Cellular hypomethylation is associated with impaired nitric oxide production by cultured human endothelial cells.
Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease, but the underlying mechanisms remain incompletely defined. Reduced bioavailability of nitric oxide (NO) is a principal manifestation of underlying endothelial dysfunction, which is an initial event in vascular disease. Inhibition of cellular methylation reactions by S-adenosylhomocysteine (AdoHcy), which accumulates during HHcy, has been suggested to contribute to vascular dysfunction. However, thus far, the effect of intracellular AdoHcy accumulation on NO bioavailability has not yet been fully substantiated by experimental evidence. The present study was carried out to evaluate whether disturbances in cellular methylation status affect NO production by cultured human endothelial cells. Here, we show that a hypomethylating environment, induced by the accumulation of AdoHcy, impairs NO production. Consistent with this finding, we observed decreased eNOS expression and activity, but, by contrast, enhanced NOS3 transcription. Taken together, our data support the existence of regulatory post-transcriptional mechanisms modulated by cellular methylation potential leading to impaired NO production by cultured human endothelial cells. As such, our conclusions may have implications for the HHcy-mediated reductions in NO bioavailability and endothelial dysfunction.


Size and positional effects of promoter RNA segments on virus-induced RNA-directed DNA methylation and transcriptional gene silencing.
DNA methylation at a gene promoter can be triggered by double-stranded RNAs (dsRNAs) through the RNA-directed DNA methylation (RdDM) pathway and induces transcriptional gene silencing (TGS). Although genes involved in the RdDM pathway have been identified, whether dsRNAs of different promoter regions have different extent of effects on RdDM and/or TGS is unknown. Here, we addressed this question by targeting the CaMV 35S promoter in the plant genome using a recombinant Cucumber mosaic virus that contained various portions of the promoter. The efficiency of the induction of TGS depended on the length of the promoter segment triggering the RdDM; the lower size limit for TGS induction was 81-91 nt. TGS was induced when 70-nt fragments were connected in tandem, none of which solely induced TGS. TGS induction did not simply depend on the production of small interfering RNAs corresponding to the promoter. Along with the induction of RdDM, spreading of DNA methylation from the originally targeted site toward the adjacent regions was detected. The maintenance of TGS in the progeny that lacks an RNA trigger depended on the promoter segments triggering the RdDM in the former generation and was correlated with the number of cytosines at symmetrical sites in the targeted region. These results indicate that both the length of dsRNA above the threshold and the frequency of cytosines at symmetric sites in the region targeted by dsRNA are the major factors that allow induction of heritable TGS via RdDM.


Development, Application, and Performance of Artificial Intelligence in Cephalometric Landmark Identification and Diagnosis: A Systematic Review.
This study aimed to analyze the existing literature on how artificial intelligence is being used to support the identification of cephalometric landmarks. The systematic analysis of literature was carried out by performing an extensive search in PubMed/MEDLINE, Google Scholar, Cochrane, Scopus, and Science Direct databases. Articles published in the last ten years were selected after applying the inclusion and exclusion criteria. A total of 17 full-text articles were systematically appraised. The Cochrane Handbook for Systematic Reviews of Interventions (CHSRI) and Newcastle-Ottawa quality assessment scale (NOS) were adopted for quality analysis of the included studies. The artificial intelligence systems were mainly based on deep learning-based convolutional neural networks (CNNs) in the included studies. The majority of the studies proposed that AI-based automatic cephalometric analyses provide clinically acceptable diagnostic performance. They have worked remarkably well, with accuracy and precision similar to the trained orthodontist. Moreover, they can simplify cephalometric analysis and provide a quick outcome in practice. Therefore, they are of great benefit to orthodontists, as with these systems they can perform tasks more efficiently.


Sex differences in circulating proteins in heart failure with preserved ejection fraction.
Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce. A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models. We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18. In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.


[Nutritional muscular dystrophy in a clutch of ostrich chicks].
Six 1 1/2-month old ostrich chickens in the Upington district of the Cape Province developed lameness. Two died and pathological examination of one of them revealed lesions identical to those of white muscle disease in the larger muscle groups. Vitamin E-selenium therapy cured the other 4. The diet of the animals consisted mainly of lucerne (alfalfa).


Antibiotics: the changing regulatory and pharmaceutical industry paradigm.
Drug licensing is changing. Previously, regulators prioritized the licensing of innovative drugs that fulfilled a high unmet medical need for a small number of patients, including orphan, cancer and HIV medicines. Alternatives to large and costly prospective, randomized, double-blind clinical trials have led to a more bespoke development, such as adaptive design studies. Regulators have recently agreed to include much-needed narrow-spectrum antibiotics, active against certain MDR bacteria, in this paradigm. The background to why big pharmaceutical companies have largely deserted the antibacterial research arena, and the proposals that are hoped to reinvigorate their interest, are presented.


The invasive Asian bush mosquito Aedes japonicus found in the Netherlands can experimentally transmit Zika virus and Usutu virus.
The Asian bush mosquito Aedes japonicus is invading Europe and was first discovered in Lelystad, the Netherlands in 2013, where it has established a permanent population. In this study, we investigated the vector competence of Ae. japonicus from the Netherlands for the emerging Zika virus (ZIKV) and zoonotic Usutu virus (USUV). ZIKV causes severe congenital microcephaly and Guillain-Barré syndrome in humans. USUV is closely related to West Nile virus, has recently spread throughout Europe and is causing mass mortality of birds. USUV infection in humans can result in clinical manifestations ranging from mild disease to severe neurological impairments. In our study, field-collected Ae. japonicus females received an infectious blood meal with ZIKV or USUV by droplet feeding. After 14 days at 28°C, 3% of the ZIKV-blood fed mosquitoes and 13% of the USUV-blood fed mosquitoes showed virus-positive saliva, indicating that Ae. japonicus can transmit both viruses. To investigate the effect of the mosquito midgut barrier on virus transmission, female mosquitoes were intrathoracically injected with ZIKV or USUV. Of the injected mosquitoes, 96% (ZIKV) and 88% (USUV) showed virus-positive saliva after 14 days at 28°C. This indicates that ZIKV and USUV can efficiently replicate in Ae. japonicus but that a strong midgut barrier is normally restricting virus dissemination. Small RNA deep sequencing of orally infected mosquitoes confirmed active replication of ZIKV and USUV, as demonstrated by potent small interfering RNA responses against both viruses. Additionally, de novo small RNA assembly revealed the presence of a novel narnavirus in Ae. japonicus. Given that Ae. japonicus can experimentally transmit arthropod-borne viruses (arboviruses) like ZIKV and USUV and is currently expanding its territories, we should consider this mosquito as a potential vector for arboviral diseases in Europe.


Transition-Metal-Free Homopolymerization of Pyrrolo[2,3-d:5,4-d']bisthiazoles via Nucleophilic Aromatic Substitution.
Novel methods to synthesize electron-deficient π-conjugated polymers utilizing transition-metal-free coupling reactions for the use of nonfunctionalized monomers are attractive due to their improved atom economy and environmental prospective. Herein we describe the use of iPrMgCl·LiCl complex to afford thiazole-based conjugated polymers in the absence of any transition metal catalyst, that enables access to well-defined polymers with good molecular weights. The mechanistically distinct polymerizations proceeded via nucleophilic aromatic substitution (SNAr) reaction supported by density functional theory (DFT) calculations. This work demonstrates the first example of fully conjugated thiazole-based aromatic homopolymers without the need of any transition metal catalyst.


The in vitro effects of opines and other compounds on DNAs originating from bacteria, and from healthy and tumorous plant tissues.
Purified total DNAs were isolated from oncogenic or nononcogenic Agrobacterium tumefaciens cells as well as from normal and crown gall tissues. Opines (octopine, nopaline, lysopine), plant hormone (auxin IAA) and some carcinogenic compounds were used in order to correlate their effects on in vitro strand separation and synthesis of DNAs with in vivo tumorous cell multiplication. Octopine (or nopaline) induced chain opening of DNAs originating from octopine (or nopaline)-metabolizing bacteria and from same bacteria strain-induced tumorous cells. This phenomenon was measured by the increase in DNA hyperchromicity which is concentration dependent. The tested compounds stimulated the in vitro synthesis of the same DNAs. Under the same conditions, in vitro strand separation and synthesis of healthy plant DNA was not (or only slightly) enhanced, except in the case of particular hormone-connected healthy cell DNA. IAA and carcinogens stimulated in vitro synthesis and induced in vitro strand separation (dose-dependent effect) of DNAs isolated from crown gall cells and inducing bacteria. Compared to healthy cell DNAs, these DNAs were thus susceptible to structurally very diversified molecules and in this way behave as do mammalian tissue DNAs. The opine and IAA actions observed here were specific for plant tissue DNA; cancerous human or animal tissue DNAs were insensitive. By their presence in the crown gall cells, opines possibly maintain destabilized areas (required for rapid growth and division) on tumor cell DNA. The cooperative actions of IAA and opines as well as small RNA and RNA fragments on gene activation, might explain the autonomy of plant tumor cells.


Circulating anti-galectin-1 antibodies are associated with the severity of ocular disease in autoimmune and infectious uveitis.
Galectin (Gal)-1, an endogenous lectin found at sites of immune privilege, plays a critical role in the regulation of the immune response. Therapeutic administration of Gal-1 or its genetic delivery suppresses chronic inflammation in experimental models of autoimmunity. The purpose of this work was to investigate the occurrence of circulating anti-Gal-1 antibodies in patients with autoimmune and infectious uveitis as potential determinant factors of disease progression. IgG, IgE, and IgA anti-Gal-1 antibodies were assessed by ELISA and Western blot in sera from patients with autoimmune (n = 47) and infectious (n = 15) uveitis compared with healthy control subjects (n = 30). The frequency of anti-Gal-1 antibodies was examined in patients experiencing poor clinical outcome (n = 21) or good evolution (n = 9). Anti-Gal-1 antibodies were eluted by incubating patient sera with nitrocellulose filters adsorbed with rGal-1. The ability of these antibodies to recognize retinal tissue was assessed by ELISA, Western blot, and immunohistochemistry. IgE, IgG, and IgA anti-Gal-1 antibodies were increased in sera from patients with autoimmune uveitis (P < 0.001 vs. controls) and toxoplasmic retinochoroiditis (P < 0.001). The level of anti-Gal-1 IgE and IgG antibodies was associated with progressive disease and poor outcome in autoimmune and infectious uveitis. Furthermore, these antibodies strongly immunoreacted with retinal lysates and recognized retinal structures mainly photoreceptors in retinal sections. Anti-retinal Gal-1 antibodies are present in sera from patients with uveitis and can be associated with the progression of ocular disease, suggesting their potential use in follow-up observations of these patients.


