Effects of rosiglitazone on serum paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus

Human serum paraoxonase contributes to the anti-atherogenic effect of high-density lipoprotein cholesterol (HDL-C) and has been shown to protect both low-density lipoprotein cholesterol (LDL-C) and HDL-C against lipid peroxidation. We investigated the effects of rosiglitazone on paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus [50 patients (30 males, 20 females); mean±SD age: 58.7±9.2 years, body mass index: 28.2±4.1'kg/m2], in whom glucose control could not be achieved despite treatment with metformin, sulphonylurea, and/or insulin. The patients were given 4'mg/day rosiglitazone for 3 months in addition to their usual treatment. Serum paraoxonase activity, malondialdehyde, homocysteine, and lipid profile were measured at the time of initiation and at the end of therapy with rosiglitazone. After rosiglitazone therapy, serum levels of HDL-C, apolipoprotein A-1, and paraoxonase activity increased significantly (P<0.05) and malondialdehyde, homocysteine, lipoprotein(a), and glucose levels decreased significantly (P<0.05), but no significant changes in levels of total cholesterol and apolipoprotein B were observed. Triglyceride levels also increased significantly (P<0.05). Rosiglitazone treatment led to an improvement in glycemic control and to an increase in paraoxonase activity and HDL-C levels. Although rosiglitazone showed favorable effects on oxidant/antioxidant balance and lipid profile, further studies are needed to determine the effect of rosiglitazone on cardiovascular risk factors and cardiovascular morbidity and mortality.

Effects of rosiglitazone on serum paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus.

Human serum paraoxonase contributes to the anti-atherogenic effect of high-density lipoprotein cholesterol (HDL-C) and has been shown to protect both low-density lipoprotein cholesterol (LDL-C) and HDL-C against lipid peroxidation. We investigated the effects of rosiglitazone on paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus [50 patients (30 males, 20 females); mean ± SD age: 58.7 ± 9.2 years, body mass index: 28.2 ± 4.1'kg/m2], in whom glucose control could not be achieved despite treatment with metformin, sulphonylurea, and/or insulin. The patients were given 4'mg/day rosiglitazone for 3 months in addition to their usual treatment. Serum paraoxonase activity, malondialdehyde, homocysteine, and lipid profile were measured at the time of initiation and at the end of therapy with rosiglitazone. After rosiglitazone therapy, serum levels of HDL-C, apolipoprotein A-1, and paraoxonase activity increased significantly (P<0.05) and malondialdehyde, homocysteine, lipoprotein(a), and glucose levels decreased significantly (P<0.05), but no significant changes in levels of total cholesterol and apolipoprotein B were observed. Triglyceride levels also increased significantly (P<0.05). Rosiglitazone treatment led to an improvement in glycemic control and to an increase in paraoxonase activity and HDL-C levels. Although rosiglitazone showed favorable effects on oxidant/antioxidant balance and lipid profile, further studies are needed to determine the effect of rosiglitazone on cardiovascular risk factors and cardiovascular morbidity and mortality.

Long-term MRI findings in neuromyelitis optica: seropositive versus seronegative patients.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) is a severe demyelinating inflammatory disorder associated with serum antibodies against aquaporin 4 (AQP4-Ab). A significant number of patients with NMO remain seronegative over time. Long-term observational magnetic resonance imaging (MRI) studies of the CNS in patients with NMO are rare or of limited duration. The objective of this study is to determine long-term MRI characteristics of seropositive and seronegative patients, and assess possible overlap with multiple sclerosis (MS). METHODS: Clinical and radiological characteristics of 28 patients with NMO at onset and of 17 patients after an average follow-up time of 9 years were recorded. Fifty percent of patients were seropositive for AQP4-Ab. Onset and final brain/spinal MRI scans were retrospectively analysed and compared. RESULTS: Significantly more patients in the seronegative group had brain lesions at onset. Spinal lesions of seropositive patients were longer and showed increased cord swelling at onset MRI scans. After the follow-up time the differences between both groups disappeared. Patients in the seropositive group tended to develop brain lesions over time. No patient fulfilled Barkhof's or McDonald's radiological criteria for MS at onset or over time. CONCLUSION: Brain MRI features show differences between seropositive and seronegative patients at time of onset in NMO, but differences between groups vanish over time. None of the AQP4-negative patients fulfill radiological MS criteria on a long-term basis, suggesting that seronegative NMO constitutes an independent entity.

