Paraoxonase, oxidized low density lipoprotein, monocyte chemoattractant protein-1 and adhesion molecules are associated with macrovascular complications in patients with type 2 diabetes mellitus.

AIM: The aim of this paper was to evaluate the association between blood glucose, oxidative stress, inflammation, endothelial dysfunction and paraoxonase activity as contributors to the accelerated atherosclerosis seen in type 2 diabetic patients. METHODS: Plasma malondialdehyde (MDA), oxidized LDL (oxLDL), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cellular adhesion molecule-1 (VCAM-1) levels and paraoxonase-1 (PON1) activity were measured in sixty type 2 diabetic patients, 30 of whom had macrovascular complications, and 30 controls. RESULTS: Diabetics with macrovascular complications had higher levels of MDA, oxLDL, MCP-1, ICAM-1, VCAM-1 than those without, and the difference was significant for all molecules except for ICAM-1. PON1 activity and ApoA1 levels of the controls were significantly higher than that of the patients, while PON1 activity and ApoA1 levels in the patients with macrovascular complications were significantly lower than that in patients without. Ambient plasma glucose concentration showed a significant positive association with plasma MDA, oxLDL, MCP-1, and VCAM, and a significant inverse association with PON1 and ApoA1 in diabetic patients. A significant positive correlation between oxLDL and MDA, a negative correlation between oxLDL and PON1; a significant inverse association between MDA and PON1; a positive correlation between MDA and MCP-1 and VCAM while a negative correlation between PON1 and MCP-1 and VCAM were detected in patients. CONCLUSION: Hyperglycemia might play a significant role in generating increased oxidative stress, and decreased PON1 activity, resulting in elevated oxLDL, MCP-1 and VCAM levels. This might be one of the causal pathogenic factors initiating accelerated atherosclerosis in patients with type 2 diabetes mellitus. The implication of these findings are unclear and therefore further studies are required.

Recurrent Cushing's syndrome after adrenal autotransplantation.

Adrenalectomy with adrenal autotransplantation used to be performed frequently for Cushing's disease in the past because of the limitations of conventional radiological techniques and the lack of adequate neurosurgical techniques. Today, however, bilateral adrenalectomy may be still required for selective patients with Cushing's syndrome when partial hypophysectomy has failed to control hypercortisolism or the source for ectopic ACTH syndrome could not be determined. Here, we report a case of recurrent Cushing's syndrome due to a pituitary adenoma, who was treated with bilateral adrenalectomy and autotransplantation for her Cushing's syndrome. Having determined pituitary adenoma as the cause of recurrent Cushing's syndrome after endocrinological investigations and imaging, we were able to treat the patient with transsphenoidal adenomectomy. We suggest that transsphenoidal resection of the adenoma rather than excision of the autotransplants and adrenal remnants should be the preferred treatment method for recurrent Cushing's disease.

Relationship between serum concentrations of interleukin-6 and tumor necrosis factor alpha in female Turkish subjects with normal and impaired glucose tolerance.

Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) concentrations were measured in subjects during two-hour glucose loading in order to investigate the effects of glucose on serum IL-6 and TNFalpha concentrations. Twenty-six female subjects (mean age 60 +/- 10 years) had normal glucose tolerance (NGT) and nineteen female subjects (mean age: 63 +/- 9 years) had impaired glucose tolerance (IGT) according to WHO criteria. Serum IL-6 and TNFalpha concentrations were measured by chemiluminescent immunometric assay. Subjects with IGT have higher fasting serum TNFalpha levels than subjects with NGT (p < 0.01). Serum IL-6 and TNFalpha concentrations were elevated during glucose loading (for each comparison, p < 0.01). The increase in serum TNFalpha concentrations in IGT was greater than in NGT (p < 0.01). Serum IL-6 and TNFalpha concentration significantly correlated with insulin and glucose in IGT group (for each comparison, p < 0.01). The correlation between serum glucose and cytokines concentrations was significant in IGT (for each comparison, p < 0.01). There was also a positive correlation between serum IL-6 and TNFalpha in NGT and IGT (for each comparison, p < 0.01). In conclusion, hyperglycemia is associated with increased circulating cytokine concentrations and fasting TNFalpha concentrations seem to be more associated with IGT than IL-6.

