Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer.
Gene expression (GE) signatures and Tumor Infiltrating Lymphocytes (TIL) enumeration are predictive for response to neoadjuvant chemotherapy in HR- and in HER2+ breast cancer, but data are conflicting in HR+/HER2- disease. This study aimed to explore their predictive value in this subset, measured both at baseline and after short exposure to chemotherapy. Specifically, the PROMIX phase 2 trial enrolled patients with locally advanced HER2- BC to receive six cycles of epirubicin and docetaxel, plus bevacizumab during cycles 3-6. Patients underwent tumor biopsies at baseline and after cycle 2 for GE profiling and enumeration of TIL, FOXP3+ T-cells and CD163+ macrophages. An immune related gene module and the quantification of the immune infiltrate were analyzed for association with pathologic complete response (pCR), decrease in tumor size and disease-free survival (DFS). Of the 150 patients enrolled in PROMIX, 113 were HR+/HER2-. Baseline GE and immune cell enumeration data were available from 71 patients, while data after 2 cycles of chemotherapy were available from 41. At baseline, only GE was statistically significantly associated with higher pCR rates (OR 2.29, 95% CI 1.05 - 5.38, p = 0.037) and decrease in tumor size (r = 0.25, p = 0.047). In contrast, longitudinal data indicate that both GE (r = 0.54, p<0.001) and TIL abundance (p = 0.009) are stronger predictors for the reduction of tumor size, while low FOXP3+ was statistically significantly associated with an improved DFS (p = 0.027). In conclusion, GE analysis, TIL and FOXP3+ enumeration after short-term exposure to chemotherapy carry important predictive information in HR+/HER2- breast cancer at the neoadjuvant setting.


[Stress induction of retrotransposon transposition in Drosophila: reality of the phenomenon, characteristic features, possible role in rapid evolution].
A polygenic system of expression of the quantitative character radius incompletus was shown to be sensitive to external and physiological stresses: heat shock, gamma-irradiation, isogenization, etc. This stress response involved mobilization of retrotransposons. Heavy heat shock induced transpositions of Dm412 and B104 in three and one isogenic lines, respectively. The induced transposition rate was (2.5-11.0) x 10(-2) per site per sperm per generation, i.e., 1-2 orders of magnitude higher than for spontaneous transpositions. Induction of transpositions by gamma-radiation yielded similar estimates. Recently, induction of transpositions and excisions by isogenization was demonstrated; transposition and excision rates were, respectively, 0.35 and 0.13 per site per sperm per generation, which was 2-3 orders of magnitude higher than in control lines. In all these cases, stress induction of retrotransposon transpositions was mediated by molecular mechanisms of the heat shock system-the general system of cell resistance to external and physiological stress factors. From the viewpoint of evolution, stress induction of transpositions is a powerful factor generating new genetic variation in populations under stressful environmental conditions. Passing through a "bottleneck," a population can rapidly and significantly alter its population norm and become the founder of new, normal forms.


Microbial communities controlling methane and nutrient cycling in leach field soils.
Septic systems inherently rely on microbial communities in the septic tank and leach field to attenuate pollution from household sewage. Operating conditions of septic leach field systems, especially the degree of water saturation, are likely to impact microbial biogeochemical cycling, including carbon (C), nitrogen (N), and phosphorus (P), as well as greenhouse gas (GHG) emissions to the atmosphere. To study the impact of flooding on microbial methane (CH4) and nutrient cycling, two leach field soil columns were constructed. One system was operated as designed and the other was operated in both flooded and well-maintained conditions. CH4 emissions were significantly higher in flooded soils (with means between 0.047 and 0.33 g CH4 m-2 d-1) as compared to well-drained soils (means between -0.0025 and 0.004 g CH4 m-2 d-1). Subsurface CH4 profiles were also elevated under flooded conditions and peaked near the wastewater inlet. Gene abundances of mcrA, a biomarker for methanogens, were also greatest near the wastewater inlet. In contrast, gene abundances of pmoA, a biomarker for methanotrophs, were greatest in surface soils at the interface of CH4 produced subsurface and atmospheric oxygen. 16S rRNA, mcrA, and pmoA amplicon library sequencing revealed microbial community structure in the soil columns differed from that of the original soils and was driven largely by CH4 fluxes and soil VWC. Additionally, active microbial populations differed from those present at the gene level. Flooding did not appear to affect N or P removals in the soil columns (between 75 and 99% removal). COD removal was variable throughout the experiment, and was negatively impacted by flooding. Our study shows septic system leach field soils are dynamic environments where CH4 and nutrients are actively cycled by microbial populations. Our results suggest proper siting, installation, and routine maintenance of leach field systems is key to reducing the overall impact of these systems on water and air quality.


Diagnostic and prognostic importance of comparing the initial to the previous electrocardiogram in patients admitted for suspected acute myocardial infarction.
Two hundred fifty-eight patients were admitted to the hospital for suspected acute myocardial infarction. Electrocardiograms recorded on admission (initial ECG) and the most recent available electrocardiogram recorded before admission (previous ECG) were compared to determine whether changes from the previous to initial ECG predicted acute myocardial infarction or complications of coronary artery disease. Initial ECGs were classed as either positive or negative, with positive indicating either infarction, injury, ischemia, strain, left ventricular hypertrophy, left bundle branch block, or paced rhythm. Negative ECGs were those that did not include any of the positive criteria. Positive and negative ECGs were subgrouped as showing change or no change from previous ECG. We found that patients with a negative initial ECG that had changed from the previous ECG had a 2.1 times greater risk for requiring interventions than those patients whose ECGs were unchanged. We also found that patients with a positive initial ECG that had changed from the previous ECG had a greater risk for interventions (2.0 times), complications (2.6 times), life-threatening complications (4.2 times), and acute myocardial infarction (6.6 times) than the sum of patients in all other ECG categories. We conclude that change is a useful predictor for interventions in patients with negative initial ECGs and a useful predictor for interventions, complications, and acute myocardial infarction in patients with positive initial ECGs.


A prospective study of the relationship between sense of coherence, depression, anxiety, and quality of life of haematopoietic stem cell transplant patients over time.
The primary aim of this study was to examine the impact of patient sense of coherence (SOC) on anxiety and depressive symptoms, and quality of life (QoL) dimensions in the acute phase of haematopoietic stem cell transplantation (HSCT). A secondary aim was to determine if SOC measured pre-transplant was predictive of psychological distress and QoL post-transplantation, after controlling for physical wellbeing. A series of measures was completed by 60 HSCT patients prior to transplantation. Follow-up data were collected at 2-3 weeks and 3 months post-transplantation. Measures administered included the Brief Symptom Inventory-18, Orientation to Life Questionnaire, and Functional Assessment of Cancer Therapy-Bone Marrow Transplantation. When compared across the three time points, depression levels, and physical and functional wellbeing were worst at 2-3 weeks post-transplantation. SOC was positively associated with physical wellbeing prior to HSCT but not after transplantation. Weaker SOC predicted higher levels of depression, and poorer social, emotional, and functional wellbeing at both follow-up points, after accounting for physical wellbeing. Given that SOC was related to depression and QoL dimensions post-transplantation, it may be important for health care professionals to conduct psychosocial assessments to determine patient SOC. This would enable provision of tailored psychological support prior to and following stem cell transplantation.


Family caregiving during 1-year follow-up in individuals with advanced chronic organ failure.
Family caregivers already have a paramount role in daily care for patients with chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), or chronic renal failure (CRF). To date, it remains unknown whether and to what extent the experience of caregiving changes over time. To examine changes in caregiver burden and positive aspects of caregiving during 1-year follow-up in patients with advanced COPD, CHF or CRF and to study determinants of changes in caregiver burden and positive aspects of caregiving. In this longitudinal observational study, patients and their family caregivers who had complete data at baseline and 12 months (n = 104) and family caregivers of patients who died during 1-year follow-up (n = 15) were included. Caregiver burden and positive aspects of caregiving were assessed using the Family Appraisal of Caregiving Questionnaire for Palliative Care (FACQ-PC). Domain scores were classified into three categories, and baseline characteristics were compared between these categories. A majority of the individuals showed 1-year changes in FACQ-PC domain scores. These individual changes were not explained by demographic or clinical patient characteristics at baseline or changes in patient characteristics during 1-year follow-up. Furthermore, caregiver burden was higher for caregivers of patients who died during 1-year follow-up compared to caregivers whose relative completed 1-year follow-up. This study showed that caregiver burden and positive aspects of caregiving can change over time, and these changes are highly individual. Therefore, healthcare providers should regularly pay attention to family caregivers, regardless the patients' characteristics.


Sodium nitrite potentiates antimicrobial photodynamic inactivation: possible involvement of peroxynitrate.
We have recently shown that a wide range of different inorganic salts can potentiate antimicrobial photodynamic inactivation (aPDI) and TiO2-mediated antimicrobial photocatalysis. Potentiation has been shown with azide, bromide, thiocyanate, selenocyanate, and most strongly, with iodide. Here we show that sodium nitrite can also potentiate broad-spectrum aPDI killing of Gram-positive MRSA and Gram-negative Escherichia coli bacteria. Literature reports have previously shown that two photosensitizers (PS), methylene blue (MB) and riboflavin, when excited by broad-band light in the presence of nitrite could lead to tyrosine nitration. Addition of up to 100 mM nitrite gave 6 logs of extra killing in the case of Rose Bengal excited by green light against E. coli, and 2 logs of extra killing against MRSA (eradication in both cases). Comparable results were obtained for other PS (TPPS4 + blue light and MB + red light). Some bacterial killing was obtained when bacteria were added after light using a functionalized fullerene (LC15) + nitrite + blue light, and tyrosine ester amide was nitrated using both "in" and "after" modes with all four PS. The mechanism could involve formation of peroxynitrate by a reaction between superoxide radicals and nitrogen dioxide radicals; formation of the latter species was demonstrated by spin trapping with nitromethane.