Changes in Long-Term Care Markets: Assisted Living Supply and the Prevalence of Low-Care Residents in Nursing Homes.
To assess the effect of changes in assisted living (AL) capacity within a market on prevalence of residents with low care needs in nursing homes. Retrospective, longitudinal analysis of nursing home markets. Twelve thousand two hundred fifity-one nursing homes in operation during 2007 and 2014. We analyzed the percentage of residents in a nursing home who qualified as low-care. For each nursing home, we constructed a market consisting of AL communities, Medicare beneficiaries, and competing nursing homes within a 15-mile radius. We estimated the effect of change in AL beds on prevalence of low-care residents using multivariate linear models with year and nursing home fixed effects. The supply of AL beds increased by an average 258 beds per nursing home market (standard deviation = 591) during the study period. The prevalence of low-care residents decreased from an average of 13.0% (median 10.5%) to 12.2% (median 9.5%). In adjusted models, a 100-bed increase in AL supply was associated with a decrease in low-care residents of 0.041 percentage points (P = .026), controlling for changes in market and nursing home characteristics, county demographics, and year and nursing home fixed effects. In markets with a high percentage of its Medicare beneficiaries (≥14%) dual eligible for Medicaid, the effect of AL is stronger, with a 0.066-percentage point decrease per 100 AL beds (P = .026) vs a 0.016-percentage point decrease in low-duals markets (P = .48). Our analysis suggests that some of the growth in AL capacity serves as a substitute for nursing homes for patients with low care needs. Furthermore, the effects are concentrated in markets with an above-average proportion of beneficiaries with dual Medicaid eligibility.


The effects of prolonged substitution of recombinant human growth hormone on renal functional reserve in growth hormone-deficient adults.
Twelve growth hormone (GH)-deficient adults with normal renal function were recruited for a 6-month, double-blind, placebo-controlled study on the effects of prolonged recombinant human growth hormone (rhGH) substitution therapy on renal functional parameters. RhGH was administered at a dose 0.125 IU/kg per week sc the first 4 wk and 0.25 IU/kg per week thereafter. At baseline and after 6 months of therapy, GFR and RPF were measured by the use of iothalamate and para- aminohippurate clearance techniques before and after an intravenous infusion of amino acids (AA) to determine the renal functional reserve capacity (RFRC). At baseline, GFR and RPF were similar in the GH-deficient patients and a group of normal, healthy controls (GFR, 117 +/- 10 mL/min; RPF, 567 +/- 57 mL/min, and filtration fraction, 22 +/- 1.6% in the patient group and GFR, 117 +/- 10 mL/min; RPF, 509 +/- 54 mL/min; and filtration fraction, 24 +/- 1.3% in the control group). GFR increased significantly in the control and patient group after AA infusion; the RFRC, however, was significantly larger in healthy individuals (GFR post-AA infusion, 141 +/- 10 mL in GH-deficient patients and 182 +/- 20 mL/min in controls). Thereafter, six patients received placebo therapy for 6 months and GFR as well as RFRC remained constant (GFR, 107 +/- 9 and 106 +/- 12 mL/min before AA infusion and 132 +/- 14 and 134 +/- 5 mL/min after AA infusion at baseline and after 6 months, respectively). Four patients of the placebo group then continued with rhGH therapy for another 6 months. They and six patients who had rhGH therapy from the beginning form the rhGH treatment study group. During rhGH treatment, plasma insulin-like growth factor activity increased significantly from 93 +/- 17 to 229 +/- 23 ng/mL. Baseline GFR and RPF as well as RFRC were unaltered by the 6 months of rhGH replacement therapy (basal GFR, 124 +/- 7 mL/min before and 123 +/- 9 mL/min after 6 months of rhGH therapy; GFR after AA infusion, 145 +/- 9 mL/min at baseline and 144 +/- 8 mL/min after 6 months of therapy). Kidney size as evaluated by ultrasonography was normal at baseline when compared with that in age- and sex-matched controls (10.3 +/- 0.2 versus 9.9 +/- 0.1 cm) and was unchanged after 6 months of therapy (10.3 +/- 0.3 cm). It was concluded from this study that rhGH substitution for 6 months at a dose of 0.25 IU/kg per week in GH-deficient patients with normal renal function has no adverse functional effects on the kidney.


Development of a fast method for determining psychophysical tuning curves.
Psychophysical tuning curves (PTCs) can be used to assess the frequency selectivity of the auditory system and to detect and delimit "dead regions" in the cochlea. However, the traditional method for determining PTCs takes too long for use in clinical practice. We evaluated a fast method for determining PTCs, using a band of noise that sweeps in centre frequency and a Békésy method to adjust the masker level required for threshold. The shapes of the PTCs were similar for the fast and traditional methods, for both normally hearing and hearing-impaired subjects. Rates of change of masker level of 2 dB/s or less gave the most reliable results. A relatively wide bandwidth (20 percent of the signal frequency or 320 Hz, whichever is the smaller) was needed to minimise the influence of beat detection. When the signal frequency fell within a dead region, the fast method gave PTCs with shifted tips.


A novel DNA platform designed for vaccine use with high transgene expression and immunogenicity.
The development of new, low-cost vaccines and effective gene therapies requires accurate delivery and high-level expression of candidate genes. We developed a plasmid vector, pIDV-II, that allows for both easy manipulation and high expression of exogenous genes in mammalian cells. This plasmid is based upon the pVax1 plasmid and shares a common structure with typical mammalian transcription units. It is composed of a chicken β-actin promoter (CAG), followed by an intron and flanked by two restriction sites, and also includes a post-transcriptional regulatory element, followed by a transcriptional termination signal. While the modification of pVax1 elements either decreased eGFP expression levels or had no effect at all, replacement of the promoter, the poly-A signal, deletion of the T7 and AmpR promoters, and inversion of the ORI-Neo/Kan cassette, significantly increased in vitro eGFP expression with the modified plasmid called pIDV-II. To further evaluate our vector, expression levels of three viral antigens were compared in cell lines transfected either with pVax1 or pCAGGS backbones as controls. Higher transgene expression was consistently observed with pIDV-II. The humoral and cellular responses generated in mice immunized with pIDV-II vs pVax1 expressing each viral antigen individually were superior by 2-fold or more as measured by ELISA and ELISPOT assays. Overall these results indicate that pIDV-II induces robust transgene expression, with concomitant improved cellular and humoral immune responses against the transgene of interest over pVax1. The new vector, pIDV-II, offers an additional alternative for DNA based vaccination and gene therapy for animal and human use.


MedPath: A process-based modeling language for designing care pathways.
Medical professionals and hospitals promote solutions like care pathways and Health Information Systems (HIS) to support medical conduct and improve the quality of medical care. This study proposes MedPath: a Domain Specific Language (DSL) for modeling care pathways based on the paradigms of Model-Based Engineering (MBE) that can be integrated into software solutions. We have developed MedPath's abstract syntax with the Eclipse Modeling Framework by employing Ecore technology and concrete syntax with the Eclipse Sirius. We have modeled over 85 care pathways that are in use in 45 hospitals in Brazil. MedPath-originated pathways have been used over 3.2 million times since October 2017. We conducted a survey among the professionals who used MedPath to evaluate user satisfaction. We believe MedPath can translate any care pathway into an action flow with its current abstractions. MedPath makes care pathways more easily integrated into HIS and electronic patient records, as it enables programmatic modeling and generates consumable artifacts.


Cholinergic intervention in intracardiac autonomic nerves in atrioventricular junctional area.
Cholinergic influence on atrioventricular (AV) junctional rhythm via its intervention in the intracardiac autonomic nerves was investigated in the canine, blood-perfused AV node preparation. Large amounts of acetylcholine (ACh) injected into the anterior septal artery (ASA) caused a rapid increase in the rate of automaticity superimposed on a slow increase. Nicotine given in the ASA caused to a rapid increased superimposed on a slow increase. Large amounts of ACh injected into the posterior septal artery (PSA) caused a slow increase, which was superimposed by a rapid icrease in the presence of l-hyoscyamine. The rapid and slow increases were abolished by dl-propranolol given in the PSA and ASA, respectively. Both types of increases were suppressed by tetrodotoxin (TTX). Nicotine given in the PSA caused a decrease superimposed by a rapid increase, both of which were abolished by TTX. These reslts indicate that cholinergic excitatory intervention induces AV junctional tachycardia via norepinephrine release from sympathetic nerve endings, distributing widely from the proximal to distal portion of the AV junctional area.


Fuzzy optimization for detecting enzyme targets of human uric acid metabolism.
Mathematical modeling and optimization have been used for detecting enzyme targets in human metabolic disorders. Such optimal drug design methods are generally differentiated as two stages, identification and decision-making, to find optimal targets. We developed a unified method named fuzzy equal metabolic adjustment to formulate an optimal enzyme target design problem for drug discovery. The optimization framework combines the identification of enzyme targets and a decision-making strategy simultaneously. The objectives of this algorithm include evaluations of the therapeutic effect of target enzymes, the adverse effects of drugs and the minimum effective dose (MED). An existing generalized mass action system model of human uric acid (UA) metabolism was used to formulate the fuzzy optimization method for detecting two types of enzymopathies: hyperuricemia caused by phosphoribosylpyrophosphate synthetase (PRPPS) overactivity and Lesch-Nyhan syndrome. The fuzzy objectives were set so that the concentrations of the metabolites were as close as possible to the healthy levels. The target design included a diet control of ribose-5-phospahate (R5P). The diet control of R5P served as an extra remedy to reduce phosphate uptake entering the purine metabolic pathway, so that we could obtain a more satisfactory treatment than obtained for those without a diet control. Moreover, enhancing UA excretion resulted in an effective treatment of hyperuricemia caused by PRPPS overactivity. This result correlates with using probenecid and benbromazone, which are uricosuric agents present in current clinical medications. By contrast, the Lesch-Nyhan syndrome required at least three enzyme targets to cure hyperuricemia.