DTI findings during spontaneous migraine attacks.

PURPOSE: Previous functional neuroimaging studies showed that the brainstem may have an important role in migraine and recently, DTI studies demonstrated that structural alterations in migraineurs may extend beyond the normal appearing brain tissue. The aim of our study was to find out if DTI may detect any abnormality during the spontaneous migraine attacks. METHODS: The DTI images obtained in a 3T system during spontaneous migraine episodes. Patients with any systemic or metabolic disorder and abnormal signal intensity in conventional sequences were excluded. We measured the FA and ADC values of red nuclei, periaquaductal gray matter, thalami, posterior limbs of internal capsules and subcortical white matter. Fifteen healthy volunteers served as control group. RESULTS: Fourteen patients enrolled in the study. The only site where we found an abnormality was the red nuclei, where the ADC values in migraineurs were statistically higher than in healthy volunteers. There was no statistical correlation between the DTI measurements and patients' ages, duration of disease, frequency of attacks and localization of pain. CONCLUSION: Our findings supported the findings of previous functional neuroimaging studies, which concluded that the brainstem might have a role in the pathogenesis of a migraine episode. We think that the increase of ADC values in red nuclei may reflect vasogenic edema, which cannot be detected in conventional sequences. However, the exact underlying mechanism for this observation is unclear and we do not know whether these changes are responsible for triggering an attack or if they are the consequents of the attack itself.

The role of homocysteine, asymmetric dimethylarginine and nitric oxide in pre-eclampsia.

Nitric oxide (NO) contributes to vasodilatation that is observed during normal pregnancy. Hyperhomocysteinaemia (HHcy) is a vascular risk factor associated with placental microvascular diseases and pre-eclampsia. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (NOS) has been linked to endothelial dysfunction. Maternal ADMA has been reported to be higher in women with pre-eclampsia and HHcy leads to accumulation of ADMA. The aim of this presented study is to evaluate the alterations of plasma homocysteine, ADMA and NO levels in mild pre-eclampsia. A total of 40 pre-eclamptic women and 40 healthy controls were included into the study. Mean systolic and diastolic blood pressure, mean serum homocysteine and ADMA levels were significantly higher and NO level was lower in patients. Serum homocysteine, ADMA and NO levels found to be correlated among them and with blood pressure. In conclusion, we found that homocysteine and ADMA levels were increased and NO levels decreased in pre-eclampsia.

Serum levels of lipids, lipoproteins and paraoxonase activity in pre-eclampsia.

Serum paraoxonase 1 (PON1) activity and the oxidation of lipoproteins were investigated in 35 women with pre-eclampsia and in 35 healthy control women with normal pregnancies. Blood pressure, body mass index (BMI), serum levels of total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and lipoprotein (a) (Lp[a]), and PON1 activity were assessed. There were no significant between-group differences in subject age, gestational age at diagnosis of pre-eclampsia, BMI, serum total cholesterol, triglycerides, LDL and ApoB levels. Mean systolic and diastolic blood pressures and serum Lp(a) were significantly higher in subjects with pre-eclampsia than in controls. Mean serum HDL, ApoA1 and PON1 activity were significantly lower in subjects with pre-eclampsia compared with controls. In conclusion, lipids and oxidized lipoproteins may play important roles in the pathogenesis of pre-eclampsia.

The importance of paraoxonase 1 activity, nitric oxide and lipid peroxidation in hepatosteatosis.

This study evaluated the changes in oxidative status in hepatosteatosis patients in terms of lipid peroxidation, nitric oxide (NO) and paraoxonase 1 (PON1) activity. A total of 49 patients with hepatosteatosis (29 males and 20 females, mean age 47.2 +/- 3.6 years) and 25 healthy subjects (15 males and 10 females, mean age 46.1 +/- 3.2 years) were enrolled in the study. Serum PON1 was measured spectrophotometrically, malondialdehyde (MDA), an end-product of lipid peroxidation, was determined using the thiobarbituric acid method, and NO was assessed using the Griess reaction. Lipid and other biochemical parameters were determined by routine laboratory methods. PON1 activity and NO levels were significantly decreased and MDA levels significantly increased in hepatosteatosis patients compared with healthy subjects. PON1 activity was correlated with MDA level and NO level. In conclusion, oxidative stress seems significantly to suppress PON1 synthesis in hepatosteatosis patients. In addition, oxidative stress and oxidant-antioxidant imbalance may be part of the cytotoxic mechanisms leading to liver cell injury.

