Polymorphisms of Interleukin-1β and β3-Adrenergic Receptor in Japanese Patients With Nonalcoholic Steatohepatitis

Background: Obesity, hypertriglyceridemia, and diabetes have been reported as frequent complications observed in patients with nonalcoholic steatohepatitis (NASH) in Western countries. The aim of this study was to investigate the genetic predisposition on NASH pathogenesis in the Japanese population.
Methods: Genotypes of two previously described functional polymorphisms—β3-adrenergic receptor 190 T/A polymorphism, which results in Trp64Arg (W64R) amino acid replacement, and interleukin-1β-511 T/C polymorphism in the promoter sequence—were determined in 63 Japanese NASH patients and 100 healthy volunteers using polymerase chain reaction and restriction fragment length polymorphism.
Results: β3-adrenergic receptor R allele frequency and the R/− (W/R and R/R) genotype frequency were significantly higher in NASH patients than those in control subjects. Interleukin-1β-511 T allele frequency and the T/T genotype frequency were significantly higher in NASH patients than those in control subjects. Obesity, hypertriglyceridemia, and hyperinsulinemia were associated with NASH patients with the R/− genotype, whereas an increase in fasting plasma glucose level and a decrease in insulinogenic index were associated with NASH patients with the W/W genotype.
Conclusion: This study confirmed the contribution of obesity, glucose intolerance, and hypertriglyceridemia to NASH development in the Japanese population. In addition to these factors, genetic predispositions to obesity and inflammation in the Japanese population were shown to contribute much to the development of NASH.     

Urinary β-Thromboglobulin in Essential Hypertension

Urinary concentrations of the platelet-specific protein beta-thromboglobulin (beta-TG) were measured in patients with essential hypertension. Values obtained for patients with normal renal function fell within the same population as those for a control group of normal individuals, but nevertheless 21% of these patients had urinary beta-TG values above the upper limit of the normal range. Values for patients with renal insufficiency were significantly different from the other groups, and 44% of these individuals had abnormally elevated urinary beta-TG concentrations. These elevated values may reflect an increased plasma concentration of beta-TG in patients with renal impairment or they could be an indicator of renal damage.     

Ophthalmically Administered β Blockers and Their Cardiopulmonary Effects

Early clinical studies revealed that timolol and other topical β blockers were effective in reducing intra-ocular pressure, without the side effects associated with other antiglaucoma agents. However, because persons with cardiovascular or respiratory diseases were generally excluded from many of these early studies, the risk of serious cardiovascular and respiratory side effects was seriously underestimated. Once these drugs were made available to the general population, reports of systemic side effects began to proliferate. Very quickly, adverse effects from topical β blockade became "old news." Despite this recognition, many treating physicians remained unaware of the potential for systemic β blockade from topically applied β blockers. A significant portion of a topically administered dose of a β blocker can be absorbed and thereby affect systemic β blockade. Sensitivity to systemic β blockade can be quite dramatic in certain highly susceptible patients, particularly those with either cardiac or pulmonary abnormalities. Careful review of patients' medications will generally lessen, but not completely eliminate, the risk of undesired complications attributable to topical P blockade.     

Calcium Channel Blocker Compared With Angiotensin Receptor Blocker for Patients With Hypertension: A Meta‐Analysis of Randomized Controlled Trials

To explore the clinical effects of a calcium channel blocker compared with an angiotensin II receptor blocker in hypertensive patients, the authors collected data from randomized controlled trials. The pooled outcomes were all‐cause mortality, stroke, myocardial infarction, and heart failure. Eight head‐to‐head trials enrolling 25,084 patients were included. There was no significant mortality difference in the two arms (relative risk, 0.99; 95% confidence interval, 0.91–1.07). However, calcium channel blockers were more effective in reducing stroke (relative risk, 0.87; 95% confidence interval, 0.76–0.99) and myocardial infarction incidence (relative risk, 0.86; 95% confidence interval, 0.76–0.98). There was no significant difference with heart failure incidence between the two arms but a lower trend in patients with angiotensin II receptor blockers was noted (relative risk, 1.4; 95% confidence interval, 0.99–1.98). The meta‐analysis suggested that initially use of a calcium channel blocker might be superior to an angiotensin II receptor blocker for prevention of stroke and myocardial infarction.     

