Mendelian bases of myopathies, cardiomyopathies, and neuromyopathies

A second genetic revolution is approaching thanks to next-generation DNA sequencing technologies. In the next few years, the 1,000$-genome sequencing promises to reveal every individual variation of DNA. There is, however, a major problem: the identification of thousands of nucleotide changes per individual with uncertain pathological meaning. This is also an ethical issue. In the middle, there is today the possibility to address the sequencing analysis of genetically heterogeneous disorders to selected groups of genes with defined mutation types. This will be cost-effective and safer. We assembled an easy-to manage overview of most Mendelian genes involved in myopathies, cardiomyopathies, and neuromyopathies. This was entirely put together using a number of open access web resources that are listed below. During this effort we realized that there are unexpected countless sources of data, but the confusion is huge. In some cases, we got lost in the validation of disease genes and in the difficulty to discriminate between polymorphisms and disease-causing alleles. In the table are the annotated genes, their associated disorders, genomic, mRNA and coding sizes. We also counted the number of pathological alleles so far reported and the percentage of single nucleotide mutations.     

Treatment Options for Sexual Dysfunction in Patients with Chronic Kidney Disease: A Systematic Review of Randomized Controlled Trials

Background and objectives: Sexual dysfunction is very common in patients with chronic kidney disease (CKD), but treatment options are limited. The benefits and harms of existing interventions for treatment of sexual dysfunction were assessed in patients with CKD.Design, setting, participants, & measurements: MEDLINE (1966 to December 2008), EMBASE (1980 to December 2008), and the Cochrane Trial Registry (Issue 4 2008) were searched for parallel and crossover randomized and quasi-randomized trials. Treatment effects were summarized as mean differences (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI) using a random effects model.Results: Fourteen trials (328 patients) were included. Phosphodiesterase-5 inhibitors (PDE5i) compared with placebo significantly increased the overall International Index of Erectile Function-5 (IIEF-5) score (three trials, 101 patients, MD 1.81, 95% CI 1.51 to 2.10), all of its individual domains, and the complete 15-item IIEF-5 (two trials, 80 patients, MD 10.64, 95% CI 5.32 to 15.96). End-of-treatment testosterone levels were not significantly increased by addition of zinc to dialysate (two trials, 22 patients, SMD 0.19 ng/dl, 95% CI −2.12 to 2.50), but oral zinc improved end-of-treatment testosterone levels. There was no difference in plasma luteinizing and follicle-stimulating hormone level at the end of the study period with zinc therapy.Conclusions: PDE5i and zinc are promising interventions for treating sexual dysfunction in CKD. Evidence supporting their routine use in CKD patients is limited. There is an unmet need for studying interventions for male and female sexual dysfunction in CKD considering the significant disease burden.Sexual dysfunction is a set of disorders characterized by physical and psychologic changes that result in the inability to perform satisfactory sexual activities. The condition has been found to be significantly more common in men and women with chronic kidney disease (CKD) than in the general population (1). Men with CKD frequently suffer from reduced libido, erectile dysfunction, and difficulty reaching orgasm (2). Approximately 50% of male predialysis CKD patients and 80% of male dialysis patients have erectile dysfunction (3–6). Moreover, the prevalence of erectile dysfunction in male dialysis patients has been found to increase with age (63% <50 years versus 90% ≥50 years) (3). Similar results have been reported in women with CKD, with 55% of female dialysis patients reporting difficulty with sexual arousal (2). Dysmenorrhea, delayed sexual development, impaired vaginal lubrication, dyspareunia, and difficulties in reaching orgasm are also frequently observed (7,8).Multiple factors contribute to the frequent occurrence of sexual dysfunction in CKD patients, including hormonal disturbances (such as hyperprolactinemia, hypogonadism in males, and changes in hypothalamic-pituitary function in women) (9), anemia (10), CKD mineral and bone disorder (4), psychosocial factors (such as depression, anxiety, poor self-esteem, social withdrawal, marital discord, body image issues, fear of disability and death, loss of employment, and financial difficulties) (2,11,12), autonomic neuropathy (13), medications (including antihypertensives, antidepressant, and histamine receptor blockers) (2), and comorbid illness (such as diabetes mellitus, cardiovascular disease, and malnutrition) (2,14). Sexual dysfunction is inversely associated with GFR (7) and is improved after renal transplantation (15,16), suggesting that CKD per se may contribute to sexual dysfunction in these patients (15).Studies have also identified significant associations between sexual dysfunction in CKD patients and depression (8,17), impaired quality of life (8,17,18), and adverse cardiovascular outcomes (19). Effective treatment of sexual dysfunction in CKD patients may therefore potentially lead to improvement in these patient-level outcomes, although a causal link has not been definitively established (18).Therapies that have been used to treat sexual dysfunction include phosphodiesterase-5 inhibitors (PDE5i), intracavernosal injections, intraurethral suppositories, hormonal therapy, mechanical devices, and psychotherapy. Although many clinical trials and reviews have explored the role of these interventions for sexual dysfunction in nonuremic patients (20–24), the effectiveness and safety of these interventions in patients with CKD have not yet been studied thoroughly. Therefore, we aimed to evaluate the benefits and harms associated with various interventions for sexual dysfunction in patients with CKD.     

Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

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White‐matter lesions along the cholinergic tracts are related to cortical sources of EEG rhythms in amnesic mild cognitive impairment

Does impairment of cholinergic systems represent an important factor in the development of amnesic mild cognitive impairment (aMCI), as a preclinical stage of Alzheimer's disease (AD)? Here we tested the hypothesis that electroencephalographic (EEG) rhythms, known to be modulated by the cholinergic system, may be particularly affected in aMCI patients with lesions along the cholinergic white‐matter tracts. Eyes‐closed resting EEG data were recorded in 28 healthy elderly (Nold) and 57 aMCI patients. Lesions along the cholinergic white‐matter tracts were detected with fluid‐attenuated inversion recovery sequences on magnetic resonance imaging. The estimation of the cholinergic lesion was performed with a validated semi‐automatic algorithm pipeline after registration to a stereotactic template, image integration with stereotactic masks of the cholinergic tracts, and normalization to intracranial volume. The aMCI patients were divided into two groups of high (MCI Ch+; N = 29; MMSE = 26.2) and low cholinergic damage (MCI Ch?; N = 28; MMSE = 26.6). EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). Cortical EEG generators were estimated by LORETA software. As main results, (i) power of occipital, parietal, temporal, and limbic alpha 1 sources was maximum in Nold, intermediate in MCI Ch?, and low in MCI Ch+ patients; (ii) the same trend was true in theta sources. These results are consistent with the hypothesis that damage to the cholinergic system is associated with alterations of EEG sources in aMCI subjects. Hum Brain Mapp 2009. © 2008 Wiley‐Liss, Inc.     

Platelet aggregation is affected by nitrosothiols in patients with chronic hepatitis： In vivo and in vitro studies

AIM： To investigate the relationship among the number of platelets and plasma levels of S-nitrosothiols （S-NO）, nitrite, total non-protein SH （NPSH）, glutathione （GSH）, cysteine （CYS）, malondialdehyde （MDA）, 4-hydroxininenal （4HNE）, tumor necrosis factor-alpha （TNFα） and interleukin （IL）-6 in patients with chronic hepatitis C （CH）.
METHODS： In vitro the aggregation of platelets derived from controls and CH patients was evaluated before and after the addition of adenosine diphosphate （ADP） and collagen, both in basal conditions and after incubation with nitrosoglutathione （GSNO）.
RESULTS： In vivo, S-NO plasma levels increased significantly in CH patients and they were significantly directly correlated with platelet numbers. Patients with platelet counts 〈 150000/μL, had a smaller increase in S-NO, lower levels of GSH, CYS, NPSH, TNFα, and IL-6, and higher levels of nitrite, MDA, and 4-HNE relative to those of patients with platelet counts 〉 150000/μL. In vitro, the ADP and collagen aggregation time was increased in platelets from patients and not from controls; in addition, platelets from CH patients but not from controls also showed a latency time after exposure to collagen.
CONCLUSION： The incubation of platelets with GSNO improved the percentage aggregation and abolished the latency time.     

