Lead-related nephrotoxicity: a review of the epidemiologic evidence.
Chronic kidney disease (CKD) represents a major global public health concern. Efforts to prevent and/or slow progression of CKD are essential. Lead nephropathy, characterized by chronic tubulointerstitial nephritis, is a well-known risk of chronic, high-level lead exposure. However, in recent years, lead exposure has declined sharply, particularly in developed countries. We reviewed epidemiologic research in general, occupational, and patient populations to assess whether lead, at current exposure levels, still contributes to nephrotoxicity. Other pertinent topics, such as risk in children, genetic susceptibility, and co-exposure to cadmium, are also considered. The data reviewed indicate that lead contributes to nephrotoxicity, even at blood lead levels below 5 microg/dl. This is particularly true in susceptible populations, such as those with hypertension (HTN), diabetes, and/or CKD. Low socioeconomic status is a risk factor for both lead exposure and diseases that increase susceptibility. Future public health risk for lead-related nephrotoxicity may be most significant in those rapidly developing countries where risk factors for CKD, including obesity and secondary HTN and diabetes mellitus, are increasing more rapidly than lead exposure is declining. Global efforts to reduce lead exposure remain important. Research is also needed to determine whether specific therapies, such as chelation, are beneficial in susceptible populations.


Recycled vertical flow constructed wetland (RVFCW)--a novel method of recycling greywater for irrigation in small communities and households.
The use of greywater for irrigation is becoming increasingly common. However, raw greywater is often contaminated and can cause environmental harm and pose health risks. Nevertheless, it is often used without any significant pretreatment, a practice mistakenly considered safe. The aim of this study was to develop an economically sound, low-tech and easily maintainable treatment system that would allow safe and sustainable use of greywater for landscape irrigation in small communities and households. The system is based on a combination of vertical flow constructed wetland with water recycling and trickling filter, and is termed recycled vertical flow constructed wetland (RVFCW). The RVFCW's properties, removal efficiency, hydraulic parameters and feasibility were studied, as well as the environmental effects of the treated greywater, as reflected by soil and plant parameters over time. The RVFCW was efficient at removing virtually all of the suspended solids and biological oxygen demand, and about 80% of the chemical oxygen demand after 8h. Fecal coliforms dropped by three to four orders of magnitude from their initial concentration after 8h, but this was not always enough to meet current regulations for unlimited irrigation. The treated greywater had no significant negative impact on plants or soil during the study period. The feasibility analysis indicated a return over investment after approximately three years. We concluded that the RVFCW is a sustainable and promising treatment system for greywater use that can be run and maintained by unskilled operators.


Authorship in biomedical research: A sweet fruit of inspiration or a bitter fruit of trade.
Achieving a place in the authorship of published scientific research is a matter of pride and fame associated with creativity, recognition, better evaluation, and financial gains. This had made assigning of authorship in a scientific publication, a complex and challenging issue. Gaining a position in authorship in scientific publications not only prompts or encourages authors to carry out more research but also recourse many of them to the unethical practice of different kinds of authorship abuses. These authorship abuses are done so cleverly and skillfully that neither the journal editors nor the readers of the journals realize that bias had crept in authorship of the publication. This nonstandard act of biased authorship has a tremendous potential to compromise the credibility of scientific research and scientific publications. The present review aims in focusing on issues pertaining to authorship and its misuse in biomedical research. Thus, it can be concluded from this review that new policies, guidelines, and laws should be made by the government agencies in association with journal editors, institution, and government agencies to curb this malpractice by protecting whistleblowers and providing adequate punishment for those who are involved.


Perceived environmental correlates of physical activity and walking in African young adults.
Evidence on environmental correlates of physical activity (PA) conducted in Western developed countries may not be generalizable to Africa. This study examined the associations between perception of the neighborhood environment and PA and walking in African young adults. Cross-sectional analysis of self-reported survey. University of Ibadan, in the capital city of Oyo State, Nigeria. A representative sample of undergraduates of a Nigerian university, age 16 to 39 years and 50.7% female. Total walking activity and PA were measured with the short version of the International Physical Activity Questionnaire. Sixteen perceived neighborhood environmental variables were measured using the Physical Activity Neighborhood Environment Scale (PANES), which was used to assess environmental correlates of PA that are internationally relevant. Outcomes were meeting health-related guidelines for sufficient PA and walking activity. After adjustments for demographics and dormitory site, the proximity of bus/transit stop (odds ratio [OR]=1.41), traffic as not a problem (OR=.45; unexpected direction), and not many four-way intersections (OR=.72; unexpected direction) were significantly associated with sufficient PA. Low crime rate at night (OR=1.53), many interesting things to look at (OR=1.90), and seeing many people active (OR=.59; unexpected direction) were significantly associated with sufficient walking. Inconsistent patterns were also observed in gender-specific analyses. Few neighborhood environment correlates of PA or walking reported in the international literature were replicated with African young adults. Environmental measures need to be developed that are tailored to low- and middle-income countries, such as those in Africa, so that research in understudied regions can advance.


Optimizing Genomic-Enabled Prediction in Small-Scale Maize Hybrid Breeding Programs: A Roadmap Review.
The usefulness of genomic prediction (GP) for many animal and plant breeding programs has been highlighted for many studies in the last 20 years. In maize breeding programs, mostly dedicated to delivering more highly adapted and productive hybrids, this approach has been proved successful for both large- and small-scale breeding programs worldwide. Here, we present some of the strategies developed to improve the accuracy of GP in tropical maize, focusing on its use under low budget and small-scale conditions achieved for most of the hybrid breeding programs in developing countries. We highlight the most important outcomes obtained by the University of São Paulo (USP, Brazil) and how they can improve the accuracy of prediction in tropical maize hybrids. Our roadmap starts with the efforts for germplasm characterization, moving on to the practices for mating design, and the selection of the genotypes that are used to compose the training population in field phenotyping trials. Factors including population structure and the importance of non-additive effects (dominance and epistasis) controlling the desired trait are also outlined. Finally, we explain how the source of the molecular markers, environmental, and the modeling of genotype-environment interaction can affect the accuracy of GP. Results of 7 years of research in a public maize hybrid breeding program under tropical conditions are discussed, and with the great advances that have been made, we find that what is yet to come is exciting. The use of open-source software for the quality control of molecular markers, implementing GP, and envirotyping pipelines may reduce costs in an efficient computational manner. We conclude that exploring new models/tools using high-throughput phenotyping data along with large-scale envirotyping may bring more resolution and realism when predicting genotype performances. Despite the initial costs, mostly for genotyping, the GP platforms in combination with these other data sources can be a cost-effective approach for predicting the performance of maize hybrids for a large set of growing conditions.


Dynamic cerebral autoregulation in subjects with Alzheimer's disease, mild cognitive impairment, and controls: evidence for increased peripheral vascular resistance with possible predictive value.
Cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). We hypothesized that cerebral autoregulation is impaired in patients with AD compared to subjects with mild cognitive impairment (MCI) and controls. Dynamic cerebral autoregulation (dCA) was investigated in 17 AD patients, 19 MCI subjects, and 20 controls (C). Groups were matched for age, gender, and level of education. Electrocardiogram and non-invasive finger arterial blood pressure were measured and transcranial doppler ultrasonography was used to measure cerebral blood flow velocity in right and left middle cerebral artery (MCA). Cerebrovascular resistance index (CVRi) was also computed. dCA in supine position was quantified based on spontaneous blood pressure variations by computation of the linear transfer function between arterial blood pressure and MCA cerebral blood flow velocity. dCA gain and phase were evaluated for different frequency bands. Results were also evaluated using a 3-parameter windkessel model (WKM). CVRi was significantly higher in AD (2.9 ± 0.2) compared to both MCI (2.3 ± 0.1, p = 0.02) and C (2.1 ± 0.1 mmHgs/cm, p = 0.002). Five MCI patients who converted to AD during the course of the study also had higher CVRi compared to non-converters (2.8 ± 0.6 versus 2.1 ± 0.5 mmHgs/cm, p < 0.05). No significant differences in dCA gain and phase were found. In terms of the WKM approach, in the order C→MCI→AD groups showed about equal arterial resistance and peripheral compliance, but increased peripheral vasculature resistance (26 ± 2 versus 36 ± 3 mmHgs/ml in C resp. AD, p = 0.004). In conclusion, AD patients compared to MCI patients and controls have increased CVRi, whereas dCA parameters do not seem to differentiate AD patients. For MCI patients, CVRi might have predictive value in developing AD.


Combined Influence of B-Cell Receptor Rearrangement and Somatic Hypermutation on B-Cell Class-Switch Fate in Health and in Chronic Lymphocytic Leukemia.
A diverse B-cell receptor (BCR) repertoire is required to bind a wide range of antigens. BCRs are generated through genetic recombination and can be diversified through somatic hypermutation (SHM) or class-switch recombination (CSR). Patterns of repertoire diversity can vary substantially between different health conditions. We use isotype-resolved BCR sequencing to compare B-cell evolution and class-switch fate in healthy individuals and in patients with chronic lymphocytic leukemia (CLL). We show that the patterns of SHM and CSR in B-cells from healthy individuals are distinct from CLL. We identify distinct properties of clonal expansion that lead to the generation of antibodies of different classes in healthy, malignant, and non-malignant CLL BCR repertoires. We further demonstrate that BCR diversity is affected by relationships between antibody variable and constant regions leading to isotype-specific signatures of variable gene usage. This study provides powerful insights into the mechanisms underlying the evolution of the adaptive immune responses in health and their aberration during disease.


