Rates of lipid fluxes in adipose tissue in vivo after a mixed meal in morbid obesity.

OBJECTIVE: Although insulin resistance in obesity is established, information on insulin action on lipid fluxes, in morbid obesity, is limited. This study was undertaken in morbidly obese women to investigate insulin action on triacylglycerol fluxes and lipolysis across adipose tissue. SUBJECTS AND DESIGN: A meal was given to 26 obese (age 35+/-1 years, body mass index 46+/-1 kg m(-2)) and 11 non-obese women (age 38+/-2 years, body mass index 24+/-1 kg m(-2)). Plasma samples for glucose, insulin, triglycerides and non-esterified fatty acids (NEFAs) were taken for 360 min from a vein draining the abdominal subcutaneous adipose tissue and from the radial artery. Adipose tissue blood flow was measured with (133)Xe. RESULTS: In obese vs non-obese: (1) Arterial glucose was similar, but insulin was increased (P=0.0001). (2) Adipose tissue blood flow was decreased (P=0.0001). (3) Arterial triglycerides (P=0.0001) and NEFAs (P=0.01) were increased. (4) Lipoprotein lipase was decreased (P=0.0009), although the arteriovenous triglyceride differences were similar. (5) Veno-arterial NEFA differences across the adipose tissue were similar. (6) NEFA fluxes and hormone-sensitive lipase-derived glycerol output from 100 g adipose tissue were not different. (7) Total adipose tissue NEFA release was increased (P=0.02). CONCLUSIONS: In morbid obesity: (a) hypertriglycerinemia could be attributed to a defect in the postprandial dynamic adjustment of triglyceride clearance across the adipose tissue, partly caused by blunted BF; and (b) postprandially, there is an impairment of adipose tissue to buffer NEFA excess, despite hyperinsulinemia.

Testicular function in poor-risk nonseminomatous germ cell tumors treated with methotrexate, paclitaxel, ifosfamide, and cisplatin combination chemotherapy.

Our objective was to investigate the impact of methotrexate, paclitaxel, ifosfamide, and cisplatin (M-TIP) on long-term fertility in poor-risk nonseminomatous germ cell tumors (NSGCT). Thirty patients with poor-risk NSGCT (median age, 29 years; range, 17-62 years) were treated with methotrexate 250 mg/m(2) with folinic acid rescue (day 1) and paclitaxel 175 mg/m(2) (day 1), followed by ifosfamide 1.2 g/m(2) and cisplatin 20 mg/m(2) (days 2-6). Treatment consisted of 4 cycles of M-TIP administered every 3 weeks. Twenty-one patients were continuously disease-free at a median follow-up of 5.3 years (range, 0.9-8.4 years). Sperm count and hormonal analyses were examined prechemotherapy (30 patients) and postchemotherapy (21 patients). Counts were classified as follows: lower than 1 x 10(6)/mL, azoospermia; 1-20 x 10(6)/mL, oligospermia (OS); higher than 20 x 10(6)/mL, normospermia (NS). Patients were followed for a median of 2.3 years (range, 0.9-3.8 years) postchemotherapy. The prechemotherapy median luteinizing hormone (LH) serum levels were slightly above the upper normal limit, whereas the serum levels of follicle-stimulating hormone (FSH) and testosterone (T) were within the reference interval. Eleven (52.3%) patients had NS prechemotherapy. Among the patients with NS, 72.7% still had NS following chemotherapy. Overall, 17 of 21 (80.9%; 33.3% OS and 47.6% NS) patients had recovery of spermatogenesis after treatment. The median FSH serum levels were significantly elevated at least 1 year postchemotherapy when compared with the pretreatment levels. Eighteen months after the completion of chemotherapy the median FSH levels had returned to the reference limits. Serum LH and T levels were unaffected by chemotherapy. Prior to chemotherapy 4 of 30 patients had fathered 5 children. Since completion of chemotherapy, 5 patients have fathered 5 children. The majority of men with poor-risk germ cell tumors who were treated with the M-TIP regimen demonstrated recovery spermatogenesis after treatment, and Leydig cell function was unaffected.

Functional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis.

