Correlation of serum ghrelin levels with body mass index and carbohydrate metabolism in patients treated with atypical antipsychotics.

The prevalence of diabetes mellitus and metabolic syndrome is higher in patients with schizophrenia than in the normal population. Atypical antipsychotic drugs are used in psychiatry since the beginning of 1990. These drugs differ from the "typical" antipsychotics used previously, as they have less extrapyramidal side effects, and because of this they are tolerated better, but are associated with weight-gain and disturbances in carbohydrate metabolism. Ghrelin is an orexigen hormone partaking in body weight regulation. It is produced in the enteroendocrine P/D1 cells of the gastric mucosa and secreted to the circulation. The aim of our study was to determine ghrelin levels of atypical antipsychotic-treated patients in relationship with their body mass index (BMI) and carbohydrate metabolism. We measured the fasting serum ghrelin levels in 56 patients (male/female: 16/40, age mean+/-S.D.: 50.6+/-5.6 years) treated with atypical antipsychotics (clozapine, olanzapine, risperidon and quetiapine), and in 75 healthy control subjects, age and gender matched (RIA Linco, USA) in relationship with their BMI and their fasting and 75 g OGTT 120 min blood glucose values. The serum ghrelin levels of the patient group were notably higher (1333+/-659 pg/ml) than in the control group (368+/-103, p<0.0001; Mann-Whitney). We found no difference among the four antipsychotics in weight-gain, diabetes prevalence and the serum ghrelin levels. The BMI of the patient group was significantly higher (29.3+/-7.2 kg/m2 versus 24.3+/-3.7 kg/m2, p<0.0001; Mann-Whitney); 32% of them had blood glucose abnormality (18/56). There was no difference between the ghrelin levels in diabetic and non-diabetic patients. We found a significant negative linear correlation between the serum ghrelin and BMI (r=-0.35, p=0.0078; Spearman), the ghrelin and fasting blood glucose (r=-0.32, p=0.015) and OGTT 75 g 120 min blood glucose levels (r=-0.27, p=0.036). The orexigen effect of elevated serum ghrelin levels can contribute to the weight-gain and high diabetes prevalence associated with atypical antipsychotic treatment. The link between atypical antipsychotic treatment and elevated serum ghrelin levels is unknown so far, but a dysregulation of the central feedback mechanism can be hypothesised.

Oestrogen and vitamin D receptor (VDR) genotypes and the expression of ErbB-2 and EGF receptor in human rectal cancers.

Oestrogen/oestrogen receptor (ER) and vitamin D/vitamin D receptor (VDR) systems have been implicated in the pathogenesis of colorectal cancers. The expression of erbB-2 and epidermal growth factor receptor (EGFR) in colorectal cancers has been suggested to have diagnostic and prognostic significance. In our study, XbaI and PvuII polymorphisms of the ER gene and the BsmI polymorphism of the VDR gene were studied in 56 Caucasian patients with rectal cancer. The relationship between the ER and VDR genotypes and the expression of oncogenes was also investigated. The presence of the x allele of ER gene significantly correlated with the overexpression of the erbB-2 and EGFR oncogenes. Significantly increased erbB-2 expression was observed in patients with the VDR B allele. The XXbb allelic combination of the ER/VDR genes was associated with a significantly lower erbB-2 expression, whereas in the other genotypes significantly higher oncogene expression was seen. Our data raise the possibility that ER/VDR gene polymorphisms accompanied by variable oncogene expression might influence the pathogenetic processes of colorectal cancers.

Fibronectin on the surface of human lymphocytes.

Fibronectin was detected by immunofluorescence technique on the surface of one part of separated normal peripheral blood lymphocytes by using FITC-conjugated anti-human fibronectin antibodies. Approximately one-fifth of isolated B cells and 7% of O cells contained surface-bound fibronectin but T cells failed to stain. There were no detectable free receptors for fibronectin on the surface of lymphocytes of different subsets as it was studied with FITC-labelled purified fibronectin. The percent of B and O cells bearing surface bound fibronectin was markedly decreased in patients with acute and chronic lymphocytic leukemias.

