Determination of the Concentration of Heavy Metals in Artisanal Cheeses Produced in the Mexican States of Tabasco and Chiapas.
Cheese consumption provides humans with minerals, proteins, carbohydrates, and vitamins. In Mexico, several cheese varieties are produced, each with its texture, scent, and flavor. The artisanal cheeses made in the states of Tabasco and Chiapas-including, among others, the varieties named crema (cream), doble crema (double cream), oaxaca, panela, fresco, bola, poro, cotija, and asadero-have a high demand in the domestic and foreign markets. The intensification of anthropic activity in these states causes an increased emission to the environment of contaminants like heavy metals, which could reach human foodstuffs through the food chains. In particular, heavy metal contents in cheeses consumed daily by these states' local populations might represent a public health risk. Because of that, our objectives in this work were to determine the concentrations of lead, cadmium, nickel, copper, zinc, and iron in artisanal cheeses produced in the states of Tabasco and Chiapas and to determine the values of the hazard quotient (HQ), total hazard quotient (THQ), and cancer risk total (CRT) for adult and young men and women. The results of our analyses of cheese samples from the states of Tabasco and Chiapas showed that the average concentrations (mg kg-1) of cadmium (0.0023 ± 0.002, 0.0023 ± 0.002 mg kg-1, respectively, for each state), lead (0.0047 ± 0.00, 0.0051 ± 0.002), nickel (0.0039 ± 0.0046, 0.0031 ± 0.0039), copper (0.0199 ± 0.021, 0.0202 ± 0.022), zinc (0.1611 ± 0.18, 0.194 ± 0.21), and iron (61.84 ± 4.23, 65.76 ± 6.61 mg kg-1), the first three values lower than the limits established by the FAO/WHO and Codex Alimentarius. The value of THQ that we obtained was less than one, and that of CRT was within the limits established by the US-EPA, which means that the consumption of artisanal cheeses from Tabasco and Chiapas by humans does not imply a risk of disease or cancer.


Learning from Errors.
Although error avoidance during learning appears to be the rule in American classrooms, laboratory studies suggest that it may be a counterproductive strategy, at least for neurologically typical students. Experimental investigations indicate that errorful learning followed by corrective feedback is beneficial to learning. Interestingly, the beneficial effects are particularly salient when individuals strongly believe that their error is correct: Errors committed with high confidence are corrected more readily than low-confidence errors. Corrective feedback, including analysis of the reasoning leading up to the mistake, is crucial. Aside from the direct benefit to learners, teachers gain valuable information from errors, and error tolerance encourages students' active, exploratory, generative engagement. If the goal is optimal performance in high-stakes situations, it may be worthwhile to allow and even encourage students to commit and correct errors while they are in low-stakes learning situations rather than to assiduously avoid errors at all costs.


The association between depression and leukocyte telomere length: a meta-analysis.
Telomeres protect the ends of chromosomes, and shorter leukocyte telomeres are associated with poor health. Depression may be associated with the shortening of leukocyte telomeres. The present study set out to consolidate the varying effect sizes found so far in studies of depression and telomere length and to identify moderators of the relationship between depression and telomere length. A meta-analytic investigation of the relationship between depression and leukocyte telomere length used information from 21,040 participants. A significant effect size, r = -.12, P < .001, indicated that depression was associated with shorter telomere length. Several variables significantly moderated effect size. Concurrent associations (k = 25) between depression and telomere length were significantly stronger than longitudinal associations (k = 5). Studies that used the Southern blot (k = 3) and fluorescent in situ hybridization (FISH; k = 2) assays to measure telomere length showed larger effect sizes than studies that used quantitative polymerase chain reaction (qPCR; k = 25). Finally, study reports that indicated that the telomere assays were conducted blind to depression level of participants (k = 11) had significantly lower effect sizes than those of other studies (k = 19). The significant relationship between depression and shorter telomere length is consistent with a theoretical model positing that distress, such as experienced in depression, results in physiological changes leading to shortened telomeres.


Optical Monitoring of Living Nerve Terminal Labeling in Hair Follicle Lanceolate Endings of the Ex Vivo Mouse Ear Skin.
A novel dissection and recording technique is described for optical monitoring staining and de-staining of lanceolate terminals surrounding hair follicles in the skin of the mouse pinna. The preparation is simple and relatively fast, reliably yielding extensive regions of multiple labeled units of living nerve terminals to study uptake and release of styryl pyridinium dyes extensively used in studies of vesicle recycling. Subdividing the preparations before labeling allows test vs. control comparisons in the same ear from a single individual. Helpful tips are given for improving the quality of the preparation, the labeling and the imaging parameters. This new system is suitable for assaying pharmacologically and mechanically-induced uptake and release of these vital dyes in lanceolate terminals in both wild-type and genetically modified animals. Examples of modulatory influences on labeling intensity are given.


Etiology of major limb amputations at a tertiary care centre in Malawi.
Amputations in low- and middle-income countries (LMICs) represent an important cause of disability and economic hardship. LMIC patients are young and suffer from preventable causes, such as trauma and trauma-related infections. We herein studied the etiology in amputations in a Malawian tertiary care hospital over a 9-year period. Operative and anaesthesia logs at Kamuzu Central Hospital (KCH) in Lilongwe, Malawi, were reviewed for 2008-2016. Baseline demographic and clinical variables and type of amputation performed were collected. Only major limb amputations, defined as above or below the knee, above or below the elbow, and above the wrist, were included in this study. A total of 610 patients underwent 630 major amputations during the study period. Of these, 170 (27%) patients were female, and the median age of the cohort was 39 (interquartile range [IQR] 25-55). Of these patients, 345 (54.8%) had infection or gangrene recorded among the indications for amputation, 203 (32.2%) had trauma, 94 (14.9%) had cancer and 67 (10.6%) had documented diabetes. Women underwent diabetes-related amputations more often than men (37 out of 67, or 56.1%), and were significantly younger when their amputations were due to diabetes (median age 48 vs 53 years old, P=0.004) or trauma (median age 21 vs 30 years old, P=0.02). The commonest operative procedures were below the knee amputations, at 271 (43%), and above the knee amputations, at 213 (33.8%). Amputations in Malawi affect primarily the young, in the most economically productive time of their lives, in contrast to amputees in high-income countries. Preventable causes, such as infection and trauma, lead to the majority of amputations. These etiologies represent an important primary prevention target for public health efforts in LMICs.


Lactobacillus diolivorans sp. nov., a 1,2-propanediol-degrading bacterium isolated from aerobically stable maize silage.
Inoculation of maize silage with Lactobacillus buchneri (5 x 10(5) c.f.u. g(-1) of maize silage) prior to ensiling results in the formation of aerobically stable silage. After 9 months, lactic acid bacterium counts are approximately 10(10) c.f.u. g(-1) in these treated silages. An important subpopulation (5.9 x 10(7) c.f.u. g(-1)) is able to degrade 1,2-propanediol, a fermentation product of L. buchneri, under anoxic conditions to 1-propanol and propionic acid. From this group of 1,2-propanediol-fermenting, facultatively anaerobic, heterofermentative lactobacilli, two rod-shaped isolates were purified and characterized. Comparative 16S rDNA sequence analysis revealed that the newly isolated bacteria have identical 16S rDNA sequences and belong phylogenetically to the L. buchneri group. DNA-DNA hybridizations, whole-cell protein fingerprinting and examination of phenotypic properties indicated that these two isolates represent a novel species, for which the name Lactobacillus diolivorans sp. nov. is proposed. The type strain is LMG 19667T (= DSM 14421T).


Modeling ion channel blockade at guarded binding sites: application to tertiary drugs.
Excitable membranes exposed to sodium channel blocking agents (D; local anesthetics and antiarrhythmic drugs) show a progressive reduction of peak sodium current when repetitively depolarized (use dependence). Thus, with repetitive excitation, use dependence reflects a net rightward shift in the balance between unblocked channels (U) and blocked channels (B): U + D in equilibrium with B. The modulated receptor hypothesis (a 7-parameter model) has been proposed to account for this shift and is based on a channel lumen binding site whose affinity varies with channel state and where drug-complexed channels exhibit modified inactivation gate kinetics. Alternatively, we consider use-dependent binding as the result of transient access to a constant-affinity binding site. In this setting, the channel gate conformation is viewed as controlling the flux of drug as it diffuses between drug pools and the binding site. Apparent variation in binding rates is therefore considered the result of variations in the fraction of accessible sites. This guarded receptor hypothesis, with three fewer parameters, is able to predict apparent changes in channel binding and apparent shifts in channel inactivation without incorporating modified gating parameters in drug-complexed channels. Furthermore, with this model one is able to characterize both relaxation kinetics and channel blockade associated with tertiary amines as well as hydrophobic and hydrophilic agents. The pH dependence of repriming rates is utilized to estimate several of the important parameters associated with this simplified hypothesis.


Demonstration of the diagnostic agreement of capillary and venous blood samples, using hepatitis-C virus SD Bioline© rapid test: A clinic-based study.
Simplifying hepatitis C virus (HCV) screening is a key step in achieving the elimination of HCV as a global public health threat by 2030. The objective of this study was to demonstrate the agreement of capillary blood and venipuncture specimens when using SD Bioline© HCV, a low-cost rapid diagnostic test (RDT), prequalified by WHO in 2016 on venous blood samples. Recruitment was conducted prospectively among adult patients presenting for HCV testing at the Médecins Sans Frontières (MSF) clinic of Preah Kossamak Hospital (Phnom Penh, Cambodia) between October and November 2017. Capillary and venous blood samples were collected from consenting patients and tested with SD Bioline© HCV. Two independent, blinded readers, and in the case of disagreement, a third reader, interpreted the results of each blood sample. Concordance between results was compared using Cohen's Kappa interrater reliability statistic. Discrepant sample pairs were tested with an enzyme immunoassay, the reference standard, at the Institute Pasteur of Cambodia. Among 421 pairs of samples collected, reader disagreement occurred for 0.7% (n = 3) of the participants. Sixty-four percent of capillary and venous blood sample pairs tested positive for HCV, with a Kappa statistic of 0.985 between the two methods. Three participants with discrepant sample pair results tested positive with EIA. Capillary and venous blood samples were concordant when tested with HCV SD Bioline© in a clinical context. This simplified testing approach is essential to the scale-up of HCV screening and useful in resource-limited settings or among populations for whom venipuncture is problematic.


