Neck circumference is associated with non-traditional cardiovascular risk factors in individuals at low-to-moderate cardiovascular risk: cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND: Neck circumference (NC) is associated with traditional cardiovascular risk factors (CVRF), but its usefulness to identify earlier atherogenic risk has been scarcely examined. Associations of NC with non-traditional CVRF were investigated in participants at low-to-moderate risk from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: 807 individuals (35-54 years) without obesity, diabetes or cardiovascular disease was stratified into quartiles of NC (cut-off for men: 36.5; 37.9 and 39.5 cm; women: 31.4; 32.5 and 34 cm) and traditional and non-traditional risk factors (lipoprotein subfractions by Vertical Auto Profile, adiponectin, leptin, E-selectin) were compared across groups. In linear regression models, associations of NC with non-traditional risk factors were tested for the entire sample and for low-risk group (≤ 2 CVRF). RESULTS: In both sexes, BMI, waist circumference, systolic and diastolic blood pressure, fasting and 2-h plasma glucose, HOMA-IR, triglycerides, leptin, E-selectin, small dense LDL-cholesterol, IDL-cholesterol, VLDL3-cholesterol and TG/HDL ratio increased significantly, while HDL2-cholesterol and HDL3-cholesterol decreased across NC quartiles. In linear regression models, a direct association [ß(95% CI)] of NC with leptin [(0.155 (0.068-0.242); 0.147 (0.075-0.220)], E-selectin [(0.105 (0.032-0.177); 0.073 (0.006 to 0.140)] and small-dense LDL [(1.866 (0.641-3.091); 2.372 (1.391-3.353)] and an inverse association with HDL2-cholesterol [(- 0.519 (- 0.773 to - 0.266); - 0.815 (- 1.115 to 0.515)] adjusted for age were detected for men and women, respectively. CONCLUSION: Our findings indicate that measurement of NC may be useful for an earlier identification of unfavorable atherogenic metabolic profile in middle-aged individuals at lower cardiovascular risk level.

Subfractions and subpopulations of HDL: an update.

High-density lipoproteins (HDL) are classified as atheroprotective because they are involved in transport of cholesterol to the liver, known as "reverse cholesterol transport (RCT)" exerting antioxidant and anti-inflammatory activities. There is also evidence for cytoprotective, vasodilatory, antithrombotic, and anti-infectious activities for these lipoproteins. HDLs are known by structural, metabolic and biologic heterogeneity. Thus, different methods are able to distinguish several subclasses of HDL. Different separation techniques appear to support different HDL fractions as being atheroprotective or related with lower cardiovascular (CV) risk. However, HDL particles are not always protective. Modification of constituents of HDL particles (primarily in proteins and lipids) can lead to the decrease in their activity and induce proatherogenic properties, especially when isolated from patients with augmented systemic inflammation. According to available studies, it seems that HDL functionality may be a better therapeutic target than HDL cholesterol quantity; however, it is still disputable which subfractions are most beneficial. There is mounting evidence supporting HDL subclasses as an important biomarker to predict and/or reduce CV risk. In this review we discuss recent notices on atheroprotective and functional characteristic of different HDL subfractions. Also, we provide a brief overview of the different methods used by clinicians and researchers to separate HDL subfractions. Ongoing and future investigations will yield important new information if any given separation method might represent a 'gold standard', and which subfractions are reliable markers of CV risk and/or potential targets of novel, more focused, and effective therapies.

Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin.

Aspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, in vivo thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB2 was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5-10 mg, 20-40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB2 (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB2 [OR=2.95 (0.1.57-5.50, p=0.0007); OR=2.25 (1.24-4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB2 was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB2 may be a useful method to optimise statin dosing in order to reduce thrombotic risk.

Atherogenic versus non-atherogenic lipoprotein profiles in healthy individuals. is there a need to change our approach to diagnosing dyslipidemia?

The electrophoretic separation of lipoproteins on polyacrylamide gels enables the quantification of nonatherogenic and atherogenic plasma lipoproteins including small dense low density lipoprotein (sdLDL) particles, which represent the atherogenic lipoprotein subpopulations in plasma. This methodology could help distinguish between nonatherogenic hyperlipidemia, normolipidemia with an atherogenic lipoprotein profile, non-atherogenic normolipidemia, and atherogenic hyperlipidemia. According to our pilot research of a normolipidemic population, the atherogenic lipoprotein profile might be present in about 6% of normolipidemic young healthy individuals. Therefore, if confirmed by other studies, it will be necessary to consider a different diagnostic approach and risk stratification for patients with atherogenic normolipidemia (as well as non-atherogenic hypercholesterolemia).

Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6-24 weeks.