Intravenous rutin in rat exacerbates isoprenaline-induced cardiotoxicity likely due to intracellular oxidative stress.
Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown various in vitro benefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24 hours. This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46 mg/kg, i.v.) after administration of ISO (100 mg/kg, s.c.) in rats within 2 hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line. Like our previous findings, rutin did not (11.5 or 46 mg/kg, i.v.) reduce the ISO-induced mortality within 2 hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formation in vitro and had the tendency to increase it in vivo. Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used.


Bioinformatic analysis of HIV-1 entry and pathogenesis.
The evolution of human immunodeficiency virus type 1 (HIV-1) with respect to co-receptor utilization has been shown to be relevant to HIV-1 pathogenesis and disease. The CCR5-utilizing (R5) virus has been shown to be important in the very early stages of transmission and highly prevalent during asymptomatic infection and chronic disease. In addition, the R5 virus has been proposed to be involved in neuroinvasion and central nervous system (CNS) disease. In contrast, the CXCR4-utilizing (X4) virus is more prevalent during the course of disease progression and concurrent with the loss of CD4(+) T cells. The dual-tropic virus is able to utilize both co-receptors (CXCR4 and CCR5) and has been thought to represent an intermediate transitional virus that possesses properties of both X4 and R5 viruses that can be encountered at many stages of disease. The use of computational tools and bioinformatic approaches in the prediction of HIV-1 co-receptor usage has been growing in importance with respect to understanding HIV-1 pathogenesis and disease, developing diagnostic tools, and improving the efficacy of therapeutic strategies focused on blocking viral entry. Current strategies have enhanced the sensitivity, specificity, and reproducibility relative to the prediction of co-receptor use; however, these technologies need to be improved with respect to their efficient and accurate use across the HIV-1 subtypes. The most effective approach may center on the combined use of different algorithms involving sequences within and outside of the env-V3 loop. This review focuses on the HIV-1 entry process and on co-receptor utilization, including bioinformatic tools utilized in the prediction of co-receptor usage. It also provides novel preliminary analyses for enabling identification of linkages between amino acids in V3 with other components of the HIV-1 genome and demonstrates that these linkages are different between X4 and R5 viruses.


Systematic evaluation of mechanistic data in assessing in utero exposures to trichloroethylene and development of congenital heart defects.
The hypothesis that in utero exposures to low levels of trichloroethylene (TCE) may increase the risk of congenital heart defects (CHDs) in offspring remains a subject of substantial controversy within the scientific community due primarily to the reliance on an inconsistent and unreproducible experimental study in rats. To build on previous assessments that have primarily focused on epidemiological and experimental animal studies in developing conclusions, the objective of the current study is to conduct a systematic evaluation of mechanistic data related to in utero exposures to TCE and the development of CHDs. The evidence base was heterogeneous; 79 mechanistic datasets were identified, characterizing endpoints which ranged from molecular to organismal responses in seven species, involving both in vivo and in vitro study designs in mammalian and non-mammalian models. Of these, 24 datasets were considered reliable following critical appraisal using a study quality tool that employs metrics specific to the study type. Subsequent synthesis and integration demonstrated that the available mechanistic data: 1) did not support the potential for CHD hazard in humans, 2) did not support the biological plausibility of a response in humans based on organization via a putative adverse outcome pathway for valvulo-septal cardiac defects, and 3) were not suitable for serving as candidate studies in risk assessment. Findings supportive of an association were generally limited to in ovo chicken studies, in which TCE was administered in high concentration solutions via direct injection. Results of these in ovo studies were difficult to interpret for human health risk assessment given the lack of generalizability of the study models (including dose relevance, species-specific biological differences, variations in the construct of the study design, etc.). When the mechanistic data are integrated with findings from previous evaluations of human and animal evidence streams, the totality of evidence does not support CHDs as a critical effect in TCE human health risk assessment.


Four-channel wavelength multiplexing composed of phase plates and polarizing beam splitters.
A new four-channel wavelength multiplexer (W-MUX) based on vibration plane multiplexing is proposed. The W-MUX is composed of phase plates and polarizing beam splitters. Each phase plate operates as a onewave plate for a certain wavelength of light and as a halfwave plate for some other wavelength of light. It is shown that this kind of phase plate can be made incorporating two kinds of birefringent crystal. In addition, the design of the phase plate is discussed. The W-MUX is experimentally fabricated, and its insertion loss is measured. The measured insertion loss for each channel is 2.8 dB or less.


[Reconstruction of the ossicular chain with titanium implants. Results of a multicenter study].
For decades, oto-surgeons have been trying to find suitable alloplastic materials for replacing ossicles in the case of morphological and functional disorders in the middle ear. The focus of attention has been on tissue tolerance and functionality. A retrospective analysis of the implantation of titanium prostheses is presented (Type "Duesseldorf", Heinz Kurz GmbH, Dusslingen, Germany) in 528 patients operated in 14 ENT hospitals. The hospitals involved are ENT hospitals with different fields of specialization presenting a representative cross-section of surgical ENT treatment. Evaluated were healing results, hearing gain and surgical handling of the implants. Despite pathological middle ear conditions, the tissue-implant healing rate was very high. In 4.4% of the patients the implants were rejected. In the case of partial ossicular reconstruction, an average hearing gain between 10 and 20 dB was achieved. Total reconstruction of the ossicular chain showed even better audiological results (15 to 20 dB on average). Due to the good morphological and functional results achieved, titanium implants have proven their worth for middle ear micro-surgery. Their advantages are their light weight and delicate structure, facilitating very good micro-surgical handling. It is advisable to place a thin layer of cartilage between the prosthesis headplate and the tympanic membrane. In this manner, the number of material extrusions can be safely reduced, however, extrusions cannot completely be avoided.


VolumeNet: A Lightweight Parallel Network for Super-Resolution of MR and CT Volumetric Data.
Deep learning-based super-resolution (SR) techniques have generally achieved excellent performance in the computer vision field. Recently, it has been proven that three-dimensional (3D) SR for medical volumetric data delivers better visual results than conventional two-dimensional (2D) processing. However, deepening and widening 3D networks increases training difficulty significantly due to the large number of parameters and small number of training samples. Thus, we propose a 3D convolutional neural network (CNN) for SR of magnetic resonance (MR) and computer tomography (CT) volumetric data called ParallelNet using parallel connections. We construct a parallel connection structure based on the group convolution and feature aggregation to build a 3D CNN that is as wide as possible with a few parameters. As a result, the model thoroughly learns more feature maps with larger receptive fields. In addition, to further improve accuracy, we present an efficient version of ParallelNet (called VolumeNet), which reduces the number of parameters and deepens ParallelNet using a proposed lightweight building block module called the Queue module. Unlike most lightweight CNNs based on depthwise convolutions, the Queue module is primarily constructed using separable 2D cross-channel convolutions. As a result, the number of network parameters and computational complexity can be reduced significantly while maintaining accuracy due to full channel fusion. Experimental results demonstrate that the proposed VolumeNet significantly reduces the number of model parameters and achieves high precision results compared to state-of-the-art methods in tasks of brain MR image SR, abdomen CT image SR, and reconstruction of super-resolution 7T-like images from their 3T counterparts.


Knockdown of JARID2 inhibits the proliferation and invasion of ovarian cancer through the PI3K/Akt signaling pathway.
Protein Jumonji (JARID2), a member of the family of JmjC domain-containing proteins, has been reported to serve an important role in tumor growth and metastasis. However, the expression pattern and role of JARID2 in ovarian cancer remains unclear. Therefore, in the present study, the role of JARID2 in ovarian cancer was investigated, as well as the underlying mechanisms. The results of the present study demonstrated that the expression of JARID2 is upregulated in human ovarian cancer cell lines. Furthermore, downregulation of JARID2 significantly suppressed proliferation, migration, invasion and epithelial‑mesenchymal transition in human ovarian cancer cells. Mechanistically, downregulation of JARID2 decreased the protein expression levels of phosphorylated phosphoinositide 3‑kinase (PI3K) and protein kinase B (Akt) in ovarian cancer cells. In conclusion the observations suggested that knockdown of JARID2 inhibited proliferation, migration and invasion in vitro through the inactivation of the PI3K/Akt signaling pathway. Therefore, JARID2 may represent a potential therapeutic target for the treatment of ovarian cancer.


Analysis of amino acid profiles of blood over time and biomarkers associated with non-alcoholic steatohepatitis in STAM mice.
The changes in free amino acid (AA) levels in blood during the progression from non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) are unclear. We investigated serum AA levels, along with biochemical and histological events, in a mouse model of NASH. We induced NASH in male C57BL/6J mice with a streptozotocin injection and high-fat diet after 4 weeks of age (STAM group). We chronologically (6, 8, 10, 12, and 16 weeks, n=4-12 mice/group) evaluated the progression from steatohepatitis to HCC by biochemical and histological analyses. The serum AA levels were determined using an AA analyzer. Serum aspartate aminotransferase and alanine aminotransferase levels were higher in the STAM group than in the normal group (non-NASH-induced mice). Histological analysis revealed that STAM mice had fatty liver, NASH, and fibrosis at 6, 8, and 10 weeks, respectively. Moreover, the mice exhibited fibrosis and HCC at 16 weeks. The serum branched-chain AA levels were higher in the STAM group than in the normal group, especially at 8 and 10 weeks. The Fischer ratio decreased at 16 weeks in the STAM group, with increasing aromatic AA levels. These results suggested that this model sequentially depicts the development of fatty liver, NASH, cirrhosis, HCC, and AA metabolism disorders within a short experimental period. Additionally, serum amyloid A was suggested to be a useful inflammation biomarker associated with NASH. We believe that the STAM model will be useful for studying AA metabolism and/or pharmacological effects in NASH.