Vitamin D and estrogen receptor gene polymorphisms in type 2 diabetes mellitus and in android type obesity.

OBJECTIVE: We studied the significance of BsmI restriction enzyme polymorphism of the vitamin D receptor (VDR) gene and the XbaI and PvuII polymorphisms of the estrogen receptor (ER) gene in patients with type 2 diabetes (n=49), android type obesity with normal carbohydrate metabolism (n=29) and healthy controls (n=138). METHODS: The distribution of genotypes in the study groups, as well as their relationship to fasting and 1 h postprandial serum C-peptide levels were analyzed. RESULTS: Postprandial serum C-peptide levels of BB genotypes were significantly higher in the diabetes and obese groups (6.18+/-5.09 ng/ml) compared with other genotypes (2.71+/-2.45 vs. 1.72+/-1.97 ng/ml, respectively, P=0.05). Among patients with type 2 diabetes and obese subjects, the XX allelic variant of the ER gene was more frequent (P=0.00015). Postprandial C-peptide levels of subjects exhibiting XX genotype were significantly lower compared with those with Xx genotype (1.67+/-2.16 vs. 3.8+/-3.72 ng/ml, P=0.021). The BBXx allelic combination of the VDR/ER receptor genes was less frequent in diabetic patients than in healthy subjects or in obese patients. The BBXx genotype was associated with significantly elevated postprandial C-peptide levels in all subjects compared with other combinations (9.65+/-3.14 vs. 1.35+/-2.82 ng/ml, P=0.003). No difference was found in the distribution of the PvuII polymorphism of the ER gene or in the association with the C-peptide levels among study groups. CONCLUSION: Polymorphisms of the VDR/ER receptor genes might play a role in the pathogenesis of type 2 diabetes by influencing the secretory capacity of beta-cells.

Binding of fibronectin to human lipoproteins.

High molecular mass adhesive glycoprotein plasma fibronectin binds to isolated HDL and LDL lipoprotein fractions in a solid phase radioimmunoassay. Mean dissociation constants of interaction of fibronectin and immobilized HDL and LDL lipoproteins isolated from eight patients with type IIa and type IV hyperlipoproteinemia are 7.8 +/- 3.2 X 10(-7) mol/l and 6.8 +/- 2.6 X 10(-7) mol/l, respectively. Fibronectin can also bind to HDL and LDL isolated from six healthy subjects with mean dissociation constants of 2.07 +/- 0.45 X 10(-6) mol/l and 2.25 +/- 0.48 X 10(-6) mol/l, respectively. The binding is not dependent on the presence of divalent cations. Fibronectin-lipoprotein interaction is inhibited by soluble lipoproteins. There is no observable interaction between fibronectin and VLDL fraction. Binding of fibronectin to HDL and LDL lipoproteins can have an in vivo significance, since the interaction may play a role in the metabolism, deposition of lipoproteins into the vessel wall and in atherogenesis.

Elevated serum tumor necrosis factor-alpha concentrations and bioactivity in Type 2 diabetics and patients with android type obesity.

The role of tumor necrosis factor-alpha in insulin resistance has been studied in 59 patients with Type 2 diabetes, 28 with android type obesity and 35 healthy lean controls. Immunoreactive concentrations and bioactivity of serum tumor necrosis factor-alpha have repeatedly been determined in 8 weeks intervals for 12 months, five times per patients, by using ELISA and L929 cell cytotoxicity bioassay. Significantly higher immunoreactive tumor necrosis factor-alpha concentrations and bioactivity have been found in both, the Type 2 diabetic and obese groups as compared to the healthy persons. Tumor necrosis factor-alpha concentrations and bioactivity have showed a significant positive linear correlation with the elevated basal serum C-peptide levels and body mass indexes in both groups of patients. According to these data the cytokine might play a role in insulin resistance in obesity as well in Type 2 diabetes.

Role of TNF-alpha and its 55 and 75 kDa receptors in bronchial hyperreactivity.