Fast on-demand droplet fusion using transient cavitation bubbles.
A method for on-demand droplet fusion in a microfluidic channel is presented using the flow created from a single explosively expanding cavitation bubble. We test the technique for water-in-oil droplets, which are produced using a T-junction design in a microfluidic chip. The cavitation bubble is created with a pulsed laser beam focused into one droplet. High-speed photography of the dynamics reveals that the droplet fusion can be induced within a few tens of microseconds and is caused by the rapid thinning of the continuous phase film separating the droplets. The cavitation bubble collapses and re-condenses into the droplet. Droplet fusion is demonstrated for static and moving droplets, and for droplets of equal and unequal sizes. Furthermore, we reveal the diffusion dominated mixing flow and the transport of a single encapsulated cell into a fused droplet. This laser-based droplet fusion technique may find applications in micro-droplet based chemical synthesis and bioassays.


Prevalence and determinants of diabetes mellitus and impaired glucose tolerance in Indonesia (a part of basic health research/Riskesdas).
To estimate the prevalence of diagnosed and undiagnosed diabetes mellitus (DM) and impaired glucose tolerance (IGT) in 15 year old and over in urban Indonesia and their association with risk factors such as age, smoking, physical inactivity, obesity, hypertension. A national sample involving 24,417 participants living in urban Indonesia aged > 15 years were examined for 2 hours of plasma glucose concentrations in a cross sectional survey using the 75-g oral glucose. Diagnostic criteria of the World Health Organization 1999 and American Diabetes Association (ADA) 2003 were used to determine the prevalence of abnormal glucose tolerance. Data on age, smoking, physical activity were obtained from the personal interview, and obesity included body mass index and waist circumference and blood pressure were measured. The prevalences of diabetes in urban Indonesia was 5.7%, consisting of diagnosed diabetes mellitus (DDM) 1.5%, undiagnosed diabetes mellitus (UDDM) 4.2% and IGT 10.2%. The prevalence of DM was 6.4% in women and 4.9% in men. In the youngest group (15-24 years) 5.3% had IGT. Prevalence increases with age with a sharp rise from middle age (35-54 years). Determinant factors for IGT and diabetes were age, smoking, obesity, central obesity and hypertension. these results indicate that diabetes has become a major public health problem in Indonesia and needs national strategies to screen, prevent and treat the disease.


Determining Prevalence of Anemia and Its Associated Factors in Cameroon: A Multilevel Analysis.
Anemia constitutes a major public health concern, which is associated with maternal and perinatal mortality. In low- and middle-income countries, the burden of anemia is profoundly high. Cameroon, as one of the low- and middle-income countries, has a disproportionate anemia burden. Factors associated with anemia prevalence are largely unknown in Cameroon. Hence, we determined the prevalence of anemia and its individual/household and community-level factors among adult women in Cameroon. We derived data from the 2018 Cameroon Demographic and Health Survey for analysis in this study. Using the Stata version 14 software, univariate multilevel logistic regression analysis was used to select variables that had significant association with anemia at p < 0.05. Statistically significant variables were included in a multivariable multilevel logistic regression modelling to examine their associations with anemia. Results were reported using adjusted odds ratios (AOR) with their respective 95% confidence interval (CI). A total of 6,809 women aged 15-49 years were involved in this study with a mean age 30 ± 11.87 years. Approximately two-fifths of women were anemic. Of them, 0.8% were severely anemic, while 17.4% and 21.5% were moderately and mildly anemic, respectively. Current employment status (yes AOR = 0.77, 95% CI; 0.61-0.96) and parity (1-2 children AOR = 0.61, 95% CI; 0.44-0.86) were the main individual level factors associated with anemia, whereas region (Douala region AOR = 2.65, 95% CI; 1.61-4.36, North-West region AOR = 0.53, 95% CI; 0.28-0.99) was the community-level factor associated with anaemia. Empowerment of women through employment opportunities as well as focusing special attention in region where high prevalence of anemia could be crucial to decrease the burden of anemia and related maternal and perinatal mortality in the country.


The acute surgical unit: An updated systematic review and meta-analysis.
To systematically review comparative studies on the acute surgical unit (ASU) model. Searches were performed of Cochrane, Embase, Medline and grey literature. Eligible articles were comparative studies of the Acute Surgical Unit (ASU) model published 01/01/2000-12/03/2020. Amongst patients with any diagnosis, primary outcomes were length of stay, after-hours operating, complications and cost. Secondary outcomes were time to surgical review, time to theatre, mortality and re-admission for patients with any diagnosis, and cholecystectomy during index admission for patients with biliary disease. Additional analyses were planned for specific cohorts, such as patients with appendicitis or cholecystitis. Searches returned 9,677 results from which 77 eligible publications were identified, representing 150,981 unique patients. Cohorts were adequately homogenous for meta-analysis of all outcomes except cost. For patients with any diagnosis, compared with the Traditional model, the introduction of an ASU model was associated with reduced length of stay (mean difference [MD] 0.68 days; 95% confidence interval [CI] 0.38-0.98), after-hours operating rates (odds ratio [OR] 0.56; 95% CI 0.46-0.69) and complications (OR 0.48, 95% CI 0.33-0.70). Regarding cost, two studies reported savings following ASU introduction, while one found no difference. Amongst secondary outcomes, for patients with any diagnosis, ASU commencement was associated with reduced time to surgical review, time to theatre and mortality. Re-admissions were unchanged. For patients with biliary disease, ASU establishment was associated with superior rates of index cholecystectomy. Compared to the Traditional structure, the ASU model is superior for most metrics. ASU introduction should be promoted in policy for widespread benefit.


Stomach cancer and occupation in Sweden: 1971-89.
To examine the relation between gastric cancer and occupation among men and women gainfully employed in 1970 in Sweden for the period 1971-89 and, more specifically, to evaluate whether any excess of incidence of gastric cancer had also occurred among the subcohort of people reporting the same occupation in 1960 and 1970. In both sexes and cohorts, relative risks adjusted for age, period of diagnosis, and geographical risk area were computed for occupational codes specified at one, two, or three level (occupational sector, occupational group, and occupation, respectively). Relative risks were calculated with all other occupations as reference and then, to take socioeconomic status into account, solely other occupations within the same occupational sector were used. Among men, occupations with increased risk included miners and quarrymen, construction and metal processing workers, supporting the possible causative role of dusty environments in stomach cancer. In men, the results also provide support for increased risks among electrical and mechanical engineers, fishermen, petrol station workers, motor vehicle drivers, butchers and meat preparers, dockers, freight handlers, launderers and dry cleaners. Furthermore, it is worth noting interesting results for women, whose occupational risks have been studied less. Excess risks were found for practical nurses, cashiers, bank employees, engineering and electronic industry workers, food industry, housekeeping and cleaning workers. Due to the many occupations studied, several significant associations may be expected by chance. The study is explorative but provides support for the relations suggested previously between occupational exposure to dusty environments and stomach cancer, together with some new high risk occupations which should be further studied.


[The etiopathogenesis of pulmonary hypertension: inflammation, vascular remodeling].
Pulmonary arterial hypertension (PAH) is a progressive disease marked by increased pulmonary artery resistance leading to right heart failure with a high mortality. PAH is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, inflammation, and thrombosis in situ. Elevated pulmonary vascular resistance is the result of an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Recent evidence demonstrates that inflammatory processes are involved in the generation of pulmonary vascular remodeling leading to PAH. Viral infections or similar immune-modulators trigger auto-antibody generation by endothelial injury and indirectly lead to PAH. All these immune-modulators associated with PAH, are also known to decrease the regulatory subgroups (CD4) of T cells. With a recognition of the important role of inflammation in the development of PAH, anti-inflammatory agents and anti-cancer drugs are accepted as potential specific targets for PAH treatment. Though clinical studies are not enough, anti-inflammatory agents seem to be promising in the treatment of this devastating disease.


Steady-state rheology and structure of soft hybrid mixtures of liquid crystals and magnetic nanoparticles.
Using non-equilibrium molecular dynamics simulations, we study the rheology of a model hybrid mixture of liquid crystals (LCs) and dipolar soft spheres (DSS) representing magnetic nanoparticles. The bulk isotropic LC-DSS mixture is sheared with different shear rates using Lees-Edwards periodic boundary conditions. The steady-state rheological properties and the effect of the shear on the microstructure of the mixture are studied for different strengths of the dipolar coupling, λ, among the DSS. We find that at large shear rates, the mixture shows a shear-thinning behavior for all considered values of λ. At low and intermediate values of λ, a crossover from Newtonian to non-Newtonian behavior is observed as the rate of applied shear is increased. In contrast, for large values of λ, such a crossover is not observed within the range of shear rates considered. Also, the extent of the non-Newtonian regime increases as λ is increased. These features can be understood via the shear-induced changes of the microstructure. In particular, the LCs display a shear-induced isotropic-to-nematic transition at large shear rates with a shear-rate dependent degree of nematic ordering. The DSS show a shear-induced nematic ordering only for large values of λ, where the particles self-assemble into chains. Moreover, at large λ and low shear rates, our simulations indicate that the DSS form ferromagnetic domains.


Genomic Analysis of Multidrug-Resistant Escherichia coli Strains Isolated in Tamaulipas, Mexico.
The global spread of antimicrobial resistance genes (ARGs) is a major public health concern. Mobile genetic elements (MGEs) are the main drivers of this spread by horizontal gene transfer (HGT). Escherichia coli is widespread in various environments and serves as an indicator for monitoring antimicrobial resistance (AMR). Therefore, the objective of this work was to evaluate the whole genome of multidrug-resistant E. coli strains isolated from human clinical, animal, and environmental sources. Four E. coli strains previously isolated from human urine (n = 2), retail meat (n = 1), and water from the Rio Grande River (n = 1) collected in northern Tamaulipas, Mexico, were analyzed. E. coli strains were evaluated for antimicrobial susceptibility, followed by whole genome sequencing and bioinformatic analysis. Several ARGs were detected, including blaCTX-M-15, blaOXA-1, blaTEM-1B, blaCMY-2, qnrB, catB3, sul2, and sul3. Additionally, plasmid replicons (IncFIA, IncFIB, IncFII, IncY, IncR, and Col) and intact prophages were also found. Insertion sequences (ISs) were structurally linked with resistance and virulence genes. Finally, these findings indicate that E. coli strains have a large repertoire of resistance determinants, highlighting a high pathogenic potential and the need to monitor them.