IS6110-RFLP and spoligotyping of Mycobacterium tuberculosis isolates in Iran.
To evaluate and compare the usefulness of IS6110-restriction fragment length polymorphism (RFLP) and spoligotyping in the epidemiology of tuberculosis in Iran, Mycobacterium tuberculosis complex strains, isolated in 2 different areas of Iran, were subjected to RFLP and spoligotyping. The average number of IS6110 copies per strain was 11 and ranged from 5 to 18 among the M. tuberculosis strains. In total, among the 62 isolates, 56 different patterns were observed. 50 strains had unique RFLP patterns (89%) and 12 (11%) revealed patterns that were found among at least 1 other isolate. Spoligotyping of 97 isolates resulted in 42 different patterns, of which 72% were found in 15 clusters. 14 (29%) out of 48 investigated isolates were resistant to 1 or more antituberculosis drugs and 57% of the resistant isolates were isolated from Afghan immigrants. Ten percent of the isolates represented the Beijing genotype, including 4 of the 14 (36%) resistant strains. Three of these resistant Beijing strains were isolated from Afghan patients. IS6110-RFLP typing could be useful for studying the epidemiology of tuberculosis in Iran. IS6110 patterns were polymorphic and the average IS6110 copy number was high.


Jungle yellow fever: clinical and laboratorial studies emphasizing viremia on a human case.
The authors report the clinical, laboratorial and epidemiological aspects of a human case of jungle yellow fever. The patient suffered from fever, chills, sweating, headaches, backaches, myalgia, epigastric pains, nausea, vomiting, diarrhea and prostration. He was unvaccinated and had been working in areas where cases of jungle yellow fever had been confirmed. Investigations concerning the yellow fever virus were performed. Blood samples were collected on several days in the course of the illness. Three of these samples (those obtained on days 5, 7 and 10) were inoculated into suckling mice in attempt to isolate virus and to titrate the viremia level. Serological surveys were carried out by using the IgM Antibodies Capture Enzyme Linked Immunosorbent Assay (MAC-ELISA), Complement Fixation (CF), Hemagglutination Inhibition (HI) and Neutralization (N) tests. The yellow fever virus, recovered from the two first samples and the virus titration, showed high level of viremia. After that, specific antibodies appeared in all samples. The interval between the end of the viremia and the appearance of the antibodies was associated with the worsening of clinical symptoms, including bleeding of the mucous membrane. One must be aware of the risk of having a urban epidemics in areas where Aedes aegypti is found in high infestation indexes.


Predictors of dislocation and revision after shoulder stabilization in Ontario, Canada, from 2003 to 2008.
Factors contributing to recurrent dislocation, revision stabilization, and complications requiring reoperation after an initial shoulder stabilization procedure for instability have not been evaluated on a population level. (1) To define the rate of ipsilateral revision stabilization, contralateral primary stabilization, postoperative dislocation, and complications after primary shoulder stabilization in a population cohort. (2) To understand which risk factors among patient, surgical, and provider factors influence these outcomes. Cohort study; Level of evidence, 3. All residents of Ontario, Canada, aged 16 to 60 years undergoing primary shoulder stabilization between July 2003 and December 2008 were identified from billing and hospital databases. Separate Cox proportional hazards survivorship models were built for the outcomes revision stabilization and postoperative physician-documented shoulder relocation (minimum 2-year follow-up). Model covariates included patient demographics (age, sex, preoperative dislocations), provider characteristics (surgeon volume, hospital academic status), and type of surgery (open, arthroscopic). The frequency and risk factors for contralateral stabilization were identified. A total of 5904 patients (80.6% male; median age, 29 years) were identified. Arthroscopic stabilization was used in ~60% of cases in 2003, increasing to ~80% in 2008. The rates of postoperative dislocation were 6.9%, revision stabilization 4%, and contralateral primary stabilization 3.9%. Patients aged younger than 20 years had a 7.7% revision rate (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.7-4.2; P < .0001) and a 12.6% rate of postoperative physician-documented dislocation (HR, 2.4; 95% CI, 1.8-3.4; P < .0001), compared with 2.8% and 5.5%, respectively, in patients 29 years old (median cohort age). Patients with 3 or more preoperative dislocations in Ontario had an increased risk of revision (HR, 2.1; 95% CI, 1.5-3.0; P < .0001) and postoperative dislocation (HR, 10.6; 95% CI, 8.1-14.0; P < .0001). Revision was more common after arthroscopic (4.3%) compared with open (3.5%) stabilization (HR, 1.4; 95% CI, 1.02-1.98; P = .04). No provider factor was predictive, including surgeon volume. Reoperation rate for complications not related to recurrent instability was 0.23% (infection, 0.07%; manipulation under anesthesia, 0.15%). The risks of revision stabilization and postoperative (either shoulder) dislocation were most influenced by young age (<20 years) and having had 3 or more preoperative dislocations. Complications requiring surgery are rare.


V-Y dorsal metacarpal flap: a new technique for the correction of syndactyly without skin graft.
A new technique for web reconstruction in congenital syndactyly is described. Twenty-one web spaces in 12 patients were treated using this method. The dorsal metacarpal flap was used as an island V-Y advancement to cover the newly created web space, thus avoiding skin graft in this space. A follow-up of 6 months to 2 years showed neither recurrence of the deformity nor web creep of any degree. The operation is rapid, easy, and reproducible. It is suggested that this technique can be used in all types of syndactyly.


A randomized comparative trial of stavudine (d4T) versus zidovudine (ZDV, AZT) in children with human immunodeficiency virus infection. AIDS Clinical Trials Group 240 Team.
To compare the safety and tolerance of stavudine (d4T) versus zidovudine (ZDV, AZT) in symptomatic human immunodeficiency virus-infected children 3 months to 6 years of age. In an initially double-blind trial, 212 evaluable human immunodeficiency virus-infected children who had received no more than 6 weeks of previous antiretroviral therapy were randomized to receive either d4T (1 mg/kg orally every 12 hours, maximum 40 mg orally every 12 hours) or zidovudine (180 mg/m2 orally every 6 hours, maximum 200 mg orally every 6 hours). The study was unblinded after a median follow-up period of 6.3 months; median follow-up at study closure was 17.3 months. Tolerance, safety, disease progression, and immunologic responses were evaluated. The patient population was young (median age, 1.2 years; range, 0.3 to 6.4 years), with a median baseline CD4+ lymphocyte count of 965 cells/microL (range, 18 to 4238 cells/microL). Neutropenia < 400/microL occurred significantly more commonly among zidovudine recipients (1-year event rates of 20% both up to the time of unblinding and throughout the entire study) than among children receiving d4T (1-year event rates of 5% up to the time of unblinding and 6% throughout the entire study). In exploratory activity analyses using all data collected until study closure, children treated with d4T showed consistently greater positive changes from baseline in weight-for-age-and-gender z scores. As expected in this population of young children, median absolute CD4+ lymphocyte counts decreased in both treatment groups. Smaller changes from baseline were noted among d4T recipients. In children between the ages of 3 months and 6 years, d4T and zidovudine are largely comparable in terms of safety and tolerance. Neutropenia occurs significantly less commonly among children treated with d4T. There was evidence that weight gain and absolute CD4+ lymphocyte counts were better maintained in children receiving d4T.


Comparing different nonlinearities in readout systems for optical neuromorphic computing networks.
Nonlinear activation is a crucial building block of most machine-learning systems. However, unlike in the digital electrical domain, applying a saturating nonlinear function in a neural network in the analog optical domain is not as easy, especially in integrated systems. In this paper, we first investigate in detail the photodetector nonlinearity in two main readout schemes: electrical readout and optical readout. On a 3-bit-delayed XOR task, we show that optical readout trained with backpropagation gives the best performance. Furthermore, we propose an additional saturating nonlinearity coming from a deliberately non-ideal voltage amplifier after the detector. Compared to an all-optical nonlinearity, these two kinds of nonlinearities are extremely easy to obtain at no additional cost, since photodiodes and voltage amplifiers are present in any system. Moreover, not having to design ideal linear amplifiers could relax their design requirements. We show through simulation that for long-distance nonlinear fiber distortion compensation, using only the photodiode nonlinearity in an optical readout delivers BER improvements over three orders of magnitude. Combined with the amplifier saturation nonlinearity, we obtain another three orders of magnitude improvement of the BER.


Validation of a Parkinson Disease Predictive Model in a Population-Based Study.
Parkinson disease (PD) has a relatively long prodromal period that may permit early identification to reduce diagnostic testing for other conditions when patients are simply presenting with early PD symptoms, as well as to reduce morbidity from fall-related trauma. Earlier identification also could prove critical to the development of neuroprotective therapies. We previously developed a PD predictive model using demographic and Medicare claims data in a population-based case-control study. The area under the receiver-operating characteristic curve (AUC) indicated good performance. We sought to further validate this PD predictive model. In a randomly selected, population-based cohort of 115,492 Medicare beneficiaries aged 66-90 and without PD in 2009, we applied the predictive model to claims data from the prior five years to estimate the probability of future PD diagnosis. During five years of follow-up, we used 2010-2014 Medicare data to determine PD and vital status and then Cox regression to investigate whether PD probability at baseline was associated with time to PD diagnosis. Within a nested case-control sample, we calculated the AUC, sensitivity, and specificity. A total of 2,326 beneficiaries developed PD. Probability of PD was associated with time to PD diagnosis (p < 0.001, hazard ratio = 13.5, 95% confidence interval (CI) 10.6-17.3 for the highest vs. lowest decile of probability). The AUC was 83.3% (95% CI 82.5%-84.1%). At the cut point that balanced sensitivity and specificity, sensitivity was 76.7% and specificity was 76.2%. In an independent sample of additional Medicare beneficiaries, we again applied the model and observed good performance (AUC = 82.2%, 95% CI 81.1%-83.3%). Administrative claims data can facilitate PD identification within Medicare and Medicare-aged samples.


