Impaired response of fibroblasts from patients with hyperapobetalipoproteinemia to acylation-stimulating protein.

Acylation-stimulating protein (ASP) is a small, basic, human plasma protein that markedly stimulates triglyceride synthesis in human adipocytes and cultured human skin fibroblasts. The present studies examine the response to ASP of cultured skin fibroblasts from normal subjects patients with hyperapobetalipoproteinemia, patients with familial hypercholesterolemia, and patients with hypertriglyceridemia without hyperapobetalipoproteinemia. Triglyceride synthesis induced by ASP did not differ significantly among the normals, the patients with familial hypercholesterolemia, and the patients with hypertriglyceridemia with normal low density lipoprotein (LDL) apolipoprotein B levels; however, on average, it was markedly reduced in the patients with hyperapobetalipoproteinemia. In all groups studied, evidence of specific saturable binding of radioiodinated ASP was present. Binding, however, was significantly reduced in the groups with hyperapobetalipoproteinemia whereas the other three groups were indistinguishable. By contrast, LDL-specific binding was reduced only in the patients with familial hypercholesterolemia. There was a significant direct relation between the degree of ASP binding and the triglyceride synthesis inducible by ASP. In addition, with the exception of the patients with familial hypercholesterolemia, there was an inverse relation between both ASP-specific binding and ASP-induced triglyceride synthesis in fibroblasts to LDL levels in plasma whereas no relation was evident to plasma high density lipoprotein and very low density lipoprotein.     

Acylation stimulating protein: a female lipogenic factor?

Acylation stimulating protein (ASP) is a potent lipogenic factor produced from adipocytes. Plasma ASP levels were shown to increase in obesity, diabetes mellitus type II and dyslipidemia, and decrease after weight loss and fasting. Growing evidence suggests that ASP may significantly contribute to subcutaneous fat storage in females. In vitro, ASP stimulated triglyceride synthesis to a larger extent in subcutaneous compared with omental adipocytes. The ASP receptor binding affinity to plasma membranes prepared from adipose tissue showed higher binding affinity to plasma membranes from female adipose tissue compared with male adipose tissue, and was more pronounced to subcutaneous compared with omental plasma membranes. Human studies demonstrated that postprandial triglyceride clearance predicted by ASP levels was more efficient in women than in men. In mice, postprandial triglyceride clearance, with intraperitoneal ASP administration, was faster in females compared with males. The ASP deficient mice were resistant to weight gain and had reduced fat mass that was more pronounced in females. Recent findings in humans and mice point to a significant association between progesterone and ASP variations in females. In this review, we highlight findings, to date, linking ASP to physiological and hormonal alterations that may contribute to subcutaneous fat distribution typical to females.     

Role of the renin-angiotensin-aldosterone system in the pathogenesis of atherosclerosis

Renin-angiotensin-aldosterone (RAAS) is a hormone system which acts on multiple physiologic pathways primarily by regulating blood pressure and fluid balance, but also by local autocrine and paracrine actions. In pathophysiologic conditions RAAS also contributes to the development of atherosclerosis and its various manifestations, both directly and indirectly through the actions on other systems. RAAS mainly acts as a promoter of atherosclerosis by its action on vessels, and by promoting the development of hypertension, insulin resistance and diabetes, obesity, vascular and systemic inflammation. As RAAS plays a key role in the pathogenesis of cardiovascular diseases, RAAS genes have been extensively studied as candidate genes for atherosclerosis and coronary artery disease. Several polymorphisms of its genes have been found to be in relationship with atherosclerosis and cardiovascular diseases. In this review we will discuss these issues and present the most recent advances about this topic.     

Myocardial infarction complicating the initial phase of an ovarian stimulation protocol

Two previous reports have reported myocardial infarction during ovarian hyperstimulation syndrome, a complication of controlled ovarian stimulation characterized by ascites, pleural effusion, hemoconcentration and an increased thromboembolic risk, but no association with the initial phase (before treatment with human chorionic gonadotropin) of a normal ovarian stimulation protocol for infertility has ever been described. We report the first case, to our knowledge, of acute myocardial infarction occurring during the initial phase of an otherwise uncomplicated ovarian stimulation protocol. A young woman with infertility associated to polycystic ovary syndrome was treated with leuprolide acetate and recombinant follicle stimulating hormone to induce ovarian stimulation for in vitro fertilization and embryo transfer. After 12 days the patient presented a non-ST elevation myocardial infarction, which was treated with aspirin, clopidogrel, enoxaparin, intravenous nitrates and beta blockers. Cardiac catheterization showed angiographically normal coronary arteries. Echocardiography showed a circumscribed akinesis of the inferior apical segment of the left ventricle and right ventricular apex, which was confirmed by cardiac magnetic resonance. A screening for thrombophilic diathesis was negative. The patient was discharged and remained asymptomatic at 1 and 3 months follow up. Further ovarian stimulations were excluded and a trial of oocyte retrieval on spontaneous cycle was planned. Myocardial infarction can complicate ovarian stimulation protocols for infertility even in their early phase without any sign of ovarian hyperstimulation syndrome.     

