A multilocus candidate approach identifies ACE and HIF1A as susceptibility genes for cellulite.

BACKGROUND: Cellulite is a common complex cosmetic problem for many post-adolescent women characterised by relief alterations of the skin surface, which give the skin an orange-peel appearance. Although genetic factors have been suggested to play a role in the development of cellulite, the genetic background of this condition remains unclear. We therefore conducted a multi-locus genetic study examining the potential associations of candidate gene variants in oestrogen receptors, endothelial function/adipose tissue hypoxia, lipid metabolism, extracellular matrix homeostasis, inflammation and adipose tissue biology, with the risk of cellulite. METHODS: Using a case-control study of 200 lean women with cellulite and 200 age- and BMI-matched controls (grade 0 according to Nurnberger-Muller scale), we examined the association of cellulite with 25 polymorphisms in 15 candidate genes. RESULTS: Two of the 25 polymorphisms were significantly associated with cellulite at the P < 0.01 level. After allowance for age, body mass index, the prevalence of contraceptive use and smoking in logistic regression analysis, the multivariable-adjusted odds ratios for cellulite were 1.19 (95% CI: 1.10-1.51; P < 0.01) for ACE rs1799752 and 0.61 (95% CI: 0.45-0.88, P < 0.01) for HIF1A rs11549465. CONCLUSIONS: This study, which demonstrates an independent role of ACE and HIF1A in predisposing to cellulite, may provide novel information on the pathophysiology of this common cosmetic problem, and offer a topic for research for novel beautification interventions.

Prevalence of antibodies to lymphadenopathy-associated retrovirus in African patients with AIDS.

The presence of antibodies to lymphadenopathy-associated retrovirus (LAV) was determined by a radioimmunoprecipitation assay and by an enzyme-linked immunosorbent solid assay of sera from Zairian patients with the acquired immune deficiency syndrome (AIDS) in 1983. Thirty-five of 37 patients (94 percent) and 32 of 36 patients (88 percent), respectively, were seropositive by the two tests. In a control group of 26 patients, six (23 percent) showed positive results in these tests. Of these six control patients, five had clinically demonstrable infectious diseases and a low ratio of T4 to T8 lymphocytes. In addition, sera collected from a control group of Zairian mothers in 1980 were positive for LAV in 5 of 100 cases. Other serologic data suggest that LAV was present as early as 1977 in Zaire.

Erectile dysfunction and angiographic extent of coronary artery disease in type II diabetic patients.

Some studies observed an association between erectile dysfunction (ED) and coronary artery disease (CAD) extent in the general population, but others did not. There are no specific studies in diabetic populations. The aim of the present study was to evaluate whether ED is correlated with the extent of angiographic CAD in a large group of type II diabetic patients. We recruited 198 consecutive type II diabetic males undergoing an elective coronary angiography to evaluate chest pain or suspected CAD. Presence and degree of ED were assessed by the International Index Erectile Function - 5 (IIEF-5) questionnaire. ED was considered present, when IIEF-5 score was < or =21. Moreover, each domain of IIEF-5 was considered. Angiographic CAD extent was expressed both by the number of vessels diseased and by the Gensini scoring system. The percentage of subjects with ED was significantly higher (45.8 versus 15.8%; P=0.0120) in patients with (n=179) than in those without (n=19) significant angiographic CAD (stenosis of the lumen > or =50%). No significant association of CAD extent with presence of ED, total IIEF-5 score and each domain of IIEF-5 was observed. Our study shows that ED was significantly more prevalent in type II diabetic males with angiographic CAD than in those with normal arteries. However, no correlation was found between the extent of angiographic CAD and the presence or the severity of ED.

Association between apolipoprotein(a) phenotypes and coronary heart disease at a young age.

OBJECTIVES: The purpose of this study was to investigate lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] phenotypes in relation to age of onset of coronary heart disease (CHD). BACKGROUND: Although Lp(a) levels have been extensively analyzed in relation to age of CHD, apo(a) phenotypes have not. METHODS: Three hundred and thirty-five consecutive CHD patients were enrolled and grouped according to their age of CHD onset (<45 years; 45 to 54 years; > or = 55 years). RESULTS: In each patient group Lp(a) levels were higher than in an age-matched control group, but among the patient groups no differences in Lp(a) levels were observed. Apolipoprotein(a) phenotype distributions showed significant differences between patients and age-matched control subjects. Among the patient groups the difference in percentage of subjects with two apo(a) isoforms of low molecular weight (MW) was highly significant (p < 0.001). Multivariate analysis showed that apo(a) phenotypes were the best predictors of early CHD (p < 0.000001). The age-specific odds ratios (ORs) of the presence of at least one apo(a) isoform of low MW for CHD declined with age; in particular apo(a) phenotypes had their highest predictive value in younger persons (OR: 14.62). The OR for the presence of two isoforms of low MW/presence of only isoforms of high MW was 40.88 in the younger age group, 27.17 in age group of 45 to 54 years and 15.83 in the older age group. CONCLUSIONS: The present article reports the first evidence of a strong independent association of apo(a) phenotypes with the age of onset of CHD. Thus, if our data are confirmed by larger studies, apo(a) phenotypes might be used together with Lp(a) levels as powerful genetic markers in assessing the actual risk of developing CHD at a young age.