Descriptive epidemiology of enteric disease in Chennai, India.
There are very few data on the prevalence of coccidian enteric parasites among low-income adults hospitalized in Chennai, India. Stool samples from 200 patients were screened for selected parasites, enteric bacterial pathogens, and other protozoa over a 3-month period. The study identified 42 (21%) Cryptosporidium, 36 (18%) V. cholerae, 17 (9%) Salmonella, 12 (6%) Isospora, six (3%) helminths, five (3%) Shigella, one (1%) Cyclospora, one (1%) other protozoan, and 0% V. parahaemolyticus cases. Co-infection was present in 21 patients. Cryptosporidium was detected in 17 (81%) of co-infected patients. Our findings highlighted the relatively high proportion of patients in this population with Cryptosporidium and Isospora and suggest that further study be undertaken to determine the utility of broader use of diagnostic testing for coccidian parasites in India. Detection may be beneficial because isosporiasis is treatable and both Isospora and Cryptosporidium are important pathogens in AIDS patients.


Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome.
Rapamycin was found to increase (11% to 16%) the lifespan of male and female C57BL/6J mice most likely by reducing the increase in the hazard for mortality (i.e., the rate of aging) term in the Gompertz mortality analysis. To identify the pathways that could be responsible for rapamycin's longevity effect, we analyzed the transcriptome of liver from 25-month-old male and female mice fed rapamycin starting at 4 months of age. Few changes (<300 transcripts) were observed in transcriptome of rapamycin-fed males; however, a large number of transcripts (>4,500) changed significantly in females. Using multidimensional scaling and heatmap analyses, the male mice fed rapamycin were found to segregate into two groups: one group that is almost identical to control males (Rapa-1) and a second group (Rapa-2) that shows a change in gene expression (>4,000 transcripts) with more than 60% of the genes shared with female mice fed Rapa. Using ingenuity pathway analysis, 13 pathways were significantly altered in both Rapa-2 males and rapamycin-fed females with mitochondrial function as the most significantly changed pathway. Our findings show that rapamycin has a major effect on the transcriptome and point to several pathways that would likely impact the longevity.


Enhanced acute response to corticosterone in genetically obese (ob/ob) mice.
Our previous work showed that ob/ob mice responded to physiological concentrations of blood corticosterone (maintained by implanted pellets of corticosterone in adrenalectomized mice) by increasing food intake and blood insulin concentration to a much greater extent than did lean mice. The present study sought to determine whether the chronic presence of corticosterone was necessary or whether a single injection would also have these effects. Lean and ob/ob mice were adrenalectomized at 4.5 wk of age, injected with corticosterone at 10.5 wk of age, and killed 6 or 15 h after injection. A markedly exaggerated hyperinsulinemia was seen in ob/ob mice at 15 h. Food intake increased in both lean and obese mice, and brown adipose tissue thermogenesis (as reflected by mitochondrial guanosine 5'-diphosphate binding) was suppressed in both. We conclude that the ob/ob mouse has an excessive central sensitivity and responsiveness to a rapid action of corticosterone that results in neural activation of insulin secretion and suppression of brown adipose tissue thermogenesis. The persistence of some degree of obesity in the adrenalectomized ob/ob mouse is attributed to the remaining slight hyperinsulinemia coupled with reduced energy expenditure due to persistent thermoregulation at a lower than normal body temperature.


Reducing gender bias in the evaluation and selection of future leaders: The role of decision-makers' mindsets about the universality of leadership potential.
Extensive research has documented organizational decision-makers' preference for men over women when they evaluate and select candidates for leadership positions. We conceptualize a novel construct-mindsets about the universality of leadership potential-that can help reduce this bias. People can believe either that only some individuals have high leadership potential (i.e., a nonuniversal mindset) or that most individuals have high leadership potential (i.e., a universal mindset). Five studies investigated the relationship between these mindsets and decision-makers' gender biases in leader evaluation and selection decisions. The more senior government officials in China held a universal mindset, the less they showed gender bias when rating their subordinates' leadership capability (Study 1). Working adults in the United Kingdom who held a more universal mindset exhibited less gender bias when evaluating and selecting job candidates for a leadership position (Study 2). In an experiment, Singaporean students exposed to a universal mindset exhibited less gender bias when evaluating and selecting candidates than those exposed to a nonuniversal mindset (Study 3). Another experiment with working adults in China replicated this pattern and added a control condition to confirm the directionality of the effect (Study 4). Last, Study 5 showed that a more universal mindset was associated with less gender bias particularly among decision-makers with stronger gender stereotypes in the domain of leadership. This research demonstrates that, although they are seemingly unrelated to gender, mindsets about the universality of leadership potential can influence the extent to which people express gender bias in the leadership context. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Gluten sensitivity enteropathy in patients with recurrent aphthous stomatitis.
Gluten sensitive enteropathy (GSE) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in susceptible individuals. Recurrent aphthous stomatitis (RAS) may be the sole manifestation of GSE. The aim of this study was to determine the prevalence of gluten sensitivity enteropathy (GSE) in a large group of patients with RAS and assess the efficacy of gluten free diet (GFD) on the improvement of aphthous lesions in those who were diagnosed with GSE. Two hundred and forty seven patients with RAS were included. The patients had at least three aphthous attacks per year. Patients were screened by IgA anti-endomysial antibody (EMA), IgA anti tissue transglutaminase (TTG) and serum IgA level. Those with a positive serology underwent endoscopic biopsies of the duodenal mucosa and patients with negative serology were excluded. The diagnosis of GSE was based on a positive serological test and abnormal duodenal histology. For patients with GSE, gluten free diet was recommended. Six out of 247 RAS patients had positive TTG test alone, and one had positive EMA and TTG. All 7 patients with positive serologic tests underwent duodenal biopsies. Histological findings were compatible with GSE in all of them (Marsh I in four patients, Marsh II in two patients and Marsh IIIB in one another.). The mean age of GSE patients was 27.42 +/- 10.56 (range, 13 to 40) years old. They were suffering from RAS for an average duration of 4.5 years. All of the 7 GSE patients had not responded to the routine anti-aphthae medications, including topical corticosteroids, tetracycline and colchicine. Four patients who adhered to a strict gluten-free diet showed noticeable improvement in their aphthous lesions over a period of 6 months. A significant minority (e.g. 2.83%) of RAS patients have GSE. This could be compared with the 0.9% prevalence of GSE in the general population of Iran. This study suggests that evaluation for celiac disease is appropriate in patients with RAS. Additionally, the unresponsiveness to conventional anti-aphthae treatment could be an additional risk indicator.


Distribution of glyphosate-resistant Amaranthus spp. in Nebraska.
Palmer amaranth (Amaranthus palmeri S. Wats.), common waterhemp (Amaranthus tuberculatus var. rudis), and redroot pigweed (Amaranthus retroflexus L.) are major weeds occurring in fields throughout Nebraska with recurrent grower complaints regarding control with glyphosate. The objective of this study was to investigate the frequency and distribution of glyphosate-resistant Palmer amaranth, common waterhemp, and redroot pigweed populations in Nebraska. The study also aimed to investigate how agronomic practices influence the occurrence of glyphosate resistance in the three Amaranthus species. Glyphosate resistance was widespread in common waterhemp (81% of the screened populations), few Palmer amaranth populations were glyphosate-resistant (6% of the screened populations), whereas no glyphosate-resistant redroot pigweed populations were identified in Nebraska. Weed species, geographic region within the state, and current crop were the most important factors predicting the occurrence of glyphosate resistance in fields infested with Amaranthus species in Nebraska. The intensive glyphosate selection pressure exerted in soybean (Glycine max) fields in eastern Nebraska is one of the major factors causing widespread occurrence of glyphosate resistance in common waterhemp in the state. The relatively low frequency of glyphosate-resistant Palmer amaranth in the state highlights the importance of the application timing and the adoption of multiple modes of action in weed management practices to delay the evolution of glyphosate resistance. © 2017 Society of Chemical Industry.


[Sociocultural aspects of epilepsy in Madagascar. K.A.P. survey carried out in Antananarivo].
A general population survey on knowledge, attitudes and practices (K.A.P.) concerning epilepsy was conducted from 1st July to 31st December 1997 in Antananarivo, a region representative of ecological and cultural patterns of the Malagasy "Highlands". The sample, randomly selected according to the two-step cluster method, recruited 1392 men and women aged 18 years and older who were interviewed with a 16-item questionnaire. Knowledge and practices have significantly evolved since 1983, when a similar study was conducted. More natural explanations are given for the condition and health-care seeking is more common. However, popular attitudes towards the epileptic patient remain contradictory: the majority of those interviewed claimed to be tolerant; work and marriage could be envisaged for the epileptic patient, but not total freedom of movement nor regular school attendance. A more active popularisation of the disease thus appears to be necessary. Since some 60% of people had a radio, broadcasting and church involvement would be the most effective means towards this end. Traditional practicer do not seem to have an overwhelming influence; rather, healthcare seeking behaviour was determined by the availability of service, the efficacy of the intervention and cost. To be representative of Madagascar as a whole, our data should be compared to those of other surveys in more culturally enclosed and disadvantaged areas.


Effect of nutrient amendments on indigenous hydrocarbon biodegradation in oil-contaminated beach sediments.
Nutrient amendment to oil-contaminated beach sediments is a critical factor for the enhancement of indigenous microbial activity and biodegradation of petroleum hydrocarbons in the intertidal marine environment. In this study, we investigated the stimulatory effect of the slow-release fertilizers Osmocote (Os; Scotts, Marysville, OH) and Inipol EAP-22 (Ip; ATOFINA Chemicals, Philadelphia, PA) combined with inorganic nutrients on the bioremediation of oil-spiked beach sediments using an open irrigation system with artificial seawater over a 45-d period. Osmocote is comprised of a semipermeable membrane surrounding water-soluble inorganic N, P, and K. Inipol, which contains organic N and P, has been used for oil cleanup on beach substrate. Nutrient concentrations and microbial activity in sediments were monitored by analyzing sediment leachates and metabolic dehydrogenase activity of the microbial biomass, respectively. Loss of aliphatics (n-C12 to n-C33, pristane, and phytane) was significantly greater (total loss between 95 and 97%) in oil-spiked sediments treated with Os alone or in combination with other nutrient amendments, compared with an unamended oil-spiked control (26% loss) or sediments treated with the other nutrient amendments (28-65% loss). A combination of Os and soluble nutrients (SN) was favorable for the rapid metabolic stimulation of the indigenous microbial biomass, the sustained release of nutrients, and the enhanced biodegradation of petroleum hydrocarbons in leached, oil-contaminated sediments.