The pathophysiological role of the tumour necrosis factor (TNF) system was studied in adults (n=37) and children (n=43) non asthmatic offspring of asthmatic parents with and without bronchial hyperreactivity proved by methacholine airway challenge test. SerumTNFalpha and its soluble receptors (sTNF-R1 and R2) were determined by enzyme-linked immunosorbent assay (ELISA). Significantly elevated TNFalpha (adults: mean +/- SD=5.18 +/- 0.87 pg ml(-1), children: 5.08 +/- 1.78) vs. non-hyperreactives (adults: 4.12 +/- 0.43, P < 0.0001, children: 3.75 +/- 0.68, P=0.0084), sTNF-R1 (adults: 144 +/- 0.31 ng ml(-1), children: 1.30 +/- 0 25 vs. adults: 1.21 +/- 0.14, P=0.0305, children: 1.13+/-0.11 ng ml(-1), P=0.0042) and sTNF-R2 (adults: 0.85 +/- 0.40ng ml(-1), children: 0.70 +/- 0.46 vs. adults: 0.56 +/- 0.56 P=0.0084, children: 0.33 +/- 0.17, P=0.0048) and decreased sTNF-R1/R2 ratio (adults: mean +/- SD=0.96 +/- 0.73, children: 2.85 +/- 2.06 vs. adults: 4.82+/-3.40, P=0.0272, children: 4 42 +/- 2 30, P=0.0167) were measured in patients with bronchial hyperreactivityThe provocation doses of methacholine causing a 20% reduction (PD20) in forced expiratory volume in 1 sec (FEV1) were found to be in a significant negative linear correlation with TNFalpha sTNF-R1 and R2 levels in hyperreactive adults and with TNFalpha, sTNF-R2 in hyperreactive children. TNFalpha correlated significantly with its receptors both in hyperreactive adults and children and with the body mass index (BMI) values of adults. The TNF system may contribute to the pathophysiology of bronchial hyperreactivity Altered shedding of sTNF-R1 seems to occur in hyperreactive patients.

Role of tumour necrosis factor-alpha in insulin resistance during normal pregnancy.

OBJECTIVE: Role of tumour necrosis factor-alpha (TNF-alpha) was studied in insulin resistance during pregnancy. STUDY DESIGN: Serum TNF-alpha (ELISA) and fasting C-peptide (Cp) (RIA) concentrations were measured in 40 healthy pregnant women (15, 12 and 13 of them in the 1st, 2nd and 3rd trimesters, respectively) and in 25 healthy non-pregnant women in a case-control study. RESULTS: TNF-alpha (X+/-S.D.: 5.33+/-0.46 pg/ml) and Cp levels (3.37+/-1.30 ng/ml) were significantly higher in the 3rd trimester as compared with matched healthy controls (TNF: 4.07+/-0.26, Cp: 1.05+/-0.36) and to the pregnant women in 1st (TNF: 4.04+/-0.26, Cp: 1.34+/-0.59) and 2nd (TNF: 4.35+/-0.32, Cp: 1.11+/-0.35) trimesters. Significant positive linear correlation was calculated among TNF-alpha, Cp, Cp/blood glucose ratio (indirect parameters of insulin resistance) and body mass indexes (BMIs) of pregnant women (P<0.01). CONCLUSION: TNF-alpha may contribute to the insulin resistance during the course of normal pregnancy.

ErbB-2/HER-2 protein expression, serum tumour necrosis factor-alpha (TFM-alpha) and soluble tumour necrosis factor receptor-2 (TNFR-2) concentrations in human carcinoma of the uterine cervix.

