The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications.

The insulin receptor (IR) presents by alternative splicing two isoforms: IRA and IRB. The differential physiological and pathological role of both isoforms is not completely known, and it is determinant the different binding affinity for insulin-like growth factor. IRB is more abundant in adult tissues and it exerts mainly the metabolic actions of insulin, whereas IRA is mainly expressed in fetal and prenatal period and exerts mitogenic actions. However, the change in the expression profile of both IR isoforms and its dysregulation are associated with the development of different pathologies, such as cancer, insulin resistance, diabetes, obesity, and atherosclerosis. In some of them, there is a significant increase of IRA/IRB ratio conferring a proliferative and migratory advantage to different cell types and favouring IGF-II actions with a sustained detriment in the metabolic effects of insulin. This review discussed specifically the role of IR isoforms as well as IGF-IR in diabetes and its associated complications as obesity and atherosclerosis. Future research with new IR modulators might be considered as possible targets to improve the treatment of diabetes and its associated complications.

Pathophysiology of HIV related thrombocytopenia: an analysis of 41 patients.

AIM: To analyse the pathogenic mechanism of HIV related thrombocytopenia. METHODS: Forty one patients with thrombocytopenia and HIV-1 infection were investigated over two years. Anticardiolipin antibodies were measured using an enzyme linked immunosorbent assay and antiplatelet antibodies were measured using an immunocapture technique. Tests for VDRL, C3 and C4, antinuclear antibodies and rheumatoid factor were also carried out in all patients and 80 control subjects (HIV-1 positive but non-thrombocytopenic). Indiumoxine labelled platelets were transfused in 13 patients. P24 antigen were also measured in 12 bone marrow aspirates. RESULTS: Antiplatelet antibodies and circulating immune complexes were found exclusively in the thrombocytopenic group; values for antiplatelet antibodies and circulating immune complexes were both higher in homosexual and bisexual patients. Three kinds of pattern were observed using 111 In-labelled platelets: splenic (n = 10); hepatic (n = 2); and destruction of bone marrow in just one case. The two most influential factors in the sequestration pattern were antiplatelet antibodies in the splenic uptake and circulating immune complexes in the hepatic and marrow sequestration. All patients, except three, had decreased platelet recovery. In those patients with a CD4 lymphocyte count of less than 200 x 10(6) cells/l the recovery was clearly greater (53%) than in patients who had more than 200 x 10(6) /l (28%). Finally, in seven of the 12 patients who were chosen for immunohistochemical study, p24 antigen was detected in the megakaryocytes, verifying that HIV-1 infects such cells. CONCLUSIONS: The pathogenic mechanism of HIV related thrombocytopenia is probably multifaceted. Antiplatelet antibodies and circulating immune complexes would cause peripheral destruction in the spleen, liver, and bone marrow, in that order; and, on the other hand, there would be an ineffective immune thrombopoiesis and direct infection of the megakaryocytes which could cause a change in the function and maturity of these cells.

Fibrinolytic activity in laparoscopic cholecystectomy.