β-Blockers in Hypertension: A Reassessment of the Benefit of Combined α-/β-Blockade

β-Blockers have a long history of use in patients with high blood pressure, either alone or in combination with other classes of antihypertensive agents. Although β-blockers can lower blood pressure effectively, they have not been convincingly shown to reduce the likelihood of some cardiovascular complications from hypertension, and their utility for this purpose has been critically questioned of late. This growing distrust of β-blocker therapy, however, is misguided. Negative sentiments about one drug in a class, as has been the case for atenolol, often become unfairly disparaging of all drugs in a class. In the process of such lumping, the heterogeneity of the various compounds making up a drug class is often neglected. Such is the case for combined α-/β-blockade, which is to be distinguished from β-blockade alone because of differences in hemodynamic and metabolic effects. This should prompt a reappraisal of the role of selected agents, such as the combined α-/β-blocker carvedilol, in the long-term treatment of hypertension.     

Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin‐Converting Enzyme Inhibitors: The Prospective EARLY Registry

For patients with newly diagnosed hypertension, angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first‐line therapies. There is, however, no real‐life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL‐M) vs ACE inhibitors in real‐world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL‐M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL‐M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL‐M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors.     

δβ-Thalassaemia in a Chinese Family

S ummary . δβ-Thalassaemia has been observed for the first time in individuals of Chinese origin. The clinical and haematological features have been characterized in the heterozygous state and in the double heterozygous state withβ-thalassaemia. Studies of haemoglobin synthesis indicate that the degree of globin chain imbalance in β-thalassaemia is less than that found in β-thalassaemia. Analysis of the foetal haemoglobin has shown that all individuals carrying the δβ-thalassaemia gene in this family synthesize only the α₂γ₂^{136 glycine} variety. This type of foetal haemoglobin has been found previously only in two Negro individuals heterozygous for hereditary persistence of foetal haemoglobin (HPFH). The genetic relationships between δβ-thalassaemia and HPFH are discussed in the light of these new findings.     

Realities of Newer β-Blockers for the Management of Hypertension

β-blockers are prescribed for a variety of cardiovascular conditions including hypertension, heart failure, primary treatment of myocardial infarction (MI), and secondary prevention of ischemic cardiac events. Yet they remain underprescribed in populations at increased risk for cardiovascular disease because of tolerability and safety concerns. β-Blockers are heterogeneous with respect to pharmacokinetic and pharmacodynamic effects. "Original" agents were nonselective, blocking both β₁-adrenoceptors and β₂-adrenoceptors. Later, new agents were developed with selectivity for β₁-adrenoceptors, and were subsequently followed by β-blockers, which exhibit additional effects, such as vasodilation. Among newer agents, labetalol, carvedilol, and nebivolol have been approved for use in the United States. Nebivolol possesses both β₁-selectivity and nitric oxide–mediated vasodilatory effects, while carvedilol has attractive effects on insulin resistance and exhibits antioxidant effects. Newer β-blockers may overcome concerns about efficacy, adverse effects, and tolerability, while delivering cardiovascular protection.     

Stimulation of thrombocytopoiesis decreases platelet β2 but not β1 or β3 integrins

The expression of CD29, CD61, CD18 and CD11a on platelets was examined by flow cytometry in mice treated with leukaemia inhibitory factor (LIF) or megakaryocyte growth and development factor (PEG-rHuMGDF or mpl-ligand). Treatment for 7–14 d with PEG-rHuMGDF or LIF increased the number of platelets in peripheral blood from 0.9 up to <2.0×10⁶/μl. These treatments decreased the expression of CD11a and CD18, whereas that of CD29 or CD61 was not markedly changed. Study after various doses or times of PEG-rHuMGDF administration indicated that a decrease of CD18 expression occurred when platelet counts started to rise. Platelet RNA content was increased in mice treated with PEG-rHuMGDF but double staining indicated that expression of CD18 was not correlated with RNA content. To evaluate integrin expression as a function of time in circulation, platelets were biotinylated in vivo . In normal or PEG-rHuMGDF-treated mice, the expression of CD29 or CD61 did not change, whereas that of CD18 decreased significantly as a function of time in circulation. These findings indicate, firstly, that stimulation of thrombocytopoiesis leads to the release of platelets with a low content of β2 integrin and, secondly, that this integrin is also selectively lost while in the circulation.     