The effects of experimental hyperthyroidism on hemorheology and plasma fibrinogen concentration.

The present study in female rats determined the effects of experimental hyperthyroidsm on hemorheological parameters and fibrinogen concentration. To induce experimental hyperthyroidism L-thyroxine (0.4 mg/100 g fodder) was added to the fodder of the experimental group rats for 20 d. After experimental duration, T3, T4, and TSH levels, plasma and blood viscosity, hematocrit, erythrocyte rigidity index, and plasma fibrinogen concentration values of both the control and the experimental group animals were determined and evaluated. In the experimental group, T3 and T4 levels were higher and TSH levels lower than that of the control rats (respectively, p < 0.01, p < 0.001, p < 0.001). Plasma viscosity and fibrinogen concentration of hyperthyroid group were found significantly higher than controls (p < 0.01). However there was no significant difference found in blood viscosity, hematocrit, and erythrocyte rigidity index between control and experimental groups. Thus, hyperthyroidism induced increased fibrinogen concentration can alter the rheological structure of blood by inducing increase in plasma viscosity.

Apolipoprotein E polymorphism in Turkish subjects with Type 2 diabetes mellitus: allele frequency and relation to serum lipid concentrations.

The role of apolipoprotein E (apoE) genotypes in modulating plasma lipid and apolipoprotein levels was studied in 112 patients with Type 2 diabetes mellitus (T2DM) and 94 healthy individuals. ApoE genotypes were identified by PCR amplification and subsequent restriction endonuclease digestion. The apoE allele and genotype frequencies were similar in both the diabetic and control subjects. The apoE allele frequencies were found to be 74.3 for e3, 10.1 for e2, 15.6 for e4 in the diabetic group, and 68.1 for e3, 13.2 for e2 and 18.7 for e4 in the control group. Sex-specific genotypic distribution of apoE polymorphism did not differ between the study groups. To elucidate the association of apoE with lipid abnormalities with respect to gender, serum lipid and apolipoprotein levels were compared among apo e2 (e2/2 and e3/2), e3 (e3/3) and e4 (e4/3 and e4/4) groups of T2DM and control subjects. Apo e2 allele was found to be associated to triglycerides for both sexes, and associated to glucose, and BMI only in females. Subjects with e2 allele had higher levels of BMI, glucose and triglyceride in comparison to e3 and e4. Our data suggest that genetic variation at the apoE locus in Turkish subjects is a genetic factor that influences lipid levels. Further studies attempting to correlate apoE polymorphism with lipid profile in a large number of individuals would be helpful in establishing the true significance of this polymorphism in the Turkish population.

Impaired glucose tolerance: its relevance to early endothelial dysfunction.

We studied the effects of acute glycemia on plasma nitric oxide (NO; nitrite plus nitrate) levels, Cu-Zn Superoxide dismutase (Cu-Zn SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels in age-matched female subjects before and two hours after glucose loading. According to the results of glucose loading, subjects were divided in the three groups as normal (n = 13, NGT), impaired (n = 11, IGT) and diabetic glucose tolerance (n = 10, DGT). Plasma NO levels were significantly higher in subjects with DGT than in subjects with NGT (p< 0.001) and IGT (p< 0.05) at baseline. Two hours after glucose loading, plasma NO levels were significantly decreased in subjects with IGT and DGT (p< 0.001 and p< 0.001). Although plasma TBARS levels in subject with NGT did not change from the baseline levels after glucose loading, TBARS levels were significantly elevated in subjects with DGT and IGT (p< 0.001 and p< 0.001). Plasma Cu-Zn SOD activities were within a similar range in all subjects at baseline. Cu-Zn SOD activities were significantly increased in subjects with NGT, and were significantly decreased in subjects with IGT and DGT (p< 0.001 and p< 0.001) after glucose loading. There was a positive correlation between NO and glucose in subjects with NGT (r = 0.34, p< 0.01) and a negative correlation between NO and TBARS in IGT sum DGT during glucose tolerance (r= -0.38, p< 0.01). We suggest that NO availability was decreased when the blood glucose levels were only moderately elevated above normal levels. This might be related with the enhanced oxidative stress.

Hypoglycemic activity of Urtica pilulifera in streptozotocin-diabetic rats.