Psychosocial variables and hospitalization in persons with chronic heart failure.
Persons with chronic heart failure (HF) must cope not only with the physical impairment of their disease but with the associated emotional distress. The primary purpose of this prospective study was to examine whether the psychosocial variables of symptom impact measured at baseline--health perception, social support and coping--differed between a group of adults with chronic HF who were hospitalized and a group who were not hospitalized during the following six months of the study. A secondary purpose was to examine indices of left ventricular dysfunction that might influence hospitalization. Within the six-month period following baseline data collection, 23 of 62 (37%) patients who completed the study were hospitalized at least once for problems pertaining to HF. Patients in the hospitalized group reported significantly more baseline symptom impact, particularly in the areas of emotional symptoms and deficits of attention and memory. Social support and coping did not differ significantly between hospitalized and nonhospitalized patients. Extent of myocardial dysfunction, age and demographic variables were not significantly different between the two groups. Heart failure decompensation requiring inpatient management was presaged by increased anxiety and disorders of mentation, suggesting that health care providers need to be sensitive to these reported symptoms and their impact, because they might be clues to impending hospitalization.


Isolation and characterization of trophoblast from murine placenta.
A discontinuous density gradient centrifugation method, devised to isolate enriched populations of trophoblast from murine definitive placentae, is described. It is concluded that the isolated adherent cells are trophoblast on the basis of the following characteristics: they are fetally derived, as determined by their donor glucose phosphate isomerase phenotype in embryo transfer experiments; epithelial cells, as shown by the presence of cytokeratin filaments and the absence of vimentin; negative for the stage-specific embryonic antigen-I (SSEA-I); and capable of progesterone secretion. Initially, they grew as individual polygonal cells, tending to form tight confluent monolayers with poorly defined intercellular boundaries. They were mono- or binucleate and increased their nuclear size with time. After two days, giant cells appeared to be formed from binucleated cells by nuclear fusion, and multinucleated cells appeared forming syncytia. Some of these cells also seemed to form giant cells. A low percentage (1 to 10 per cent) of contaminating cells, mainly macrophage-like cells, was observed. The isolated cells were a mixture of alkaline phosphatase- (AP-)positive and AP-negative cells, with some of the latter having phagocytic capacity. All were Fc receptor-negative. The possible identity of these cells in relation to trophoblast in the intact placenta is discussed. This method of isolating and characterizing trophoblast cells from the definitive mouse placenta will be a useful tool for studying the biology and immunology of trophoblast.


Strain sensitivity and superconducting properties of Nb3Sn from first principles calculations.
Using calculations from first principles based on density-functional theory we have studied the strain sensitivity of the A15 superconductor Nb3Sn. The Nb3Sn lattice cell was deformed in the same way as observed experimentally on multifilamentary, technological wires subject to loads applied along their axes. The phonon dispersion curves and electronic band structures along different high-symmetry directions in the Brillouin zone were calculated, at different levels of applied strain, ε, on both the compressive and the tensile side. Starting from the calculated averaged phonon frequencies and electron-phonon coupling, the superconducting characteristic critical temperature of the material, T(c), has been calculated by means of the Allen-Dynes modification of the McMillan formula. As a result, the characteristic bell-shaped T(c) versus ε curve, with a maximum at zero intrinsic strain, and with a slight asymmetry between the tensile and compressive sides, has been obtained. These first-principle calculations thus show that the strain sensitivity of Nb3Sn has a microscopic and intrinsic origin, originating from shifts in the Nb3Sn critical surface. In addition, our computations show that variations of the superconducting properties of this compound are correlated to stress-induced changes in both the phononic and electronic properties. Finally, the strain function describing the strain sensitivity of Nb3Sn has been extracted from the computed T(c)(ε) curve, and compared to experimental data from multifilamentary, composite wires. Both curves show the expected bell-shaped behavior, but the strain sensitivity of the wire is enhanced with respect to the theoretical predictions for bulk, perfectly binary and stoichiometric Nb3Sn. An understanding of the origin of this difference might open potential pathways towards improvement of the strain tolerance in such systems.


Insulin resistance according to β-cell function in women with polycystic ovary syndrome and normal glucose tolerance.
Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and compensatory hyperinsulinemia. IR is recognized as a major risk factor for the development of type 2 diabetes mellitus. However, few studies have investigated IR in women with PCOS and normal glucose tolerance. The objective of this study was to evaluate IR and β-cell function in women with PCOS and normal glucose tolerance. Additionally, we sought to evaluate the usefulness of oral glucose tolerance test (OGTT)-derived IR indices in lean women with PCOS. We recruited 100 women with PCOS and normal glucose tolerance and 100 age- and BMI-matched women as controls. IR and insulin secretory indices, including the homeostasis-model assessment (HOMA)-IR, HOMA-M120, HOMA-F and the Stumvoll index, were calculated from an OGTT. Increased β-cell function was defined as>75th percentile for the HOMA-F in control women. Women with PCOS had higher values for post-load 2-hour glucose, fasting insulin, post-load 2-hour insulin, HOMA-IR, HOMA-M120, HOMA-F and lower values for the Stumvoll index than the controls (all Ps<0.05). Women with PCOS and increased β-cell function showed lower Stumvoll index values than the matched controls (P<0.05). The HOMA-F was significantly associated with the HOMA-M120 and Stumvoll index when adjusted for age and BMI in a multiple regression analysis (all Ps<0.05). The HOMA-M120 was positively correlated with triglycerides and free testosterone, and the Stumvoll index was negatively correlated with triglycerides and free testosterone in lean women with PCOS (all Ps<0.05). Women with PCOS and normal glucose tolerance showed higher IR than controls matched for age, BMI, and β-cell function. β-cell function was increased in women with PCOS when compared to the matched controls, but not when the lean subjects were compared to the matched controls separately. Therefore, early evaluation of IR in women with PCOS and normal glucose tolerance may be needed.


Vaping Associated Acute Eosinophilic Pneumonia: A Clinical and Radiologic Mimicker of COVID-19.
Acute eosinophilic pneumonia (AEP) is a rare cause of respiratory failure. It is primarily a disease of smokers, either a new smoker or an existing one with a recent increase in cigarette consumption. Other risk factors include toxic gas exposure, inhalational illicit drugs, and smoking marijuana. AEP has also been reported in patients with e-cigarette or vaping associated lung injury (EVALI). We present the case of a 20-year-old male who presented to the hospital with acute respiratory failure. The patient has been vaping heavily for the past three months and started smoking three days before presenting to the emergency department. He was hypertensive, tachycardic, tachypneic, and required high-flow nasal cannula to maintain SpO2 > 92%. His condition deteriorated in the first 24 hours following hospitalization requiring noninvasive positive pressure ventilation. Bronchoalveolar lavage revealed an eosinophil count of 36%. Bronchoalveolar lavage (BAL) cytology revealed lipid-laden macrophages. He was diagnosed with AEP due to EVALI, and the patient was treated with high dose corticosteroid with subsequent improvement. Before the bronchoscopic evaluation, the clinical and radiologic findings were consistent with COVID-19, and the patient was tested twice for SARS-CoV-2 PCR. In the appropriate clinical setting, AEP should be considered in the differential diagnoses of community-acquired pneumonia, acute respiratory distress syndrome (ARDS), and COVID-19, especially in this pandemic era.


Rhodobacter maris sp. nov., a phototrophic alphaproteobacterium isolated from a marine habitat of India.
During investigations into the diversity of anoxygenic phototrophic bacteria in marine habitats, an ovoid to rod-shaped purple non-sulfur bacterium, designated strain JA276(T), was isolated from enrichments under photoheterotrophic conditions from a marine sediment sampled from the seashore of Cochin, India. Strain JA276(T) is a Gram-negative, motile, chain-forming bacterium that shows optimum growth under photoheterotrophic conditions and is also able to grow chemoorganotrophically. Thiamine is required as a growth factor. Strain JA276(T) contains vesicular intracytoplasmic membranes, bacteriochlorophyll a and the carotenoids spheroidene and spheroidenone. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain JA276(T) belongs to the genus Rhodobacter and is closely related to the type strain of Rhodobacter capsulatus (96.2 % sequence similarity). On the basis of the results of 16S rRNA gene sequence analysis and morphological and physiological data, strain JA276(T) is significantly different from other species of the genus Rhodobacter and represents a novel species of the genus, for which the name Rhodobacter maris sp. nov. is proposed. The type strain is JA276(T) (=JCM 14794(T) =ATCC BAA-1549(T) =CCUG 55129(T)).


Venous Thromboembolism in Patients With Autoimmune Disorders: Findings From the RIETE Registry.
Patients with autoimmune disorders are at an increased risk of venous thromboembolism (VTE), but this association has not been consistently evaluated. We used the RIETE (Registro Informatizado Enfermedad Trombo Embólica) database to compare the rates of VTE recurrences, major bleeding, and death during the course of anticoagulation, according to the presence or absence of autoimmune disorders. Of 71 625 patients with VTE recruited in February 2018, 1800 (2.5%) had autoimmune disorders. Median duration of anticoagulant therapy was slightly longer in patients with autoimmune disorders (median, 190 vs 182 days; P = .001). On multivariable analysis, patients with autoimmune disorders had a similar risk of VTE recurrences (hazard ratio [HR]: 0.93; 95% confidence interval [CI]: 0.68-1.27) or major bleeding (HR: 1.07; 95% CI: 0.82-1.40) and a lower risk to die (HR: 0.66; 95% CI: 0.54-0.81) than those without autoimmune disorders. Patients with giant cell arteritis had the highest rates of major bleeding (8.6 events per 100 patient-years) and the lowest rate of recurrences (zero). In other subgroups, the rates of both events were more balanced. During anticoagulation, patients with or without autoimmune disorders had similar rates of VTE recurrences or major bleeding. However, there were some differences between subgroups of patients with autoimmune disorders.


