High mitochondrial DNA copy number is a protective factor from vision loss in heteroplasmic leber’s hereditary optic neuropathy (LHON)

PURPOSE. Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. It is characterized by as yet undisclosed genetic and environmental factors affecting the incomplete penetrance. METHODS. We identified 27 LHON subjects who possess heteroplasmic primary LHON mutations. Mitochondrial DNA (mtDNA) copy number was evaluated. RESULTS. The presence of centrocecal scotoma, an edematous, hyperemic optic nerve head, and vascular tortuosity, as well as telangiectasia was recognized in affected subjects. We found higher cellular mtDNA content in peripheral blood cells of unaffected heteroplasmic mutation carriers with respect to the affected. CONCLUSIONS. The increase of cellular mtDNA content prevents complete loss of vision despite the presence of a heteroplasmic state of LHON primary mutation, suggesting that it is a key factor responsible for penetrance of LHON

An integrated approach to evaluate PAH exposure

Introduction - An integrated evaluation of PAH exposure should consider different routes of absorption, reliability and specificity of biomarkers of dose, and individual susceptibility. Material and Methods - The present study investigated the exposure to PAHs in coke oven workers (n=100), asphalt pavers (n=98) and ground construction workers (n=47), by means of environmental exposure and biological monitoring. Results \u2013 Personal exposure to total airborne PAHs [from naphtalene to indeno(1,2,3-cd)pyrene] in coke oven workers (median 140 \ub5g/m3), was much higher than in pavers exposed to bitumen fumes (0.6 \ub5g/m3), or in construction workers (0.4 \ub5g/m3),. Urinary 1-hydroxypyrene (1-HOP) in end-shift samples was significantly higher in cokeoven workers (2.2 \ub5g/l) than in asphalt pavers (0.7 \ub5g/l) and in construction workers (0.4 \ub5g/l). An increasing trend in 1-HOP levels, over the workweek and the workshift was registered. A similar trend was observed for urinary 2-hydroxyfluorene (2-FLE) and 3-hydroxyphenanthrene (3-PHE) as well as for some unmetabolised PAH in urine. In smokers with low exposures an important contribution to biomarkers was given by tobacco smoking. PAH-DNA adducts in peripheral blood lymphocytes were not associated with external exposure. Genetic polymorphisms of metabolic and DNA repairing enzymes (CYP1A1, GSTM1, GSTT1, XPD) did not appear to influence the levels of biomarkers. Total dermal contamination of PAHs in pavers, assessed in a subgroup of workers (n=22), ranged from 23 to 623 \ub5g. Significant correlations between dermal phenanthrene or pyrene and 1-HOP (r = 0.41 and 0.55), suggest that dermal exposure significantly contributes to the internal dose of these compounds. Conclusion \u2013 Our results suggest that urinary biomarkers of PAHs, integrating exposure from all sources and routes, are reliable tools for risk assessment in occupational health

Predictor Analysis in Radiofrequency Ablation of Benign Thyroid Nodules: A Single Center Experience

PURPOSE: To confirm the efficacy of ultrasound (US) guided radiofrequency ablation (RFA) in the treatment of benign thyroid nodules, we evaluated as primary outcome the technical efficacy and clinical success in a single center dataset. The secondary outcome was to find a correlation between nodules’ pre-treatment features and volume reduction rate (VRR) ≥75% at 12 months after RFA and during follow-up period. METHODS: This retrospective study included 119 consecutive patients (99 females, 20 males, 51.5 ± 14.4 years) with benign thyroid nodules treated in our hospital between October 2014 and December 2018 with a mean follow-up of 26.8 months (range 3–48). Clinical and US features before and after RFA were evaluated by a US examination at 1, 3, 6, 12 months and annually thereafter up to 48 months. RESULTS: The median pre-treatment volume was 22.4 ml; after RFA we observed a statistically significant volume reduction from the first month (11.7 ml) to the last follow-up (p 22.4 ml (HR 0.54, p 0.036) were found to be independent positive and negative predictors of VRR ≥75% respectively. One-month post RFA VRR ≥50% represented the best positive predictor of technical success. CONCLUSIONS: This study confirmed the efficacy of RFA in the treatment of benign thyroid nodules. In particular we show that by selecting macrocystic nodules smaller than 22.4 ml better long-term response can be achieved, which is predicted by an early shrinkage of the nodule

Cumulative asbestos exposure and mortality from asbestos related diseases in a pooled analysis of 21 asbestos cement cohorts in Italy

