Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology

Assessment of non-alcoholic fatty liver disease (NAFLD) severity with novel serum-based markers: A pilot study

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) represents a significant public health issue. Identifying patients with simple steatosis from those with non-alcoholic steatohepatitis (NASH) is crucial since NASH is correlated with increased morbidity and mortality. Serum-based markers, including adipokines and cytokines, are important in the pathogenesis and progression of NAFLD. Here we assessed the usefulness of such markers in patients with NAFLD. METHODS: This prospective, cross-sectional study included 105 adult patients with varying severity of NAFLD. Twelve serum-based markers were measured by 3 biochip platforms and 2 enzyme-linked immunosorbent assay (ELISA) methods. We also developed a NAFLD individual fibrosis index (NIFI) using the serum-based markers mostly correlated with fibrosis severity. RESULTS: Sixty-one out of 105 patients were male (58.1%) with mean age was 53.5 years. Higher Interleukin-6 (IL-6) increased (p = 0.0321) and lower Matrix Metalloproteinase-9 (MMP-9) serum levels (p = 0.0031) were associated with higher fibrosis as measured by Fibroscan® in multivariable regression analysis. Using receiver-operating characteristic (ROC) curve analysis for the NIFI, area under the curve for predicting Fibroscan values ≥ 7.2 kPa was 0.77 (95%CI: 0.67, 0.88, p<0.001), with sensitivity of 89.3%, specificity of 57.9% and a positive likelihood ratio of 2.8. CONCLUSIONS: Increasing fibrosis severity in NAFLD is associated with differential expression of IL-6 and MMP-9. NIFI could be valuable for the prediction of advanced NAFLD fibrosis and potentially help avoid unnecessary interventions such as liver biopsy in low-risk patients

Post-treatment levels of plasma 25- and 1,25-dihydroxy vitamin D and mortality in men with aggressive prostate cancer.

Vitamin D may reduce mortality from prostate cancer (PC). We examined the associations of post-treatment plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with PC mortality. Participants were PC cases from the New South Wales Prostate Cancer Care. All contactable and consenting participants, at 4.9 to 8.6 years after diagnosis, were interviewed and had plasma 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) measured in blood specimens. Cox regression allowing for left-truncation was used to calculate adjusted mortality hazards ratios (HR) and 95% confidence intervals (95% CI) for all-cause and PC-specific mortality in relation to vitamin D levels and other potentially-predictive variables. Of the participants (n = 111; 75·9% response rate), there were 198 deaths from any cause and 41 from PC in the study period. Plasma 25(OH)D was not associated with all-cause or PC-specific mortality (p-values > 0·10). Plasma 1,25(OH)2D was inversely associated with all-cause mortality (HR for highest relative to lowest quartile = 0·45; 95% CI: 0·29-0·69), and PC-specific mortality (HR = 0·40; 95% CI: 0·14-1·19). These associations were apparent only in men with aggressive PC: all-cause mortality HR = 0·28 (95% CI·0·15-0·52; p-interaction = 0·07) and PC-specific mortality HR = 0·26 (95% CI: 0·07-1.00). Time spent outdoors was also associated with lower all-cause (HR for 4th relative to 1st exposure quartile = 0·42; 95% CI: 0·24-0·75) and PC-specific (HR = 0·48; 95% CI: 0·14-1·64) mortality, although the 95% CI for the latter was wide. The inverse association between post-treatment plasma 1,25(OH)2D levels and all-cause and PC-specific mortality in men with aggressive PC, suggest a possible beneficial effect of vitamin D supplementation in these men

ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity

Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3’UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS

The Prevalence of Latent Mycobacterium Tuberculosis Infection Based on an Interferon-γ Release Assay: A Cross-Sectional Survey Among Urban Adults in Mwanza, Tanzania.

One third of the world's population is estimated to be latently infected with Mycobacterium tuberculosis (LTBI). Surveys of LTBI are rarely performed in resource poor TB high endemic countries like Tanzania although low-income countries harbor the largest burden of the worlds LTBI. The primary objective was to estimate the prevalence of LTBI in household contacts of pulmonary TB cases and a group of apparently healthy neighborhood controls in an urban setting of such a country. Secondly we assessed potential impact of LTBI on inflammation by quantitating circulating levels of an acute phase reactant: alpha-1-acid glycoprotein (AGP) in neighborhood controls. The study was nested within the framework of two nutrition studies among TB patients in Mwanza, Tanzania. Household contacts- and neighborhood controls were invited to participate. The study involved a questionnaire, BMI determination and blood samples to measure AGP, HIV testing and a Quantiferon Gold In tube (QFN-IT) test to detect signs of LTBI. 245 household contacts and 192 neighborhood controls had available QFN-IT data. Among household contacts, the proportion of QFT-IT positive was 59% compared to 41% in the neighborhood controls (p = 0.001). In a linear regression model adjusted for sex, age, CD4 and HIV, a QFT-IT positive test was associated with a 10% higher level of alpha-1-acid glycoprotein(AGP) (10(B) 1.10, 95% CI 1.01; 1.20, p = 0.03), compared to individuals with a QFT-IT negative test. LTBI is highly prevalent among apparently healthy urban Tanzanians even without known exposure to TB in the household. LTBI was found to be associated with elevated levels of AGP. The implications of this observation merit further studies

A review of RCTs in four medical journals to assess the use of imputation to overcome missing data in quality of life outcomes

