Inhibitors of 7-Dehydrocholesterol Reductase: Screening of a Collection of Pharmacologically Active Compounds in Neuro2a Cells.
A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS.


Six3 is required for ependymal cell maturation.
Ependymal cells are part of the neurogenic niche in the adult subventricular zone of the lateral ventricles, where they regulate neurogenesis and neuroblast migration. Ependymal cells are generated from radial glia cells during embryonic brain development and acquire their final characteristics postnatally. The homeobox gene Six3 is expressed in ependymal cells during the formation of the lateral wall of the lateral ventricles in the brain. Here, we show that Six3 is necessary for ependymal cell maturation during postnatal stages of brain development. In its absence, ependymal cells fail to suppress radial glia characteristics, resulting in a defective lateral wall, abnormal neuroblast migration and differentiation, and hydrocephaly.


Effectiveness of protocol for the isolation of Wharton's Jelly stem cells in large-scale applications.
The Wharton's Jelly (WJ) of the umbilical cord (UC) is an excellent source of mesenchymal stem cells (MSCs) with a range of potential therapeutic applications. The present study was conducted to demonstrate the efficiency of the protocols used by Biogenea-Cellgenea Ltd. for isolation and expansion of WJ MSCs from donors across Greece. Umbilical cord samples were collected from 599 females following childbirth and processed for WJ MSC isolation. Stem cells were expanded using DMEM-based media and cell counts and overall viability figures derived using Trypan blue exclusion. To investigate the application of isolation and expansion protocols on samples received 1, 2, 3, 4 and 5 d after their collection, ten fresh samples were processed at these time intervals and evaluated. The cellular yield of most WJ samples was 1.1–5.0×10(6) cells at 21–30 d after processing. As culture time increased, cell counts decreased. Statistical analysis of mean cell counts showed a significant reduction after 21 d. Finally, we demonstrate for the first time that it is possible to obtain satisfactory cell numbers from samples processed 1, 2, 3, 4 and even 5 d after collection. We have derived favourable data on the protocols used at Biogenea-Cellgenea Ltd. to isolate and culture MSCs from the WJ. Protocol choice is crucial when handling large numbers of samples on a daily basis and should be made to ensure the best possible outcome.


Tunable Coherent X-rays.
A modern 1- to 2-billion-electron-volt synchrotron radiation facility (based on high-brightness electron beams and magnetic undulators) would generate coherent (laser-like) soft x-rays of wavelengths as short as 10 angstroms. The radiation would also be broadly tunable and subject to full polarization control. Radiation with these properties could be used for phase- and element-sensitive microprobing of biological assemblies and material interfaces as well as reserch on the production of electronic microstructures with features smaller than 1000 angstroms. These short wavelength capabilities, which extend to the K-absorption edges of carbon, nitrogen, and oxygen, are neither available nor projected for laboratory XUV lasers. Higher energy storage rings (5 to 6 billion electron volts) would generate significantly less coherent radiation and would be further compromised by additional x-ray thermal loading of optical components.


Does empiric antibiotic therapy change MRSA [corrected] hand infection outcomes? Cost analysis of a randomized prospective trial in a county hospital.
The incidence of community-acquired methicillin-resistant Staphylococcus aureus infections is rising at an alarming pace. Effective treatment has historically involved early débridement and antibiotic administration. This study was designed to prospectively determine the effectiveness of empiric therapy in treating hand infections. A prospective randomized trial was conducted at a level I county hospital. Patients with a hand infection received either empiric intravenous vancomycin at admission or intravenous cefazolin. Outcomes were tracked using severity of infection, appropriate clinical response, and length of stay. Cost-effectiveness was calculated using total cost for each patient in both groups. Statistical analyses were performed. Forty-six patients were enrolled in the study. Twenty-four were randomized to cefazolin (52.2 percent) and 22 (47.8 percent) to vancomycin. There was no statistical difference between cost of treatment (p < 0.20) or mean length of stay (p < 0.18) between the groups. Patients randomized to cefazolin had higher mean costs of treatment compared with patients who were randomized to vancomycin (p < 0.05). Patients with more severe infections had more expensive mean costs of treatment (p < 0.0001) and longer mean length of stay (p = 0.0002). Near the end of the study, the incidence of community-acquired methicillin-resistant S. aureus at the authors' county hospital was discovered to be 72 percent, which caused the study to be terminated prematurely by the institutional review board because of the high incidence precluding further randomization. Appropriate early treatment for methicillin-resistant S. aureus has not been definitively established. No difference in outcome using cefazolin versus vancomycin as a first-line agent was identified.


Total costs and predictors of costs in patients with systemic lupus erythematosus.
To determine the annual direct, indirect and total costs and predictors of costs in patients with systemic lupus erythematosus (SLE). One hundred and five patients with SLE completed questionnaires on health-care utilization and employment history. Predictors of costs were determined by multiple regression analyses using direct, indirect and total costs as outcome variables. Demographics, health status, disease activity, end-organ damage, social support and satisfaction with care were used as predictor variables. The mean annual total cost per patient was pounds sterling 7913. Direct costs were a third and indirect costs two-thirds of the total cost. Higher education level, greater disease activity and lower physical functioning were associated with higher direct, indirect and total costs. Higher direct costs were also associated with greater damage and younger age. SLE has a considerable impact on the health-care system and society. Improvement in disease activity and physical health and prevention of end-organ damage may reduce costs in SLE.


Turkish newspaper articles mentioning people with mental illness: A retrospective study.
Because a great majority of the public knows about mental disorders primarily through printed or visual media, the attitudes exhibited in mass media might be predictive in stigmatizing individuals with mental disorders. The aim of this study was to retrospectively assess the articles in Turkish newspapers that mention individuals with mental disorders. This study was designed to retrospectively investigate and analyze newspaper content in Turkey; the newspapers' circulation information was collected by examining the websites of the four newspapers with above 1% of the total circulation. The News Evaluation Form was used to evaluate a sampling of articles that met the inclusion criteria of having appeared in the lifestyle and agenda pages of newspapers, and of using neutral or negative labeling keywords about psychiatric patients. Almost all the articles reviewed were negative toward individuals with mental disorders. Three quarters of the reports were forensic, among which two thirds of the individuals with mental disorders were criminalized, and one third were victims of crime. In approximately half of the news reports, most images were related to the news and were not protected. Although not all the articles contain stigmatizing elements directed toward people with mental disorders, two thirds of the subjects' images in the news were found to have stigmatizing elements. Media has an impact on attitudes toward people with mental disorders mostly negatively along with individual experiences and peer interactions.


Nutrition education: a questionnaire for assessment and teaching.
It is generally recognized that there is a need for improved teaching of nutrition in medical schools and for increased education of the general population. A questionnaire, derived in part from a study of physician knowledge, was administered to first year medical students in order to assess their knowledge of various aspects of nutrition and metabolism, and as a teaching tool to transmit information about the subject. The performance of first year students was consistent with a generally educated population but there were surprising deficits in some fundamental areas of nutrition. Results of the questionnaire are informative about student knowledge, and immediate reinforcement from a questionnaire may provide a useful teaching tool. In addition, some of the subject matter can serve as a springboard for discussion of critical issues in nutrition such as obesity and markers for cardiovascular disease. A major barrier to improved teaching of nutrition is the lack of agreement on some of these critical issues and there are apparent inconsistencies in recommendations of government and health agencies. It seems reasonable that improved teaching should address the lack of knowledge of nutrition, rather than knowledge of official guidelines. Student awareness of factual information should be the primary goal.


The Pagerank-Index: Going beyond Citation Counts in Quantifying Scientific Impact of Researchers.
Quantifying and comparing the scientific output of researchers has become critical for governments, funding agencies and universities. Comparison by reputation and direct assessment of contributions to the field is no longer possible, as the number of scientists increases and traditional definitions about scientific fields become blurred. The h-index is often used for comparing scientists, but has several well-documented shortcomings. In this paper, we introduce a new index for measuring and comparing the publication records of scientists: the pagerank-index (symbolised as π). The index uses a version of pagerank algorithm and the citation networks of papers in its computation, and is fundamentally different from the existing variants of h-index because it considers not only the number of citations but also the actual impact of each citation. We adapt two approaches to demonstrate the utility of the new index. Firstly, we use a simulation model of a community of authors, whereby we create various 'groups' of authors which are different from each other in inherent publication habits, to show that the pagerank-index is fairer than the existing indices in three distinct scenarios: (i) when authors try to 'massage' their index by publishing papers in low-quality outlets primarily to self-cite other papers (ii) when authors collaborate in large groups in order to obtain more authorships (iii) when authors spend most of their time in producing genuine but low quality publications that would massage their index. Secondly, we undertake two real world case studies: (i) the evolving author community of quantum game theory, as defined by Google Scholar (ii) a snapshot of the high energy physics (HEP) theory research community in arXiv. In both case studies, we find that the list of top authors vary very significantly when h-index and pagerank-index are used for comparison. We show that in both cases, authors who have collaborated in large groups and/or published less impactful papers tend to be comparatively favoured by the h-index, whereas the pagerank-index highlights authors who have made a relatively small number of definitive contributions, or written papers which served to highlight the link between diverse disciplines, or typically worked in smaller groups. Thus, we argue that the pagerank-index is an inherently fairer and more nuanced metric to quantify the publication records of scientists compared to existing measures.