Fusion of raft-like lipid bilayers operated by a membranotropic domain of the HSV-type I glycoprotein gH occurs through a cholesterol-dependent mechanism.
A wealth of evidence indicates that lipid rafts are involved in the fusion of the viral lipid envelope with the target cell membrane. However, the interplay between these sterol- and sphingolipid-enriched ordered domains and viral fusion glycoproteins has not yet been clarified. In this work we investigate the molecular mechanism by which a membranotropic fragment of the glycoprotein gH of the Herpes Simplex Virus (HSV) type I (gH625) drives fusion of lipid bilayers formed by palmitoyl oleoyl phosphatidylcholine (POPC)-sphingomyelin (SM)-cholesterol (CHOL) (1 : 1 : 1 wt/wt/wt), focusing on the role played by each component. The comparative analysis of the liposome fusion assays, Dynamic Light Scattering (DLS), spectrofluorimetry, Neutron Reflectivity (NR) and Electron Spin Resonance (ESR) experiments, and Molecular Dynamics (MD) simulations shows that CHOL is fundamental for liposome fusion to occur. In detail, CHOL stabilizes the gH625-bilayer association by specific interactions with the peptide Trp residue. The interaction with gH625 causes an increased order of the lipid acyl chains, whose local rotational motion is significantly hampered. SM plays only a minor role in the process, favoring the propagation of lipid perturbation to the bilayer inner core. The stiffening of the peptide-interacting bilayer leaflet results in an asymmetric perturbation of the membrane, which is locally destabilized thus favoring fusion events. Our results show that viral fusion glycoproteins are optimally suited to exert a high fusogenic activity on lipid rafts and support the relevance of cholesterol as a key player of membrane-related processes.


The variant form of angina pectoris.
Variant angina pectoris, usually not precipitated by exertion or emotional stress, often is more severe and lasts longer than classic angina. The pain tends to recur at about the same time each day. Arrhythmias, usually ventricular, occur in about 50% of cases during the peak of pain. Electrocardiograms show a characteristic ST segment elevation during pain, which is in contrast to the ST segment depression of classic angina pectoris. Pain may be due, at least in some cases, to a temporary increase in tonus of a single, large, narrowed coronary artery. Chemical changes in the myocardium and plasma catecholamine changes differ from those occurring in classic angina pectoris. The course of the disease is highly variable but the prognosis must be regarded as grave, since single large vessel disease, present in most cases, is associated with severe myocardial ischemia. Patients with variant angina pectoris should be studied early with coronary arteriography and considered for coronary artery bypass surgery if appropriate.


Discovering social events through online attention.
Twitter is a major social media platform in which users send and read messages ("tweets") of up to 140 characters. In recent years this communication medium has been used by those affected by crises to organize demonstrations or find relief. Because traffic on this media platform is extremely heavy, with hundreds of millions of tweets sent every day, it is difficult to differentiate between times of turmoil and times of typical discussion. In this work we present a new approach to addressing this problem. We first assess several possible "thermostats" of activity on social media for their effectiveness in finding important time periods. We compare methods commonly found in the literature with a method from economics. By combining methods from computational social science with methods from economics, we introduce an approach that can effectively locate crisis events in the mountains of data generated on Twitter. We demonstrate the strength of this method by using it to locate the social events relating to the Occupy Wall Street movement protests at the end of 2011.


Staphylococcus aureus skin and soft tissue infections: can we anticipate the culture result?
This prospective study was designed to evaluate predictors of skin and soft tissue infections (SSTI) due to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Consecutive patients who were hospitalized with S aureus SSTI were enrolled. CA-MRSA infection was diagnosed in 76% of the children. MRSA SSTI was associated with black race (P = .0001) and with infection involving the lower trunk (P = .008). Only 21% of the patients in this study had S aureus colonization in their nares, and in 3 cases there was discordance between the nares and the infection site cultures. Sensitivity, specificity, and predictive values of the risk factors examined were limited in their ability to predict CA-MRSA infection. Given the high prevalence of MRSA in our community and the inability of nasal cultures to reliably predict CA-MRSA infection, empirical antibiotic therapy active against CA-MRSA and contact isolation of patients are recommended.


Intercostal variation for age estimation--are the standards for the right 4th rib applicable for other ribs?
Age estimation of unknown skeletal remains is very important in forensic medicine. Morphologic methods are fast and easy to use for purpose of age determination. The sternal ends of the ribs are a reliable method of age estimation from late adolescence to old age. Iscan et al developed a phase analysis method for the right 4th rib that was sex and race specific. The purpose of this study is to determine the accuracy of the standards of age estimation from the right 4th and other rib using the phase analysis for the Turkish population. The sample consisted of right and left 3rd, 4th and 5th ribs from 34 Turkish women and 76 men. There were statistically significant variations found on the right 5th, left 3rd, 4th, and 5th ribs according to these standards in men for phases 5, 6, and 7. For women, all the right and left ribs included in this study were in concordance with right 4th rib standards in all phases.


[Action of strong and weak nitrogenous bases on respiratory chain enzymes of mitochondria].
The action of nitrogenous basis--electroneutral hydrazides (pK less than 7,50 and positive charged arylhydrazones (pK greater than 8)--on the respiratory chain enzymes and the influence of the electric charge and the size of alkoxylic group on biological activity compounds have been investigated. It has been shown that the size of alkoxylic group defines the selective action of nitrogenous basis on the enzymes of mitochondrial respiratory chain. The nitrogenous basis with a long alkoxylic group is shown to be inhibitors of NADH-dehydrogenase, their action is similar to rotenone. At the same time compounds with a short group are more effective in the inhibition of the enzymes of the initial segment in the respiratory chain mitochondria. The affinity of the organic cations of arylhydrazones to NADH-dehydrogenase is 100-1000 times higher than the affinity of electric neutral compounds.


A case of "precocious" mummification.
Mummification is a peculiar transformative process consisting of the total drying of the body soft tissues. It is produced, in particular conditions, between 6 and 12 months after death. "Precocious" mummification has been reported in countries where recorded weather conditions are more extreme than in Italy, in a confined environment, or with particular micro-climate conditions. Here we present a case of mummification produced in a central region of Italy in four weeks. We also analyze conditions allowing for the rapidity of this phenomenon.


Causes of death in older peritoneal dialysis patients--can we depend on registry reports?
Despite significant improvements in renal management the mortality associated with dialysis care remains high. Many renal registries report mortality statistics on an annual basis. The objectives of this study were (1) to establish the accuracy of the registered cause of death (CoD) against that determined by a panel of physicians; and (2) to test the feasibility of using the HEMO study CoD classification system in patients on peritoneal dialysis (PD). Single centre tertiary-care hospital. Patients were selected from those aged > or = 65 years who died while receiving PD. The CoD was identified from that registered with the local renal registry, and from clinical records. (1) Sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and kappa score comparing registered and extracted CoD. (2) The proportions of deaths in seven categories using two classification systems. A total of 51 patient charts were reviewed. The agreement between the registered and extracted CoD was poor for all causes of death except malignancy. Kappa scores ranged from 0.55 to 1.0 for different causes. PPV were poor for all except malignancy. Comparison of the CoD was highly dependent on the classification method used (e.g., death secondary to infection was 4% and 25% for CORR and HEMO, respectively). The registered CoD for patients who die while on PD is often inaccurate. Different policies for classifying deaths can have a significant effect on the final reports, which show the proportion of deaths attributed to different diseases. Standardization across registries is required.


[Membranous glomerulonephritis (MGN), ongoing studies].
The membranous nephropathy (MN) is the major cause of nephrotic syndrome in in the adult, account for 20% of cases with annual incidence is 1 in 100.000. In the past 10 years, the role of podocytes has been identified; environmental triggers in genetically predisposed patients can activate podocytes to exhibit antigenic epitopes (receptor of phospholipase A2, thrombospondin type 1) that become targets of specific autoantibodies with subsequent complement activation. The discovery of this mechanisms has opened new horizons in the therapy of MN and novel drugs are available with more specific mechanism of action. Rituximab, a monoclonal antibody directed against CD20 expressed by lymphocytes B, has been used in several trials and appears able to induce remission of nephrotic syndrome in 60% of patients (GEMRITUX trial) with similar risk profile. Nowadays it remains to define the most effective therapeutic pattern. In MN, the concept of targeting disease control, has permit novel therapies with specific blocking mechanisms (belimumab) and non-specific (ACTH) and new therapeutic options, such as ofatumumab, bortezomib and eculizumab, that have allowed to recognize pathological processes involved in the glomerular diseases.


Gender-related differences among Turkish patients with obsessive-compulsive disorder.
The purpose of the present study was to investigate gender-related sociodemographic and clinical differences among Turkish patients with obsessive-compulsive disorder (OCD). A total of 169 patients diagnosed with OCD by DSM-III-R or DSM-IV criteria were included in this study. Male (n = 73) and female (n = 96) OCD patients were compared with respect to the demographic variables and the scores obtained from the Hamilton Rating Scale for Anxiety (HRSA), the Hamilton Rating Scale for Depression (HRSD) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). We found a significantly earlier age at onset in male patients. No significant difference in terms of HARS, HDRS, and Y-BOCS scores was detected between the two groups. We observed a significantly higher frequency of contamination obsessions in females, and that of aggression and sexual obsessions in males. There was no significant difference in terms of the frequency of compulsions between the two groups. We also found that compulsion severity on obsessions/compulsions was higher in females and comorbidity rates of social phobia and schizophrenia were higher in males. Considering our results in combination with those of other studies, similarities rather than differences in gender-related sociodemographic and clinical characteristics of OCD patients across different populations seem to be present.