The hypoglycemic activity of lectin isolated from Urtica pilulifera L. seeds (Urticaceae) was investigated in streptozotocin (STZ) induced diabetic rats. Significant hypoglycemic effect was found at the dose of 100 mg/kg after i.p. administration for 30 days. Blood glucose (BG) level, food and fluid intake, body weight (BW) loss and histopathologic findings of the normal and diabetic animals were evaluated. The group treated with UPSL (U. pilulifera seed lectin) was also compared against glipizide (oral antidiabetic agent, Carlo-Erba) as a standard.

Age dependency of serum insulin - like growth factor (IGF)-1 in healthy Turkish adolescents and adults.

BACKGROUND: Serum levels of insulin-like growth factor-1 (IGF-1) reflect endogenous growth hormone (GH) secretion in healthy subjects. Measurements of IGF-1 are useful for diagnosis and follow-up of patients with acromegaly and the diagnosis of GH deficiency in children. AIMS: To assess age dependency and normal ranges of serum IGF-1 levels in healthy Turkish population. SETTING AND DESIGN: We therefore studied 272 healthy adolescents and adults between 15-75 years of age. None had diabetes or other endocrine disease or had received estrogen therapy. MATERIAL AND METHODS: Height, weight, body mass index (BMI) and waist-hip ratio were measured in all subjects. Serum samples were obtained during morning hours and IGF-1 was measured by radioimmunoassay. STATISTICAL ANALYSIS: The age-dependent reference range for serum IGF-1 concentrations was calculated by simple least linear regression analysis: the regression line represents the means with 95 percent confidence intervals. Correlation analysis was also done. RESULTS: Ageing was negatively related to serum levels of IGF-1 (P= 0.0001, r=-0.931) with a mean decrease (youngest vs. oldest). IGF-1 levels increased during adolescence, with the highest mean values during puberty. After puberty, a subsequent decline in serum levels of IGF-1 was apparent. There were also a significant difference according to gender; females had significantly higher levels (357.909+/-219.167 mg/L) than males (307.962+/-198.41 mg/L) (P=0.012). IGF-1 levels were correlated with body height (P=0.001, r=0.223), body weight (P=0.002,r=-0.188) and BMI (P=0.039, r=0.128). CONCLUSION: IGF-1 serum levels increase in adolescents with a peak in puberty, whereafter IGF-1 levels return to prepubertal levels.

Plasma viscosity in female patients with hypothyroidism: effects of oxidative stress and cholesterol.

Hypothyroidism is associated with atherosclerotic events, however, the mechanism is unclear. We investigated the effects of oxidative stress and cholesterol on plasma viscosity in female patients with hypothyroidism (n = 20; mean age: 45.5 +/- 5.5 years) at baseline and after L-thyroxine replacement therapy (average daily dose being 0.1 to 0.15 mg). Two blood samples were taken after 2.3 +/- 1.2 months. In hypothyroid state plasma viscosity and thiobarbituric acid reactive substance (TBARS; marker of oxidative stress were significantly higher (p < 0.001 and p < 0.001), and plasma protein thiol (antioxidants) levels were significantly lower (p < 0.001) than in the healthy state (female; n = 15). After L-thyroxine replacement therapy, patients reached to euthyroid state. In this state, the levels of plasma viscosity and TBARS were decreased (p < 0.001 and p < 0.001), and protein thiol levels were significantly elevated (p < 0.001). There was a significant correlation between plasma cholesterol and viscosity (r = 0.64, p < 0.001), as well as plasma protein thiol (r = -0.59, p < 0.001) in the patients. The correlation between viscosity and TBARS was weak (r = 0.29, p < 0.01). Therefore hypothyroidism may be associated with atherosclerotic process by different mechanisms.

Protein carbonyl content in erythrocyte membranes in type 2 diabetic patients.

