Clinicopathologic and Histopathologic Renal Abnormalities in Dogs with Coccidioidomycosis.

BackgroundWe observed evidence of protein-losing nephropathy in some dogs with coccidioidomycosis, suggestive of immune complex glomerulonephritis (ICGN). The goal of this study was to understand the prevalence of renal histopathologic lesions and proteinuria in dogs with coccidioidomycosis.HypothesisBiochemical and histopathological evidence of glomerular lesions is present in dogs with coccidioidomycosis.AnimalsHundred and fifty-six dogs with naturally occurring coccidioidomycosis.MethodsRetrospective case series. Clinical information and results of clinicopathologic testing were retrieved from the University of California, Davis Veterinary Medical Teaching Hospital (VMTH). Microscopic sections of renal tissue procured from necropsy of dogs with coccidioidomycosis were examined to evaluate the nature and distribution of lesions.ResultsA total of 156 dogs with coccidioidomycosis were identified; 87 dogs had serum biochemistry and a urinalysis performed, 17 had urine protein:creatinine ratios (UPCs), and 24 had renal tissue available for histopathology. Eleven (13%) of the 87 dogs were azotemic, 55 (63%) were proteinuric (of which 14 [25%] had clinically relevant proteinuria defined as ≥3+ or ≥500 mg/dL), and 14 dogs had UPC ≥0.5 (range, 0.5-21.5, median 4.2). Thirteen (54%) of 24 dogs had renal histopathologic lesions suggestive of ICGN. Seven of these dogs had urinalyses performed; 5 (71%) had clinically relevant proteinuria as described above. Two dogs (33%) with normal glomeruli had granulomatous nephritis, 1 of which had intralesional Coccidioides spherules.Conclusions and clinical importanceCoccidioidomycosis should be considered as a possible contributor to glomerular disease in dogs. Whether similar lesions occur in other mammalian hosts, including humans, warrants further investigation

Definitive chemoradiation in patients with inoperable oesophageal carcinoma

We performed a retrospective study of 90 consecutive cases with inoperable carcinoma of the oesophagus treated with definitive chemoradiation at a single cancer centre between 1995 and 2002. For the last 4 years, 73 patients have received therapy according to an agreed protocol. This outpatient-based regimen involves four cycles of chemotherapy, cycles 3 and 4 given concurrently with 50 Gy external beam radiotherapy (XRT) delivered in 25 fractions over 5 weeks. Cisplatin 60 mg m-2 day-1 is given every 3 weeks together with continuous infusional 5-fluorouracil 300 mg m-2 day-1, reduced to 225 mg m-2 day-1 during the XRT. In all, 45 (50%) patients suffered one or more WHO grade 3/4 toxicity, grade 3 in 93% cases. Patients received more than 90% of the planned chemoradiation schedule. The median overall survival was 26 (15, >96) months, 51% (41, 64) and 26% (13, 52) surviving 2 and 5 years, respectively. Advanced stage, particularly T4 disease, was associated with a worse prognosis. Patients considered not suitable for surgery for reasons other than their disease, mainly co-morbidity, had a significantly better outcome, median survival 40 (26, >96) months, 2- and 5-year survivals 67% (54, 84) and 32% (13, 79), respectively (P<0.001). This schedule is a feasible, tolerable and effective treatment for patients with oesophageal cancer considered unsuitable for surgery

Comparative effectiveness of lifestyle interventions on cardiovascular risk factors among a Dutch overweight working population: A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Overweight (Body Mass Index [BMI] ≥ 25 kg/m²) and obesity (BMI≥ 30 kg/m²) are associated with increased cardiovascular risk, posing a considerable burden to public health. The main aim of this study was to investigate lifestyle intervention effects on cardiovascular risk factors in healthy overweight employees.</p> <p>Methods</p> <p>Participants were 276 healthy overweight employees (69.2% male; mean age 44.0 years [SD 9.2]; mean BMI 29.7 kg/m²[SD 3.1]). They were randomized to one of two intervention groups receiving a six month lifestyle intervention with behavior counseling by phone (phone group) or e-mail (Internet group), or to a control group receiving usual care. Body weight, height, waist circumference, sum of skinfolds, blood pressure, total cholesterol level and predicted aerobic fitness were measured at baseline, at 6 and at 24 months. Regression analyses included the 141 participants with complete data.</p> <p>Results</p> <p>At 6 months a significant favorable effect on total cholesterol level (-0.2 mmol/l, 95%CI -0.5 to -0.0) was observed in the phone group and a trend for improved aerobic fitness (1.9 ml/kg/min, 95%CI -0.2 to 3.9) in the Internet group. At two years, favorable trends for body weight (-2.1 kg, 95%CI -4.4 to 0.2) and aerobic fitness (2.3 ml/kg/min, 95%CI -0.2 to 4.8) were observed in the Internet group.</p> <p>Conclusions</p> <p>The intervention effects were independent of the used communication mode. However short-term results were in favor of the phone group and long-term results in favor of the internet group. Thus, we found limited evidence for our lifestyle intervention to be effective in reducing cardiovascular risk in a group of apparently healthy overweight workers.</p> <p>Trial registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN04265725">ISRCTN04265725</a></p