Medication supervision and adherence of persons with psychotic disorders in residential treatment settings: a pilot study.
Little is known about risk factors for and predictors of medication nonadherence within residential facilities. This pilot study examined the association between medication adherence and level of supervision and other environmental and clinical variables among patients with schizophrenia and related psychotic disorders living in supported housing. A convenience sample of 74 adult residents with schizophrenia and related psychotic disorders (DSM-IV criteria) living in 4 supported housing facilities in New York City were assessed by their treating psychiatrist for medication cessation during the previous month. Demographic characteristics, medications, supervision, global function as measured by the Global Assessment of Functioning (GAF), and substance abuse were also assessed. A priori hypotheses were that regimen complexity would be directly and medication supervision would be inversely related to medication nonadherence. In multivariate models, lack of direct medication supervision, negative medication attitude, and lower GAF score were associated with increased medication nonadherence in the recent past. This pilot study suggests that direct supervision of medication is associated with better adherence in residential treatment settings. This finding is relevant for mental health service planners and clinicians working in these settings.


Three-dimensional information in face recognition: an eye-tracking study.
One unresolved question about face perception is: what is the role of three-dimensional information in face recognition? In this study, recognition performance was compared across changes in viewpoint in different depth conditions: a 2D condition without stereo information and a 3D condition where stereo information was present (by viewing the same face images as anaglyphs through 3D glasses). Subjects' eye movements were recorded during both 3D and 2D sessions. The findings revealed that participants were more accurate in the 3D condition. Moreover, individual differences in interpupillary distance predicted recognition performance in the 3D but not in the 2D condition. A "region of interest" analysis of gaze data showed that rich volumetric properties provided by certain facial features (e.g., the nose and the cheeks) were attended more in the 3D condition compared to the 2D condition. Taken together, these findings support the conclusion that face recognition across viewpoint transformation is facilitated by the addition of stereoscopic depth cues.


Evidence for a new role of natriuretic peptides: control of intraocular pressure.
To study the possible physiological role of atrial natriuretic peptide (ANP) in the regulation of intraocular pressure (IOP) the effects of an increase of endogenous ANP within the physiological range induced by the neutral endopeptidase 24.11 (NEP) inhibitor candoxatril were examined. In a single masked placebo controlled trial, seven patients were studied with normal IOP (six male, one female; average age 50 (range 37-62 years). Intraocular pressure in each eye was measured after 2 weeks of placebo, after 4 weeks of candoxatril 200 mg twice daily, and during the first 3 days of placebo washout. With 4 weeks of candoxatril, endogenous plasma ANP levels increased from 4.2 (SEM 1.5) to 6.0 (1.5) pmol/l (p < 0.04) and there was a significant decrease in mean arterial pressure from 119 (4) to 110 (3) mm Hg (p < 0.02; 12 hours after treatment). There was a significant reduction in IOP after 4 weeks' treatment with candoxatril (right eye 2.1 (0.8) mm Hg, p < 0.05 paired t test, left eye 2.8 (0.8) mm Hg, p < 0.02). The mean fall in IOP was 11% (4%) in the right eye and 16% (3%) in the left eye and the fall in IOP was greater the higher the initial IOP. The reduction in IOP with chronic NEP inhibition was positively correlated with the increase in ANP levels but not with changes in blood pressure. These findings suggest that ANP may play a physiological role in the regulation of IOP. As the fall in IOP was greater in subjects with higher initial IOP, NEP inhibitors may be of therapeutic value in the management of glaucoma.


Driver speed compliance following automatic incident detection: Insights from a naturalistic driving study.
Automatic incident detection (AID) systems and variable speed limits (VSLs) can reduce crash probability and traffic congestion. Studies based on loop detector data have shown that AID systems decrease the variation in speeds between drivers. Despite the impact on driver behaviour characteristics, most mathematical models evaluating the effect of AID systems on traffic operations do not capture driver response realistically. This study examines the main factors related to driver speed compliance with a sequence of three VSLs triggered by an AID system. For this purpose, the variable speed limit database of the executive agency of the Dutch Ministry of Infrastructure and Water Management (Rijkswaterstaat) was integrated into the UDRIVE naturalistic driving database for passenger car data collected in the Netherlands. The video data were annotated to analyse driver glance behaviour and secondary task engagement. A logistic regression model was estimated to predict driver speed compliance after each VSL in the sequence. The results reveal that the factors predicting compliance to the VSLs differ based on which of the three VSLs the driver is subjected to. Low speeds and accelerations before the gantry, approaching a slower leader, high proportion of time with eyes-on-road and close consecutive gantries were associated with high compliance with the first VSL in the sequence (i.e., indicating a speed limit of 70 km/h with flashing attention lights). Low speeds and accelerations before the gantry, close consecutive gantries and a small number of lanes resulted in high compliance with the second VSL (i.e., a speed limit of 50 km/h with flashing attention lights). Low speeds before the gantry and close consecutive gantries were linked to high compliance with the third VSL (i.e., indicating a speed limit of 50 km/h). Although further investigations based on a larger sample are needed, these findings are relevant to the development of human-like driving assistance systems and of traffic simulations that assess the impact of AID systems on traffic operations realistically.


Psychological benefits of a high-protein, low-carbohydrate diet in obese women with polycystic ovary syndrome--a pilot study.
This study compared the psychological effects of a low-protein high-carbohydrate (LPHC) diet and a high-protein low-carbohydrate (HPLC) diet in women with polycystic ovary syndrome (PCOS). Twenty-five overweight women with PCOS were matched for age, weight, and whether they were trying to conceive. They were randomly allocated to the LPHC or HPLC diet for 16 weeks. All participants attended a weekly exercise, group support and educational program. The Hospital Anxiety and Depression Scale and the Rosenberg Self Esteem Scale were administered at the beginning and end of the study. The HPLC diet was associated with significant reduction in depression and improvement in self-esteem. There was no change in any psychological measures for the LPHC group. There was no difference in weight loss between the groups. Due to enhanced feelings of well-being, it is possible that HPLC diets may be associated with better compliance and hence be more successful in the long term treatment of obesity.


The impact of implementing a pharmacy technician role as part of a nursing team in an acute admissions unit.
The National Patient Safety Agency reported over 20 000 safety incidents over a 3-year period, including 68 severe harms and 27 deaths. Dose delays and omissions persistently contributed to more than 50% of the reported incidents. A pilot was designed and data were collected before and after to measure how these ward-based technician roles affected the reporting of omitted or delayed doses, time efficiency, cost implications and the general productivity of the ward. Three months after the start of the pilot, omitted doses were reduced from 14% to 5% and no incidents of harm had been reported. The 'perfect medication ward round' with no interruptions lasted 23 min compared with the longest medication ward round which lasted 116 min and was interrupted 11 times. The pilot shows that the introduction of pharmacy technicians results in fewer omitted doses and also addresses persistent staffing issues by ensuring better use of nursing time.


Experimental violation of multipartite Bell inequalities with trapped ions.
We report on the experimental violation of multipartite Bell inequalities by entangled states of trapped ions. First, we consider resource states for measurement-based quantum computation of between 3 and 7 ions and show that all strongly violate a Bell-type inequality for graph states, where the criterion for violation is a sufficiently high fidelity. Second, we analyze Greenberger-Horne-Zeilinger states of up to 14 ions generated in a previous experiment using stronger Mermin-Klyshko inequalities, and show that in this case the violation of local realism increases exponentially with system size. These experiments represent a violation of multipartite Bell-type inequalities of deterministically prepared entangled states. In addition, the detection loophole is closed.


Rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement.
Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) × 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.


Interleukin-10 gene promoter polymorphism in English and Polish healthy controls. Polymerase chain reaction haplotyping using 3' mismatches in forward and reverse primers.
A polymerase chain reaction with sequence-specific primers (PCR-SSP) system using primers with mismatches at the 3' ends was developed to determine polymorphisms in IL-10 promoter region. Three previously described biallelic polymorphisms in IL-10 were linked in a 12 reaction PCR-SSP system and the method used to provide genotype data on 233 UK and 166 Polish controls. There are eight possible polymorphic combinations in IL-10 promoter gene but only three were observed in both control groups. Population frequencies of IL-10 genotypes show, in contrast to HLA, that UK and Polish frequencies are remarkably similar.


Alternative DNA Structures In Vivo: Molecular Evidence and Remaining Questions.
Duplex DNA naturally folds into a right-handed double helix in physiological conditions. Some sequences of unusual base composition may nevertheless form alternative structures, as was shown for many repeated sequences in vitro However, evidence for the formation of noncanonical structures in living cells is difficult to gather. It mainly relies on genetic assays demonstrating their function in vivo or through genetic instability reflecting particular properties of such structures. Efforts were made to reveal their existence directly in a living cell, mainly by generating antibodies specific to secondary structures or using chemical ligands selected for their affinity to these structures. Among secondary structure-forming DNAs are G-quadruplexes, human fragile sites containing minisatellites, AT-rich regions, inverted repeats able to form cruciform structures, hairpin-forming CAG/CTG triplet repeats, and triple helices formed by homopurine-homopyrimidine GAA/TTC trinucleotide repeats. Many of these alternative structures are involved in human pathologies, such as neurological or developmental disorders, as in the case of trinucleotide repeats, or cancers triggered by translocations linked to fragile sites. This review will discuss and highlight evidence supporting the formation of alternative DNA structures in vivo and will emphasize the role of the mismatch repair machinery in binding mispaired DNA duplexes, triggering genetic instability.