Background: Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos. Methods: The cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40 years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution. Results: Mortality was significantly increased for ‘All Causes’ and ‘All Malignant Neoplasm (MN)’, in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40 years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40 years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%. Conclusions: Mortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studie

Italian pool of asbestos workers cohorts: asbestos related mortality by industrial sector and cumulative exposure

Objective. Italy has been a large user of asbestos and asbestos containing materials until the 1992 ban. We present a pooled cohort study on long-term mortality in exposed workers. Methods. Pool of 43 Italian asbestos cohorts (asbestos cement, rolling stock, shipbuilding, glasswork, harbors, insulation and other industries). SMRs were computed by industrial sector for the 1970-2010 period, for the major causes, using reference rates by age, sex, region and calendar period. Results. The study included 51 801 subjects (5741 women): 55.9% alive, 42.6% died (cause known for 95%) and 1.5% lost to follow-up. Asbestos exposure was estimated at the plant and period levels. Asbestos related mortality was significantly increased. All industrial sectors showed increased mortality from pleural malignancies, and most als

Galectin-8 in IgA Nephritis: Decreased Binding of IgA by Galectin-8 Affinity Chromatography and Associated Increased Binding in Non-IgA Serum Glycoproteins

Background Immunoglobulin A nephritis (IgAN) is the most common primary glomerulonephritis worldwide. It is caused by accumulation of IgA1-containing immune complexes in the kidney resulting in renal failure, which is thought to be due to altered glycosylation of IgA with a decrease of 2-3-sialylated galactosides (NeuAc alpha 2-3Gal). less thanbrgreater than less thanbrgreater thanPurpose The purpose of this study was to analyze whether altered glycosylation of IgA would lead to an altered binding to galectin-8, an endogenous lectin with strong affinity for 2-3-sialylated galactosides. Galectins are a family of beta-galactoside-binding proteins; by binding various glycoproteins, they play important roles in the regulation of cellular functions in inflammation and immunity. Hence, an altered binding of IgA to galectin-8 could lead to pathologic immune functions, such as glomerulonephritis. less thanbrgreater than less thanbrgreater thanMethods Affinity chromatography of serum glycoproteins on the human sialogalactoside-binding lectin galectin-8N permitted quantitation of bound and unbound fractions, including IgA. less thanbrgreater than less thanbrgreater thanResults Analysis of similar to 100 IgA nephritis sera showed that the galectin-8N unbound fraction of IgA increased compared to similar to 100 controls, consistent with the known loss of galactosylation. A subgroup of similar to 15% of the IgAN patients had a ratio of galectin-8 bound/unbound IgA andlt;0.09, not found for any of the controls. Unexpectedly, the galectin-8N-binding fraction of serum glycoproteins other than IgA increased in the sera of IgAN patients but not in controls, suggesting a previously unrecognized change in this disease. less thanbrgreater than less thanbrgreater thanConclusion This is the first study that relates a galectin, an endogenous lectin family, to IgA nephritis and thus should stimulate new avenues of research into the pathophysiology of the disease.Funding Agencies|Swedish Research Council (Vetenskapsradet)|2008-3356|Swedish Foundation for Swedish Research|FFL4|Swedish Healthcare System (ALF)||Region Skane||</p

Genetic studies of IgA nephropathy: past, present, and future

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and an important cause of kidney disease in young adults. Highly variable clinical presentation and outcome of IgAN suggest that this diagnosis may encompass multiple subsets of disease that are not distinguishable by currently available clinical tools. Marked differences in disease prevalence between individuals of European, Asian, and African ancestry suggest the existence of susceptibility genes that are present at variable frequencies in these populations. Familial forms of IgAN have also been reported throughout the world but are probably underrecognized because associated urinary abnormalities are often intermittent in affected family members. Of the many pathogenic mechanisms reported, defects in IgA1 glycosylation that lead to formation of immune complexes have been consistently demonstrated. Recent data indicates that these IgA1 glycosylation defects are inherited and constitute a heritable risk factor for IgAN. Because of the complex genetic architecture of IgAN, the efforts to map disease susceptibility genes have been difficult, and no causative mutations have yet been identified. Linkage-based approaches have been hindered by disease heterogeneity and lack of a reliable noninvasive diagnostic test for screening family members at risk of IgAN. Many candidate-gene association studies have been published, but most suffer from small sample size and methodological problems, and none of the results have been convincingly validated. New genomic approaches, including genome-wide association studies currently under way, offer promising tools for elucidating the genetic basis of IgAN