Timing of antibiotic administration, wound debridement, and the stages of reconstructive surgery for open long bone fractures of the upper and lower limbs.
Open fractures of the major long bones are complex limb-threatening injuries that are predisposed to deep infection. Treatment includes antibiotics and surgery to debride the wound, stabilise the fracture and reconstruct any soft tissue defect to enable infection-free bone repair. There is a need to assess the effect of timing and duration of antibiotic administration and timing and staging of surgical interventions to optimise outcomes. To assess the effects (risks and benefits) of the timing of antibiotic administration, wound debridement and the stages of surgical interventions in managing people with open long bone fractures of the upper and lower limbs. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trial registers in February 2021. We also searched conference proceedings and reference lists of included studies. We included randomised controlled trials (RCTs) or quasi-RCTs that recruited adults with open fractures of the major long bones, comparing: 1) timings of prophylactic antibiotic treatment, 2) duration of prophylactic antibiotic treatment, 3) timing of wound debridement following injury or 4) timing of the stages of reconstructive surgery. We used standard methodological procedures expected by Cochrane. We aimed to collect data for the following outcomes: limb function, health-related quality of life (HRQoL), deep surgical site infection, delayed or non-union, adverse events (in the short- and long-term course of recovery), and resource-related outcomes. We included three RCTs of 613 randomised participants with 617 open fractures. Studies were conducted in medical and trauma centres in the USA and Kenya. Where reported, there was a higher proportion of men and a mean age of participants between 30 and 34 years old. Fractures were in the upper and lower limbs in one study, and were tibia fractures in two studies; where reported, these were the result of high-energy trauma such as road traffic accidents. No studies compared the timing of antibiotic treatment or wound debridement. Duration of prophylactic antibiotic treatment (1 study, 77 participants available for analysis) One study compared antibiotic treatment for 24 hours with antibiotic treatment for five days. We are very uncertain about the effects of different durations of antibiotic treatment on superficial infections (risk ratio (RR) 1.19, 95% CI 0.49 to 2.87, favours 5 day treatment; 1 study, 77 participants); this was very low-certainty evidence derived from one small study with unclear and high risks of bias, and with an imprecise effect estimate. This study reported no other review outcomes. Reconstructive surgery: timing of the stages of surgery (2 studies, 458 participants available for analysis) Two studies compared the timing of wound closure, which was completed immediately or delayed. In one study, the mean time of delay was 5.9 days; in the other study, the time of delay was not reported. We are very uncertain about the effects of different timings of wound closure on deep infections (RR 0.82, 95% CI 0.37 to 1.80, favours immediate closure; 2 studies, 458 participants), delayed union or non-union (RR 1.13, 95% CI 0.83 to 1.55, favours delayed closure; 1 study, 387 participants), or superficial infections (RR 6.45, 95% CI 0.35 to 120.43, favours delayed closure; 1 study, 71 participants); this was very low-certainty evidence. We downgraded the certainty of the evidence for very serious risks of bias because both studies had unclear and high risks of bias. We also downgraded for serious imprecision because effect estimates were imprecise, including the possibility of benefits as well as harms, and very serious imprecision when the data were derived from single small study. These studies reported no other review outcomes. We could not determine the risks and benefits of different treatment protocols for open long bone fractures because the evidence was very uncertain for the two comparisons and we did not find any studies addressing the other possible comparisons. Well-designed randomised trials with adequate power are needed to guide surgical and antibiotic treatment of open fractures, particularly with regard to timing and duration of antibiotic administration and timing and staging of surgery.


Improvement in the outcome of invasive fusariosis in the last decade.
Invasive fusariosis (IF) has been associated with a poor prognosis. Although recent series have reported improved outcomes, the definition of optimal treatments remains controversial. The objective of this study was to evaluate changes in the outcome of IF. We retrospectively analysed 233 cases of IF from 11 countries, comparing demographics, clinical findings, treatment and outcome in two periods: 1985-2000 (period 1) and 2001-2011 (period 2). Most patients (92%) had haematological disease. Primary treatment with deoxycholate amphotericin B was more frequent in period 1 (63% vs. 30%, p <0.001), whereas voriconazole (32% vs. 2%, p <0.001) and combination therapies (18% vs. 1%, p <0.001) were more frequent in period 2. The 90-day probabilities of survival in periods 1 and 2 were 22% and 43%, respectively (p <0.001). In period 2, the 90-day probabilities of survival were 60% with voriconazole, 53% with a lipid formulation of amphotericin B, and 28% with deoxycholate amphotericin B (p 0.04). Variables associated with poor prognosis (death 90 days after the diagnosis of fusariosis) by multivariable analysis were: receipt of corticosteroids (hazard ratio (HR) 2.11, 95% CI 1.18-3.76, p 0.01), neutropenia at end of treatment (HR 2.70, 95% CI 1.57-4.65, p <0.001), and receipt of deoxycholate amphotericin B (HR 1.83, 95% CI 1.06-3.16, p 0.03). Treatment practices have changed over the last decade, with an increased use of voriconazole and combination therapies. There has been a 21% increase in survival rate in the last decade.


PR Interval Associated Genes, Atrial Remodeling and Rhythm Outcome of Catheter Ablation of Atrial Fibrillation-A Gene-Based Analysis of GWAS Data.
Background: PR interval prolongation has recently been shown to associate with advanced left atrial remodeling and atrial fibrillation (AF) recurrence after catheter ablation. While different genome-wide association studies (GWAS) have implicated 13 loci to associate with the PR interval as an AF endophenotype their subsequent associations with AF remodeling and response to catheter ablation are unknown. Here, we perform a gene-based analysis of GWAS data to test the hypothesis that PR interval candidate genes also associate with left atrial remodeling and arrhythmia recurrence following AF catheter ablation. Methods and Results: Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing AF catheter ablation were genotyped for ~1,000,000 SNPs. Gene-based association was investigated using VEGAS (versatile gene-based association study). Among the 13 candidate genes, SLC8A1, MEIS1, ITGA9, SCN5A, and SOX5 associated with the PR interval. Of those, ITGA9 and SOX5 were significantly associated with left atrial low voltage areas and left atrial diameter and subsequently with AF recurrence after radiofrequency catheter ablation. Conclusion: This study suggests contributions of ITGA9 and SOX5 to AF remodeling expressed as PR interval prolongation, low voltage areas and left atrial dilatation and subsequently to response to catheter ablation. Future and larger studies are necessary to replicate and apply these findings with the aim of designing AF pathophysiology-based multi-locus risk scores.


Iridium oxide nanotube electrodes for sensitive and prolonged intracellular measurement of action potentials.
Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive and large-scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes of a new geometry, namely nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow centre. We show that this nanotube geometry enhances cell-electrode coupling and results in larger signals than solid nanoelectrodes. The nanotube electrodes also afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the nanoelectrode performance can be significantly improved by optimizing the electrode geometry.


Social perceptions of the impacts of Colombo water supply projects.
The complexity of development activities, in which the interactions between various forces often mean that outcomes are unpredictable and unanticipated, highlights the importance of objective and comprehensive evaluations. In the specific case of the evaluation of towns east and south of Colombo water supply projects, the findings have major implications for the implementation of the Millennium Development Goals, if the water-related objectives are to be fulfilled. The study found that 30% of the households of these towns that are receiving clean, piped water are not using it for drinking. Instead, they are continuing to drink contaminated well water. Whereas it is considered that the main beneficiaries of water supply projects have been women and people who are sick, elderly, or disabled, the general perception is that the health conditions of the families have not improved with the provision of clean water (in fact, many claim that their health conditions have deteriorated). In spite of the higher cost of the supplied water, people are willing to pay for it as long as the supply is reliable.


Inflammatory effects of Edwardsiella ictaluri lipopolysaccharide modifications in catfish gut.
Bacterial lipopolysaccharides (LPS) are structural components of the outer membranes of Gram-negative bacteria and also are potent inducers of inflammation in mammals. Higher vertebrates are extremely sensitive to LPS, but lower vertebrates, like fish, are resistant to their systemic toxic effects. However, the effects of LPS on the fish intestinal mucosa remain unknown. Edwardsiella ictaluri is a primitive member of the Enterobacteriaceae family that causes enteric septicemia in channel catfish (Ictalurus punctatus). E. ictaluri infects and colonizes deep lymphoid tissues upon oral or immersion infection. Both gut and olfactory organs are the primary sites of invasion. At the systemic level, E. ictaluri pathogenesis is relatively well characterized, but our knowledge about E. ictaluri intestinal interaction is limited. Recently, we observed that E. ictaluri oligo-polysaccharide (O-PS) LPS mutants have differential effects on the intestinal epithelia of orally inoculated catfish. Here we evaluate the effects of E. ictaluri O-PS LPS mutants by using a novel catfish intestinal loop model and compare it to the rabbit ileal loop model inoculated with Salmonella enterica serovar Typhimurium LPS. We found evident differences in rabbit ileal loop and catfish ileal loop responses to E. ictaluri and S. Typhimurium LPS. We determined that catfish respond to E. ictaluri LPS but not to S. Typhimurium LPS. We also determined that E. ictaluri inhibits cytokine production and induces disruption of the intestinal fish epithelia in an O-PS-dependent fashion. The E. ictaluri wild type and ΔwibT LPS mutant caused intestinal tissue damage and inhibited proinflammatory cytokine synthesis, in contrast to E. ictaluri Δgne and Δugd LPS mutants. We concluded that the E. ictaluri O-PS subunits play a major role during pathogenesis, since they influence the recognition of the LPS by the intestinal mucosal immune system of the catfish. The LPS structure of E. ictaluri mutants is needed to understand the mechanism of interaction.