Diagnostic and therapeutic percutaneous cardiac interventions without on-site surgical backup--review of 11 years experience.
Current clinical guidelines restrict catheterization laboratory activity without on-site surgical backup. Recent improvements in technical equipment and pharmacologic adjunctive therapy increase the safety margins of diagnostic and therapeutic cardiac catheterization. To analyze the reasons for urgent cardiac surgery and mortality in the different phases of our laboratory's activity in the last 11 years, and examine the impact of the new interventional and therapeutic modalities on the current need for on-site cardiac surgical backup. We retrospectively reviewed the mortality and need for urgent cardiac surgery (up to 12 hours post-catheterization) through five phases of our laboratory's activity: a) diagnostic (years 1989-2000), b) valvuloplasties and other non-coronary interventions (1990-2000), c) percutaneous-only balloon angioplasty (1992-1994), d) coronary stenting (1994-2000), and e) use of IIb/IIIa antagonists and thienopiridine drugs (1996-2000). Forty-eight patients (0.45%) required urgent cardiac surgery during phase 1, of whom 40 (83%) had acute coronary syndromes with left main coronary artery stenosis or the equivalent, and 8 (17%) had mechanical complications of acute myocardial infarction. Two patients died (0.02%) during diagnostic procedures. In phase 2, eight patients (2.9%) were referred for urgent cardiac surgery due to either cardiac tamponade or severe mitral regurgitation, and two patients (0.7%) died. The combined need for urgent surgery and mortality was significantly lower in phase 4 plus 5 as compared to phase 3 (3% vs. 0.85%, P = 0.006). In the current era using coronary stents and potent antithrombotic drugs, after gaining experience and crossing the learning curve limits, complex cardiac therapeutic interventions can safely be performed without on-site surgical backup.


Thyrotropin-releasing hormone receptors -- similarities and differences.
Thyrotropin-releasing hormone (TRH) initiates its effects by interacting with cell-surface membrane receptors. Two G protein-coupled receptors for TRH, TRH receptor type 1 (TRH-R1) and TRH receptor type 2 (TRH-R2), have been cloned from mammals. In this review, we compare TRH-R1 and TRH-R2 with regard to their tIssue distribution, binding affinities for TRH and TRH analogs, basal and activated signaling activities and characteristics of internalization. TRH-R1 and TRH-R2 are distributed differently in the brain and peripheral tIssues, but exhibit indistinguishable binding affinities for TRH and TRH analogs. Although they both can be stimulated by TRH to similar maximal signaling levels, TRH-R2 exhibits higher basal signaling activity and is more rapidly internalized than TRH-R1. These differences in signaling and internalization properties are probably important in the distinct parts that TRH-R1 and TRH-R2 may play in mammalian physiology.


Framework of behavioral indicators for outcome evaluation of TB health promotion: a Delphi study of TB suspects and Tb patients.
Health promotion for prevention and control of Tuberculosis (TB) is implemented worldwide because of its importance, but few reports have evaluated its impact on behavior due to a lack of standard outcome indicators. The objective of this study was to establish a framework of behavioral indicators for outcome evaluation of TB health promotion among TB suspects and patients. A two-round modified Delphi method involving sixteen TB control experts was used to establish a framework of behavioral indicators for outcome evaluation of TB health promotion targeted at TB suspects and patients. Sixteen of seventeen invited experts in TB control (authority score of 0.91 on a 1.0 scale) participated in round 1 survey. All sixteen experts also participated in a second round survey. After two rounds of surveys and several iterations among the experts, there was consensus on a framework of indicators for measuring outcomes of TB health promotion for TB suspects and patients. For TB suspects, the experts reached consensus on 2 domains ("Healthcare seeking behavior" and "Transmission prevention"), 3 subdomains ("Seeking care after onset of TB symptoms", "Pathways of seeking care" and "Interpersonal contact etiquette"), and 8 indicators (including among others, "Length of patient delay"). For TB patients, consensus was reached on 3 domains ("Adherence to treatment", "Healthy lifestyle" and "Transmission prevention"), 8 subdomains (including among others, "Adherence to their medication"), and 14 indicators (including "Percentage of patients who adhered to their medication"). Operational definitions and data sources were provided for each indicator. The findings of this study provide the basis for debate among international experts on a framework for achieving global consensus on outcome indicators for TB health promotion interventions targeted at TB patients and suspects. Such consensus will help to increase effectiveness of TB health promotion, while ensuring international comparability of outcome data.


Measuring the acute cardiovascular effects of shisha smoking: a cross-sectional study.
To investigate the acute cardiovascular effects of smoking shisha. A cross-sectional study was carried out in six shisha cafes. Participants smoked shisha for a period between 45 min (minimum) and 90 min (maximum). The same brand of tobacco and coal was used. London, UK. Participants were those who had ordered a shisha to smoke and consented to have their blood pressure, heart rate and carbon monoxide levels measured. Excluded subjects were those who had smoked shisha in the previous 24 h, who smoke cigarettes or who suffered from cardiorespiratory problems. Blood pressure was measured using a sphygmomanometer. Pulse was measured by palpation of the radial artery. Carbon monoxide levels were obtained via a carbon monoxide monitor. These indices were measured before the participants began to smoke shisha and after they finished or when the maximum 90 min time period was reached. Mean arterial blood pressure increased from 96 mmHg to 108 mmHg (p < 0.001). Heart rate increased from 77 to 91 bpm (p < 0.001). Carbon monoxide increased from an average of 3 to 35 ppm (p < 0.001). A correlation analysis showed no relationship between carbon monoxide and the other indices measured. The acute heart rate, blood pressure and carbon monoxide levels were seen to rise significantly after smoking shisha. The weak correlation between carbon monoxide levels and the other variables suggests that carbon monoxide levels had not contributed to their significant increase.


[Reaction of rat fetal adrenals to stress exposure under encephalectomy].
The concentration of corticosterone in the suprarenals after the stress effect (injection of formol) was studied in 20.5 days old foetuses of the adrenalectomized rats, using the method of competitive binding. The concentration of corticosterone in the suprarenals of normal foetuses increased reliably within 30 min after the injection of formol; this reaction was absent in the encephalectomized foetuses. The results obtained suggest the participation of embryonic hypothalamus in the organization of stress response during prenatal development of rats.


Identification of xanthurenic acid 8-O-beta-D-glucoside and xanthurenic acid 8-O-sulfate as human natriuretic hormones.
Hormonal regulation of salt excretion and water balance by the kidneys is well documented. Before 1961, it was widely believed that the glomerular filtration rate and the steroid hormone aldosterone controlled sodium balance in the body. In 1961, deWardener et al. [de Wardener HE, Mills IH, Clapham WF, Hayter CJ (1961) Clin Sci 21:249-258] showed that when these two variables were controlled, the kidney was still able to increase sodium excretion in response to a salt load. Several lines of evidence argued for a small-molecule signal as a definitive modulator of sodium excretion by the kidney. However, the chemical nature of the suspected natriuretic agent remained unknown. Here we report the identification and natriuretic activity of two closely related small molecules isolated from human urine, xanthurenic acid 8-O-beta-d-glucoside and xanthurenic acid 8-O-sulfate. The two compounds were partially purified by activity-guided fractionation and subsequently identified by using NMR spectroscopic analyses of enriched active fractions. Both compounds caused substantial and sustained (1- to 2-h) natriuresis in rats and no or minimal concomitant potassium excretion. We believe these compounds constitute a class of kidney hormones that also could influence sodium transport in nonkidney tissues given that these tryptophan metabolites presumably represent evolutionarily old structures.


Resources, key traits and the size of fungal epidemics in Daphnia populations.
Parasites can profoundly affect host populations and ecological communities. Thus, it remains critical to identify mechanisms that drive variation in epidemics. Resource availability can drive epidemics via traits of hosts and parasites that govern disease spread. Here, we map resource-trait-epidemic connections to explain variation in fungal outbreaks (Metschnikowia bicuspidata) in a zooplankton host (Daphnia dentifera) among lakes. We predicted epidemics would grow larger in lakes with more phytoplankton via three energetic mechanisms. First, resources should stimulate Daphnia reproduction, potentially elevating host density. Secondly, resources should boost body size of hosts, enhancing exposure to environmentally distributed propagules through size-dependent feeding. Thirdly, resources should fuel parasite reproduction within hosts. To test these predictions, we sampled 12 natural epidemics and tracked edible algae, fungal infection prevalence, body size, fecundity and density of hosts, as well as within-host parasite loads. Epidemics grew larger in lakes with more algal resources. Structural equation modelling revealed that resource availability stimulated all three traits (host fecundity, host size and parasite load). However, only parasite load connected resources to epidemic size. Epidemics grew larger in more dense Daphnia populations, but host density was unrelated to host fecundity (thus breaking its link to resources). Thus, via energetic mechanisms, resource availability can stimulate key trait(s) governing epidemics in nature. A synthetic focus on resources and resource-trait links could yield powerful insights into epidemics.


Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation.
Several centers have identified colorectal cancer in patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) who have undergone orthotopic liver transplantation. Increased frequency of surveillance colonoscopy and prophylactic colectomy has been recommended. To address these concerns, we reviewed the posttransplantation experience with colorectal neoplasia in patients with PSC and UC at our institution. All patients with PSC and UC who underwent liver transplantation at Mayo Clinic between April 1985 and December 1993 were followed up through their complete history for colorectal dysplasia, cancer, or death. Eighty-one of 108 patients with PSC (75%) had concomitant inflammatory bowel disease (all but 1 had UC). Proctocolectomy had been performed before transplantation in 24 (30%). Median follow-up after transplantation was 4.2 years. Among the 57 patients with intact colons, 3 developed colorectal cancer, an incidence of approximately 1% per person per year. The cumulative incidence of dysplasia was 15% at 5 years and 21% at 8 years. Overall actuarial survival stratified by presence or absence of an intact colon at transplantation was similar (86% and 86%, respectively, at 5 years). The risk of carcinoma after transplantation compared with that expected for patients during a comparable (pretransplantation) period was increased fourfold but was not statistically significant. The risk of colorectal neoplasia (dysplasia and cancer) after liver transplantation in patients with PSC and UC is clinically important. However, this risk had no impact on patient survival. Prophylactic proctocolectomy does not appear necessary, but annual surveillance colonoscopy is recommended.


Comparison of acute kidney injury between open and laparoscopic liver resection: Propensity score analysis.
The inflammatory response has been shown to be a major contributor to acute kidney injury. Considering that laparoscopic surgery is beneficial in reducing the inflammatory response, we compared the incidence of postoperative acute kidney injury between laparoscopic liver resection and open liver resection. Among 1173 patients who underwent liver resection surgery, 222 of 926 patients who underwent open liver resection were matched with 222 of 247 patients who underwent laparoscopic liver resection, by using propensity score analysis. The incidence of postoperative acute kidney injury assessed according to the creatinine criteria of the Kidney Disease: Improving Global Outcomes definition was compared between those 1:1 matched groups. A total 77 (6.6%) cases of postoperative acute kidney injury occurred. Before matching, the incidence of acute kidney injury after laparoscopic liver resection was significantly lower than that after open liver resection [1.6% (4/247) vs. 7.9% (73/926), P < 0.001]. After 1:1 matching, the incidence of postoperative acute kidney injury was still significantly lower after laparoscopic liver resection than after open liver resection [1.8% (4/222) vs. 6.3% (14/222), P = 0.008; odds ratio 0.273, 95% confidence interval 0.088-0.842, P = 0.024]. The postoperative inflammatory marker was also lower in laparoscopic liver resection than in open liver resection in matched set data (white blood cell count 12.7 ± 4.0 × 103/μL vs. 14.9 ± 3.9 × 103/μL, P < 0.001). Our findings suggest that the laparoscopic technique, by decreasing the inflammatory response, may reduce the occurrence of postoperative acute kidney injury during liver resection surgery.


Enhanced efficacy of conditionally replicating herpes simplex virus (G207) combined with 5-fluorouracil and surgical resection in peritoneal cancer dissemination models.
The therapeutic efficacy of G207, a replication-competent herpes simplex virus, for malignancies is increased when combined with certain chemotherapies, but the mechanism is unclear and the interaction between G207 and surgical resection has not been extensively studied. The goals of the current study were to examine the performance of combination treatments for peritoneal disseminated cancers and to explore the mechanism of effective combinations. Hamsters and SCID and BALB/c mice harboring peritoneal dissemination of gallbladder, gastric or colon cancer cells were treated with G207, 5-fluorouracil (5FU), or surgical resection alone, or G207 combined with 5FU or surgery. Animal survival, antiviral immunity, intratumoral ribonucleotide reductase activity, and viral spread were compared between the groups. The combination of G207 and 5FU prolonged the survival of hamsters bearing peritoneal dissemination of gallbladder cancer compared with the controls, G207 alone and 5FU alone. 5FU did not suppress the production of neutralizing antibodies against G207, but increased ribonucleotide reductase activity and viral spread in subcutaneous gallbladder tumors. The enhanced efficacy of the combination treatment was also observed in immunodeficient mice with disseminated gastric cancer. Although surgical resection did not significantly prolong animal survival or increase the intratumoral activity of ribonucleotide reductase, long-term survivors emerged from groups of animals treated with surgical resection and G207 for gallbladder and colon disseminated cancers. These results indicate that the increased activity of ribonucleotide reductase in tumors mediated by 5FU and the decreased tumor burden resulting from surgical resection may enhance the therapeutic efficacy of oncolytic herpes virus for peritoneal disseminated cancer.


Floral organs act as environmental filters and interact with pollinators to structure the yellow monkeyflower (Mimulus guttatus) floral microbiome.
Assembly of microbial communities is the result of neutral and selective processes. However, the relative importance of these processes is still debated. Microbial communities of flowers, in particular, have gained recent attention because of their potential impact to plant fitness and plant-pollinator interactions. However, the role of selection and dispersal in the assembly of these communities remains poorly understood. Here, we evaluated the role of pollinator-mediated dispersal on the contribution of neutral and selective processes in the assembly of floral microbiomes of the yellow monkeyflower (Mimulus guttatus). We sampled floral organs from flowers in the presence and absence of pollinators within five different serpentine seeps in CA and obtained 16S amplicon data on the epiphytic bacterial communities. Consistent with strong microenvironment selection within flowers we observed significant differences in community composition across floral organs and only a small effect of geographic distance. Pollinator exposure affected the contribution of environmental selection and depended on the rate and intimacy of interactions with flower visitors. This study provides evidence of the importance of dispersal and within-flower heterogeneity in shaping epiphytic bacterial communities of flowers, and highlights the complex interplay between pollinator behaviour, environmental selection and additional abiotic factors in shaping the epiphytic bacterial communities of flowers.


Papillomavirus E6 and E7 proteins and their cellular targets.
The mucosal human papillomaviruses (HPVs) infect human genital and oral epithelial cells and cause lesions ranging in severity from benign to malignant. HPV associated malignancies include cervical and other anogenital cancers as well as a subpopulation of head and neck cancers. Viral infection of epidermal stem or transit amplifying cells can result in long term viral persistence, and the development of carcinogenesis over a significant amount of time then requires additional cooperating genetic hits. Only the so-called high risk HPV types mediate human carcinogenesis, whereas the low risk HPVs have been linked to benign epithelial lesions that are not generally life threatening, but nonetheless are a major health burden. Expression of the high risk HPV E6 and E7 oncogenes is sufficient for primary human keratinocyte immortalization and is required for initiation and all subsequent stages of carcinogenic progression. Together with the finding that high levels of E6/E7 are a unifying hallmark of HPV positive cancers, these two genes are presumed to be the relevant virus-derived transformation stimuli in humans. E6 and E7 proteins do not possess intrinsic enzymatic activities, but instead function though a number of direct and indirect interactions with cellular proteins, a number of which are well known cellular tumor suppressors. We will summarize here current insights into E6 and E7 interactions with specific cellular targets that stimulate aspects of the viral life cycle, interfere with cell cycle controls and promote carcinogenic processes.


Surveillance for Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease: Universal or Selective?
Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, is the sixth most common cancer, the fourth leading cause of cancer-related deaths worldwide, and accounts globally for about 800,000 deaths/year. Early detection of HCC is of pivotal importance as it is associated with improved survival and the ability to apply curative treatments. Chronic liver diseases, and in particular cirrhosis, are the main risk factors for HCC, but the etiology of liver disease is rapidly changing due to improvements in the prevention and treatment of HBV (Hepatitis B virus) and HCV (Hepatitis C virus) infections and to the rising incidence of the metabolic syndrome, of which non-alcoholic fatty liver (NAFLD) is a manifestation. NAFLD is now a recognized and rapidly increasing cause of cirrhosis and HCC. Indeed, the most recent guidelines for NAFLD management recommend screening for HCC in patients with established cirrhosis. Screening in NAFLD patients without cirrhosis is not recommended; however, the prevalence of HCC in this group of NAFLD patients has been reported to be as high as 38%, a proportion significantly higher than the one observed in the general population and in non-cirrhotic subjects with other causes of liver disease. Unfortunately, solid data regarding the risk stratification of patients with non-cirrhotic NAFLD who might best benefit from HCC surveillance are scarce, and specific recommendations in this field are urgently needed due to the increasing NAFLD epidemic, at least in Western countries. To further complicate matters, liver ultrasonography, which represents the current standard for HCC surveillance, has a decreased diagnostic accuracy in patients with NAFLD, and therefore disease-specific surveillance tools will be required for the early identification of HCC in this population. In this review, we summarize the most recent evidence on the epidemiology and risk factors for HCC in patients with NAFLD, with and without cirrhosis, and the evidence supporting surveillance for early HCC detection in these patients, reviewing the potential limitations of currently recommended surveillance strategies, and assessing data on the accuracy of potential new screening tools. At this stage it is difficult to propose general recommendations, and best clinical judgement should be exercised, based on the profile of risk factors specific to each patient.


Safety Evaluation of Green Tea Polyphenols Consumption in Middle-aged Ovariectomized Rat Model.
This work evaluates chronic safety in middle-aged ovariectomized rats supplemented with different dosages of green tea polyphenols (GTP) in drinking water. The experiment used 6-mo-old sham (n = 39) and ovariectomized (OVX, n = 143) female rats. All sham (n = 39) and 39 of the OVX animals received no GTP treatment and their samples were collected for outcome measures at baseline, 3 mo, and 6 mo (n = 13 per group for each). The remaining OVX animals were randomized into 4 groups receiving 0.15%, 0.5%, 1%, and 1.5% (n = 26 for each) of GTP (wt/vol), respectively, in drinking water for 3 and 6 mo. No mortality or abnormal treatment-related findings in clinical observations or ophthalmologic examinations were noted. No treatment-related macroscopic or microscopic findings were noted for animals administered 1.5% GTP supplementation. Throughout the study, there was no difference in the body weight among all OVX groups. In all OVX groups, feed intake and water consumption significantly decreased with GTP dose throughout the study period. At 6 mo, GTP intake did not affect hematology, clinical chemistry, and urinalysis, except for phosphorus and blood urea nitrogen (increased), total cholesterol, lactate dehydrogenase, and urine pH (decreased). This study reveals that the no-observed-adverse-effect level (NOAEL) of GTP is 1.5% (wt/vol) in drinking water, the highest dose used in this study.


