Ovariectomy exacerbates oxidative stress and cardiopathy induced by adriamycin.

Ovarian hormone depletion in ovariectomized experimental animals is a useful model with which to study the physiopathological consequences of menopause in women. It has been suggested that menopause is a risk factor for the induction of several cardiovascular disorders. In the present study we analyzed the effects of ovarian hormone depletion by ovariectomy (OVX) in a model of oxidative stress and cardiopathy induced by adriamycin (AD). To evaluate these effects, we measured parameters related to cardiac damage (creatinine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase) and oxidative stress (malondialdehyde, catalase, superoxide dismutase, glutathione peroxidase, reduced glutathione, nitric oxide and carbonyl proteins) in cardiac tissue and erythrocytes. OVX was found to alter all markers of oxidative stress and cell damage in cardiac tissue. Similarly, the OVX-derived loss of ovarian hormones enhanced cardiac damage and oxidative stress induced by AD. Our results suggest that antioxidant status in cardiac tissue and erythrocytes is seriously compromised by OVX during the cardiomyopathy induced by AD in experimental animals. In conclusion, the absence of hormones caused by OVX or menopause may induce or accelerate pre-existing cardiovascular dysfunctions.     

Viewpoint: developing a research ethics consultation service to foster responsive and responsible clinical research.

Although clinical ethics has become a central, and welcome, component of the health care landscape, research ethics consultation services are still uncommon. Indeed, the usual approach to ethical concerns in research with human subjects has been primarily a regulatory one. Nonetheless, ethical problems also arise in the context of research and thus collaborations between investigators and research ethicists are as essential as those between physicians and clinical ethicists. The authors argue that the use of research ethics consultation services can be of benefit to clinical scientists, bioethicists, research institutions, and research subjects. Such services can increase sensitivity among researchers to the ethical implications of their work, result in better institutional research policies, and facilitate the development of an organizational culture that is receptive to the identification and resolution of ethical conflicts. The authors conclude by describing the process of development and implementation of such a research ethics consultation service at Weill Medical College of Cornell University.     

Insular cortex lesions and taste aversion learning: effects of conditioning method and timing of lesion

The specific role of insular cortex in acquisition and expression of a conditioned taste aversion was assessed using two different conditioning methods, which vary mode of taste delivery. Involvement of insular cortex in the induction of c-Fos-immunoreactivity in the nucleus of the solitary tract, a cellular correlate of the behavioral expression of a conditioned taste aversion, was also assessed. Electrolytic lesions of insular cortex blocked behavioral expression of a conditioned taste aversion and this was evident not only when lesions were placed prior to conditioning, but also when they were made after conditioning but before testing. In contrast to the effects on behavior, lesions did not completely block the c-Fos-immunoreactivity which accompanies re-exposure to the aversive taste. In addition, the blocking of behavioral evidence of aversion conditioning by cortical lesions was seen both in animals trained under an intraoral acquisition procedure and those trained with bottle-conditioning. This contrasts with previous work with amygdala lesions which showed that amygdala was absolutely necessary for taste aversions conditioned with the intraoral method but not for those conditioned using bottle presentation of the taste. Overall, these findings imply that the details of the neural circuitry involved in taste aversion learning, including its anatomical distribution, complexity and degree of redundancy, vary with the type of conditioning method employed.     

Characteristics and Outcomes in Adult Patients Receiving Mechanical Ventilation: A 28-Day International Study

Context  The outcome of patients receiving mechanical ventilation for particular indications has been studied, but the outcome in a large number of unselected, heterogeneous patients has not been reported. Objective  To determine the survival of patients receiving mechanical ventilation and the relative importance of factors influencing survival. Design, Setting, and Subjects  Prospective cohort of consecutive adult patients admitted to 361 intensive care units who received mechanical ventilation for more than 12 hours between March 1, 1998, and March 31, 1998. Data were collected on each patient at initiation of mechanical ventilation and daily throughout the course of mechanical ventilation for up to 28 days. Main Outcome Measure  All-cause mortality during intensive care unit stay. Results  Of the 15 757 patients admitted, a total of 5183 (33%) received mechanical ventilation for a mean (SD) duration of 5.9 (7.2) days. The mean (SD) length of stay in the intensive care unit was 11.2 (13.7) days. Overall mortality rate in the intensive care unit was 30.7% (1590 patients) for the entire population, 52% (120) in patients who received ventilation because of acute respiratory distress syndrome, and 22% (115) in patients who received ventilation for an exacerbation of chronic obstructive pulmonary disease. Survival of unselected patients receiving mechanical ventilation for more than 12 hours was 69%. The main conditions independently associated with increased mortality were (1) factors present at the start of mechanical ventilation (odds ratio [OR], 2.98; 95% confidence interval [CI], 2.44-3.63; P<.001 for coma), (2) factors related to patient management (OR, 3.67; 95% CI, 2.02-6.66; P<.001 for plateau airway pressure >35 cm H₂O), and (3) developments occurring over the course of mechanical ventilation (OR, 8.71; 95% CI, 5.44-13.94; P<.001 for ratio of PaO₂ to fraction of inspired oxygen <100). Conclusion  Survival among mechanically ventilated patients depends not only on the factors present at the start of mechanical ventilation, but also on the development of complications and patient management in the intensive care unit.      

Increased density of galanin binding sites in the dorsal raphe in a genetic rat model of depression.