Enzyme activities in perikaryal and synaptic mitochondrial fractions from rat hippocampus during development.

When pharmacological or basic neurochemical systematic characterization of mitochondrial enzymatic systems correlated to energy transduction processes is attempted, studies must be based on subcellular fractions with a high degree of purity from specific brain areas and from individual animals. Distinct populations of mitochondria heterogenous with respect to biochemical enzyme characteristics from rat brain hippocampus are described. Two mitochondrial populations were derived from synaptosomes by lysis and a third consists of free non-synaptic mitochondria. The maximum rate of some cerebral enzyme activities which are part of energy transduction (citrate synthase, malate dehydrogenase; total NADH-cytochrome c reductase, cytochrome oxidase) and amino acid metabolism (glutamate dehydrogenase) were tested on these mitochondrial populations of 8- and 16-week-old rats. A comprehensive analysis of the data suggests that extensive but highly diversified catalytic expressions of the enzymes studied occur in the hippocampus. This is true even when a short period of the rat life span is studied. Hence the varying pattern of evolution of the differing cerebral mitochondria, probably a consequence of different metabolic functions, should be taken into account in any pharmacological study on these systems.

Association of lipoprotein(a) levels and apolipoprotein(a) phenotypes with coronary heart disease in patients with essential hypertension.

BACKGROUND: Besides hypertension, several cardiovascular risk factors can play a role in the development of coronary heart disease (CHD) in hypertensive patients. Lipoprotein(a) [Lp(a)] is an important and independent cardiovascular risk factor, but its role in the development of CHD in hypertensives has not been studied. OBJECTIVE: To investigate whether or not Lp(a) levels and isoforms of apolipoprotein(a) [apo(a)] are predictors of CHD in patients with essential hypertension. METHODS: Lp(a) levels and apo(a) polymorphism were evaluated in 249 patients with essential hypertension, in 142 non-hypertensive patients with CHD and in 264 healthy controls. RESULTS: Hypertensives with CHD (n = 61) had Lp(a) levels [19 (range 0.5-73.5) versus 7 mg/dl (range 0-83.5), P < 0.001] and a percentage of apo(a) isoforms of low (< 655 kDa) relative molecular mass (RMM, 59.2 versus 25.9%, P < 0.001) higher than did those without CHD (n = 188). Moreover, there were more subjects with at least one apo(a) isoform of low RMM in the subgroup of patients with CHD than there were in that of those without CHD (80.3 versus 30.8%, P< 0.001). Lp(a) levels and apo(a) polymorphism did not differ significantly between hypertensive and non-hypertensive patients with CHD. Stepwise regression analysis indicated that high Lp(a) levels (P= 0.002073) and particularly the presence of at least one apo(a) isoform of low RMM (P < 0.000001) are strong predictors of CHD in hypertensive patients. CONCLUSIONS: Our data show that high Lp(a) levels and the presence of at least one apo(a) isoform of low RMM are strong and independent genetic risk factors for CHD in hypertensive patients. These findings suggest that Lp(a) and apo(a) isoforms should be assessed together with other cardiovascular risk factors to establish the overall CHD risk status of each hypertensive patient

Enhanced antithrombotic mechanisms in patients with maturity-onset diabetes mellitus without thromboembolic complications.

Some haemostatic parameters have been evaluated in a group of rigorously selected patients with maturity-onset diabetes mellitus without thromboembolic complications and in apparently normal subjects of the same age before and after the venous occlusion test (VOT). In basal conditions diabetics had higher levels of AT III as biological activity and higher fibrinolytic and antifibrinolytic activities than controls. After VOT, F VIII R:Ag increased significantly in both groups, more markedly in controls than in diabetics, while F VIII: C showed no modification. Also AT III R:Ag increased after the test, but such variation was significant only in diabetics; on the contrary, the biological activity of AT III was always significantly decreased after the test. After VOT there were also in both groups highly significant increases in the fibrinolytic and antifibrinolytic activities. Finally, HbA1c levels directly correlated with AT III as biological activity before VOT, but with no other parameter either before or after the test. These data suggest the existence in patients with diabetes mellitus without thromboembolic complications of an activated protective mechanism against intravascular clotting.