Relationship between leptin, insulin resistance, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in patients with chronic kidney disease.

This study examined the relationship between leptin, insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3) and insulin resistance in patients with chronic kidney disease (CKD). Levels of leptin, insulin, IGF-1, IGFBP-3 and common routine parameters were measured in 45 patients (23 males and 22 females) with CKD and 45 healthy controls matched for age, gender and body mass index. IGF-1 and IGFBP-3 levels were measured using a two-site immunoradiometric assay. Leptin levels were measured using an enzyme-linked immunosorbent assay. A homeostasis model assessment computer-solved model was used to assess insulin resistance (HOMA-IR). Levels of serum leptin, insulin, IGF-1, IGFBP-3 and HOMA-IR were significantly increased in patients with CKD compared with healthy subjects, whereas fasting blood glucose was not significantly different between the two groups. In patients with CKD, the serum leptin level was significantly correlated with IGF-1, IGFBP-3 and HOMA-IR. In conclusion, this study suggests that there is an interaction between leptin, IGF-1, IGFBP-3 and insulin resistance in patients with CKD.

The role of asymmetric dimethylarginine (ADMA) and leptin in hypertensive patients.

We investigated the role of leptin and asymmetric dimethylarginine (ADMA) in uncomplicated hypertension. We also investigated their relationship with insulin resistance and serum levels of several metabolic parameters, including homocysteine, lipoprotein(a) and malondialdehyde (MDA). A total of 34 untreated newly-diagnosed hypertensive patients (seven men and 27 women; mean age, 57.4 +/- 10.1 years) and 38 normotensive healthy subjects (20 men and 18 women; mean age, 55.9 +/- 8.7 years) were studied prospectively. Serum leptin, homocysteine, lipoprotein(a), MDA and insulin resistance (HOMA-IR) were significantly higher in hypertensive patients compared with normotensive subjects. There were no significant differences in ADMA, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 between the two groups. No correlation was found between serum ADMA and leptin levels. Our findings suggest that high serum leptin and homocysteine levels, oxidative stress and insulin resistance may be important risk factors for atherosclerosis among patients with uncomplicated hypertension.

Serum levels of leptin and homocysteine in women with polycystic ovary syndrome and its relationship to endocrine, clinical and metabolic parameters.

We examined the relationship between endocrine, clinical and metabolic parameters in 35 women (mean age 27.3 years) with polycystic ovary syndrome (PCOS) and 30 age- and body mass index-matched normal ovulatory women. In PCOS women, serum leptin, homocysteine, insulin, insulin-like growth factor-1, insulin-like growth factor binding protein-3 levels and the insulin resistance index (HOMA-IR) were significantly higher, while sex hormone-binding globulin and high-density lipoprotein cholesterol levels were lower compared with healthy women. Serum luteinizing hormone (LH), estradiol (E(2)), androstenedione, testosterone and dehydroepiandrosterone sulphate levels were found to be significantly higher in PCOS women compared with healthy women. The levels of E(2), LH and testosterone were positively correlated with leptin levels in PCOS women. Similarly, androstenedione levels and HOMA-IR were positively correlated with homocysteine levels and insulin levels were positively correlated with LH. We conclude that increased homocysteine levels, hyperandrogenaemia, insulin resistance and impaired lipid metabolism contribute to the risk of premature atherosclerosis in PCOS women.

Serum levels of leptin, insulin-like growth factor-I and insulin-like growth factor binding protein-3 in women with pre-eclampsia, and their relationship to insulin resistance.