Evaluation of systemic insecticides as a treatment option in integrated pest management of the elm leaf beetle, Xanthogaleruca luteola (Müller) (Coleoptera: Chrysomelidae).
This study evaluates the efficacy of two systemic insecticides (imidacloprid and abamectin) in an operational setting and their suitability to be incorporated into an integrated pest management program. Elm leaf beetle abundance and leaf damage were compared between treated trees and untreated control trees from 1995 through 1999. Laboratory bioassays using first-instar larvae were also used to measure the toxicity of leaves collected from treated trees at varying times after treatment. Trunk injections of abamectin and imidacloprid reduced the defoliation caused by elm leaf beetle when applied after monitoring at the peak density of elm leaf beetle eggs. Treatment in the first generation appeared to provide protection against damage in that generation as well as the second and third beetle generations. Both of these materials become active within the tree canopy very quickly and are therefore compatible with a management program that determines the need for treatment based on monitoring for egg clusters at peak density of eggs. Laboratory bioassays showed no toxicity of leaves in the year following treatment.


Malnutrition is associated with HIV infection in children less than 5 years in Bobo-Dioulasso City, Burkina Faso: A case-control study.
Pediatric human immunodeficiency virus (HIV) infection and malnutrition are still 2 major health issues in sub-Saharan Africa including Burkina Faso where few studies have been conducted on child malnutrition and HIV infection. This study assessed the effects of antiretroviral therapy (ART) in HIV infection and also compared the prevalence of malnutrition in terms of an inadequate diet, underweight, stunting, and wasting among HIV-infected and uninfected children less than 5 years in Bobo-Dioulasso city, Burkina Faso.This was a case-control study matching for age and sex in 164 HIV-infected and 164 HIV-uninfected children. The sociodemographic characteristics of mothers and children, household food security, drinking water source, child feeding and care practices, and child anthropometric data such as body weight, height, and mid-upper arm circumference were collected.The prevalence of food insecurity and inadequate diet was 58% and 92% of children less than 5 years of age, respectively. The prevalence of underweight, stunting, and wasting was 77% versus 35%, 65% versus 61%, and 63% versus 26% in HIV-infected and uninfected children less than 5 years of age, respectively. Out of 164 HIV-infected children, 59% were on ART initiation during data collection and the median of CD4 cell counts was 1078 cells/μL. HIV-infected children on ART had greater CD4 cell counts (P = .04) and higher weight-for-age Z (P = .01) and weight-for-height Z scores (P = .03) than those without ART. HIV infection was a risk factor for those who had inadequate dietary intake [adjusted odds ratio (AOR) = 2.17, 95% confidence interval (CI) 1.17-3.62, P = .04]. In addition, HIV-infected children were more likely of being underweight (AOR = 10.24, 95% CI 4.34-24.17, P < 0.001) and wasting (AOR = 5.57, 95% CI 2.49-12.46, P < 0.001) than HIV-uninfected children less than 5 years of age.High prevalence of malnutrition was observed in HIV-infected children compared with HIV-uninfected children. Except for ART, nutritional assessment and support should be included in pediatric HIV management.


Fos-Related Antigen 1 May Cause Wnt-Fzd Signaling Pathway-Related Nephroblastoma in Children.
This study aimed to investigate the role of the primary Fos-related antigen 1 (Fosl-1) oncogene in nephroblastoma by studying 60 childhood nephroblastoma and 58 paraneoplastic carcinoma cases. The Fosl-1 expression was detected using immunohistochemistry. In vitro culture of nephroblastoma cells was performed by viral transfection to establish Fosl-1 overexpression and gene knockout models. Flow cytometry and nano-PCR were used to detect apoptosis and mRNA expression in related pathway genes. Immunohistochemical results showed that the positive expression of Fosl-1 in the nuclei of nephroblastoma tissue was 78%, among which metastasis rate was 61.7%; correspondingly, it was 8%, and 100% in adjacent tissues. The qPCR results indicated that MMP9, Wnt1, and Fzd1 were significantly upregulated after Fosl-1 overexpression compared with the normal embryonic tissue cells, control, and gene knockout groups (P <0.05). Fosl-1 could cause the occurrence, development, and metastasis of childhood nephroblastoma through wingless/int1/Frizzled-related signaling pathways.


Estimation of Eating Disorders Prevalence by Age and Associations With Mortality in a Simulated Nationally Representative US Cohort.
Eating disorders (EDs) are common psychiatric disorders associated with high mortality. However, data on ED disease dynamics and treatment coverage are sparse. To model the individual-level disease dynamics of ED from birth to age 40 years and to estimate the association of increased treatment coverage with ED-related mortality. In this decision analytical model study, an individual-level Markov state transition model was empirically calibrated in April 2019 using a Bayesian approach to synthesize available clinical and epidemiologic ED data. The simulation model was calibrated to nationally representative US survey data from 2007 and 2011. A virtual cohort of 100 000 individuals (50 000 [50%] male) was modeled from birth to age 40 years for 4 ED diagnoses: anorexia nervosa, bulimia nervosa, binge eating disorder, and other specified feeding and eating disorders. Age-specific ED incidence and mortality rates and background (all-cause) mortality. The main outcomes were age-specific 12-month and lifetime ED prevalence and number of deaths per 100 000 general population individuals by age 40 years. The mean and 95% uncertainty intervals (UIs) of 1000 simulations, accounting for stochastic and parameter uncertainty, are reported. The highest estimated mean annual prevalence of ED occurred at approximately age 21 years for both male individuals (7.4%; 95% UI, 3.5%-11.5%) and female individuals (10.3%; 95% UI, 7.0%-14.2%), with lifetime mean prevalence estimates increasing to 14.3% (95% UI, 9.7%-19.0%) for male individuals and 19.7% (95% UI, 15.8%-23.9%) for female individuals by age 40 years. Ninety-five percent of first-time cases occurred by age 25 years. Current treatment coverage averts an estimated mean of 41.7 deaths per 100 000 people (95% UI, 13.0-82.0 deaths per 100 000 people) by age 40 years, whereas increasing treatment coverage for all patients with ED could avert an estimated mean of 70.5 deaths per 100 000 people by age 40 years (95% UI, 26.0-143.0 deaths per 100 000 people). In this simulation modeling study, the estimated lifetime prevalence of ED was high, with approximately 1 in 7 male and 1 in 5 female individuals having an ED by age 40 years. The initial onset of EDs was highly concentrated during adolescence and young adulthood, suggesting that this is a critical period for prevention efforts. However, the high estimated prevalence of recurring ED later in life highlights the importance of identification and treatment of ED at older ages as well. These findings suggest that increasing treatment coverage could substantially reduce ED-related mortality.


Positive response to imatinib mesylate therapy for childhood chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is rare in the pediatric population, accounting for 2-3% of childhood leukemia cases, with an annual incidence of one case per million children. The low toxicity profile of imatinib mesylate has led to its approval as a front-line therapy in children for whom interferon treatment has failed or who have relapsed after allogeneic transplantation. We describe the positive responses of 2 children (case 1 - from a 7-year-old male since May 2005; case 2 - from a 5-year-old female since June 2006) with Philadelphia-positive chromosome CML treated with imatinib (300 mg/day, orally) for up to 28 months, as evaluated by morphological, cytogenetic, and molecular approaches. Our patients are alive, are in the chronic phase, and are in continuous morphological complete remission.


Corneal wavefront-guided retreatments for significant night vision symptoms after myopic laser refractive surgery.
To evaluate the results of corneal wavefront (WF)-guided enhancements in patients with night vision symptoms and significantly high positive spherical aberration (SA) after myopic laser refractive surgery. Noncomparative, interventional case series. Twenty-eight eyes of 20 patients with significant night vision symptoms and positive corneal SA (Z(4)(0)) higher than 0.5 microm after myopic laser refractive surgery were included in the study at Vissum-Instituto Oftalmologico de Alicante, Spain. Enhancement surgery was planned to remove residual refractive error and corneal SA (Z(4)(0)) in all cases. All patients underwent corneal WF-guided excimer laser retreatments using the ESIRIS/SCHWIND excimer laser system (Schwind Eye Tech Solutions, Kleinostham, Germany). The main outcome measures were visual symptoms, change in corneal SA (Z(4)(0)), and corneal asphericity (Q-value). Subjective reports of night vision symptoms were improved in all patients. Mean corneal SA (Z(4)(0)) decreased from 0.75 +/- 0.19 microm before surgery to 0.43 +/- 0.42 microm after surgery (P < .001). Mean asphericity in the 4.5-mm zone significantly decreased from 1.02 +/- 1.07 before surgery to 0.52 +/- 0.88 after surgery (P = .008), and the mean asphericity in 8 mm did not change significantly (P = .362). The mean spherical equivalent significantly shifted to hyperopia from -0.22 +/- 1.14 diopters (D) before surgery to 0.33 +/- 0.54 D after surgery (P = .025). Cornea wavefront-guided retreatment was effective in improving subjective night vision symptoms, reducing corneal SA, and decreasing asphericity in eyes that underwent myopic laser refractive surgery.


Late Bronze Age glass production at Qantir-Piramesses, Egypt.
It has been uncertain whether the glass produced during the Late Bronze Age (LBA) originated in Egypt or Mesopotamia. Here we present evidence for the production of glass from its raw materials in the eastern Nile Delta during the LBA. Glass was made in workshops that were separate from where the production of objects took place. The initial melting of the raw materials to semi-finished glass was done at temperatures of 900 degrees to 950 degrees C, followed by coloration and ingot production at 1000 degrees to 1100 degrees C.