Dietary intake of specific carotenoids and vitamins A, C, and E, and prevalence of colorectal adenomas.
We determined whether intakes of the main dietary carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein plus zeaxanthin, and lycopene) and of vitamins A, C, and E were associated with the prevalence of colorectal adenomas among male and female members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy (n = 488 matched pairs). Participants, ages 50-74 years, completed a 126-item semiquantitative food-frequency questionnaire and a non-dietary questionnaire from 1991 to 1993. In the univariate-matched analysis, alpha-carotene, beta-carotene (with and without supplements), beta-cryptoxanthin, lutein plus zeaxanthin, vitamin A (with and without supplements), and vitamin C (with and without supplements) were associated with a decreased prevalence of colorectal adenomas. After adjustment for intake of calories, saturated fat, folate, fiber, and alcohol, and for current smoking status, body mass index, race, physical activity, and use of nonsteroidal anti-inflammatory drugs, only beta-carotene including supplements was inversely associated with adenomas (odds ratio (OR), 0.6; 95% confidence interval (CI), 0.41.1; trend, P= 0.04; ORs compare highest to lowest quartiles0; vitamin C showed a weaker inverse association (OR, 0.8; 95% CI, 0.5-1.5; trend, P = 0.08); and the remaining compounds were no longer clearly associated with risk. After including beta-carotene with supplements and vitamin C simultaneously in the mutivariate model, the association of beta-carotene with supplements with adenomas was weakened (OR, 0.8; 95% CI, 0.5-1.3; trend P = 0.15), and vitamin C was no longer associated with risk. These data provide only modest support for a protective association of beta-carotene with colorectal adenomatous polyps.


Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching.
Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itajaí, a southern city in Brazil in the state of Santa Catarina. The objective of this study was to evaluate the impact of regular ivermectin use on subsequent COVID-19 infection and mortality rates. We analyzed data from a prospective, observational study of the citywide COVID-19 prevention with ivermectin program, which was conducted between July 2020 and December 2020 in Itajaí, Brazil. Study design, institutional review board approval, and analysis of registry data occurred after completion of the program. The program consisted of inviting the entire population of Itajaí to a medical visit to enroll in the program and to compile baseline, personal, demographic, and medical information. In the absence of contraindications, ivermectin was offered as an optional treatment to be taken for two consecutive days every 15 days at a dose of 0.2 mg/kg/day. In cases where a participating citizen of Itajaí became ill with COVID-19, they were recommended not to use ivermectin or any other medication in early outpatient treatment. Clinical outcomes of infection, hospitalization, and death were automatically reported and entered into the registry in real time. Study analysis consisted of comparing ivermectin users with non-users using cohorts of infected patients propensity score-matched by age, sex, and comorbidities. COVID-19 infection and mortality rates were analyzed with and without the use of propensity score matching (PSM). Of the 223,128 citizens of Itajaí considered for the study, a total of 159,561 subjects were included in the analysis: 113,845 (71.3%) regular ivermectin users and 45,716 (23.3%) non-users. Of these, 4,311 ivermectin users were infected, among which 4,197 were from the city of Itajaí (3.7% infection rate), and 3,034 non-users (from Itajaí) were infected (6.6% infection rate), with a 44% reduction in COVID-19 infection rate (risk ratio [RR], 0.56; 95% confidence interval (95% CI), 0.53-0.58; p < 0.0001). Using PSM, two cohorts of 3,034 subjects suffering from COVID-19 infection were compared. The regular use of ivermectin led to a 68% reduction in COVID-19 mortality (25 [0.8%] versus 79 [2.6%] among ivermectin non-users; RR, 0.32; 95% CI, 0.20-0.49; p < 0.0001). When adjusted for residual variables, reduction in mortality rate was 70% (RR, 0.30; 95% CI, 0.19-0.46; p < 0.0001). There was a 56% reduction in hospitalization rate (44 versus 99 hospitalizations among ivermectin users and non-users, respectively; RR, 0.44; 95% CI, 0.31-0.63; p < 0.0001). After adjustment for residual variables, reduction in hospitalization rate was 67% (RR, 0.33; 95% CI, 023-0.66; p < 0.0001). In this large PSM study, regular use of ivermectin as a prophylactic agent was associated with significantly reduced COVID-19 infection, hospitalization, and mortality rates.


The effects of photoperiod on testes in rat: a morphometric and immunohistochemical study.
The aim of this study was to examine the effects of photoperiod on testes in rat. For this purpose 21 male Wistar rats were used. Animals were divided into three groups. Control rats in group I were kept under 12 hrs light: 12 hrs dark conditions (12L: 12D) for 10 weeks. Animals in group II were exposed to long photoperiods (18L: 6D), while rats in group III were exposed to short photoperiods (6L: 18D) for 10 weeks. At the end of the experiment, all animals were killed by decapitation and blood samples were obtained. Serum testosterone levels were determined with the use of a chemiluminescent enzyme immunoassay. The testes of all rats were removed and weighed. Testicular tissue was processed semiquantitative evaluation of immunohistochemical testosterone staining. Intensity of immunostaining was determined on a scale between 0 (no staining) and 5 (heavy staining). For morphometric comparison, diameters of seminiferous tubules in each group were measured. In rats exposed to long photoperiods, testicular weights, diameters of seminiferous tubules and serum testosterone levels were significantly increased as compared to those in control rats. Whereas, exposure of rats to short photoperiods resulted in significantly decrease of testicular weights, diameters of seminiferous tubules and serum testosterone levels as compared to those in control rats and rats maintained in long photoperiods. Immunostaining of testosterone was moderate (3+) in control rats, heavy (5+) in rats exposed to long photoperiods and minimal (1+) in rats exposed to short photoperiods. The results of our study indicate that testicular functions increase after exposure to long photoperiods and decrease after exposure to short photoperiods.


Sex-dependent interactions between leptin, wasting and humoral immunity in two ethnic communities of school-aged children differentially exposed to Schistosoma haematobium.
Leptin is a nutritional hormone whose production is generally higher in females. We investigated how leptin is associated with sex dimorphism during urinary schistosomiasis in relation with wasting. A cross-sectional study was carried out in three villages in northern Senegal. Ninety-eight school-aged children belonging to the Fulani or Wolof villages were enrolled. We performed parasitic diagnosis and anthropometric measurement to evaluate nutritional status. We collected peripheral blood to determine the amount of circulating leptin and immunoglobulin G (IgG), IgG4 and IgE directed to soluble worm antigen preparation (SWAP). The prevalence of Schistosoma haematobium infection was higher among boys regardless of ethnic group, but exposure to parasites did not exacerbate malnutrition. The greater ability of girls to produce leptin was not altered by schistosomiasis and was recovered in both ethnic groups. However, while the usual correlation between leptin and fat storage was preserved in Fulani girls, it was disrupted in Fulani boys, who displayed a remarkable susceptibility for wasting. Finally, we observed that leptin was negatively associated with the level of antibodies in Wolof boys. Leptin can be disconnected from body fat and may exert a sex-dependent influence on host immune response to S. haematobium infection in Senegalese children.


A Comparison of Dependence across Different Types of Nicotine Containing Products and Coffee.
Few studies have compared the dependence to different tobacco and nicotine products. Even less is known about how it relates to dependence on other common drugs, e.g., caffeine. In this study degree of dependence was compared between snus, cigarettes, nicotine replacement (NR), electronic cigarettes and coffee. A random sample of Swedish citizens belonging to an internet panel were contacted from September to October 2017. The responders were asked among other related things about their use of snus, NR, traditional cigarette or e-cigarette use and coffee consumption. The indicators of dependence used were: (A) the Heavy Smoking Index, (B) The proportions that used within 30 min after raising in the morning, (C) rating the first use in the morning as the most important and (D) Stating that it would be very hard to give up entirely. Significantly fewer coffee drinkers started use within 30 min of awakening compared with all other products. The first use of the day was found to be more important for snus users compared with other products. On HSI there was no difference between snus and cigarettes. Snus and cigarettes were rated as being more difficult to give up than NR and coffee. Dependence to traditional cigarettes and snus seem to be relatively similar while NR was rated lower and coffee lowest. Since the prevalence of caffeine use in all forms is so much more prevalent than nicotine there might be more persons in the society heavily dependent on caffeine. Tobacco products are likely more dependence forming than NR products and coffee although there might be more people dependent on caffeine. The addiction to coffee or caffeine is seldom discussed in the society probably because of the little or no harm it causes. The Snus Commission in Sweden (snuskommissionen) funded the data collection. No funding used for the analysis and writing of manuscript.