A pragmatic randomised controlled trial of the Welsh National Exercise Referral Scheme: protocol for trial and integrated economic and process evaluation

Background: The benefits to health of a physically active lifestyle are well established and there is evidence that a sedentary lifestyle plays a significant role in the onset and progression of chronic disease. Despite a recognised need for effective public health interventions encouraging sedentary people with a medical condition to become more active, there are few rigorous evaluations of their effectiveness. Following NICE guidance, the Welsh national exercise referral scheme was implemented within the context of a pragmatic randomised controlled trial. Methods/Design: The randomised controlled trial, with nested economic and process evaluations, recruited 2,104 inactive men and women aged 16+ with coronary heart disease (CHD) risk factors and/or mild to moderate depression, anxiety or stress. Participants were recruited from 12 local health boards in Wales and referred directly by health professionals working in a range of health care settings. Consenting participants were randomised to either a 16 week tailored exercise programme run by qualified exercise professionals at community sports centres (intervention), or received an information booklet on physical activity (control). A range of validated measures assessing physical activity, mental health, psycho-social processes and health economics were administered at 6 and 12 months, with the primary 12 month outcome measure being 7 day Physical Activity Recall. The process evaluation explored factors determining the effectiveness or otherwise of the scheme, whilst the economic evaluation determined the relative cost-effectiveness of the scheme in terms of public spending. Discussion: Evaluation of such a large scale national public health intervention presents methodological challenges in terms of trial design and implementation. This study was facilitated by early collaboration with social research and policy colleagues to develop a rigorous design which included an innovative approach to patient referral and trial recruitment, a comprehensive process evaluation examining intervention delivery and an integrated economic evaluation. This will allow a unique insight into the feasibility, effectiveness and cost effectiveness of a national exercise referral scheme for participants with CHD risk factors or mild to moderate anxiety, depression, or stress and provides a potential model for future policy evaluations. Trial registration: Current Controlled Trials ISRCTN4768044

Nutrition, mental health and violence: from pregnancy to postpartum Cohort of women attending primary care units in Southern Brazil - ECCAGE study

<p>Abstract</p> <p>Background</p> <p>Woman's nutritional status, before and during pregnancy, is a strong determinant of health outcomes in the mother and newborn. Gestational weight gain and postpartum weight retention increases risk of overweight or obesity in the future and they depend on the pregestational nutritional status and on food consumption and eating behavior during pregnancy. Eating behavior during pregnancy may be the cause or consequence of mood changes during pregnancy, especially depression, which increases likelihood of postpartum depression. In Brazil, a study carried out in the immediate postpartum period found that one in three women experienced some type of violence during pregnancy. Violence and depression are strongly associated and both exposures during pregnancy are associated with increased maternal stress and subsequent harm to the infant. The main objectives of this study are: to identify food intake and eating behaviors patterns; to estimate the prevalence of common mental disorders and the experience of violence during and after pregnancy; and to estimate the association between these exposures and infant's health and development.</p> <p>Methods/Design</p> <p>This is a cohort study of 780 pregnant women receiving care in 18 primary care units in two cities in Southern Brazil. Pregnant women were first evaluated between the 16^thand 36^thweek of pregnancy at a prenatal visit. Follow-up included immediate postpartum assessment and around the fifth month postpartum. Information was obtained on sociodemographic characteristics, living circumstances, food intake, eating behaviors, mental health and exposure to violence, and on infant's development and anthropometrics measurements.</p> <p>Discussion</p> <p>This project will bring relevant information for a better understanding of the relationship between exposures during pregnancy and how they might affect child development, which can be useful for a better planning of health actions aiming to enhance available resources in primary health care.</p

Crackling Noise

Crackling noise arises when a system responds to changing external conditions through discrete, impulsive events spanning a broad range of sizes. A wide variety of physical systems exhibiting crackling noise have been studied, from earthquakes on faults to paper crumpling. Because these systems exhibit regular behavior over many decades of sizes, their behavior is likely independent of microscopic and macroscopic details, and progress can be made by the use of very simple models. The fact that simple models and real systems can share the same behavior on a wide range of scales is called universality. We illustrate these ideas using results for our model of crackling noise in magnets, explaining the use of the renormalization group and scaling collapses. This field is still developing: we describe a number of continuing challenges

Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis

Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18) and one strain of Paracoccidioides lutzii (Pb01). These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic species of Onygenales to transfer from soil to animal hosts.National Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health. Department of Health and Human Services (contract HHSN266200400001C)National Institutes of Health. Department of Health and Human Services(contract HHSN2722009000018C)Brazil. National Council for Scientific and Technological Developmen

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

Estimating global injuries morbidity and mortality: methods and data used in the Global Burden of Disease 2017 study

BACKGROUND: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. METHODS: In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. RESULTS: GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. CONCLUSIONS: GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future