Lectin, hemolysin and protease inhibitors in seed fractions with ovicidal activity against Haemonchus contortus.
Bioactive molecules of plant species are promising alternatives for the chemical control of gastrointestinal nematodes in ruminants. Extracts of native and exotic seed species from Brazil's semi-arid region were tested in vitro in an egg hatch assay and the bioactivity of their proteins was investigated. Each seed species was subjected to three extractions with three types of solvents. All the seeds showed ovicidal activity, which varied according to the solvents. Higher ovicidal activity was found in the molecule fractions of low molecular weight (<12 kDa) for Albizia lebbeck, Ipomoea asarifolia, Jatropha curcas, Libidibia ferrea, Moringa oleifera and Ricinus communis (P<0.05, Bonferroni test). The two fractions of Crotalaria spectabilis showed the same ovicidal activity (P>0.05, Bonferroni test). Hemagglutinating activity was detected in the fractions of C. spectabilis and M. oleifera fractions, hemolysin activity in the A. lebbeck and M. oleifera fractions, serine protease inhibitory activity in the A. lebbeck, I. asarifolia, J. curcas, M. oleifera and R. communis fractions, cysteine protease inhibitor activity in the M. oleifera fraction, and no protein activity in the L. ferrea fraction. The results of this work reveal new plant species with a potential for use in controlling nematode parasites in goats, thus opening a new field of research involving plant protein molecules with ovicidal properties.


Exploring Multilevel Factors for Family Engagement in Home Visiting Across Two National Models.
The associations of family, home visitor and site characteristics with family engagement within the first 6 months were examined. The variation in family engagement was also explored. Home visiting program participants were drawn from 21 Healthy Families America sites (1707 families) and 9 Nurse-Family Partnership sites (650 families) in New Jersey. Three-level nested generalized linear mixed models assessed the associations of family, home visitor and site characteristics with family receipt of a high dose of services in the first 6 months of enrollment. A family was considered to have received a high dose of service in the first 6 months of enrollment if they were active at 6 months and had received at least 50% of their expected visits in the first 6 months. In general, both home visiting programs engaged, at a relatively high level (Healthy Families America (HFA) 59%, Nurse-Family Partnership (NFP) 64%), with families demonstrating high-risk characteristics such as lower maternal education, maternal smoking, and maternal mental health need. Home visitor characteristics explained more of the variation (87%) in the receipt of services for HFA, while family characteristics explained more of the variation (75%) in the receipt of services for NFP. At the family level, NFP may improve the consistency with which they engage families by increasing retention efforts among mothers with lower education and smoking mothers. HFA sites seeking to improve engagement consistency should consider increasing the flexible in home visitor job responsibilities and examining the current expected-visit policies followed by home visitors on difficult-to-engage families.


Detection of antibodies to Toxoplasma gondii in wild animals in Brazil.
Toxoplasmosis is a worldwide zoonosis caused by an obligate intracellular protozoan parasite, Toxoplasma gondii, that affects all warm-blooded animals, including wild animals. The increased number of cases of parasitic infections is mainly due to the destruction of environmental conservation areas, which is driving wild animals out of their habitats and towards urban areas. In this study, the occurrence of T. gondii infection was investigated by the modified agglutination test (MAT) in 26 different species of run over and injured wild animals that were treated at a Brazilian university veterinary hospital, from June 2007 to August 2008. Of the studied animals, six (23.1%; CI95% 11.1-42.2%) had T. gondii antibodies, with titers equal to 10 (4; 66.7%) and 40 (2; 33.3%). The species Pseudalopex vetulus, Cerdocyon thous, Hydrochoerus hydrochaeris and Tapyrus terrestris had titers of 10, while Alouatta caraya and Puma concolor had titers of 40. There was no significant association regarding age, gender or purpose of care (p > 0.05). Carnivorous, herbivorous and omnivorous wild animals are potential sentinels of human toxoplasmosis, especially when wild felids are present, maintaining the environmental contamination.


Chemically modified mRNA beyond COVID-19: Potential preventive and therapeutic applications for targeting chronic diseases.
Chemically modified mRNA represents a unique, efficient, and straightforward approach to produce a class of biopharmaceutical agents. It has been already approved as a vaccination-based method for targeting SARS-CoV-2 virus. The COVID-19 pandemic has highlighted the prospect of synthetic modified mRNA to efficiently and safely combat various diseases. Recently, various optimization advances have been adopted to overcome the limitations associated with conventional gene therapeutics leading to wide-ranging applications in different disease conditions. This review sheds light on emerging directions of chemically modified mRNAs to prevent and treat widespread chronic diseases, including metabolic disorders, cancer vaccination and immunotherapy, musculoskeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.


Comparative study of the sorption of clomipramine and viloxazine hydrochlorides in Stedim 6 and PVC bags.
The stability of two antidepressant drugs, clomipramine and viloxazine hydrochlorides, was studied as was their possible sorption on Stedim 6, a new multilayer polyethylene-lined film, which was considered comparatively to polyvinyl chloride (PVC) and glass surfaces. Appropriate amounts of the drugs were added to 500 ml of 5% dextrose and 0.9% sodium chloride solutions in Stedim 6 and PVC bags, and in glass flasks, in order to obtain the concentrations currently used in clinical practice. All the containers were stored at room temperature in daylight for 72 hours. Samples were taken at various times and evaluated for remaining drug concentrations by UV spectrometry. The two drugs appeared stable under the given conditions. No concentration decrease was observed in glass flasks. Viloxazine hydrochloride showed an excellent compatibility with the PVC bags, but a slight concentration decrease (about 6-7% in 72 hours) was observed for clomipramine hydrochloride, depending on the contact duration. The compatibility of the two drugs with the new material Stedim 6 was found to be perfect. The behavioral differences observed between the two drugs with regard to PVC are explained in terms of differences of lipophilicity of the drugs. Those observed for a given drug with regard to the two materials are due to the crystalline structure of polyethylene and the amorphous one of PVC.


Butaclamol in the treatment of schizophrenia. A standard-controlled clinical trial.
A 16-week, standard-controlled, double-blind study was conducted to compare the efficacy of butaclamol with that of fluphenazine in the treatment of 24 newly admitted schizophrenic patients. Statistically significant improvement occurred in the entire population in the total scores of the BPRS and PAS; in the activation, anergia, thought disturbance and hostile/suspiciousness factor scores of the BPRS; and in the scores of 9 of the 12 factors of the PAS. There were no statistically significant differences between the scores of the two treatment groups on the total or factor scores of either scale during the course of the clinical trial. The most frequently occurring adverse effects in the butaclamol group were rigidity, akathisia and excitement/agitation. The most frequently occurring adverse effects in the fluphenazine group were insomnia, decreased motor activity and tremor. It is concluded that butaclamol exerts potent neuroleptic effects on schizophrenic patients.


What defines the maternal transcriptome?
In somatic cells, RNA polymerase II (Pol II) transcription initiation starts by the binding of the general transcription factor TFIID, containing the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs), to core promoters. However, in growing oocytes active Pol II transcription is TFIID/TBP-independent, as during oocyte growth TBP is replaced by its vertebrate-specific paralog TBPL2. TBPL2 does not interact with TAFs, but stably associates with TFIIA. The maternal transcriptome is the population of mRNAs produced and stored in the cytoplasm of growing oocytes. After fertilization, maternal mRNAs are inherited by the zygote from the oocyte. As transcription becomes silent after oocyte growth, these mRNAs are the sole source for active protein translation. They will participate to complete the protein pool required for oocyte terminal differentiation, fertilization and initiation of early development, until reactivation of transcription in the embryo, called zygotic genome activation (ZGA). All these events are controlled by an important reshaping of the maternal transcriptome. This procedure combines cytoplasmic readenylation of stored transcripts, allowing their translation, and different waves of mRNA degradation by deadenylation coupled to decapping, to eliminate transcripts coding for proteins that are no longer required. The reshaping ends after ZGA with an almost total clearance of the maternal transcripts. In the past, the murine maternal transcriptome has received little attention but recent progresses have brought new insights into the regulation of maternal mRNA dynamics in the mouse. This review will address past and recent data on the mechanisms associated with maternal transcriptome dynamic in the mouse.


Restricted access media-molecularly imprinted polymer for propranolol and its application to direct injection analysis of beta-blockers in biological fluids.
A restricted access media-molecularly imprinted polymer (RAM-MIP) for propranolol (PRP) has been prepared for direct injection analysis of beta-blockers in biological fluids. First, the MIP for PRP was prepared using methacrylic acid and ethylene glycol dimethacrylate as the functional monomer and cross-linker, respectively, by a multi-step swelling and polymerization method. Next, a 1:1 mixture of glycerol monomethacrylate and glycerol dimethacrylate was used for hydrophilic surface modification, and added directly to the MIP for PRP after 4 h from the start of polymerization. Then further polymerization was carried out for 20 h. The obtained RAM-MIP for PRP showed excellent molecular recognition ability for PRP, good ones for alprenolol (ALP) and pindolol, and fair ones for other beta-blockers. The RAM-MIP was applied for direct injection analysis of ALP enantiomers in a rat plasma sample by a column-switching HPLC system using a beta-cyclodextrin phenylcarbamate-bonded silica column as the analytical column. The calibration graph, constructed from peak area versus each ALP enantiomer concentration, was linear with a correlation coefficient of > 0.999 over the concentration ranges of 12.5-250 ng ml(-1). The limit of quantitation was 12.5 ng ml(-1) with a 50 microl injection. This method could be applicable for the assay of ALP enantiomers at the therapeutic plasma levels, and have wide applicability for the assay of beta-blockers in biological fluids.