The present study was carried out to compare serum levels of leptin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3), homeostasis model assessment--(pancreatic beta-cell function) (HOMA-(%B)) and homeostasis model assessment--(tissue insulin sensitivity) (HOMA-(%S)) in women with mild and severe pre-eclampsia and normotensive pregnant women; and to evaluate the possible relationships between these parameters in the pathogenesis of pre-eclampsia. Seventy-three women were divided into three groups: group A consisted of 20 normotensive pregnant women (NPW); group B consisted of 25 women with mild pre-eclampsia (MPE); and group C consisted of 28 women with severe pre-eclampsia (SPE). Serum level of leptin was measured by enzyme immunoassay using a commercial kit. Serum levels of IGF-I and IGFBP-3 were measured with a two-site immunoradiometric assay. Serum level of insulin was measured by the electrochemiluminescence immunoassay method. HOMA used indices of pancreatic beta-cell function and tissue insulin sensitivity. Differences between groups were compared by one-way analyses of variance and the post hoc Tukey-HSD test for multiple comparisons; however, when a variable was not normally distributed, the Mann-Whitney U test was used. Associations between variables were tested using Pearson's coefficient of correlation. Birth weight was significantly lower (p < 0.001) in the MPE and SPE groups than in the NPW group. Serum levels of leptin and insulin in women with SPE and MPE were significantly higher (p < 0.001) than in NPW. Serum levels of IGF-I and IGFBP-3 were significantly lower in women with SPE and MPE compared with NPW (p < 0.001). The mean HOMA-(%B) level in women with SPE and MPE was significantly higher than in NPW (p < 0.001), whereas the mean HOMA-(%S) level in women with SPE and MPE was significantly lower than in NPW (p < 0.001). In the SPE group, systolic blood pressure correlated significantly with serum levels of IGF-I and leptin (r = 0.375, p < 0.05 and r = 0.495, p < 0.01, respectively). A negative correlation between mean HOMA-(%S) level and serum IGFBP-3 level was noted (r = -0.357, p < 0.05). There was a positive correlation between serum level of IGF-I and mean HOMA-(%B) level in mildly pre-eclamptic women (r = 0.541, p < 0.01). We conclude that pre-eclampsia is associated with insulin resistance; and that existing hyperinsulinemia and insulin resistance in women with pre-eclampsia seem not to correlate with leptin and birth weight, but may correlate positively with IGF-1 and IGFBP-3. Therefore we think that hyperleptinemia, low IGF-I or IGFBP-3, and insulin resistance may contribute to the pathogenesis of pre-eclampsia.

Changes in serum levels of leptin, cytokines and lipoprotein in pre-eclamptic and normotensive pregnant women.

The aim of this study was to investigate the changes in serum levels of leptin, cytokines and lipoproteins in women with pre-eclampsia and to evaluate their clinical significance in the pathogenesis of pre-eclampsia. We performed a prospective study involving 45 women with pre-eclampsia in the third trimester of pregnancy and 30 normotensive women in the third trimester of pregnancy. Serum level of leptin was measured by enzyme immunoassay using a Cayman chemical kit. Serum levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, soluble IL-2 receptor (slL-2R), IL-6 and IL-8 were measured by using a non-radioimmunoassay chemiluminescent method. Serum lipid concentrations were measured by an Abbott Aeroset (USA) autoanalyzer. Serum levels of apolipoprotein (Apo)A-I and ApoB were evaluated by nephelometrics assays. Differences between groups were evaluated with Student's unpaired t test and, when a variable was not normally distributed, the Mann-Whitney U test was used. The relationship between the variable was explored by the Pearson correlation test. Serum levels of leptin, TNF-alpha, IL-1beta, sIL-2R, IL-6 and IL-8 in the pre-eclamptic women were significantly higher than in normotensive women (p < 0.001). In the pre-eclamptic women serum levels of triglycerides, total cholesterol and low-density lipoprotein (LDL)-cholesterol were significantly increased (p < 0.001), while high-density lipoprotein (HDL)-cholesterol and Apo-A were significantly decreased compared to levels in normotensive pregnant women (p < 0.001). No significant differences were noted between the groups in Apo-B (p > 0.05). Serum levels of TNF-alpha were significantly correlated with the serum levels of IL-6, IL-8, triglycerides, sIL-2R, Apo-A and hematocrit in pre-eclamptic women (r = 0.418, p < 0.05; r= 0.389, p < 0.01; r=0.312, p < 0.05; r= -0.318, p < 0.05; r= -0.340, p < 0.05 and r=0.41, p < 0.01, respectively). A negative correlation was seen between serum level of leptin and both IL-1beta and Apo-A in pre-eclamptic women (r=-0.44, p < 0.05; r=-0.39, p < 0.05, respectively). Serum levels of IL-6 were also significantly correlated with the serum levels of HDL-cholesterol, LDL-cholesterol and body mass index (BMI) in pre-eclamptic women (r=0.40, p < 0.01; r=-0.568, p < 0.01; r= -0.30, p < 0.05, respectively). In addition, serum level of IL-8 were significantly correlated with the serum levels of HDL-cholesterol, total cholesterol and BMI in pre-eclamptic women (r= 0.368, p < 0.05; r=0.513, p < 0.01 and r= -0.41, p < 0.01, respectively). We found that the pre-eclampsia associated with increases in serum levels of leptin, TNF-alpha, cytokines, triglycerides, total cholesterol and LDL-cholesterol was associated with a significant reduction in serum levels of HDL-cholesterol and Apo-A. These association may be due to the abnormal lipid metabolism and immune activation involved in the pathogenesis of this disease.