In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR.
The most common cystic fibrosis transmembrane conductance regulator mutation, delta F508-CFTR, is a partially functional chloride channel that is retained in the endoplasmic reticulum and degraded. We hypothesize that a known transcriptional regulator, sodium 4-phenylbutyrate (4PBA), will enable a greater fraction of delta F508-CFTR to escape degradation and appear at the cell surface. Primary cultures of nasal polyp epithelia from CF patients (delta F508 homozygous or heterozygous), or the CF bronchial epithelial cell line IB3-1 (delta F508/W1282X) were exposed to 4PBA for up to 7 d in culture. 4PBA treatment at concentrations of 0.1 and 2 mM resulted in the restoration of forskolin-activated chloride secretion. Protein kinase A-activated, linear, 10 pS chloride channels appeared at the plasma membrane of IB3-1 cells at the tested concentration of 2.5 mM. Treatment of IB3-1 cells with 0.1-1 mM 4PBA and primary nasal epithelia with 5 mM 4PBA also resulted in the appearance of higher molecular mass forms of CFTR consistent with addition and modification of oligosaccharides in the Golgi apparatus, as detected by immunoblotting of whole cell lysates with anti-CFTR antisera. Immunocytochemistry in CF epithelial cells treated with 4PBA was consistent with increasing amounts of delta F508-CFTR. These data indicate that 4PBA is a promising pharmacologic agent for inducing correction of the CF phenotype in CF patients carrying the delta F508 mutation.


Experimental studies of electroosmotic flow dynamics during sample stacking for capillary electrophoresis.
Electroosmotic flow dynamics during a field-amplified sample stacking experiment have been studied experimentally using the periodic photobleaching of a dilute, neutral fluorophore added to the separation buffer. The effects of hydrodynamically injecting different sample plug lengths containing a mixture of arsenic compounds dissolved in 0.125 mM (120, 240, and 600 s) and 41.7 microM (27, 45, and 74 s) phosphate buffer with a separation buffer concentration of 12.5 mM phosphate buffer were examined. Changes in electroosmotic flow during sample stacking and separation were monitored at a rate of 1 Hz. The observed effects of increasing the sample plug length on electroosmotic flow and electrophoretic current agreed qualitatively with predictions by theoretical models presented in the literature. Electroosmotic flow changes on the order of 100% (1.6-3.3 mm/s) were observed. Broadening of the flow monitoring peaks has been used to examine parabolic flow due to the discontinuous buffer systems used for sample stacking.


Renal cell carcinoma may evade the immune system by converting CD4+Foxp3- T cells into CD4+CD25+Foxp3+ regulatory T cells: Role of tumor COX-2-derived PGE2.
Increased CD4+CD25+Foxp3+ regulatory T cells (Tregs) predict poor prognosis in renal cell carcinoma (RCC). The aim of this study was to investigate the underlying causes of the aberrant accumulation of Tregs in RCC. pcDNA3.1-hCOX-2 and control pcDNA3.1 were transfected into the RCC cell line OS-RC-2. Under stimulation of anti-CD3/CD28 antibody and APC cells, isolated CD4+Foxp3- T cells were co-cultured with transfected OS-RC-2 culture medium supernatants and different control supernatants, respectively, and 96 h later, the proportion of Tregs in each group was detected using FACS. The suppressive ability of naturally isolated Tregs and transformed Tregs was also analyzed using [3H]-thymidine methods. The results showed that overexpression of COX-2 in OS-RC-2 cells led to higher expression of prostaglandin E2 (PGE2) in the culture medium supernatants. In addition, there was an apparent incremental increase in the percentage of Tregs in the CD4+Foxp3- T cells cultured with the COX-2-overexpressing OS-RC-2 culture medium supernatants. Furthermore, transformed Tregs had the same suppressive ability as naturally isolated Tregs. In summary, transfected RCC cell line culture medium supernatants were capable of converting CD4+Foxp3- T cells to Tregs by producing high levels of PGE2, while COX-2 inhibitors reduced the proportion of transformed Tregs in a dose-dependent manner. Thus, COX-2 inhibitors may induce a local anti-tumor effect and, in turn, may contribute to the eradication of RCC by decreasing transformed Tregs.


Locus Reference Genomic sequences: an improved basis for describing human DNA variants.
As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specific purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-file record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)-approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants affecting human health. Further information can be found on the LRG web site: http://www.lrg-sequence.org.


Frequent release of low amounts of herpes simplex virus from neurons: results of a mathematical model.
Herpes simplex virus-2 (HSV-2) is a sexually transmitted infection that is the leading cause of genital ulcers worldwide. Infection is life long and is characterized by repeated asymptomatic and symptomatic shedding episodes of virus that are initiated when virus is released from neurons into the genital tract. The pattern of HSV-2 release from neurons into the genital tract is poorly understood. We fit a mathematical model of HSV-2 pathogenesis to curves generated from daily quantification of HSV in mucosal swabs performed from patients with herpetic genital ulcers. We used virologic parameters derived from model fitting for stochastic model simulations. These simulations reproduced previously documented estimates for shedding frequency, and herpetic lesion diameter and frequency. The most realistic model output occurred when we assumed minimal amounts of daily neuronal virus introduction. In our simulations, small changes in average total quantity of HSV-2 released from neurons influenced detectable shedding frequency, while changes in frequency of neuronal HSV-2 release had little effect. Frequent HSV-2 shedding episodes in humans are explained by nearly constant release of small numbers of viruses from neurons that terminate in the genital tract.


Hypothermia and the trauma patient.
Hypothermia has profound effects on every system in the body, causing an overall slowing of enzymatic reactions and reduced metabolic requirements. Hypothermic, acutely injured patients with multisystem trauma have adverse outcomes when compared with normothermic control patients. Trauma patients are inherently predisposed to hypothermia from a variety of intrinsic and iatrogenic causes. Coagulation and cardiac sequelae are the most pertinent physiological concerns. Hypothermia and coagulopathy often mandate a simplified approach to complex surgical problems. A modification of traditional classification systems of hypothermia, applicable to trauma patients is suggested. There are few controlled investigations, but clinical opinion strongly supports the active prevention of hypothermia in the acutely traumatized patient. Preventive measures are simple and inexpensive, but the active reversal of hypothermia in much more complicated, often invasive and controversial. The ideal method of rewarming is unclear but must be individualized to the patient and institution specific. An algorithm reflecting newer approaches to traumatic injury and technical advances in equipment and techniques is suggested. Conversely, hypothermia has selected clinical benefits when appropriately used in cases of trauma. Severe hypothermia has allowed remarkable survivals in the course of accidental circulatory arrest. The selective application of mild hypothermia in severe traumatic brain injury is an area with promise. Deliberate circulatory arrest with hypothermic cerebral protection has also been used for seemingly unrepairable injuries and is the focus of ongoing research.


Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles.
Allostery describes altered protein function at one site due to a perturbation at another site. One mechanism of allostery involves correlated motions, which can occur even in the absence of substantial conformational change. We present a novel method, "MutInf", to identify statistically significant correlated motions from equilibrium molecular dynamics simulations. Our approach analyzes both backbone and sidechain motions using internal coordinates to account for the gear-like twists that can take place even in the absence of the large conformational changes typical of traditional allosteric proteins. We quantify correlated motions using a mutual information metric, which we extend to incorporate data from multiple short simulations and to filter out correlations that are not statistically significant. Applying our approach to uncover mechanisms of cooperative small molecule binding in human interleukin-2, we identify clusters of correlated residues from 50 ns of molecular dynamics simulations. Interestingly, two of the clusters with the strongest correlations highlight known cooperative small-molecule binding sites and show substantial correlations between these sites. These cooperative binding sites on interleukin-2 are correlated not only through the hydrophobic core of the protein but also through a dynamic polar network of hydrogen bonding and electrostatic interactions. Since this approach identifies correlated conformations in an unbiased, statistically robust manner, it should be a useful tool for finding novel or "orphan" allosteric sites in proteins of biological and therapeutic importance.


Interaction of L-arginine analogs with L-arginine uptake in rat renal brush border membrane vesicles.
The dibasic amino acid, L-arginine, is a substrate for both nitric oxide synthase (NOS) and arginase and therefore, plays an important role in cell signaling and cell growth. We examined the effects of various NOS inhibitors on L-arginine transport into rat renal brush border membrane (BBM) vesicles. L-Arginine uptake was stimulated in the presence of an inwardly directed Na+ gradient and an imposed inside negative potential in BBM but not basolateral membrane vesicles. In BBM vesicles, the L-arginine analogs, N-iminoethyl-L-orinithine and Nw-monomethyl-L-arginine (L-NMMA) were potent inhibitors of L-arginine uptake (IC50 of 0.48 and 0.82 mM, respectively), while Nw-nitro-L-arginine was less active (IC50 = 10 mM) and Nw-nitro-L-arginine methyl ester (L-NAME) was inactive. The inhibition of L-arginine transport by L-NMMA was competitive in nature. L-NIO, L-NMMA as well as L-arginine and L-lysine but not Nw-nitro-L-arginine methyl ester, trans-stimulated L-arginine uptake when preloaded into BBM vesicles. The L-arginine analogs had no effect on the transport of the neutral amino acid, L-leucine, in the same preparations. The data suggest that in addition to inhibiting NOS, the L-arginine analogs, N-iminoethyl-L-orinithine, L-NMMA and to a lesser extent L-NA, also inhibit L-arginine transport across the BBM of proximal tubules.


Biogenesis of rosmarinic acid in Mentha.
The biogenesis of rosmarinic acid (alpha-O-caffeoyl-3,4-dihydroxyphenyl-lactic acid), the second most common ester of caffeic acid in the plant kingdom, was studied in Mentha arvense and Mentha piperita. Administration of (14)C-labelled compounds showed that, whereas the caffeoyl moiety was formed from phenylalanine via cinnamic acid and p-coumaric acid, the 3,4-dihydroxyphenyl-lactic acid moiety was formed from tyrosine and 3,4-dihydroxyphenylalanine. Time-course studies and the use of labelled rosmarinic acid showed that endogenous rosmarinic acid had a low turnover rate. The caffeoyl moiety did not appear to contribute to the formation of insoluble polymers, as has been suggested for chlorogenic acid in other plants.