Carotid artery stenting in octogenarians: periprocedural stroke risk predictor analysis from the multicenter Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE 2) clinical trial.
Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE 2) is an ongoing prospective, nonrandomized, multicenter clinical trial enrolling patients undergoing carotid artery stenting. The aim of this analysis is to identify risk predictors for periprocedural stroke in patients > or = 80 years old. Symptomatic patients with > or = 50% stenosis and asymptomatic patients with > or = 80% stenosis were enrolled. Patients' neurological status was assessed by an independent neurologist before as well as 24 hours and 30 days postprocedure. All strokes and suspected strokes were adjudicated by an independent committee. Logistic regression analysis was conducted to identify baseline demographic, lesion, procedural, or comorbidity parameters associated with outcomes in patients > or = 80 years of age. As of January 10, 2009, 5297 patients underwent carotid artery stenting in 186 US CAPTURE 2 clinical centers and 1166 were > or = 80 years old. Octogenarians were similar to nonoctogenarians in terms of gender and symptomatic status but had fewer of certain risk factors (prior myocardial infarction or carotid endarterectomy, diabetes, smoking history) and more cardiac arrhythmia and renal insufficiency. For the overall cohort, death/stroke rate was 3.3%; stroke rate was 2.7% (0.8% major, 1.9% minor). Death/stroke rates were significantly higher for octogenarians than nonoctogenarians (4.5% versus 3.0%) as were stroke rates (3.8% versus 2.4%). Symptomatic status, embolic protection device dwell time, and lesion length were risk predictors for periprocedural stroke in octogenarians. Patients > or = 80 years old have higher periprocedural event rates than nonoctogenarians. Age, symptomatic status, and lesion length should be considered when identifying appropriate candidates for the procedure.


[Genetic analysis of predator aggressiveness in mice].
The character of inheritance of mouse predatory aggression towards crickets and locusts was investigated. The percentage of aggressive animals in the group and the latency of attack were indices of aggression. The hybridological analysis included obtaining reciprocal F1 and F2 hybrids and backcrosses of CBA and DD mice lines exhibiting polar parameters in predatory tests. Examination of hybrids and backcrosses showed that the high level of aggressiveness is dominant. Sex differences in aggression were seen neither in parent strains, nor in hybrids, reciprocal effects being also absent. The results of the hybridological analysis indicated that the predatory aggressions are under control of a small number of genes with a pronounced dominant effect. As a result of diallele analysis in three strains of mice, BALB/c, C57BL/6, DD and all combinations of first generation hybrids, it was found that almost all hybrids exhibited greater aggressiveness than that of parent strains or that it was similar to the indices of highly aggressive parents. Analysis of a strain combinative ability showed that the genotypic component is conditioned by a specific combinative ability, the influence of the total combinating ability and of the reciprocal effects being not significant. It was once more confirmed that the predatory aggression in mice is inherited as a high level dominancy of aggression and genes influencing its manifestation are localized in autosomes.


Reciprocal interactions between tumour cell populations enhance growth and reduce radiation sensitivity in prostate cancer.
Intratumoural heterogeneity (ITH) contributes to local recurrence following radiotherapy in prostate cancer. Recent studies also show that ecological interactions between heterogeneous tumour cell populations can lead to resistance in chemotherapy. Here, we evaluated whether interactions between heterogenous populations could impact growth and response to radiotherapy in prostate cancer. Using mixed 3D cultures of parental and radioresistant populations from two prostate cancer cell lines and a predator-prey mathematical model to investigate various types of ecological interactions, we show that reciprocal interactions between heterogeneous populations enhance overall growth and reduce radiation sensitivity. The type of interaction influences the time of regrowth after radiation, and, at the population level, alters the survival and cell cycle of each population without eliminating either one. These interactions can arise from oxygen constraints and from cellular cross-talk that alter the tumour microenvironment. These findings suggest that ecological-type interactions are important in radiation response and could be targeted to reduce local recurrence.


Biomarkers of browning of white adipose tissue and their regulation during exercise- and diet-induced weight loss.
A hypothesis exists whereby an exercise- or dietary-induced negative energy balance reduces human subcutaneous white adipose tissue (scWAT) mass through the formation of brown-like adipocyte (brite) cells. However, the validity of biomarkers of brite formation has not been robustly evaluated in humans, and clinical data that link brite formation and weight loss are sparse. We used rosiglitazone and primary adipocytes to stringently evaluate a set of biomarkers for brite formation and determined whether the expression of biomarker genes in scWAT could explain the change in body composition in response to exercise training combined with calorie restriction in obese and overweight women (n = 79). Gene expression was derived from exon DNA microarrays and preadipocytes from obesity-resistant and -sensitive mice treated with rosiglitazone to generate candidate brite biomarkers from a microarray. These biomarkers were evaluated against data derived from scWAT RNA from obese and overweight women before and after supervised exercise 5 d/wk for 16 wk combined with modest calorie restriction (∼0.84 MJ/d). Forty percent of commonly used brite gene biomarkers exhibited an exon or strain-specific regulation. No biomarkers were positively related to weight loss in human scWAT. Greater weight loss was significantly associated with less uncoupling protein 1 expression (P = 0.006, R(2) = 0.09). In a follow-up global analysis, there were 161 genes that covaried with weight loss that were linked to greater CCAAT/enhancer binding protein α activity (z = 2.0, P = 6.6 × 10(-7)), liver X receptor α/β agonism (z = 2.1, P = 2.8 × 10(-7)), and inhibition of leptin-like signaling (z = -2.6, P = 3.9 × 10(-5)). We identify a subset of robust RNA biomarkers for brite formation and show that calorie-restriction-mediated weight loss in women dynamically remodels scWAT to take on a more-white rather than a more-brown adipocyte phenotype.


Action research in action: reflections on a project to introduce Clinical Practice Facilitators to an acute hospital setting.
The process and philosophical basis of action research are discussed in this article by reviewing the insights that were gained from a study designed to enhance the support available to junior nursing staff in an acute hospital setting. It has been well documented that newly qualified nurses require help to develop professional competencies. With this in mind, the role of Clinical Practice Facilitator was established within a National Health Service (NHS) Trust to enhance clinical skill acquisition and the professional development of newly registered nurses and health care assistants. In order to facilitate the inception, development and subsequent evaluation of these new roles, an action research approach was adopted. Strategies used to encourage collaboration and flexibility during the project are also discussed. The primary aims of the project were achieved and the authors suggest that the choice of action research was significant to the successful outcome. However, a number of issues arose which deserve more attention including the importance of the interpersonal skills of the action researcher and the value of action research to facilitate change which is relevant at both an individual and organizational level.


What do the terms wellness and wellbeing mean in dietary practice: an exploratory qualitative study examining women's perceptions.
Wellness and wellbeing are terms associated with health within dietetic discourse. More broadly, these terms are found in social discourse as represented in food and nutrition consumer communications. With the increasing requirement for evidence-based healthcare, there is an imperative to understand whether these terms are meaningful to individuals typically targeted for nutrition interventions and whether there are any implications for dietetic education. To explore the understanding of these terms, eight semi-structured focus groups were conducted with 32 female participants (age range 23-79 years) who were actively engaged in managing their health. Overall understanding of the terms, factors that impacted perceptions and any relationships with food behaviour were investigated with the groups. Group discussions were transcribed verbatim and each transcript was examined by two researchers. Inductive analysis linking codes into main thematic categories was conducted using the constant comparison approach across the full data set. Wellness and wellbeing were identified as meaningful terms associated with health. A theoretical framework of wellness and wellbeing reflecting these meanings was developed linking four dominant thematic areas. These were Desired outcomes (most sought after result); Taking control (self management strategies); Internal influences (various personal inner factors influencing behaviours); and External influences (plethora of peripheral factors influencing behaviours). Wellness and wellbeing are terms that are relevant and aspirational for individuals typically targeted for nutrition intervention. A theoretical framework of dominant areas of influence on notions of wellness and wellbeing was identified. This theoretical framework is worthy of further research to determine usefulness and effectiveness in dietetic practice settings.


Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma.
Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacy is hampered by low tumor selectivity. To identify a potent and selective oncolytic virotherapy, we carried out large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non-small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of the viral receptors, coxsackievirus and adenovirus receptor, and decay-accelerating factor, on NSCLC cells. In vitro assays revealed that the CVB3 induced apoptosis and phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of preestablished NSCLC tumors in vivo. Furthermore, administrations of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well tolerated without treatment-related deaths. In addition, after CVB3 infection, NSCLC cells expressed abundant cell surface calreticulin and secreted ATP as well as translocated extranuclear high-mobility group box 1, which are required for immunogenic cell death. Moreover, intratumoral CVB3 administration markedly recruited natural killer cells and granulocytes, both of which contributed to the antitumor effects as shown by depletion assays, macrophages, and mature dendritic cells into tumor tissues. Together, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC.


Computational exploration of Fe55@C240-catalyzed Fischer-Tropsch synthesis.
Single-shell carbon-encapsulated iron nanoparticles (SCEINs), Fe@C, have been shown to be charge-transfer complexes that can act as effective catalysts in the hydrogen and oxygen evolution reactions. A new generation of Fe-based catalysts for Fischer-Tropsch synthesis (FTS) which resembles SCEINs, e.g. single carbide nanoparticles encapsulated in carbon shells, has demonstrated enhanced activity and stability for FTS as compared to other carbon-supported Fe-based FTS. Thus the catalytic ability of SCEINs for the water splitting reactions and the Fe-based FTS catalyst with SCEINs-like features stimulated our exploration of SCEINs-catalyzed FTS. We performed ab initio DFT calculations using a realistic SCEINs model system Fe55@C240 to investigate for the first time the adsorption of the main reactants in FTS (CO and H/H2) and further to evaluate the catalytic ability of Fe55@C240 by reproducing the key steps of the well-known Fe-based FTS mechanisms (carbide, enol and CO insertion). Our calculations revealed: (i) a determinant role of Fe in enhancing CO adsorption (ii) strong cooperative effects with the adsorbates that stabilize the binding (iii) a less favourable two-sites reaction on Fe55@C240 due to preferential positions of the reactants farther to each other which prevent enol and carbide FTS mechanisms. We propose therefore a possible CO insertion path for hydrocarbon growth on Fe55@C240.


