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

Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called "IGAN1," on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 ( alpha =0.50) and 2.56 ( alpha =0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgA

Metastatic melanoma in an esophagus demonstrating Barrett esophagus with high grade dysplasia

BACKGROUND: Metastatic melanoma involving the esophagus is rare; the occurrence of metastatic melanoma in a background of Barrett esophagus is rarer still. We report a case of an 80 year-old male who presented to our institution for workup of Barrett esophagus with high-grade dysplasia and who proved to have metastatic melanoma occurring in the background of Barrett esophagus, the first report of this kind, to our knowledge, in the English literature. CASE PRESENTATION: An 80 year-old Caucasian male was diagnosed at an outside institution with Barrett’s esophagus with high grade dysplasia and presented to our institution for therapy. The patient underwent endoscopic mucosal resection using a band ligation technique of an area of nodularity within the Barrett esophagus. Microscopic examination demonstrated extensive Barrett esophagus with high-grade dysplasia as well as a second tumor which was morphologically different from the surrounding high-grade dysplasia and which was positive for S-100, HMB 45 and Melan-A on immunohistochemistry, consistent with melanoma. Further workup of the patient demonstrated multiple radiologic lesions consistent with metastases. Molecular studies demonstrated that the melanoma was positive for the 1799T>A (V600E) mutation in the BRAF gene. The overall features of the tumor were most consistent with metastatic melanoma occurring in a background of Barrett esophagus with high-grade dysplasia. CONCLUSION: This case demonstrates a unique intersection between a premalignant condition (Barrett esophagus with high grade dysplasia) and a separate malignancy (melanoma). This report also shows the utility of molecular testing to support the hypothesis of primary versus metastatic disease in melanoma

Serum thyroglobulin and 131I whole body scan after recombinant human TSH stimulation in the follow-up of low-risk patients with differentiated thyroid cancer

OBJECTIVE: The 'standard' postoperative follow-up of patients with differentiated thyroid cancer (DTC) has been based upon serum thyroglobulin (Tg) measurement and (131)I whole body scan ((131)I-WBS) after thyroid hormone (T(4)) treatment withdrawal. However, (131)I-WBS sensitivity has been reported to be low. Thyroid hormone withdrawal, often associated with hypothyroidism-related side effects, may now be replaced by recombinant human thyroid stimulating hormone (rhTSH). The aim of our study was to evaluate the diagnostic accuracy of (131)I-WBS and serum Tg measurement obtained after rhTSH stimulation and of neck ultrasonography in the first follow-up of DTC patients. DESIGN: Ninety-nine consecutive patients previously treated with total thyroidectomy and (131)I ablation, with no uptake outside the thyroid bed on the post-ablative (131)I-WBS (low-risk patients) were enrolled. METHODS: Measurement of serum Tg and (131)I-WBS after rhTSH stimulation, and ultrasound examination (US) of the neck. RESULTS: rhTSH-stimulated Tg was 1 ng/ml (Tg+) in 21 patients, including 6 patients with Tg levels >5 ng/ml. (131)I-WBS was negative for persistent or recurrent disease in all patients (i.e. sensitivity = 0%). US identified lymph-node metastases (confirmed at surgery) in 4/6 (67%) patients with stimulated Tg levels >5 ng/ml, in 2/15 (13%) with Tg>1<5 ng/ml, and in 2/78 (3%) who were Tg-negative. CONCLUSIONS: (i) diagnostic (131)I-WBS performed after rhTSH stimulation is useless in the first follow-up of DTC patients; (ii) US may identify lymph node metastases even in patients with low or undetectable serum Tg levels

Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue

Parathyroid carcinoma (PaC) is a rare cause of primary hyperparathyroidism. Though the loss of the oncosuppressor CDC73/HRPT2 gene product, parafibromin, has been involved in the hyperparathyroidism–jaw tumor syndrome and in a consistent set of sporadic PaCs, parathyroid carcinogenesis remains obscure. MicroRNAs are a new class of small, non-coding RNAs implicated in development of cancer, since their deregulation can induce aberrant expression of several target genes. The aim of the present study was to identify differentially expressed microRNAs in parathyroid cancers compared with normal tissues. We performed a TaqMan low-density array profiling of four parathyroid cancers harboring CDC73 inactivating mutations and negative for parafibromin immunostaining. Their microRNA profiling was compared with that of two normal parathyroid biopsies. Out of 362 human microRNAs assayed, 279 (77%) were successfully amplified. Fourteen and three microRNAs were significantly down- and over-expressed in parathyroid cancers respectively. Of these, miR-296 and miR-139 were down-regulated, and miR-503 and miR-222 were over-expressed with a null false discovery rate. Carcinomas could be discriminated from parathyroid adenomas by a computed score based on the expression levels of miR-296, miR-222, and miR-503 as miR-139 was similarly down-regulated in both cancers and adenomas. Finally, miR-296 and miR-222 levels negatively correlated with mRNA levels of the hepatocyte growth factor receptor-regulated tyrosine kinase substrate and p27/kip1 levels respectively. These results suggest the existence of an altered microRNA expression pattern in PaCs together with a potential role of miR-296 as novel oncosuppressor gene in these neoplasia

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