Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity

OBJECTIVE: To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome (PCOS), without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone. DESIGN: Randomized controlled double-blind trial. SETTING: A referral center in Caracas, Venezuela. PATIENT(S): One hundred twenty-eight nonobese PCOS women with normal indices of insulin sensitivity-that is, normal glucose tolerance, fasting insulin, peak insulin during an oral glucose tolerance test (OGTT), and fasting glucose-to-insulin ratio. Twenty-eight women were lost to follow-up initially and did not receive any intervention. INTERVENTION(S): One hundred women received twice daily one of the following for 6 months: metformin (850 mg), rosiglitazone (4 mg), combination of both drugs, or at least one placebo. MAIN OUTCOME MEASURE(S): Frequencies of ovulation and serum free T after 6 months. RESULT(S): Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug (ovulations per subject in 6 months: metformin, 3.3; rosiglitazone, 2.4; and combination, 3.4) than with placebo (0.4). Ovulatory frequencies increased significantly more with metformin than rosiglitazone, and the combination was not more potent. After treatment, serum free-T levels were comparable among all active treatment groups (metformin: 2.34 pg/mL, rosiglitazone: 3.06 pg/mL, and combination: 2.39 pg/mL) and were significantly lower than in the placebo group (7.26 pg/mL). Compared with placebo, fasting insulin levels, area under the insulin curve during OGTT, the homeostatic model assessment of insulin sensitivity, and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone. CONCLUSION(S): These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyperandrogenemia, even in nonobese women with PCOS who appear to have normal insulin sensitivity.     

Stability of leukemia-associated aberrant immunophenotypes in patients with acute myeloid leukemia between diagnosis and relapse: comparison with cytomorphologic, cytogenetic, and molecular genetic findings

BACKGROUND: Multiparameter flow cytometry is increasingly used to monitor minimal residual disease in patients with acute myeloid leukemia to identify leukemic cells by leukemia-associated aberrant immunophenotypes (LAIPs). Changes in LAIPs during the course of the disease may be a limitation for this approach. METHODS: We analyzed 49 patients at diagnosis and relapse by flow cytometry, cytomorphology, cytogenetics, and molecular genetics. RESULTS: In 37 patients (76%), at least one LAIP detectable at diagnosis was present at relapse; in 12 patients (24%), none of the original LAIPs were present in at least 1% of bone marrow cells. Three groups were identified: no change in LAIPs, partial changes in LAIPs, and complete change in LAIPs. There were significant differences across these groups with regard to changes in cytomorphology (11%, 40%, and 58% of all cases, respectively; P = 0.007), cytogenetics (15%, 20%, and 25%; not significant), and molecular genetics (18%, 0, and 86%; P = 0.002). CONCLUSIONS: These data indicate that, in a subset of patients with acute myeloid leukemia, the disease is biologically different at relapse; therefore, monitoring of minimal residual disease is difficult to accomplish. In most patients with acute myeloid leukemia, multiparameter flow cytometry may be used to monitor minimal residual disease.     

Temperature-independent Inhibition of L-type calcium currents by halothane and sevoflurane in human atrial cardiomyocytes

BACKGROUND: Cardiac L-type calcium currents (ICa,L) are affected by volatile anesthetics, possibly contributing to their side effects. Actions of anesthetics on ion channels are usually studied in vitro at room temperature. However, the solubility of anesthetic gases as well as ICa,L are markedly sensitive to the study temperature. Therefore, temperature-dependent effects of halothane and sevoflurane on cardiac ICa,L were analyzed. METHODS: ICa,L were studied at 21 degrees C and 36 degrees C with the patch clamp technique in isolated human atrial cardiomyocytes. Concentrations of anesthetics brought into solution by gassing at both temperatures were determined with gas chromatography. RESULTS: The aqueous concentrations of halothane and sevoflurane were linearly related to their concentration in the gas phase (1 to 3 minimum alveolar concentration [MAC]). At 21 degrees C, the slope of this relation was 0.52 and 0.12 mm/vol % for halothane and sevoflurane, respectively, and decreased at 36 degrees C to 0.29 and 0.09 mm/vol %, respectively. ICa,L displayed significantly higher current amplitudes at 36 degrees C than at 21 degrees C and significantly accelerated time-dependent inactivation. Halothane (1-2 MAC) and sevoflurane (1-3 MAC) evoked stronger inhibitions of ICa,L at 21 degrees C than at 36 degrees C. In spite of different temperature-dependent current amplitudes, the fractional (percent) inhibition of ICa,L showed the same linear relationship to the concentrations of halothane and sevoflurane in the bath medium at both temperatures, as revealed from present and previous experiments. CONCLUSIONS: Inhibition of ICa,L by halothane and sevoflurane is determined by the aqueous concentration of the anesthetics, independently of the temperature. Increased solubility may explain the stronger effects of the anesthetics at lower temperatures.     