The aim of this study was to examine the fibrinolytic activity in laparoscopic cholecystectomy (LC) to determine whether changes occur that might indicate a greater risk of thrombosis. The study was carried out in 20 patients who had undergone laparoscopic surgery for cholelithiasis without complications. The average age was 59.4 years (34-77 years). Seventy-five percent were women. The mean operating time was 70 minutes (35-120 minutes). Pneumoperitoneum at 14 mm Hg was maintained in all patients, and they were in 30 degrees reverse Trendelenburg position. Postoperative mobilization was obtained before 24 hours, and patients were discharged 48 hours after surgery. The control group was composed of 12 patients, evenly distributed by age, sex, and length of surgery, who had undergone Bassini herniorrhaphy without complications or relapses. The following hemostatic parameters were studied: plasma fibrinolytic activity (PFA), euglobulin fibrinolytic activity (EFA), tissue-type plasminogen activator (t-PA), fast-acting plasminogen activator inhibitor-1 (PAI-1), and D-dimer (D-D). Samples were obtained at the following times: (1) under basal conditions the day before surgery, (2) preoperatively, (3) at the end of surgery, (4) 24 hours after surgery, and (5) on the seventh day following surgery. No patient had clinical manifestations of thromboembolic disease immediately after surgery or during an average follow-up period of 16 months (range 15-18 months). Analysis of the results of global fibrinolysis showed that fibrinolytic activity was enhanced only in the postoperative period (third sample) of the LC patients. The fraction of euglobulins enhances fibrinolytic activity in both groups in the third sample with regard to the other determinations; the LC patients showed a higher degree of significance (p<0.005). A significant increase of postoperative t-PA in both groups was found, being more significant in the LC group (p<0.005). In the PAI-1 values, no significant differences existed between either determinations or groups. A significant increase in D-dimer (p<0.05) occurred in the immediate postoperative period (third sample) and 24 hours later (fourth sample), returning to normal basal values on the seventh day. No significant differences were found between the two groups. These results seem to indicate that LC produces an increase in the fibrinolytic activity in plasma as a result of the liberation of tissue plasminogen activator from the venous endothelium, which could indicate hypocoagulability during the immediate postoperative period and, therefore, signify less thrombotic risk for patients undergoing this procedure.

[Variable response to the biological inhibition of platelets by abciximab in patients subjected to percutaneous coronary angioplasty]. / Respuesta variable a la inhibición biológica de las plaquetas por abciximab en pacientes sometidos a revascularización coronaria percutánea.

INTRODUCTION AND OBJECTIVES: Abciximab has been shown to reduce the risk of thrombotic complications during coronary angioplasty, however there are still many aspects to be resolved. The aim of this study was to investigate the various biological effects of abciximab on platelets during coronary angioplasty. METHODS: The degree of platelet inhibition (with 5 and 20 mol/l concentrations of ADP), occlusion time (measurement of platelet haemostatic capacity, PFA-100), and the platelet activation markers were determined in 15 patients who underwent basal coronary angioplasty and abciximab treatment. Determinations were obtained before, 15 minutes after procedure initiation, at procedure termination, and 24 hours after procedure termination. RESULTS: More than 80% platelet aggregation inhibition was observed in 13 patients during the procedure, but after 24 hours (p < 0.05) was only detected in two. The occlusion time during the procedure was > 300 sec. in 13 patients, 6 of whom evolved to normal values after 24 hours (p < 0.05). A high correlation (p = 0.02) was found between these two parameters during the intervention, but not after 24 hours. No platelet inhibition or occlusion time changes were observed in 2 patients during the study. The expression of p-selectin increased significantly during the procedure (p < 0.05). CONCLUSIONS: The variability of platelet function inhibition and existence of circulating activation during coronary angioplasty following the administration of abciximab support the use of early analytical controls with the objective of modifying guidelines for use in order to optimize its effect or to combine it with other antithrombotic agents.

[Epidemiology, clinical course++, prognosis and treatment of thrombocytopenia associated with human immunodeficiency virus type 1 infection: analysis of 41 cases]. / Epidemiología, clínica, pronóstico y tratamiento de la trombocitopenia asociada a la infección por el virus de la inmunodeficiencia humana tipo 1: análisis de 41 casos.

BACKGROUND: Thrombocytopenia is one of the manifestations of infection by the human immunodeficiency virus-1 (HIV-1). A series of 41 patients were studied over a period of 2 years. METHODS: The study was prospectively carried out with a control group of 80 patients with the epidemiology, clinical manifestations, prognosis and treatment of this process being evaluated. RESULTS: The risk groups were: intravenous drug users (IVDU) (78%), homosexuals (12%) and heterosexuals (7%), patients with thrombocytopenia as the only manifestation (group IV-E) constituted the largest group with 30 cases. In 50% of the patients both diseases (thrombocytopenia and HIV infection) were simultaneously diagnosed. Nine patients (22%) vs 35% in the control group evolved to more advanced stages of the infection. Only 39% of the cases had hemorrhagic manifestations being more frequent in the IV-E group (47%) than in the remaining patients (18%). With regards to treatment, only 1 case responded completely with danazol. Steroids had variable, although evaluable, results with minimum secondary effects. The infusion of gammaglobulins achieved 80% of complete, although transitory, responses. Zidovudine obtained a positive response in 17/25 cases. Finally, splenectomy was performed in three patients definitively resolving the thrombocytopenia. CONCLUSIONS: In thrombocytopenia associated with human immunodeficiency virus-1 (HIV-1) infection the distribution by groups of risk is equal to that of the rest of infected patients. Appearing early in the natural history of HIV infection, thrombocytopenia presents few clinical manifestations and does not constitute a factor of bad prognosis. The treatment of choice is zidovudine at doses of 500 mg/day.