An expert system for fault management assistance on a space sleep experiment.

The expert system, Principal Investigator-in-a-box, or [PI], was designed to assist astronauts or other operators in performing experiments outside their expertise. Currently, the software helps astronauts calibrate instruments for a Sleep and Respiration Experiment without contact with the investigator on the ground. It flew on the Space Shuttle missions STS-90 and STS-95. [PI] displays electrophysiological signals in real time, alerts astronauts via the indicator lights when a poor signal quality is detected, and advises astronauts how to restore good signal quality. Thirty subjects received training on the sleep instrumentation and the [PI] interface. A beneficial effects of [PI] and training reduced troubleshooting time. [PI] benefited subjects on the most difficult scenarios, even though its lights were not 100% accurate. Further, questionnaires showed that most subjects preferred monitoring waveforms with [PI] assistance rather than monitoring waveforms alone. This study addresses problems of complex troubleshooting and the extended time between training and execution that is common to many human operator situations on earth such as in power plant operation, and marine exploration.

Significance of changes in lipid peroxides and antioxidant enzyme activities in pregnant women with preeclampsia and eclampsia.

This review addresses the general hypothesis that the pathogenesis of preeclampsia and eclampsia are related to an imbalance of increased oxidative stress and lipid peroxidation coupled with a deficiency of antioxidant protection. Accordingly, this study was initiated to assess total antioxidant status and free-radical activity in preeclampsia and eclampsia. The patients studied were 44 healthy pregnant women and 45 women with hypertension classified as having preeclampsia (n=27), and eclampsia (n=18). The serum levels of lipid peroxide were significantly increased (p<0.0001) and antioxidant enzyme activities (superoxide dismutase and glutathione levels) in erythrocytes were significantly decreased (p<0.0001) in women with preeclampsia and eclampsia compared with the controls. The groups of preeclampsia and eclampsia had similar values of catalase activities as the controls (p>0.05). There were no correlations between serum levels of lipid peroxide and antioxidant enzyme activities or systolic-diastolic blood pressure of pregnant women with preeclampsia and eclampsia. The mean systolic and diastolic blood pressure, the serum lactate dehydrogenase (LDH) and aspartate transaminase (AST) levels of preeclamptic and eclamptic women were high, whereas haemoglobin (Hb), Hematocrit (Htc) and platelet levels were lower than those of the control subjects (p<0.0001). There were no differences in mean gestational week, whereas the mean age of eclamptic women was lower than that of the other two groups (p<0.001). The serum levels of Alanine-transaminase (ALT) and urea in eclamptic women were significantly higher compared with the other two groups (p<0.0001), whereas creatinine levels were lower than those of the other two groups (p<0.05). Our findings give support to those few studies considering lipid peroxidation as an important factor in the pathogenesis of preeclampsia and eclampsia. Further studies are needed to clarify the relations between lipid peroxidation and antioxidative function and their pathophysiological significance in preeclampsia and eclampsia.