Seizures after a Bier block with clonidine and lidocaine

A 47-yr-old man with history of complex regional pain syndrome type 1 underwent an IV Bier block with a mixture of lidocaine and clonidine. The tourniquet was deflated after 60 min, and approximately 10 min later he presented with complex partial seizures. The possible mechanisms for this are discussed, and the effects of clonidine, lidocaine, and the mixture of both are reviewed, as are four additional published cases reporting seizures after the administration of clonidine.     

Numerical simulation of electroporation in spherical cells

This article presents a numerical study of the electroporation process of spherical cells suspended in an electrolyte solution, using the equivalent circuit method (ECM) for field calculation proposed by Ramos et al. A model for the electric conductance of the cell membrane derived from the analytical and experimental results obtained by Glaser et al. for planar lipidic membranes was applied. The influence of the cell concentration and membrane properties (described in the model) on the membrane current, membrane potential, and dependence of the electrolyte conductivity on the applied electric field was studied. These results clarify the electric events connected with the pore opening process and allow the planning of experimental approaches to study reversible membrane rupture in real cells.     

Partial versus Total Adrenalectomy by the Posterior Retroperitoneoscopic Approach: Early and Long-term Results of 325 Consecutive Procedures in Primary Adrenal Neoplasias

The retroperitoneoscopic approach is a standardized operative procedure for primary adrenal gland tumors. It allows direct access with a detailed view of the adrenal gland. Thereby, a clear differentiation between normal and neoplastic adrenal tissue is often possible, which permits a planned partial resection of the gland in selected cases. Between July 1994 and November 2003 325 posterior retroperitoneoscopic adrenalectomies were performed for primary benign adrenal gland tumors (106 Conns adenomas, 83 pheochromocytomas, 76 Cushings adenomas, 60 nonfunctioning tumors; size: 2.8 ± 1.5 cm; site: 160 right, 165 left) in 318 patients (122 M, 196 F, age: 49.0 ± 14.3 years). In 96 patients 100 tumors were removed by partial adrenalectomy (30 Conns adenomas, 33 pheochromocytomas, 20 Cushings adenomas, 17 nonfunctioning tumors; site: 61 right, 59 left) maintaining tumor-free parts of the adrenal gland. Of this group, 15 patients suffered from bilateral adrenal neoplastic diseases. During the same period, 225 total adrenalectomies (76 Conns adenomas, 50 pheochromocytomas, 56 Cushings adenomas, 34 nonfunctioning tumors; site: 109 right, 116 left) were performed in 224 patients. There was no mortality. Major complications were seen in 1.8%, minor complications in 14.5%. Three conversions were necessary to an open or a laparoscopic approach (2 patients and 1 patient, respectively). There are no differences between the two groups (total versus partial adrenalectomy) with regard to tumor size (2.8 ± 1.6 cm versus 2.8 ± 1.5 cm), operating time (80 ± 44 minutes versus 79 ± 42 minutes), and blood loss (33 ± 71 ml versus 29 ± 31 ml). In all patients with partial adrenalectomy, biochemical healing was proven. Fourteen of 15 patients with bilateral diseases had preservation of adrenocortical function. After a mean follow up of 51 months (range: 7–120 months) local recurrence or relapse of the initial diseases was noticed in 6 patients after total adrenalectomy: in 4 patients with Conns syndrome and bilateral hyperplasia, and in 2 patients with malignant pheochromocytoma and adrenocortical carcinoma, respectively. Our data demonstrate that partial adrenalectomy is a safe procedure not only perioperatively but also in the long-term follow-up.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden, June 14–17, 2004.     

