Pathology and Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a primary heart muscle disease characterized by progressive myocardial atrophy of the right ventricle, with transmural fatty or fibrofatty replacement, either segmental or diffuse, accounting for electrical instability at risk of life-threatening ventricular arrhythmias. It was recently included among cardiomyopathies in the revised WHO classification. The disease was found to be a major cause of sudden death in the young and in athletes of the Veneto Region, Italy. A familial occurrence with autosomic dominant inheritance was then discovered with a prevalence estimated to be 6/10,000 inhabitants and 5 loci have been identified by linkage analysis so far, 2 mapping to chromosome 14 and to chromosome 1, 2 and 3 one each. A recessive form associated with palmoplantar keratosis has also been reported, mapping to chromosome 17. Nonetheless, the specific gene defects as well as the defective coded proteins have not yet been identified. At gross examination, the right side of the heart appears yellowish or whitish as to suggest a fatty or fibrofatty infiltration of the underlying myocardium; the myocardial loss frequently accounts for a parchment like, translucent look of the right ventricular free wall. Aneurysms of the right ventricular free wall, whether single or multiple, were reported in about 50% of cases in a recent pathologic investigation, and are considered a pathognomonic feature of arrhythmogenic right ventricular cardiomyopathy; they are typically located in the inferior, diaphragmatic wall, underneath the posterior leaflet of the tricuspid valve, as well as in the infundibulum and at the apex. Right ventricular enlargement, whether mild, moderate or severe, is a constant feature. Involvement of the left ventricle has been reported in almost 50% of cases. At histology, the pathologic process generally starts from the subepicardium and extends to the endocardium in a wave-front phenomenon. The residual, spared myocytes are located within the subendocardial trabeculae and few myocardial fascicles are scattered throughout the fibrofatty tissue. All stages of myocardial injury and repair are recognizable: acute cell death with sarcolysis and inflammatory infiltrates; subacute damage with "active fibrosis", including dying myocytes, lymphocytes and macrophages, or otherwise adipocytes replacing vanished myocytes; and, eventually, chronic stage with fibrous tissue and adipocytes surrounding residual surviving myocytes. Both the etiology and pathogenesis of arrhythmogenic right ventricular cardiomyopathy are still unknown. In particular, the mechanisms leading to progressive loss of myocardium and fibrofatty replacement are speculative. According to the frequent finding of inflammatory infiltrates at histology, an inflammatory theory has been advanced and infective, toxic or immune mechanisms have been investigated. Recently, apoptosis has been documented both in autoptic and bioptic material, suggesting that recurrent bouts of apoptosis may account for progressive atrophy of the myocardium which is then replaced by fibrofatty tissue. Apoptosis may be triggered by T-lymphocytes.     

Combined therapeutic effects of vinblastine and rapamycin on human neuroblastoma growth, apoptosis, and angiogenesis.

PURPOSE: Vinblastine and rapamycin displayed synergistic inhibition of human neuroblastoma-related angiogenesis. Here, we studied the antitumor activity of vinblastine and rapamycin against human neuroblastoma. EXPERIMENTAL DESIGN: Cell proliferation, cell cycle progression, and apoptosis were evaluated by measuring (3)H-thymidine incorporation, bromodeoxyuridine uptake, and phosphatidylserine exposure, respectively. The in vivo sensitivity of neuroblastoma cells to vinblastine and rapamycin was determined in orthotopic neuroblastoma-engrafted mice. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. RESULTS: Each compound alone was able to induce a dose-dependent significant inhibition of cell proliferation, with a dramatically enhanced antiproliferative effect for the drugs used in combination. A marked G(2)-M cell cycle arrest with a nearly complete depletion of S phase was associated. The combined treatment triggered an increased apoptosis compared with either drug tested alone. A significant inhibition of tumor growth and microvessel area was obtained in neuroblastoma-bearing mice when treated with vinblastine or rapamycin alone, and a more dramatic effect with the combined treatment, compared with control mice. The therapeutic effectiveness, expressed as increased life span, was statistically improved by the combined therapy, compared with mice treated with either drug tested separately. Histologic evaluation of primary tumors showed that the combined treatment inhibited proliferation and angiogenesis and induced apoptosis. Combined treatment of neuroblastoma cells and neuroblastoma-bearing mice with vinblastine and rapamycin induced the down-modulation of both vascular endothelial growth factor production and vascular endothelial growth factor receptor 2 expression. In the chorioallantoic membrane assay, angiogenesis induced by human neuroblastoma biopsy specimens was significantly inhibited by vinblastine and rapamycin. CONCLUSIONS: These results may be relevant to design new therapeutic strategies against neuroblastoma.     