Psychometric properties of the Swedish version of the Purpose in Life scale.
The aim of this study was to test the theoretical assumptions beyond the Purpose in Life (PIL) scale, and to elucidate the underlying structure of the Swedish version of the PIL. The PIL, originally created by Crumbaugh and Maholick, is a 20-item scale of the Lickert type with possible scores ranges from 20 to 140, the higher score, the stronger PIL. The analysis was based on 449 participants, 62% of whom were women, from five different samples, ranging from 19 to 103 years old. An exploratory factor analysis restricted to three factors was performed. The factors were labelled meaning in existence, freedom to create meaning in daily life, and will to find meaning in future challenges. These factors reflected the three dimensions described by Frankl. Cronbach's alpha coefficient for the total scale was 0.83 and varied between 0.54 and 0.83 in the three factors. We concluded that the Swedish version of the PIL scale seems to have construct validity and reliability. Our results give support to the fact that the PIL scale captures and confirms the theoretical assumptions of Frankl's existential theory. We consider the PIL scale to be both feasible and appropriate for use in nursing research.


The influence of hydrogen bonds on NIAD-4 for use in the optical imaging of amyloid fibrils.
The fast and accurate detection of amyloid fibrils, which are associated with many neurodegenerative diseases, is important for their early diagnosis. {[50-(p-Hydroxyphenyl)-2,20-bithienyl-5-yl]-methylidene}-propanedinitrile (NIAD-4) is a new promising fluorescent marker for amyloid fibrils, and the photophysical behaviour of NIAD-4 is controversial. Nonadiabatic dynamic simulations, density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations were performed to determine the influence of the environment on NIAD-4 and the photophysical behaviour of NIAD-4. The results indicate that NIAD-4 is in the NIAD-4·3H2O compound form in the ground state in water. The torsion process of NIAD-4 proposed by Hu et al. (Phys. Chem. Chem. Phys. 2016, 18, 28) does not occur in the excited state. In addition, the fluorescence behaviour of NIAD-4 is sensitive to a hydrogen bonding environment, the maximum fluorescence wavelengths of NIAD-4 show considerable red-shifts, and the fluorescence intensity of NIAD-4 increases significantly in a hydrogen bonding environment. Intermolecular hydrogen bonds are vital for the phenomenon observed in the experiment because the fluorescence intensity of NIAD-4 becomes unusually high with increasing solvent polarities. Therefore, the influence of the intermolecular hydrogen bond should be carefully taken into consideration when NIAD-4 is used to probe the amyloid fibrils in hydrogen-bonding surroundings, especially in complex bioenvironments.


Evaluation of various filling techniques in distal canals of mandibular molars instrumented with different single-file nickel-titanium systems.
The aim of this study was to evaluate the quality of various filling techniques in distal canals of mandibular molars instrumented with different single-file nickel-titanium (NiTi) systems. A total of 150 distal roots of mandibular molar teeth were randomly assigned into three main groups and instrumented by using Reciproc (VDW, Munich, Germany), WaveOne (Dentsply Tulsa, Tulsa, OK, USA), or One Shape (MicroMega, Besancon, France) NiTi file systems. The roots were then treated using one of five filling techniques: (1) Matched-single-cone, (2) cold lateral compaction with matched gutta-percha (GP) cone, (3) Thermafil filling, (4) System B/Obtura II, and (5) lateral compaction with standardized GP cones. The roots were then sectioned at three levels (coronal, middle, and apical). Photographs were acquired under a stereomicroscope, and the percentage of GP-filled areas (PGFAs), percentage of sealer-filled areas (PSFAs), and voids were measured using the ImageJ software. Comparisons between groups were applied using Student's t-test or one-way ANOVA for normally distributed data. The Mann-Whitney U-test or Kruskal-Wallis test was used when variables were not normally distributed. Canals filled with the System B/Obtura showed the highest PGFA and lowest PSFA, whereas those filled with matched-single-cone showed the highest PSFA and lowest PGFA (P < 0.05). The cold lateral compaction with matched GP cone group, lateral compaction group, and Thermafil filling group showed no statistically significant differences in PSFA and PGFA (P > 0.05). System B/Obtura technique appears to be the best technique to properly fill root canals, whereas the matched-single-cone technique in oval-shaped distal canals of mandibular molars was inadequate.


Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues.
To generate a molecular description of synovial tissue from rheumatoid arthritis (RA) patients that would allow us to unravel novel aspects of pathogenesis and to identify different forms of disease. We applied complementary DNA microarray analysis to profile gene expression, with a focus on immune-related genes, in affected joint tissues from RA patients and in tissues from osteoarthritis (OA) patients as a control. To validate microarray data, real-time polymerase chain reaction was performed on genes of interest. The gene expression signatures of synovial tissues from RA patients showed considerable variability, resulting in the identification of at least two molecularly distinct forms of RA tissues. One class of tissues revealed abundant expression of clusters of genes indicative of an involvement of the adaptive immune response. Detailed analysis of the expression profile provided evidence for a prominent role of an activated signal transducer and activator of transcription 1 pathway in these tissues. The expression profiles of another group of RA tissues revealed an increased tissue remodeling activity and a low inflammatory gene expression signature. The gene expression pattern in the latter tissues was reminiscent of that observed in the majority of OA tissues. The differences in the gene expression profiles provide a unique perspective for distinguishing different pathogenetic RA subsets based on molecular criteria. These data reflect important aspects of molecular variation that are relevant for understanding the biologic dysregulation underlying these subsets of RA. This approach may also help to define homogeneous groups for clinical studies and evaluation of targeted therapies.


Ethics review in compassionate use.
Compassionate use is the use of unapproved drugs outside of clinical trials. So far, compassionate use regulations have been introduced in the US, Canada, many European countries, Australia and Brazil, and treatment on a compassionate use basis may be performed in Japan and China. However, there are important differences between relevant regulations in individual countries, particularly that approval by a research ethics committee (institutional review board) is a requirement for compassionate use in some countries (e.g. the US, Spain, and Italy), but not in others (e.g. Canada, the UK, France, and Germany). The main objective of this article is to present aspects of compassionate use that are important for the discussion of the role of research ethics committees in the review of compassionate use. These aspects include the nature of compassionate use, potential risks to patients associated with the use of drugs with unproven safety and efficacy, informed consent, physicians' qualifications, and patient selection criteria. Our analysis indicates that the arguments for mandatory review substantially outweigh the arguments to the contrary. Approval by a research ethics committee should be obligatory for compassionate use. The principal argument against mandatory ethical review of compassionate use is that it is primarily a kind of treatment rather than biomedical research. Nonetheless, compassionate use is different from standard clinical care and should be subject to review by research ethics committees. First, in practice, compassionate use often involves significant research aspects. Second, it is based on unapproved drugs with unproven safety and efficacy. Obtaining informed consent from patients seeking access to unapproved drugs on a compassionate use basis may also be difficult. Other important problems include the qualifications of the physician who is to perform treatment, and patient selection criteria.


Mutations Associated with Resistance-Breaking Isolates of Beet necrotic yellow vein virus and Their Allelic Discrimination Using TaqMan Technology.
ABSTRACT Genetic resistance in sugar beet (Beta vulgaris) to Beet necrotic yellow vein virus (BNYVV), which causes the disease rhizomania, is conferred by the single dominant gene Rz1. However, since 2002, Rz1 cultivars grown in the Imperial Valley of California have been increasingly damaged by a new strain of BNYVV. Viral RNA 3 was extracted from asymptomatic and symptomatic sugar beets and, after amplification and sequencing of a region including the p25 cistron, two polymorphic sites, A67V and D135E, associated with the capability of the virus to overcome resistance were identified. Using the real-time reverse transcription-polymerase chain reaction allelic discrimination technique, TaqMan probes designed to detect the responsible nucleotide substitutions permitted the differentiation between wild type (WT) and resistance-breaking (RB) isolates. This method also allowed easy detection of mixed infections by giving a heterozygous call, which was verified by DNA sequencing of individual clones. The capability of this technology to typify numerous isolates facilitated the analysis of the spatial distribution of virus haplotypes in the field. Thus, RB variants were mostly baited from yellow strips with high incidence of rhizomania, whereas WT variants predominated in the surrounding green areas. Mixed infections were found mainly in green areas and transitional zones. The predominance of the RB isolates in yellow strips suggests that they have gained fitness in Rz1 cultivars and will eventually become the dominant haplotype.


Enhanced recognition of human NK receptors after influenza virus infection.
The NK cell cytotoxic activity is regulated by both inhibitory and activating NK receptors. Thus, changes in the expression levels and in the affinity or avidity of those receptors will have a major effect on the killing of target cells. In this study, we demonstrate that the binding of NK-inhibitory receptors is enhanced after influenza virus infection. Surprisingly, however, no change in the level of class I MHC protein expression was observed on the surface of the infected cells. The increased binding was general, because it was observed in both the killer cell Ig-like receptor 2 domain long tail 1 and leukocyte Ig-like receptor-1. The increased binding was functional, was not dependent on the interaction with viral hemagglutinin-neuraminidase, was not dependent on the glycosylation site, and was not abolished after mutating the transmembrane or cytosolic portions of the class I MHC proteins. Confocal microscopy experiments showed increased binding of NK receptor-coated beads to infected cells expressing the appropriate class I MHC proteins. In addition, specific cell-free bead aggregates covered with class I MHC proteins were observed only in infected cells. We therefore suggest that the influenza virus use a novel mechanism for the inhibition of NK cell activity. This mechanism probably involves the generation of class I MHC complexes in infected cells that cause increased recognition of NK receptors.