Innovative solutions to enhance safe and green environments for ageing well using co-design through patient and public involvement.
There is a need to develop innovative solutions to enhance safe and green physical environments, which optimise health, wellbeing and community participation among older adults. To develop solutions that meet the needs of a diverse ageing population, an interdisciplinary approach is needed. Our aim was to identify the needs of older people in relation to ageing well in the environment by bringing together knowledge from different perspectives using Patient and Public Involvement. An international consortium (Retrofit living For ageing well through Understanding and Redesign of Built environments consortium: ReFURB) was established in April 2018, including ten core members, to (i) explore cutting-edge solutions to safe living for ageing populations and (ii) develop innovative approaches to everyday physical environments, which bring about health benefits. We used a co-design, interdisciplinary framework involving older adults, carers, physiotherapists, geriatricians, engineers, human movement experts, geographers and psychologists from the UK and Australia. This engaged people in a 1 day workshop that comprised a series of presentations from international speakers on urban design, social connectedness, hazards and injury prevention, and the physical environment. Small group discussions (facilitated by consortium members) followed presentations to consider the opportunities, challenges and barriers encountered with ageing, which included the use of creative engagement activities (LEGO® Serious Play, mind maps, poster gallery walk), to help participants share personal stories and reflect on the issues raised. Thematic coding was used to synthesise the outputs of the small group work. Five themes were identified across the workshops: access and transport; involvement of the whole community; restoration rather than redesign; assistive and digital technology; and intergenerational approaches. These dimensions related to the physical, social and nature-based qualities of everyday environments, as they pertain to ageing well. Co-design was a valuable tool that helped understand the perceptions of participants and essential to develop effective interventions and solutions. Participants highlighted several issues affecting people as they age and key environmental considerations to promote wellbeing, activity, and participation. The consortium identified gaps in the existing evidence base and are now planning activities to further develop research ideas in collaboration with our co-design participants.


Discriminative Tracking Using Tensor Pooling.
How to effectively organize local descriptors to build a global representation has a critical impact on the performance of vision tasks. Recently, local sparse representation has been successfully applied to visual tracking, owing to its discriminative nature and robustness against local noise and partial occlusions. Local sparse codes computed with a template actually form a three-order tensor according to their original layout, although most existing pooling operators convert the codes to a vector by concatenating or computing statistics on them. We argue that, compared to pooling vectors, the tensor form could deliver more intrinsic structural information for the target appearance, and can also avoid high dimensionality learning problems suffered in concatenation-based pooling methods. Therefore, in this paper, we propose to represent target templates and candidates directly with sparse coding tensors, and build the appearance model by incrementally learning on these tensors. We propose a discriminative framework to further improve robustness of our method against drifting and environmental noise. Experiments on a recent comprehensive benchmark indicate that our method performs better than state-of-the-art trackers.


Cyclic Incrementality in Competitive Coevolution: Evolvability through Pseudo-Baldwinian Switching-Genes.
Coevolving systems are notoriously difficult to understand. This is largely due to the Red Queen effect that dictates heterospecific fitness interdependence. In simulation studies of coevolving systems, master tournaments are often used to obtain more informed fitness measures by testing evolved individuals against past and future opponents. However, such tournaments still contain certain ambiguities. We introduce the use of a phenotypic cluster analysis to examine the distribution of opponent categories throughout an evolutionary sequence. This analysis, adopted from widespread usage in the bioinformatics community, can be applied to master tournament data. This allows us to construct behavior-based category trees, obtaining a hierarchical classification of phenotypes that are suspected to interleave during cyclic evolution. We use the cluster data to establish the existence of switching-genes that control opponent specialization, suggesting the retention of dormant genetic adaptations, that is, genetic memory. Our overarching goal is to reiterate how computer simulations may have importance to the broader understanding of evolutionary dynamics in general. We emphasize a further shift from a component-driven to an interaction-driven perspective in understanding coevolving systems. As yet, it is unclear how the sudden development of switching-genes relates to the gradual emergence of genetic adaptability. Likely, context genes gradually provide the appropriate genetic environment wherein the switching-gene effect can be exploited.


How intensive does anomia therapy for people with aphasia need to be?
The intensity of aphasia therapy has been a key clinical question. The aim of this case-series study was to compare the outcome of intensive and non-intensive therapy in the relearning of words for people with aphasia. Eight participants took part in a study comparing the intensity of delivery of the therapy. Participants received two courses of the same therapy (each lasting 10 sessions) delivered either intensively or non-intensively. Therapy consisted of confrontation naming with progressive phonemic and orthographic cues. Post-therapy assessments were carried out immediately after the study and one month later. Performance was also monitored during each therapy session. Immediately post-therapy, both types of therapy had improved naming accuracy considerably and there was no significant difference between the two interventions. One month later, seven out of eight participants showed a small yet significant difference in naming accuracy, favouring non-intensive over intense therapy. There were no differences in the learning patterns during the therapy sessions between the intensive and non-intensive therapies. For the majority of people with aphasia post-stroke, both intense and non-intense therapy for anomia leads to improved naming performance. Retention at one-month post therapy is relatively superior after non-intensive therapy.


Application of fecal near-infrared spectroscopy and nutritional balance software to monitor diet quality and body condition in beef cows grazing Arizona rangeland.
Monitoring the nutritional status of range cows is difficult. Near-infrared spectroscopy (NIRS) of feces has been used to predict diet quality in cattle. When fecal NIRS is coupled with decision support software such as the Nutritional Balance Analyzer (NUTBAL PRO), nutritional status and animal performance can be monitored. Approximately 120 Hereford and 90 CGC composite (50% Red Angus, 25% Tarentaise, and 25% Charolais) cows grazing in a single herd were used in a study to determine the ability of fecal NIRS and NutbalPro to project BCS (1 = thin and 9 = fat) under commercial scale rangeland conditions in central Arizona. Cattle were rotated across the 31,000 ha allotment at 10 to 20 d intervals. Cattle BCS and fecal samples (approximately 500 g) composited from 5 to 10 cows were collected in the pasture approximately monthly at the midpoint of each grazing period. Samples were frozen and later analyzed by NIRS for prediction of diet crude protein (CP) and digestible organic matter (DOM). Along with fecal NIRS predicted diet quality, animal breed type, reproductive status, and environmental conditions were input to the software for each fecal sampling and BCS date. Three different evaluations were performed. First, fecal NIRS and NutbalPro derived BCS was projected forward from each sampling as if it were a "one-time only" measurement. Second, BCS was derived from the average predicted weight change between 2 sampling dates for a given period. Third, inputs to the model were adjusted to better represent local animals and conditions. Fecal NIRS predicted diet quality varied from a minimum of approximately 5% CP and 57% DOM in winter to a maximum of approximately 11% CP and 60% DOM in summer. Diet quality correlated with observed seasonal changes and precipitation events. In evaluation 1, differences in observed versus projected BCS were not different (P > 0.1) between breed types but these values ranged from 0.1 to 1.1 BCS in Herefords and 0.0 to 0.9 in CGC. In evaluation 2, differences in observed versus projected BCS were not different (P > 0.1) between breed types but these values ranged from 0.00 to 0.46 in Hereford and 0.00 to 0.67 in CGC. In evaluation 3, the range of differences between observed and projected BCS was 0.04 to 0.28. The greatest difference in projected versus observed BCS occurred during periods of lowest diet quality. Body condition was predicted accurately enough to be useful in monitoring the nutrition of range beef cows under the conditions of this study.


Getting the message out about cognitive health: a cross-cultural comparison of older adults' media awareness and communication needs on how to maintain a healthy brain.
Evidence suggests that physical activity and healthy diets may help to maintain cognitive function, reducing risks of developing Alzheimer's disease and vascular dementia. Using a cross-cultural focus, we describe older adults' awareness about cognitive health, and their ideas about how to inform and motivate others to engage in activities that may maintain brain health. Nineteen focus groups were conducted in 3 states (California, North Carolina, South Carolina) with 177 adults aged 50 years and older. Six groups were with African Americans (AAs), 4 with Chinese, 3 with Vietnamese, 4 with non-Hispanic Whites, and 2 with American Indians (AIs). A qualitative thematic analysis was conducted. Many participants did not recall reading or hearing about brain health in the media. Participants recommended a multimedia approach to inform others about brain health. Both interpersonal and social/group motivational strategies were suggested. Word of mouth and testimonials were recommended most often by Chinese and Vietnamese. AAs and AIs suggested brain health education at church; AAs, Chinese, and Vietnamese said brain health slogans should be spiritual. Participants' perceived barriers to seeking brain health information included watching too much TV and confusing media information. Findings on communication strategies for reaching racial/ethnic groups with brain health information will help guide message and intervention development for diverse older adults.


Effectiveness of Health System Services and Programs for Youth to Adult Transitions in Mental Health Care: A Systematic Review of Academic Literature.
Youth shifting to adult mental health services often report experiencing frustrations with accessing care that adequately replaces the youth services they had received. This systematic review assesses the peer reviewed evidence on services/programs aimed at addressing youth to adult transitions in mental health services. Findings suggest little data exists on the effectiveness of transition services/programs. While the available evidence supports meetings between youth and youth caseworkers prior to transitions occurring, it also verifies that this is not common practice. Other identified barriers to effective transitions were categorized as logistical (ineffective system communication), organizational (negative incentives), and related to clinical governance.


The influence of nitrogen supply on antioxidant enzymes in plant roots.
Plants of Zea mays L., Hordeum vulgare L. and Arabidopsis thaliana (L.) Heynh. were grown at different concentrations of nitrogen, as NH4NO3, and the antioxidant enzyme activities and quantities in the roots, were studied. Maize plants were grown at 1 and 10 mM N for 32 d after germination and their roots were analysed by native PAGE for the isoenzymic profiles of glutathione reductase (GR; EC 184.108.40.206), catalase (CAT; EC 126.96.36.199) and superoxide dismutase (SOD; EC 188.8.131.52) and by spectrophotometric assays for total activity of CAT and GR. Barley and A. thaliana plants were grown at five N concentrations (0.25, 0.5, 1, 10 and 20 mM) for 27 and 26 d, respectively, and the isoenzymic profile of the three enzymes were analysed in their roots. The number of GR isoforms in the three plant species was increased at high N supply compared with low N. In addition, the CAT and GR activities detected in the roots were increased in plants grown at higher N. The increase in activity and number of bands of GR at high N in the roots of all three plants studied was not accompanied by a change in activity or the number of SOD isoforms. The possibility that the application of high N promotes the formation of reactive oxygen species by stimulating an increased rate of growth is discussed.