Biliopancreatic diversion: long-term effects on gonadal function in severely obese men

BACKGROUND: This study investigated hormonal parameters of gonadal function in severely obese men before and 1 year after undergoing biliopancreatic diversion (BPD). METHODS: This observational 1-year postoperative study conducted at medical and surgical clinics at an academic medical center in Italy followed 20 severely obese men age 21 to 63 years, with a mean (+/- standard deviation) body mass index (BMI) of 47.3 +/- 13.1. The following parameters were evaluated: body composition, using body impedance analysis (BIA), and serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone, estradiol 17beta, and leptin. RESULTS: At a mean 12 +/- 1 months after surgery, the patients showed a significant decrease in weight, from 132.1 +/- 36.9 before surgery to 93.5 +/- 20 kg (P < .0001), and BMI, from 47.3 +/- 13.1 before surgery to 33.5 +/- 7 (P < .0001). LH increased from 2.42 +/- 1.59 to 4.97 +/- 2.6 mIU/ml (P < .0001), FSH increased from 2.85 +/- 1.85 to 4.9 +/- 4.2 mIU/mL (P = .021), and total testosterone increased from subnormal presurgical values to within normal range (2.81 +/- 1.08 to 9.12 +/- 1.37 ng/mL; P < .0001), whereas estradiol 17beta decreased from elevated basal levels of 44.0 +/- 29 to 16.7 +/- 6.9 pg/mL (P < .0001). The basal leptin level dropped from 33.0 +/- 9.23 to 16.6 +/- 5.12 ng/mL (P < .0001), reflecting the decrease in body fat. Subjective improvement in sexual performance was reported by 80% of patients. CONCLUSIONS: Severe obesity is coupled with some significant alterations of the gonadotropin-testicular axis and estradiol 17beta and leptin blood levels. These derangements were substantially corrected by 1 year after BPD.     

Cervicovaginal secretions contribute to innate resistance to herpes simplex virus infection

Defining and preserving the innate antiviral activity found in cervicovaginal secretions is critical. Cervicovaginal lavage (CVL) samples were obtained from 20 healthy women and evaluated for anti-herpes simplex virus (HSV) activity. CVL samples reduced HSV-2 yields by 23-fold (median), and the anti-HSV activity of CVL samples correlated with the concentration of human neutrophil peptides (HNP)-1-3. Both CVL samples and HNP-1-3 interacted with virus and prevented entry after binding. Substantially less protective activity was observed in CVL samples obtained from 20 human immunodeficiency virus--infected subjects, but the addition of CVL samples from healthy subjects enhanced the antiviral activity. The significance of the innate activity was further demonstrated by showing that CVL samples prevented murine genital herpes. Fourteen of 15 mice were protected from genital herpes if they were challenged with HSV-2 pretreated with CVL samples from healthy subjects. In contrast, all 15 mice challenged with untreated HSV-2 died. These findings are evidence that cervicovaginal secretions contribute to innate resistance to HSV-2 and identify defensins as contributors to this activity.     