Protein carbonyl groups result from free radical-induced protein oxidation; their level in tissues and plasma is a relatively stable marker of oxidative damage. Protein carbonyl contents in erythrocyte membranes were investigated in the type 2 diabetic patients with good (n = 16) and poor (n = 30) glycemic control. Diabetic patients were classified as patients with (n = 20) and without (n = 26) angiopathy. Protein carbonyl content was evaluated using the 2,4-dinitro-phenyl-hydrazine method. Protein carbonyl content and GHb levels were significantly higher in both patients with poor and good glycemic control than in control subjects (p < 0.001 in each case). There was a significant difference in protein carbonyl content between patients with poor and good glycemic control (p < 0.001). Diabetic patients with angiopathy had significantly higher protein carbonyl content and GHb levels than the diabetic patients without angiopathy (p < 0.001). These results suggest that impaired glycemic control is connected to protein oxidation, and protein oxidation may be related to underlying metabolic abnormalities and complications of diabetes.

Oxidative stress in heart tissue of hyperthyroid and iron supplemented rats.

This study was designed to investigate the effect of hyperthyroidism and/or iron supplementation or cardiac oxidative stress parameters--the lipid peroxidation end product glutathione (GSH), glutathione peroxidase (CSH-Px), and superoxide dismutase (CuZnSOD)--in rats. In plasma, ferritin as an indicator of iron status and glutamate oxaloacetate transaminase (GOT) as an indicator of damage to the heart tissue were analyzed. Our findings show that hyperthyroidism increased lipooxidative damage as reflected by higher lipid peroxidation end product levels and elevated antioxidant defense parameters-GSH and GSH-Px. Iron supplementation per se does not affect oxidative stress parameters studied in the euthyroid state. Although iron increased lipid peroxidation in the hyperthyroid state, this effect was less than that seen in euthyroidism. Iron supplementation to hyperthyroid rats significantly lowered plasma ferritin levels, suggesting increased iron elimination with consequently reduced oxidative stress.

Comparison of the effects of cabergoline and bromocriptine on prolactin levels in hyperprolactinemic patients.

OBJECTIVE: It is well known that bromocriptine has a suppressive effect on the prolactin release in hyperprolactinemic patients. But it also has some adverse effects. The new, long-acting dopaminergic drug, cabergoline, has been reported to be an effective agent in these patients. However, there are relatively few reports comparing the beneficial and adverse effects of these drugs in the treatment of hyperprolactinemic patients. Therefore, here we studied and compared the efficacy and tolerability of cabergoline with bromocriptine in hyperprolactinemic patients. PATIENTS: Seventeen patients (7 with microprolactinoma, 4 with macroprolactinoma, 6 with idiopathic hyperprolactinemia) were given bromocriptine at a dose of 2.5 mg (or 5 mg for macroprolactinomas) twice daily, and 17 patients (8 with microprolactinoma, 4 with macroprolactinoma, 5 with idiopathic hyperprolactinemia) were given cabergoline at a dose of 0.5 mg twice weekly for 12 weeks. RESULTS: At the end of the study, the prolactin reduction was significantly greater in the cabergoline group than in the bromocriptine group (-93 vs. -87.5 %, respectively, p < 0.05). Normalization of prolactin levels was achieved in 10 of 17 patients (59%) in the bromocriptine group, and in 14 of 17 patients (82%) in the cabergoline group (p = 0.13). Two patients (50%) with macroprolactinoma in the bromocriptine group and three patients (75%) with macroprolactinoma in the cabergoline group demonstrated a normalization of their serum prolactin levels. Adverse events were noted in 53% of bromocriptine patients and in 12% of cabergoline patients (p < 0.01). CONCLUSION: These data indicate that cabergoline is a very effective agent for lowering the prolactin levels in hyperprolactinemic patients and that it appears to offer considerable advantage over bromocriptine in terms of efficacy and tolerability.

Effect of sex hormones on lipid peroxidation in women with polycystic ovary syndrome, healthy women, and men.