Economic cost and epidemiological characteristics of patients with fibromyalgia claims.
Fibromyalgia (FM) is characterized by widespread pain that can lead to significant patient disability, complex management decisions for physicians, and economic burden on society. We investigated the total costs of FM in an employer population. Administrative claims data of a Fortune 100 manufacturer were used to quantify direct (i.e., medical and pharmaceutical claims) and indirect (i.e., disability claims and imputed absenteeism) costs associated with FM. A total of 4699 patients with at least one FM claim between 1996 and 1998 were contrasted with a 10% random sample of the overall beneficiary population. Employee-only subsets of both samples also were drawn. Medical utilization, receipt of prescription drugs, and annual total costs were proportionately similar yet significantly greater among FM claimants than the overall sample (all p < 0.0001). Total annual costs for FM claimants were $5945 versus $2486 for the typical beneficiary (p < 0.0001). Six percent of these costs were attributable to FM-specific claims. The prevalence of disability was twice as high among FM employees than overall employees (p < 0.0001). For every dollar spent on FM-specific claims, the employer spent another $57 to $143 on additional direct and indirect costs. Hidden costs of disability and comorbidities greatly increase the true burden of FM. Regardless of the clinical understanding of FM, when a claim for FM is present, considerable costs are involved. Findings suggest that within the management of FM there may be large cost-offset opportunities for reductions in patient, physician, and employer burdens.


Flexible ureterorenoscopy (URS): technique and results.
This paper has two main objectives: First, to expose the URS technique used in our Department because there are important differences with respect to others centres published, explaining same aspect that can benefit to the better development of the technique. Second, we present the results of a series of 100 cases. Flexible ureterorenoscopy (Flex URS) has been little used to date, mainly because of the technical difficulties created by the deficient quality of the instruments used, such as ureteroscopes offering scant visibility, poor illumination, a small working channel, deficient quality of the forceps and baskets, etc. We present our recent series of flexible URS for the treatment of renal lithiasis. We performes a retrospective analysis of this treatment corresponding to the period between January 2007 and March 2010. In this period we have treated 100 patients. The medium size of the stone treated is 1.5cm (0.5-6cm) and we used ureteroscopic protector sheath in all cases. The lithotripter system used in all cases was Ho:YAG Laser with 200 and 365 micras fibers The stone-free rate (SFR) in the immediate postoperative period was 77% (77/100 patients). Residual stones, defined as stone fragments visualized in the operating room via fluoroscopy and directly with the flexible ureteroscope. Three months after surgery, the SFR was 92.7% (89/96 patients) confirmed by intravenous urography. Regarding complications, we had 5 patients with ureteral lesions during protector sheath pass and 9 patients that presented at the emergency room with pain secondary to the double J catheter. Flexible URS for of renal lithiasis can be defended in stones measuring up to 2 cm in diameter, based on our treatment algorithm.


Structural basis of RNA-dependent recruitment of glutamine to the genetic code.
Glutaminyl-transfer RNA (Gln-tRNA(Gln)) in archaea is synthesized in a pretranslational amidation of misacylated Glu-tRNA(Gln) by the heterodimeric Glu-tRNA(Gln) amidotransferase GatDE. Here we report the crystal structure of the Methanothermobacter thermautotrophicus GatDE complexed to tRNA(Gln) at 3.15 angstroms resolution. Biochemical analysis of GatDE and of tRNA(Gln) mutants characterized the catalytic centers for the enzyme's three reactions (glutaminase, kinase, and amidotransferase activity). A 40 angstrom-long channel for ammonia transport connects the active sites in GatD and GatE. tRNA(Gln) recognition by indirect readout based on shape complementarity of the D loop suggests an early anticodon-independent RNA-based mechanism for adding glutamine to the genetic code.


Swedish general practitioners' attitudes towards treatment guidelines - a qualitative study.
Drug therapy in primary care is a challenge for general practitioners (GPs) and the prescribing decision is influenced by several factors. GPs obtain drug information in different ways, from evidence-based sources, their own or others' experiences, or interactions with opinion makers, patients or colleagues. The need for objective drug information sources instead of drug industry-provided information has led to the establishment of local drug and therapeutic committees. They annually produce and implement local treatment guidelines in order to promote rational drug use. This study describes Swedish GPs' attitudes towards locally developed evidence-based treatment guidelines. Three focus group interviews were performed with a total of 17 GPs working at both public and private primary health care centres in Skåne in southern Sweden. Transcripts were analysed by conventional content analysis. Codes, categories and themes were derived from data during the analysis. We found two main themes: GP-related influencing factors and External influencing factors. The first theme emerged when we put together four main categories: Expectations and perceptions about existing local guidelines, Knowledge about evidence-based prescribing, Trust in development of guidelines, and Beliefs about adherence to guidelines. The second theme included the categories Patient-related aspects, Drug industry-related aspects, and Health economic aspects. The time-saving aspect, trust in evidence-based market-neutral guidelines and patient safety were described as key motivating factors for adherence. Patient safety was reported to be more important than adherence to guidelines or maintaining a good patient-doctor relationship. Cost containment was perceived both as a motivating factor and a barrier for adherence to guidelines. GPs expressed concerns about difficulties with adherence to guidelines when managing patients with drugs from other prescribers. GPs experienced a lack of time to self-inform and difficulties managing direct-to-consumer drug industry information. Patient safety, trust in development of evidence-based recommendations, the patient-doctor encounter and cost containment were found to be key factors in GPs' prescribing. Future studies should explore the need for transparency in forming and implementing guidelines, which might potentially increase adherence to evidence-based treatment guidelines in primary care.


Polymerically modified layered silicates: an effective route to nanocomposites.
Polymer/clay nanocomposites have been under an extensive investigation for about 15 years. Traditional methods to modify the clay are usually limited to small organic cations, preferably containing long alkyl chain(s), which are exchanged with the inorganic cations in the clay gallery. This article provides a comprehensive review on the strategies for clay modification using polymeric surfactants or polycations: from the synthesis of such surfactants, through the preparation of the polymerically modified clays, and to the fabrication of the respective polymer nanocomposites and their properties.


Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape.
A diverse subset of pattern recognition receptors (PRRs) detects pathogen-associated nucleic acids to initiate crucial innate immune responses in host organisms. Reflecting their importance for host defense, pathogens encode various countermeasures to evade or inhibit these immune effectors. PRRs directly engaged by pathogen inhibitors often evolve under recurrent bouts of positive selection that have been described as molecular 'arms races.' Cyclic GMP-AMP synthase (cGAS) was recently identified as a key PRR. Upon binding cytoplasmic double-stranded DNA (dsDNA) from various viruses, cGAS generates the small nucleotide secondary messenger cGAMP to signal activation of innate defenses. Here we report an evolutionary history of cGAS with recurrent positive selection in the primate lineage. Recent studies indicate a high degree of structural similarity between cGAS and 2'-5'-oligoadenylate synthase 1 (OAS1), a PRR that detects double-stranded RNA (dsRNA), despite low sequence identity between the respective genes. We present comprehensive comparative evolutionary analysis of cGAS and OAS1 primate sequences and observe positive selection at nucleic acid binding interfaces and distributed throughout both genes. Our data revealed homologous regions with strong signatures of positive selection, suggesting common mechanisms employed by unknown pathogen encoded inhibitors and similar modes of evasion from antagonism. Our analysis of cGAS diversification also identified alternately spliced forms missing multiple sites under positive selection. Further analysis of selection on the OAS family in primates, which comprises OAS1, OAS2, OAS3 and OASL, suggests a hypothesis where gene duplications and domain fusion events result in paralogs that provide another means of escaping pathogen inhibitors. Together our comparative evolutionary analysis of cGAS and OAS provides new insights into distinct mechanisms by which key molecular sentinels of the innate immune system have adapted to circumvent viral-encoded inhibitors.


The zinc finger transcription factor RP58 negatively regulates Rnd2 for the control of neuronal migration during cerebral cortical development.
The zinc finger transcription factor RP58 (also known as ZNF238) regulates neurogenesis of the mouse neocortex and cerebellum (Okado et al. 2009; Xiang et al. 2011; Baubet et al. 2012; Ohtaka-Maruyama et al. 2013), but its mechanism of action remains unclear. In this study, we report a cell-autonomous function for RP58 during the differentiation of embryonic cortical projection neurons via its activities as a transcriptional repressor. Disruption of RP58 expression alters the differentiation of immature neurons and impairs their migration and positioning within the mouse cerebral cortex. Loss of RP58 within the embryonic cortex also leads to elevated mRNA for Rnd2, a member of the Rnd family of atypical RhoA-like GTPase proteins important for cortical neuron migration (Heng et al. 2008). Mechanistically, RP58 represses transcription of Rnd2 via binding to a 3'-regulatory enhancer in a sequence-specific fashion. Using reporter assays, we found that RP58 repression of Rnd2 is competed by proneural basic helix-loop-helix transcriptional activators. Finally, our rescue experiments revealed that negative regulation of Rnd2 by RP58 was important for cortical cell migration in vivo. Taken together, these studies demonstrate that RP58 is a key player in the transcriptional control of cell migration in the developing cerebral cortex.