BACKGROUND & AIMS: The role of the interleukin (IL)-1 receptor antagonist (IL-1ra) in predisposing an individual to inflammatory bowel disease (IBD) is controversial. This study aimed to determine the association between intron 2 IL-1ra polymorphism and IBD by performing a multiethnic case-control study and to assess its functional significance. METHODS: A total of 236 patients with ulcerative colitis (UC), 196 patients with Crohn's disease (CD), and 338 ethnically matched control patients treated at LAC-USC and Cedars-Sinai Medical Centers and the University of Milan Medical Center were genotyped for a variable length polymorphism in intron 2 of the IL-1ra gene (IL-1RN). Total IL-1ra protein production rates in peripheral blood mononuclear cells (PBMCs) were correlated with carriage of allele 2 of the IL-1RN gene (IL-1RN*2). RESULTS: In the LAC-USC group, UC patients (n = 60) had an increased frequency of at least 1 copy of IL-1RN*2 compared with controls (n = 129) (70% vs. 33%; P < 0.01; odds ratio [OR], 4.7). The frequency of IL-1RN*2 carriage in the Cedars-Sinai group was 59% in UC, 45% in CD, and 42% in controls (P < 0.01; OR, 2.0). A significant difference was observed only in the Jewish subgroup (P = 0.003; OR, 5.0). The association was not detected in UC or CD patients treated at the University of Milan. The ORs of 4.7 and 5.0 appear to be the highest reported in any UC population for any genetic markers. Further, carriage of IL-1RN*2 was associated with decreased production of total IL-1ra protein in cultured PBMCs from both UC patients and controls. CONCLUSIONS: These results provide further evidence that IL-1ra is important in the predisposition to UC, there may be genetic or pathogenetic heterogeneity between different ethnic groups, and UC and CD are genetically distinct diseases.

Long-term effectiveness of a new alpha-glucosidase inhibitor (BAY m1099-miglitol) in insulin-treated type 2 diabetes mellitus.

In a double-blind, randomized study, miglitol (BAY m 1099), an alpha-glucosidase inhibitor, 100 mg tds or placebo was given orally with meals for a period of 24 weeks in 117 patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) treated with insulin. Fasting and 1 h postprandial plasma glucose and C-peptide were measured at the beginning and at the end of each 4-week interval and glycosylated haemoglobin was determined at day 0 and at the end of the 12th and 24th week. One hour postprandial plasma glucose was significantly lower in the miglitol group at the end of the 24th week (placebo: 11.6 +/- 1.5 vs miglitol: 8.2 +/- 1.5 mmol l-1, mean +/- SD, p = 0.001). Diabetes control improved in the same group as the HbA1 was lowered by 16% (p = < 0.0001) at the end of the treatment. Mild reversible adverse effects were observed in 37 patients of the miglitol group (mainly flatulence and mild hypoglycaemia) and 2 of the placebo group. Urinary glucose was rendered negative in 41 patients in the miglitol group only. Thus miglitol appears to be a safe and effective adjunct in the management of Type 2 DM, in association with insulin.

Coronary microcirculation evaluation with transesophageal echocardiography Doppler in type II diabetics.

Evaluation of coronary microvascular function can be obtained through coronary flow reserve measurements. The aim of this study was to evaluate the coronary microvascular function by using transesophageal-Doppler echocardiographic assessment of coronary flow reserve. The study included 32 normotensive patients with type II diabetes mellitus (group A) of short duration (6.1+/-3.8 years) aged 55.4+/-9.4 years and 14 healthy volunteers matched for age, gender and BMI (group B). No patients had clinical evidence of coronary artery disease and all of them produced a negative recent stress ECG test. Excluded from the study were patients with anemia, left ventricular hypertrophy, arrhythmia, congenital, or acquired structural heart disease. All subjects underwent transesophageal-Doppler echocardiography. Satisfactory coronary blood flow velocity recordings could be obtained from the initial segment of the left anterior descending coronary artery in healthy volunteers and in 27 patients at baseline and 2 min after dipyridamole infusion (0.56 mg/kg, for 4 min). In the remaining 5 patients no satisfactory recordings were available. The indexes of coronary flow reserve, i.e. the ratios of dipyridamole over basal maximum and mean diastolic velocities were calculated. Dipyridamole/rest maximal coronary reserve (Table 3) was 1.946+/-0.743, while this ratio for the mean diastolic velocity was 1.969+/-0.805 in group A. The respective values for group B, were 2.811+/-0.345 (P=0.000 vs. group A) and 2.914+/-0.303 (P=0.000 vs. group A). Thus, the increase in coronary flow reserve although present in both groups, it was more impressive in the normal group. Multiple regression logistic analysis of: age, sex, smoking, glucosylated hemoglobin, duration of diabetes and type of therapy, did not show any correlation of these parameters with the above ratios. This study shows that coronary flow reserve, as measured with transesophageal echocardiography-Doppler, is severely impaired in normotensive patients with type II diabetes, with relatively short duration of the disease.

A new syndrome of Crohn's disease and pachydermoperiostosis in a family.