Recently, the influence of free radicals and lipid peroxides on many diseases, the effect of sex hormones on lipid peroxidation and antioxidant effects of estrogens have received considerable interest. In the present study we aimed to investigate the relationship between sex hormones and both lipid peroxidation and glutathione content in women with polycystic ovary syndrome (POS), in healthy women and in healthy men. We measured levels of lipid peroxides and sex hormones in plasma and levels of glutathione in erythrocytes of all cases. We evaluated the level of thiobarbituric acid reactive substances (TBARS) as an index of lipid peroxides and erythrocyte glutathione level as an index of antioxidant. We found that plasma levels of free testosterone, dehydroepiandrosterone sulfate (DHEAS) and estradiol significantly higher in the women with POS group than in the healthy women group. There was no significant difference in the levels of both plasma TBARS and erythrocyte glutathione, between women with POS group and healthy women group. Plasma DHEAS levels of healthy men and women with POS were similar. Plasma TBARS level was higher and erythrocyte glutathione level was lower in the healthy men group than in both the healthy women group and in the women with POS group. These data imply that testosterone has an oxidant effect. DHEAS which is an antioxidant, has a protective role in females with POS. Estrogens have an antioxidant effect but this action changes according to its dominant degradation pathway.

Effect of acute hyperglycemia on potassium (86Rb+) permeability and plasma lipid peroxidation in subjects with normal glucose tolerance.

Hyperglycemia is likely to be one of the important determinants of ion transport as it is known to induce oxidative stress and may thus enhance non-specific permeability of membranes. The aim of the present study was to evaluate the effects of an acute increase in glycemia on 86Rb+ (a marker for K+) influx and lipid peroxidation. We evaluated the 75-g oral glucose tolerance test (OGTT)-induced modification on 86Rb+ influx and plasma lipid peroxidation in 20 subjects with normal glucose tolerance (NGT). After 2-hour glucose loading, the levels of passive 86Rb+ influx and plasma lipid peroxidation were significantly increased, whereas the active influx of 86Rb+ was unchanged. The total and passive influx of 86Rb+ into erythrocytes was significantly correlated with the level of plasma lipid peroxidation. This study demonstrates that acute hyperglycemia induces an increase in the passive influx of 86Rb+ in subjects with NGT, suggesting that acute hyperglycemia may produce an oxidative stress in plasma. These changes may be among the earliest changes occurring in response to hyperglycemia.

Effects of oxidative stress on the erythrocyte Na+,K+ ATPase activity in female hyperthyroid patients.

This study was planned to determine the effects of free-radical-induced damage on the Na+,K+-ATPase activity of erythrocytes during hyperthyroidism and 4 wk after propylthiouracil (PTU) therapy (400 mg/d). The levels of plasma thiobarbituric acid-reactive substances (TBARS) as a marker of lipid peroxidation, erythrocyte glutathione (GSH) concentration as an antioxidant, blood ATP concentration, and erythrocyte membrane Na+,K+-ATPase activity were determined in female hyperthyroid patients (n = 22, mean age 40.5 +/- 6.5 yr). Before the PTU therapy, plasma TBARS concentration was significantly higher and the levels of blood ATP and erythrocyte GSH and the activity of membrane Na+,K-+-ATPase were significantly lower in the hyperthyroid patients (n = 15 women, mean age 40.8 +/- 7.3 yr). Four weeks after PTU therapy, plasma TBARS concentration was decreased, and levels of erythrocyte GSH and blood ATP and of Na+,K+-ATPase activity of erythrocytes were elevated in the treated patients. There was a significant positive correlation between blood ATP concentration and Na+,K+-ATPase activity, and a negative correlation between plasma TBARS concentration and Na+,K+-ATPase activity before PTU. Our results might help to clarify the effects of the oxidative mechanisms on the erythrocyte membrane Na+,K+-ATPase activity in hyperthyroid patients.

Effect of acute hyperglycemia on potassium (86Rb+) permeability and plasma lipid peroxidation in subjects with normal glucose tolerance.

Hyperglycemia is likely to be one of the important determinants of ion transport as it is known to induce oxidative stress and may thus enhance non-specific permeability of membranes. The aim of the present study was to evaluate the effects of an acute increase in glycemia on 86Rb+ (a marker for K+) influx and lipid peroxidation. We evaluated the 75-g oral glucose tolerance test (OGTT)-induced modification on 86Rb+ influx and plasma lipid peroxidation in 20 subjects with normal glucose tolerance (NGT). After 2-hour glucose loading, the levels of passive 86Rb+ influx and plasma lipid peroxidation were significantly increased, whereas the active influx of 86Rb+ was unchanged. The total and passive influx of 86Rb+ into erythrocytes was significantly correlated with the level of plasma lipid peroxidation. This study demonstrates that acute hyperglycemia induces an increase in the passive influx of 86Rb+ in subjects with NGT, suggesting that acute hyperglycemia may produce an oxidative stress in plasma. These changes may be among the earliest changes occurring in response to hyperglycemia.