Human T-lymphotropic virus type 1 oncoprotein tax promotes S-phase entry but blocks mitosis.
Human T-lymphotropic virus type 1 (HTLV-1) Tax exerts pleiotropic effects on multiple cellular regulatory processes to bring about NF-kappaB activation, aberrant cell cycle progression, and cell transformation. Here we report that Tax stimulates cellular G(1)/S entry but blocks mitosis. Tax expression in naive cells transduced with a retroviral vector, pBabe-Tax, leads to a significant increase in the number of cells in the S phase, with an accompanying rise in the population of cells with a DNA content of 4N or more. In all cell types tested, including BHK-21, mouse NIH 3T3, and human diploid fibroblast WI-38, Tax causes an uncoupling of DNA synthesis from cell division, resulting in the formation of multinucleated giant cells and cells with decondensed, highly convoluted and lobulated nuclei that are reminiscent of the large lymphocytes with cleaved or cerebriform nuclei seen in HTLV-1-positive individuals. This contrasts with the Tax-transformed cell lines, PX1 (fibroblast) and MT4 (lymphocyte), which produce Tax at high levels, but without the accompanying late-stage cell cycle abnormalities. PX1 and MT4 may have been selected to harbor somatic mutations that allow a bypass of the Tax-induced block in mitosis.


Aversive Behavior in the Nematode C. elegans Is Modulated by cGMP and a Neuronal Gap Junction Network.
All animals rely on their ability to sense and respond to their environment to survive. However, the suitability of a behavioral response is context-dependent, and must reflect both an animal's life history and its present internal state. Based on the integration of these variables, an animal's needs can be prioritized to optimize survival strategies. Nociceptive sensory systems detect harmful stimuli and allow for the initiation of protective behavioral responses. The polymodal ASH sensory neurons are the primary nociceptors in C. elegans. We show here that the guanylyl cyclase ODR-1 functions non-cell-autonomously to downregulate ASH-mediated aversive behaviors and that ectopic cGMP generation in ASH is sufficient to dampen ASH sensitivity. We define a gap junction neural network that regulates nociception and propose that decentralized regulation of ASH signaling can allow for rapid correlation between an animal's internal state and its behavioral output, lending modulatory flexibility to this hard-wired nociceptive neural circuit.


An fMRI Study of Responses to Sexual Stimuli as a Function of Gender and Sensation Seeking: A Preliminary Analysis.
Although sexual cues produce stronger neural activation in men than in women, mechanisms underlying this differential response are unclear. We examined the relationship of sensation seeking and the brain's response to sexual stimuli across gender in 27 subjects (14 men, M = 25.2 years, SD = 3.6, 85.2% Caucasian) who underwent functional magnetic resonance imaging (fMRI) while viewing sexual and nonsexual images. Whole-brain corrected significant clusters of regional activation were extracted and associated with gender, sensation seeking, and sexual behaviors. Men responded more to sexual than nonsexual images in the anterior cingulate/medial prefrontal cortex (ACC/mPFC), anterior insula/lateral orbitofrontal cortex, bilateral amygdala, and occipital regions. Sensation seeking related positively to ACC/mPFC (r = 0.65, p = 0.01) and left amygdala (r = 0.66, p = 0.01) response in men alone, with both of these correlations being significantly larger in men than in women (ps < 0.03). The relationship between brain responses and self-reported high-risk and low-risk sexual behaviors showed interesting, albeit nonsignificant, gender-specific trends. These findings suggest the relationship between sexual responsivity, sensation seeking, and sexual behavior is gender specific. This study indicates a need to identify the gender-specific mechanisms that underlie sexual responsivity and behaviors. In addition, it demonstrates that the nature of stimuli used to induce positive mood in imaging and other studies should be carefully considered.


Bone mass effects of a BMP4 gene polymorphism in postmenopausal women.
The pathogenesis of osteoporosis involves both genetic and environmental factors. On the basis of linkage data suggesting gene effects on bone density at chromosome 14q and data locating the BMP4 gene to 14q, we performed a positional candidate study to examine a possible association of BMP4 gene polymorphisms, hip bone density (n = 1012) and fracture rates (n = 1232) in postmenopausal women (mean age 75). On genotype analysis of the three selected single nucleotide polymorphisms (SNP), the 6007C > T polymorphism was associated with total and intertrochanteric hip BMD and BMD was lower in the 32% of subjects homozygous for the C allele. This polymorphism codes for a nonsynonymous amino acid change with the T allele coding for valine, while the C allele codes for alanine. The difference in BMD was 3.1% (TT vs. CC) and 2.3% (CT versus CC) for the total hip (P = 0.023), and 3.7% (TT vs. CC) and 2.8% (CT versus CC) for the intertrochanter site (P = 0.012). Haplotype analysis demonstrated 6 haplotypes of frequency greater than 2%. A major haplotype defined by G-C-T alleles in SNPs -5826G > A, 3564C > T and 6007C > T respectively, showed association with high bone mass. No SNP showed association with fracture rates. We conclude that a polymorphism found in the BMP4 gene, affecting amino acid sequence, is associated with hip bone density in postmenopausal women, presumably via regulation of anabolic effects on the skeleton.


What factors determine disclosure of suicide ideation in adults 60 and older to a treatment provider?
Correlates of patient disclosure of suicide ideation to a primary care or mental health provider were identified. Secondary analyses of IMPACT trial data were conducted. Of the 107 patients 60 years of age or older who endorsed thoughts of ending their life at least "a little bit" during the past month, 53 indicated they had disclosed these thoughts to a mental health or primary care provider during this period. Multiple logistic regression was used to identify predictors of disclosure to a provider. Significant predictors included poorer quality of life and prior mental health specialty treatment. Among participants endorsing thoughts of suicide, the likelihood of disclosing these thoughts to a provider was 2.96 times higher if they had a prior history of mental health specialty treatment and 1.56 times higher for every one-unit decrease in quality of life. Variation in disclosure of thoughts of suicide to a mental health or primary care provider depends, in part, on patient characteristics. Although the provision of evidence-based suicide risk assessment and guidelines could minimize unwanted variation and enhance disclosure, efforts to routinize the process of suicide risk assessment should also consider effective ways to lessen potential unintended consequences.


Identification of ApoA1, HPX and POTEE genes by omic analysis in breast cancer.
Breast cancer is the most common cancer among women and accounts for 23% of all female types of cancers. It is well recognized that breast cancer represents a heterogeneous group of tumors, and the molecular events involved in the progression to cancer remain undetermined. Moreover, available prognostic and predictive markers are not sufficient for the accurate determination of the risk for many breast cancer patients. Thus, it is necessary to discover new molecular markers for accurate prediction of clinical outcome and individualized therapy. In the present study, we performed omics-based whole-genome trancriptomic and whole proteomic profiling with network and pathway analyses of breast tumors to identify gene expression patterns related to clinical outcome. A total of 20 samples from tumors and 14 normal appearing breast tissues were analyzed using both gene expression microarrays and LC-MS/MS. We identified 585 downregulated and 413 upregulated genes by gene expression microarrays. Among these genes, HPX, POTEE and ApoA1 were the most significant genes correlated with the proteomic profile. Our data revealed that these identified genes are closely related to breast cancer and may be involved in robust detection of disease progression.


Psychometric properties of the Danish versions of headache-specific locus of control scale and headache management self-efficacy scale.
The purpose of the study is to test the cross-cultural adaptation and psychometric properties of a Danish version of the Headache-Specific Locus of Control Scale (HSLC) and the Headache Management Self-Efficacy Scale (HMSE) in a tertiary headache centre. HSLC and HMSE are headache-specific measures of locus of control (LOC) and SE. The Danish versions of the HSLC and the HMSE were created according to the guidelines for cross-cultural adaptation of self-report measures. The HSLC and HMSE were administered to 135 consecutively referred headache patients in a tertiary headache centre together with other self-report measures concerning general distress, anxiety, depression, and health-related quality of life. Internal stability of the HSLC subscales and the HMSE were analysed using Chronbach's alpha coefficient. The psychometric properties of the Danish version of the HSLC and the HMSE were analysed using Spearman's rank correlation test. Cronbach's alpha ranged from 0.71 to 0.88 and the corrected item-total correlations were acceptable. The mean corrected item-total correlations for the three subscales of HSLC (health-care LOC, internal LOC, and chance LOC) were 0.40, 0.59, and 0.40 respectively. The mean corrected item-total correlation for HMSE was 0.42. High HMSE scores were found to be associated with high scores on internal LOC and low scores on chance LOC. High scores on chance LOC were positively associated with low scores on social functioning independently of headache frequency. The results are consistent with the earlier findings of the original American versions of HMSE and HSLC. These scales seem to be valid and valuable tools for testing of psychological aspects related to level of functioning and quality of life for headache patients across different cultures of Western society. The HMSE and the HSLC proved valuable in clinical headache research. Since scores on HSLC and HMSE were associated with measures of physical and social functioning the HSLC and HMSE may be of particular interest for intervention studies aimed at enhancing level of functioning for headache patients.


The relationship between charge movements associated with ICa and INa-Ca in cardiac myocytes.
Ventricular myocytes exhibit a nifedipine-sensitive inward calcium current (ICa) and contracture when they are voltage clamped from -40 to 0 millivolt in the presence of caffeine and in the absence of extracellular sodium. However, upon repolarization they fail to relax because neither the sarcoplasmic reticulum nor the sodium-calcium exchange can reduce intracellular calcium. Sudden application of extracellular sodium during the contracture (but after repolarization) causes immediate relaxation and activates a transient inward sodium-calcium exchange current (INa-Ca), whose peak slightly precedes mechanical relaxation. The total charge carried by the nifedipine-sensitive ICa is twice the total charge carried by the transient inward INa-Ca. Assuming an exchange stoichiometry of three sodium to one calcium, these results indicate that all the calcium entering the cell during the initial depolarization is extruded by the sodium-calcium exchange.


