva. The enamel surfaces were monitored by three criteria: erosion depth, surface hardness, and SEM. Erosion depth increased progressively in all groups. Surface microhardness progressively decreased in all groups except the OR:APF group, where hardness was significantly higher than other groups at 60 days (P < .05). SEM inspection revealed preferential loss of rod crystallites with retention of interrod crystallites in all specimens exposed to orange juice. The enamel exposed to only drinkable yogurt revealed modest and uniform etching. Drinkable yogurt alone or posttreatment of enamel after exposure to an acidic drink with either 1.23% APF or drinkable yogurt leads to enamel dissolution and does not reduce enamel erosion, in vitro.


Cost-effectiveness of a physical exercise programme for residents of care homes: a pilot study.
Oomph! Wellness organises interactive exercise and activity classes (Oomph! classes) for older people in care homes. We investigated the cost-effectiveness of Oomph! classes. Health-related quality of life was measured using the EQ-5D-5 L questionnaire at three time points; 3 months and 1 week prior to the start of the classes and after 3 months of Oomph! classes. Costs included the costs of organising the classes, training instructors and health service use (General Practitioner (GP) and hospital outpatient visits). To determine the cost-effectiveness of Oomph! classes, total costs and quality-adjusted life-years (QALYs) during the 3 months after initiation of the classes were compared to the total costs and QALYs of the 3 months prior to the classes and extrapolated to a 1-year time horizon. Uncertainty was taken into account using one-way and probabilistic sensitivity analysis. Sixteen residents completed all three EQ-5D-5 L questionnaires. There was a decrease in mean health related quality of life per participant in the 3 months before Oomph! classes (0.56 to 0.52, p = 0.26) and an increase in the 3 months after the start of Oomph! classes (0.52 to 0.60, p = 0.06), but the changes were not statistically significant. There were more GP visits after the start of Oomph! classes and fewer hospital outpatient visits, leading to a slight decrease in NHS costs (mean £132 vs £141 per participant), but the differences were not statistically significant (p = 0.79). In the base case scenario, total costs for Oomph! classes were £113 higher per participant than without Oomph! classes (£677 vs £564) and total QALYs were 0.074 higher (0.594 vs 0.520). The incremental costs per QALY gained were therefore £1531. The 95 % confidence intervals around the cost/QALY gained varied from dominant to dominated, meaning there was large uncertainty around the cost-effectiveness results. Given a willingness to pay threshold of £20,000 per QALY gained, Oomph! classes had a 62 %-86 % probability of being cost-effective depending on the scenario used. Preliminary evidence suggests that Oomph! classes may be cost-effective, but further evidence is needed about its impact on health-related quality of life and health service use.


Possible role of accessibility of protein-SH groups to the cancer state.
From out histochemical studies, protein-sulfhydryl (SH) groups are found mainly concentrated in the nucleus and in cell nuclear membranes. Both clinically and in sensitivity tests, selected SH inhibitors have been found to be more active than other commonly used anticancer agents, against an array of cancers, than against normal tissues. The same SH inhibitors can induce immunity against some cancers in animals, while causing blunting of microvilli and alterations in cell surface of the cancer cells. From recent electron spin resonance data (ESR), selected SH inhibitors and glyoxal derivatives can raise the low ESR signal of cancers towards or above normal. The variety of important roles of protein-SH groups to the cancerous state underscores the possible role of accessibility of protein-SH groups to cancer. This very importance of protein-SH groups to cancer, with their highly variable chemical reactivity, underscores also the lack of validity of randomized protocols for clinical cancer therapy. None of these take into account any measure of the chemical sensitivity of each patient's own cancer.


Novel benzoxazinone derivative as potent human neutrophil elastase inhibitor: Potential implications in lung injury.
Neutrophil elastase, a powerful physiological defence tool, may serve as drug target for diverse diseases due to its bystander effect on host cells like chronic obstructive pulmonary disease (COPD). Here, we synthesised seven novel benzoxazinone derivatives and identified that these synthetic compounds are human neutrophil elastase inhibitor that was demonstrated by enzyme substrate kinetic assay. One such compound, PD05, emerged as the most potent inhibitor with lower IC50 as compared to control drug sivelestat. While this inhibition is competitive based on substrate dilution assay, PD05 showed a high binding affinity for human neutrophil elastase (Kd = 1.63 nM) with faster association and dissociation rate compared to notable elastase inhibitors like ONO 6818 and AZD9668, and its interaction with human neutrophil elastase was fully reversible.Preclinical pharmacokinetic studies were performed in vitro where protein binding was found to be 72% with a high recovery rate, aqueous solubility of 194.7 μM, low permeability along with a favourable hERG. Experiments with cell line revealed that the molecule successfully prevented elastase induced rounding and retracted cell morphology and cell cytotoxicity. In mouse model PD05 is able to reduce the alveolar collapse induced by neutrophil elastase. In summary, we demonstrate the in situ, in vitro and in vivo anti-elastase potential of the newly synthesised benzoxazinone derivative PD05 and thus this could be promising candidate for further investigation as a drug for the treatment of COPD.


Self-reported occupational health issues among Lithuanian dentists.
This article describes the second phase of a large study of Lithuanian dentists' health, and focuses on self-reported physical health complaints, general health state and associations between the two. In 2006, a postal questionnaire survey of all (N=2,449) licensed dentists registered with the Lithuanian Dental Association was conducted, obtaining a response rate of 68.2%. Fatigue (94.7%) and back pain (91.0%) were the most prevalent physical complaints reported, and they were also the most likely to become chronic among all physical disorders. Hypertension, joint diseases and allergy were the most prevalent diagnosed and treated diseases during the previous 12 months. Only half of the surveyed Lithuanian dentists (50.4%) rated their health as satisfactory. Logistic regression revealed that fatigue (Odds Ratio: 0.52; 95%CI: 0.29-0.94), headache (OR: 0.62; 95%CI: 0.42-0.90), hand problems (OR: 0.62; 95%CI: 0.44-0.87), chest pain (OR: 0.51; 95%CI: 0.40-0.64) and musculoskeletal complaints (OR: 0.41; 95%CI: 0.28-0.60) had a significant negative impact on dentists' self-reported general health. Overall, this study suggests that Lithuanian dentists do experience a certain amount of occupationally-related health problems. It is therefore important to increase health knowledge on occupational hazards and also to emphasize the importance of early diagnosis and treatment for these disorders in Lithuania, as elsewhere.


Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias.
Constitutively active tyrosine kinases promote leukemogenesis by increasing cell proliferation and inhibiting apoptosis. However, mechanisms underlying apoptotic inhibition have not been fully elucidated. In many settings, apoptosis occurs by mitochondrial cytochrome c release, which nucleates the Apaf-1/caspase-9 apoptosome. Here we report that the leukemogenic kinases, Bcr-Abl, FLT3/D835Y, and Tel-PDGFRbeta, all can inhibit apoptosome function. In cells expressing these kinases, the previously reported apoptosome inhibitor, Hsp90beta, bound strongly to Apaf-1, preventing cytochrome c-induced Apaf-1 oligomerization and caspase-9 recruitment. Hsp90beta interacted weakly with the apoptosome in untransformed cells. While Hsp90beta was phosphorylated at Ser 226/Ser 255 in untransformed cells, phosphorylation was absent in leukemic cells. Expression of mutant Hsp90beta (S226A/S255A), which mimics the hypophosphorylated form in leukemic cells, conferred resistance to cytochrome c-induced apoptosome activation in normal cells, reflecting enhanced binding of nonphosphorylatable Hsp90beta to Apaf-1. In Bcr-Abl-positive mouse bone marrow cells, nonphosphorylatable Hsp90beta expression conferred imatinib (Gleevec) resistance. These data provide an explanation for apoptosome inhibition by activated leukemogenic tyrosine kinases and suggest that alterations in Hsp90beta-apoptosome interactions may contribute to chemoresistance in leukemias.


