Andrea Tancredi

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

The mechanisms of incomplete penetrance in Leber’s hereditary optic neuropathy are elusive. Giordano et al. show that mitochondrial DNA content and mitochondrial mass are both increased in tissues and cells from unaffected mutation carriers relative to affected relatives and control individuals. Upregulation of mitochondrial biogenesis may represent a therapeutic target.

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Chronic intestinal pseudo-obstruction is a life-threatening condition of unknown pathogenic mechanisms. Chronic intestinal pseudo-obstruction can be a feature of mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare autosomal-recessive syndrome, resulting from mutations in the thymidine phosphorylase gene. MNGIE patients show elevated circulating levels of thymidine and deoxyuridine, and accumulate somatic mitochondrial DNA (mtDNA) defects. The present study aimed to clarify the molecular basis of chronic intestinal pseudo-obstruction in MNGIE. Using laser capture microdissection, we correlated the histopathological features with mtDNA defects in different tissues from the gastrointestinal wall of five MNGIE and ten control patients. We found mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach and in the small intestine of MNGIE patients. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. We also observed mitochondrial proliferation and mtDNA depletion in small vessel endothelial and smooth muscle cells. Thus, visceral mitochondrial myopathy likely causes gastrointestinal dysmotility in MNGIE patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in the small vessel wall.

A hierarchical Bayesian approach to record linkage and population size problems

We propose and illustrate a hierarchical Bayesian approach for matching statistical records observed on different occasions. We show how this model can be profitably adopted both in record linkage problems and in capture--recapture setups, where the size of a finite population is the real object of interest. There are at least two important differences between the proposed model-based approach and the current practice in record linkage. First, the statistical model is built up on the actually observed categorical variables and no reduction (to 0--1 comparisons) of the available information takes place. Second, the hierarchical structure of the model allows a two-way propagation of the uncertainty between the parameter estimation step and the matching procedure so that no plug-in estimates are used and the correct uncertainty is accounted for both in estimating the population size and in performing the record linkage. We illustrate and motivate our proposal through a real data example and simulations.

Serum sclerostin levels decline in post-menopausal women with osteoporosis following treatment with intermittent parathyroid hormone.

Objective: This study was carried out in order to evaluate the effect of 18-month treatment with PTH (1–34) or PTH (1–84) on serum sclerostin levels in humans. Subjects and methods: We investigated 10 women with severe osteoporosis, previously treated with alendronate and 20 untreated osteoporotic women. Subjects with severe osteoporosis were randomly divided into 2 groups of 5 patients each; the first group was treated with 20 µg of PTH (1–34) and the second one with 100 µg of PTH (1–84) according to an open-label design. Fasting blood samples were collected at baseline and at 2, 4, and 24 h after hormone administration. The same protocol was followed at month 1,6, 12, 18. Serum sclerostin levels were measured at each time point by a sandwich-type enzyme-linked immunosorbent assay. Results: Basal serum sclerostin levels were not significantly different between patients previously treated with alendronate and those never treated. No significant acute change of serum sclerostin levels was observed after PTH administration. Fitting a mixed effect regression model, we found a significant time effect (p=0.0012) using the sclerostin level as the response variable and the month of drug administration as a single covariate. Treatment with both PTH molecules induced a monthly mean reduction of sclerostin levels of 0.1956 pmol/l. Conclusions: Our results indicate that long-term therapy with PTH (1–34) or PTH (1–84) in women with osteoporosis previously treated with alendronate is associated with a reduction in circulating sclerostin levels. This is a putative mechanism through which PTH performs its anabolic action.

A Bayesian model averaging approach for cost‐effectiveness analyses

We consider the problem of assessing new and existing technologies for their cost-effectiveness in the case where data on both costs and effects are available from a clinical trial, and we address it by means of the cost-effectiveness acceptability curve. The main difficulty in these analyses is that cost data usually exhibit highly skew and heavy-tailed distributions so that it can be extremely difficult to produce realistic probabilistic models for the underlying population distribution, and in particular to model accurately the tail of the distribution, which is highly influential in estimating the population mean. Here, in order to integrate the uncertainty about the model into the analysis of cost data and into cost-effectiveness analyses, we consider an approach based on Bayesian model averaging: instead of choosing a single parametric model, we specify a set of plausible models for costs and estimate the mean cost with a weighted mean of its posterior expectations under each model, with weights given by the posterior model probabilities. The results are compared with those obtained with a semi-parametric approach that does not require any assumption about the distribution of costs.

Muscle strength and bone in healthy women: effect of age and gonadal status

OBJECTIVEThe aim of this work was to examine the effects of age and menopause on muscle strength and on the muscle-bone interaction.DESIGNOne hundred ninety-four healthy women (mean age 49.8 ± 12.6 SD years) were assessed. Maximal Voluntary Contraction (MVC, Newton, N) by Hand Grip Dynamometer, bone mineral density at one third of the radius (R-BMD) by dual-energy X-ray absorptiometry (DXA) and phalangeal ultrasound by the DBM Sonic 1200 device were evaluated at the upper dominant limb. Ultrasonometric parameters considered were Amplitude-Dependent Speed of Sound (ADSoS) and Ultrasound Bone Profile Index (UBPI).RESULTSMVC significantly decreased with age (r2=−0.12, p<0.005). For each level of age, fertile women had a greater MVC compared to postmenopausal women (r2=0.015, p<0.005). In the whole sample, a statistically significant correlation between MVC and R-BMD (r=0.354, p<0.001) and between MVC and ADSoS (r=0.294) and UBPI (r=0.311)(p<0.001 for both) were observed.CONCLUSIONSWe conclude that age and menopausal status significantly contributed to the reduction of muscle strength. The decline of muscular strength significantly correlated with quantitative and qualitative bone features.

Contrast-enhanced magnetic resonance activity in relapsing remitting multiple sclerosis patients: a short term natural history study.

Magnetic resonance imaging (MRI) has been used to study the history of multiple sclerosis (MS). We analyze the relationship between MRI activity in the first scan compared to the subsequent five scans, and we evaluate whether a shorter observation period of 3 months may predict the subsequent 3 months. Monthly enhanced MRI was performed in 103 relapsing remitting (RR) MS patients for 6 months. Thirty-five per cent of patients had an inactive scan on the initial examination. More than 80% of them developed MRI activity during the following 5 months. Eighteen per cent of patients had three consecutive inactive scans; 65% of them had at least one active scan on the subsequent 3 monthly MRIs. The relationship between the first scan and all subsequent scans demonstrates a clear weakening over time. Eighty-two per cent of patients had at least one active scan during the initial 3 consecutive months, the chance of becoming inactive decreased from 23% to 0% over the subsequent 3 months, according with the mean number of enhancing lesions during the first 3 months. These results suggest that neither a single scan nor a short baseline of 3 months may adequately describe the natural history of disease in an individual RRMS patient.

Accounting for matching uncertainty in two stage capture–recapture experiments using photographic measurements of natural marks

We propose a Bayesian hierarchical modeling approach for estimating the size of a closed population from data obtained by identifying individuals through photographs of natural markings. We assume that noisy measurements of a set of distinctive features are available for each individual present in a photographic catalogue. To estimate the population size from two catalogues obtained during two different sampling occasions, we embed the standard two-stage

Bayesian Inference for a Finite Population Total Using Linked Data

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