Characterization of apo(a) polymorphism by a modified immunoblotting technique in an Italian population sample.

Apo(a), the specific lipoprotein(a) (Lp(a)) apolipoprotein, is characterized by different isoforms (from 6 to 11 on SDS-PAGE) encoded by a system of autosomal codominant alleles. Electrophoresis on agarose gel displays a better resolving power than SDS-PAGE (a larger number of apo(a) isoforms is detected). The aim of this work was to set up a simple technique that uses a capillary blotting apparatus and a polyvinylidene difluoride membrane for protein transfer. We tested an Italian population sample of 202 healthy subjects (123 men and 79 women) and we detected 22 apo(a) isoforms varying from 280 to 775 kDa. In our sample, 135 subjects (66.5%) had a single-band phenotype, 64 (31.7%) had a double-band phenotype and 3 subjects (1.5%) had no detectable bands ('null' phenotype). This simple and reproducible technique could be applied in the genetic screening of apo(a) polymorphisms and for clinical investigations of the risk of developing cardiovascular diseases.

Apolipoprotein(a) phenotypes as genetic markers of coronary atherosclerosis severity.

We investigated Lp(a) levels and apo(a) polymorphism in relation to the severity of coronary artery disease, expressed both by the number of coronary arteries stenosed and three different coronary scoring systems. In a sample of 267 patients with coronary artery disease, a Mono-, Bi- or Multi-vessel coronary stenosis was documented by angiography. Twenty-five apo(a) isoforms were detected by a high resolution phenotyping method. Lp(a) levels did not show any differences among subgroups of patients. Both the percentage of apo(a) isoforms of low molecular weight (<655 kDa) (P=0.00015) and the percentage of subjects with at least one apo(a) isoform of low molecular weight (P=0.00027) were significantly correlated with increasing number of coronary vessels stenosed. In multivariate analysis, only apo(a) isoforms of low molecular weight were predictors of coronary atherosclerosis severity, when we used as the dependent variable both the '1-2-multi-vessels' categorization (P=0.000067) and the Gensini (P=0.008767), or Green Lane (P= 0.000001) or Dahlen (P=0.000102) coronary scoring system. Our data show that apo(a) isoforms of low molecular weight are associated with a greater severity of coronary atherosclerosis. If these data are confirmed by prospective studies, apo(a) phenotypes might be used as genetic markers of a greater severity of coronary atherosclerotic lesions.

Silent myocardial ischemia in diabetic and nondiabetic patients with coronary artery disease.

BACKGROUND: Patients with diabetes mellitus are at increased risk for CAD; silent ischemia is reported to be frequent in diabetic populations. The aim of the present study was to evaluate the prevalence of silent ischemia in diabetic and nondiabetic patients with assessed CAD. METHODS AND RESULTS: We recruited a total of 618 patients with CAD: 309 were consecutive diabetic patients and 309 were age- and gender-matched nondiabetic patients. Myocardial ischemia was evaluated both during daily life and during exercise testing. Angina pectoris during daily life was more frequent in diabetic than in nondiabetic patients (80% vs. 74%, P<0.05). The anginal pain intensity either during daily life or acute myocardial infarction (MI), the prevalence of a previous MI, the extent of CAD and ergometric parameters were similar in diabetics and nondiabetics. Silent ischemia during exercise was documented in 179 (58%) diabetics and in 197 (64%) nondiabetics (nonsignificant, ns). Both diabetics and nondiabetics with silent exertional myocardial ischemia differed from symptomatic subjects in higher heart rate values (P<0.01), systolic blood pressure (P<0.01), rate-pressure product (P<0.001), work load (P<0.01) and maximum ST-segment depression at peak exercise (P<0.05). CONCLUSIONS: The incidence of silent myocardial ischemia during exercise was similar in diabetic and nondiabetic CAD patients. Surprisingly, diabetics showed a higher prevalence of angina pectoris during daily activity than nondiabetics. A significant association between the presence of symptoms during daily life and exercise was observed in both groups. Our results may contribute to the planning of the clinical management of diabetic CAD patients and confirm the individual attitude to pain of CAD patients independent of the presence of diabetes.

Lipoprotein(a) levels and apolipoprotein(a) polymorphism in type 1 diabetes mellitus: relationships to microvascular and neurological complications.