Normalization of multiple hemostatic abnormalities in uremic type 1 diabetic patients after kidney-pancreas transplantation

To evaluate the effects of kidney-pancreas transplantation on hemostatic abnormalities in uremic type 1 diabetic patients, we conducted a cross-sectional study involving 12 type 1 diabetic patients, 30 uremic type 1 diabetic patients, 27 uremic type 1 diabetic patients who had a kidney-pancreas transplant, 12 uremic type 1 diabetic patients who had a kidney-alone transplant, and 13 healthy control subjects. We evaluated platelet and clotting system. Platelets in the group of uremic type 1 diabetic patients were significantly larger than platelets in the other groups. Resting calcium levels were significantly higher in the uremic type 1 diabetic patients and uremic type 1 diabetic patients who had a kidney-alone transplant than in the type 1 diabetic patients who had a kidney-pancreas transplant and control subjects. CD41 expression was significantly reduced in platelets from the uremic type 1 diabetic patients compared with the other groups. Levels of hypercoagulability markers in the type 1 diabetic patients who had a kidney-pancreas transplant and, to a lesser extent, the uremic type 1 diabetic patients who had a kidney-alone transplant but not the uremic type 1 diabetic patients were similar to those of the control subjects. A reduction in natural anticoagulants was evident in the uremic type 1 diabetic patients, whereas near-normal values were observed in the type 1 diabetic patients who had a kidney-pancreas transplant and uremic type 1 diabetic patients who had a kidney-alone transplant. Hemostatic abnormalities were not observed in type 1 diabetic patients who had a kidney-pancreas transplant. This finding might explain the lower cardiovascular death rate observed in type 1 diabetic patients who had a kidney-pancreas transplant compared with uremic type 1 diabetic patients who had a kidney-alone transplant or uremic type 1 diabetic patients.     

Cognitive and emotional alterations in periadolescent mice exposed to 2 g hypergravity field

The development of the nervous system is a dynamic process where epigenetic factors play a fundamental role. Both ground-based and space research indicate that exposure to an altered gravitational environment affects rodent neurobehavioral profile and stage of development as well as duration of exposure appear to be critical for the observed effects. The behavioral profile of adolescent (28-day-old) male and female CD-1 mice upon acute 2 g exposure was characterized and emotional/anxiety responses (plus-maze), as well as spatial learning performance (Morris water-maze), were assessed respectively 24 and 48 h after hypergravity exposure. Behavioral observation indicated a transient mild sickness associated with hypergravity, with a decrease in spontaneous activity. Rotation per se induced an increase in emotional/anxious responses and a deterioration of spatial learning acquisition, while hypergravity specifically improved flexibility of spatial orientation.     

Non-invasive diagnosis of Helicobacter pylori infection: simplified 13C-urea breath test, stool antigen testing, or DNA PCR in human feces in a clinical laboratory setting?

OBJECTIVES: (1) To compare two stool antigen EIAs (HpSA, FemtoLab) and PCR of ureaseA and cagA in feces, with (13)C-urea breath test (UBT). (2) To ascertain whether a simplified UBT (breath collection time = 10 min) is as reliable as the standard assay (30 min). DESIGN AND METHODS: Helicobacter pylori status was recorded in Group 1 (n = 187) by UBT, H. pylori stool antigen, ureA and cagA PCR in feces. UBT with 10, 20 and 30 min sampling was performed in Group 2 patients (n = 283). RESULTS: The sensitivity and specificity of HpSA, FemtoLab, and ureA were 67% and 99%, 90% and 96%, 35% and 98%, respectively. cagA results were positive in 16/48 H. pylori-positive, and in 5/100 H. pylori-negative patients. The results of UBT with a 10- and 30-min sampling strictly overlapped. CONCLUSION: UBT with 10 min breath collection and FemtoLab stool antigen assay are the most reliable non-invasive tests to diagnose H. pylori infection.