Can carbon emission trading improve carbon emission performance? Evidence from a quasi-natural experiment in China.
Carbon emission trading policies play a key role in reducing carbon emissions through market-based mechanisms. In the context of China's carbon neutrality goals and carbon peaking targets, it is important to predict and evaluate the effectiveness of such policies. The combined impact of carbon trading policies on carbon emission reduction and economic output has not been well investigated in previous studies. In this study, the impact of carbon emission trading policies on regional carbon emission performance was assessed through mechanism analysis and empirical tests. The mechanism analysis showed that carbon emission intensity reduction relied on three mediating effects: technological innovation incentives, industrial structure optimization, and energy substitution. For the empirical test, the multi-time difference-in-differences (DID) method was adopted to study the impact using panel data from 30 provinces in China between 2005 and 2019. Moreover, the specific impact mechanism was further tested using mediating effects. The results showed that China's carbon trading policy has significantly affected the carbon emission performance of the pilot regions, and factors such as GDP per capita, urbanization level, and capital-labor ratio have notably contributed to the reduction of carbon emission intensity. The proportions of the three mediating effects in the total effect were estimated to be 60.98%, 23.17%, and 10.14%, respectively. This study provides an empirical approach to the study of the impact of carbon trading policy on carbon emission reduction and economic output and can serve as a reference for addressing climate change and alleviating conflicts between the environment and economic growth in similar regions.


[Canine brucellosis in dogs in the city of Buenos Aires].
Canine brucellosis, caused by Brucella canis, provokes epidydimitis, testicular atrophy and sterility in male dogs, while in females the major symptom is miscarriage. Transmission to humans may be through contact with semen, urine and/or aborted fetuses of infected animals. Our study, observational and cross-sectional, focused on dogs in lower class neighborhoods and slums with a high rate of unmet basic needs (UBN) in 8 areas of the city of Buenos Aires. We studied 219 dogs: 184 females and 35 males, that tested negative to the buffered plate antigen test (BPAT), which ruled out infection with smooth species of Brucella. We detected anti-B. canis antibodies in 16 dogs (7.3%): 9 females and 7 males, relevant data since the urine of males is considered one of the vectors for the spread of the infection. Although we could run blood cultures on only 175 animals, we isolated B. canis in 3 (2 females and 1 male). Only 3 of the owners of dogs that tested positive consented to a serological diagnosis and two of them were positive. We highlight that the agar gel immunodiffusion test (IGID) proved to have low sensitivity, having detected only one of the 16 positive cases and none of the three confirmed by isolation. We conclude that in the areas studied, the detection of serologically positive dogs and the isolation of B. canis in 3 cases are indicators of the health hazard for the population exposed to it.


Circulating miR-103a-3p and miR-660-5p are associated with bone parameters in patients with controlled acromegaly.
Background Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis. Aims Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters. Patients and methods Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR. Results In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001). Conclusions Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.


Cerium Pyrazolates Grafted onto Mesoporous Silica SBA-15: Reversible CO2 Uptake and Catalytic Cycloaddition of Epoxides and Carbon Dioxide.
The activation and catalytic conversion of CO2 is a current topic relating to molecular chemistry and materials science alike. As a transdisciplinary field of research, surface organometallic chemistry (SOMC) might be applicable to perform synergistically, thus striking a new path in sustainable chemistry. Both ceric and cerous rare-earth-metal pyrazolates, which were recently shown to reversibly insert CO2 and to promote the catalytic cycloaddition of epoxides and carbon dioxide, were grafted onto large-pore mesoporous silica SBA-15500, thermally pretreated at 500 °C. The obtained hybrid materials [Ce(Me2pz)4]2@SBA-15500, Ce(Me2pz)4(thf)@SBA-15500, Ce4(Me2pz)12@SBA-15500, and [Ce(Me2pz)3(thf)]2@SBA-15500 (Me2pz = 3,5-dimethylpyrazolato) were characterized by DRIFTS (diffuse reflectance infrared Fourier transform spectroscopy), solid-state 1H/13C NMR spectroscopy, elemental analysis, ICP/OES, and N2 physisorption. The lanthanum(III)-based material [La(Me2pz)3(thf)]2@SBA-15500 was synthesized for better assessment of the cerous materials being highly sensitive to oxidation. To mimic ceric surface species, Ce[OSi(OtBu)3]3Cl was treated with 1 equiv of K(Me2pz), generating the mixed pyrazolyl/siloxy complex KCe[OSi(OtBu)3]4(Me2pz) featuring a cerium(IV)-bonded terminal pyrazolato ligand. All hybrid materials show efficient and reversible carbon dioxide uptake of maximum 20 wt % in the solid state. When combined with tetra-n-butylammonium bromide (TBAB), the hybrid materials catalyze the cycloaddition of CO2 and epoxides, displaying good conversion of various epoxides and reusability.


Development and validation of an ELISA method for quantification of the anti-HER3 antibody HMBD-001 in human serum.
Background: HMBD-001 is an IgG1 humanized monoclonal antibody specifically targeting HER3, a receptor highly expressed on cancer cells in certain tumors. A bioanalytical method was required to quantify HMBD-001 in human serum, with high selectivity and without interference from HER3. Methods and results: A bridging ELISA using an anti-idiotypic monoclonal capture and detection was developed and validated for quantitative measurement of HMBD-001 in human serum. The assay is sensitive, with a lower limit of quantification of 250 ng/ml, has a broad dynamic range of 250-7000 ng/ml HMBD-001, and exhibits excellent precision and overall accuracy. Conclusion: We have developed and validated a sensitive and selective method for measuring HMBD-001 in human serum. This assay is now being used in a clinical trial setting.


Effect of Fluoride Varnish Containing CPP-ACP on Preventing Enamel Erosion.
This study aimed to investigate the effect of a fluoride varnish with added casein phosphopeptide-amorphous calcium phosphate treatment on the prevention of enamel erosion, and it compared the results with those of other fluoride varnishes. Fifty enamel specimens obtained from bovine incisors were randomly divided into five groups (n = 10) based on the type of surface pretreatment used: intact enamel (Group 1); intact enamel+erosive cycles (Group 2); intact enamel+MI varnish+erosive cycles (Group 3); intact enamel+Clinpro White varnish+erosive cycles (Group 4); and intact enamel+Duraphat varnish+erosive cycles (Group 5). The specimens were subjected to erosive cycles for five days. The surface roughness was evaluated using atomic force microscopy. The results were statistically analyzed using one-way ANOVA and Tukey's tests. Group 1 had the smoothest surfaces. After the erosive cycles, the greatest surface roughness values were observed in Group 2, followed by Groups 5, 4, and 3, respectively. Statistically significant differences were observed among all groups (p < 0.05). The application of fluoride varnishes had some positive effects on preventing enamel erosion; however, the most effective agent was fluoride varnish with added casein phosphopeptide-amorphous calcium phosphate.


Structural Insights into the Free-Standing Condensation Enzyme SgcC5 Catalyzing Ester-Bond Formation in the Biosynthesis of the Enediyne Antitumor Antibiotic C-1027.
C-1027 is a chromoprotein enediyne antitumor antibiotic, consisting of the CagA apoprotein and the C-1027 chromophore. The C-1027 chromophore features a nine-membered enediyne core appended with three peripheral moieties, including an ( S)-3-chloro-5-hydroxy-β-tyrosine. In a convergent biosynthesis of the C-1027 chromophore, the ( S)-3-chloro-5-hydroxy-β-tyrosine moiety is appended to the enediyne core by the free-standing condensation enzyme SgcC5. Unlike canonical condensation domains from the modular nonribosomal peptide synthetases that catalyze amide-bond formation, SgcC5 catalyzes ester-bond formation, as demonstrated in vitro, between SgcC2-tethered ( S)-3-chloro-5-hydroxy-β-tyrosine and ( R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core as an acceptor substrate. Here, we report that (i) genes encoding SgcC5 homologues are widespread among both experimentally confirmed and bioinformatically predicted enediyne biosynthetic gene clusters, forming a new clade of condensation enzymes, (ii) SgcC5 shares a similar overall structure with the canonical condensation domains but forms a homodimer in solution, the active site of which is located in a cavity rather than a tunnel typically seen in condensation domains, and (iii) the catalytic histidine of SgcC5 activates the 2-hydroxyl group, while a hydrogen-bond network in SgcC5 prefers the R-enantiomer of the acceptor substrate, accounting for the regio- and stereospecific ester-bond formation between SgcC2-tethered ( S)-3-chloro-5-hydroxy-β-tyrosine and ( R)-1-phenyl-1,2-ethanediol upon acid-base catalysis. These findings expand the catalytic repertoire and reveal new insights into the structure and mechanism of condensation enzymes.