Aims: The aim of this analysis was to assess the overall safety and tolerability profiles of various statins + ezetimibe vs. statin monotherapy and to explore tolerability in sub-populations grouped by age, race, and sex. Methods: Study-level data were combined from 27 double-blind, placebo-controlled or active-comparator trials that randomized adult hypercholesterolemic patients to statin or statin + ezetimibe for 6-24 weeks. In the full cohort, % patients with AEs within treatment groups (statin: N = 10,517; statin + ezetimibe: N = 11,714) was assessed by logistic regression with terms for first-/second-line therapy (first line = drug-naïve or rendered drug-naïve by washout at study entry; second line = ongoing statin at study entry or statin run-in), trial within first-/second-line therapy, and treatment. The same model was fitted for age (< 65, ≥ 65 years), sex, race (white, black, other) and first-/second-line subgroups with additional terms for subgroup and subgroup-by-treatment interaction. Results: In the full cohort, the only significant difference between treatments was consecutive AST or ALT elevations ≥ 3 × upper limit of normal (ULN) (statin: 0.35%, statin + ezetimibe: 0.56%; p = 0.017). Significantly more subjects reported ≥ 1 AE; drug-related, hepatitis-related and gastrointestinal-related AEs; and CK elevations ≥ 10 × ULN (all p ≤ 0.008) in first-line vs. second-line therapy studies with both treatments. AEs were generally similar between treatments in subgroups, and similar rates of AEs were reported within age and race subgroups; however, women reported generally higher AE rates. Conclusions: In conclusion, in second-line studies, ongoing statin treatment at study entry likely screened out participants for previous statin-related AEs and tolerability issues. These results describe the safety profiles of widely used lipid-lowering therapies and encourage their appropriate and judicious use in certain subpopulations.

Clinical insights from the Fenofibrate Intervention and Event Lowering in Diabetes study: a community practice perspective.

Achieving adequate control of cardiovascular risk in type 2 diabetes mellitus (DM) is crucially important; however, the atherogenic dyslipidaemia (including low high-density lipoprotein cholesterol and hypertriglyceridaemia) typically encountered in type 2 DM is often managed inadequately. Evidence from the Fenofibrate Intervention and Event Lowering in Diabetes study suggests that fenofibrate reduces the risk of long-term macrovascular and microvascular type 2 diabetic complications, especially in patients demonstrating features of the metabolic syndrome. Fenofibrate represents a useful treatment option for controlling cardiovascular risk in type 2 diabetes patients in the community setting.

Subclinical atherosclerosis: what it is, what it means and what we can do about it.

Atherosclerosis is a chronic, progressive, inflammatory disease with a long asymptomatic phase. Disease progression can lead eventually to the occurrence of acute cardiovascular events such as myocardial infarction, unstable angina pectoris and sudden cardiac death. While the disease is still in a subclinical stage, however, the presence of atherosclerosis can be identified by several methods, including coronary angiography, intravascular ultrasonography, B-mode ultrasonography, computed tomography and magnetic resonance imaging. Based on the results of imaging studies, statin therapy can slow, halt or even reverse the progression of atherosclerotic disease, depending on the intensity of treatment. Whether to screen and treat patients for subclinical atherosclerosis remains controversial. Although atheromatous plaque burden reduction has not yet been definitively correlated with significant decreases in risk for acute coronary events in asymptomatic patients, statin therapy contributes significantly to the risk reduction observed in clinical trials in patients with and without overt coronary disease.

Spontaneous splenic infarction secondary to diabetes-induced microvascular disease.

Splenic infarction is a clinical entity seldom encountered. The most frequent causes of splenic infarction include thromboembolic phenomena, hematologic malignant neoplasms, and vasculitides. We describe a patient who sustained splenic infarction secondary to diabetes-induced, small-vessel atherosclerotic disease.

Predictors of neonatal resuscitation, low Apgar scores, and umbilical artery pH among growth-restricted neonates.