Hormesis, cellular stress response, and redox homeostasis in autism spectrum disorders.
In the United States, 1.1-1.5% of children have been diagnosed with autism spectrum disorders (ASD), corresponding to a 30% increase in incidence and prevalence. Social and communication impairments are the main signs and symptoms of ASD, and currently available medications have been ineffective in reducing these core deficits. Observational studies have indicated that children with ASD tend to show improved cognition and behavior after febrile illness, which is associated with alteration of metabolic pathways, leading to cellular stress responses and increased expression of heat shock proteins (Hsps). Sulforaphane and hydroxytyrosol, phytochemicals derived from cruciferous vegetables and extra virgin olive oil, respectively, can induce metabolic effects in cellular stress responses that are similar to those produced by fever. Thus, modulation of endogenous cellular defense mechanisms may be an innovative approach for therapeutic intervention in ASD and other disorders associated with neuroinflammation and neurodegeneration. This Review introduces the hormetic dose-response concept and presents possible mechanisms and applications for neuroprotection. We address the emerging role of Hsps in the neuroprotective network of redox stress-responsive mechanisms and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of ASD. We argue that such research findings must be approached with pragmatism and prudence. It is vital to capitalize on recent and ongoing investments in brain science research and to refine neuroscientific knowledge and capability for more accurate diagnosis and safe, effective, and ethically sound treatment of ASD and other neuropsychiatric spectrum disorders. © 2016 Wiley Periodicals, Inc.


Regulation of the Raf kinase by phosphorylation.
The Raf serine/threonine kinase plays an essential role to relay intracellular signals from the protooncogene Ras to activation of the mitogen-activated protein kinase (MAPK) cascade. The Raf kinase family consists of C-Raf (Raf-1), B-Raf, and A-Raf. Extensive efforts have been made in the last decade to study Raf regulation; however, precise molecular mechanism for Raf activation is still not fully understood. In this report, we discuss the current model of Raf regulation. Here we also report our recent findings that phosphorylation of Thr598 and Ser601, which lie between kinase subdomains VII and VIII, is essential for B-Raf activation by Ras. Substitution of these residues to alanine (B-RafAA) abolished Ras-induced B-Raf activation, without altering the association of B-Raf with other signaling proteins. Phosphopeptide mapping and immunoblotting with phosphospecific antibodies, which selectively recognize Thr598 and Ser601, phosphorylated B-Raf, confirmed that Thr598 and Ser601 are in vivo phosphorylation sites induced by Ras. Further, replacement of these two sites with acidic residues (B-RafED) renders B-Raf constitutively active. Consistent with these data, B-RafAA and B-RafED exhibited diminished and enhanced ability, respectively, to stimulate extracellular signal-regulated kinase (ERK) and Elk-dependent transcription. Moreover, functional studies revealed that B-RafED was able to promote NIH3T3 cell transformation and PC12 cell differentiation. Because Thr598 and Ser601 are conserved in all Raf family members, from Caenorhabditis elegans to mammals, we propose that phosphorylation of these two residues may be a general mechanism for Raf activation.


Effect of a contact lens on mouse retinal in vivo imaging: Effective focal length changes and monochromatic aberrations.
For in vivo mouse retinal imaging, especially with Adaptive Optics instruments, application of a contact lens is desirable, as it allows maintenance of cornea hydration and helps to prevent cataract formation during lengthy imaging sessions. However, since the refractive elements of the eye (cornea and lens) serve as the objective for most in vivo retinal imaging systems, the use of a contact lens, even with 0 Dpt. refractive power, can alter the system's optical properties. In this investigation we examined the effective focal length change and the aberrations that arise from use of a contact lens. First, focal length changes were simulated with a Zemax mouse eye model. Then ocular aberrations with and without a 0 Dpt. contact lens were measured with a Shack-Hartmann wavefront sensor (SHWS) in a customized AO-SLO system. Total RMS wavefront errors were measured for two groups of mice (14-month, and 2.5-month-old), decomposed into 66 Zernike aberration terms, and compared. These data revealed that vertical coma and spherical aberrations were increased with use of a contact lens in our system. Based on the ocular wavefront data we evaluated the effect of the contact lens on the imaging system performance as a function of the pupil size. Both RMS error and Strehl ratios were quantified for the two groups of mice, with and without contact lenses, and for different input beam sizes. These results provide information for determining optimum pupil size for retinal imaging without adaptive optics, and raise critical issues for design of mouse optical imaging systems that incorporate contact lenses.


An audit of hospital mortality: general compared with vascular surgery.
We have prospectively analysed hospital mortality for general and vascular surgical patients on a single surgical unit. During 1990, 1277 patients were admitted (836 general, 368 vascular, 73 varicose veins). The mortality for the general surgical patients was 1.3 per cent, vascular 6.2 per cent and no varicose vein patients died. All of the general surgical deaths and 70 per cent of the vascular deaths were in-patients admitted as an emergency. The major causes of death in general surgical patients were peritonitis and gastrointestinal bleeding, whilst those of the vascular patients were ruptured abdominal aortic aneurysms and acutely ischaemic legs. The implications of these findings are discussed.


Diuretics as initial and sole treatment in chronic cardiac failure.
Six patients with chronic congestive cardiac failure, who had never received any drug treatment, were studied before and after one month of therapy with frusemide alone at a dose of 40 mg a day. Measurements were made at rest of plasma epinephrine, norepinephrine, renin activity, aldosterone, atrial natriuretic peptide, cortisol, growth hormone and prolactin, together with central hemodynamics, body fluid volumes and renal function. The initial measurements of hemodynamics, body fluid compartments and renal function confirmed the presence of the physiopathology typical of congestive cardiac failure. Plasma concentrations of norepinephrine, atrial natriuretic peptide, aldosterone and growth hormone were significantly increased. The mean value of plasma renin activity, although high, was not significantly different from normal. After one month of treatment, body weight, body fluid volumes and exchangeable sodium were reduced. Hemodynamics and renal plasma flow and glomerular filtration were not significantly affected. Plasma norepinephrine fell to within normal limits; atrial natriuretic peptide increased significantly; plasma renin activity and cortisol increased to levels which were abnormally high; growth hormone increased to levels similar to those associated with acromegaly. Increased circulating concentrations of atrial natriuretic peptide during treatment by frusemide may have an important influence on the kidney, blood vessels and neuro-endocrine response.


How to Identify Invasive Candidemia in ICU-A Narrative Review.
The incidence of invasive fungal infection in ICUs has increased over time, and Candida spp. is the most common cause. Critical care patients are a particular set of patients with a higher risk of invasive fungal infections; this population is characterized by extensive use of medical devices such as central venous lines, arterial lines, bladder catheters, hemodialysis and mechanical intubation. Blood cultures are the gold standard diagnosis; still, they are not an early diagnostic technique. Mannan, anti-mannan antibody, 1,3-β-D-glucan, Candida albicans germ tube antibody, Vitek 2, PNA-FISH, MALDI-TOF, PCR and T2Candida panel are diagnostic promising microbiological assays. Scoring systems are tools to distinguish patients with low and high risk of infection. They can be combined with diagnostic tests to select patients for pre-emptive treatment or antifungal discontinuation. Candidemia is the focus of this narrative review, an approach to contributing factors and diagnosis, with an emphasis on critical care patients.


Levels of IgD in patients with rheumatoid arthritis.
It has been proposed that IgD may have a pathophysiological role in certain autoimmune diseases, since antinuclear IgD antibodies were revealed in patients with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerodermia. The studies on the problem of evaluation of serum IgD levels in patients with rheumatoid arthritis (RA) are scanty and their results are controversial. We studied IgD levels in patients with RA in order to demonstrate possible correlations with selected immunologic parameters, and to determine the relevance of IgD quantitation in the diagnosis of RA. We determined IgD levels in 30 patients with classic or proven RA, and in 30 age and sex-matched volunteers. Immunoglobulins of A, M, G classes were also determined. E-rosettes were assayed by the method of Jondal et al. in a modification. The distribution of IgD concentrations in donors revealed two modes, and also showed bimodal distributions in the patients. IgG and IgA levels were practically equal in the IgD-positive patients, but IgM was significantly lower than in the IgD-negative subjects. E-rosette values were also different in these subgroups. IgD-positive patients had significantly higher numbers of E-rosettes (1254 +/- 215), compared to IgD-negative individuals (497 +/- 146). IgD was found more often in the seropositive patients to rheumatoid factor (60%) than in seronegative ones (33%) but the difference was not statistically significant.


Mesenteric venous thrombosis.
The prevalence of mesenteric venous thrombosis has increased over the past 2 decades with the routine use of contrast-enhanced computed tomography (CT) in patients presenting with abdominal pain and those with portal hypertension. Concurrent with increasing recognition, routine and frequent use of anticoagulation has reduced the need for surgical intervention and improved outcome in these patients. Acute thrombosis often presents with abdominal pain, whereas chronic disease manifests either as an incidental finding on CT or with features of portal hypertension. Contrast-enhanced CT diagnoses about 90% of cases. The presence of collateral circulation and cavernoma around a chronically thrombosed vein differentiates chronic from acute disease. The superior mesenteric vein is often involved, whereas involvement of the inferior mesenteric vein is rare. Associated portal venous thrombosis can be seen if the disease originates in the major veins instead of the small vena rectae. Thrombophilia and local abdominal inflammatory conditions are common causes. Management is aimed at preventing bowel infarction and recurrent thrombosis. Anticoagulation, the mainstay of management, has also been safely used in patients with cirrhosis and portal hypertension. This review discusses the pathogenesis of thrombosis of mesenteric veins, the diagnosis and differentiation from arterial ischemia, the emergence of the JAK2 (Janus kinase 2) sequence variation as a marker of thrombophilia and myelodysplastic neoplasms, and new anticoagulants. Algorithms for the management of acute and chronic mesenteric venous thrombosis are provided to help readers understand and remember the approach to the management of acute and chronic mesenteric venous thrombosis.