The expression of erbB-2 protein (by immunohistochemistry), serum TNF-alpha, soluble TNF-receptor 2 (sTNFR-2, ELISA) concentrations and mitogenic (LPS, ConA, PHA) induced TNF-alpha production of the peripheral blood mononuclear cells (PBMNC) were studied in 91 (UICC Stage 1: 39, Stage 2: 33, Stage 3: 14, Stage 4: 5) patients with carcinoma of the uterine cervix. During a follow-up period of seven years 30 patients died (Stage 4: 5, Stage 3: 12, Stage 2: 11, Stage 1: 2). ErbB-2 protein expression was significantly more frequent in patients with UICC Stages 3-4 (14/19), and in those with fatal outcomes (14/30, p < 0.0001, chi-square test). Serum TNF-alpha (2.70 +/- 0.69 pg/ml) and sTNFR-2 (3.85 +/- 1.05 ng/ml) concentrations were significantly lower in cancer patients (p < 0.0001, Mann-Whitney test) as compared to 64 age-matched control women (TNF-alpha: 4.32 +/- 0.36, TNFR-2: 4.85 +/- 0.82). The mitogenic induced TNF-alpha production of PBMNC was also significantly less with all the three mitogens applied (LPS: 35.24 +/- 8.84, ConA: 26.28 +/- 7.81, PHA: 20.48 +/- 7.04 pg/l million of cells/24 hours, p < 0.0001) as compared to the controls (LPS: 65.33 +/- 8.82, ConA: 51.00 +/- 8.87, PHA: 41.80 +/- 9.01). Serum TNF-alpha, sTNFR-2 concentrations and the mitogenic induced TNF-alpha production of PBMNC was significantly decreased in patients with erbB-2 positivity as compared to those with negativity. In conclusion the expression of the oncoprotein and the lower levels of the members of the TNF system seem to be poor prognostic parameters in patients with carcinoma of the uterine cervix.

[Tumor necrosis factor-alpha; a possible pathogenic factor in obesity in insulin resistant and non-insulin-dependent diabetes mellitus?]. / Tumor necrosis faktor-alpha: az elhízás-inzulinrezisztencia-nem inzulindependens diabetes mellitus kapcsolat lehetséges patogenetikai faktora?

The role of tumor necrosis factor (TNF)-alpha in the development of insulin resistance has repeatedly been emphasized in the past few years. The present paper summarizes the data (including the authors' observations as well) focusing on the potential role of TNF-alpha in the pathogenesis of obesity and non-insulin-dependent diabetes mellitus: alteration of insulin receptor function, lipid metabolism, expression of sulphonylurea receptors, all of them suggested to be related to the TNF-alpha. The potential clinical relevances are shortly reviewed.

[The role of the central nervous system in lupus erythematosus]. / A központi idegrendszer részvétele systemás lupus erythematosusban.

Central nervous system involvement of systemic lupus erythematosus was observed in 34 (36%) of the 94 patients studied between 1970-1990. A review of the diagnostic methods and therapy for central nervous system lupus is presented. The diagnosis of primary cerebral lupus was based on the history, physical examination and on the results of the cerebrospinal fluid analysis, CT-scan and EEG. Intractable headache (22/34), behavioural abnormalities (18/34), cranial neuropathy (16/34) occurred most frequently among neuropsychiatric symptoms. Immunoglobulin analysis of the cerebrospinal fluid proved to be the most sensitive method for detecting clinical activity (in 20/23). Central nervous system involvement was suggested by conventional serological test to a lesser degree. Alterations on CT scan and EEG were found in 17/27 and 14/26 of cases, respectively. IgM, IgA, and IgG indexes (indicators of intratechal immunglobulin synthesis) decreased when the central nervous system events subsided after successful treatment but the CT abnormalities (e. g. atrophy) were not altered.

[Effect of estrogen on the blast transformation of lymphocytes and interleukin-2 production in lupus erythematosus]. / Oestrogen hatása a lymphocyta blastos transformatióra és az interleukin-2 termelésre systemás lupus erythematosusban.