OBJECTIVE: To identify risk factors associated with poorer immediate neonatal outcomes among growth-restricted neonates. METHODS: Records of all 530 growth-restricted neonates born between January 1989 and February 1995 were reviewed. Outcomes included resuscitation measures, Apgar scores, and umbilical blood gas values. Neonates were assigned to one of six anesthetic groups, and outcomes were compared. Predictors of poorer outcomes were examined using logistic and linear regression. RESULTS: Neonates exposed to general anesthesia were more likely to be intubated (37.9% versus 4.1%, P < .001, Pearson chi2) and had lower mean 1- (4.0 versus 7.0) and 5-minute (6.5 versus 8.4) Apgar scores (P < .01, Scheffé) than those in all other anesthetic groups. They also had significantly lower umbilical artery (UA) pH values than neonates who received nalbuphine, epidural, or no anesthesia (7.21 versus 7.28, 7.26, 7.29, respectively; P < .01, Scheffé). Factors that significantly and independently predicted intubation among all neonates included exposure to general anesthesia (odds ratio [OR] 4.1; 95% confidence interval [CI] 1.9, 8.9) and lower infant weight (OR 10.1 per kg decrease; CI 5.1, 20). Factors predicting UA pH at most 7.15 included preeclampsia (OR 3.0; CI 1.5, 5.9) and older maternal age (OR 1.3 per 5 years; CI 1.02, 1.64); vertex delivery (OR 0.5; CI 0.2, 0.9) was protective. Factors predicting a 5-minute Apgar less than 7 were meconium (OR 1.5 per category going from none to terminal to light to heavy; CI 1.04, 2.3), general anesthesia (OR 6.9; CI 2.6, 18.2), lower infant weight (OR 16.5 per kg decrease; CI 7.8, 34.5), and vaginal breech delivery (OR 7.0; CI 1.8, 28.6); cesarean delivery (OR 0.2; CI 0.08, 0.66) was protective. Spontaneous vertex delivery raised the UA pH, and preeclampsia, amnioinfusion, breech delivery, and general anesthesia significantly and independently lowered the UA pH among all neonates. For infants delivered by cesarean, "fetal distress," preeclampsia, previous spontaneous abortion, failed forceps use, and nalbuphine significantly and independently predicted lower UA pH. CONCLUSION: Risk factors for poorer immediate neonatal outcomes among growth-restricted neonates include preeclampsia, fetal distress, breech delivery, forceps use, nalbuphine during labor, lower infant weight, and general anesthesia.

[Refugees arriving in Hungary, 1988-1994]. / A Magyarorszagra menekulok, 1988-1994.

PIP: The distribution of refugees arriving in Hungary between 1988 and 1994, mainly from Romania and Yugoslavia, is analyzed by citizenship, ethnicity, age, and sex. (SUMMARY IN ENG)^ieng

Identification of Turner's syndrome in an elderly woman. Case report and review.

Turner's syndrome is one of the most frequently occurring chromosomal defects and is associated with a well-characterized set of anatomic malformations. We studied clinical findings in an elderly woman who was diagnosed as having cytogenetically proved Turner's syndrome late in life. Because most patients with Turner's syndrome have normal intelligence and mild phenotypic abnormalities, the condition was never properly diagnosed in many affected women born earlier in this century. Given the range of clinical abnormalities and physiologic deficits to which these women are predisposed, it remains important to diagnose and treat them accurately irrespective of age.

Transient improvement of congenital lactic acidosis in a male infant with pyruvate decarboxylase deficiency treated with dichloroacetate.

A comatose male newborn infant with congenital lactic acidosis caused by pyruvate decarboxylase deficiency was treated with dichloroacetate (DCA), which stimulated an 88% drop in serum lactate concentration and reversed his coma. The response to DCA was temporary and the lactic acidosis worsened until his death, but DCA may confer more lasting benefit in less severely affected infants.

The effect of inorganic phosphate on chick (Gallus domesticus) heart mitochondrial volume and cation content.

1. In the absence of exogenous Ca(II), Pi induces a swelling change that is kinetically first order with k = 1.08 +/- 0.1 min-1. The first-order rate constant is independent of [Pi] over the range of 0.5-45 mM. 2. In the presence of exogenous substrate, the volume change induced by Pi is monophasic and can be reversed by ADP. 3. The swelling process and the approach to steady state is accompanied by controlled losses of both K+ and Mg(II) from within the mitochondria. 4. The loss of K+ is biphasic as a function of time with ki = 14.1 +/- 1.6 and k2 = 4.4 +/- 0.34 nmol min-1 mg mitochondria-1. 5. The loss of Mg(II) is monophasic and the rate at which this cation is released decreases as a function of time. Ca(II) fluxes are not involved in the volume occurring secondary to Pi uptake. 6. In the absence of exogenous substrate, Pi induces a triphasic change in mitochondrial volume. 7. The sequence of volume changes corresponds to an initial first-order swelling secondary to the addition of Pi, a contraction apparently triggered by the loss of approximately 85% of total intra-mitochondrial Mg(II), and a second larger swelling phase that cannot be reversed with ADP. 8. The Pi-induced swelling of chick heart mitochondria is not inhibited by EGTA and does not depend on the provision of exogenous Ca(II). 9. The Ca(II) and Mg(II) ions released from within the mitochondria are responsible for activating divalent cation-dependent ATPases which cosediment with isolated chick heart mitochondria.