Silica nanoparticles as promising drug/gene delivery carriers and fluorescent nano-probes: recent advances.
The application of nanotechnology to biomedical research is expected to have a major impact leading to the development of new types of diagnostic and therapeutic tools. One focus in nanobiotechnology is to develop safe and efficient drug/gene delivery vehicles. Research into the rational delivery and targeting of pharmaceutical, therapeutic and diagnostic agents is at the forefront of projects in nanomedicine. Silica, as a major and natural component of sand and glass, is a versatile material due to the variety of available chemical and physical modifications that are available, and recently have been widely applied in nanobiotechnology as drug/gene carriers or fluorescent nano-probes. The goal of this brief review is to illustrate selected examples of various functionalized silica nanoparticles as drug/gene delivery systems that have been applied to the arenas of human disease therapy or detection (molecular and cellular imaging).


Influence of body weight unloading on human gait characteristics: a systematic review.
Body weight support (BWS) systems have shown promise as rehabilitation tools for neurologically impaired individuals. This paper reviews the experiment-based research on BWS systems with the aim: (1) To investigate the influence of body weight unloading (BWU) on gait characteristics; (2) To study whether the effects of BWS differ between treadmill and overground walking and (3) To investigate if modulated BWU influences gait characteristics less than unmodulated BWU. A systematic literature search was conducted in the following search engines: Pubmed, Scopus, Web of Science and Google Scholar. Statistical analysis was used to quantify the effects of BWU on gait parameters. 54 studies of experiments with healthy and neurologically impaired individuals walking in a BWS system were included and 32 of these were used for the statistical analysis. Literature was classified using three distinctions: (1) treadmill or overground walking; (2) the type of subjects and (3) the nature of unloading force. Only 27% studies were based on neurologically impaired subjects; a low number considering that they are the primary user group for BWS systems. The studies included BWU from 5% to 100% and the 30% and 50% BWU conditions were the most widely studied. The number of participants varied from 1 to 28, with an average of 12. It was seen that due to the increase in BWU level, joint moments, muscle activity, energy cost of walking and ground reaction forces (GRF) showed higher reduction compared to gait spatio-temporal and joint kinematic parameters. The influence of BWU on kinematic and spatio-temporal gait parameters appeared to be limited up to 30% unloading. 5 gait characteristics presented different behavior in response to BWU for overground and treadmill walking. Remaining 21 gait characteristics showed similar behavior but different magnitude of change for overground and treadmill walking. Modulated unloading force generally led to less difference from the 0% condition than unmodulated unloading. This review has shown that BWU influences all gait characteristics, albeit with important differences between the kinematic, spatio-temporal and kinetic characteristics. BWU showed stronger influence on the kinetic characteristics of gait than on the spatio-temporal parameters and the kinematic characteristics. It was ascertained that treadmill and overground walking can alter the effects of BWU in a different manner. Our results indicate that task-specific gait training is likely to be achievable at a BWU level of 30% and below.


GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma.
We previously reported a profound long-term neuroprotection subsequent to a single radiation-therapy in the DBA/2J mouse model of glaucoma. This neuroprotection prevents entry of monocyte-like immune cells into the optic nerve head during glaucoma. Gene expression studies in radiation-treated mice implicated Glycam1 in this protection. Glycam1 encodes a proteoglycan ligand for L-selectin and is an excellent candidate to modulate immune cell entry into the eye. Here, we experimentally test the hypothesis that radiation-induced over-expression of Glycam1 is a key component of the neuroprotection. We generated a null allele of Glycam1 on a DBA/2J background. Gene and protein expression of Glycam1, monocyte entry into the optic nerve head, retinal ganglion cell death, and axon loss in the optic nerve were assessed. Radiation therapy potently inhibits monocyte entry into the optic nerve head and prevents retinal ganglion cell death and axon loss. DBA/2J mice carrying a null allele of Glycam1 show increased monocyte entry and increased retinal ganglion cell death and axon loss following radiation therapy, but the majority of optic nerves were still protected by radiation therapy. Although GlyCAM1 is an L-selectin ligand, its roles in immunity are not yet fully defined. The current study demonstrates a partial role for GlyCAM1 in radiation-mediated protection. Furthermore, our results clearly show that GlyCAM1 levels modulate immune cell entry from the vasculature into neural tissues. As Glycam1 deficiency has a more profound effect on cell entry than on neurodegeneration, further experiments are needed to precisely define the role of monocyte entry in DBA/2J glaucoma. Nevertheless, GlyCAM1's function as a negative regulator of extravasation may lead to novel therapeutic strategies for an array of common conditions involving inflammation.


Gene expression variability as a unifying element of the pluripotency network.
Heterogeneity is a hallmark of stem cell populations, in part due to the molecular differences between cells undergoing self-renewal and those poised to differentiate. We examined phenotypic and molecular heterogeneity in pluripotent stem cell populations, using public gene expression data sets. A high degree of concordance was observed between global gene expression variability and the reported heterogeneity of different human pluripotent lines. Network analysis demonstrated that low-variability genes were the most highly connected, suggesting that these are the most stable elements of the gene regulatory network and are under the highest regulatory constraints. Known drivers of pluripotency were among these, with lowest expression variability of POU5F1 in cells with the highest capacity for self-renewal. Variability of gene expression provides a reliable measure of phenotypic and molecular heterogeneity and predicts those genes with the highest degree of regulatory constraint within the pluripotency network.


Polyprenols of Aspergillus niger. Their characterization, biosynthesis and subcellular distribution.
A polyprenol complex of Aspergillus niger was shown, by using spectrometric methods, to consist of a family of exo-methylene-hexahydroprenols that contain between 18 and 24 isoprene residues per molecule. Each prenol contains two trans residues, three saturated residues (alpha, omega and psi) and an exo-methylene substituent on the carbon atom beta to the isopropyl group in each omega-residue. The ubiquinone complex consisted of 90% ubiquinone-9, 9% ubiquinone-8 and 1% ubiquinone-10. The amount of polyprenol complex present reached a maximum of 1.7mg/culture bottle after 9-10 days of growth, coincident with the maximum weight of mycelium. The amount of ergosterol (10mg/culture bottle) and ubiquinone (1mg/culture bottle) reached a peak at 8 days. By the 13th day of growth the yield of ergosterol had fallen by 20% and that of ubiquinone by 85%. A study of the incorporation of [2-(14)C]mevalonate over different time-intervals confirmed that there was a slow turnover of prenol, a more rapid turnover of ergosterol and a very rapid turnover of ubiquinone. At any one time each member of the prenol complex had essentially the same specific radioactivity as other members of the complex. A similar conclusion was made about the ubiquinone mixture. Just over half of the polyprenol present was esterified to fatty acids. Subcellular fractionation studies indicated that the unesterified prenol is associated primarily with a mitochondrial fraction, whereas the ester is more widely distributed.


Durable natural killer cell response after three doses of SARS-CoV-2 inactivated vaccine in HIV-infected individuals.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine can induce a potent cellular and humoral immune response to protect against SARS-CoV-2 infection. However, it was unknown whether SARS-CoV-2 vaccination can induce effective natural killer (NK) cell response in people living with human immunodeficiency virus (PLWH) and healthy individuals. Forty-seven PLWH and thirty healthy controls (HCs) inoculated with SARS-CoV-2 inactivated vaccine were enrolled from Beijing Youan Hospital in this study. The effect of SARS-CoV-2 vaccine on NK cell frequency, phenotype, and function in PLWH and HCs was evaluated by flow cytometry, and the response of NK cells to SARS-CoV-2 Omicron Spike (SARS-2-OS) protein stimulation was also evaluated. SARS-CoV-2 vaccine inoculation elicited activation and degranulation of NK cells in PLWH, which peaked at 2 weeks and then decreased to a minimum at 12 weeks after the third dose of vaccine. However, in vitro stimulation of the corresponding peripheral blood monocular cells from PLWH with SARS-2-OS protein did not upregulate the expression of the aforementioned markers. Additionally, the frequencies of NK cells expressing the activation markers CD25 and CD69 in PLWH were significantly lower than those in HCs at 0, 4 and 12 weeks, but the percentage of CD16+ NK cells in PLWH was significantly higher than that in HCs at 2, 4 and 12 weeks after the third dose of vaccine. Interestingly, the frequency of CD16+ NK cells was significantly negatively correlated with the proportion of CD107a+ NK cells in PLWH at each time point after the third dose. Similarly, this phenomenon was also observed in HCs at 0, 2, and 4 weeks after the third dose. Finally, regardless of whether NK cells were stimulated with SARS-2-OS or not, we did not observe any differences in the expression of NK cell degranulation markers between PLWH and HCs. SARS-CoV-2 vaccine elicited activation and degranulation of NK cells, indicating that the inoculation of SARS-CoV-2 vaccine enhances NK cell response.


Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives.
In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.


Cutaneous extranodal NK/T-cell lymphoma: a clinicopathologic study of 5 patients with array-based comparative genomic hybridization.
Extranodal natural killer/T-cell (ENK/T) lymphoma is a rare neoplasm, subcategorized into ENK/T-nasal (ENK/T-N) and ENK/T-nasal type (ENK/T-NT) lymphomas. ENK/T-NT lymphoma with initial presentation in the skin is known as primary cutaneous ENK/T-NT (PC-ENK/T-NT) lymphoma. The aim of this study was to investigate pathogenesis, genomic alterations, and prognosis of cutaneous ENK/T lymphomas to provide further insights into clinicopathologic features and genetic mechanism of lymphomagenesis. A retrospective case study of 5 white patients affected by ENK/T lymphoma (4 PC-ENK/T-NT and 1 ENK/T-N with cutaneous involvement) was performed. Most of the cases presented with multiple nodules and ulcerations localized on the extremities. A considerable percentage had disease in advanced stage with a 12-month survival rate of 40%. Genomic alterations were detected by array-based comparative genomic hybridization that showed gains of 1q, 7q and loss of 17p in the cases of PC-ENK/T-NT lymphomas and gain of 7q and loss of 9p, 12p, 12q in the case of ENK/T-N lymphoma. In conclusion, ENK/T lymphoma is a very aggressive entity, and, in our cases, the exclusively cutaneous presentation was not associated with a better prognosis. The results of our array comparative genomic hybridization analysis could be useful to better define the different ENK/T lymphoma subgroups with cutaneous involvement.


Capacitive Sensing of Glucose in Electrolytes Using Graphene Quantum Capacitance Varactors.
A novel graphene-based variable capacitor (varactor) that senses glucose based on the quantum capacitance effect was successfully developed. The sensor utilizes a metal-oxide-graphene varactor device structure that is inherently compatible with passive wireless sensing, a key advantage for in vivo glucose sensing. The graphene varactors were functionalized with pyrene-1-boronic acid (PBA) by self-assembly driven by π-π interactions. Successful surface functionalization was confirmed by both Raman spectroscopy and capacitance-voltage characterization of the devices. Through glucose binding to the PBA, the glucose concentration in the buffer solutions modulates the level of electrostatic doping of the graphene surface to different degrees, which leads to capacitance changes and Dirac voltage shifts. These responses to the glucose concentration were shown to be reproducible and reversible over multiple measurement cycles, suggesting promise for eventual use in wireless glucose monitoring.


National survey: Developing a common approach to grading of practice in pre-registration midwifery.
This paper presents the final phase of a national project exploring grading of practice in programmes leading to registration as a midwife in the United Kingdom. The aim was to develop a generic framework for grading practice, enhancing standardisation while enabling flexibility in application of current and new educational standards. A mixed method on-line survey considered existing practice assessment tools, factors contributing to robust and reliable assessment and perceptions of two assessment tools developed by the research team: a 'Lexicon Framework' and 'Rubric', which were tested through scenarios. Participants included 170 midwifery and nursing academics, clinicians and students, representing 20 universities in the UK. Seven key themes emerged, from which an 'Evidence Based Model for Professional Practice Assessment' was developed. The proposed tools were overall positively evaluated and demonstrated a good level of reliability. A national tool to standardise midwifery practice assessment is recommended, and scope for transferability of our tools to all midwifery programmes and to nursing was identified. Other recommendations include engagement of key stakeholders in development of practice assessment documentation, and maintaining the professional purpose of grading practice as central to the process. A set of key principles for assessing practice is presented.


Coinfection with HIV-1 alleviates iron accumulation in patients with chronic hepatitis C virus infection.
Most chronically-infected hepatitis C virus (HCV) patients have increased levels of iron in the liver. Iron overload reduces sustained responses to antiviral therapy, leading to more rapid progression to liver cirrhosis and the development of hepatocellular carcinoma. However, it is still unclear how HIV-1 infection affects iron status in patients chronically infected with HCV. The present study recruited 227 patients from a village in central China. These patients were either monoinfected with HCV (n = 129) or coinfected with HCV/HIV-1 (n = 98). Healthy controls (n = 84) were also recruited from the same village. Indicators of iron status, such as serum levels of iron, ferritin, and transferrin, total iron-binding capacity (TIBC), transferrin saturation (Tfs), and hepcidin, were analyzed and compared across the three groups. The results showed that serum levels of iron (p = 0.001) and ferritin (p = 0.009) and the Tfs (p = 0.002) were significantly higher in HCV-monoinfected patients than in the healthy controls; however, there were no differences in iron levels and Tfs between HCV/HIV-1 coinfected patients and healthy controls. Additionally, although serum hepcidin levels in HCV-monoinfected and HCV/HIV-1-coinfected patients were lower (p<0.001) than those in health controls, the levels in coinfected patients were higher (p = 0.025) than those in HCV-monoinfected patients. Serum iron and ferritin levels in HCV-monoinfected patients were positively correlated with serum ALT/AST. Serum transferrin levels were negatively correlated with ALT/AST levels. The levels of iron in the serum of coinfected patients with a CD4+T-cell count <500/µl were lower than those in patients with a CD4+T-cell count ≥500/µl, whereas serum hepcidin levels showed the opposite trend. Taken together, these results suggest that coinfection with HIV-1 alleviates iron accumulation caused by chronic HCV infection. Our study indicated that determining the status of serum iron and other iron-associated parameters will be helpful to understand the complexity of alternations in iron distribution in HCV/HIV-1-coinfected patients.


Rheumatic fever and rheumatic heart disease in Barbados: detection and prophylaxis.
The objectives of this study were to improve our methods of secondary prophylaxis of rheumatic fever and rheumatic heart disease in Barbados, to estimate the overall prevalence of these diseases and the relative load imposed by them on available health services, and to measure the yield, feasibility, and effectiveness of mass programmes for the detection and prophylactic management of rheumatic heart disease in schoolchildren.Improved methods of surveillance and follow-up resulted in 97% adherence to therapy by patients on prophylactic penicillin. Thirty-four children, 27 with a first attack, were admitted with acute rheumatic fever, representing a 7% occupancy of children's medical beds during the 12-month period of the study. Out of a possible 3,942 schoolchildren aged 5-11 years, 3,882 (98%) were screened for rheumatic heart disease. Four cases (about 1 per 1,000) were discovered.


Modular organization of the Sulfolobus solfataricus mini-chromosome maintenance protein.
Mini-chromosome maintenance (MCM) proteins form ring-like hexameric complexes that are commonly believed to act as the replicative DNA helicase at the eukaryotic/archaeal DNA replication fork. Because of their simplified composition with respect to the eukaryotic counterparts, the archaeal MCM complexes represent a good model system to use in analyzing the structural/functional relationships of these important replication factors. In this study the domain organization of the MCM-like protein from Sulfolobus solfataricus (Sso MCM) has been dissected by trypsin partial proteolysis. Three truncated derivatives of Sso MCM corresponding to protease-resistant domains were produced as soluble recombinant proteins and purified: the N-terminal domain (N-ter, residues 1-268); a fragment comprising the AAA+ and C-terminal domains (AAA+-C-ter, residues 269-686); and the C-terminal domain (C-ter, residues 504-686). All of the purified recombinant proteins behaved as monomers in solution as determined by analytical gel filtration chromatography, suggesting that the polypeptide chain integrity is required for stable oligomerization of Sso MCM. However, the AAA+-C-ter derivative, which includes the AAA+ motor domain and retains ATPase activity, was able to form dimers in solution when ATP was present, as analyzed by size exclusion chromatography and glycerol gradient sedimentation analyses. Interestingly, the AAA+-C-ter protein could displace oligonucleotides annealed to M13 single-stranded DNA although with a reduced efficiency in comparison with the full-sized Sso MCM. The implications of these findings for understanding the DNA helicase mechanism of the MCM complex are discussed.