The mitogenic response of peripheral lymphocytes was investigated in 12 patients with systemic lupus erythematosus and in healthy female volunteers who were on 11 and without 9 contraceptive pills. The effect of estrogen (ethinyl-estradiol 10(-5)-10(-6)-10(-7)M) was studied on Phytohaemagglutinin and Pokeweed mitogen induced blastogenic transformation and interleukin-2 production of peripheral lymphocytes in vitro. We observed a significantly depressed Phytohaemagglutinin induced lymphoblastic transformation both in patients and women taking oral contraceptive in presence of 10(-5)M estrogen as compared to normal controls. However there was no significant alteration neither in the response of lymphocyte nor in the production of interleukin-2 using of Pokeweed mitogen. The stimulataneous inhibition of the interleukin-2 production proved to be moderate. Marked significant correlation (r greater than = 0.8) vas detected between lymphoblastic transformation and interleukin-2 production in healthy females. Correlation coefficient measured in females taking oral contraceptive (r less than = 0.64) and patients with systemic lupus erythematosus (r less than = 0.34) suggest that in these groups the inhibition of lymphoblastic transformation is due to the inhibition effect of estrogen on the interleukin-2 production.

PIP: 12 patients with systemic lupus erythematosus (SLE) (8 in the active stage) with an average age of 26 years (17-54) and 20 healthy control subjects (9 were aged 18-49 years and 11 were oral contraceptives [OC] users aged 17-44) were studied to assess the inhibiting effect of estrogen in vitro on phytohemagglutinin (PHA) and Pokeweed (PWM) mitogen induced blast transformation of lymphocytes (lymphoblastic transformation=LBT) gained from periphral blood and simultaneous interleukin-2 (IL-2) production. 8 women were taking Anteovin, 2 Ovidon, and 1 Rigevidon. The average duration of OC use was 5.2 years. 1 SLE patient did not need immunosuppressive treatment, 3 patients received corticosteroid maintenance therapy, and 4 patients were also taking 50 mg of Imuran. In 4 active SLE patients the tests were done before raising the dose of immunosuppressive drugs, and in the case of 2 other patients the administration of 75 mg and 25 mg/die Prednisolone was necessary in addition to 50 mg and 100 mg/die Imuran. LBT decreased significantly in patients and OC users. The LBT values induced by PWM were similar but not significant. The IL-2 production induced by PHA decreased in all 3 groups but not significantly. I1-2 production was 6 E/ml in patients, 5 E/ml in OC users, and 11.5 E/ml in nonusers, but the differences did not prove significant because of wide individual fluctuations. The amount of IL-2 produced by lymphocytes at PWM stimulation was almost the same in all 3 groups with or without estrogen. There was a positive, significant relationship between the extent of LBT and the amount of IL-2 produced in the healthy group of nonusers, it was less solid in the OC users, and in the SLE group trhe low correlation coefficient of .34 suggested the reduction of IL-2 through the inhibition of LBT.

[The role of estrogen receptor, vitamin D receptor and calcium receptor genotypes in the pathogenesis of colorectal cancer]. / Osztrogén-, D-vitamin- és kalcium-érzékeló receptorok genotípusainak szerepe a colorectalis daganatok patogenezisében.

In this study, the Xbal polymorphisms of the estrogen-, the Bsml polymorphism of the vitamin D- as well as the A986S polymorphism of the calcium-sensing receptor genes were investigated in 56 patients with colorectal cancer. The expression of erbB-2, epidermal growth factor receptor, ras, p53 and their relationship to estrogen-, vitamin D- and calcium-sensing receptor genotypes were also studied. In subjects exhibiting XX genotype of the estrogen receptor gene or bb genotype of the vitamin D receptor gene, erbB-2 expression was significantly lower compared to those with xx, Xx or BB, Bb (6/56 and 11/56 vs. 31/56 and 26/56; p = 0.0043 and 0.041). The presence of the XX alleles of estrogen receptor gene significantly correlated with the overexpression of the epidermal growth factor receptor expression in tumors, whereas in xx and Xx genotypes, significantly higher expression was seen (7/56 vs. 30/56; p = 0.049). Analyzing the combinations of the two gene allelic variants, we have found XXbb genotype to be associated with a significantly lower erbB-2 expression, compared to other combinations (Xxbb, XxBb, XXBb) (2/7 vs. 7/7, 4/5, 4/5; p = 0.0011). Patients with AA calcium-sensing receptor genotype were in higher UICC stages at the time of discovery of their disease than those with AS genotype. The AA allelic variant of the calcium-sensing gene was more frequent among patients with colorectal cancer compared to controls (36/56 vs. 36/112; p = 0.0004). Our observations raise the possibility that estrogen-, and vitamin D receptor gene polymorphisms accompanied with variable oncogene expression might influence the pathogenic processes resulting in the development of colorectal cancer. The A986S polymorphism of calcium-sensing receptor might also be a prognostic marker of the disease.