Laboratory evaluation of the effect of prophylaxis for thromboembolism with fractionated heparin in patients undergoing laparoscopic cholecystectomy.

OBJECTIVE: We studied the effect of prophylaxis for thromboembolism with low-molecular-weight heparin (LMWH) during hospitalization on the biological hemostasis system in patients who had undergone laparoscopic cholecystectomy. METHODS: This was a prospective paired cohort study without a control group (i.e., a before-after study). The subjects were 20 patients operated on laparoscopically for uncomplicated cholelithiasis. All patients received LMWH 2 h before the operation and 24 h after the first dose. Mean duration of surgery was 70 min. Pneumoperitoneum was accomplished at 14 mmHg, and all patients were operated on in the inverted Trendelenberg position (30 degrees). Patients were mobilized within 24 h, and were discharged within 48 h after surgery. As parameters of hemostasis we studied anti-Xa factor activity (anti-Xa), antithrombin III (AT III), partial active thromboplastin time (PTT) and fibrinogen. Samples were taken for laboratory analyses under basal conditions the day before the operation (first determination), 1 h after the first preoperative dose of LMWH was given (second), at the end of the operation (third), 24 h after surgery (fourth), and on postoperative day 7 (fifth). RESULTS: Mean basal values of all parameters were within the normal range. Mean anti-Xa activity was significantly higher in the second and third determinations than in the first and fifth measurements (p < 0.05). Mean PTT was significantly elevated on the second determination and decreased thereafter; however, none of the results differed significantly from the normal value. Mean AT III was significantly lower in the third determination in comparison with the first and fifth measurements. Fibrinogen was significantly higher in the fourth and fifth determinations than in the second and third measurements. Among all parameters and sampling times, the only values outside the normal range were anti-Xa activity on the second, third and fourth determinations. CONCLUSIONS: Plasma anti-Xa factor activity was increased preoperatively, and remained elevated for 24 h after surgery, returning to basal values on postoperative day 7. Partial thromboplastin time was slightly prolonged after the first dose of LMWH, indicating good antithrombotic action.

[Are statins indicated in the prevention of cerebral infarct?]. / Están indicadas las estatinas en la prevención del infarto cerebral?

INTRODUCTION: Some studies of ischemic cardiopathy have shown that when pravastatin is used for the prevention of strokes, these are reduced. Whilst we await suitable clinical trials, we discuss the possible role played by these drugs in this subgroup of patients. DEVELOPMENT: A panel of experts from different specialties assess the data published on dislipemias in the epidemiology of strokes, the possible effect of statins in the prevention of cerebral infarcts in patients with atheromatous stenosis of the carotid artery and their mode of action. CONCLUSIONS: Pravastatin is indicated in all patients with ictus of atheromatous origin as primary prevention of ischemic cardiopathy, in patients with strokes and hypercholesterolemia, and in patients with symptomatic or asymptomatic carotid stenosis while we wait for more specific clinical trials.

Effect of apoE genotype on the hypolipidaemic response to pravastatin in an outpatient setting.