Sedentary Behavior, Physical Activity, and All-Cause Mortality: Dose-Response and Intensity Weighted Time-Use Meta-analysis.
Previous studies have placed those with excessive sedentary behavior at increased risk of all-cause mortality. There is evidence of interdependency of sedentary behavior with physical activity, and its elucidation will have implications for guidelines and practice. This study investigated if sedentary behavior-related mortality risk can be offset by moderate- to vigorous-intensity physical activity (MVPA) considered in a time-use fashion. PubMed was searched (from its inception till May 2018) for studies or meta-analyses that used data harmonized for MVPA. Of the 17 data-custodians located, 7 provided data on sitting time or TV viewing time, or both. A dose-response meta-analysis modeling log relative risks of all-cause mortality against uncompensated sedentary behavior metabolic equivalent hours (USMh) was run using the robust error meta-regression method. (Registration: CRD42017062439) SETTING: Individual subject data held by data custodians on this topic. General adults. Sedentary time, MVPA. Five harmonized cohorts of sitting time (258,688 participants) and 4 of TV viewing time (156,593 participants) demonstrated that sedentary behavior was significantly associated with mortality, but this risk was attenuated with increasing energy expenditure through MVPA modeled in a time-use fashion. The average increment in mortality per USMh spent on sitting was 1% [relative risk (RR) 1.01, 95% confidence interval (CI) 1.00, 1.02; P = .01] and that per USMh spent on TV viewing was 7% (RR 1.07, 95% CI 1.04, 1.10; P < .001). The thresholds for risk started at 7 USMh for sitting and 3 USMh for TV viewing. Our findings suggest that overall daily sitting time energy expenditure of 7 MET-hours (or TV viewing of 3 MET-hours) in excess of that expended on MVPA is independently related to all-cause mortality. These findings support the view that sitting is strongly influenced by consideration of concurrent MVPA in its impact on adverse health consequences and that the USMh is a more practical metric of sedentary behavior.


The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.
The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.


Anti-obesity effects of germinated brown rice extract through down-regulation of lipogenic genes in high fat diet-induced obese mice.
Lipid accumulation using Oil Red O dye was measured in 3T3-L1 murine adipocytes to examine the anti-obesity effect of four types of germinated rice, including germinated brown rice (GBR), germinated waxy brown rice (GWBR), germinated black rice (GB-R), and germinated waxy black rice (GWB-R). GBR methanol extract exhibited the highest suppression of lipid accumulation in the 3T3-L1 cell line and also the anti-obesity effect of GBR on high fat induced-obese mice. The mice were divided into three groups and were administered: ND, a normal diet; HFD control, a high fat diet; and GBR, a high fat diet plus 0.15% GBR methanol extract for 7 weeks. GBR administration significantly decreased body weight gain and lipid accumulation in the liver and epididymal adipose tissue as compared to the HFD control group. In addition, serum triglycerides (TGs) and total cholesterol (TC) levels were significantly decreased by following GBR administration compared with those in the HFD control group, whereas the high-density lipoprotein (HDL) cholesterol level increased. Furthermore, the mRNA levels of adipogenic transcriptional factors, such as CCAAT enhancer binding protein (C/EBP)-α, sterol regulatory element-binding protein (SREBP)-1c, and peroxisome proliferator activated receptors (PPAR)-γ, and related genes (aP2, FAS), decreased significantly. Taken together, GBR administration suppressed body weight gain and lipid accumulation in the liver and epididymal adipocytes, and improved serum lipid profiles, in part, by controlling adipogenesis through a reduction in transcriptional factors. These results suggest that GBR is a potential agent against obesity.


Carpal tunnel syndrome - is high-frequency ultrasound a useful diagnostic tool?
This study assessed the clinical use of three ultrasound measurements; median nerve cross-sectional area, median nerve flattening ratio and palmar displacement of the flexor retinaculum, for the diagnosis of carpal tunnel syndrome. The measurements were made in 20 carpal tunnel sufferers and 20 controls. The sensitivity, specificity and predictive values of each were calculated in various clinical settings. Values for each of the three variables were significantly different in the patient and control populations. The differences we recorded were smaller than those found in previous studies. The tests had a sensitivity of 72% and a specificity of 90%. Alterations in the morphology of the carpal tunnel in patients with carpal tunnel syndrome can be measured in the district general hospital setting. The measurements described maybe a useful non-invasive confirmatory test in patients in whom there is a strong clinical suspicion of carpal tunnel syndrome. However, they would be of no benefit in epidemiological surveys of populations with a low incidence of carpal tunnel syndrome.


Querying Co-regulated Genes on Diverse Gene Expression Datasets Via Biclustering.
Rapid development and increasing popularity of gene expression microarrays have resulted in a number of studies on the discovery of co-regulated genes. One important way of discovering such co-regulations is the query-based search since gene co-expressions may indicate a shared role in a biological process. Although there exist promising query-driven search methods adapting clustering, they fail to capture many genes that function in the same biological pathway because microarray datasets are fraught with spurious samples or samples of diverse origin, or the pathways might be regulated under only a subset of samples. On the other hand, a class of clustering algorithms known as biclustering algorithms which simultaneously cluster both the items and their features are useful while analyzing gene expression data, or any data in which items are related in only a subset of their samples. This means that genes need not be related in all samples to be clustered together. Because many genes only interact under specific circumstances, biclustering may recover the relationships that traditional clustering algorithms can easily miss. In this chapter, we briefly summarize the literature using biclustering for querying co-regulated genes. Then we present a novel biclustering approach and evaluate its performance by a thorough experimental analysis.


Integration in vivo into simian virus 40 DNA of a sequence that resembles a certain family of genomic interspersed repeated sequences.
The isolation and characterization of a viable mutant of simian virus 40 (SV40) called "in1449" are described. the mutant DNA is found to have a 157-nucleotide-long insertion at map position 0.649 within the 5' untranslated sequence of the early region of SV40. The complete nucleotide sequence of the insert is presented. Sequence comparisons show that the insert is not of SV40 origin. The insert is presumably of monkey origin since in1449 was produced within monkey kidney cells. The sequence of the in1449 insert matches remarkably well with sequences of a certain predominant family of interspersed repeated sequences in human DNA (called the Alu family) and cloned members thereof. This high degree of sequence homology suggests that the in1449 insert is derived from a member of a family of interspersed repeated sequences in monkey DNA related to the human Alu family. The in1449 insert (and the Alu family members) contain certain oligonucleotide sequences that also are found conserved in the replication origins of papovaviruses and certain other oligonucleotides found in repetitive double-stranded regions of mammalian heterogeneous nuclear RNAs. Sequences around the two recombinant joints in in1449 exhibit a definite pattern of homology. An octanucleotide present in the SV40 part of the first recombinant joint is exactly repeated 15 nucleotides away within the insert; another octanucleotide present within the insert at the second joint is exactly repeated 21 nucleotides away in the viral DNA. The viral DNA sequences flanking the insert in in1449 also exhibit some homology.


Physical activity in aging: comparison among young, aged, and nonagenarian individuals.
Physical activity (PA) is known to decline with age; however, there is a paucity of data on activity in persons who are in their nineties and beyond. We used objective and reliable methods to measure PA in nonagenarians (>or=90 yr; n=98) and hypothesized that activity would be similar to that of aged (60-74 yr; n=58) subjects but less than in young (20-34 yr; n=53) volunteers. Total energy expenditure (TEE) was measured by doubly labeled water over 14 days and resting metabolic rate (RMR) by indirect calorimetry. Measures of PA included activity energy expenditure adjusted for body composition, TEE adjusted for RMR, physical activity level (PAL), and activity over 14 days by accelerometry expressed as average daily durations of light and moderate activity. RMR and TEE were lower with increasing age group (P<0.01); however, RMR was not different between aged and nonagenarian subjects after adjusting for fat-free mass, fat mass, and sex. Nonagenarians had a lower PAL and were more sedentary than the aged and young groups (P<0.01); however, the nonagenarians who were more active on a daily basis walked further during a timed test, indicating higher physical functionality. For all measures of activity, no differences were found between young and aged volunteers. PA was markedly lower in nonagenarians compared with young and aged adults. Interestingly, PA was similar between young volunteers and those who were in their 60s and 70s, likely due to the sedentary nature of our society, particularly in young adults.


Incorporating equity in regulatory and benefit-cost analysis using risk-based preferences.
The analysis of federal regulations focuses on the analysis of economic efficiency through standard benefit-cost analysis in which reductions in risk tend to represent benefits and variability may be investigated through sensitivity or simulation methods. Such analyses typically ignore distributional consequences that can affect decisions. Although analytical guidance from the Office of Management and Budget (OMB) mentions distributional consequences, there is little specificity regarding how it might be analyzed. Specificity might be improved by OMB: (1) communicating and enforcing distributional impacts as more central to the process, (2) identifying default types of descriptive distributional statistics, (3) identifying whether legislation has created a constraint to not harm a subgroup, and (4) requesting a distributional sensitivity test of the net benefits along with a standard benefit-cost analysis. Although such actions have a data collection and analysis cost, they may make the results of regulatory analysis more relevant by investigating both efficiency and equity measures.