Temporal dynamics of plastic changes in human primary somatosensory cortex after finger webbing

The primary somatosensory cortex (SI) exhibits a detailed topographic organization of the hand and fingers, which has been found to undergo plastic changes following modifications of the sensory input. Although the spatial properties of these changes have been extensively investigated, little is known about their temporal dynamics. In this study, we adapted the paradigm of finger webbing, in which 4 fingers are temporarily webbed together, hence modifying their sensory feedback. We used magnetoencephalography, to measure changes in the hand representation in SI, before, during, and after finger webbing for about 5 h. Our results showed a decrease in the Euclidean distance (ED) between cortical sources activated by electrical stimuli to the index and small finger 30 min after webbing, followed by an increase lasting for about 2 h after webbing, which was followed by a return toward baseline values. These results provide a unique frame in which the different representational changes occur, merging previous findings that were only apparently controversial, in which either increases or decreases in ED were reported after sensory manipulation for relatively long or short duration, respectively. Moreover, these observations further confirm that the mechanisms that underlie cortical reorganization are extremely rapid in their expression and, for the first time, show how brain reorganization occurs over time.     

Frequency of slow coronary flow following successful stent implantation and effect of Nitroprusside

Nitroprusside (NTP) is used for the treatment of slow coronary flow (SCF) after coronary interventions. The wide variation in dosage, route, and timing of its administration in the reported studies prevents an objective assessment of its efficacy. We report the incidence and response to a standardized NTP protocol of SCF after successful stent implantation. Selective intracoronary administration of incremental doses (initial bolus of 80 microg incremented by 40 microg) of NPT was assessed in 21 patients who developed SCF in a series of 2,212 consecutive patients who underwent successful stent placement from January to October 2005. SCF was observed only in patients treated for acute myocardial infarction (AMI; 11.5%, 12 of 105) or saphenous vein graft (SVG) stenosis (8.2%, 9 of 109). An intracoronary bolus of nitroglycerin did not restore normal Thrombolysis In Myocardial Infarction (TIMI) flow in any patient. The first 80-microg dose of NTP restored normal TIMI flow in 58% of patients (7 of 12) with AMI and in 44% of patients (4 of 9)with SVG stenosis. The maximal dose (120/160 microg) restored normal TIMI flow in all remaining patients with AMI but in only 1 additional patient with SVG stenosis. At the end of the procedure, the percent decrease in corrected TIMI frame count was significantly larger in patients with AMI (-44+/-10%) than in those with SVG stenosis (-24+/-16%, p=0.02). In a large consecutive series of successful stent procedures, SCF was found only in patients with ST-elevation AMI (11.5%) or with a stenosed SVG (8.2%). In conclusion, the standardized protocol of intracoronary NTP administration succeeded in normalizing SCF in all patients with AMI but in only 5 of 9 patients with SVG stenosis. This latter subgroup requires other therapeutic strategies.     

Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women

OBJECTIVE: Ghrelin [acylated (AG) and nonacylated (NAG)] has been shown to play a pivotal role in the regulation of food intake and insulin sensitivity. It is presently unclear whether variation in insulin sensitivity is related to AG and NAG levels in obese individuals. To address this issue, we determined whether insulin-sensitive overweight or obese (ISO) and insulin-resistant overweight or obese (IRO) individuals display different total ghrelin (TotG), AG, and NAG profiles during a euglycemic/hyperinsulinemic clamp (EHC). DESIGN: Eighty-nine nondiabetic overweight and obese postmenopausal women underwent EHC to evaluate insulin sensitivity. Body composition and blood lipid profiles were assessed. Subjects within the highest tertile of insulin sensitivity were described as ISO (n = 31), whereas those within the lowest tertile of insulin sensitivity were considered as IRO (n = 29). Plasma TotG, AG, and NAG profiles were assessed by RIA at 0, 60, 160, 170, and 180 min during the EHC. RESULTS: TotG and NAG levels were significantly decreased for ISO and IRO individuals during the EHC, whereas only ISO subjects displayed a significant reduction of AG concentrations (P < 0.05). AG area under the curve value and the ratio of AG/NAG (fasting and area under the curve) were significantly decreased in ISO individuals. Furthermore, maximal reduction of TotG and AG concentrations was greater in ISO compared with IRO individuals (P < 0.05). Insulin sensitivity was significantly correlated with maximal reduction of TotG (r = 0.36; P < 0.01) and AG (r = 0.36; P < 0.05) concentrations. CONCLUSION: The dysregulation of ghrelin secretion profiles during EHC is associated with insulin resistance. AG may contribute to the variation of insulin sensitivity in overweight or obese postmenopausal women.     

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

P-glycoprotein (P-gp), traditionally linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and Bcl-x(L) and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs. P-gp/Bcl-x(L) colocalization was investigated by confocal immunofluorescence microscopy and protein-protein interaction by co-immunoprecipitation, in basal conditions and after stress-induced apoptosis, in GC cell lines AGS and MKN-28 and hepatocellular carcinoma cell line Hep-G2. The role of P-gp in controlling apoptosis was evaluated by knocking down its expression with a specific small interfering RNAs in stressed AGS and MKN-28 cell lines. P-gp is expressed in the gastric mucosa of all human fetuses while, it is undetectable in adult normal mucosa and re-expressed in 30/110 Hp-positive non-IM-CG, 28/28 IM-CG and 40/45 GCs. P-gp expression directly correlates with that of Bcl-x(L) and with the promoter hypomethylation of the MDR1 gene. In GC cell lines, P-gp is localized on the plasma membrane and mitochondria where it colocalizes with Bcl-x(L). Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-x(L) in AGS, MKN-28 and Hep-G2, at both basal level and after stress-induced apoptosis. The selective silencing of P-gp sensitizes GC cells to stress-induced apoptosis. P-gp behaves as an oncofetal protein that, by cross-talking with Bcl-x(L), acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.