Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (≤8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4–8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1–8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.     

Essential role of diastolic oscillatory potentials in adrenergic control of guinea pig sino-atrial node discharge

Background  

The diastolic oscillatory after-potential V_os and pre-potential ThV_os play an essential role in the pacemaker mechanism of sino-atrial node (SAN). The aim of this study was to investigate whether these oscillatory potentials are also involved in adrenergic control of SAN discharge.     

Coexistence of 21-hydroxylase and 11 beta-hydroxylase deficiency in adrenal incidentalomas and in subclinical Cushing's syndrome

OBJECTIVE: The prevalence of steroid secretion abnormalities was studied by evaluating the 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (S) responses to adrenocorticotropic hormone (ACTH) stimulation in 48 patients with 'nonfunctioning' incidentalomas and in 10 patients with 'subclinical' Cushing's syndrome. METHODS: In all patients the cortisol, 17-OHP, and S levels were measured after ACTH test. Eight patients were reinvestigated after surgery. RESULTS: In patients with nonfunctioning lesions, the ACTH test induced 17-OHP and S peaks higher than in normals (p < 0.005). In 10 cases an augmented rise of 17-OHP and S was observed. In patients with subclinical Cushing's syndrome, the 17-OHP peak after ACTH was greater than in patients with nonfunctioning lesions and in normals (p < 0.005); the S peak was also higher than in controls (p < 0.005). In 7 of 8 operated patients, the exaggerated 17-OHP peak was normalized. CONCLUSIONS: A combined impairment of different enzyme activities is frequently present in adrenal incidentalomas; the alteration of enzymatic pathways can also coexist with the presence of partial cortisol autonomy.     

Parameter estimation in a model for multidimensional recording of neuronal data: a Gibbsian approximation approach

This article proposes improved numerical procedures for estimating parameters in a spatiotemporal lattice model introduced for the analysis of cortical activities monitored from arrays of diodes. The numerical algorithms are based on approximations inspired by statistical physics. Both Gibbsian and mean-field approximations are used; they allow for computing local conditional probabilities inside the lattice. The statistical procedures rely on the computation of pseudomaximum-likelihood estimators. The estimators are evaluated on the basis of Monte Carlo simulations. These simulations show that mean-field approximations are useful for reducing the variance of estimators when the data are recorded from arrays of 144 diodes (which are in accordance with standard practice). In light of these improved methods, we give new interpretations for a data set obtained from optical recording of a Guinea pig's auditory cortex in response to pure tone stimulations.     

When enough is enough: genetic diseases associated with transcriptional derepression

For many human genetic diseases, the underlying genetic defect has been determined. Thus, although traditionally a field only for researchers in medicine or human genetics, human diseases are now opening up to molecular biologists, cell biologists and biochemists. Here we discuss four human genetic disorders, Familial Alzheimer's disease, Rett syndrome, Klippel-Trenaunay syndrome and Facioscapulohumeral muscular dystrophy, and how investigations into these diseases are providing important lessons about human biology.     

Free radical generation during chemical depolymerization of heparin

Low-molecular weight heparins (LMWHs), as compared with unfractionated heparin (UFH), present superior bioavailability, much longer plasma half-life, and lower incidence of side effects. For these reasons, over the past two decades LMWHs have become the drugs of choice for the treatment of deep venous thrombosis, pulmonary embolism, arterial thrombosis, and unstable angina. Furthermore, their use in acute ischemic stroke is currently under study. LMWHs are obtained by UFH depolymerization, which can be performed using various methods, including nitrous acid depolymerization, cleavage by beta-elimination of benzyl ester, enzymatic depolymerization, and peroxyl radical-dependent depolymerization. This article addresses the chemical depolymerization, obtained by free radical attack (mainly hydroxyl radical), of heparin. The electron spin resonance (ESR) spectroscopy, coupled to the spin trapping technique, was employed to study this reaction. Free radical-mediated heparin depolymerization was performed under different chemical conditions. The final products of the reactions were purified and classified on the basis of their molecular weight and other characteristics. The level of heparin fragmentation was different depending on the type of depolymerization reaction used. Moreover, the level of reproducibility and the resulting radical species were different for every type of reaction performed.