Interaction of dopamine, methyldopa and reserpine in the sympatho-adrenal system in essential hypertension.
1. The interactions of dopamine, reserpine and methyldopa on blood pressure of normal subjects and of those with essential hypertension were examined. 2. When biosynthesis of noradrenaline from dopamine was blocked by reserpine, dopamine induced a prominent depressor effect in essential hypertension. 3. The long-term treatment with methyldopa induced a marked potentiateion of the pressor action of domapine in hypertension, although no significant pressor response was found in normal subjects. 4. It is suggested that methylnoradrenaline may accumulate in peripheral nerve endings of patients with essential hypertension in comparison with normal subjects, and this accumulated methylnoradrenaline potentiates the pressor response to dopamine in essential hypertension.


Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene.
Familial glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hypercortisolism, but with manifestations of androgen and mineralocorticoid excess. This condition is mainly caused by mutations of the GR gene that cause inadequate transduction of the glucocorticoid signal in glucocorticoid target tissues. The clinical features of glucocorticoid resistance in females include hirsutism, acne, male pattern baldness, oligomenorrhea, and oligoanovulation. We describe here a new phenotype, female pseudohermaphroditism and severe hypokalemia, caused by a homozygous inactivating mutation of the GR gene. The proband was born with ambiguous genitalia from consanguineous parents and was mistreated as a 21-hydroxylase deficiency case since the age of 5 yr. She had very high levels of plasma ACTH (759 pg/ml or 167 pmol/liter) and high levels of cortisol (28-54 microg/dl or 772-1490 nmol/liter), androstenedione (5-14 ng/ml or 17-48 nmol/liter), T (174-235 ng/dl or 7-8 nmol/liter), and 17-hydroxyprogesterone (8-12 ng/ml or 24-36 nmol/liter). Her cortisol and 17-hydroxyprogesterone levels were not compatible with the diagnosis of classic congenital adrenal hyperplasia; furthermore, cortisol was not properly suppressed after dexamethasone administration (28 microg/d or 772 nmol/liter). Her laboratory evaluation indicated a diagnosis of glucocorticoid resistance. To investigate this puzzling clinical and biochemical picture, we analyzed both GR and CYP21 genes. Indeed, a homozygous T to C substitution at nucleotide 1844 in exon 5 of the GR gene was identified in the patient that caused a valine to alanine substitution at amino acid 571 in the ligand domain of the receptor. Her parents and an older sister were heterozygous for this mutation. A whole Epstein-Barr virus-transformed cell dexamethasone-binding assay revealed that this Ala(571) mutant had a 6-fold reduction in binding affinity compared with the wild-type receptor. In a functional assay using mouse mammary tumor virus promoter-driven luciferase reporter gene, the mutant receptor displayed 10- to 50-fold less trans-activation activity than the wild-type receptor. In addition, a large heterozygous CYP21 conversion was identified in the patient and her father. In conclusion, we described the first case of female pseudohermaphroditism caused by a novel homozygous GR gene mutation. This phenotype indicates that pre- and postnatal virilization can occur in females with the glucocorticoid resistance syndrome.


Comment on "Athabasca Valles, Mars: a lava-draped channel system".
Jaeger et al. (Reports, 21 September 2007, p. 1709) presented images of the Athabasca Valles channel system on Mars and asserted that the observed deposits are composed of thin, fluid lavas. However, all the features they described are secondary and postdate the surface by many millions of years, as documented by structural relationships with small, young impact craters.


[Cephalometric study of the cranial base in 133 cases of Down's syndrome].
Previous studies in patients with Down's syndrome have revealed signs of major anomalies of base of skull. A cephalometric radiography study was conducted to determine extent of these anomalies by quantitative methods. Skull morphology and structure were investigated in two groups of patients with Down's syndrome in whom cytogenetic analysis had demonstrated the presence of an extra chromosome in group G. The first group included 100 patients of both sexes aged between 9 and 30 years, the second group consisted of 33 patients aged 5 to 19 years. A matched control group was also studied. Cephalometric analysis (Björk, Delaire) showed shortening of anterior segment of base of skull in patients with Down's syndrome, as well as an increase in angle of base of skull when compared with controls, the differences being statistically significant.


Age-based discrimination in Covid-19 patient care.
Although all age groups are at risk of contracting Covid-19 disease, older people are facing the highest risk due to ageing and underlying health conditions. According to the US Centers for Disease Control and Prevention report, 8 out of 10 deaths reported in the US have been of adults 65 years old and older. Therefore, the global recommendation for older populations includes social isolation, which involves staying at home and avoiding contact with other people, possibly for an extended period of up to three or four months. Such distancing presents serious challenges to the health and well-being of older adults, more so those who are frail or have multiple chronic conditions.

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Why are young people drinking less than earlier? Identifying and specifying social mechanisms with a pragmatist approach.
Recent surveys have found a strong decrease in alcohol consumption among young people and this trend has been identified in European countries, Australia and North America. Previous research suggests that the decline in alcohol consumption may be explained by changes in parenting style, increased use of social media, changes in gender identities or a health and fitness trend. We use qualitative interviews with drinking and non-drinking young people from Sweden (N = 49) to explore in what way and in what kinds of contexts these explanations may hold true and how they alone or together may explain declining alcohol consumption among young people. By using the pragmatist approach, we pay attention to what kinds of concerns, habits, practices, situations and meanings our interviewees relate to adolescents' low alcohol consumption or decline in drinking. By analyzing these matters, we aim to specify the social mechanisms that have reduced adolescents' drinking. Our paper discovers social mechanisms similar to previous studies but also a few that have previously been overlooked. We propose that the cultural position of drinking may have changed among young people so that drinking has lost its unquestioned symbolic power as a rite of passage into adulthood. There is less peer pressure to drink and more room for competing activities. This opening of a homogeneous drinking culture to the acceptance of differences may function as a social mechanism that increases the success of other social mechanisms to reduce adolescents' drinking. Furthermore, the results of the paper suggest a hypothesis of the early maturation of young people as more individualized, responsible, reflective, and adult-like actors than in earlier generations. Overall, the paper provides hypotheses for future quantitative studies to examine the prevalence and distribution of the identified social mechanisms, as well as recommends directions for developing effective interventions to support young people's healthy lifestyle choices.


A mixed-method research to investigate the adoption of mobile devices and Web2.0 technologies among medical students and educators.
The past decade has witnessed the increasing adoption of Web 2.0 technologies in medical education. Recently, the notion of digital habitats, Web 2.0 supported learning environments, has also come onto the scene. While there has been initial research on the use of digital habitats for educational purposes, very limited research has examined the adoption of digital habitats by medical students and educators on mobile devices. This paper reports the Stage 1 findings of a two-staged study. The whole study aimed to develop and implement a personal digital habitat, namely digiMe, for medical students and educators at an Australian university. The first stage, however, examined the types of Web 2.0 tools and mobile devices that are being used by potential digiMe users, and reasons for their adoption. In this first stage of research, data were collected through a questionnaire and semi-structured interviews. Questionnaire data collected from 104 participants were analysed using the Predictive Analytics SoftWare (PASW). Frequencies, median and mean values were pursued. Kruskal Wallis tests were then performed to examine variations between views of different participant groups. Notes from the 6 interviews, together with responses to the open-ended section of the questionnaire, were analysed using the constructivist grounded theory approach, to generate key themes relevant to the adoption of Web 2.0 tools and mobile devices. The findings reflected the wide use of mobile devices, including both smart phones and computing tablets, by medical students and educators for learning, teaching and professional development purposes. Among the 22 types of Web 2.0 tools investigated, less than half of these tools were frequently used by the participants, this reflects the mismatch between users' desires and their actual practice. Age and occupation appeared to be the influential factors for their adoption. Easy access to information and improved communication are main purposes. This paper highlights the desire of medical students and educators for a more effective use of Web 2.0 technologies and mobile devices, and the observed mismatch between the desire and their actual practice. It also recognises the critical role of medical education institutions in facilitating this practice to respond to the mismatch.


Predictors of heavy drinking during and following treatment.
Alcohol dependence has been described as a relapsing condition and it has been proposed that alcohol lapses could potentially be explained by dynamic associations between contextual, interpersonal, and intrapersonal risk factors. Yet, few studies have tested the associations between risk factors in the prediction of lapse dynamics. The current study was a secondary analysis of data from the COMBINE study (n = 1,383; COMBINE Study Research Group, 2003). The goal of the current study was to examine static (alcohol dependence severity, treatment history, marital status, psychiatric symptoms) and dynamic (negative affect, craving, stress) predictors of heavy drinking during the course of treatment and up to one year following treatment. Results from dynamic latent difference score models indicated that higher levels of static and dynamic risk and increased dynamic risk over time were significantly associated with greater increases in heavy drinking. Likewise, more frequent heavy drinking and higher static risk predicted higher levels of dynamic risk. In addition, changes in dynamic risk factors significantly mediated the association between changes in heavy drinking and both psychiatric symptoms and treatment history. It is important to note that while the effects of static and dynamic risk factors in the prediction of heavy drinking were statistically significant, the magnitude of the effects were small. The current study provided partial support for a dynamic model of relapse; however future research using intensive longitudinal data collection and more advanced statistical techniques could further elucidate lapse dynamics and potentially improve relapse prevention planning.


