High-fat diet-induced resistance to helminth infection via alternative induction of type 2 immunity

Gastrointestinal nematode infections cause morbidity and socioeconomic loss in the most deprived communities. The shift in the context of obesity has led to spatial overlap with endemic gastrointestinal nematode regions resulting in the emergence of a novel comorbidity. Despite this, the impact of a high-fat diet (HFD) on immune-regulated protection against gastrointestinal infections remains largely unknown. We employed the murine model of nematode infection, Trichuris muris, to investigate the effect of an HFD on the immune response against chronic infection. Surprisingly, diet-induced obesity drove parasite expulsion in both single and repeated trickle low doses of T. muris eggs. Mechanistically, an HFD increased the expression of the ST2 receptor on CD4+ T cells, priming an enhanced type 2 helper T (Th2) cell cytokine production following interleukin (IL)-33 stimulation ex vivo. Despite IL-33−/− mice demonstrating that IL-33 is not critical for host protective immunity to T. muris under a conventional diet, HFD-fed T-cell deplete mice adoptively transferred with ST2−/− CD4 T cells were unable to expel a T. muris infection unlike those transferred with ST2-sufficient cells. Collectively, this study demonstrates that an HFD primes CD4+ T cells to utilize the IL-33-ST2 axis in a novel induction of type 2 immunity, providing insights into the emerging comorbidities of obesity and nematode infection

Spatial extent and historical context of North Sea oxygen depletion in August 2010

Prompted by recent observations of seasonal low dissolved oxygen from two moorings in the North Sea, a hydrographic survey in August 2010 mapped the spatial extent of summer oxygen depletion. Typical near-bed dissolved oxygen saturations in the stratified regions of the North Sea were 75–80 % while the well-mixed regions of the southern North Sea reached 90 %. Two regions of strong thermal stratification, the area between the Dooley and Central North Sea Currents and the area known as the Oyster Grounds, had oxygen saturations as low as 65 and 70 % (200 and 180 µmol dm-3) respectively. Low dissolved oxygen was apparent in regions characterised by low advection, high stratification, elevated organic matter production from the spring bloom and a deep chlorophyll maximum. Historical data over the last century from the International Council for the Exploration of the Sea oceanographic database highlight an increase in seasonal oxygen depletion and a warming over the past 20 years. The 2010 survey is consistent with, and reinforces, the signal of recent depleted oxygen at key locations seen in the (albeit sparse) historical data

Clinical and morphological characteristics of head-facial haemangiomas

BACKGROUND: Haemangiomas of the head or face are a frequent vascular pathology, consisting in an embryonic dysplasia that involves the cranial-facial vascular network. Haemangiomas show clinical, morphological, developmental and structural changes during their course. METHODS: The clinical characteristics of head-facial haemagiomas were studied in 28 individuals (9 males and 19 females) admitted in our Hospital. Sixteen of these patients(n = 16) underwent surgery for the removal of the haemangiomas. All the removed tissues were transferred in experimental laboratories for the staining of microanatomical details, somatic and visceral nerve fibres, adrenergic and catecholaminergic nerve fibres. Beta-adrenergic receptors were died with a fluorescent method. All results were submitted to the quantitative analysis of images and statistical evaluation of the data. RESULTS: The morphological results revealed numerous micro-anatomical characteristics of the haemangiomatous vessels. The somatic and visceral nerve fibres were poor and located exclusively in the adventitial layer. There was a marked decrease of adrenergic nerve fibres in the haemangiomatous vessels. The fluorescence of catecholaminergic nerve fibres and the overall area of fluorescent structures were also decreased in haemangiomatous vessels. Beta adrenergic receptors are strongly decreased in haemangiomatous vessels. The morphometrical analysis of images and statistical evaluation of the data confirmed all our experimental results. CONCLUSION: The catecholaminergic innervation of the human haemangiomatous vessels comprises nerve fibres containing the main catecholaminergic neurotransmitters that are sympathetic in nature. These neurotransmitters are closely related to beta-adrenergic receptors. The sympathetic nervous system plays a key role in the control of the vascular bed flow and vascular motility in both normal and haemangiomatous vessels

Diabetes with Hypertension as Risk Factors for Adult Dengue Hemorrhagic Fever in a Predominantly Dengue Serotype 2 Epidemic: A Case Control Study

Dengue is a major vector borne disease in the tropical and subtropical regions. An estimated 50 million infections occur per annum in over 100 countries. A severe form of dengue, characterized by bleeding and plasma leakage, known as dengue hemorrhagic fever (DHF) is estimated to occur in 1–5% of hospitalized cases. It can be fatal if unrecognized and not treated in a timely manner. Previous studies had found a number of risk factors for DHF. However, screening and clinical management strategies based on these risk factors may not be applicable to all populations and epidemics of different serotypes. In this study, we found significant association between DHF and diabetes mellitus and diabetes mellitus with hypertension during the epidemic of predominantly serotype 2 (year 2007 and 2008), but not during the epidemic of predominantly serotype 1 (year 2006). Diabetes mellitus and hypertension are prevalent in Singapore and most parts of South-East Asia, where dengue is endemic. Therefore, it is important to address the risk effect of these co-morbidities on the development of DHF so as to reduce morbidity and mortality. Our findings may have impact on screening and clinical management of dengue patients, when confirmed in more studies