Background: Randomised controlled trials (RCTs) are perceived as the gold-standard method for evaluating healthcare interventions, and increasingly include quality of life (QoL) measures. The observed results are susceptible to bias if a substantial proportion of outcome data are missing. The review aimed to determine whether imputation was used to deal with missing QoL outcomes. Methods: A random selection of 285 RCTs published during 2005/6 in the British Medical Journal, Lancet, New England Journal of Medicine and Journal of American Medical Association were identified. Results: QoL outcomes were reported in 61 (21%) trials. Six (10%) reported having no missing data, 20 (33%) reported ≤ 10% missing, eleven (18%) 11%–20% missing, and eleven (18%) reported >20% missing. Missingness was unclear in 13 (21%). Missing data were imputed in 19 (31%) of the 61 trials. Imputation was part of the primary analysis in 13 trials, but a sensitivity analysis in six. Last value carried forward was used in 12 trials and multiple imputation in two. Following imputation, the most common analysis method was analysis of covariance (10 trials). Conclusion: The majority of studies did not impute missing data and carried out a complete-case analysis. For those studies that did impute missing data, researchers tended to prefer simpler methods of imputation, despite more sophisticated methods being available.The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorate. Shona Fielding is also currently funded by the Chief Scientist Office on a Research Training Fellowship (CZF/1/31)

A review of RCTs in four medical journals to assess the use of imputation to overcome missing data in quality of life outcomes

Peer reviewedPublisher PD

Alternatively Activated Mononuclear Phagocytes from the Skin Site of Infection and the Impact of IL-4Rα Signalling on CD4+T Cell Survival in Draining Lymph Nodes after Repeated Exposure to Schistosoma mansoni Cercariae

In a murine model of repeated exposure of the skin to infective Schistosoma mansoni cercariae, events leading to the priming of CD4 cells in the skin draining lymph nodes were examined. The dermal exudate cell (DEC) population recovered from repeatedly (4x) exposed skin contained an influx of mononuclear phagocytes comprising three distinct populations according to their differential expression of F4/80 and MHC-II. As determined by gene expression analysis, all three DEC populations (F4/80-MHC-IIhigh, F4/80+MHC-IIhigh, F4/80+MHC-IIint) exhibited major up-regulation of genes associated with alternative activation. The gene encoding RELMα (hallmark of alternatively activated cells) was highly up-regulated in all three DEC populations. However, in 4x infected mice deficient in RELMα, there was no change in the extent of inflammation at the skin infection site compared to 4x infected wild-type cohorts, nor was there a difference in the abundance of different mononuclear phagocyte DEC populations. The absence of RELMα resulted in greater numbers of CD4+ cells in the skin draining lymph nodes (sdLN) of 4x infected mice, although they remained hypo-responsive. Using mice deficient for IL-4Rα, in which alternative activation is compromised, we show that after repeated schistosome infection, levels of regulatory IL-10 in the skin were reduced, accompanied by increased numbers of MHC-IIhigh cells and CD4+ T cells in the skin. There were also increased numbers of CD4+ T cells in the sdLN in the absence of IL-4Rα compared to cells from singly infected mice. Although their ability to proliferate was still compromised, increased cellularity of sdLN from 4x IL-4RαKO mice correlated with reduced expression of Fas/FasL, resulting in decreased apoptosis and cell death but increased numbers of viable CD4+ T cells. This study highlights a mechanism through which IL-4Rα may regulate the immune system through the induction of IL-10 and regulation of Fas/FasL mediated cell death

Household Tobacco Smoke and Admission Weight Predict Severe Bronchiolitis in Infants Independent of Deprivation: Prospective Cohort Study

To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors

Pheochromocytoma presenting as recurrent urinary tract infections : a case report

<p>Abstract</p> <p>Introduction</p> <p>Pheochromocytomas are rare, potentially fatal, neuroendocrine tumors of the adrenal medulla or extra-adrenal paraganglia. Their clinical presentation varies greatly from the classic triad of episodic headache, diaphoresis and tachycardia to include a spectrum of non-specific symptomatology.</p> <p>Case presentation</p> <p>A 43-year-old Caucasian woman was referred to us from primary care services with a three-month history of recurrent urinary tract infections on a background of hypertension, latent autoimmune diabetes of adulthood and autoimmune hypothyroidism. At 38 years she required insulin therapy. Despite medication compliance and dietary control, she reported a recent history of increased insulin requirements and uncontrolled hypertension with concomitant recurrent urinary tract infections. A renal ultrasound examination, to rule out underlying renal pathology, revealed an incidental 8cm right adrenal mass of both solid and cystic components. A subsequent computed tomography of her abdomen and pelvis confirmed a solid heterogeneous mass consistent with a pheochromocytoma. There were no other features suggestive of multiple endocrine neoplasia. Urinary collection over 24 hours revealed grossly elevated levels of catecholamines and metabolites. Following an open right adrenalectomy, our patient's insulin requirements were significantly reduced and her symptoms resolved. Two weeks post-operatively, an iodine-131-metaiodobenzylguanidine scintigraphy was negative for residual tumor and metastatic disease. Urinary catecholamine and metabolite concentrations were within the normal range at a follow-up six months later.</p> <p>Conclusion</p> <p>Pheochromocytoma is a rare catecholamine-producing tumor requiring a high index of suspicion for early diagnosis. Our case report serves to highlight the importance of considering pheochromocytoma as a differential diagnosis in the atypical setting of recurrent urinary tract infections and concomitant autoimmune disease.</p