Comparison of the changes in sexual function of premenopausal and postmenopausal women following transvaginal mesh surgery.
The effect of transvaginal mesh (TVM) surgery on sexual function between premenopausal and postmenopausal women remains controversial. To compare the changes in sexual function of premenopausal and postmenopausal women following TVM repair. One hundred and fifty-two consecutive women with symptomatic pelvic organ prolapse (POP) stages II to IV were referred for TVM procedures at our hospitals. Sixty-eight women were included because they were sexually active and had complete follow-up. All subjects were divided into the premenopausal (N = 36) and postmenopausal (N = 32) groups. Preoperative and postoperative assessments included pelvic examination using the POP quantification (POP-Q) system and a personal interview with the Female Sexual Function Index (FSFI), Urogenital Distress Inventory (UDI-6), and Incontinence Impact Questionnaire (IIQ-7). The FSFI, UDI-6, and IIQ-7 questionnaires. The mean age, rates of hypertension, and previous hysterectomy were significantly higher in the postmenopausal group (P < 0.05) compared with the premenopausal group. As for the POP-Q analysis, there was a significant improvement at points Aa, Ba, C, Ap, and Bp (P < 0.001) in both groups except for total vaginal length (P > 0.05). Similarly, the UDI-6 and IIQ-7 scores significantly decreased postoperatively (P < 0.01). After POP surgery, the score of the dyspareunia domain decreased significantly in the premenopausal group (P < 0.01) but was not the case for the postmenopausal group (P > 0.05). There were no significant changes in other domains and total scores in both groups (P > 0.05). However, higher rates of worsening dyspareunia and total scores were noted in the premenopausal group (P = 0.03 vs. 0.033). TVM procedure is effective for the anatomical restoration of POP. However, individual domain of FSFI such as dyspareunia may worsen in the premenopausal women. Additionally, our results revealed that over one third of premenopausal women could have a worsening sexuality domain postoperatively, with significantly higher rate of deteriorated dyspareunia and total FSFI scores than postmenopausal women.


Communication tools and sources of education and information: a national survey of rural and remote nurses.
This study examined accessibility of communication tools in the workplace, use of education to update nursing knowledge, and use of information to make specific decisions in practice among registered nurses (RNs) and licensed practical nurses (LPNs) in rural and remote communities in Canada. Data were analyzed from the cross-sectional survey, "Nursing Practice in Rural and Remote Canada II," of regulated nurses practicing in all provinces and territories of Canada. Data were collected from April 2014 to August 2015. The survey was completed by 3,822 of 9,622 nurses (40% response), and the present analysis was conducted with a subsample of 2,827 nurses. High-speed Internet was the most accessible communication tool, and nurses used "online/electronic education" more often than "in-person education" to update their nursing knowledge. Internet searches were used more often than several other online/electronic sources to inform decision making. Compared to LPNs, RNs reported greater workplace access to most communication tools and greater use of online/electronic education as well as information sources in online/electronic and print formats. Compared to nurses in community-based health care and hospital settings, nurses in long-term care settings reported lower access to most communication tools, lower use of online/electronic and in-person education, and lower use of online/electronic information. Access to continuing education and up-to-date information is important for effective patient care. This study points to a need for further research on the continuing education and information needs of rural and remote RNs and LPNs, and on their capacity to incorporate and apply new knowledge in practice.


Construction of new ligand binding sites in proteins of known structure. II. Grafting of a buried transition metal binding site into Escherichia coli thioredoxin.
In an accompanying paper a computational procedure is described, which introduces new ligand-binding sites into proteins of known structure. Here we describe the experimental implementation of one of the designs, which is intended to introduce a copper-binding site into Escherichia coli thioredoxin. The new binding site can be introduced with a minimum of four amino acid changes. The binding site is buried so that structural rules for making mutations in the hydrophobic core of a protein, as well as for the introduction of new functions, are being tested in this experiment. The mutant protein is folded even in the absence of metals, and variants that retain the original activity of thioredoxin can be isolated. The protein has gained a metal-binding site specific for transition metals. The metal co-ordination chemistry at the binding site varies depending on the metal that is introduced into it. Mercury(II) is co-ordinated in the expected manner. Copper(II) binds in a way that was not anticipated in the original design. It appears to use two of the four residues intended to form the co-ordination sphere, and two other residues that were not part of the original set of mutations. It is therefore necessary not only to introduce new functional groups to form a new site, but also to consider and remove alternative modes of binding.


Deliberate self-harm in the emergency department: experience from Karachi, Pakistan.
Suicidal behavior is an understudied subject in Pakistan, a South-Asian developing country with a predominantly Muslim population. This study examined the characteristics and management of patients presenting with Deliberate Self-Harm (DSH) to the Emergency Department (ED) of a tertiary care teaching hospital in Karachi, Pakistan. A retrospective chart review of all patients (n = 98), over a period of 12 months was carried out. The demographic details of patients; method of DSH and, if drugs were used, their type, route, and quantity; reason for DSH; past psychiatric history; and outcome were recorded. The mean age of subjects was 23.5 years. The majority of patients were female; most had used drugs for DSH. After initial treatment in the ED, 34 patients were admitted to medical wards for further treatment, 12 were discharged from ED, while 52 patients left against medical advice. The main reasons for leaving against medical advice were financial constraints and fear of legal issues. Seven patients had at least one previous episode of DSH. Patients who left the ED without psychosocial assessment are at increased risk for repetition of DSH as well as suicide.


Current Controversies in Caring for the Critically Ill Pulmonary Embolism Patient.
Emergency physicians must be prepared to rapidly diagnose and resuscitate patients with pulmonary embolism (PE). Certain aspects of PE resuscitation run counter to typical approaches. A specific understanding of the pathophysiology of PE is required to avoid cardiovascular collapse potentially associated with excessive intravenous fluids and positive pressure ventilation. Once PE is diagnosed, rapid risk stratification should be performed and treatment guided by patient risk class. Although anticoagulation remains the mainstay of PE treatment, emergency physicians also must understand the indications and contraindications for thrombolysis and should be aware of new therapies and models of care that may improve outcomes.


Stress, pre-term labour and birth outcomes.
Stress, pre-term labour and birth outcomes Preliminary studies have suggested that stress may be associated with the onset, treatment and outcomes of pre-term labour; however, a systematic comparison of the stress of women with and without pre-term labour has not been reported. Therefore, the purpose of this exploratory study was to compare the stress (daily hassles and mood states) and birth outcomes of black and white women who experienced pre-term labour (PTL) during pregnancy with those who did not. The convenience sample consisted of 35 pregnant women hospitalized in 1996-1997 for the treatment of PTL (24-35 weeks gestation) and 35 controls matched on age, race, parity, gestational age and method of hospital payment. Women in the PTL group had significantly higher tension-anxiety and depression-dejection on the Profile of Mood States (POMS), lower mean birthweight and mean gestational age, and a higher percentage of babies born <37 weeks and weighing 2500 g or less. Black women in the PTL group and white women in the control group had significantly higher scores on the fatigue sub-scale of the POMS and the work and future security sub-scales of the Daily Hassles Scale. Women in the PTL group whose babies weighed 2500 g or less had significantly higher scores on the health, inner concern and financial responsibility sub-scales of the Daily Hassles Scale. The findings from this study indicate the need for further exploration of the interaction of race and stress in understanding and preventing PTL and low birthweight and the need to examine the role of social support in preventing pre-term birth after an episode of PTL.


Challenging proximal hypospadias repairs: An evolution of technique for two stage repairs.
Proximal hypospadias repair remains challenging. Our approach to the first stage of two-stage proximal hypospadias repairs has evolved from using Byars' flaps to preputial inlay grafts in anatomically suitable cases and pedicled preputial flaps in more complex repairs. We reviewed our outcomes, hypothesizing that inlay grafts and pedicled preputial flaps were associated with lower complication risks than Byars' flaps. A single institution, retrospective, cohort study of consecutive two-stage, primary, proximal hypospadias repairs performed from 2007 to 2017 was conducted. Patients with <6 months follow-up and incomplete operative reports were excluded. Risk of complications (fistula, dehiscence, diverticulum, meatal stenosis, stricture) were evaluated following urethroplasty and stratified by first-stage repair technique. As technique refinements have been made since 2012, comparisons between two temporal subgroups (those who underwent repair in 2007-2012 and in 2013-2017) were made. 78 of 127 patients met inclusion criteria. Overall complication rate was 47% (Summary Table). Median follow-up was 25.4 months (range 6.4-128.5 months) after urethroplasty. Pedicled preputial flaps (hazards ratio [HR] 0.30; 95% Confidence Interval [CI] 0.14-0.65) and inlay grafts (HR 0.32; 95% CI 0.11-0.95) were associated with lower complication risks compared to Byars' flaps (Summary Table). Median time to complication was significantly shorter for Byars' flaps (5.7 months) than for inlay grafts (40.6 months) and pedicled preputial flaps (79.2 months) by Kaplan Meier analysis. Temporal subgroup comparisons showed that overall complication rates decreased from 70% to 31% (p = 0.001), but differences in complication rates by first-stage technique were not statistically significant. In our cohort, repairs with Byars' flaps had the highest complication rate, which is consistent with our observations that urethras tubularized from Byars' flaps lack appropriate backing and are hypermobile and irregular. To overcome these shortcomings, modifications were made to our approach to two-stage proximal hypospadias repairs with the use of inlay grafts and pedicled preputial flaps quilted to the underlying corporal bodies to optimize the stability of the urethral plate. Our preliminary results are promising. Approach to the first stage of two-stage repairs affects outcomes. Pedicled preputial flaps and inlay grafts were associated with lower complication risks than Byars' flaps. Refinement of technique and patient selection may have resulted in fewer complications in the short term. However, long-term follow-up is needed.