Early changes in parameters of bone and mineral metabolism during therapy for hyper- and hypothyroidism.

The effects of thyroid hormones on various organs and metabolic systems have been the focus of intensive research. In this study we investigated the mechanisms of the changes in some parameters of bone and mineral metabolism before and during treatment of hyper- and hypothyroidism. Our study groups were as follows; 1) Untreated hyperthyroid patients (n= 38), 2) Hyperthyroid patients treated for three months (n=21), 3) Untreated hypothyroid patients (n=27), 4) Hypothyroid patients treated for three months (n= 20), and 5) Euthyroid control subjects (age, weight, sex and menopausal status matched) (n = 47). As expected, the mean serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and urinary Ca/creatinine and deoxypyridinoline (D-Pyr)/creatinine levels were higher in group-1 than in the control group. Serum PTH level was lower in group-1 than in group-5. However, after treatment for three months (group-2) we found that the serum and urinary levels of these parameters (except ALP) were not different than in the control group. Group-3 and group-4 did not show any differences in these parameters compared with group-5. Covariance analysis showed that urinary D-Pyr excretion had a positive, independent relationship to the serum free T3 level and age (P < 0.001 and P = 0.02, respectively). These results suggest that both bone formation and resorption markers increase in hyperthyroid patients, and with the treatment, particularly, in the period of first three months the bone resorption markers decrease rapidly. If the treatment is maintained the decrease slows, becoming more gradual. However, bone formation markers like ALP remain high in hyperthyroid patients during the treatment. In the light of this data, it is possible to conclude that osteoblastic activity lasts longer in hyperthyroidism. On the other hand, we demonstrated that these bone formation and resorption markers do not seem to be different in hypothyroid patients, even during the treatment, compared to the euthyroid controls.

[Evolution of the history of Turkish medicine]. / Türk Tip Tarihinin Asamalari.

Evolution of Turkish medicine through the ages from Central Asia to actual time.

[Nevzat Esref Bengin MD and the beginning of the education of modern psychiatry in Afghanistan]. / Doktor Nevzat esref Bengin ve Afganistan'da modern psikiyatri egitiminin baslangici.

In this paper, the life of Turkish physician Nevzat Esref Bengin, his studies in Afghanistan, the status of medicine and especially the status of psychiatry in Afghanistan in 1930s, introduction of first Persian textbook of neurology and textbook of psychiatry which were published in Afghanistan by Bengin, are presented.

Impact of initial surgical treatment on survival of patients with differentiated thyroid cancer: experience of an endocrine surgery center in an iodine-deficient region.

This retrospective clinical study was designed to analyze the impact of the initial surgical procedure on the survival of 1000 patients with differentiated thyroid cancer of follicular cell origin who had a thyroid operation and were followed for the 30 years between 1968 and 1998 (median 14 years) in an iodine-deficient region where goiter is endemic. There were 753 women and 247 men with a mean age of 42.8 +/- 6.7 years (range 17-86 years). Patients were divided into three groups. All patients had undergone thyroxine treatment and thyroid-stimulating hormone (TSH) suppression, and most had had iodine-131 treatment postoperatively. Group A consisted of 336 patients with differentiated thyroid cancer (DTC) who were treated with bilateral subtotal thyroidectomy in our institution or elsewhere. Group B consisted of 158 patients with DTC who were treated initially with unilateral total lobectomy and contralateral subtotal lobectomy in our institution or elsewhere and underwent reoperation in our department. Group C consisted of 506 patients with DTC who were treated initially with total or near-total thyroidectomy in our department. Kaplan-Meyer survival analysis was used. Recurrence was seen in 23% and death in 8% of the patients. The 20-year survival rates were 76%, 85%, and 92% for groups A, B, and C, respectively. The survival difference among the patients of group A and groups B and C was found to be statistically different (p < 0.001). Long-term survival of patients with differentiated thyroid cancer living in endemic areas for goiter can be influenced by the initial surgical treatment. Patients treated initially with total or near-total thyroidectomy appear to have a better prognosis.