Genetic Mapping and Tailored Antihypertensive Therapy

A tailored or individualized antihypertensive therapy represents the new frontier for the treatment of essential hypertension and its organ complications. Indeed, individual variation in the efficacy and tolerability of antihypertensive drugs in human essential hypertension is currently experienced by all physicians and is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate specific responsiveness to the therapy with phenotypic traits of the patients, but with poor results. More recently, the genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure both in animal models and in patients.But the relevance of these polymorphisms for defining and classifying patients in terms of therapy responsiveness must be analyzed in a more complex context that takes into account the crucial aspects of environmental influences, stage of disease, previous treatments, efficacy, tolerance, and duration of the treatment. Only a few examples of a pharmacogenomic approach to hypertension therapy are now available. In particular, the association of different variants of ACE, angiotensinogen, and G-protein genes with the blood pressure response to drugs interfering with RAS or -adrenergic receptor has been studied. However, the results of these studies cannot be considered conclusive, since not all the criteria have been fully applied for proper assessment of an association between genetic polymorphism and drug response. Our group has identified a polymorphism of the genes coding for the cytoskeletal protein, adducin, which is associated with both rat and human hypertension, sodium sensitivity, and the antihypertensive effects of diuretics. A modification of the renal Na–KATPase leading to an increase of tubular sodium reabsorption seems to be the most likely underlying mechanism. A new antihypertensive compound has been developed that can correct the abnormality of the renal Na–KATPase and the blood pressure increase associated with adducin polymorphism in the rat. At present, the antihypertensive activity of this compound is under evaluation in patients with different adducin genotypes.     

Angiotensin-converting enzyme inhibition, catecholamines and hemodynamics in essential hypertension

Captopril was given to 15 unselected patients with essential hypertension (WHO II) at a dose range of 300 to 600 mg/day. Hemodynamic indexes (thermodilution) as well as levels of plasma norepinephrine, epinephrine, renin activity and aldosterone were determined simultaneously at the end of 2 weeks of placebo and after 8 weeks of captopril treatment. Systolic and diastolic arterial pressures were reduced significantly by treatment both supine (p less than 0.0025) and standing (p less than 0.0025). The diastolic arterial pressure was normalized (less than 95 mm Hg) in five patients and significantly reduced in four, whereas six patients were considered poor responders (mean arterial pressure decrease 10 mm Hg or less). The decrease in arterial pressure correlated significantly with the reduction in total peripheral resistance (r = 0.71), whereas cardiac index did not change and stroke index increased because of a slight decrease of heart rate. Plasma and urinary norepinephrine and epinephrine did not change during treatment. Moreover, the response of both heart rate and plasma catecholamines to upright posture was not altered by captopril treatment. Plasma renin activity increased and plasma aldosterone concentration decreased during treatment. These results suggest that inhibition of converting enzyme activity by captopril induces a reduction in arterial pressure through a reduction in total peripheral resistance. There was no evidence of an appreciable reduction in sympathetic nervous system activity during therapy.     

Acute hypotensive and renin-stimulating actions of captopril before and during treatment with a beta-blocking drug

There is no general agreement on the relation between the hypotensive effect of captopril and the pretreatment plasma renin levels of hypertensive patients. To determine whether the hypotensive effect of captopril was directly related to plasma renin, the angiotensin-converting enzyme inhibitor was administered acutely to 10 essential hypertensive patients with normal or suppressed plasma renin activity before and after inhibition of renin secretion with propranolol. Captopril was equally effective in reducing blood pressure both when administered alone (25 mg: -29/-17; 50 mg: -37/-23 mm Hg) and after chronic treatment with propranolol (25 mg: -33/-20; 50 mg: -30/-20 mm Hg). The increase in renin induced by captopril was not decreased by propranolol therapy. The persistence of the hypotensive effect of captopril after renin suppression by propranolol suggests that this drug has some blood pressure decreasing properties independent of plasma renin.     

Living donor liver transplantation in hepatocellular carcinoma beyond the Milan criteria

Background/Aims: In patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, the recurrence rate after liver transplantation is over 50%. We investigated pretransplant factor(s) that could predict recurrence after living donor liver transplantation (LDLT) in patients with HCC exceeding the Milan criteria. Methods: Pre‐operative imaging showed that, of the 111 HCC patients who underwent LDLT between June 1995 and January 2006, 37 exceeded the Milan criteria. Clinical factors before LDLT were evaluated. Results: The 1‐ and 3‐year cumulative recurrence rates were 35 and 55% respectively. Pretransplant risk factors for HCC recurrence were large tumour size (>6 cm, P=0.001), tumour exposed to the liver surface (P=0.014) and progressive disease after pretransplant treatment (P=0.038). The 2‐year HCC recurrence rates in patients with 0, 1, 2 and 3 factors were 0% (0/4), 9% (1/16), 80% (8/10) and 100% (7/7) respectively (P<0.001). The 2‐year survival rate was significantly higher in patients with 0 or 1 factor than in patients with two or more factors (P=0.022). Conclusions: In patients with HCC exceeding the Milan criteria, the three pretransplant factors that may be useful for identifying those with high HCC recurrence potential after LDLT are tumour size >6 cm, progressive disease after pretransplant treatment and tumour exposed to the liver surface.     

Psychological distress,job satisfaction,and work engagement among Palestinian teachers: a cross-sectional study

Background

Work engagement is a positive, fulfilling affective and motivational state of work-related wellbeing and a protective factor for workers' mental health. The aim of the present study was to examine the association between psychological distress (conceptualised as the target variable), job satisfaction, and work engagement in contexts of low-intensity warfare and political violence. According to the salutogenic perspective, the relationship between job satisfaction and psychological distress is influenced by the level of work engagement.

Evaluation of systolic time intervals in patients with angina pectoris

We have explored the systolic time intervals of 52 patients with angina pectoris at the time of their hospitalization in our wards. Our results are in close agreement with published data, essentially indicating prolongation of the preejection time and shortening of the ejection time. These alterations of systolic times can be interpreted pathophysiologically as as expressing reduced myocardial contractility. The long PEP-short LVET polygraph picture, occurring in the course of chronic ischemic heart disease, reveals the deficit of myocardial contractility at a stage of the disease at which clinical evidence of left ventricular failure is usually not yet detectable.     

肝癌肝移植适应证标准——验证及再思考

目的对不同的原发性肝细胞癌(肝癌)肝移植适应证标准进行评价与验证。方法 2001年至2007年上海七家肝移植中心施行的肝癌肝移植病例共948例,采用Kaplan-Meier法分析符合米兰标准、加利福尼亚标准和上海复旦标准的肝癌肝移植患者的术后4年总体生存率及无复发生存率,并作比较。结果符合米兰标准(369例)、加利福尼亚标准(470例)和上海复旦标准(554例)的患者的术后4年总体生存率及无复发生存率分别为65.8%和74.1%、66.0%和73.6%、63.9%和70.4%。三种标准的总体生存率及无复发生存率比较差异无统计学意义(均为P0.05)。与符合米兰标准的病例相比,超出米兰标准但符合上海复旦标准的185例,其术后4年生存率及无复发生存率分别为61.5%、65.0%,比较差异亦无统计学意义(均为P0.05)。结论上海复旦标准适度扩大了肝癌肝移植适应证范围且生存率满意,可能更符合中国国情。