[Approach to the causes of discharge and health needs of transgender people through the National Hospital Discharge Survey in Spain during the period 2001 to 2013].
The health of transgender people is a little studied topic and hospital records can be an opportunity to make an approach. The aim of this study was to describe the cause for admission and the associated comorbidities of transgender people in Spain between 2001 and 2013. Retrospective observational study with population-based administrative records (Minimum Basic Data Set). The discharges generated by the transgender in Spanish public and private hospitals were selected using one of the following ICD-9-CM codes in any diagnostic field: Trans-sexualism (302.5), Disorders of psychosexual identity (302.6) and Gender identity disorder in adolescents or adults (302.85). The causes of admission and comorbidity according were described. The qualitative variables were described in their frequency distribution according to their number(n) and proportion(%) and the quantitative variables according to their mean and standard deviation (SD) or median (MD) and interquartile range (RIQ) according to their distribution. A total of 2,010 highs were recorded corresponding to 1,878 patients. The mean age was 33 years (SD = 10). 51% were male, 46% female and 3% undetermined or unspecified. The discharges were motivated in 59% by the process of body modification, followed by HIV (4%) and personality disorders (3%). The most common comorbidities were those associated with body modification (49%), mental health problems (40%) and infectious diseases (15%). It is necessary to address the health of transgender people in a comprehensive way that takes into account their specific health needs, including bodily modification, mental health, HIV and other infections, through strategies that include improve research, tailor health information systems and develop guidelines and training of healthcare providers in this transgender health.


Sleepless in COVID-19: racial disparities during the pandemic as a consequence of structural inequity.
Insomnia has been on the rise during the 2019 coronavirus disease (COVID-19) pandemic, which may disproportionately affect racial minorities. This study characterized racial disparities in insomnia during the pandemic and evaluated mechanisms for such disparities. Participants included 196 adults (48 Black) from a 2016-2017 clinical trial of insomnia treatment who were reevaluated in April 2020. Race was evaluated as a predictor of change in insomnia, impact of COVID-19, and COVID-19 stress. Mediation models using the PRODCLIN method evaluated the extent to which: (1) COVID-19 impact accounted for Black-White disparities in change in insomnia, and (2) COVID-19 stress accounted for associations between discrimination and change in insomnia. Increases in insomnia symptoms during COVID-19 were greater in Black compared to White participants, with 4.3 times the odds of severe insomnia (Insomnia Severity Index ≥ 22). Symptom severity was associated with pre-pandemic experiences of discrimination. Black participants were also disproportionately impacted by COVID-19, with twice the odds of irreparable loss of income/employment and four times the rate of COVID-19 diagnoses in their sociofamilial network compared to White participants. The disproportionate impact of COVID-19 accounted for 69.2% of the relationship between race and change in insomnia severity, and COVID-19 related stress accounted for 66.5% of the relationship between prior history of racial discrimination and change in insomnia severity. Black-White disparities in insomnia severity during COVID-19 may be driven by structural inequities resulting in the disproportionate impact of COVID-19 on Black Americans. Results lend support for the minority stress model in the context of sleep health. Sleep to Prevent Evolving Affecting Disorders (SPREAD). NCT number: NCT02988375. https://clinicaltrials.gov/ct2/show/NCT02988375.


Interactions of new synthesized fluorescent cationic amphiphiles bearing pyrene hydrophobe with plasmid DNA: binding affinities, aggregation and intracellular uptake.
In this work, we prepared a novel series of cationic amphiphiles denoted as the Py-cations (Py-Gly, Py-Ala, Py-Cap, Py-G(1)-Lys and Py-G(2)-Lys) bearing fluorescent pyrene and various hydrocarbon linkers between the pyrene hydrophobe and cationic block. Employing these new cationic amphiphiles with pyrene as the fluorescent probe, the interactions between these Py-cations and plasmid DNA (pDNA) in distilled water and 0.1 M PBS buffer solution have been explored by means of UV-vis and fluorescent spectrometers, and ethidium bromide dye displacement and agarose-gel retardant assays were also implemented to evaluate their pDNA binding affinities in aqueous solution. Furthermore, the average sizes and morphologies of self-assembled Py-cation/pDNA lipoplex aggregates were examined by dynamic laser light scattering (DLS) and atomic force microscopy (AFM). It was found that these fluorescent cationic amphiphiles showed blue fluorescence emission of pyrene probe at λ = 340 nm in distilled water while their interactions with pDNA led to new strong green emission at λ = 490 nm, and this may be due to the stacking of pyrene and new formation of excimers via the rigid pDNA templated self-assembly. It was also revealed that the binding between new Py-cations and pDNA in aqueous solution was strongly influenced by the Py-cation hydrophobicity, charges of the cation and the presence of electrolytes. With respect to the Py-cation/pDNA aggregate morphologies, very interesting 1-D hybrid nanofibers were predominantly observed by AFM for the Py-Cap/pDNA aggregates. In addition, utilizing a COS-7 cell-line, in-vitro cellular uptakes of new cationic amphiphiles with pyrene probe were studied and visualized by fluorescent microscopy. As a result, this may provide a new approach to investigate the interactions between synthetic cationic lipids and nucleic acids, and pave an alternative clue to design new organic gene delivery carriers.


Neuromuscular training injury prevention strategies in youth sport: a systematic review and meta-analysis.
Youth have very high participation and injury rates in sport. Sport is the leading cause of injury in youth. Sport injury reduces future participation in physical activity which adversely affects future health. Sport injury may lead to overweight/obesity and post-traumatic osteoarthritis. The objective of the systematic review and meta-analysis was to evaluate the efficacy of injury prevention neuromuscular training strategies in youth sport. Three electronic databases were systematically searched up to September 2014. Studies selected met the following criteria: original data; analytic prospective design; investigated a neuromuscular training prevention strategy intervention(s) and included outcomes for injury sustained during sport participation. Two authors assessed the quality of evidence using Downs and Black (DB) criteria. Meta-analyses including randomised controlled trials only (RCTs) to ensure study design homogeneity were completed for lower extremity and knee injury outcomes. Of 2504 potentially relevant studies, 25 were included. Meta-analysis revealed a combined preventative effect of neuromuscular training in reducing the risk of lower extremity injury (incidence rate ratio: IRR=0.64 (95% CI 0.49 to 0.84)). Though not statistically significant, the point estimate suggests a protective effect of such programmes in reducing the risk of knee injury (IRR=0.74 (95% CI 0.51 to 1.07)). There is evidence for the effectiveness of neuromuscular training strategies in the reduction of injury in numerous team sports. Lack of uptake and ongoing maintenance of such programmes is an ongoing concern. A focus on implementation is critical to influence knowledge, behaviour change and sustainability of evidence informed injury prevention practice.


Burden of infection in patients with end-stage renal disease requiring long-term dialysis.
This study examines the spectrum of infections in a selected population of patients requiring long-term dialysis, enlarging the focus beyond infections associated with the dialysis process. Infection data were reviewed from complete archived inpatient and outpatient dialysis records of 433 patients who were treated at a single hospital-based dialysis program and its dialysis satellites over a 9-year period, from 1 January 1992 to 31 December 2000. The study period included 424,700 days of dialysis experience. A total of 2412 episodes of bacterial or fungal infections were treated in 433 patients. The infection rate was 5.7 episodes per 1000 days of dialysis. Patients received 5111 courses of antibiotics over 42,627 days of treatment, which cumulatively accounted for 10% of the total days of the study. Infections associated with hemodialysis vascular access devices comprised 20.5% of the total episodes. Infections below the knee (19.3% of infection episodes), pneumonia (13%), and other skin and soft-tissue infections (9%) were also important types and sources of infection, accounting for >42% of the total episodes. Eighty-two percent of the infections (1971 episodes) were acquired in the community. Of these, 868 (44%) required hospitalization. An additional 441 episodes were nosocomial. The profile of bacteria isolated from patients with community-acquired infections mirrored that of bacteria recovered from patients with nosocomial infections. Patients with end-stage renal disease have an enormous burden of infection. The majority of the infections are unrelated to dialysis. Frequent and long-term antibiotic use and cohorting of patients in the dialysis unit have altered the microbiological flora of such individuals, with clinical and epidemiological implications.


Mesothelial pelvic lymph node inclusion in a patient with ovarian microinvasive borderline mucinous tumor: case report with review of the literature.
The presence of mesothelial cell inclusions in lymph nodes is rare. Localization of these inclusions in abdominal and pelvic lymph nodes is an exceedingly rare event, with only eight cases reported. We report here a case of mesothelial cell inclusions in pelvic lymph node of a patient with ovarian microinvasive borderline mucinous tumor. This case differs from the previously reported cases for the following reasons. First, there was no evidence of serosal effusion. Second, it is the first reported case of nodal mesothelial inclusions in a patient with ovarian microinvasive mucinous borderline tumor. Last, histologically, mesothelial cell inclusions were accompanied by psammoma bodies. The potential problem of misdiagnosis as a metastatic tumor can be avoided by an awareness of these inclusions, supported by immunohistochemical results.