Optimised frequency modulation for continuous-wave optical magnetic resonance sensing using nitrogen-vacancy ensembles.
Magnetometers based on ensembles of nitrogen-vacancy centres are a promising platform for continuously sensing static and low-frequency magnetic fields. Their combination with phase-sensitive (lock-in) detection creates a highly versatile sensor with a sensitivity that is proportional to the derivative of the optical magnetic resonance lock-in spectrum, which is in turn dependant on the lock-in modulation parameters. Here we study the dependence of the lock-in spectral slope on the modulation of the spin-driving microwave field. Given the presence of the intrinsic nitrogen hyperfine spin transitions, we experimentally show that when the ratio between the hyperfine linewidth and their separation is ≳ 1/4, square-wave based frequency modulation generates the steepest slope at modulation depths exceeding the separation of the hyperfine lines, compared to sine-wave based modulation. We formulate a model for calculating lock-in spectra which shows excellent agreement with our experiments, and which shows that an optimum slope is achieved when the linewidth/separation ratio is ≲ 1/4 and the modulation depth is less then the resonance linewidth, irrespective of the modulation function used.


Acute respiratory distress syndrome criteria in trauma patients: why the definitions do not work.
The international consensus definitions for acute respiratory distress syndrome (ARDS) have formed the basis for recruitment into randomized, controlled trials and, more recently, standardized the protocols for ventilatory treatment of acute lung injury. Although possibly appropriate for sepsis-induced ARDS, these criteria may not be appropriate for posttraumatic ARDS if the disease patterns are widely divergent. This study tests the hypothesis that standard ARDS criteria applied to the trauma population will capture widely disparate forms of acute lung injury and are too nonspecific to identify a population at risk for prolonged respiratory failure and associated complications. Patients with and Injury Severity Score > or = 16 ventilated for > 12 hours were prospectively enrolled. Clinical data, including elements of cardiovascular, renal, hepatic, hematologic, neurologic, and pulmonary function, were collected daily. Two hundred fifty-four patients were enrolled over a 36-month period, of whom 70 met the consensus definitions of ARDS. Patients from whom support was withdrawn within 48 hours were excluded. The remaining 61 patients were stratified into two groups on the basis of intubation (n = 12) days. There was considerable disparity in severity and clinical course. A mild, limited form of ARDS was characterized by earlier onset (group 1, 2 days; group 2, 4 days; p = 0.002), fewer intubation days (7 days vs. 28 days; p < 0.001), and less severe derangements in lung mechanics. A significant difference between the two groups was also seen in systemic inflammatory response syndrome score, incidence of sepsis, and incidence of multiple organ failure. The criteria for ARDS, when applied to the trauma population, capture a widely disparate group and has poor specificity for identifying patients at risk. Recruitment of trauma patients for ARDS studies or preemptive ventilatory management based solely on these criteria may be ill-advised.


Applications of micromixing technology.
This review presents an application of micromixer technologies, which have driven a number of critical research trends over the past few decades, particularly for chemical and biological fields. Micromixer technologies in this review are categorized according to their applications: (1) chemical applications, including chemical synthesis, polymerization, and extraction; (2) biological applications, including DNA analysis, biological screening enzyme assays, protein folding; and (3) detection/analysis of chemical or biochemical content combined with NMR, FTIR, or Raman spectroscopies. In the chemical application, crystallization, extraction, polymerization, and organic synthesis have been reported, not only for laboratory studies, but also for industrial applications. Microscale techniques are used in chemical synthesis to develop microreactors. In clinical medicine and biological studies, microfluidic systems have been widely applied to the identification of biochemical products, diagnosis, drug discovery, and investigation of disease symptoms. The biological and biochemical applications also include enzyme assays, biological screening assays, cell lysis, protein folding, and biological analytical assays. Nondestructive analytical/detection methods have yielded a number of benefits to chemical and biochemical processes. In this chapter, we introduce analytical methods those are frequently integrated into micromixing technologies, such as NMR, FT-IR, and Raman spectroscopies. From the study of micromixers, we discovered that the Re number and mixing time depends on the specific application, and we clustered micromixers in various applications according to the Re number and mixing performance (mixing time). We expect that this clustering will be helpful in designing of micromixers for specific applications.


Plasmodium falciparum in Kenya: high prevalence of drug-resistance-associated polymorphisms in hospital admissions with severe malaria in an epidemic area.
During an epidemic of Plasmodium falciparum malaria in Chogoria, Kenya, P. falciparum DNA was collected from 24 cases of severe malaria admitted to hospital for parenteral quinine treatment. These patients had all failed first- (chloroquine) and second-line (sulfadoxine-pyrimethamine or amodiaquine) drug treatments. Twenty-two (92%) of the 24 patients sampled carried parasites with the (Asn)86(Tyr) point mutation in the pfmdr1 gene (chromosome 5), 20 (83%) had an (Asp)1246(Tyr) mutation and 18 (82%) had both of these mutations. These alleles are both reported to be associated with chloroquine-resistance. Polymorphisms in the cg2 gene (chromosome 7) are also associated with chloroquine resistance, and 18 (75%) of the 24 parasite samples each had the cg2 and pfmdr1 polymorphisms. These 18 samples also had the mutations associated with resistance to pyrimethamine and sulfadoxine: (Asn)51(Ile), (Cys)59(Arg) and (Ser)108(Asn) of gene dhfr (chromosome 4) and (Ala)437(Gly) and (Lys)540(Glu) of dhps (chromosome 8), respectively. Genotyping of the parasites from all 24 patients revealed extensive diversity in the sequences for the merozoite surface antigens (MSA-1 and MSA-2) and the glutamate-rich protein (GLURP) and indicated that each sample contained more than one parasite clone. Although samples from non-admitted malaria cases were not available, it appears that drug resistance may have played an important role in the development of severe malaria in this epidemic.


Sequence-specific DNA binding by the MspI DNA methyltransferase.
The MspI methyltransferase (M.MspI) recognizes the sequence CCGG and catalyzes the formation of 5-methylcytosine at the fist C-residue. We have investigated the sequence-specific DNA-binding properties of M.MspI under equilibrium conditions, using gel-mobility shift assays and DNasel footprinting. M.MspI binds to DNA in a sequence-specific manner either alone or in the presence of the normal methyl donor S-adenosyl-L-methionine as well as the analogues, sinefungin and S-adenosyl-L-homocysteine. In the presence of S-adenosyl-L-homocysteine, M.MspI shows the highest binding affinity to DNA containing a hemimethylated recognition sequence (Kd = 3.6 x 10(-7) M), but binds less well to unmethylated DNA (Kd = 8.3 x 10(-7) M). Surprisingly it shows specific, although poor, binding to fully methylated DNA (Kd = 4.2 x 10(-6) M). M.MspI binds approximately 5-fold more tightly to DNA containing its recognition sequence, CCGG, than to nonspecific sequences in the absence of cofactors. In the presence of S-adenosyl-L-methionine, S-adenosyl-L-homocysteine or sinefungin the discrimination between specific and non-specific sequences increases up to 100-fold. DNasel footprinting studies indicate that 16 base pairs of DNA are covered by M.MspI, with the recognition sequence CCGG located asymmetrically within the footprint.


Editorial.
In November 2016, during a workshop organised by the Robert Koch Institute together with the Federal Centre for Health Education, we presented and discussed activities and models surrounding prevention reporting with health reporting representatives from the federal states. The motive for the event was the prevention report, which the National Prevention Conference will prepare every four years beginning in 2019 in order to document, monitor and evaluate its activities. The workshop revealed the desire of stakeholders to discuss survey methods and indicators and harmonise the different reporting systems in the long-term.


Leveling the Landscape: Landscape Performance as a Green Infrastructure Evaluation Tool for Service-Learning Products.
As part of the ongoing recovery from catastrophic flooding associated with Hurricanes Harvey and Florence, communities along the U.S. Atlantic and Gulf Coasts must plan for adaptations that integrate resilience into the redevelopment of community spaces. In designing resilient community spaces, particular consideration must be paid to socially vulnerable communities. Community visioning and neighborhood-scaled design is the first step in the development process. However, it can be a hurdle for communities that lack the capacity to conduct and evaluate such work collaboratively. Service-learning projects implemented through university-community partnerships can help communities increase resilience by developing master plans. The products generated through service-learning projects often conclude at the conceptual level, with no evaluation of the feasibility of their implementation. This study examines the use of landscape performance models in evaluating proposed master plan parameters. It is situated in Manchester, a community in Houston that is physically and socially vulnerable to flooding. Findings demonstrate that landscape performance models can objectively evaluate the costs and performance measures of service-learning products rooted in local conditions and community feedback.


The intellectual structure and substance of the knowledge utilization field: a longitudinal author co-citation analysis, 1945 to 2004.
It has been argued that science and society are in the midst of a far-reaching renegotiation of the social contract between science and society, with society becoming a far more active partner in the creation of knowledge. On the one hand, new forms of knowledge production are emerging, and on the other, both science and society are experiencing a rapid acceleration in new forms of knowledge utilization. Concomitantly since the Second World War, the science underpinning the knowledge utilization field has had exponential growth. Few in-depth examinations of this field exist, and no comprehensive analyses have used bibliometric methods. Using bibliometric analysis, specifically first author co-citation analysis, our group undertook a domain analysis of the knowledge utilization field, tracing its historical development between 1945 and 2004. Our purposes were to map the historical development of knowledge utilization as a field, and to identify the changing intellectual structure of its scientific domains. We analyzed more than 5,000 articles using citation data drawn from the Web of Science. Search terms were combinations of knowledge, research, evidence, guidelines, ideas, science, innovation, technology, information theory and use, utilization, and uptake. We provide an overview of the intellectual structure and how it changed over six decades. The field does not become large enough to represent with a co-citation map until the mid-1960s. Our findings demonstrate vigorous growth from the mid-1960s through 2004, as well as the emergence of specialized domains reflecting distinct collectives of intellectual activity and thought. Until the mid-1980s, the major domains were focused on innovation diffusion, technology transfer, and knowledge utilization. Beginning slowly in the mid-1980s and then growing rapidly, a fourth scientific domain, evidence-based medicine, emerged. The field is dominated in all decades by one individual, Everett Rogers, and by one paradigm, innovation diffusion. We conclude that the received view that social science disciplines are in a state where no accepted set of principles or theories guide research (i.e., that they are pre-paradigmatic) could not be supported for this field. Second, we document the emergence of a new domain within the knowledge utilization field, evidence-based medicine. Third, we conclude that Everett Rogers was the dominant figure in the field and, until the emergence of evidence-based medicine, his representation of the general diffusion model was the dominant paradigm in the field.


