Day-restricted feeding during pregnancy and lactation programs glucose intolerance and impaired insulin secretion in male rat offspring.

AIM: The maternal environment during pregnancy and lactation plays a determining role in programming energy metabolism in offspring. Among a myriad of maternal factors, disruptions in the light/dark cycle during pregnancy can program glucose intolerance in offspring. Out-of-phase feeding has recently been reported to influence metabolism in adult humans and rodents; however, it is not known whether this environmental factor impacts offspring metabolism when applied during pregnancy and lactation. This study aims to determine whether maternal day-restricted feeding (DF) influences energy metabolism in offspring. METHODS: Pregnant and lactating Wistar rats were subjected to ad libitum (AL) or DF during pregnancy and lactation. The offspring born to the AL and DF dams were intra- and interfostered, which resulted in 4 group types. RESULTS: The male offspring born to and breastfed by the DF dams (DF/DF off) were glucose intolerant, but without parallel insulin resistance as adults. Experiments with isolated pancreatic islets demonstrated that the male DF/DF off rats had reduced insulin secretion with no parallel disruption in calcium handling. However, this reduction in insulin secretion was accompanied by increased miRNA-29a and miRNA34a expression and decreased syntaxin 1a protein levels. CONCLUSION: We conclude that out-of-phase feeding during pregnancy and lactation can lead to glucose intolerance in male offspring, which is caused by a disruption in insulin secretion capacity. This metabolic programming is possibly caused by mechanisms dependent on miRNA modulation of syntaxin 1a.

Renal and cardiovascular risk predictive value of two different microalbuminuria screening methods in patients with hypertension with/without diabetes in Portugal.

MicRoAlbuminuria sCreening survEy (RACE) was a multicentre, observational, cross-sectional study conducted in primary health-care settings of Portugal. Here, we present a post-hoc analysis from the RACE study, assessing the renal and cardiovascular (CV) risk predictive value of two different microalbuminuria (MA) screening methods, nephelometry with 24-h urine (MA-24 h) and Micral test with occasional urine (MicralA) in patients with hypertension (HTN) with/without type 2 diabetes mellitus (T2DM). Out of 3065 patients, 1173 (38.3%) were in the HTN group without T2DM (HTN) and 1892 (61.7%) in the HTN group with T2DM (HTN+T2DM). The overall prevalence of MA was 50.6% determined by MicralA and 22.1% with MA-24 h. Urinary albumin excretion data obtained by both techniques correlated significantly (rs=0.586; P<0.001). In all subjects, MicralA showed a sensitivity of 93%, specificity of 62% for detection of MA, with a positive predictive value of 41% and negative predictive value of 97%. With both methods, the presence of MA was independently associated with a higher risk (1.5- to 2.9-fold) of CV and renal organ damage in both HTN and HTN+T2DM groups. MicralA, due to its high sensitivity and negative predictive value, can be considered as a valid and reliable method for MA screening in patients with HTN with/without T2DM.

Ethnicity and route of HCV infection can influence the associations of HLA with viral clearance in an ethnically heterogeneous population.

Approximately 20% of hepatitis C virus (HCV) infected individuals clear the virus. Host factors that influence the course of HCV infection are still under investigation, and the data on the association of human leukocyte antigen (HLA) alleles and HCV clearance are scarce and controversial. The aims of this study were to investigate whether HLA alleles are associated with clearance of HCV infection in a highly admixed Brazilian population and whether these associations could be influenced by ethnicity and route of infection. HLA-A, -B, -C, -DRB1 and -DQB1 genotyping were performed in 135 HCV-infected Brazilian patients among which 45 cleared HCV infection (cases) and 90 had persistent viral infection (controls). Controls were matched by sex, ethnicity (withes and non-whites) and route of infection (high infectious dose or low infectious dose). No significant association was identified between HLA alleles and the outcome of HCV infection when analyzing the sample as a single group. However, a new protective association of HLA-DQB1*04 (P = 0.006; P(c) = 0.030) and a rarely described association of HLA-DRB1*08 (P = 0.004; P(c) = 0.048) were found only among white patients. The DRB1*11 allele, previously reported in homogeneous population, was associated with HCV clearance (P = 0.020) only among patients with expected high-dose exposure. These findings confirm the influence of ethnicity on the associations of HLA with spontaneous viral clearance of HCV infection and emphasize the possible influence of route of infection in this process.

Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in Europe and Canada: results of the Dyslipidaemia International Study.

AIM: To assess the prevalence of persistent lipid abnormalities in statin-treated patients with diabetes with and without the metabolic syndrome. METHODS: This was a cross-sectional study of 22,063 statin-treated outpatients consecutively recruited by clinicians in Canada and 11 European countries. Patient cardiovascular risk factors, risk level, lipid measurements and lipid-modifying medication regimens were recorded. RESULTS: Of the 20,129 subjects who had documented diabetes and/or metabolic syndrome status, 41% had diabetes (of whom 86.8% also had the metabolic syndrome). Of those with diabetes, 48.1% were not at total cholesterol target compared with 58% of those without diabetes. Amongst those with diabetes, 41.6 and 41.3% of those with and without the metabolic syndrome, respectively, were not at their LDL cholesterol goal relative to 54.2% of those with metabolic syndrome and without diabetes, and 52% of those with neither condition. Twenty per cent of people with diabetes but without the metabolic syndrome were not at the optimal HDL cholesterol level compared with 9% of those with neither condition. Of people with diabetes and the metabolic syndrome, 49.9% were not at optimal triglyceride level relative to 13.5% of people with neither diabetes nor the metabolic syndrome. Simvastatin was the most commonly prescribed statin (>45%) and the most common statin potency was 20-40 mg/day (simvastatin equivalent). Approximately 14% of patients were taking ezetimibe alone or in combination with a statin. CONCLUSIONS: Despite evidence supporting the benefits of lipid modification and international guideline recommendations, statin-treated patients with diabetes had a high prevalence of persistent lipid abnormalities. There is frequently room to optimize therapy through statin dose up-titration and/or addition of other lipid-modifying therapies.

Barriers to cardiovascular disease risk scoring and primary prevention in Europe.

The prevalence and burden of cardiovascular disease (CVD) is high, and it remains the leading cause of death worldwide. Unfortunately, many individuals who are at high risk for CVD are not recognized and/or treated. Therefore, programs are available to ensure individuals at risk for CVD are identified through appropriate risk classification and offered optimal preventative interventions. The use of algorithms to determine a global risk score may help to achieve these goals. Such global risk-scoring algorithms takes into account the synergistic effects between individual risk factors, placing increases in individual risk factors into context relative to the overall disease, allowing for a continuum of disease risk to be expressed, and identifying patients most likely to derive benefit from an intervention. The predictive value of risk scoring such as using the Framingham equation is reasonable, analogous to cervical screening, with area under the receiver operated characteristic curve a little over 70%. However, limitations do exist, and as they are identified adjustments can be made to the global risk-scoring algorithms. Limitations include patient-specific issues, such as variations in lifetime risk level, ethnicity or socio-economic strata, and algorithm-specific issues, such as discrepancies between different algorithms arising from varying risk factors evaluated. The use of currently developed algorithms is low in general practice, in part, because of the belief that the assessment may oversimplify the risk and/or lead to medication overuse. Additional hindrances to the use of risk scoring include government or local health policy, patient compliance issues and lack of time. A thorough, easy-to-use, and standardized tool for risk estimation would allow for improvements in the primary prevention of CVD.

[Efficacy and safety of diltiazem in the treatment of arterial hypertension in the elderly]. / Eficácia e segurança do Diltiazem no tratamento da hipertensão arterial no idoso.