Prevalence and characteristics of overweight and obesity in indigenous Australian children: A systematic review.
Evidence-based profiling of obesity and overweight in Indigenous Australian children has been poor. This study systematically reviewed evidence of the prevalence and patterns of obesity/overweight, with respect to gender, age, remoteness, and birth weight, in Indigenous Australian children, 0-18 years (PROSPERO CRD42014007626). Study quality and risk of bias were assessed. Twenty-five publications (21 studies) met inclusion criteria, with large variations in prevalence for obesity or overweight (11 to 54%) reported. A high degree of heterogeneity in study design was observed, few studies (6/21) were representative of the target population, and few appropriately recruited Indigenous children (8/21). Variability in study design, conduct, and small sample sizes mean that it is not possible to derive a single estimate for prevalence although two high-quality studies indicate at least one in four Indigenous Australian children are overweight or obese. Four of six studies reporting on gender, found overweight/obesity higher in girls and eight studies reporting on overweight/obesity by age suggest prevalence increases with age with one high quality large national study reporting total overweight/obesity as 22.4% of children aged 2-4 years, 27.5% of those aged 5-9, 38.5% aged 10-14, and 36.3% aged 15-17. Three of four studies, reporting obesity/overweight by region, found lower rates for children living in more remote areas than urban areas.


Immunohistochemical expression of ATRX in gliomas.
Glioma is one of the primary tumors of the central nervous system that occurs in the spinal cord or brain and the origin of the tumor is from glial cell cells. The most common site of glioma tumors is the brain. Glioma accounts for 30% of all central nervous system tumors and 80% of malignant brain tumors. Alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations are frequently distinguished in gliomas. Current research is an attempt to assess ATRX immunoexpression in different types of gliomas diagnosed, in Erbil-Iraq, and to evaluate its association with patient's age, gender, tumor location, grade and type. From January 2015 to January 2017, we reviewed and analyzed 97 cases of glioma. Immunohistochemical staining, for ATRX, was performed using an automated immunostainer technique. According to the WHO grading system for brain tumors, 16 (16.5%) cases were grade I gliomas, 27 (27.8%) were grade II, 10 (10.3%) were anaplastic gliomas (grade III), and 44 (45.3%) cases were glioblastomas WHO (grade IV). Positive ATRX immunoexpression was demonstrated in 27 (27.8%) cases. The highest rates of ATRX expression (55.6%) were among 30-39 years' age group, supratentorial (34.2%), and among grade II and III tumors (40.7% and 30% respectively). A significant association was observed between ATRX expression and patient's age, tumor location, tumor type and grade (p-values 0.010, 0.004, 0.004, and 0.037 respectively). No significant association was found between ATRX expression and patient's gender (p-value 0.097). It was found that ATRX is frequently expressed in grade II and III astrocytomas and was significantly related to the patient's age, tumor location, type and grade, so it can be used as a good diagnostic and prognostic indicator for glioma.


Telerehabilitation for persons with multiple sclerosis.
Telerehabilitation, an emerging method, extends rehabilitative care beyond the hospital, and facilitates multifaceted, often psychotherapeutic approaches to modern management of patients using telecommunication technology at home or in the community. Although a wide range of telerehabilitation interventions are trialed in persons with multiple sclerosis (pwMS), evidence for their effectiveness is unclear. To investigate the effectiveness and safety of telerehabilitation intervention in pwMS for improved patient outcomes. Specifically, this review addresses the following questions: does telerehabilitation achieve better outcomes compared with traditional face-to-face intervention; and what types of telerehabilitation interventions are effective, in which setting and influence which specific outcomes (impairment, activity limitation and participation)? We performed a literature search using the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Review Group Specialised Register( 9 July, 2014.) We handsearched the relevant journals and screened the reference lists of identified studies, and contacted authors for additional data. Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) that reported telerehabilitation intervention/s in pwMS and compared them with some form of control intervention (such as lower level or different types of intervention, minimal intervention, waiting-list controls or no treatment (or usual care); interventions given in different settings) in adults with MS. Two review authors independently selected studies and extracted data. Three review authors assessed the methodological quality of studies using the GRADEpro software (GRADEpro 2008) for best-evidence synthesis. A meta-analysis was not possible due to marked methodological, clinical and statistical heterogeneity between included trials and between measurement tools used. Hence, we performed a best-evidence synthesis using a qualitative analysis. Nine RCTs, one with two reports, (N = 531 participants, 469 included in analyses) investigated a variety of telerehabilitation interventions in adults with MS. The mean age of participants varied from 41 to 52 years (mean 46.5 years) and mean years since diagnosis from 7.7 to 19.0 years (mean 12.3 years). The majority of the participants were women (proportion ranging from 56% to 87%, mean 74%) and with a relapsing-remitting course of MS. These interventions were complex, with more than one rehabilitation component and included physical activity, educational, behavioural and symptom management programmes.All studies scored 'low' on the methodological quality assessment. Overall, the review found 'low-level' evidence for telerehabilitation interventions in reducing short-term disability and symptoms such as fatigue. There was also 'low-level' evidence supporting telerehabilitation in the longer term for improved functional activities, impairments (such as fatigue, pain, insomnia); and participation measured by quality of life and psychological outcomes. There were limited data on process evaluation (participants'/therapists' satisfaction) and no data available for cost effectiveness. There were no adverse events reported as a result of telerehabilitation interventions. There is currently limited evidence on the efficacy of telerehabilitation in improving functional activities, fatigue and quality of life in adults with MS. A range of telerehabilitation interventions might be an alternative method of delivering services in MS populations. There is insufficient evidence to support on what types of telerehabilitation interventions are effective, and in which setting. More robust trials are needed to build evidence for the clinical and cost effectiveness of these interventions.


A simple genetic basis of adaptation to a novel thermal environment results in complex metabolic rewiring in Drosophila.
Population genetic theory predicts that rapid adaptation is largely driven by complex traits encoded by many loci of small effect. Because large-effect loci are quickly fixed in natural populations, they should not contribute much to rapid adaptation. To investigate the genetic architecture of thermal adaptation - a highly complex trait - we performed experimental evolution on a natural Drosophila simulans population. Transcriptome and respiration measurements reveal extensive metabolic rewiring after only approximately 60 generations in a hot environment. Analysis of genome-wide polymorphisms identifies two interacting selection targets, Sestrin and SNF4Aγ, pointing to AMPK, a central metabolic switch, as a key factor for thermal adaptation. Our results demonstrate that large-effect loci segregating at intermediate allele frequencies can allow natural populations to rapidly respond to selection. Because SNF4Aγ also exhibits clinal variation in various Drosophila species, we suggest that this large-effect polymorphism is maintained by temporal and spatial temperature variation in natural environments.


Observational evaluation of sertaconazole nitrate cream 2% in the treatment of pruritus related to tinea pedis.
Tinea pedis typically presents as a pruritic, erythematous, and scaly eruption on the foot, with symptoms correlated with the severity of infection. Although many clinical studies have assessed the antifungal action of various agents, relatively little attention has been devoted to evaluating if antifungal agents are capable of improving subjective symptoms while treating the infection. A single-center, open-label, observational, proof of concept study was conducted in 21 participants (age range, 16-74 years) to evaluate if sertaconazole nitrate cream 2% used twice daily for 7 days was able to reduce participants' perceived itching while treating the infection. Findings included participants' overall assessment of quality of life (QOL) with the Dermatology Life Quality Index (DLQI) and participants' overall satisfaction with treatment. The pruritus visual analog scale (VAS) was used to assess the subjective symptom of itching. Results indicated the mean total score of changes in perception of QOL was 8.95 at baseline and 3.38 at day 7, a within-group change of -5.57 (P < .0001), and the mean reduction in reported itching from baseline to day 7 was -63.10% (P < .0001). Fifteen of 21 participants (71.4%) were somewhat or very satisfied with the results of their treatment. The implication of these findings is that successful elimination of the inflammatory symptoms of tinea. pedis, such as pruritus, may promote adherence to therapy by directly affecting participants' perception of QOL. Furthermore, early and rapid relief of symptoms, as seen in this study, may encourage patients to continue therapy for the full recommended period of 4 to 6 weeks, thereby reducing the risk for relapse that leads to chronic disease.


Caspase cleavage of the amyloid precursor protein is prevented after overexpression of bcl-2 in a triple transgenic mouse model of Alzheimer's disease.
A recent study demonstrated the lack of beta-amyloid (Abeta) plaque formation and accumulation of the amyloid precursor protein (APP) in a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) following overexpression of the anti-apoptotic protein, Bcl-2 (Rohn et al., J. Neurosci. 28: 3051-9, 2008). The supposition from that study was the accumulation of APP resulted from a decrease in caspase-mediated processing of APP. To determine a direct role for the caspase-cleavage of APP in 3xTg-AD mice, we designed a site-directed caspase-cleavage antibody to APP and demonstrated it is a specific marker for caspase-cleaved APP. Application of this antibody revealed neuronal staining in the hippocampus and subiculum of 3xTg-AD mice. These results were confirmed utilizing a similar site-directed antibody to caspase-cleaved APP (APPneo). The caspase cleavage of APP as well as the formation of extracellular Abeta plaques was prevented in 3xTg-AD animals overexpressing Bcl-2. These results provide further support that caspases play a proximal role in promoting the pathology associated with AD.


Meat and fish consumption and the risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition.
Renal cell cancer (RCC) incidence varies worldwide with a higher incidence in developed countries and lifestyle is likely to contribute to the development of this disease. We examined whether meat and fish consumption were related to the risk of RCC in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 493,179 EPIC participants, recruited between 1992 and 2000. Until December 2008, 691 RCC cases have been identified. Meat and fish consumption was assessed at baseline using country-specific dietary assessment instruments; 24-hour recalls were applied in an 8% subsample for calibration purposes. Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Women with a high consumption of red meat (HR = 1.36, 95% CI 1.14-1.62; calibrated, per 50 g/day) and processed meat (HR = 1.78, 95% CI 1.05-3.03; calibrated, per 50 g/day) had a higher risk of RCC, while no association existed in men. For processed meat, the association with RCC incidence was prominent in premenopausal women and was lacking in postmenopausal women (p interaction = 0.02). Neither poultry nor fish consumption were statistically significantly associated with the risk of RCC. The results show a distinct association of red and processed meat consumption with incident RCC in women but not in men. A biological explanation for these findings remains unclear.


A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia.
Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).