Collective intelligence defines biological functions in Wikipedia as communities in the hidden protein connection network.
English Wikipedia, containing more than five millions articles, has approximately eleven thousands web pages devoted to proteins or genes most of which were generated by the Gene Wiki project. These pages contain information about interactions between proteins and their functional relationships. At the same time, they are interconnected with other Wikipedia pages describing biological functions, diseases, drugs and other topics curated by independent, not coordinated collective efforts. Therefore, Wikipedia contains a directed network of protein functional relations or physical interactions embedded into the global network of the encyclopedia terms, which defines hidden (indirect) functional proximity between proteins. We applied the recently developed reduced Google Matrix (REGOMAX) algorithm in order to extract the network of hidden functional connections between proteins in Wikipedia. In this network we discovered tight communities which reflect areas of interest in molecular biology or medicine and can be considered as definitions of biological functions shaped by collective intelligence. Moreover, by comparing two snapshots of Wikipedia graph (from years 2013 and 2017), we studied the evolution of the network of direct and hidden protein connections. We concluded that the hidden connections are more dynamic compared to the direct ones and that the size of the hidden interaction communities grows with time. We recapitulate the results of Wikipedia protein community analysis and annotation in the form of an interactive online map, which can serve as a portal to the Gene Wiki project.


Methylphenidate use and poly-substance use among undergraduate students attending a South African university.
Methylphenidate hydrochloride (MPH) is used in the treatment of attention deficit hyperactivity disorder (ADHD). The non-medical use of MPH by learners and students has been reported by numerous studies from abroad. The practice stems from beliefs about the benefits of MPH in achieving academic success. Little is known about the use of MPH in South African student populations. The study set out to determine (1) the extent and dynamics associated with MPH use and (2) poly-substance use among undergraduate students attending a South African university. 818 students took part in a written, group-administered survey. Data analysis resulted in descriptive results regarding MPH use and tests of association identified differences in MPH and poly-substance use among respondents. One in six respondents (17.2%) has used MPH in the past, although only 2.9% have been diagnosed with ADHD. Nearly a third (31.7%) of users obtained MPH products illegally. The majority (69.1%) used MPH only during periods of academic stress. A significant association (p < 0.001) was found between MPH use and the frequency of using alcohol, tobacco, cannabis, hard drugs (e.g. cocaine) and prescription medication. MPH use among students appears similar to experiences abroad, especially in the absence of clinical diagnosis for ADHD. Institutions of higher education should inform parents and students about the health risks associated with the illicit use of MPH. Prescribers and dispensers of MPH products should pay close attention to practices of stockpiling medication and poly-substance use among students who use MPH.


Phytochemical analysis and antileukemic activity of polyphenolic constituents of Toona sinensis.
Toona sinensis is a traditional Chinese medicine belonging to the Meliaceae family. The aim of this study was to identify the potential compounds responsible for anticancer activity of T. sinensis. The EtOAc extracts of leaves and woods of T. sinensis inhibited cell proliferation and induced apoptosis in human leukemia HL-60 cells. Our phytochemical research of these extracts led to the isolation of various polyphenolic constituents. The chemical structures were determined by spectroscopic analyses. Among isolates, gallic acid and loropetalin D showed inhibition of cell proliferation and possible induction of apoptosis in these cells. Overall, our results revealed the importance of T. sinensis as a chemopreventive medicinal plant. In addition, an analysis of structure-activity relationship indicated that the number of galloyl groups affects their antileukemic potency.


Control of high-dose-cisplatin-induced emesis with an all-oral three-drug antiemetic regimen.
In this pilot trial, the antiemetic efficacy and tolerability of an all-oral antiemetic combination in the prevention of both acute and delayed nausea and vomiting following high-dose cisplatin was evaluated. Fifty-two patients receiving cisplatin (median dose 100 mg/m2) were entered. Patients received (1) 60 min prior to cisplatin: prochlorperazine spansule 15 mg, dexamethasone 20 mg, granisetron 2 mg; (2) 12 h after cisplatin: prochlorperazine spansule 15 mg, dexamethasone 10 mg; (3) on days 2 and 3: prochlorperazine spansule 15 mg b.i.d., dexamethasone 8 mg b.i.d.; (4) on days 4 and 5: dexamethasone 4 mg b.i.d. All antiemetics were administered orally. The study period was the 120 h after cisplatin administration. The primary efficacy end-point was complete control (no vomiting, retching or antiemetic rescue) of delayed emesis (24-120 h after cisplatin). Complete control of delayed emesis was achieved in 26 patients (53%). Nineteen patients (39%) noted no delayed nausea. Complete control of acute emesis (24 h after cisplatin) was attained in 44 patients (86%). The no nausea rate during the first 24 h was 74%. Overall, 39 patients (80%) were satisfied or very satisfied with their outcome. Treatment was well tolerated with infrequent and minor adverse events. In conclusion, an all-oral combination of granisetron, dexamethasone and prochlorperazine is a highly effective and well-tolerated regimen for preventing acute cisplatin-induced emesis. Control of delayed emesis was not better than with current standard treatment, and more effective approaches are needed.


Neutralising antibodies for Mayaro virus in Pantanal, Brazil.
The Pantanal hosts diverse wildlife species and therefore is a hotspot for arbovirus studies in South America. A serosurvey for Mayaro virus (MAYV), eastern (EEEV), western (WEEV) and Venezuelan (VEEV) equine encephalitis viruses was conducted with 237 sheep, 87 free-ranging caimans and 748 equids, including 37 collected from a ranch where a neurologic disorder outbreak had been recently reported. Sera were tested for specific viral antibodies using plaque-reduction neutralisation test. From a total of 748 equids, of which 264 were immunised with vaccine composed of EEEV and WEEV and 484 had no history of immunisation, 10 (1.3%) were seropositive for MAYV and two (0.3%) for VEEV using criteria of a ≥ 4-fold antibody titre difference. Among the 484 equids without history of immunisation, 48 (9.9%) were seropositive for EEEV and four (0.8%) for WEEV using the same criteria. Among the sheep, five were sero- positive for equine encephalitis alphaviruses, with one (0.4%) for EEEV, one (0.4%) for WEEV and three (1.3%) for VEEV. Regarding free-ranging caimans, one (1.1%) and three (3.4%), respectively, had low titres for neutralising antibodies to VEEV and undetermined alphaviruses. The neurological disorder outbreak could not be linked to the alphaviruses tested. Our findings represent strong evidence that MAYV and all equine encephalitis alphaviruses circulated in the Pantanal.


Amino acid metabolism in human subcutaneous adipose tissue in vivo.
1. Arteriovenous differences for alanine, glutamate and glutamine were measured across subcutaneous adipose tissue and forearm muscle in normal subjects. 2. After an overnight fast, adipose tissue showed net production of alanine and glutamine and uptake of glutamate in each of 11 subjects. 3. In seven subjects, adipose tissue blood flow was measured and the measurements were continued for 6 h after eating a mixed meal. The pattern of amino acid metabolism across the adipose tissue was remarkably little disturbed after the meal, except for a short period of apparent uptake of alanine as the concentration of that amino acid rose. 4. The pattern of amino acid metabolism across adipose tissue was qualitatively similar to that across the forearm, although it differed quantitatively in that glutamate uptake was more prominent (compared with glutamine release) in the adipose tissue. 5. The rates of alanine and glutamine release observed suggest that adipose tissue may play a substantial role in the whole-body production of these amino acids.


Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling.
One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy number variation data from single-nucleotide polymorphism array of the primary tumors (P = .042). SI-NET patients with PC have poor survival, which diminishes with increasing PC load after surgery. Clustering based on copy number variation and loss of heterozygosity data suggests different genotypes in primary tumors comparing patients with and without PC.


CO2 Capture in the Sustainable Wheat-Derived Activated Microporous Carbon Compartments.
Microporous carbon compartments (MCCs) were developed via controlled carbonization of wheat flour producing large cavities that allow CO2 gas molecules to access micropores and adsorb effectively. KOH activation of MCCs was conducted at 700 °C with varying mass ratios of KOH/C ranging from 1 to 5, and the effects of activation conditions on the prepared carbon materials in terms of the characteristics and behavior of CO2 adsorption were investigated. Textural properties, such as specific surface area and total pore volume, linearly increased with the KOH/C ratio, attributed to the development of pores and enlargement of pores within carbon. The highest CO2 adsorption capacities of 5.70 mol kg-1 at 0 °C and 3.48 mol kg-1 at 25 °C were obtained for MCC activated with a KOH/C ratio of 3 (MCC-K3). In addition, CO2 adsorption uptake was significantly dependent on the volume of narrow micropores with a pore size of less than 0.8 nm rather than the volume of larger pores or surface area. MCC-K3 also exhibited excellent cyclic stability, facile regeneration, and rapid adsorption kinetics. As compared to the pseudo-first-order model, the pseudo-second-order kinetic model described the experimental adsorption data methodically.