To investigate plasma concentrations of lipoprotein(a) [Lp(a)] and apolipoprotein(a) [apo(a)] polymorphism in relation to the presence of microvascular and neurological complications in type 1 diabetes mellitus, 118 young diabetic patients and 127 age-matched controls were recruited. Lp(a) levels were higher in patients than in controls, but the apo(a) isoforms distribution did not differ between the two groups [higher prevalence of isoforms of high relative molecular mass (RMM) in both groups]. Microalbuminuric patients had Lp(a) levels significantly greater than normoalbuminuric patients, and normoalbuminuric patients showed higher Lp(a) levels than controls. Patients with retinopathy or neuropathy showed similar Lp(a) levels to those without retinopathy or neuropathy. No differences in apo(a) isoforms frequencies were observed between subgroups with and without complications (higher prevalence of isoforms of high RMM in every subgroup). However, among patients with retinopathy, those with proliferative retinopathy had higher Lp(a) levels and a different apo(a) isoforms distribution (higher prevalence of isoforms of low RMM) than those with non-proliferative and background retinopathy (higher prevalence of isoforms of high RMM). Our data suggest that young type 1 diabetic patients without microalbuminuria have Lp(a) levels higher than healthy subjects of the same age. Lp(a) levels are further increased in microalbuminuric patients. High Lp(a) levels and apo(a) isoforms of low RMM seem to be associated with the presence of proliferative retinopathy, but have no relation to neuropathy.

Severe hypercalcemia and systemic lupus erythematosus.

A rare case of severe hypercalcemia strongly associated with Systemic Lupus Erythematosus (SLE) is reported. On admission, a young woman showed severe hypercalcemia and photosensitivity. Criteria for diagnosis of SLE were not sufficient. All causes, common and uncommon, of hypercalcemia were excluded. Radiographs of the skeleton were normal. One year later diagnosis of SLE was evident. In addition, diffuse and severe osteopenia and chest deformities had occurred. The treatment of SLE normalized persistently calcemia. Mild elevation of calcium levels occurred during flares of SLE. It has been hypothesized that hypercalcemia in patients with SLE could be caused by the presence of stimulatory anti-PTH receptor antibodies. This case report suggests that in patients with severe hypercalcemia associated with SLE early diagnosis and treatment of SLE may prevent bone loss. In these patients the prevention of severe bone damage is very important. Indeed, severe osteopenia may favour skeletal deformities and fractures; in addition it may represent a serious obstacle in using adequate doses of glucocorticoids for treatment of SLE.

Action of piracetam and clonidine on different mitochondrial populations from hippocampus.

The maximum rate (Vmax) of some mitochondrial enzymatic activities related to energy transduction (citrate synthase, malate dehydrogenase, NADH-cytochrome c reductase (as total activity), cytochrome oxidase) and amino acid metabolism (glutamate dehydrogenase) were evaluated in non-synaptic (free) and synaptic mitochondria from rat brain hippocampus. Three types of mitochondria were isolated from rats subjected to single i.p. treatments with piracetam (300 mg.kg-1) or with clonidine (750 micrograms.kg-1). With respect to the enzymatic pattern of three types of non-synaptic and synaptic mitochondria, in hippocampus a different maximum rate of both NADH-cytochrome c reductase and cytochrome oxidase was observed, these activities in particular being lowest in the "synaptic heavy" mitochondrial subfraction than in the "synaptic light" one; in addition, other enzyme activities are different in the "free" as compared to both the "light" and "heavy" mitochondria. This confirms that in various types of brain mitochondria a different metabolic machinery exists. Acute treatment with piracetam decreased citrate synthase, glutamate dehydrogenase, NADH-cytochrome c reductase and cytochrome oxidase activities only in the "heavy" mitochondria obtained from synaptosomes. Acute treatment with clonidine decreased the citrate synthase, NADH-cytochrome c reductase and cytochrome oxidase activities only in the same type of mitochondria, i.e. synaptic "heavy" mitochondria. However, this drug increased the same enzymatic activities in "free" mitochondria, some of them being increased or decreased in "light" intrasynaptic ones. Therefore in vivo administration of piracetam mainly affects some specific enzyme activities (suggesting a specific molecular trigger mode of action) of the intrasynaptic mitochondria (suggesting a specific subcellular trigger site of action), the effect on enzyme activities by clonidine being more complex.

[Apolipoprotein(a) phenotypes as markers of genetic susceptibility for cardiovascular risk in occupational medicine]. / Fenotipi di apolipoproteina(a) come indicatori di suscettibilità genetica per rischio cardiovascolare in medicina del lavoro.