Few syndromic associations with Crohn's disease are described. The aim of this study was to characterize a new syndrome of Crohn's disease associated with pachydermoperiostosis in 3 brothers. Three probands, 6 siblings, both parents, 20 of 21 third-generation relatives, and 9 spousal controls were evaluated. Serological evaluation for antineutrophil cytoplasmic antibodies and human leukocyte antigens as well as genetic testing for tumor necrosis factor microsatellites, intercellular adhesion molecule 1 polymorphisms, the interleukin 1 receptor antagonist gene, and the interleukin 1 beta gene were performed. Only the 3 probands were affected and developed pachydermoperiostosis between ages 14 and 17 years. Pachydermoperiostosis preceded Crohn's ileocolitis by 6 and 20 years in two probands, excluding secondary hypertrophic osteoarthropathy. Two probands were antineutrophil cytoplasmic antibody positive vs. 1 of 27 unaffected relatives (P < 0.001, chi 2). Haplotypes for human leukocyte antigen and tumor necrosis factor microsatellites were discordant. The probands' generation was homozygous for the common allele 1 of the interleukin 1 receptor antagonist and interleukin 1 beta genes. Two probands carried a rare polymorphism of the intercellular adhesion molecule 1 gene. A new syndrome of Crohn's disease and pachydermoperiostosis associated with antineutrophil cytoplasmic antibodies is described. Inheritance is most likely autosomal recessive by pedigree. No clear association was found between this syndrome and the gene regions evaluated.

Therapeutic effect of glibenclamide in a fixed combination with metformin or phenformin in NIDDM patients.

The combination of a sulfonylurea with a biguanide improves the pancreatic beta-cell insulin secretion and the insulin utilization in peripheral tissues in NIDDM. This open, crossover, randomised and prospective study was designed to compare the effects of the fixed combination glibenclamide-metformin (GL-METF)-2.5 and 400 mg respectively, with the fixed combination glibenclamide-phenformin (GL-PHEN)-2.5 and 25 mg respectively, on NIDDM diabetes control. Thirty NIDDM patients, in ideal metabolic control, who were being treated with GL-PHEN were divided in two groups. One group received GL-PHEN for 12 weeks followed by 12 weeks treatment with GL-METF and the reverse treatment was given to the second group. A statistically significant decrease of post-prandial blood glucose (p = 0.034) and glycosylated haemo-globin (p < 0.02) values was observed under GL-METF treatment compared to those with GL-PHEN. The values of lactic acid were within normal limits during both treatments. The insulin secretion after breakfast was similar with both drug compounds. The BMI of the patients remained the same during a follow-up study of 24 weeks. Lipid metabolism did not change significantly during the trial and the safety parameters (renal and liver function, full blood count) remained unchanged. In conclusion, the administration of GL-METF leads to better diabetes control in NIDDM patients compared to that of GL-PHEN.

Globin chain synthesis in myelodysplastic syndromes.

Globin chain synthesis was studied in the reticulocytes of 30 patients with various myelodysplastic syndromes (MDS) to determine the alpha:beta globin chain synthetic ratio and its probable prognostic value. The mean (SD) value of the total alpha:beta ratio was 0.82 (0.45) ranging from 0.05 to 1.73. The same ratio in 10 normal controls was 1.01 (0.04). This difference was significant. Furthermore, the alpha:beta ratios were lower than normal in 14 patients (alpha-thalassaemia-like) (group I), almost within normal limits in 11 (group II), and higher than normal in five (beta-thalassaemia-like) (group III). In each group almost all the FAB subtypes were represented. The addition of exogenous haem in several of the test samples resulted in a slight to pronounced increase in the alpha:beta ratios, particularly in group I. In 92% of the high risk cases (refractory anaemia with excess blasts (RAEB), chronic myelomonocytic leukaemia (CMML] or 87.5% of patients who finally developed acute non-lyphoid leukaemia (ANLL) low or normal alpha:beta ratios were found. No significant correlation was noticed between alpha:beta ratios and various haematological variables or survival. It is concluded that in MDS the alpha:beta ratio varied enormously across the entire population of patients, as well as within each FAB subtype, thereby restricting its prognostic value. Although haem deficiency may be implicated in some cases of MDS, why this should be remains unclear.

Comparative study of the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide or chlorpropamide.

This study was designed to compare the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide, chlorpropamide or biguanides in non-insulin-dependent diabetes. It is divided into two parts: a) in the retrospective study (473 subjects), glucose control of patients who were transferred from chlorpropamide, gliclazide, glibenclamide, glibenclamide + biguanide or metformin to the fixed combination glibenclamide-phenformin in the same tablet (2.5 mg and 25 mg, respectively) was monitored. A statistically significant decrease of blood glucose and glycosylated hemoglobin values was found under the combination of glibenclamide-phenformin contained in the same tablet in contrast to the values obtained with the treatment with glibenclamide, gliclazide, chlorpropamide, combination of glibenclamide and biguanides, metformin, and insulin. b) In the prospective study (57 subjects), the patients were transferred from chlorpropamide or gliclazide to glibenclamide for 3 months and then reallocated to the previous treatment for 3 additional months. It was found that under glibenclamide, glucose control was significantly better than under chlorpropamide or gliclazide. In conclusion, glibenclamide, a second generation sulfonylurea, and the fixed combination glibenclamide-phenformin in the same tablet are more effective compared to the other antidiabetic agents here studied and lead to a better control of type II diabetic patients. There was no increase in plasma lactic acid concentration in all patients studied before and after having received the fixed combination of glibenclamide-phenformin in the single tablet form.