Hematological abnormalities in severe anorexia nervosa.
Little is known about the prevalence of hematologic abnormalities in adults with severe anorexia nervosa. We report the first major analysis of hematologic dysfunction in such patients. We retrospectively analyzed the charts of 53 men and women with severe anorexia nervosa, admitted between October 2008 and December 2010 for medical stabilization to our center, which has a national referral base. Patients were predominantly female (89 %), with a median age of 28 years (range 17-65), and were hospitalized for a median duration of 15 days (I.Q.R. 9-29). Nadir body mass index during hospitalization was markedly low at 12.4 kg/m(2) (range 8.4-15.7), and the mean discharge BMI was 13.8 kg/m(2) (range 10.2-16.8). 83 % of patients were anemic (hematocrit <37 %), with only 3 (6 %) having iron deficiency. 79 % were leukopenic (WBC < 4.5 k/μL), 29 % were neutropenic (ANC < 1.0 k/μL), 25 % were thrombocytopenic (platelets < 150 k/μL), and 17 % of patients developed thrombocytosis (platelets > 400 k/μL) during their hospitalization. Eighty-nine percent of patients had resolved their neutropenia by discharge. Marked hematologic deficiencies are often present in patients with severe anorexia nervosa, generally attributed to starvation-mediated gelatinous marrow transformation which resolves with proper nutritional rehabilitation. Improved provider awareness of this association may reduce unnecessary testing and costly treatment interventions.


gamma-Aminobutyric acid receptor-mediated regulation of periventricular-hypophysial dopaminergic neurons: possible role in mediating stress- and 5-hydroxytryptamine-induced decreases in neuronal activity.
The present study examined the effects of gamma-aminobutyric acid (GABA) agonists and antagonists on basal periventricular-hypophysial dopaminergic (PHDA) neuronal activity with a focus on the role of endogenous GABA in mediating 5-hydroxytryptamine- and stress-induced decreases in PHDA neuronal activity. PHDA neuronal activity was estimated by measuring concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in terminals of these neurons in the intermediate lobe of the pituitary. Plasma concentrations of alpha-melanocyte-stimulating hormone (alpha MSH) also were determined to provide a further index of PHDA neuronal activity. Administration of the GABAB agonist baclofen, but not the GABAA agonist isoguvacine, produced dose- and time-related decreases in intermediate lobe DOPAC concentrations and corresponding increases in plasma alpha MSH concentrations. Administration of either the GABAA antagonist SR-95,531 [2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)-pyridazinium bromide] or GABAB antagonists 2-hydroxysaclofen and CGP-35,348 [P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid; SR-95-531 did not alter basal intermediate lobe DOPAC concentrations or plasma alpha MSH concentrations per se, indicating that endogenous GABA does not tonically inhibit PHDA neuronal activity or alpha MSH secretion. 2-Hydroxysaclofen and CGP-35,348 did, however, reverse the baclofen-induced decrease in intermediate lobe DOPAC concentrations and increase in plasma alpha MSH concentrations. In a similar fashion, 2-hydroxysaclofen blocked the inhibitory effects of stress and the 5-hydroxytryptamine2/1c receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane] on PHDA neuronal activity. These results indicate that GABAB and not GABAA receptor activation inhibits basal PHDA neuronal activity, and that GABAB receptor activation mediates the inhibitory effects of 5-hydroxytryptamine and stress on PHDA neurons.


Citalopram for Acute and Preventive Efficacy in Bipolar Depression (CAPE-BD): A Randomized, Double-Blind, Placebo-Controlled Trial.
To assess the efficacy and safety of citalopram in the acute and maintenance phases of bipolar depression in a randomized, double-blind, placebo-controlled trial. Between 2007 and 2014, 119 subjects with acute major depressive episodes diagnosed with DSM-IV bipolar disorder, type I or type II, were randomized blindly to citalopram or placebo, added to standard mood stabilizers. They were followed for 6 weeks for acute efficacy (primary outcome) and up to 1 year for maintenance efficacy (secondary outcome) using scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Mania Rating Scale of the Schedule for Affective Disorders and Schizophrenia (MRS-SADS). The study was powered for a clinically meaningful effect size. Mean ± SD MADRS scores changed from a baseline value of 27.4 ± 9.1 to 13.1 ± 8.4 at the end of the acute phase for citalopram versus a change from 27.4 ± 7.3 to 15.2 ± 9.9 for placebo, a clinically and statistically nonsignificant difference. Maintenance efficacy also was not better with citalopram than with placebo. Acute manic/hypomanic episodes were similar in both groups, and subjects with type II illness did not have better outcomes than subjects with type I illness. In maintenance treatment, MRS-SADS scores were greater overall, especially in subjects with a rapid-cycling illness course, with citalopram versus placebo. Citalopram, added to standard mood stabilizers, did not have clinically meaningful benefit versus placebo for either acute or maintenance treatment of bipolar depression. Acute mania did not worsen with citalopram, but maintenance treatment led to worsened manic symptoms, especially in subjects with a rapid-cycling course. ClinicalTrials.gov identifier: NCT00562861.


Optic nerve crush induces spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice.
Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets. Only 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR. A number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue-specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure.


Chlorogenic acid relieves lead-induced cognitive impairments and hepato-renal damage via regulating the dysbiosis of the gut microbiota in mice.
Lead (Pb), a heavy metal which is widely recognized as an environmental toxicant, is transported from the earth's crust into the human body to a significant extent. To control and reduce the hazard of Pb burdens in the human body, chlorogenic acid (CGA) has been used to antagonize Pb-induced cognitive impairments, and hepatic and renal toxicity in the present study. Seven-week-old male Kunming mice were treated with PbCl2 (1.34 g L-1 in drinking water) and/or CGA (30 mg per kg mouse per day) by gavage administration for 8 weeks. In this study, we evaluated behavior tests, serum biochemical parameters, biomarkers of oxidative stress, and community structure of gut microbiota in mice to explore the potential mechanism of the protective effect. Based on our results, CGA appreciably prevented memory impairment, the release of serum biomarkers, and oxidative stress caused by Pb intake. CGA significantly inhibited Pb-induced increase of cytoplasmic NF-κB, Bax, cytochrome C, and caspase-9 protein expressions. Furthermore, Pb + CGA treatment had a remarkable reversion effect of the gut microbiota composition change induced by Pb, for example increasing the ratio of Helicobacter from 2.95% (Pb) to 11.24% (Pb + CGA) and decreasing the ratio of the Lachnospiraceae_NK4A136_ group from 7.09% (Pb) to 2.68% (Pb + CGA), which suggests that CGA is a superior natural product to eliminate Pb-induced nephrotoxicity and hepatotoxicity.


[Quality of life in intracranial aneurysm: surgery versus endovascular treatment].
Based on earlier studies, we aimed to determine the quality of life of patients with intracranial aneurysm after their treatment by surgery or embolization and to compare the quality of life of these two groups. The SF-36 health questionnaire was retrospectively applied to 93 patients with intracranial aneurysm treated with surgery (n=56) or embolization (n=37). The quality of life of some patients was impaired but 50% of patients treated with surgery and 40.5% of patients treated with embolization showed no impairment in any SF-36 domain. The quality of life in the Physical Functioning domain was higher in embolization-treated than in surgery-treated patients. Some patients with intracranial aneurysms treated with surgery or endovascular embolization have an impaired quality of life. Endovascular treatment may cause less limitation in physical function. The quality of life of these patients is affected by numerous factors, in addition to the type of treatment.


Prospective comparison study of franseen needle and standard needle use for pancreatic lesions under EUS guidance.
A needle with Franseen geometry for fine needle aspiration is now available. However, no reports have described prospective evaluations of the Franseen needle or comparisons with the standard needle. The aim of this comparative prospective study was to evaluate the histological diagnostic yield of the Franseen needle and the standard needle using tissue obtained by a single pass of each for the same lesion. In this study, only tissue obtained by the first pass using the Franseen needle was used. As a comparison group, only tissue obtained from the same lesion by a second pass using the standard needle was used. Evaluation of the histological diagnostic yield of the needles was based on tissue obtained by each single pass with no additional passes. A total of 56 patients were prospectively enrolled. The rate of adequate tissue obtained was significantly higher for the Franseen needle than for the standard needle (89.4% vs. 62.5%, respectively; P < 0.05). The sensitivity and accuracy of the Franseen needle were 80.7%, and 84.6%, respectively, while those for the standard needle were 59.6% and 63.5%, respectively. The Franseen needle offers a better rate of obtaining adequate tissue and higher diagnostic accuracy than the standard needle.