Differential expression of dicer, miRNAs, and inflammatory markers in diabetic Ins2+/- Akita hearts.
Diabetic cardiomyopathy is a leading cause of morbidity and mortality, and Insulin2 mutant (Ins2+/-) Akita is a genetic mice model of diabetes relevant to humans. Dicer, miRNAs, and inflammatory cytokines are associated with heart failure. However, the differential expression of miRNAs, dicer, and inflammatory molecules are not clear in diabetic cardiomyopathy of Akita. We measured the levels of miRNAs, dicer, pro-inflammatory tumor necrosis factor alpha (TNFα), and anti-inflammatory interleukin 10 (IL-10) in C57BL/6J (WT) and Akita hearts. The results revealed increased heart to body weight ratio and robust expression of brain natriuretic peptide (BNP: a hypertrophy marker) suggesting cardiac hypertrophy in Akita. The multiplex RT-PCR, qPCR, and immunoblotting showed up regulation of dicer, whereas miRNA array elicited spread down regulation of miRNAs in Akita including dramatic down regulation of let-7a, miR-130, miR-142-3p, miR-148, miR-338, miR-345-3p, miR-384-3p, miR-433, miR-450, miR-451, miR-455, miR-494, miR-499, miR-500, miR-542-3p, miR-744, and miR-872. Conversely, miR-295 is induced in Akita. Cardiac TNFα is upregulated at mRNA (RT-PCR and qPCR), protein (immunoblotting), and cellular (immunohistochemistry and confocal microscopy) levels, and is robust in hypertrophic cardiomyocytes suggesting direct association of TNFα with hypertrophy. Contrary to TNFα, cardiac IL-10 is downregulated in Akita. In conclusion, induction of dicer and TNFα, and attenuation of IL-10 and majority of miRNA are associated with cardiomyopathy in Akita and could be used for putative therapeutic target for heart failure in diabetics.


Long-term control of Mycobacterium bovis BCG infection in the absence of Toll-like receptors (TLRs): investigation of TLR2-, TLR6-, or TLR2-TLR4-deficient mice.
Live mycobacteria have been reported to signal through both Toll-like receptor 2 (TLR2) and TLR4 in vitro. Here, we investigated the role of TLR2 in the long-term control of the infection by the attenuated Mycobacterium, Mycobacterium bovis BCG, in vivo. We sought to determine whether the reported initial defect of bacterial control (K. A. Heldwein et al., J. Leukoc. Biol. 74:277-286, 2003) resolved in the chronic phase of BCG infection. Here we show that TLR2-deficient mice survived a 6-month infection period with M. bovis BCG and were able to control bacterial growth. Granuloma formation, T-cell and macrophage recruitment, and activation were normal. Furthermore, the TLR2 coreceptor, TLR6, is also not required since TLR6-deficient mice were able to control chronic BCG infection. Finally, TLR2-TLR4-deficient mice infected with BCG survived the 8-month observation period. Interestingly, the adaptive response of TLR2- and/or TLR4-deficient mice seemed essentially normal on day 14 or 56 after infection, since T cells responded normally to soluble BCG antigens. In conclusion, our data demonstrate that TLR2, TLR4, or TLR6 are redundant for the control of M. bovis BCG mycobacterial infection.


Saturn's Magnetic Field and Magnetosphere.
The Pioneer Saturn vector helium magnetometer has detected a bow shock and magnetopause at Saturn and has provided an accurate characterization of the planetary field. The equatorial surface field is 0.20 gauss, a factor of 3 to 5 times smaller than anticipated on the basis of attempted scalings from Earth and Jupiter. The tilt angle between the magnetic dipole axis and Saturn's rotation axis is < 1 degrees , a surprisingly small value. Spherical harmonic analysis of the measurements shows that the ratio of quadrupole to dipole moments is < 10 percent, indicating that the field is more uniform than those of the Earth or Jupiter and consistent with Saturn having a relatively small core. The field in the outer magnetosphere shows systematic departures from the dipole field, principally a compression of the field near noon and an equatorial orientation associated with a current sheet near dawn. A hydromagnetic wake resulting from the interaction of Titan with the rotating magnetosphere appears to have been observed.


Insulin sensitivity in pregnancy.
Quantitation of insulin sensitivity (SI) with the insulin suppression test, glucose clamp, or the minimal model method has been achieved in various clinical circumstances. The application of these techniques to pregnancy has been limited. It is important to utilize sensitive and reproducible methods to study SI changes in pregnancy to fully understand the normal and pathological metabolic alterations that occur during gestation. These techniques demonstrate that various factors (obesity, body fat distribution, age, dietary manipulation, and exercise) may affect SI measures. The various pregnancy hormones have differential effects on insulin action. There is consensus among the limited in vivo studies in human pregnancy that late gestation is associated with significantly impaired SI compared with the nonpregnant state. Studies with appropriate matching between control and gestational diabetic subjects have failed to demonstrate a significant difference in SI between groups in the third trimester.


Epigenetic therapy for Friedreich ataxia.
To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.


[Pharmaceutical interventions and clinical outcomes in an antimicrobial stewardship program].
The pharmacist's participation in the antimicrobial stewardship program (AMSP) has been associated with better outcomes. To describe the pharmaceutical interventions and clinical outcomes of a PGA focused on broad-spectrum antibiotics in hospitalized patients in a tertiary healthcare setting. Prospective observational study in patients admitted to a tertiary healthcare setting between August-2016 and September-2017. In the context of a AMSP, a pharmacist training in infectious diseases evaluated and intervened antibiotic therapy, with the infectious disease specialist, who performed relevant modification of the antibiotic therapy. In addition, the clinical outcome was evaluated and documented. 258 patients were included. 16.1% of antibiotics were assessed as not indicated. A total of 126 pharmaceutical interventions were performed with 82.5% acceptance. The main outcome was the clinical and/or microbiological cure of infection. The problem associated with the antibiotic most frequently in the study population was the antimicrobial spectrum. Being consistent, de-escalation was the pharmaceutical intervention with the highest prevalence. A high percentage of acceptance of the interventions performed by the pharmacist in the environment of the PGAn was considered. Clinical and/or microbiological cure was the main cause of hospital discharge.


Interstitial deletion of chromosome 2q32-34 associated with multiple congenital anomalies and a urea cycle defect (CPS I deficiency).
A de novo deletion of the long arm of chromosome 2 at 2q31-33 was observed in the fetal amniocyte G-banded karyotype performed because of possible multiple malformations identified by ultrasound at 23 weeks gestation. Two days after the uneventful term delivery of a 2.45 kg male, the neonate experienced cardiopulmonary decompensation and biochemical changes compatible with carbamoyl phosphate synthetase I (CPS I) deficiency (elevated ammonia with a peak of 948 micromol/L, deficiency of citrulline, and no increase in orotic acid). The child died on day 3 of life. Physical anomalies confirmed at autopsy included double superior vena cava, ectopic adrenal tissue, and metatarsus adductus. The autopsy also revealed histologic evidence consistent with CPS deficiency, most notably microvesicular steatosis of the liver and Alzheimer's Type II changes with hypertrophic astrocytes in the basal ganglia. A postnatal lymphocyte karyotype confirmed the chromosome 2q31-33 deletion. Enzyme analysis on postmortem liver tissue confirmed the diagnosis of CPS deficiency. CPS I is reported to be mapped to 2q35 by NCBI (http://www.ncbi.nlm.nih.gov/mapview/) and 2q34 by ENSEMBL (http://www.ensembl.org/). The UCSC Human Genome Browser July 2003 assembly also places the gene at 2q34 (http://genome.UCSC.edu/). Fluorescence in situ hybridization (FISH) analysis with a BAC clone (RP11-349G4) of CPS I demonstrated that one copy of the gene was deleted in this infant. Using additional probes corresponding to the bands in the region of deletion, we identified the deleted region as 2q32-2q34. Our observations support the CPS I map position (ENSEMBL, UCSC) at 2q34. Additionally, potential conditions associated with deletions narrowly defined by standard cytogenetic techniques merit consideration in prenatal counseling. As demonstrated here, deletions may not only result in malformations and mental retardation but also increase the likelihood of revealing mutated genes located in the undeleted region of the homologous chromosome.


Effects of dendrobium polysaccharides on human brain microvascular endothelial cell injury induced by ox-LDL via regulating the miR-378 expression.
Brain microvascular endothelial cells are a key part of the blood-brain barrier. This experiment was set up to investigate the effect and molecular mechanism of Dendrobium polysaccharide on oxidized low-density lipoprotein (ox-LDL)-induced damage to the human brain microvascular endothelial cells. For this purpose, human brain microvascular endothelial cells HBMEC were divided into control group (without any treatment), ox-LDL group (50 μg/mL ox-LDL), Dendrobium polysaccharide low, medium and high concentration group (0.1 μg/L, 0.2 μg/L, 0.4 μg/L Dendrobium polysaccharide+50 μg/mL ox-LDL), ox-LDL+miR-NC group (transfection miR-378 mimic negative control+50 μg/mL ox-LDL), ox-LDL+miR-378 group (transfected miR-378 mimics+50 μg/mL ox-LDL), ox-LDL+DP+anti-miR-NC group (transfected miR-378 inhibitor negative control +0.4 μg/L Dendrobium polysaccharide+50 μg/mL ox-LDL), ox-LDL+DP+anti-miR-378 group (transfected miR-378 inhibitor+0.4 μg/L Dendrobium polysaccharide+50 μg/mL ox-LDL ). The kit was used to detect the levels of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) and catalase (CAT); flow cytometry to detect apoptosis; and Western blot to detect B-cell lymph tumor/leukemia-2 (Bcl-2) and Bcl-2 related X (Bax) protein expression; real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expression of miR-378. Results showed that after treatment with different concentrations of Dendrobium polysaccharides, MDA levels were decreased in ox-LDL-induced human brain microvascular endothelial cells, SOD and CAT activities were increased, apoptosis rate was decreased, Bcl-2 expression was increased, Bax expression was decreased, miR-378 expression was increased, in a dose-dependent manner (P<0.05). Overexpression of miR-378 inhibits ox-LDL-induced oxidative stress and apoptosis in human brain microvascular endothelial cells. Inhibition of miR-378 expression reversed the effect of Dendrobium polysaccharide on ox-LDL-induced damage to human brain microvascular endothelial cells. Then dendrobium polysaccharide may inhibit ox-LDL-induced oxidative stress and apoptosis in human brain microvascular endothelial cells by up-regulating the expression of miR-378.


Paracoccidioides brasiliensis: phylogenetic and ecological aspects.
The knowledge on the biological aspects of Paracoccidioides brasiliensis has evolved greatly since the first description of the disease in 1908. From the pioneers, who were able to clearly demonstrate the fungal nature of the agent, to the recent genomic era, important advances have been achieved. P. brasiliensis is a true fungus, belonging to the Ascomycetous Division, although its sexual phase has not been demonstrated morphologically. A better understanding of the fundamental aspects of the agent, especially its phylogeny and evolutionary history, will provide us with valuable insights allowing a better comprehension of the disease and our capacity to deal with the problem. Concerning the fungus's ecology, although some progress had been observed, the ecological niche of the pathogen has not been determined yet. The aim of the present review is to focus on the biological aspects of P. brasiliensis from an evolutionary point of view, addressing the fungus's phylogenetic aspects, in those special points that might be relevant for the pathogen/host interactions, the biological forces that have been acting on its origin and maintenance of virulence, as well as in determining the fungus's ecology and epidemiology.