[Age characteristics of the immune response in rats with multiple administraion of different doses of sheep erythrocytes].
A study was made of the number of antibody-forming cells and of the serum antibody titres in adult and old rats under conditions of a 10-fold immunization with "low" (4 X 10(8) cells) and "high" (4 X 10(10) cells) doses of sheep erythrocytes. The titres of antibodies (hemolysins and hemagglutinins) in the animals of both groups were either close to one another or greater in adult rats (hemolysins - in administration of "high" doses of the antigen). The content of the direct plaque-forming cells was greater in the spleen of old than of adult animals at all the immunization periods, of this period. The data obtained pointed to differences in the maturation of the immune response in the animals of various age.


Refractive Associations With Whole Eye Movement Distance and Time Among Chinese University Students: A Corvis ST Study.
Eye movement has been frequently studied in clinical conditions, but the association with myopia has been less explored, especially in population-based samples. The purpose of this study was to assess the associations of eye movement measured by the Corvis ST with refractive status in healthy university students. A total of 1640 healthy students were included in the study (19.0 ± 0.9 years). Eye movement parameters (whole eye movement [WEM]; whole eye movement time [WEMT]) were measured by the Corvis ST. Spherical equivalent (SE) was measured using an autorefractor without cycloplegia. IOL Master was used to assess axial length (AL). AL was negatively correlated with WEM and WEMT (rWEM = -0.28, rWEMT = -0.08), and SE was positively correlated with WEM and WEMT (rWEM = 0.21, rWEMT = 0.14). For the risk of high myopia, breakpoint analysis and restricted cubic spline model showed that the knots of the significant steep downward trend of WEM and WEMT were 0.27 mm and 20.4 ms, respectively. The piecewise linear regression model revealed a significant correlation between AL, SE, and WEM when the value of WEM was below 0.27 mm. Additionally, when WEMT exceeded 20.4 ms, a significant decrease in AL and an increase in SE were observed with increasing WEMT. A larger distance and longer duration of eye movement were correlated with a lower degree of myopia and shorter AL, and there was a threshold effect. The findings might aid in understanding the pathogenesis of myopia and provide a theoretical foundation for clinical diagnosis and prediction.


[Level of blood metalloproteins during fluothane anesthesia in experimental animals].
Changes in the concentrations of antioxidant (Cu, Zn superoxide dismutase catalase, ceruloplasmin, and transferrin) and recently discovered pro-oxidant (cytochrome B-558 I-IV and suprol, a superoxide producing lipoprotein) metalloproteins and cytochrome B-5 were assessed in the blood of anesthesized and control rats. The concentrations of antioxidant and pro-oxidant metalloproteins varied. They were not changed during anesthesia, except suprol. As for the qualitative changes, phospholipid composition was altered, superoxide production decreased, and lipid peroxidation of suprol increased during anesthesia. The authors propose using antioxidant metalloproteins for decrease of the undesirable consequences of halothane anesthesia in experimental medicine.


Multitarget Stool DNA Screening in Clinical Practice: High Positive Predictive Value for Colorectal Neoplasia Regardless of Exposure to Previous Colonoscopy.
Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.


The labour market returns to sleep.
Despite the growing prevalence of insufficient sleep among individuals, we still know little about the labour market return to sleep. To address this gap, we use longitudinal data from Germany and leverage exogenous fluctuations in sleep duration caused by variations in time and local sunset times. Our findings reveal that a one-hour increase in weekly sleep is associated with a 1.6 percentage point rise in employment and a 3.4% increase in weekly earnings. Such effect on earnings stems from productivity improvements given that the number of working hours decreases with longer sleep duration. We also identify a key mechanism driving these effects, namely the enhanced mental well-being experienced by individuals who sleep longer hours.


Co-infection status of novel parvovirus's (PPV2 to 4) with porcine circovirus 2 in porcine respiratory disease complex and porcine circovirus-associated disease from 1997 to 2012.
As global pig health diseases, porcine respiratory disease complex (PRDC) and porcine circovirus-associated disease (PCVAD) generate substantial economic losses despite pigs been vaccinated against the primary causative virus, highlighting the importance of understanding virome interactions and specifically co-factor infections. Established primary endemic pathogens for PRDC include porcine circovirus 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSv) and swine influenza virus (SIV), and PCV2 aetiology in interaction with other co-infecting viruses can result in PCVAD. Porcine parvovirus (PPV) 1 is a well-characterized virus with an available vaccine preventing reproductive failure in sows. However, whilst novel PPV 2 to 7 viruses have been identified since 2001, their viral pathogenic potential in clinical and subclinical disease remains to be determined. Therefore, this study has sought to develop a better understanding of their potential role as associated co-infections in PRDC and PCVAD by examining archival samples for the presence of PCV2 and the novel parvoviruses PPV2-4 from clinically diseased pigs across production age stages. Epidemiologically, the novel PPV2 was found to be the most prevalent within the fattener age group with PPV2-4 statistically associated with pig respiratory disease and enteric ulcers. Additionally, statistical modelling by latent class analysis (LCA) on veterinary pathology scored pigs found a clustering co-factor association between PPV2 and PCV2, suggesting the novel PPV may be involved in PRDC and PCVAD. Phylogenetic analysis of novel PPVs revealed the PPV2 capsid evolution to be diverged from the original strains with a low nucleotide homology of 88%-96% between two distinct clades. These findings determine that novel PPV 2-4 viruses are statistically associated as co-infectors in a diseased pig population, and significantly detected PPV2 clustering co-infection frequency with PCV2 in PRDC and PCVAD diseased pigs through LCA analysis.


Spectro-Electrochemical Examination of the Formation of Dimethyl Carbonate from CO and Methanol at Different Electrode Materials.
In this work, we report a fundamental mechanistic study of the electrochemical oxidative carbonylation of methanol with CO for the synthesis of dimethyl carbonate on metallic electrodes at low overpotentials. For the first time, the reaction was shown to take place on the metallic catalysts without need of oxidized metals or additives. Moreover, in-situ spectroelectrochemical techniques were applied to this electrosynthesis reaction in order to reveal the reaction intermediates and to shed light into the reaction mechanism. Fourier transformed infrared spectroscopy was used with different electrode materials (Au, Pd, Pt, and Ag) to assess the effect of the electrode material on the reaction and the dependence of products and intermediates on the applied potentials. It was observed that the dimethyl carbonate is only formed when the electrode is able to decompose/oxidize MeOH to form (adsorbed) methoxy groups that can further react with CO to dimethyl carbonate. Furthermore, the electrode needs to adsorb CO not too strongly; otherwise, further reaction will be inhibited because of surface poisoning by CO.


Platform switching minimises crestal bone loss around dental implants: truth or myth?
The aim was to assess the role of platform switching (PS) in minimising crestal bone loss around dental implants through a systematic review of the currently available clinical evidence. To address the focused question 'Does PS minimise crestal bone loss compared with non-platform-switched (NPS) implants?', PubMed/Medline and Google Scholar databases were explored from 1986 up to and including December 2013 using the following key words in different combinations: 'bone loss', 'dental implant', 'diameter', 'mandible', 'maxilla' and 'platform switching'. Letters to the Editor, unpublished data, historical reviews, case reports and articles published in languages other than English were excluded. Fifteen clinical studies were included. In seven studies, PS and NPS implants were placed in both the maxilla and mandible. In 13 studies, implants were placed at crestal bone levels whereas in one study, implants were placed supracrestally. Three studies reported the bucco-lingual (or transversal) width of the alveolar ridge which ranged between 7-8 mm. Seven studies reported that implants placed according to the PS concept did not minimise crestal bone loss as compared with NPS implants. 3D-Implant positioning, width of alveolar ridge and control of micromotion at the implant-abutment interface are the more critical factors that influence crestal bone levels than PS.