A multicentric, non-comparative study was made to evaluate the efficacy and safety of diltiazem 180 mg in the elderly, with dose titration in subjects above the age of 60 years. The blood pressure measurements were done by ambulatory blood pressure monitoring (ABPM). We achieved a reduction of at least 10 mmHg in systolic blood pressure in 52.2% and in diastolic blood pressure in 42.5% of the patients. The estimated differences between the initial values and those after treatment are 30% (CI95%: 22-38%) for diurnal blood pressure load, 22% (CI95%: 14-29%) for nocturnal blood pressure load, 13 mmHg (CI95%: 10-16 mmHg) for median systolic BP, and 8 mmHg (CI95%: 6-10 mmHg) for median diastolic BP. In 62.5% of the subjects the daily dose of diltiazem was increased to 240 mg (180 mg in the morning and 60 mg at night). All the cardiovascular parameters evaluated showed a significant decrease at the end of the study. A significant change was not recorded in the laboratory parameters and the adverse event average was minimal. The results showed that diltiazem in monotherapy is effective in the control of hypertension in the elderly and can improve compliance to the treatment.

[Biological and practical aspects of hormone replacement therapy: an approach to cardiovascular disease prevention in postmenopausal women]. / Aspectos biológicos e práticos da terapêutica hormonal de substituição: uma abordagem da prevenção cardiovascular na menopausa.

Epidemiological and experimental clinical studies as well as basic laboratory research suggest that estrogen replacement therapy reduces the cardiovascular risk in postmenopausal women. Estrogens have different potential favourable effects (which remain to be fully proven in randomised clinical trials) on lipid metabolism, vascular endothelium and fibrinolysis. The molecular mechanisms adjacent to the vasodilator effects of estrogens have not yet been clearly defined, but many of the processes have already been characterised. Progestagens should be added to the estrogen therapy in women with an intact uterus in cyclic or continuous regimens, although the effects of progestagens on these processes (lipid metabolism and vascular function) are still being discussed. In an attempt to optimise and improve hormone replacement therapy compliance in postmenopausal women, we discuss the risks and benefits of this treatment according to the best available evidence. This evidence should help women decide which type of therapy is the most appropriate for them.

[The genetic contribution to coronary disease. The genetic factors related to lipid metabolism]. / Contribuição genética na doença coronária. Factores genéticos relacionados com o metabolismo lipídico.

The increasing development of molecular genetics, the progress of the Human Genome Project, and the widespread application of its new methods and molecular techniques provide a new perception of coronary heart disease and a better recognition of genetic markers (mutations and polymorphism) related to new or traditional cardiovascular risk factors. An example of this has been the major effort made over the last years to evaluate and establish the genetic molecular mechanisms that are the basis of the synthesis of apolipoproteins, lipoprotein processing enzymes and lipoprotein receptors. These are some of the subjects discussed in this review [apoB, apoE, atherogenic lipid profile and CETP, and Lp(a)], in which the role of polymorphic alleles and isoforms in cardiovascular risk and coronary heart disease is stressed.

[HMG-CoA reductase inhibitors: a brief review of their pharmacological properties and clinical efficacy in cardiovascular disease]. / Inibidores da redutase da HMG-CoA: breve revisão das suas propriedades farmacológicas e eficácia clínica na doença cardiovascular.

The results of recently published studies on primary and secondary prevention of coronary heart disease with HMG-CoA reductase inhibitors--statins--support their use in patients with primary hypercholesterolaemia or mixed hyperlipidaemia, with or without atherosclerotic vascular disease. From a pharmacological point of view, statins inhibit HMG-CoA reductase, reduce the endogenous synthesis of cholesterol and increase the apoB/apoE lipoprotein clearance from plasma. Recent studies confirm that HMG-CoA reductase inhibitors may also decrease hepatic production of VLDL and LDL-cholesterol. However, they have different pharmacokinetic properties and variable effectiveness with potential clinical implications. These drugs are generally well tolerated with a similar profile of adverse effects (gastrointestinal effects, hepatic dysfunction and myopathy). The knowledge of their pharmacodynamic and pharmacokinetic properties can lead to a rational use and greater understanding of their potential benefits.

[Pharmacokinetic and pharmacodynamic aspects of angiotensin II antagonists. Focus on arterial hypertension]. / Aspectos farmacocinéticos e farmacodinâmicos dos antagonistas da angiotensina II. Foco na hipertensão arterial.