The Plasticizer Bisphenol A Perturbs the Hepatic Epigenome: A Systems Level Analysis of the miRNome.
Ubiquitous exposure to bisphenol A (BPA), an endocrine disruptor (ED), has raised concerns for both human and ecosystem health. Epigenetic factors, including microRNAs (miRNAs), are key regulators of gene expression during cancer. The effect of BPA exposure on the zebrafish epigenome remains poorly characterized. Zebrafish represents an excellent model to study cancer as the organism develops a disease that resembles human cancer. Using zebrafish as a systems toxicology model, we hypothesized that chronic BPA-exposure impacts the miRNome in adult zebrafish and establishes an epigenome more susceptible to cancer development. After a 3 week exposure to 100 nM BPA, RNA from the liver was extracted to perform high throughput mRNA and miRNA sequencing. Differential expression (DE) analyses comparing BPA-exposed to control specimens were performed using established bioinformatics pipelines. In the BPA-exposed liver, 6188 mRNAs and 15 miRNAs were differently expressed (q ≤ 0.1). By analyzing human orthologs of the DE zebrafish genes, signatures associated with non-alcoholic fatty liver disease (NAFLD), oxidative phosphorylation, mitochondrial dysfunction and cell cycle were uncovered. Chronic exposure to BPA has a significant impact on the liver miRNome and transcriptome in adult zebrafish with the potential to cause adverse health outcomes including cancer.


The ratio of miR-21/miR-24 as a promising diagnostic and poor prognosis biomarker in colorectal cancer.
Optimal management of cancer treatment will be guided by sensitive and specific biomarkers. Searching for potential biomarkers is always a hot spot in cancer research, including colorectal cancer (CRC). MicroRNAs (miRNAs) have been recently proposed as biomarkers for cancers. Based on previous miRNA analysis in our hospital and data mining, we hypothesized that the ratio of miR-21/miR-24 (miR-21/24) may serve as plasma biomarkers in CRC patients. The plasma levels of miR-21 and miR-24 were analyzed from the 186 CRC patients before surgery and 97 healthy controls by qRT-PCR. Receiver operating characteristic (ROC) analysis was further used to evaluate the difference in diagnostic accuracy associated with the expression of miR-21, miR-24 and their ratio. Chi-square2-test or Fisher's exact test was performed to determine the relationship between the ratio of miR-21/24 and clinicopathological parameters. Kaplan-Meier and log-rank testing were performed to evaluate the effect of miR-21/24 ratio on the survival of colon cancer. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated by Cox regression models. ROC curves revealed that the diagnostic accuracy AUC (area under the curve) in CRC tissue of miR-24, miR-21, and the ratio of miR-21/24 were 0.8971, 0.9128 and 0.9875, respectively. Notably, the ratio of miR-21/24, with the best accuracy among these miRNAs, was significantly correlated with several important prognosis factors in CRC, such as tumor size, TNM stage, lymph metastasis and histologic differentiation (all p<0.05). By Kaplan-Meier survival analysis and Cox regression analysis, the ratio of miR-21/24 was shown to be a significant survival risk factor for CRC patients. We showed that the plasma ratio of miR-21/24 is a potentially powerful tool for detecting CRC and predicting prognosis.


The role of observational investigations in comparative effectiveness research.
Comparative effectiveness research (CER) seeks to inform clinical decisions between alternate treatment strategies using data that reflects real patient populations and real-world clinical scenarios for the purpose of improving patient outcomes. There are multiple clinical situations where the unique characteristics of observational investigations can inform medical decision-making within the CER paradigm. Accordingly, it is critical for clinicians to appreciate the strengths and limitations of observational research, particularly as they apply to CER. This review focuses on the role of observational research in CER. We discuss the concept of evidence hierarchies as they relate to observational research and CER, review the scope and nature of observational research, present the rationale for its inclusion in CER investigations, discuss potential sources of bias in observational investigations as well as strategies used to compensate for these biases, and discuss a framework to implement observational research in CER. The CER paradigm recognizes the limitations of hierarchical models of evidence and favors application of a strength-of-evidence model. In this model, observational research fills gaps in randomized clinical trial data and is particularly valuable to investigate effectiveness, harms, prognosis, and infrequent outcomes as well as in circumstances where randomization is not possible and in studies of many surgical populations. Observational investigations must be designed with careful consideration of potential sources of bias and must incorporate strategies to control such bias prospectively, and their results must be reported in a uniform and transparent fashion. When these conditions can be achieved, observational research represents a valuable and critical component of modern CER.


The role of fabric in the large strain compressive behavior of human trabecular bone.
Osteoporosis-related vertebral body fractures involve large compressive strains of trabecular bone. The small strain mechanical properties of the trabecular bone such as the elastic modulus or ultimate strength can be estimated using the volume fraction and a second order fabric tensor, but it remains unclear if similar estimations may be extended to large strain properties. Accordingly, the aim of this work is to identify the role of volume fraction and especially fabric in the large strain compressive behavior of human trabecular bone from various anatomical locations. Trabecular bone biopsies were extracted from human T12 vertebrae (n=31), distal radii (n=43), femoral head (n=44), and calcanei (n=30), scanned using microcomputed tomography to quantify bone volume fraction (BV/TV) and the fabric tensor (M), and tested either in unconfined or confined compression up to very large strains (∼70%). The mechanical parameters of the resulting stress-strain curves were analyzed using regression models to examine the respective influence of BV/TV and fabric eigenvalues. The compressive stress-strain curves demonstrated linear elasticity, yielding with hardening up to an ultimate stress, softening toward a minimum stress, and a steady rehardening followed by a rapid densification. For the pooled experiments, the average minimum stress was 1.89 ± 1.77 MPa, while the corresponding mean strain was 7.15 ± 1.84%. The minimum stress showed a weaker dependence with fabric as the elastic modulus or ultimate strength. For the confined experiments, the stress at a logarithmic strain of 1.2 was 8.08 ± 7.91 MPa, and the dissipated energy density was 5.67 ± 4.42 MPa. The latter variable was strongly related to the volume fraction (R(2)=0.83) but the correlation improved only marginally with the inclusion of fabric (R(2)=0.84). The influence of fabric on the mechanical properties of human trabecular bone decreases with increasing strain, while the role of volume fraction remains important. In particular, the ratio of the minimum versus the maximum stress, i.e., the relative amount of softening, decreases strongly with fabric, while the dissipated energy density is dominated by the volume fraction. The collected results will prove to be useful for modeling the softening and densification of the trabecular bone using the finite element method.


Percutaneous electrical nerve stimulation: an alternative to TENS in the management of sciatica.
Sciatica is a common pain problem and current pharmacologic therapies have proven inadequate for many patients. The objective of this sham-controlled investigation was to compare a novel non-pharmacologic technique, percutaneous electrical nerve stimulation (PENS), to transcutaneous electrical nerve stimulation (TENS) in the management of the radicular pain associated with sciatica. Sixty-four consenting patients with sciatica due to lumbar disc herniation were treated with PENS, TENS and sham-PENS according to a randomized, single-blinded, cross-over study. All patients had been maintained on a stable oral non-opioid analgesic regimen for at least 6 weeks prior to entering the study. Each treatment modality was administered for a period of 30 min three times per week for 3 weeks, with 1 week 'off' between each modality. Both PENS and TENS treatments were administered using a stimulation frequency of 4 Hz. The pre-treatment assessment included the health status survey short form (SF-36), as well as visual analog scales (VAS) for radicular pain, physical activity and quality of sleep. The pain VAS was also repeated after each treatment session. At the end of each 3-week treatment block, the SF-36 was repeated. After receiving all three treatment modalities, a global assessment questionnaire was completed. Both PENS (42%) and TENS (23%) were significantly more effective than the sham (8%) treatments in decreasing VAS pain scores. The daily oral analgesic requirements were also significantly reduced compared to the pre-treatment values with PENS (P<0.01) and TENS (P<0.05). However, PENS was significantly more effective than TENS (and sham-PENS) in improving physical activity and quality of sleep. The SF-36 evaluation confirmed the superiority of PENS (versus TENS and sham-PENS) with respect to post-treatment functionality. In the overall assessment, 73% of the patients reported that PENS was the most desirable modality (versus 21% for TENS and 6% for sham-PENS). Finally, 71% of the patients stated that they would be willing to pay extra to receive PENS therapy compared to 22% and 3% for TENS and sham-PENS, respectively. In this sham-controlled study, we concluded that PENS was more effective than TENS when administered at a stimulation frequency of 4 Hz in providing short-term pain relief and improved functionality in patients with sciatica.


The Use of the Anticoagulant Heparin and Corticosteroid Dexamethasone as Prominent Treatments for COVID-19.
COVID-19 is spreading worldwide at disturbing rates, overwhelming global healthcare. Mounting death cases due to disease complications highlight the necessity of describing efficient drug therapy strategies for severe patients. COVID-19 severity associates with hypercoagulation and exacerbated inflammation, both influenced by ACE2 downregulation and cytokine storm occurrence. In this review, we discuss the applicability of the anticoagulant heparin and the anti-inflammatory corticosteroid dexamethasone for managing severe COVID-19 patients. The upregulated inflammation and blood clotting may be mitigated by administrating heparin and its derivatives. Heparin enhances the anticoagulant property of anti-thrombin (AT) and may be useful in conjunction with fibrinolytic drugs for severe COVID-19 patients. Besides, heparin can also modulate immune responses, alleviating TNF-α-mediated inflammation, impairing IL-6 production and secretion, and binding to complement proteins and leukotriene B4 (LTB4). Moreover, heparin may present anti-SARS-CoV-2 potential once it can impact viral infectivity and alter SARS-CoV-2 Spike protein architecture. Another feasible approach is the administration of the glucocorticoid dexamethasone. Although glucocorticoid's administration for viral infection managing is controversial, there is increasing evidence demonstrating that dexamethasone treatment is capable of drastically diminishing the death rate of patients presenting with Acute Respiratory Distress Syndrome (ARDS) that required invasive mechanical ventilation. Importantly, dexamethasone may be detrimental by impairing viral clearance and inducing hyperglycemia and sodium retention, hence possibly being deleterious for diabetics and hypertensive patients, two major COVID-19 risk groups. Therefore, while heparin's multitarget capacity shows to be strongly beneficial for severe COVID-19 patients, dexamethasone should be carefully administered taking into consideration underlying medical conditions and COVID-19 disease severity. Therefore, we suggest that the multitarget impact of heparin as an anti-viral, antithrombotic and anti-inflammatory drug in the early stage of the COVID-19 could significantly reduce the need for dexamethasone treatment in the initial phase of this disease. If the standard treatment of heparins fails on protecting against severe illness, dexamethasone must be applied as a potent anti-inflammatory shutting-down the uncontrolled and exacerbated inflammation.