Topical microbicides for the prevention of genital herpes infection

Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is the most common cause of genital ulcers. Despite increased public awareness and the initiation of efforts to prevent transmission, the prevalence of herpes simplex virus (HSV) type 2 continues to increase. What makes HSV so difficult to control is that most sexual and perinatal transmission occurs during unrecognized or asymptomatic shedding. The impact of genital herpes as a public health threat is amplified because of its epidemiological synergy with HIV/AIDS. Thus, there is an urgent need for novel prophylactic methods, such as topical microbicides designed for genital application, to prevent both HSV and HIV transmission. Several candidate microbicides are being advanced to clinical trials based on in vitro activity and animal studies. These include compounds that inactivate virus directly, those that enhance innate immunity, and drugs that block viral binding and entry. A more vigorous evaluation of the safety of these and other candidate topical microbicides in development should include assessment of the impact of repeated application on innate host defences in the genital tract.     

Effects of irbesartan on the growth and differentiation of adipocytes in obese zucker rats

OBJECTIVE: The aim of this study was to evaluate the effects of the selective angiotensin receptor 1 antagonist irbesartan on the growth and differentiation of the adipocytes in obese Zucker fa/fa rats. RESEARCH METHODS AND PROCEDURES: Obese Zucker fa/fa rats were treated by oral route for 3 weeks with irbesartan at doses of 3-10-30 mg/kg per day. The adipocyte differentiation was evaluated by analyzing tissue samples of white (retroperitoneal) or brown (interscapular) adipose tissue for the presence of peroxisome proliferator activated receptor gamma, leptin, and the activity of glycerol-3-phosphate dehydrogenase. RESULTS: This study showed that the treatment of obese Zucker fa/fa with irbesartan effectively reduced the differentiation of adipocytes within brown (interscapular) and white (retroperitoneal) adipose tissue. In fact, irbesartan significantly (p < 0.01) and dose-dependently reduced the tissue levels of leptin, peroxisome proliferator activated receptor gamma, and the activity of the enzyme glycerol-3-phoshate dehydrogenase accepted markers of adipocyte differentiation. None of the tested doses of irbesartan affected these markers in non-obese rats. DISCUSSION: The antagonism of the angiotensin receptor 1 receptors with irbesartan reduces the adipogenic activity of angiotensin II in obese Zucker rats, with the endpoint being reduction of the growth and differentiation of the adipocytes within the adipose tissue.     

Effect of manidipine as compared to atenolol on platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus

This study was done to evaluate the effect of treatment with manidipine as compared with atenolol on thrombin-mediated platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus. After a 2-week washout placebo period, 60 elderly patients (aged 65-80 years) with isolated systolic hypertension (SBP > 140 mm Hg and DBP < 90 mm Hg) were randomly assigned to manidipine 10 mg or atenolol 50 mg 6-week treatment according to a double-blind, crossover design. Thirty patients had a concomitant well-controlled type 2 diabetes mellitus (HbA1c < or = 6.5%). At the end of the washout and of each treatment period, blood pressure (BP) (by mercury sphygmomanometer) and platelet aggregation (by Born-type aggregometer) were evaluated. Blood samples were collected using sodium citrate as anticoagulant, and platelet aggregation was induced by 2 different concentrations of ADP and collagen. Manidipine and atenolol produced a significant BP reduction in both diabetic and nondiabetic patients, with no difference between treatments. Despite the similar BP effect, in diabetic patients manidipine produced a significant reduction in platelet aggregation induced by both doses of either ADP or collagen. In nondiabetic hypertensives, manidipine inhibited platelet aggregation only at the highest doses of both inducers. The difference in the platelet inhibitory effect of manidipine between diabetic and nondiabetic subjects was statistically significant (P < 0.05) at both inducer concentrations. No changes in platelet aggregation were observed in the atenolol group. These data indicate that, unlike atenolol, manidipine inhibits platelet aggregation in elderly hypertensive patients, expecially in those with associated type II diabetes mellitus. The clinical impact of this positive effect in terms of prevention of cardiovascular complications in these high-risk patients remains to be clarified.