Respiratory control and ADP:O coupling ratios of isolated chick heart mitochondria.

Heart mitochondria isolated from 14- to 21-day-old chicks are highly coupled and often have respiratory control ratio (RCR) values exceeding 100. This paper presents data from a study of some of the properties of these mitochondria. The studies show that: (a) The ADP:O ratios and the state 4 rates of respiration are highly dependent upon the concentration of mitochondria at which these parameters are measured. (b) The mitochondrial isolate is contaminated with at least two divalent cation-stimulated ATPase, of which one is the F1F0-ATPase of broken mitochondria. (c) The oligomycin-sensitive component of state 4 respiration is completely inhibited by ethylene glycol bis(beta-amino-ethylether) N,N'-tetraacetic acid (EGTA). This inhibition is biphasic and attributable to the differential affinity of EGTA for Ca(II) and Mg(II). (d) Ca(II) and Mg(II) stimulate state 4 respiration, thereby depressing RCR values. These cations also decrease ADP:O ratios from greater than or equal to 3.25 to 3.0 for some NAD-linked substrates. (e) Uncoupled (i.e., oligomycin-insensitive) state 4 respiration can be abolished by treating the mitochondria with Nagarse and by preincubating mitochondria with exogenous substrate. (f) The ADP:O ratios obtained when these heart mitochondria oxidize pyruvate/malate, alpha-ketoglutarate, and beta-hydroxybutyrate are fractional and significantly greater than 3.0.

Quantitation of the effect of L-carnitine on the levels of acid-soluble short-chain acyl-CoA and CoASH in rat heart and liver mitochondria.

The steady state levels of mitochondrial acyl-CoAs produced during the oxidation of pyruvate, alpha-ketoisovalerate, alpha-ketoisocaproate, and octanoate during state 3 and state 4 respiration by rat heart and liver mitochondria were determined. Addition of carnitine lowered the amounts of individual short-chain acyl-CoAs and increased CoASH in a manner that was both tissue- and substrate-dependent. The largest effects were on acetyl-CoA derived from pyruvate in heart mitochondria using either state 3 or state 4 oxidative conditions. Carnitine greatly reduced the amounts of propionyl-CoA derived from alpha-ketoisovalerate, while smaller effects were obtained on the branched-chain acyl-CoA levels, consistent with the latter acyl moieties being poorer substrates for carnitine acetyltransferase and also poorer substrates for the carnitine/acylcarnitine translocase. The levels of acetyl-CoA in heart and liver mitochondria oxidizing octanoate during state 3 respiration were lower than those obtained with pyruvate. The rate of acetylcarnitine efflux from heart mitochondria during state 3 (with pyruvate or octanoate as substrate, in the presence or absence of malate with 0.2 mM carnitine) shows a linear response to the acetyl-CoA/CoASH ratio generated in the absence of carnitine. This relationship is different for liver mitochondria. These data demonstrate that carnitine can modulate the aliphatic short-chain acyl-CoA/CoA ratio in heart and liver mitochondria and indicate that the degree of modulation varies with the aliphatic acyl moiety.

Quantitation of the efflux of acylcarnitines from rat heart, brain, and liver mitochondria.

The efflux of individual short-chain and medium-chain acylcarnitines from rat liver, heart, and brain mitochondria metabolizing several substrates has been measured. The acylcarnitine efflux profiles depend on the substrate, the source of mitochondria, and the incubation conditions. The largest amount of any acylcarnitine effluxing per mg of protein was acetylcarnitine produced by heart mitochondria from pyruvate. This efflux of acetylcarnitine from heart mitochondria is almost 5 times greater with 1 mM than 0.2 mM carnitine. Apparently the acetyl-CoA generated from pyruvate by pyruvate dehydrogenase is very accessible to carnitine acetyltransferase. Very little acetylcarnitine effluxes from heart mitochondria when octanoate is the substrate except in the presence of malonate. Acetylcarnitine production from some substrates peaks and then declines, indicating uptake and utilization. The unequivocal demonstration that considerable amounts of propionylcarnitine or isobutyrylcarnitine efflux from heart mitochondria metabolizing alpha-ketoisovalerate and alpha-keto-beta-methylvalerate provides evidence for a role (via removal of non-metabolizable propionyl-CoA or slowly metabolizable acyl-CoAs) for carnitine in tissues which have limited capacity to metabolize propionyl-CoA. These results also show propionyl-CoA must be formed during the metabolism of alpha-ketoisovalerate and that extra-mitochondrial free carnitine rapidly interacts with matrix short-chain aliphatic acyl-CoA generated from alpha-keto acids of branched-chain amino acids and pyruvate in the presence and absence of malate.