Evaluation of recombinant adenovirus vaccines based on glycoprotein D and truncated UL25 against herpes simplex virus type 2 in mice.
The high prevalence of herpes simplex virus 2 (HSV-2) infections in humans necessitates the development of a safe and effective vaccine that will need to induce vigorous T-cell responses to control viral infection and transmission. We designed rAd-gD2, rAd-gD2ΔUL25, and rAd-ΔUL25 to investigate whether recombinant replication-defective adenoviruses vaccine could induce specific T-cell responses and protect mice against intravaginal HSV-2 challenge compared with FI-HSV-2. In the present study, recombinant adenovirus-based HSV-2 showed higher reductions in mortality and stronger antigen-specific T-cell responses compared with FI-HSV-2 and the severity of genital lesions in mice immunized with rAd-gD2ΔUL25 was significantly decreased by eliciting IFN-γ-secreting T-cell responses compared with rAd-gD2 and rAd-ΔUL25 groups. Our results demonstrated the immunogenicity and protective efficacy of recombinant adenovirus vaccines in acute HSV-2 infection following intravaginal challenge in mice.


A peptide prodrug approach for improving bisphosphonate oral absorption.
This work was aimed at improving the absorption of bisphosphonates by targeting carrier systems in the intestine and the intestinal peptide carrier system (hPEPT1), in particular. (14)C-Labeled pamidronate and alendronate as well as radiolabeled and "cold" peptidyl-bisphosphonates, Pro-[(3)H]Phe-[(14)C]pamidronate, and Pro-[(3)H]Phe-[(14)C]alendronate were synthesized. In situ single-pass perfusion studies revealed competitive inhibition of transport by Pro-Phe, suggesting peptide carrier-mediated transport. Prodrug transport in the Caco-2 cell line was significantly better than that of the parent drugs, and the prodrugs exhibited high affinity to the intestinal tissue. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration in rats, and the bioavailability of Pro-Phe-alendronate was 3.3 (F(TIBIA)) and 1.9 (F(URINE)) times higher than that of the parent drug. The results indicate that the oral absorption of bisphosphonates can be improved by peptidyl prodrugs via the hPEPT1; however, other transporters may also be involved.


Competitive hydration of quinazoline at the montmorillonite-water interface.
Ultraviolet spectroscopic analyses of suspensions of quinazoline and Na(+)-saturated montmorillonite have indicated that covalent hydration of the monovalent organic cation is inhibited at or near the clay surface. A similar lack of hydration was observed in solutions of quinazoline and high-ionic-strength calcium chloride. The inhibition is attributed to a local competition between quinazoline and the inorganic cations for water of hydration.


Relative developmental toxicity potencies of retinoids in the embryonic stem cell test compared with their relative potencies in in vivo and two other in vitro assays for developmental toxicity.
The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking obtained in the ES-D3 cell differentiation assay is similar to the reported potency rankings in the two other in vitro assays for developmental toxicity. TTNPB ((E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid) was the most potent retinoid, whereas etretinate and retinol had the lowest potency. All-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and acitretin showed an intermediate potency. In vivo potency rankings of the developmental toxicity of retinoids appear to be dependent on the species and/or exposure regimens used. The obtained in vitro potency ranking does not completely correspond with the in vivo potency rankings, although TTNPB is correctly predicted to be the most potent and retinol the least potent congener. The lack of in vivo kinetic processes in the ES-D3 cell differentiation assay might explain the deviating potency predictions of some retinoids. Therefore, knowledge on the species-dependent in vivo kinetics is essential when using in vitro toxicity data for the estimation of in vivo developmental toxicity potencies within series of related compounds.


Pars Plana Vitrectomy for the Treatment of Uveitis.
To review and summarize evidence in the medical literature regarding the use of pars plana vitrectomy in the management of uveitis. Systematic literature review. A systematic literature search was conducted for relevant articles on pars plana vitrectomy for the management of uveitis. Results from the studies were compiled and analyzed. Thirty-four articles, published from 2005 through 2014, were included in the final data analysis. Thirty-two manuscripts were from retrospective case series and 2 manuscripts were from randomized pilot studies. The median Scottish Intercollegiate Guidelines Network level of evidence grade was 3 and the median Oxford Center for Evidence-based Medicine level of evidence grade was 4. Fewer than 50% of the articles in the current study applied Standardization of Uveitis Nomenclature (SUN) criteria in regard to reporting the anatomic location of uveitis, fewer than 25% of studies applied SUN criteria in regard to the reporting of anterior chamber cells before and after PPV, fewer than 10% of studies applied SUN criteria to the grading of anterior chamber flare before and after PPV, and fewer than 10% of studies applied standardized criteria to the grading of vitreous haze after PPV. Overall, 627 patients and 708 total eyes undergoing PPV for uveitis were included. The average reported age of all patients was 43.4 years. The median duration of uveitis prior to PPV reported in the studies was 36.1 months (range 4-198 months). The median follow-up after PPV reported in the studies was 18.9 months (range 2-114 months). Vision was reported for 519 eyes and was improved in 356 eyes (69%), unchanged in 95 eyes (18%), and worse in 68 eyes (13%) following PPV. Preoperatively, 157 of 300 (52%) eyes in these studies had documented cystoid macular edema compared to 112 of 300 (37%) postoperatively. Median use of oral corticosteroids improved from 48% preoperatively to 12% postoperatively among the reporting studies. Median use of other immunosuppressive medications decreased from 56% preoperatively to 36% postoperatively among the reporting studies. Although nearly all studies continue to report favorable outcomes of PPV in the management of uveitis, the quality of data remains limited by a lack of application of standardized reporting outcomes, limitations in study design, and a paucity of prospective data.


Structure and function of a novel purine specific nucleoside hydrolase from Trypanosoma vivax.
The purine salvage pathway of parasitic protozoa is currently considered as a target for drug development because these organisms cannot synthesize purines de novo. Insight into the structure and mechanism of the involved enzymes can aid in the development of potent inhibitors, leading to new curative drugs. Nucleoside hydrolases are key enzymes in the purine salvage pathway of Trypanosomatidae, and they are especially attractive because they have no equivalent in mammalian cells. We cloned, expressed and purified a nucleoside hydrolase from Trypanosoma vivax. The substrate activity profile establishes the enzyme to be a member of the inosine-adenosine-guanosine-preferring nucleoside hydrolases (IAG-NH). We solved the crystal structure of the enzyme at 1.6 A resolution using MAD techniques. The complex of the enzyme with the substrate analogue 3-deaza-adenosine is presented. These are the first structures of an IAG-NH reported in the literature. The T. vivax IAG-NH is a homodimer, with each subunit consisting of ten beta-strands, 12 alpha-helices and three small 3(10)-helices. Six of the eight strands of the central beta-sheet form a motif resembling the Rossmann fold. Superposition of the active sites of this IAG-NH and the inosine-uridine-preferring nucleoside hydrolase (IU-NH) of Crithidia fasciculata shows the molecular basis of the different substrate specificity distinguishing these two classes of nucleoside hydrolases. An "aromatic stacking network" in the active site of the IAG-NH, absent from the IU-NH, imposes the purine specificity. Asp10 is the proposed general base in the reaction mechanism, abstracting a proton from a nucleophilic water molecule. Asp40 (replaced by Asn39 in the IU-NH) is positioned appropriately to act as a general acid and to protonate the purine leaving group. The second general acid, needed for full enzymatic activity, is probably part of a flexible loop located in the vicinity of the active site.


Paraspinal Muscle Degeneration: A Potential Risk Factor for New Vertebral Compression Fractures After Percutaneous Kyphoplasty.
The paraspinal muscle is essential for maintaining normal spine function and structure, which degeneration is closely related to various spinal diseases. The main objective of this study was to identify the potential role of paraspinal muscle degeneration in the occurrence of new vertebral compression fractures (NVCF) and develop a clinically applicable nomogram for prospective NVCF risk prediction. A total of 202 patients with single-level osteoporotic vertebral compression fractures (OVCF) who underwent percutaneous kyphoplasty treatment between January 2016 and March 2019 were included in this study. Demographic, clinical, radiological, and treatment data were collected and analyzed. The paraspinal muscle cross-sectional area (CSA) and fat signal fraction (FSF) were measured to quantify the extent of muscle degeneration. Multivariate binary logistic regression analysis was performed to select risk factors to build a nomogram that predicted the occurrence of NVCF. The concordance index (C-index) and calibration curve were used to evaluate the discriminative capacity and predictive accuracy of the nomogram. NVCF occurred in 54 of 202 patients (26.7%). The erector spinae FSF (OR = 1.064; P = 0.001), psoas major FSF (OR = 1.326; P < 0.001), and the difference index of the muscle CSA between multifidus and psoas major (OR = 1.048; P < 0.001) were independent risk factors for the occurrence of NVCF. The nomogram performance was good after evaluation using the calibration curves and C-index (95% confidence interval, 0.854-0.943). Paraspinal muscle degeneration is a potential risk factor for NVCF occurrence. A nomogram was designed to precisely predict the risk of NVCF. This predictive nomogram may help clinicians to make better clinical decisions and provide more accurate functional exercise protocol for OVCF patients.


Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's disease: a randomized placebo-controlled trial.
Endogenous opioid peptides have been shown to play a role in the development and/or perpetuation of inflammation. We hypothesize that the endogenous opioid system is involved in inflammatory bowel disease, and antagonism of the opioid-opioid receptor will lead to reversal of inflammation. A randomized double-blind placebo-controlled study was designed to test the efficacy and safety of an opioid antagonist for 12 weeks in adults with active Crohn's disease. Forty subjects with active Crohn's disease were enrolled in the study. Randomized patients received daily oral administration of 4.5-mg naltrexone or placebo. Providers and patients were masked to treatment assignment. The primary outcome was the proportion of subjects in each arm with a 70-point decline in Crohn's Disease Activity Index score (CDAI). The secondary outcome included mucosal healing based upon colonoscopy appearance and histology. Eighty-eight percent of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (p = 0.009). After 12 weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn's disease endoscopy index severity score (CDEIS) from baseline compared to 28% response in placebo-treated controls (p = 0.008), and 33% achieved remission with a CDEIS score <6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo. Naltrexone improves clinical and inflammatory activity of subjects with moderate to severe Crohn's disease compared to placebo-treated controls. Strategies to alter the endogenous opioid system provide promise for the treatment of Crohn's disease.


Associations between gender, coping patterns and functioning for individuals with chronic pain: a systematic review.
Developing strategies for coping with chronic pain is an integral part of successfully living with this often debilitating health condition. While gender differences in pain coping strategies have long been investigated, the relationship between gender-specific engagement in coping and associated functioning in individuals experiencing chronic pain is yet to be clearly understood. The present systematic review focused on studies that address these relationships to critically evaluate the available evidence. A systematic search was conducted using MEDLINE via Ovid, EMBASE, PsycINFO and CINAHL, with 7247 titles retrieved. To be included, studies had to be in English, focus on adult participants, consider chronic nonmalignant pain, use measures of coping and functioning (or disability), report on gender-specific outcomes (for coping and functioning [or disability]), and investigate a relationship among gender, coping and functioning. One researcher screened abstracts and full-text articles, and extracted and tabulated data, while two researchers independently assessed potential articles for eligibility and methodological quality. Only seven studies met the inclusion criteria - six of high quality and one of moderate quality. The presented findings suggest that women in pain are more likely to use coping strategies considered to be maladaptive, resulting in poorer functioning, while men tend to engage in coping strategies considered to be adaptive, leading to better functional outcomes. While there is some evidence supporting gender-specific engagement in coping and associated functioning, future research is necessary to expand understanding of these interrelations.


High-speed free-space optical continuous-variable quantum key distribution enabled by three-dimensional multiplexing.
A high-speed four-state continuous-variable quantum key distribution (CV-QKD) system, enabled by wavelength-division multiplexing, polarization multiplexing, and orbital angular momentum (OAM) multiplexing, is studied in the presence of atmospheric turbulence. The atmospheric turbulence channel is emulated by two spatial light modulators (SLMs) on which two randomly generated azimuthal phase patterns yielding Andrews' spectrum are recorded. The phase noise is mitigated by the phase noise cancellation (PNC) stage, and channel transmittance can be monitored directly by the D.C. level in our PNC stage. After the system calibration, a total SKR of >1.68 Gbit/s can be reached in the ideal system, featured with lossless channel and free of excess noise. In our experiment, based on commercial photodetectors, the minimum transmittances of 0.21 and 0.29 are required for OAM states of 2 (or -2) and 6 (or -6), respectively, to guarantee the secure transmission, while a total SKR of 120 Mbit/s can be obtained in case of mean transmittances.


Induction of allogeneic islet tolerance in a large-animal model.
For islet allotransplantation to become a therapy widely applicable to patients with insulin-dependent diabetes, it will be important to avoid conventional immunosuppression and yet maintain long-term rejection-free islet survival. This possibility was tested in a large-animal model using mixed allogeneic chimeras established using total lymphoid irradiation (TLI) and donor-specific bone marrow transplantation (BMTX). Four recipient sex-mismatched and DLA class II-matched English springer spaniels became chimeric after TLI and donor-specific BMTX. Subsequent donor-specific renal allografts survived for more than a year. Acceptance of a donor-specific skin graft and rejection of a third-party graft demonstrated tolerance with maintenance of immunocompetence. Pancreatic microfragments containing islets were refluxed into the splenic vein of the recipient. Purified islets were placed under the capsule of spleen and liver. After 75 days, recipients underwent total native pancreatectomy. All four chimeric pancreatectomized dogs had functioning islet grafts 75 days after transplantation, evidenced by a prompt rise in serum insulin levels following an IVGTT and histological demonstration of islet tissue at the site of transplantation. After removal of the transplanted islet tissue, no insulin was released after IVGTT. In summary, intrasplenic allogeneic canine islets transplanted into chimeric dogs rendered tolerant to donor MHC survive and function for greater than 75 days in the absence of immunosuppression. This study represents proof of the concept that allogeneic islet transplants have the potential to reverse diabetes without the use of conventional immunosuppression.


A Novel PCR Assay for Detecting Brucella abortus and Brucella melitensis.
Brucellosis is a major zoonotic disease that poses a significant public health threat worldwide. The classical bacteriological detection process used to identify Brucella spp. is difficult and time-consuming. This study aimed to develop a novel molecular assay for detecting brucellosis. All complete sequences of chromosome 1 with 2.1-Mbp lengths were compared among all available Brucella sequences. A unique repeat sequence (URS) locus on chromosome 1 could differentiate Brucella abortus from Brucella melitensis. A primer set was designed to flank the unique locus. A total of 136 lymph nodes and blood samples were evaluated and classified by the URS-polymerase chain reaction (PCR) method in 2013-2014. Biochemical tests and bacteriophage typing as the golden standard indicated that all Brucella spp. isolates were B. melitensis biovar 1 and B. abortus biovar 3. The PCR results were the same as the bacteriological method for detecting Brucella spp. The sensitivity and specificity of the URS-PCR method make it suitable for detecting B. abortus and B. melitensis. Quick detection of B. abortus and B. melitensis can provide the most effective strategies for control of these bacteria. The advantage of this method over other presented methods is that both B. abortus and B. melitensis are detectable in a single test tube. Furthermore, this method covered 100% of all B. melitensis and B. abortus biotypes. The development of this URS-PCR method is the first step toward the development of a novel kit for the molecular identification of B. abortus and B. melitensis.


Daily protein intake and patient outcomes in severe acute kidney injury: findings of the randomized evaluation of normal versus augmented level of replacement therapy (RENAL) trial.
We aimed to examine the association between daily protein intake (DPI) and outcomes in patients from the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial. We analyzed the association between DPI and clinical outcomes using multivariable logistic regression, Cox proportional hazards models and time-adjusted analysis. During ICU stay, mean DPI was 37.6 g/day among survivors and 37.7 g/day among nonsurvivors (p = 0.96; DPI of 0.5 g/kg/day). Only 159 (10.9%) of the patients received a mean DPI of >1 g/kg. Patients with a DPI above the median had a 43.1% mortality compared with 46.1% for a DPI below the median (p = 0.25). On multivariate analysis, a lower DPI was not associated with increased odds ratios for 90-day mortality or any secondary outcomes. Cox proportional hazards models and time-adjusted analysis confirmed these findings. In the RENAL study, mean DPI was low. Within the confines of such low DPI, greater amounts of DPI were not independently associated with improved clinical outcomes. Video Journal Club "Cappuccino with Claudio Ronco" at www.karger.com/?doi=363175.


Prognosis prediction of patients with malignant pleural mesothelioma using conditional variational autoencoder on 3D PET images and clinical data.
Deep learning (DL) has been widely used for diagnosis and prognosis prediction of numerous frequently occurring diseases. Generally, DL models require large datasets to perform accurate and reliable prognosis prediction and avoid overlearning. However, prognosis prediction of rare diseases is still limited owing to the small number of cases, resulting in small datasets. This paper proposes a multimodal DL method to predict the prognosis of patients with malignant pleural mesothelioma (MPM) with a small number of 3D positron emission tomography-computed tomography (PET/CT) images and clinical data. A 3D convolutional conditional variational autoencoder (3D-CCVAE), which adds a 3D-convolutional layer and conditional VAE to process 3D images, was used for dimensionality reduction of PET images. We developed a two-step model that performs dimensionality reduction using the 3D-CCVAE, which is resistant to overlearning. In the first step, clinical data were input to condition the model and perform dimensionality reduction of PET images, resulting in more efficient dimension reduction. In the second step, a subset of the dimensionally reduced features and clinical data were combined to predict 1-year survival of patients using the random forest classifier. To demonstrate the usefulness of the 3D-CCVAE, we created a model without the conditional mechanism (3D-CVAE), one without the variational mechanism (3D-CCAE), and one without an autoencoder (without AE), and compared their prediction results. We used PET images and clinical data of 520 patients with histologically proven MPM. The data were randomly split in a 2:1 ratio (train : test) and three-fold cross-validation was performed. The models were trained on the training set and evaluated based on the test set results. The area under the receiver operating characteristic curve (AUC) for all models was calculated using their 1-year survival predictions, and the results were compared. We obtained AUC values of 0.76 (95% confidence interval [CI], 0.72-0.80) for the 3D-CCVAE model, 0.72 (95% CI, 0.68-0.77) for the 3D-CVAE model, 0.70 (95% CI, 0.66-0.75) for the 3D-CCAE model, and 0.69 (95% CI 0.65-0.74) for the without AE model. The 3D-CCVAE model performed better than the other models (3D-CVAE, p = 0.039; 3D-CCAE, p = 0.0032; and without AE, p = 0.0011). This study demonstrates the usefulness of the 3D-CCVAE in multimodal DL models learned using a small number of datasets. Additionally, it shows that dimensionality reduction via AE can be used to learn a DL model without increasing the overlearning risk. Moreover, the VAE mechanism can overcome the uncertainty of the model parameters that commonly occurs for small datasets, thereby eliminating the risk of overlearning. Additionally, more efficient dimensionality reduction of PET images can be performed by providing clinical data as conditions and ignoring clinical data-related features.