The Effect of a Silybin-Vitamin E-Phospholipid Complex on Nonalcoholic Fatty Liver Disease: A Pilot Study

Oxidative stress leads to chronic liver damage. Silybin has been conjugated with vitamin E and phospholipids to improve its antioxidant activity. Eighty-five patients were divided into 2 groups: those affected by nonalcoholic fatty liver disease (group A) and those with HCV-related chronic hepatitis associated with nonalcoholic fatty liver disease (group B), nonresponders to treatment. The treatment consisted of silybin/vitamin E/phospholipids. After treatment, group A showed a significant reduction in ultrasonographic scores for liver steatosis. Liver enzyme levels, hyperinsulinemia, and indexes of liver fibrosis showed an improvement in treated individuals. A significant correlation among indexes of fibrosis, body mass index, insulinemia, plasma levels of transforming growth factor-β, tumor necrosis factor-α, degree of steatosis, and γ-glutamyl transpeptidase was observed. Our data suggest that silybin conjugated with vitamin E and phospholipids could be used as a complementary approach to the treatment of patients with chronic liver damage. Other members of the Real Sud Group: L. Cimino, Federico II University, Naples; V. De Girolamo and A. Marone, Ascalesi Hospital, Naples; C. De Stefano, S. Carlo Hospital, Potenza; G. De Stefano, Madonna delle Grazie Hospital, Matera; D. Disalvo and B. Provenzano, Villa D’Agri Hospital, Potenza; P. Esposito and A. Simonetti, Second University, Naples; M. D. Iannece and R. Pempinello, Cotugno Hospital, Naples; R. Iorio, Giugliano Hospital, Naples; S. Monastra and M. Di Pierro, S. Gennaro Hospital, Naples.     

Single-center randomized evaluation of paclitaxel-eluting versus conventional stent in acute myocardial infarction (SELECTION)

OBJECTIVES: To evaluate the superiority of the paclitaxel-eluting stent (PES) in reducing neointimal hyperplasia (NIH) over its corresponding bare metal stent (BMS) during primary percutaneous coronary intervention (PCI). BACKGROUND: Primary PCI with stent implantation is the repercussion strategy of choice for ST-elevation myocardial infarction (STEMI); nonetheless restenosis rate is still high. Drug-eluting stents have been proven to reduce restenosis rate in many settings, but their use during primary PCI is still controversial. METHODS: Consecutive patients with STEMI <12 hours were randomized to receive PES or BMS. The primary end-point was the percentage of the stent volume obstructed by neointimal proliferation (NIH) measured by intravascular ultrasound (IVUS) at a 7-month angiographic follow-up. Secondary end-points were binary restenosis rate and major adverse cardiac events (MACE, i.e., death, nonfatal myocardial infarction, and target lesion revascularization). RESULTS: Eighty patients with STEMI were randomized into the PES or BMS group. Patients were well matched for baseline characteristics and the index procedure was always successful. In-hospital and 1-month MACE were 2.5% per group. NIH at 7 months was 4.6% versus 20% (P< 0.01), late lumen loss 0.1 versus 1.01 mm (P = 0.01). MACE were 7.5% versus 42.5% (P = 0.001) with no difference in death and recurrent myocardial infarction rates. Late-acquired incomplete stent apposition (ISA) rate was 5.1% versus 2.7% (P = 0.65). One subacute stent thrombosis was reported in each group. CONCLUSIONS: PES was superior to its corresponding BMS in reducing NIH in the STEMI setting without any increase in early and long-term clinical adverse events.