Homozygous β-thalassaemia resulting in the β-thalassaemia carrier state phenotype

Summary. This paper describes the phenotypic manifestations of a very mild β-thalassaemia mutation detected in several members of two families of Italian descent. The molecular defect, defined by denaturing gradient gel electrophoresis analysis and direct sequencing. consists of a C G substitution at position 844 of IVSII of the β-globin gene within the consensus sequence of IVSII acceptor splice site. Heterozygotes for this mutation show a haematological phenotype ranging in severity from silent β-thalassaemia to that of a mild β-thalassaemia carrier silent β-thalassaemia to that of a mild β-thalassaemia carrier state, whereas homozygotes have the typical manifestations commonly resulting from heterozygosity for a β-thalassaemia mutation. Compound heterozygotes for the IVSII nt844 (C G) mutation and a severe β-thalassaemia mutation have the phenotype of thalassaemia intermedia.
This paper indicates that the presence of borderline red blood cell indices or HbA₂ values should make one suspect the presence of a very mild or silent β-thalassaemia.     

Epstein-Barr Virus Infection in Polytransfused Patients with Homozygous β-Thalassaemia

The frequency of Epstein-Barr virus (EBV) and hepatitis B virus (HBV) infection has been studied in 149 polytransfused thalassaemic patients and in healthy controls. Evidence for EBV infection was based on the detection of antibodies to viral capsid antigen (anti-VCA) and for HBV infection on the detection of either hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (anti-HBs). The frequency of anti-VCA was not significantly higher in the patients (16.4%) compared to the controls (69.8%) whereas HBV infection was more frequently observed in the patients (91.3%) than in the controls (17.3%). There was also no evidence of repeated infection or recent infection with EBV in the polytransfused patients. These data suggest that transfusion of stored blood does not represent a significant factor of spread for EBV.     

Metabolic Properties of Vasodilating β Blockers: Management Considerations for Hypertensive Diabetic Patients and Patients With the Metabolic Syndrome

Type 2 diabetes and hypertension are both insulin-resistant states that impose an excessive risk burden for future major cardiovascular events, including coronary heart disease, stroke, and heart failure. β-adrenergic receptor antagonists are effective for the treatment of hypertension, but they are underused in diabetic patients because of possible adverse effects on carbohydrate and lipid metabolism, including insulin resistance, glucose intolerance, and dyslipidemia. Traditional β blockers, both nonselective and selective, are vasoconstrictive due to unopposed α₁ activity; however, vasodilating β blockers are not associated with these negative metabolic effects. This review discusses the background of insulin resistance and its link to diabetes and hypertension, emphasizing the role of vascular control by the renin-angiotensin and sympathetic nervous systems on insulin sensitivity and glucose utilization. Clinical evidence is reviewed for the use of vasodilating β blockers in the treatment of hypertension and in reducing cardiovascular risk in the diabetic population.     

Should β Blockers Be Used in the Treatment of Hypertension in the Elderly?

The lack of benefit and the potential negative side effects of β blockers are overstated, especially in the elderly. This emphasis has led to recommendations by some investigators that these agents not be used in the management of hypertension in this age group. There are numerous reasons why these recommendations should not be followed. The use of β blockers in the elderly hypertensive has resulted in a reduction in strokes and congestive heart failure. In addition, it should be emphasized that elderly patients are more likely to have silent coronary artery disease or sustain myocardial infarctions. There is abundant evidence that β blockers are effective therapy in reducing mortality once a myocardial infarction has occurred. In fact, there is a clear reduction in sudden cardiac death. Furthermore, national statistics document that elderly patients have a prevalence of congestive heart failure that varies from 6%–10%. Multiple studies have now documented that β blockers are additive to angiotensin-converting enzyme inhibitors in reducing mortality for congestive heart failure. Thus, elderly hypertensive patients may benefit from the use of β blockers, especially if there is evidence of ischemic heart disease, cardiac arrhythmias, or congestive heart failure.     