The Flinders Sensitive Line rats showed an increased immobility response by 104% (P<0.01) in the forced swim test with respect to the Flinders Resistant Line rats (control). The Flinders Sensitive Line rats also had an increase of [(125)I]galanin (porcine) binding in the dorsal raphe (55+/-3.3 fmol/mg protein) with respect to the Flinders Resistant Line rats (38+/-3.6 fmol/mg protein) (42%, P<0.05) without changes in galanin receptor affinity and with a significant reduction (32.3%, P<0.05) of galanin-like immunoreactivity in the dorsal raphe. The results indicate that enhancement of galanin receptor function in the dorsal raphe rich in 5-HT neurons could be a mechanism involved in the production of depressive-like activity in this animal model of depression.     

Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy.

OBJECTIVES: We aimed to study the prevalence of Fabry disease (FD) in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: There are limited and controversial data about the prevalence of FD in patients with HCM. METHODS: We screened the plasma alpha-galactosidase A activity from 508 unrelated patients with HCM (328 men, 180 women, ages 58 +/- 16 years). Patients with low activity (0% to 30% of the normal control in men, and 0% to 50% in women) underwent genetic study of the GLA gene. RESULTS: We found low plasma activity in 15 patients (3%). Three men had GLA mutations (0.9%): S238N (novel) in 2 and E358del (described) in 1. Two women had described mutations (1.1%): L89P and A143T. Three unrelated men had the D313Y variant previously associated with enzyme pseudo-deficiency. Two women had polymorphisms that did not segregate with the disease in their families. Five women (activity 39% to 47%) had no sequence variants. The familial studies allowed the diagnosis of 14 carriers: 6 women without Fabry manifestations, 3 women with cardiomyopathy, 2 men with renal and cardiac disease, 1 man with microhematuria, 1 woman with first-degree atrioventricular block, and a 32-year-old woman with only renal disease. CONCLUSIONS: By means of a screening based on genotyping of patients with low plasma enzymatic activity, the prevalence of FD in our population of HCM is 1% (0.9% in men and 1.1% in women). This diagnosis is relevant, because it allows the identification of disease carriers that might benefit from enzyme replacement therapy.     

Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis

BACKGROUND: Since primary biliary cirrhosis (PBC) is usually diagnosed in postmenopausal women with minor cholestasis, it has been questioned whether PBC itself represents a further risk for osteoporosis. AIM: To assess the prevalence and risk factors for osteoporosis in an unselected series of women with PBC. PATIENTS AND METHODS: 142 women with PBC (age: 54.3+/-0.8 years) and an age-matched control group. Osteoporosis was established by densitometry (bone mineral density below -2.5 T-score). Age, duration and severity of PBC, body mass index, menopausal status, histological stage and markers of bone turnover were assessed. RESULTS: Prevalence of osteoporosis was higher in PBC (32.4%) than in normal women (11. 1%) (RR: 3.83, 95%CI: 2.59-5.67, P<0.001). Osteoporosis was associated with older age, menopausal status, body mass index, longer PBC duration, advanced histological stage, high bilirubin and alkaline phosphatase, and low albumin and prothrombin index. Regression analysis identified older age, higher Mayo risk score, lower body mass index and advanced histological stage but not menopause as the independent risk factors for osteoporosis. CONCLUSIONS: Osteoporosis is more prevalent in women with PBC than in the general population. Age and severity of the disease, but not menopausal status, are the main risk factors for osteoporosis in this liver disease.     

Diagnostic accuracy of liver and spleen stiffness measured by fibroscan® in the prediction of esophageal varices in HCV-related cirrhosis patients treated with oral antivirals

IntroductionThe aim of this study was to investigate the accuracy of liver and spleen stiffness measurement by transient elastography for the prediction of gastroesophageal varices in patients with HCV-associated cirrhosis treated with new direct-acting antiviral agents.Patients and methodsThis cross-sectional observational study included patients with compensated HCV-related cirrhosis and sustained virological response after direct-acting antiviral therapy. Patients underwent liver and spleen stiffness measurement, abdominal ultrasound and oesophago-gastroduodenoscopy. Clinical and laboratory data and non-invasive markers such as the liver stiffness–spleen diameter to platelet ratio score, variceal risk index and platelet count to spleen diameter ratio were analyzed.ResultsNinety-seven consecutive patients were included. Liver stiffness measurement (12.2 vs 16; p = 0.02), spleen stiffness measurement (39.4 vs 46.05; p = 0.04), liver stiffness–spleen diameter to platelet ratio score (1.21 vs 2.02; p = 0.008), platelet count to spleen diameter ratio (1102.19 vs 829.7; p = 0.04) and variceal risk index (?3.4 vs ?1.02; p = 0.01) showed significant differences between patients without/with gastroesophageal varices. The best cut-off value to discard the presence of gastroesophageal varices was 12.3 kPa for liver stiffness measurement and 27 kPa for spleen stiffness measurement. However, diagnostic accuracy was moderate (AUROC: 0.671 and 0.624 respectively). Combining different non-invasive parameters did not significantly improve the overall performance.DiscussionLiver and spleen stiffness measurement showed suboptimal results for non-invasive assessment of gastroesophageal varices in HCV cirrhotic patients treated with direct-acting antiviral agents. Our results suggest that non-invasive methods cannot substitute standard procedures for predicting gastroesophageal varices in this population.