BACKGROUND: Considerable variability exists in the plasma lipid and lipoprotein response to statin treatment due, in part, to genetic factors. The gene for apolipoprotein E (ApoE) is polymorphic and the different genotypes modulate baseline lipid levels. The objective of the present study was to evaluate the effect of the apoE genotype on the lipoprotein response to pravastatin treatment in an outpatient population followed-up in several different clinics across Spain. Subjects and methods. Subjects (n=401; 56% female; mean age 57 years), who were hypercholesterolaemic despite a diet poor in saturated fat and cholesterol, were treated according to NCEP-ATP II guidelines. Plasma lipids and lipoproteins were measured centrally before and after 16 weeks of treatment with 20 mg day-1 of pravastatin. RESULTS: ApoE genotype distributions were 3.2% with varepsilon2/3, 73.1% with varepsilon3/3 and 22.4% with varepsilon3/4 or varepsilon4/4. ApoE genotype did not have any effect on baseline lipid levels except on triglycerides such that the carriers of the varepsilon2 allele had concentrations significantly greater than those subjects with varepsilon3/3 genotype and carriers of the varepsilon4 allele after adjustment for age, gender and body mass index (BMI) (P < 0.001). Once adjusted for age, gender, BMI and baseline lipid levels, the apoE polymorphism did not significantly influence the plasma lipid and lipoprotein response to pravastatin. CONCLUSION: ApoE genotype appears not to influence the hypolipidaemic effect of pravastatin in patients monitored in a general outpatient setting.

Coagulation abnormalities in patients with eosinophilia.

Haematological variables in patients with eosinophilia and in healthy control subjects were studied in order to determine whether there were abnormalities in the coagulation system in patients. We found significantly elevated levels of fibrinogen, fibrin degradation products, platelet number and beta-thromboglobulin in patients. The abnormalities were not related to the causes of eosinophilia nor to its severity. This lack of correlation could be due to the heterogeneity of human peripheral blood eosinophils.

Changes in hemostasis after laparoscopic cholecystectomy.

BACKGROUND: The aim of this work was to study hemostasis in laparoscopic cholecystectomy in order to determine if there are any changes that indicate a greater risk of thrombosis. METHODS: The study was carried out in 20 patients who underwent laparoscopic surgery for noncomplicated cholelithiasis. The average age was 59.4 years (range, 34-77). A total of 75% were female. Mean operation time was 70 min (ranges 35-120). Pneumoperitoneum at 14 mmHg was performed on all patients, who were positioned in the 30 degrees reverse Trendelenburg position. Postoperative mobilization was acheived in 24 hs and patients were discharged 48 hs after the operation. The control group was composed of 12 patients, who were evenly distributed by age, sex, and length of surgery. These patients underwent Bassini herniorraphy for inguinal hernia without any complications or relapse. The following hemostatic parameters were studied: prothrombin activity (PA), activated partial thromboplastin time (APTT), fibrinogen (Fg), anti-thrombin III (ATIII), plasma fibrinolytic activity (PFA), euglobulin fibrinolytic activity (EFA), and D-dimer (D-D). Samples were obtained at the following times: (a) under basal conditions the day before surgery, (b) preoperatively, (c) at the end of the operation, (d) 24 hs after the operation, and (e) On the 7th day following the operation. RESULTS: No patient showed any clinical manifestations of thromboembolic disease immediately after surgery or during a medium follow-up period of 16 months (range, 15-18 months). All hemostatic parameters values were within normal range in the basal samples of both groups. In both groups, the mean value of PA showed a significant decrease (p < 0.05) in the second, third, and fourth basal samples, returning to normal levels by the fifth determination. The mean value of fibrinogen decreased slightly in the second and third samples, increasing significantly with respect to the fourth and fifth determinations in both groups (p < 0.05). The mean value of APTT in both groups was slightly enhanced in the second and third determinations in relation to the first and fifth. The global activity of fibrinolysis (PFA and EFA) increased significantly in the third sample with respect to the other determinations in the group who had laparoscopic surgery (p < 0.005). Only EFA increased in the control group (p < 0.05). D-D decreased in the preoperative second determination followed by a significant enhancement immediate postoperatively (third), and 24 hs (fourth) (p < 0.05); it returned to normal basal values on the seventh day. No significant differences were found between the two groups. CONCLUSIONS: These results indicate that laparoscopic cholecystectomy leads to no greater activation of plasma coagulation than low-risk surgery. On the contrary, the increase of fibrinolytic activity in plasma would extend a certain degree of hypocoagulability during surgery, maintaining it for 24 hs and thus possibly reducing thromboembolic risk in patients undergoing this type of surgery.