HummingFlow: novel single twist-drill access for ventricular drainage, irrigation, monitoring, and automated local drug delivery in subarachnoid hemorrhage.
The management of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH) remains one of the most important targets for neurocritical care. Advances in monitoring technology have facilitated a more thorough understanding of the pathophysiology and therapeutic approaches, but interventions are generally limited to either systemic therapies or passive CSF drainage. The authors present a novel approach that combines a multimodal monitoring bolt-based system with an irrigating ventricular drain capable of delivering intrathecal medications and describe their early experience in patients with aSAH. The authors performed a retrospective review of cases treated with the combined Hummingbird multimodal bolt system and the IRRAflow irrigating ventriculostomy. Nine patients were treated with the combined multimodal bolt system with irrigating ventriculostomy approach. The median number of days to clearance of the third and fourth ventricles was 3 days in patients with obstructive intraventricular hemorrhage. Two patients received intrathecal alteplase for intraventricular hemorrhage clearance, and 2 patients received intrathecal nicardipine as rescue therapy for severe symptomatic angiographic vasospasm. Combined CSF drainage, irrigation, multimodality monitoring, and automated local drug delivery are feasible using a single twist-drill hole device. Further investigation of irrigation settings and treatment approaches in high-risk cases is warranted.


Sleep deprivation alters gene expression and antioxidant enzyme activity in mice splenocytes.
Cellular defence against the formation of reactive oxygen species (ROS) involves a number of mechanisms in which antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) play an important role. The relation between sleep deprivation and oxidative stress has not yet been completely elucidated. Although some authors did not find evidence of this relationship, others found alterations in some oxidative stress markers in response to sleep deprivation. Thus, the objective of this study was to identify changes induced by sleep deprivation in the activity and gene expression of antioxidant enzymes in mice splenocytes, ideally corroborating a better understanding of the observed effects related to sleep deprivation, which could be triggered by oxidative imbalance. Splenocytes from mice sleep deprived for 72 h showed no significant difference in CAT and CuZnSOD gene expression compared with normal sleep mice. However, sleep-deprived mice did show higher MnSOD gene expression than the control group. Concerning enzymatic activity, CuZnSOD and MnSOD significantly increased after sleep deprivation, despite the expression in CuZnSOD remained unchanged. Moreover, CAT activity was significantly lower after sleep deprivation. The data suggest that the antioxidant system is triggered by sleep deprivation, which in turn could influence the splenocytes homoeostasis, thus interfering in physiological responses.


[The effectiveness of early rehabilitation of the patients presenting with ischemic stroke].
In this paper we evaluate the clinical effectiveness of rehabilitation of 92 patients who survived after acute ischemic stroke and received the combined treatment with the use of transcranial magnetic stimulation (the study group, n=32). The first control group (n=30) included the patients given transcranial magnetic stimulation in the function of placebo (n=30) and the second control group was comprised of the patients who received low-frequency magnetic therapy (n=30). The course of transcranial magnetic stimulation (TMS) resulted in the significant regression of the locomotor deficiency in the patients of the study group compared with those in both control groups (χ2>3,8). In addition, a significant decrease in anxiety and depression was documented in the patients of the study group. Dynamics of these characteristics in the patients of the control groups group was significantly less pronounced (χ2>3,8). The well apparent improvement of the cognitive function evaluated with the help of the MMSE test was observed in the patients of the study group and control group 2, but this effect of transcranial magnetic stimulation was significantly more pronounced than that of low-frequency magnetic therapy (χ2>3,8). Transcranial magnetic stimulation significantly normalized cerebral hemodynamics on the side of the stroke-affected hemisphere and improved the daily activities of the patients. Studying the long-term results within 6 months after the onset of rehabilitation in the hospital environment, most patients rated their health with improving. The evaluation of long-term results of the treatment during the 6 month rehabilitation period demonstrated that the majority of the patients reported the marked improvement of their health status.


Precision medicine in pediatric rheumatology.
Precision medicine is the tailoring of medical care to subcategories of disease. In pediatric rheumatology, these subcategories must first be defined by their specific molecular immunological profiles, and then the effects of growth and puberty, developmental immunological changes, and differences in treatment options and adherence considered when designing therapeutic strategies. In the present review, we summarize the unmet needs in pediatric rheumatology before such precision medical care can be effectively delivered to affected patients. The current clinical classification of pediatric rheumatic diseases does not provide all the information necessary for prognostication and accurate therapeutic selection. Many studies have highlighted the molecular differences between disease subcategories and the dissimilarities in the molecular manifestations of the same disease between patients. Harnessing such discoveries by collaborating with various research networks and laboratories is required to interrogate the multifactorial nature of rheumatic diseases in a holistic manner. Integration of big data sets generated from well defined pediatric cohorts with rheumatic diseases using different high-dimensional technological platforms will help to elucidate the underlying disease mechanisms. Distilling these data will be necessary for accurate disease stratification and will have a positive impact on prognosis and treatment choice.


Harm reduction in the USA: the research perspective and an archive to David Purchase.
The history of harm reduction in the USA has led to the development of some of the most important methods for treating persons for drug use disorders, such as methadone and buprenorphine for opiate use disorder. However, there has been fierce political resistance to implementation and scale-up of harm reduction in the USA. This resistance is rooted in historical demonization of particular psychoactive drugs that were associated with stigmatized racial/ethnic groups.With the discovery of acquired immunodeficiency syndrome (AIDS) in 1981, harm reduction became important not only for treating substance use disorders, but for reducing transmission of blood-borne infection. However, within the context of the crack cocaine epidemic in the 1980s, it was very difficult to implement any programs that appeared to "condone" drug use.It was not until the late 1980s that syringe exchange programs began at the state and local level in the USA. With funding primarily from state and local governments and the support of the North American Syringe Exchange Network (NASEN), there are now approximately 200 programs for syringe exchange in the USA. Research has shown that these programs have been extremely effective in reducing human immunodeficiency virus (HIV) transmission among persons who inject drugs (PWID). The programs in the USA also offer many additional services for drug users, including condom distribution, referrals to substance abuse treatment, HIV, hepatitis C virus (HCV), hepatitis B virus (HBV) counseling and testing, overdose education and naloxone distribution to reverse for overdose.Currently, the USA is experiencing an opioid/heroin epidemic, with significant increases in overdose deaths among drug users. Much of this epidemic is occurring in suburban and rural of the country without harm reduction services. The current challenges for harm reduction and harm reduction research involve expansion of services to suburban and rural areas and implementation science on how to effectively and efficiently address HCV transmission and overdose. Most importantly, continued research efforts are needed to reduce the stigma of psychoactive drug use. While political opposition continues, harm reduction activists and researchers have developed a highly effective partnership based on a common core values.


Biting Behavior and Molecular Identification of Aedes aegypti (Diptera: Culicidae) Subspecies in Some Selected Recent Yellow Fever Outbreak Communities in Northern Ghana.
Aedes aegypti (L.) (Diptera: Culicidae) is a diurnal feeder that lives in close association with human populations. It is the principal vector of yellow fever, dengue fever and the Zika Virus. Issues of arboviral diseases have been on the ascendency in most countries including Ghana where Aedes mosquito is the main vector of yellow fever. A comparative study of the biting behavior of Ae. aegypti and the identification of subspecies were undertaken using molecular technique. Standard human landing technique was used to collect both indoor and outdoor biting mosquitoes at three zones located in the Upper East (Bolgatanga), Upper West (Nadowli), and Northern (Damongo) Regions of Ghana during the dry and rainy seasons between 0600 and 1800 Greenwich Mean Time (GMT). All collected mosquitoes were identified morphologically using taxonomic keys. random amplified polymorphic DNA polymerase chain reaction was used to categorize Ae. aegypti into subspecies. Adult female Aedes mosquitoes identified formed 62% (n = 1,206) of all female mosquitoes collected. Aedes aegypti 98% and Aedes vittatus 2% were the only Aedes species identified. Bolgatanga recorded the largest number of Ae. aegypti 42%, whereas Nadowli 22% recorded the least. Aedes vittatus was observed in Nadowli. Aedes aegypti exhibited a bimodal biting behavior peaking at 0600-0800 GMT and 1500-1600 h GMT. Molecular findings revealed 69% Ae. aegypti aegypti and 31% Ae. aegypti formosus as the two subspecies (n = 110). This information is important for implementing effective vector control programs in the three regions of the northern Ghana.


Efficient charge recovery method for driving piezoelectric actuators with quasi-square waves.
In this paper, an efficient charge recovery method for driving piezoelectric actuators with low frequency square waves in low-power applications such as mobile microrobots is investigated. Efficiency issues related to periodic mechanical work of the actuators and the relationship among the driving electronics efficiency, the piezoelectric coupling factor, and the actuator energy transmission coefficient are discussed. The proposed charge recovery method exploiting the energy transfer between an inductor and a general capacitive load is compared with existing techniques that lead to inherent inefficiencies. A charge recovery method is then applied to piezoelectric actuators, especially to bimorph ones. Unitary efficiency can be obtained theoretically for purely capacitive loads while intrinsic losses such as hysteresis necessarily lower the efficiency. In order to show the validity of the method, a prototype driving electronics consisting of an extended H-bridge is constructed and tested by experiments and simulations. Preliminary results show that 75% of charge (i.e., more than 56% of energy) can be recovered for bending actuators such as bimorphs without any component optimization at low fields.


Crossover comparison of benoxaprofen and naproxen in rheumatoid arthritis.
This multicenter double-blind clinical trial compared the efficacy and safety of benoxaprofen and naproxen in the treatment of rheumatoid arthritis. The studies followed a crossover design which provided 6 wk therapy with each of the 2 study drugs. Benoxaprofen at a single daily dose of 600 mg compared favorably to naproxen, 750 mg, administered in 2 equally divided doses. All efficacy results indicated slightly more improvement with benoxaprofen although the difference between the 2 drugs was not significant. Side effects were generally mild and only 1 patient discontinued benoxaprofen therapy because of a reactivation of a duodenal ulcer.