Neuropsychiatric Events in Systemic Lupus Erythematosus: Predictors of Occurrence and Resolution in a Longitudinal Analysis of an International Inception Cohort

Objective: To determine predictors of change in neuropsychiatric (NP) event status in a large, prospective, international inception cohort of patients with systemic lupus erythematosus (SLE). // Methods: Upon enrollment and annually thereafter, NP events attributed to SLE and non-SLE causes and physician-determined resolution were documented. Factors potentially associated with the onset and resolution of NP events were determined by time-to-event analysis using a multistate modeling structure. // Results: NP events occurred in 955 (52.3%) of 1,827 patients, and 593 (31.0%) of 1,910 unique events were attributed to SLE. For SLE-associated NP (SLE NP) events, multivariate analysis revealed a positive association with male sex (P = 0.028), concurrent non-SLE NP events excluding headache (P < 0.001), active SLE (P = 0.012), and glucocorticoid use (P = 0.008). There was a negative association with Asian race (P = 0.002), postsecondary education (P = 0.001), and treatment with immunosuppressive drugs (P = 0.019) or antimalarial drugs (P = 0.056). For non-SLE NP events excluding headache, there was a positive association with concurrent SLE NP events (P < 0.001) and a negative association with African race (P = 0.012) and Asian race (P < 0.001). NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache, which had comparable resolution rates. For SLE NP events, multivariate analysis revealed that resolution was more common in patients of Asian race (P = 0.006) and for central/focal NP events (P < 0.001). For non-SLE NP events, resolution was more common in patients of African race (P = 0.017) and less common in patients who were older at SLE diagnosis (P < 0.001). // Conclusion: In a large and long-term study of the occurrence and resolution of NP events in SLE, we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution

Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-β and extracellular matrix proteins

<p>Abstract</p> <p>Background</p> <p>Liver fibrosis is the result of continuous liver injury stemming from different etiological factors. Bile duct injury induces an altered expression of TGF-β, which has an important role in liver fibrosis because this cytokine induces the expression of target genes such as collagens, PAI-1, TIMPs, and others that lead to extracellular matrix deposition. Smad7 is the principal inhibitor that regulates the target gene transcription of the TGF-β signaling. The aim of the study was to determine whether Smad7 mRNA expression correlates with the gene expression of <it>TGF-β, Col I</it>, <it>Col III</it>, <it>Col IV</it>, or <it>PAI-1 </it>in liver fibrosis secondary to bile duct injury (BDI).</p> <p>Results</p> <p>Serum TGF-β concentration was higher in BDI patients (39 296 pg/ml) than in liver donors (9008 pg/ml). Morphometric analysis of liver sections showed 41.85% of tissue contained fibrotic deposits in BDI patients. mRNA expression of Smad7, Col I, and PAI-1 was also significantly higher (<it>P </it>< 0.05) in patients with BDI than in controls. Smad7 mRNA expression correlated significantly with TGF-β concentration, Col I and Col III expression, and the amount of fibrosis.</p> <p>Conclusion</p> <p>We found augmented serum concentration of TGF-β and an increase in the percentage of fibrotic tissue in the liver of BDI patients. Contrary to expected results, the 6-fold increase in <it>Smad7 </it>expression did not inhibit the expression of <it>TGF-β, collagens</it>, and <it>PAI-1</it>. We also observed greater expression of Col I and Col III mRNA in BDI patients and significant correlations between their expression and TGF-β concentration and Smad7 mRNA expression.</p

Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation

INTRODUCTION: The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk. METHODS: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit. RESULTS: Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P ≤ 0.001). CONCLUSION: It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer

Study of Flare Assessment in Systemic Lupus Erythematosus Based on Paper Patients.

OBJECTIVE: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. METHODS: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity. RESULTS: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features. CONCLUSION: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved

Association Between Severe Nonadherence to Hydroxychloroquine and Systemic Lupus Erythematosus Flares, Damage, and Mortality in 660 Patients From the SLICC Inception Cohort

OBJECTIVE: The goals of this study were to assess the associations of severe nonadherence to hydroxychloroquine (HCQ), objectively assessed by HCQ serum levels, and risks of systemic lupus erythematosus (SLE) flares, damage, and mortality rates over five years of follow-up. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort is an international multicenter initiative (33 centers throughout 11 countries). The serum of patients prescribed HCQ for at least three months at enrollment were analyzed. Severe nonadherence was defined by a serum HCQ level <106 ng/mL or <53 ng/mL for HCQ doses of 400 or 200 mg/day, respectively. Associations with the risk of a flare (defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/American College of Rheumatology Damage Index [SDI] increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS: Of the 1,849 cohort participants, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/mL (244–566); 48 patients (7.3%) had severe HCQ nonadherence. No covariates were clearly associated with severe nonadherence, which was, however, independently associated with both flare (odds ratio 3.38; 95% confidence interval [CI] 1.80–6.42) and an increase in the SDI within each of the first three years (hazard ratio [HR] 1.92 at three years; 95% CI 1.05–3.50). Eleven patients died within five years, including 3 with severe nonadherence (crude HR 5.41; 95% CI 1.43–20.39). CONCLUSION: Severe nonadherence was independently associated with the risks of an SLE flare in the following year, early damage, and five-year mortality