Hypotensive transfusion reactions can occur with blood products that are leukoreduced before storage.
Leukoreduction before storage, rather than bedside white blood cell filtration, is recommended to prevent hypotensive transfusion reactions. Investigation of hypotensive transfusion reactions during radical prostatectomy in two patients on angiotensin-converting enzyme inhibitors. In Patient A, hypotension occurred during the transfusion of each of the following blood products: 2 units of autologous blood deposited and leukoreduced (LR) before storage; 3 units of allogeneic red cells LR before storage; and 2 units of non-LR acute normovolemic hemodilution (ANH) whole blood. When each of the transfusions was stopped, the blood pressure recovered. In Patient B, hypotension occurred during the transfusion of non-LR ANH whole blood. All implicated units were administered rapidly using a blood infuser at 37 degrees C. Bradykinin (BK) and des-Arg9-BK formation and degradation and the activity of kinin-degrading metallopeptidases were measured in plasma samples from both patients. Degradation of des-Arg9-BK was severely impaired and the activity of aminopeptidase P severely reduced in Patient A, but not in Patient B. BK degradation was mildly impaired in both patients. Hypotensive reactions can occur with blood products that are LR before storage and non-LR ANH. An inherent defect in the metabolism of kinins may be a risk factor for the development of hypotensive transfusion reactions.


[Character of the immune response in guinea pigs following immunization with brucellosis protective antigen].
In studying guinea pigs immunized with brucella protective antigen and the immunological response in them it was found that the antigen could be determined for 30 days by the method of fluorescent antibodies in the cells of the lymph nodes and the spleen following its intravenous injection. The optimal immunizing dose was 0.6 mg; in difference from a dose of 2 mg it produced an earlier and a more pronounced humoral effect. The phagocytic activity of the peritoneal macrophages of guinea pigs immunized with low doses was much more intensive than of those immunized with high doses of the antigen. Brucella protective antigen in a dose of 2 mg produced a disturbance of the carbohydrate metabolism in phagocytes, this influencing negatively their phagocytic function.


Is subject-specific musculoskeletal modelling worth the extra effort or is generic modelling worth the shortcut?
The majority of musculoskeletal modelling studies investigating healthy populations use generic models linearly scaled to roughly match an individual's anthropometry. Generic models disregard the considerable variation in musculoskeletal geometry and tissue properties between individuals. This study investigated the physiological implications of personalizing musculoskeletal model geometry (body segment mass, inertia, joint center, and maximum isometric muscle force). Nine healthy athletes performed ten repetitions of 15 meter sprints at 75-95% of their maximum sprinting speed and ten repetitions of unanticipated sidestep cut trials with a 4.5-5.5 m/s approach running speed. Structural magnetic resonance imaging was collected on the lower extremities, from which subject-specific musculoskeletal models were developed. A one-dimensional statistical parametric mapping paired t-test was used to compare generic and subject-specific musculoskeletal models for: lower-limb kinematics, kinetics, torque matching, as well as hamstrings, adductors, and quadriceps muscle activations and fiber dynamics. Percentage change of geometric parameters between generic and subject-specific models were determined. Compared to generic models, subject-specific models showed significantly lower ankle dorsi/plantar flexion angle during sprinting and several significantly different net joint moments during sprint and cut tasks. Additionally, subject-specific models demonstrated better torque matching, more physiologically plausible fiber lengths, higher fiber velocities, lower muscle forces, and lower simulated activations in a subset of investigated muscles and motor tasks. Furthermore, subject-specific models identified between-limb differences that were not identified with generic models. Use of subject-specific modeling, even in healthy populations, may result in more physiologically plausible muscle fiber mechanics. Implementing subject-specific models may be especially beneficial when investigating populations with substantial geometric between-limb differences, or unilateral musculoskeletal pathologies, as these are not captured by a generic model.


Tumor immunity produced by the intradermal inoculation of living tumor cells and living Mycobacterium bovis (strain BCG).
The intradermal inoculation of mixtures containing living tumor cells and living Mycobacterium bovis (strain BCG) into unimmunized syngeneic guinea pigs results in an inflammatory reaction to the BCG, and there is no progressive tumor growth. In the absence of BCG the tumor grows progressively, metastasizes, and kills the animal. By conventional methods, it has not been possible to immunize syngeneic guinea pigs to the tumor used. Guinea pigs that receive mixtures of BCG and tumor cells, however, develop specific systemic tumor immunity as measured by delayed cutaneous hypersensitivity and by suppression of tumor growth.


Health Care Resource Utilization and Costs in Patients with Chronic Myeloid Leukemia with Better Adherence to Tyrosine Kinase Inhibitors and Increased Molecular Monitoring Frequency.
Frequent molecular monitoring (qPCR tests), as recommended by evidence-based monitoring guidelines, is associated with higher adherence to tyrosine kinase inhibitors (TKIs) in the management of chronic myeloid leukemia (CML); both factors have been associated with better clinical and economic outcomes. To (a) estimate the effect of more frequent qPCR tests on health care resource utilization (HRU) and associated costs, including direct (effect of qPCR test frequency on HRU) and indirect (through TKI adherence) effects, and (b) develop an economic model applicable to multiple clinical practice scenarios. Adult patients newly diagnosed with CML who started TKI firstline therapy were identified from U.S. administrative claims data (2010-2015). TKI adherence (medication possession ratio [MPR]), number of inpatient days, emergency room (ER) visits, outpatient service days, and mean costs per HRU event were measured during the first year of CML treatment. Direct and indirect effects of qPCR test frequency were estimated using multivariate regression models. Subsequently, an economic model was developed to assess the overall effect of varying qPCR test frequency on HRU and associated costs during the first year of CML treatment under different clinical practice scenarios; the scenario reported is the increase from 1 to 2 qPCR tests. Of the 1,431 patients included, 36% had no qPCR tests, the average qPCR test frequency was 1.6, and the average MPR was 0.86 during the first year of CML treatment. The direct effect of increasing qPCR test frequency by 1 was associated with 13.0% fewer inpatient days (adjusted incidence rate ratio [adjusted IRR] = 0.87; P = 0.010); 8.3% fewer ER visits (adjusted IRR = 0.92; P = 0.043); and 3.0% more outpatient service days (adjusted IRR = 1.03; P = 0.002). Each increase of 1 test was associated with an increase in TKI adherence by 2.2 percentage points (adjusted MPR difference = 0.022; P < 0.001). When considering the indirect effect of qPCR test frequency through TKI adherence, an increase of 1 qPCR test combined with an increase in TKI adherence by 2.2 percentage points was associated with a greater reduction of inpatient days from 13.0% to 15.2%, ER visits from 8.3% to 8.6%, and a smaller increase of outpatient service days from 3.0% to 2.6%. Based on the economic model, an increase from 1 to 2 qPCR tests, considering the increase in TKI adherence, was associated with a reduction of 0.87 (95% CI = -1.49, -0.18) inpatient days and 0.06 (95% CI = -0.12, 0.05) ER visits, an increase of 0.98 (95% CI = 0.25, 1.60) outpatient service days and a cost savings of $2,918 (95% CI = -5,213, -349) per patient per year. Closer alignment with the monitoring guidelines' recommended qPCR test frequency and better adherence to TKIs were associated with lower HRU and medical service costs. Managed care initiatives to increase qPCR test frequency and TKI adherence might benefit from an enhanced reduction because of the interaction between both factors. This study was funded by Novartis Pharmaceuticals, which was involved in all stages of the study and in the decision to submit the report for publication. Latremouille-Viau, Guerin, Gagnon-Sanschagrin, and Dea are employees of Analysis Group, which received consulting fees from Novartis Pharmaceuticals for work on this study. Joseph is an employee of Novartis Pharmaceuticals and owns stock in Amgen and Pfizer. Cohen was an employee of Novartis Pharmaceuticals at the time of this study. Portions of this study were presented online (beginning May 20, 2016) as part of the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, on June 3-7, 2016, and as a poster at the American Society of Hematology (ASH) Annual Meeting in San Diego, California, on December 3-6, 2016. Study concept and design were contributed by Latremouille-Viau and Guerin, along with the other authors. Gagnon-Sanschagrin and Dea took the lead in data collection, assisted by the other authors, and data interpretation was performed by Cohen and Joseph, along with the other authors. The manuscript was written by Latremouille-Viau, along with the other authors, and revised by Joseph, along with the other authors.