Several agents (e.g. chemical or physical) present in the work environment may be harmful for the cardiovascular system. Recent studies on the cardiovascular diseases linked to hyperlipidemia have demonstrated a strong correlation between high lipoprotein(a) [Lp(a)] levels and Coronary Heart Disease (CHD). In particular, the severity of this pathological condition correlates well with the molecular weight (MW) of the apolipoprotein(a) [apo(a)] isoforms supporting Lp(a) (low MW = high risk; high MW = low risk), which are characterized by a high degree of individual variability. Since apo(a) isoforms are genetically determined, a genetic predisposition for CHD has been identified, i.e. the apo(a) phenotype is considered a marker of genetic susceptibility for cardiovascular risk. After a brief presentation of the main occupational cardiovascular risk factors (e.g. carbon disulfide, carbon monoxide, noise, psycho-physical stress) and of the most updated theories on atherogenesis, the present review proposes to utilize the measurement of the plasmatic Lp(a) level to screen for occupational cardiovascular risk susceptibility. Apo(a) phenotype characterization of workers with medium-high Lp(a) levels is then suggested. Our proposal may be realized by means of simple and relatively unexpensive laboratory methods.

Decreased plasma levels of soluble receptor for advanced glycation end products in mild cognitive impairment.

Growing evidence advanced the idea that the soluble form of the receptor for advanced glycation end-products (sRAGE) might serve as a risk marker for several disorders including Alzheimer disease. We found a reduced level of circulating sRAGE in patients with mild cognitive impairment (MCI). The reduction of sRAGE in MCI, as well as the anticipation of the disease in patients with the lowest sRAGE levels (

Markers of eosinophilic inflammation and risk prediction in patients with coronary artery disease.

BACKGROUND: The eotaxin family comprises three distinct peptides (eotaxin, eotaxin-2 and eotaxin-3) which have been implicated in eosinophilic inflammation. In vitro and clinical studies suggest that eotaxins could play a role in vascular inflammation, but no data are available on their prognostic significance in patients with angiographically documented coronary artery disease (CAD). MATERIALS AND METHODS: Baseline plasma samples were obtained from 1014 patients with documented CAD. We tested the predictive effect of markers of eosinophilic inflammation and C-reactive protein (CRP) on death from cardiovascular causes and nonfatal myocardial infarction over a 2.7-4.1-year follow-up period. RESULTS: Unexpectedly, lower eotaxin-3 concentrations were observed in patients with adverse cardiovascular events, whereas both eotaxin and eotaxin-2 showed no association with risk. After adjustment for most potential confounders, patients in the upper-quartile of eotaxin-3 levels had a 0.42 hazard-ratio (95% CI, 0.29-0.61, P < 0.001) for adverse events compared with subjects in the lower-quartile. The highest risk of future cardiovascular events was observed in subjects with combined elevation of CRP and reduction of eotaxin-3; 4.4 hazard-ratio (95% CI, 2.1-9.5, P < 0.001). Importantly, receiver-operating-characteristic curves analysis suggested a superior prognostic value of eotaxin-3 compared with CRP for predicting cardiac events in patients with CAD. CONCLUSIONS: Low levels of eotaxin-3 are an independent predictor of future adverse cardiovascular events in patients with CAD and may be useful for risk stratification.

Apo(a) size in ischemic stroke: relation with subtype and severity on hospital admission.

OBJECTIVE: To determine the distribution of apolipoprotein (a) (apo[a]) isoforms and their relation to the clinical severity of different ischemic stroke subtypes. METHODS: Ninety-four hospital cases with a first-ever ischemic stroke and 188 randomly selected control subjects matched for age, gender, and ethnicity were enrolled. Stroke etiology was defined according to Trial of Org 10172 in Acute Stroke Treatment criteria. NIH Stroke Scale (NIHSS) was used to assess the severity of stroke on admission. RESULTS: In univariate analysis, the presence of at least one small apo(a) isoform was associated with ischemic stroke in men (p = 0.02) but not in women (p = 0.33). After allowance for age, gender and traditional vascular risk factors, subjects carrying at least one small apo(a) isoform were at increased risk of atherothrombotic stroke (odds ratio [OR] 7.1, 95% CI 2.8 to 17.5, p = 0.00001) but not of lacunar infarction (OR 1.1, 95% CI 0.5 to 2.7, p = 0.78). Multivariate logistic regression analysis revealed that in the atherothrombotic stroke group, the presence of at least one small-sized apo(a) phenotype was associated with an NIHSS score > or =6 (OR 13.6, 95% CI 1.6 to 111.9, p = 0.015). CONCLUSION: Small apolipoprotein (a) isoforms distinguish atherothrombotic stroke from lacunar infarction and are associated with the severity of atherothrombotic stroke.