Paeoniflorin prevents TLR2/4-mediated inflammation in type 2 diabetic nephropathy.
Paeoniflorin is an effective Chinese traditional medicine with anti-inflammatory and immune-regulatory effects. The aim of this study was to investigate the underlying renoprotective mechanism of Paeoniflorin. In vivo, db/db mice were intraperitoneally injected with Paeoniflorin at a dose of 15, 30, or 60 mg/kg respectively. The immunostaining of TLR2, TLR4, CD68, NF-kB p65 and the mRNA level of inflammatory factors, together with the protein expression of TLR2/4 signaling were evaluated. Our data demonstrated that Paeoniflorin could decrease the urinary albumin excretion rate and inhibit macrophage infiltration and activation through blockage of the TLR2/4 signaling pathway compared with the db/db group in vivo. In vitro, RAW264.7 cells were categorized into control, bovin serum albumin (BSA)-stimulated, advanced glycation end products (AGEs)-stimulated, Paeoniflorin intervention and oxidized phospholipid (OxPAPC)-inhibited groups. The cell viability, the optimal stimulated time and concentration were measured as well as the TLR2/4 signaling activation determined by RT-PCR, Western blot and ELISA. Our data demonstrated that Paeoniflorin reduced the AGEs-induced TLR2/4 activation and inflammatory responses, which was consistent with the TLR2/4 inhibitor group. These findings indicate that Paeoniflorin prevents macrophage activation via inhibition of TLR2/4 signaling expression in type 2 diabetic nephropathy.


Validation of Computer-Adaptive Contrast Sensitivity as a Tool to Assess Visual Impairment in Multiple Sclerosis Patients.
Impairment of visual function is one of the major symptoms of people with multiple sclerosis (pwMS). A multitude of disease effects including inflammation and neurodegeneration lead to structural impairment in the visual system. However, the gold standard of disability quantification, the expanded disability status scale (EDSS), relies on visual assessment charts. A more comprehensive assessment of visual function is the full contrast sensitivity function (CSF), but most tools are time consuming and not feasible in clinical routine. The quantitative CSF (qCSF) test is a computerized test to assess the full CSF. We have already shown a better correlation with visual quality of life (QoL) than for classical high and low contrast charts in multiple sclerosis (MS). To study the precision, test duration, and repeatability of the qCSF in pwMS. In order to evaluate the discrimination ability, we compared the data of pwMS to healthy controls. We recruited two independent cohorts of MS patients. Within the precision cohort (n = 54), we analyzed the benefit of running 50 instead of 25 qCSF trials. The repeatability cohort (n = 44) was assessed by high contrast vision charts and qCSF assessments twice and we computed repeatability metrics. For the discrimination ability we used the data from all pwMS without any previous optic neuritis and compared the area under the log CSF (AULCSF) to an age-matched healthy control data set. We identified 25 trials of the qCSF algorithm as a sufficient amount for a precise estimate of the CSF. The median test duration for one eye was 185 s (range 129-373 s). The AULCSF had better test-retest repeatability (Mean Average Precision, MAP) than visual acuity measured by standard high contrast visual acuity charts or CSF acuity measured with the qCSF (0.18 vs. 0.11 and 0.17, respectively). Even better repeatability (MAP = 0.19) was demonstrated by a CSF-derived feature that was inspired by low-contrast acuity charts, i.e., the highest spatial frequency at 25% contrast. When compared to healthy controls, the MS patients showed reduced CSF (average AULCSF 1.21 vs. 1.42, p < 0.01). High precision, usability, repeatability, and discrimination support the qCSF as a tool to assess contrast vision in pwMS.


Psychosocial work experiences related to health: A study of Lithuanian hospital employees.
Research in the area of workplace health promotion from a salutogenic perspective is lacking in Eastern Europe. To evaluate the relationship between psychosocial work environment and health from a salutogenic perspective among Lithuanian hospital workers. Using a cross-sectional design a questionnaire was distributed to staff in a large hospital in Lithuania. Out of 811 employees, 714 completed the survey: 151 physicians, 449 nurses and 114 other staff members (e.g., psychologists, technicians, therapists). A response rate of 88.0% was achieved. The Work Experience Measurement Scale (WEMS) and the Salutogenic Health Indicator Scale (SHIS) were linguistically adapted and used for the first time in a Lithuanian context. Logistic and multiple linear regression models were used for the analyses. Supportive working conditions, positive internal work experiences and time experience contributed the most to good health, defined as a high SHIS index. Having an executive post was significantly related to good work experiences, i.e. a high WEMS score, while being at the age of 40-54 years was associated with a low WEMS score. Physicians had the highest score on supportive working conditions; while nurses had the lowest scores on autonomy. A salutogenic approach enables an organisation to identify how to improve working conditions for the employees by focusing on possibilities and resources. Individual activities for workplace health promotion among different work groups seem necessary.


Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency.
There is increasing interest in studying the epidemiology of subjects with mild to moderate chronic renal insufficiency (CRI), defined as reduced glomerular filtration rate (GFR) not requiring renal replacement therapy. This review discusses some of the methodological challenges presented by the epidemiological study of mild to moderate CRI that have not been adequately addressed in the literature. Issues that relate to defining the prevalence of CRI include between-laboratory differences in serum creatinine (SCr) assays, within-person measurement errors in SCr, and differences in SCr in different demographic groups that are independent of GFR. Issues that relate to examining CRI as an outcome include the choice between a "slope" or "threshold" analysis. Issues that relate to examining CRI as an exposure include the choice of renal function measure (for example, SCr vs. estimated GFR) in multivariable analysis, whether to normalize renal function to body surface area or other body size parameters, potential effect modification of the association between CRI and the outcome and the complex relation between CRI, adverse outcomes, potential confounders and intermediary variables. As we enter an era of more intensive study of mild to moderate CRI, recognition of these potential pitfalls should guide researchers toward improving the quality of epidemiological research in this field.


The treatment of severe psoriasis. A national survey.
In 1974, we conducted a randomized survey of dermatologists to determine trends in the use of chemotherapeutic agents for psoriasis. The present survey updates and extends the earlier one to include phototherapy, photochemotherapy, and other modalities being used in the treatment of psoriasis too extensive or severe for topical agents alone. Questionnaires were sent to approximately 20% of dermatologists nationwide and also to all training/research programs. Results of the survey include: (1) approximately 523,000 patients with psoriasis were treated by dermatologists in 1984, and 30% of these were severe enough to require more than topical care; (2) the majority of dermatologists use ultraviolet B (71%) and methotrexate (58%), while 36% use psoralen and ultraviolet A; (3) creatinine clearance rates and liver biopsy specimens are being obtained for approximately half of methotrexate-treated patients; and (4) of those physicians using methotrexate, most (74%) use weekly divided orally administered methotrexate doses.


In vivo optogenetics reveals control of cochlear electromechanical responses by supporting cells.
Cochlear sensitivity, essential for communication and exploiting the acoustic environment, results from sensory-motor outer hair cells (OHCs) operating in a structural scaffold of supporting cells and extracellular cortilymph (CL) within the organ of Corti (OoC). Cochlear sensitivity control is hypothesized to involve interaction between the OHCs and OoC supporting cells (e.g., Deiters' cells (DCs) and outer pillar cells (OPCs)), but this has never been established in vivo Here, we conditionally expressed channelrhodopsins (ChR2) specifically in male and female mouse DCs and OPCs. illumination of the OoC activated the nonselective ChR2 cation conductance and depolarized DCs when measured in vivo and in isolated OoC. Measurements of sound-induced cochlear mechanical and electrical responses revealed OoC illumination suppressed the normal functions of OoC supporting cells transiently and reversibly. OoC illumination blocked normally occurring continuous minor adjustments of tone-evoked basilar membrane (BM) displacements over their entire dynamic range and OHC voltage responses to tones at levels and frequencies subject to cochlear amplification. OoC illumination altered the OHC MET conductance operating point, which reversed the asymmetry of OHC voltage responses to high level tones. OoC illumination accelerated recovery from temporary loud sound-induced acoustic desensitization. We concluded that DCs and OPCs are involved in both the control of cochlear responses that are essential for normal hearing, and the recovery from temporary acoustic desensitization. This is the first direct in vivo evidence for the interdependency of the structural, mechanical, and electrochemical arrangements of OHCs and OoC supporting cells that together provide fine control of cochlear responses.Significance statement:A striking feature of the mammalian cochlear sensory epithelium, the organ of Corti, is the cellular architecture and supporting cell arrangement that provides a structural scaffold for the sensory-motor outer hair cells. The role of the supporting cell scaffold, however, has never been elucidated in vivo, although in vitro and modelling studies indicate the scaffold is involved in exchange of forces between the outer hair cells and the organ of Corti. We used in vivo techniques, including optogenetics, that do not disrupt arrangements between the outer hair cells and supporting cells, but selectively, transiently, and reversibly interfere with supporting cell normal function. We revealed the supporting cells provide continuous adjustment of cochlear sensitivity, which is instrumental in normal hearing.


Opposite regulation of calbindin and calretinin expression by brain-derived neurotrophic factor in cortical neurons.
Regulation of calbindin and calretinin expression by brain-derived neurotrophic factor (BDNF) was examined in primary cultures of cortical neurons using immunocytochemistry and northern blot analysis. Here we report that regulation of calretinin expression by BDNF is in marked contrast to that of calbindin. Indeed, chronic exposure of cultured cortical neurons for 5 days to increasing concentrations of BDNF (0.1-10 ng/ml) resulted in a concentration-dependent decrease in the number of calretinin-positive neurons and a concentration-dependent increase in the number of calbindin-immunoreactive neurons. Consistent with the immunocytochemical analysis, BDNF reduced calretinin mRNA levels and up-regulated calbindin mRNA expression, providing evidence that modifications in gene expression accounted for the changes in the number of calretinin- and calbindin-containing neurons. Among other members of the neurotrophin family, neurotrophin-4 (NT-4), which also acts by activating tyrosine kinase TrkB receptors, exerted effects comparable to those of BDNF, whereas nerve growth factor (NGF) was ineffective. As for BDNF and NT-4, incubation of cortical neurons with neurotrophin-3 (NT-3) also led to a decrease in calretinin expression. However, in contrast to BDNF and NT-4, NT-3 did not affect calbindin expression. Double-labeling experiments evidenced that calretinin- and calbindin-containing neurons belong to distinct neuronal subpopulations, suggesting that BDNF and NT-4 exert opposite effects according to the neurochemical phenotype of the target cell.