Age‐ and Sex‐Related Differences in Efficacy With an Angiotensin II Receptor Blocker and a Calcium Channel Blocker in Asian Hypertensive Patients

Overseas guidelines to manage hypertension recommend selecting different drugs depending on age, but no studies have investigated the relationship between drug selection and age‐ and sex‐related differences, although such information may help to reduce the risk of cardiovascular mortality. The Azilsartan Circadian and Sleep Pressure––the First Study (ACS1) trial was a multicentered, randomized, open‐label, two‐parallel group study comparing the effects of an angiotensin II receptor blocker (azilsartan) and a calcium channel blocker (amlodipine). The present study is a post hoc analysis of ACS1 to investigate age‐ and sex‐related differences in the antihypertensive effects between azilsartan and amlodipine. Azilsartan significantly reduced diastolic blood pressure in male patients younger than 60 years compared with amlodipine, but amlodipine significantly reduced systolic blood pressure in female patients 60 years and older compared with azilsartan. A randomized controlled trial to evaluate cardiovascular outcomes will demonstrate whether a diastolic blood pressure–lowering effect with azilsartan is significantly effective in male patients younger than 60 years.     

Therapeutic Considerations in the African-American Patient With Hypertension: Considerations With Calcium Channel Blocker Therapy

African Americans have a higher prevalence, earlier onset, and more rapid progression of hypertensive end-organ disease, as well as excessive hypertensive mortality compared with other racial/ethnic groups. Most differences in hypertension and pressure-related complications between African Americans and whites appear to be quantitative and not qualitative. Improving the diagnosis, treatment, and control of hypertension in this highly vulnerable population is a major health care goal for the new millennium. In this regard the dietary pattern to be promoted for reduction of hypertension risk in African Americans is one of increased consumption of dairy products, fruit, and vegetables as well as a continued emphasis on decreased Na⁺ intake. When pharmacologic therapy is considered, multi-drug approaches are generally required, with diuretics, angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), and calcium channel blocker therapy as oft-selected components of most such treatment regimens.     

Haemoglobin Synthesis in β-Thalassaemia

S ummary . The incorporation of radioactive amino acids into the polypeptide chains of haemoglobin has been studied in reticulocyte preparations from five patients with β-thalassaemia and four control patients. In both groups of patients an intracellular pool of free α-chains has been found, but the pool is much larger in patients with β-thalassaeniia major. The α-chains exist in two forms: α-dimers and α-monomers, but the results suggest that they are released as dimers from the ribosomes and that the α-chains for Hb-A and Hb-F synthesis are derived from the α-dimer pool. The α-dimers are also gradually converted to the monomers, and this may be the first stage in the denaturation of this protein. The results also show that the α-dimer can exchange with the α-chains of Hb-A and that this exchange is more rapid in the presence of in vivo aged Hb-A. In one patient with thalassaemia it was shown that there was no pool of unreleased β-chains on the ribosomes. There is also no evidence for the release of incompleted β-chains in our patients.     

Some Features of Bone Marrow Macrophages in Patients with Homozygous β-Thalassaemia

The bone marrow macrophages of patients with homozygous beta-thalassaemia were frequently situated adjacent to collagen fibres and sometimes formed intrasinusoidal cytoplasmic protrusions. They also appeared to phagocytose processes of erythroblast cytoplasm (at times containing precipitated alpha-chains) which projected into them from neighbouring erythroblasts. The cytoplasm of the macrophages included large numbers of heavily-iron-loaded secondary lysosomes of various sizes and shapes in addition to phagocytosed erythroblasts, erythrocytes and extruded erythroblast nuclei. Numerous ferritin molecules were found in the cytoplasmic matrix but there were hardly any in the mitochondria, endoplasmic reticulum or golgi saccules. A small number of ferritin molecules were present within the nucleus. Electron microscope autoradiographs of marrow fragments which had been incubated with [3H]leucine for 1 h revealed the presence of newly-synthesized protein molecules in all types of secondary lysosomes. Light microscope autoradiographs showed the [3H]thymidine labelling index of the bone marrow macrophages was less than 1% and suggested that only a very small proportion of these cells were actively preparing for division.