The major pharmacokinetic and pharmacodynamic properties of angiotensin II receptor antagonists in humans are reviewed, this analysis being focused on its antihypertensive effect. Common characteristics of the members of this new therapeutic class: nonpeptidic nature, lipophilia, oral intermediate bioavailability and selectivity for AT1 receptor are discussed. The liver metabolism and the presence of active metabolites of some of these molecules are specially stressed. Angiotensin II antagonists block the blood pressure response to angiotensin II, reduce the high baseline blood pressure in hypertensive patients, increase the plasma renin activity and endogenous angiotensin II plasma levels, have natriuretic effects and increase the renal blood flow without altering the glomerular filtration rate. These and other dose-dependent effects of angiotensin II receptor antagonists are discussed and criticized, in an attempt to characterize their pharmacokinetic profile and to define the pharmacodynamic relation able to support its therapeutical use.

[Dystrophia myotonica]. / Distrofia miotónica.

The authors present two cases of myotonic dystrophy (Steinert's disease) with cardiac involvement in young adults. They point out the rareness of this disease, the multisystemic involvement and also the diagnostic problems in the absence of the classic clinical picture.

[Sheehan's syndrome]. / Síndrome de Sheehan.

The authors describe a case of Sheehan's syndrome that followed hemorrhagic complications due to late abortion, and emphasise the infrequency of changes in plasma lipid levels in this disease. They report a particular case of hypopituitarism and point out the main concepts of pathophysiology, diagnosis, therapeutics and complications that follow this increasingly rarer condition.

[Hypertensive crises]. / Crises hipertensivas.

The goal of the accurate treatment of an hypertensive crisis is to reduce the critically elevated blood pressure to a safer level, in an hemodynamic point of view, although not necessarily normal. The authors stress that a prompt and correct diagnosis in distinguishing hypertensive emergencies from urgencies, in understanding its pathophysiology and the knowledge of available drugs is essential for a successful management.

[Nonalcoholic steatohepatitis]. / Esteatohepatite não alcoólica.

The authors present a case of a nonalcoholic steatohepatitis, with progression to liver cirrhosis in an obese female patient. A review of the literature, possible evolution, and principle pathological processes involved is made. Attention is drawn to obesity as a risk factor in the progression of steatohepatitis and the advantage of performing liver biopsies in selected cases as a fundamental technique of diagnosis.

[Diagnostic criteria for primary dyslipidemia]. / Critérios de diagnóstico de dislipidemias primárias.

The accurate treatment of a dyslipidaemia is based on correct diagnosis. Together with the laboratory values. A good clinical interview, focusing on the family history, is the bases for a good diagnosis strategy. The author schematze the rules of etiological diagnosis of inherited defects of lipid metabolism.

[Biological rhythms in man. Particular aspects in medicine]. / Ritmos biológicos no homem. Aspectos particulares em medicina.

The concepts of chronobiology and chronopharmacology have become more and more important in medical practice nowadays. Today, the circadian variation in blood pressure and heart rate as well as in the occurrence of acute cardiovascular disease is quite obvious (ischemia, infarction, stroke and sudden death). However, biological rhythms are also present in episodes of dyspnoea in nocturnal asthma, in hormonal pulses, in the organization of the immunological system and in the processes of cellular proliferation. These acknowledgments have been leading to changes in our therapeutical approaches implying the definition of correct anti-hypertensive and anti-ischemic strategy was well as in the use of xanthins, corticosteroids, immunomodulators and cytostatics.

[Somatostatin and SMS 201-995 (octreotide): clinical and therapeutic aspects]. / Somatostatina e SMS 201-995 (octreótido): aspectos clínicos e terapêuticos.

Nowadays, the digestive system, must be considered as an actual endocrinous gland. The authors, after pointing out the pharmacological and immunomodulating actions of endogenous somatostatine, briefly describe a new synthetic octapeptid, somatostatine-analogue, with similar pharmacological effects (octreotide). Finally they stress the therapeutic trials in which the adverse effects, dosage and administration have been studied.