Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis

The mitochondrial enzyme monoamine oxidase (MAO), its isoform MAO-A, plays a major role in reactive oxygen species-dependent cardiomyocyte apoptosis and postischemic cardiac damage. In the current study, we investigated whether sphingolipid metabolism can account for mediating MAO-A- and reactive oxygen species-dependent cardiomyocyte apoptosis. In H9c2 cardiomyoblasts, MAO-A-dependent reactive oxygen species generation led to mitochondria-mediated apoptosis, along with sphingosine kinase-1 (SphK1) inhibition. These phenomena were associated with generation of proapoptotic ceramide and decrease in prosurvival sphingosine 1-phosphate. These events were mimicked by inhibition of SphK1 with either pharmacological inhibitor or small interfering RNA, as well as by extracellular addition of C(2)-ceramide or H(2)O(2). In contrast, enforced expression of SphK1 protected H9c2 cells from serotonin- or H(2)O(2)-induced apoptosis. Analysis of cardiac tissues from wild-type mice subjected to ischemia/reperfusion revealed significant upregulation of ceramide and inhibition of SphK1. It is noteworthy that SphK1 inhibition, ceramide accumulation, and concomitantly infarct size and cardiomyocyte apoptosis were significantly decreased in MAO-A-deficient animals. In conclusion, we show for the first time that the upregulation of ceramide/sphingosine 1-phosphate ratio is a critical event in MAO-A-mediated cardiac cell apoptosis. In addition, we provide the first evidence linking generation of reactive oxygen species with SphK1 inhibition. Finally, we propose sphingolipid metabolites as key mediators of postischemic/reperfusion cardiac injury.     

The emerging role of endothelial progenitor cells in pulmonary hypertension and diffuse lung diseases

The discovery that circulating bone marrow-derived cells contribute to the repair of many organs and tissues has provided new perspectives for the comprehension of the pathogenesis of lung diseases. Endothelial progenitor cells (EPCs) provide a circulating pool of cells for maintenance of the systemic and pulmonary circulation. By preserving an appropriate vascular support and/or by means of transdifferentiation, EPCs contribute to the homeostasis of the lung parenchyma. Alterations in EPCs and other extrapulmonary progenitor cells may impact on the chronic remodelling taking place in many diffuse lung diseases. In this review, we will focus on the experimental and clinical data suggesting that EPC deregulation may have a role in the pathogenesis of vascular and parenchymal lung diseases.     

Viral infections and lower urinary tract symptoms in the third national health and nutrition examination survey

PURPOSE: Previous epidemiological studies described suggestive positive associations between sexually transmitted infections, particularly gonorrhea and human immunodeficiency virus infection, and lower urinary tract symptoms. To our knowledge no groups have investigated other infections, such as human papillomavirus type 16, herpes simplex virus type 2, cytomegalovirus, human herpesvirus type 8, herpes simplex type 1, and hepatitis B and C virus infection, in relation to lower urinary tract symptoms. Therefore, we examined each of these associations in the Third National Health and Nutrition Examination Survey. MATERIALS AND METHODS: The Third National Health and Nutrition Examination Survey is a representative, cross-sectional survey of the population in the United States that was done between 1988 and 1994. Each participant provided a blood sample and completed a computer assisted interview including questions on lower urinary tract symptoms (nocturia, incomplete emptying, hesitancy and weak stream). Blood samples were tested for IgG antibodies against each virus. RESULTS: In younger men (ages 30 to 49 years) positive associations were observed between cytomegalovirus, human herpesvirus type 8, herpes simplex virus type 1, and hepatitis B and C virus antibody seropositivity, and lower urinary tract symptoms. In 50 to 59-year-old men positive associations were observed between human papillomavirus type 16, herpes simplex virus type 2, cytomegalovirus, human herpesvirus type 8 and hepatitis C virus antibody seropositivity and lower urinary tract symptoms. In men 60 years or older only a slight, nonsignificant positive association was observed between cytomegalovirus antibody seropositivity and lower urinary tract symptoms. CONCLUSIONS: In this cross-sectional survey of American men suggestive positive associations were observed between several viral infections and lower urinary tract symptoms, primarily in 30 to 59-year-old men. These findings provide interesting hypotheses and preliminary evidence for future etiological studies of infections and lower urinary tract symptoms.     

Anatomical identification of active contacts in subthalamic deep brain stimulation

BACKGROUND: Subthalamic Deep Brain Stimulation is a valid surgical procedure for the treatment of idiopathic PD, although its precise mechanism of action is still unclear; moreover, there are no conclusive data about the functional anatomy of the human subthalamic region. Identifying the location of active contacts for StnDBS can yield interesting insights on the mechanisms of action of DBS and the different role played by the anatomical structures of the subthalamic region. METHODS: Twenty-five patients operated on for bilateral StnDBS were considered. During the surgical procedure, a complete intraoperative neurophysiological study was obtained by means of semimicrorecordings and stimulations. After surgery, an MRI study confirmed the position of the electrodes; MR images were subsequently superimposed onto a stereotactic atlas by using a dedicated workstation. The coordinates relative to the tip of the electrodes and active contacts were then calculated. RESULTS: Most of the electrode tips are located inside the subthalamus or immediately ventrally to it. Of the active contacts used for chronic stimulation, 96.5% are located in a well-defined anatomical region, which includes subthalamus, zona incerta, and FF. CONCLUSIONS: Our findings seem to suggest that other structures beyond the subthalamus itself play a clinical role in symptoms control after DBS for PD.     

The effect of topiramate on energy balance in obese men: a 6-month double-blind randomized placebo-controlled study with a 6-month open-label extension

Objective Topiramate (TPM) has been reported to reduce body weight beyond a placebo in the treatment of obese participants, but the effect of this agent on components of energy balance has not yet been established in humans. Thus, the aim of this study was to study the impact of TPM on food preferences, measures of satiety, food intake, resting metabolic rate (RMR), and 24-h energy expenditure. Methods The study design consisted of a 6-month, single-center, randomized, double-blind, parallel group, placebo-controlled trial with a 6-month open-label extension. The study included 68 sedentary men with abdominal obesity (waist circumference ≥100 cm), of between 25 and 55 years of age, with a dyslipidemic profile and a body mass index (BMI) ≥27 and ≤40 kg/m². Results Treatment with TPM produced significant changes in anthropometric variables and body composition compared with placebo. However, at the end of the 1-year study, the placebo/TPM group showed similar weight loss and reduction in body fatness compared with the TPM/TPM group. For instance, at the end of the 12-month intervention, mean percentage of body weight loss from baseline was about −5% in both groups (−4 kg fat loss). Topiramate treatment reduced energy intake, be it in the context of an ad libitum buffet-type meal or under free living conditions. The 24-h daily energy expenditure (DEE) assessed by whole-body indirect calorimetry adjusted for body weight and age was not altered by TPM treatment. Conclusion Topiramate treatment produced significantly greater weight loss than placebo and the majority of this loss was explained by a decrease in body fat stores. Most of the weight loss effect produced by TPM therapy was observed within a period of 6 months. Finally, TPM treatment had an impact on energy balance through a reduction in food intake that appears to have created an energy deficit of about 30,000–40,000 kcal compared with treatment with the placebo over 6 months.