Syntactic parsing of clinical text: guideline and corpus development with handling ill-formed sentences.
To develop, evaluate, and share: (1) syntactic parsing guidelines for clinical text, with a new approach to handling ill-formed sentences; and (2) a clinical Treebank annotated according to the guidelines. To document the process and findings for readers with similar interest. Using random samples from a shared natural language processing challenge dataset, we developed a handbook of domain-customized syntactic parsing guidelines based on iterative annotation and adjudication between two institutions. Special considerations were incorporated into the guidelines for handling ill-formed sentences, which are common in clinical text. Intra- and inter-annotator agreement rates were used to evaluate consistency in following the guidelines. Quantitative and qualitative properties of the annotated Treebank, as well as its use to retrain a statistical parser, were reported. A supplement to the Penn Treebank II guidelines was developed for annotating clinical sentences. After three iterations of annotation and adjudication on 450 sentences, the annotators reached an F-measure agreement rate of 0.930 (while intra-annotator rate was 0.948) on a final independent set. A total of 1100 sentences from progress notes were annotated that demonstrated domain-specific linguistic features. A statistical parser retrained with combined general English (mainly news text) annotations and our annotations achieved an accuracy of 0.811 (higher than models trained purely with either general or clinical sentences alone). Both the guidelines and syntactic annotations are made available at https://sourceforge.net/projects/medicaltreebank. We developed guidelines for parsing clinical text and annotated a corpus accordingly. The high intra- and inter-annotator agreement rates showed decent consistency in following the guidelines. The corpus was shown to be useful in retraining a statistical parser that achieved moderate accuracy.


Identification of cytochrome P450-reductase as the enzyme responsible for NADPH-dependent lucigenin and tetrazolium salt reduction in rat epididymal sperm preparations.
Lucigenin-dependent chemiluminescence and WST-1 reduction can be detected following addition of NADPH to many cell types, including rat epididymal sperm suspensions. Although many reports suggest that such a phenomenon is due to reactive oxygen species production, other probes-such as MCLA and luminol-that are capable of detecting reactive oxygen metabolites do not produce a chemiluminescent signal in this model system. Our aim was to purify and identify the enzyme catalyzing the NADPH-dependent lucigenin and WST-1 reduction from rat epididymal spermatozoa preparations. Here, we show the identity of this enzyme as cytochrome P450-reductase. In support of this, a homogenous preparation of this protein was capable of reducing lucigenin and WST-1 in the presence of NADPH. Moreover, COS-7 cells overexpressing cytochrome P450-reductase displayed a 3-fold increase in the aforementioned activity compared with mock-transfected cells. Immunolocalization studies and biochemical analysis suggest that the majority of the NADPH-lucigenin activity is localized to the epithelial cells present within the epididymis. These results emphasize the importance of the direct NADPH-dependent reduction of superoxide-sensitive probes by cytochrome P450-reductase even though this enzyme does not, on its own accord, produce reactive oxygen species.


Survival and morbidity outcomes for very low birth weight infants with Down syndrome.
Our objective was to compare survival and neonatal morbidity rates between very low birth weight (VLBW) infants with Down syndrome (DS) and VLBW infants with non-DS chromosomal anomalies, nonchromosomal birth defects (BDs), and no chromosomal anomaly or major BD. Data were collected prospectively for infants weighing 401 to 1500 g who were born and/or cared for at one of the study centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network in 1994-2008. Risk of death and morbidities, including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late-onset sepsis (LOS), retinopathy of prematurity, and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups. Infants with DS were at increased risk of death (adjusted relative risk: 2.47 [95% confidence interval: 2.00-3.07]), PDA, NEC, LOS, and BPD, relative to infants with no BDs. Decreased risk of death (relative risk: 0.40 [95% confidence interval: 0.31-0.52]) and increased risks of NEC and LOS were observed when infants with DS were compared with infants with other non-DS chromosomal anomalies. Relative to infants with nonchromosomal BDs, infants with DS were at increased risk of PDA and NEC. The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for anticipating the need for enhanced surveillance for prevention of these morbidities.


Regulation of NF-κB activation through a novel PI-3K-independent and PKA/Akt-dependent pathway in human umbilical vein endothelial cells.
The transcription factor NF-κB regulates numerous inflammatory diseases, and proteins involved in the NF-κB-activating signaling pathway are important therapeutic targets. In human umbilical vein endothelial cells (HUVECs), TNF-α-induced IκBα degradation and p65/RelA phosphorylation regulate NF-κB activation. These are mediated by IKKs (IκB kinases) viz. IKKα, β and γ which receive activating signals from upstream kinases such as Akt. Akt is known to be positively regulated by PI-3K (phosphoinositide-3-kinase) and differentially regulated via Protein kinase A (PKA) in various cell types. However, the involvement of PKA/Akt cross talk in regulating NF-κB in HUVECs has not been explored yet. Here, we examined the involvement of PKA/Akt cross-talk in HUVECs using a novel compound, 2-methyl-pyran-4-one-3-O-β-D-2',3',4',6'-tetra-O-acetyl glucopyranoside (MPTAG). We observed that MPTAG does not directly inhibit IKK-β but prevents TNF-α-induced activation of IKK-β by blocking its association with Akt and thereby inhibits NF-κB activation. Interestingly, our results also revealed that inhibitory effect of MPTAG on Akt and NF-κB activation was unaffected by wortmannin, and was completely abolished by H-89 treatment in these cells. Thus, MPTAG-mediated inhibition of TNF-α-induced Akt activation was independent of PI-3K and dependent on PKA. Most importantly, MPTAG restores the otherwise repressed activity of PKA and inhibits the TNF-α-induced Akt phosphorylation at both Thr308 and Ser473 residues. Thus, we demonstrate for the first time the involvement of PKA/Akt cross talk in NF-κB activation in HUVECs. Also, MPTAG could be useful as a lead molecule for developing potent therapeutic molecules for diseases where NF-κB activation plays a key role.


Improvement of circadian rhythm of heart rate variability by eurythmy therapy training.
Background. Impairment of circadian rhythm is associated with various clinical problems. It not only has a negative impact on quality of life but can also be associated with a significantly poorer prognosis. Eurythmy therapy (EYT) is an anthroposophic movement therapy aimed at reducing fatigue symptoms and stress levels. Objective. This analysis of healthy subjects was conducted to examine whether the improvement in fatigue symptoms was accompanied by improvements in the circadian rhythm of heart rate variability (HRV). Design. Twenty-three women performed 10 hours of EYT over six weeks. Electrocardiograms (ECGs) were recorded before and after the EYT trial. HRV was quantified by parameters of the frequency and time domains and the nonlinear parameters of symbolic dynamics. Results. The day-night contrast with predominance of vagal activity at night becomes more pronounced after the EYT training, and with decreased Ultralow and very low frequencies, the HRV shows evidence of calmer sleep. During the night, the complexity of the HRV is significantly increased indicated by nonlinear parameters. Conclusion. The analysis of the circadian patterns of cardiophysiological parameters before and after EYT shows significant improvements in HRV in terms of greater day-night contrast caused by an increase of vagal activity and calmer and more complex HRV patterns during sleep.


Alkaloids and polyketides from Penicillium citrinum, an endophyte isolated from the Moroccan plant Ceratonia siliqua.
The endophytic fungus Penicillium citrinum was isolated from a fresh stem of the Moroccan plant Ceratonia siliqua. Extracts of P. citrinum grown on rice and white bean media yielded five new compounds, namely, citriquinochroman (1), tanzawaic acids G and H (2 and 3), 6-methylcurvulinic acid (4), 8-methoxy-3,5-dimethylisoquinolin-6-ol (5), and one new natural product, 1,2,3,11b-tetrahydroquinolactacide (6), which had previously been described as a synthetic compound. In addition, 13 known compounds including seven alkaloids and six polyketides were isolated. The structures of the new compounds were unambiguously determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. Citriquinochroman (1) features a new skeleton, consisting of quinolactacide and (3S)-6-hydroxy-8-methoxy-3,5-dimethylisochroman linked by a C-C bond. 1,2,3,11b-Tetrahydroquinolactacide (6) may be a biogenetic precursor of quinolactacide. Citriquinochroman (1) showed cytotoxicity against the murine lymphoma L5178Y cell line with an IC50 value of 6.1 μM, while the other compounds were inactive (IC50 >10 μM) in this assay.


Does government supervision improve stop-smoking counseling in midwifery practices?
Smoking-cessation counseling during pregnancy is important to prevent smoking-related harm in pregnant smokers and their children. Therefore we evaluated the effects of an Inspectorate's supervision programme on the provision of smoking-cessation counseling by midwifery practices in the Netherlands. The supervision programme consisted of 3 elements: A) A deadline was announced by which all practices should comply with professional norms on such counseling (2011); B) A set of randomly selected practices were assessed using a questionnaire and a personal feedback report (2010); C) Another set of randomly selected practices were assessed through a site visit and a personal feedback report (2012). Programme A was evaluated in a before-after study, Programmes B and C were evaluated in a randomized controlled trial (RCT) with only a post-intervention measurement. Primary outcome was provision of smoking-cessation counseling through a minimal-intervention strategy (V-MIS). Linear and logistic regression models were used to analyze data from 233 primary-care midwifery practices. A) After announcement of the deadline, Dutch midwifery practices reported significantly more provision of smoking-cessation counseling. For example, the use of V-MIS increased substantially from 28% to 80%; B) In practices that were assessed with a questionnaire, the provision of counseling improved partially compared to controls; C) The provision of counseling did not differ between practices that were visited and their controls. While the training participation rate in counseling by midwifery practices did not differ between the intervention and control groups, the rate increased significantly in all practices after the start of the supervision programme. The provision of smoking-cessation counseling improved spectacularly in Dutch midwifery practices. Despite some limitations of our study, the Inspectorate's supervision programme is likely to have contributed to the improvements in provision of counseling.