[Diagnostic value of the determination of serum alpha2-HS-glycoprotein]. / A szérum alpha 2-HS-glycoprotein meghatározások diagnosztikus értékéröl.

Opsonic glycoprotein, alpha 2-HS-glycoprotein concentration was studied in the serum of 753 patients with various hematological, malignant, immunological, metabolic, endocrine and liver diseases and 68 healthy controls. Decreased serum alpha 2-HS-glycoprotein levels were detected in patients with acute leukemias, chronic granulocyte and myelomonocyte leukemias, lymphomas, myelofibrosis, multiple myeloma, metastatizing solid tumors, systemic lupus erythematosus, rheumatoid arthritis, acute alcoholic hepatitis, fatty liver, chronic active hepatitis, liver cirrhosis, acute and chronic pancreatitis, and Crohn's disease. Elevated levels were measured in patients with B and NANB/C hepatitis. Further decreased levels were observed in some groups with secondary infections. Serum alpha 2-HS-glycoprotein levels are affected by many factors, influencing the synthesis and elimination of the protein. The detection of serum alpha 2-HS-glycoprotein concentration has no specific diagnostic value as a marker for tumors or other diseases, however, its determination can be useful for the assessment of a non-specific regulator of the host defence.

[Effect of female sex hormones on blastic transformation of lymphocytes in systemic lupus erythematosus and in healthy women]. / A nöl nemi hormonok hatása a lymphocyta blastos transformatióra systhemás lupus erythematosusban és egészséges nökben.

PIP: The susceptibility of women to autoimmune diseases is well-documented, of which systemic lupus erythematosus (SLE) is especially important. The use of oral contraceptives often activate SLE from a quiescent condition. The inductive effect of estrogen has been shown in animal studies indicating that female hormones can trigger autoimmune reaction. The effect of ethinyl estradiol, an estrogen (E), and d-norgestrel, a progesterone (P), on the mitogenic response of peripheral lymphocytes, and particularly on phytohemagglutinin (PHA)- and concanavalin-A (Con-A)-induced blastic transformation of lymphocytes (LBT) was studied in vitro. 25 patients with SLE and 27 healthy controls participated in the study. SLE was inactive in 16 patients, 7 took corticosteroids, and 3 also received 50 mg/day Imuran. 13 patients and 10 controls took contraceptives (Bisecurin, Infecundin, Ovidon, Rigevidon). The LBT value fell significantly in patients with active SLE, in contraceptive users, and the value was significantly lower in inactive patients than in those not using contraceptives. E and P separately or together significantly reduced LBT values. Contraceptives containing P only can be prescribed for women suffering from SLE, as its role in inducing the disease compared to E is negligible.^ieng

[Role of the thymus and normal microbial flora on plasma fibronectin concentration in mice treated with immunomodulatory drugs]. / A thymus és a mikrobaflóra plazma fibronektin szintet befolyásoló szerepének vizsgálata immunmoduláns készítményekkel kezelt egerekben.

The plasma fibronectin (pFN) concentration (cc)-determined by electro-immunodiffusion method-of untreated genetically or artificially athymic mice, or treated with TP-4 (thymus hormone sequence analog synthetic preparation) showed no significant difference from their euthymic or untreated controls. In contrast, the pFN cc in mice with different microbiological state showed significant alterations; the highest level occurred in conventional mice. The lower level in germfree mice was increased by bacterial monocontamination. The alternation from SPF into conventional state in athymic mice or treatment of athymic and euthymic mice with Bordetella pertussis vaccine also resulted in the increase of the pFN cc. Based on these and earlier results, it was assumed that the pFN cc is independent from the presence or absence of the thymus, but it depends on the actual microbiological state of the macroorganism.