Primary care burden and treatment of patients with heart failure and chronic obstructive pulmonary disease in Scotland.
Heart failure (HF) and chronic obstructive pulmonary disease (COPD) frequently coexist and present major challenges to healthcare providers. The epidemiology, consultation rate, and treatment of patients with HF and COPD in primary care are ill-defined. This was an analysis of cross-sectional data from 61 primary care practices (377 439 patients) participating in the Scottish Continuous Morbidity Recording scheme. The prevalence of COPD in patients with HF increased from 19.8% in 1999 to 23.8% in 2004. In 2004, the prevalence was similar in men and women (24.8% vs. 22.9%, P = 0.09), increased with age up to 75 years, and increased with greater socioeconomic deprivation (most deprived 31.3% vs. least deprived 18.6%, P = 0.01). Contact rates for HF or COPD in those with both conditions were greater than disease-specific contact rates in patients with either condition alone. Although overall beta-blocker prescribing increased over time; the adjusted odds of beta-blocker prescription in patients with COPD was low and failed to improve [odds ratio 0.30 (0.28-0.32), P < 0.001]. In 2004, only 18% of individuals with HF and COPD were prescribed beta-blockers vs. 41% in those without COPD. Chronic obstructive pulmonary disease is a frequent comorbidity in patients with HF and represents a significant healthcare burden to primary care. Although beta-blocker prescribing in the community has increased, less than a fifth of patients with HF and COPD received beta-blockers.


Characterization of plant XRCC1 and its interaction with proliferating cell nuclear antigen.
In plants, there are no DNA polymerase beta (Pol beta) and DNA ligase III (Lig3) genes. Thus, the plant short-patch base excision repair (short-patch BER) pathway must differ considerably from that in mammals. We characterized the rice (Oryza Sativa L. cv. Nipponbare) homologue of the mammalian X-ray repair cross complementing 1 (XRCC1), a well-known BER protein. The plant XRCC1 lacks the N-terminal domain (NTD) which is required for Pol beta binding and is essential for mammalian cell survival. The recombinant rice XRCC1 (OsXRCC1) protein binds single-stranded DNA (ssDNA) as well as double-stranded DNA (dsDNA) and also interacts with rice proliferating cell nuclear antigen (OsPCNA) in a pull-down assay. Through immunoprecipitation, we demonstrated that OsXRCC1 forms a complex with PCNA in vivo. OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin, but not of MMS, H(2)O(2) or UV-B. Bleomycin also increased the fraction of OsXRCC1 associated with chromatin. These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system.


Plasma natriuretic peptides and incidence of subtypes of ischemic stroke.
Natriuretic peptides predict poor outcomes in cardiovascular disease. However, the knowledge of their relationship to stroke is limited and prospective studies from the general population are few. The purpose of this study was to explore the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and midregional pro-atrial natriuretic peptide (MR-proANP) plasma levels and the risk for ischemic stroke and its subtypes. NT-proBNP and MR-proANP were measured in fasting blood samples from 4,862 subjects (40.2% men, mean age 57.5 ± 6.0 years) without cardiovascular disease from the Malmö Diet and Cancer Study, a prospective, population-based study in Sweden. Incidence of ischemic stroke was monitored over a mean follow-up of 14.9 ± 3.0 years. Stroke cases were etiologically classified according to the TOAST classification. Cox proportional-hazards regression was used to study the incidence of stroke in relationship to NT-proBNP and MR-proANP. During follow-up, 227 had a first-ever ischemic stroke (large-artery atherosclerosis, n = 35; cardioembolic stroke, n = 44; small-artery occlusion, n = 80; undetermined cause, n = 68). In the age- and sex-adjusted model, only NT-proBNP was associated with total ischemic stroke. This association was completely explained by an increased incidence of cardioembolic stroke. Adjusted for cardiovascular risk factors (age, sex, hypertension, diabetes, smoking, body mass index and low-density lipoprotein cholesterol), the hazard ratios (HRs, 95% confidence interval, 95% CI) for cardioembolic stroke were 1.00 (reference), 1.42 (0.34-6.00), 2.79 (0.77-10.12) and 5.64 (1.66-19.20), respectively, for the 1st, 2nd, 3rd and 4th quartiles of NT-proBNP. The corresponding HRs (95% CIs) for quartiles of MR-proANP were 1.00 (reference), 1.83 (0.55-6.14), 1.20 (0.33-4.34) and 3.96 (1.31-11.99), respectively. In total, 335 (6.9%) subjects were diagnosed with atrial fibrillation during follow-up. Among the cardioembolic stroke cases, 30% were diagnosed with atrial fibrillation before the stroke event and another 36% within 6 months after the stroke. Of the cardioembolic stroke cases with atrial fibrillation, 59% were in the top quartile of NT-proBNP, 69% in the top quartile of MR-proANP and 79% were either in the top quartile of NT-proBNP or in the top quartile of MR-proANP. High plasma levels of NT-proBNP and MR-proANP are associated with a substantially increased risk of cardioembolic stroke, but not with other subtypes of ischemic stroke. The results suggest that assessment of stroke risk, including electrocardiography, is warranted in subjects with high NT-proBNP or MR-proANP.


Alteration of BMP-4 and Runx2 expression patterns in mouse temporomandibular joint after ovariectomy.
Temporomandibular disorder (TMD) includes a number of clinical conditions involving the masticatory musculature or the temporomandibular joint (TMJ) and associated structures. Previous studies have shown the presence of high-affinity estrogen receptors in the TMJ articular cartilage. The aim of this study was to evaluate the developmental changes in mouse TMJ under estrogen deficiency. Four-month-old ovariectomized mice were killed after certain weeks. We examined the significant alterations of the expression patterns of bone morphogenetic protein (BMP)-4, Runx2, and bone sialoprotein (BSP) after ovariectomy. In the control group, BMP-4, Runx2, and BSP expressions showed no definite difference at any stage. In the ovariectomy group, the intensity of BMP-4 and Runx2 expression increased after ovariectomy. BSP immunoreactivity, however, increased slightly at 2 weeks but then decreased gradually. Estrogen plays important roles in the metabolism and maintenance of TMJ via regulations of signaling molecules such as BMP-4, Runx2, and BSP. Our results suggest that estrogen deficiency is a candidate cause of TMD. This study revealed further osteogenetic properties of estrogen that may be useful in the clinical treatment and prevention of TMD.


Phosphatidylcholine synthesis in the developing small intestine.
1. Phosphatidylcholine synthesis in the foetal, newborn and adult small intestine of rats was studied by determination of cytidine diphosphocholine-1,2-diacylglycerocholine phosphotransferase (cholinephosphotransferase) and acyl-CoA-1-acyl-sn-glycerol-3-phosphocholine acyltransferase (lysophosphatidylcholine acyltransferase) activities and the incorporation of [1-14C]oleic acid into phosphatidylcholine. 2. Cholinephosphotransferase activity was low in foetal jejunum and ileum, increased 3-4 fold in the ileum by 6 days of age and by 12 days in the jejunum. Jejunal activity remained constant throughout weaning; ileal activity gradually decreased to values 25% of that of the jejunum. 3. Lysophosphatidylcholine acyltransferase activity was high in foetal jejunum and ileum, decreased 70% immediately after birth in the jejunum and increased to adult values by 12 days of age. Ileal activity decreased by 20% after birth, but decreased more rapidly at weaning to 30% of the activity in jejunum. 4. Initial rates and steady-state incorporation of [1-14C]oleic acid into phosphatidylcholine by jejunal rings of 10 day-old rats exceeded that observed in jejunal rings from adult rats by 2-4-fold. 5. In the postnatal jejunum, neither cholinephosphotransferase and lysophosphatidylcholine acyltransferase activities nor oleic acid incorporation were stimulated by cortisone administration in vivo.


A model of tight junction function in central nervous system myelinated axons.
The insulative properties of myelin sheaths in the central and peripheral nervous systems (CNS and PNS) are widely thought to derive from the high resistance and low capacitance of the constituent membranes. Although this view adequately accounts for myelin function in large diameter fibers, it poorly reflects the behavior of small fibers that are prominent in many regions of the CNS. Herein, we develop a computational model to more accurately represent conduction in small fibers. By incorporating structural features that, hitherto, have not been simulated, we demonstrate that myelin tight junctions (TJs) improve saltatory conduction by reducing current flow through the myelin, limiting axonal membrane depolarization and restraining the activation of ion channels beneath the myelin sheath. Accordingly, our simulations provide a novel view of myelin by which TJs minimize charging of the membrane capacitance and lower the membrane time constant to improve the speed and accuracy of transmission in small diameter fibers. This study establishes possible mechanisms whereby TJs affect conduction in the absence of overt perturbations to myelin architecture and may in part explain the tremor and gait abnormalities observed in Claudin 11-null mice.