The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >/=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >/=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >/=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.     

Liver fibrosis in mice induced by carbon tetrachloride and its reversion by luteolin

Hepatic fibrosis is effusive wound healing process in which excessive connective tissue builds up in the liver. Because specific treatments to stop progressive fibrosis of the liver are not available, we have investigated the effects of luteolin on carbon tetrachloride (CCl₄)-induced hepatic fibrosis. Male Balb/C mice were treated with CCl₄ (0.4 ml/kg) intraperitoneally (i.p.), twice a week for 6 weeks. Luteolin was administered i.p. once daily for next 2 weeks, in doses of 10, 25, and 50 mg/kg of body weight. The CCl₄ control group has been observed for spontaneous reversion of fibrosis. CCl₄-intoxication increased serum aminotransferase and alkaline phosphatase levels and disturbed hepatic antioxidative status. Most of these parameters were spontaneously normalized in the CCl₄ control group, although the progression of liver fibrosis was observed histologically. Luteolin treatment has increased hepatic matrix metalloproteinase-9 levels and metallothionein (MT) I/II expression, eliminated fibrinous deposits and restored architecture of the liver in a dose-dependent manner. Concomitantly, the expression of glial fibrillary acidic protein and α-smooth muscle actin indicated deactivation of hepatic stellate cells. Our results suggest the therapeutic effects of luteolin on CCl₄-induced liver fibrosis by promoting extracellular matrix degradation in the fibrotic liver tissue and the strong enhancement of hepatic regenerative capability, with MTs as a critical mediator of liver regeneration.     

B-type Natriuretic Peptide as Predictor of Heart Failure in Patients with Acute ST Elevation Myocardial Infarction,Single-vessel Disease,and Complete Revascularization: Follow-up Study

Aim

To assess the concentration of B-type natriuretic peptide (BNP) as a predictor of heart failure in patients with acute ST elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) with successful and complete revascularization.

Methods

Out of a total of 220 patients with acute STEMI admitted to the Sisters of Mercy University Hospital in the period January 1 to December 31, 2007, only patients with acute STEMI undergoing primary PCI who had single vessel disease and were successfully revascularized were included in the study. Selected patients had no history of myocardial infarction or heart failure and a normal or near-normal left ventricular ejection fraction (≥50%) assessed by left ventriculography at admission. Only 58 patients met the inclusion criteria for the study. Out of those, 6 patients refused to participate in the study, and another 5 could not be followed up, so a total of 47 patients were evaluated. Blood samples were taken for measurement of BNP levels at admission, 24 hours later, and 7 days later. Patients were followed up for 1 year. The primary outcome was reduction in left ventricular ejection fraction (LVEF) to <50% after 1 year.

Results

Patients who developed echocardiographic signs of reduced systolic function defined as LVEF<50% had significantly higher values of BNP (≥80 pg/mL) at 24 hours (P = 0.001) and 7 days (P = 0.020) after STEMI and successful reperfusion. Patients who had BNP levels ≥80 pg/mL after 7 days were 21 times more likely to develop LVEF<50 (odds ratio, 20.8; 95% confidence interval, 2.2-195.2; P = 0.008).

Conclusion

BNP can be used as a predictor of reduced systolic function in patients with STEMI who underwent successful reperfusion and had normal ejection fraction at admission.Natriuretic peptides are peptides that are released from the heart in situations of pressure and volume overload of the ventricles. There are 3 types of natriuretic peptides: atrial natriuretic peptide, B-type natriuretic peptide (BNP), and C-type natriuretic peptide. Atrial natriuretic peptide is released predominantly from the atria, BNP from the ventricles, and C-type natriuretic peptide from the endothelium (1-4). BNP is a 32-amino acid neurohormone synthesized in the form of pre-proBNP, which is first cleaved to proBNP and then to active BNP and inactive fragment NT-proBNP. Its serum levels are increased in left ventricular dysfunction, atrial fibrillation, acute myocardial ischemia (acute coronary syndromes, acute myocardial infarction), pulmonary embolism, advanced age, renal dysfunction, etc (4). The actions of BNP include natriuresis, vasodilatation, inhibition of renin-angiotensin-aldosterone axis, and inhibition of sympathetic nerve activity.In the first hours of acute myocardial infarction, BNP is released as a result of ischemia and necrosis of myocardial cells. BNP then rises as a result of systolic and diastolic dysfunction and increased wall stress of the left ventricle (5).Patients with acute ST elevation myocardial infarction (STEMI) who had higher levels of BNP have been shown to have worse prognosis (death, congestive heart failure, myocardial infarction, and no-reflow phenomenon) (5). Also, patients who died after the STEMI had significantly higher values of BNP (5).We assessed the predictive value of BNP for heart failure in patients who underwent primary percutaneous coronary intervention (PCI) for acute STEMI with single-vessel disease and the optimal timing for the measurement of BNP. We included only patients with no previous known heart failure and normal or near-normal global left ventricular systolic function at admission (LV≥50%). To our knowledge, none of the previous studies evaluated BNP as predictor of heart failure in STEMI patients with previously normal LVEF who underwent successful reperfusion.     

Chemotactic and Immunoregulatory Properties of Bone Cells are Modulated by Endotoxin-Stimulated Lymphocytes

In our study, we explored the bidirectional communication via soluble factors between bone cells and endotoxin-stimulated splenic lymphocytes in an in vitro coculture model that mimics the inflammatory environment. Both the ability of lymphocytes to affect differentiation and immune properties of bone cells, osteoblasts (OBL) and osteoclasts (OCL), and of bone cells to modulate cytokine and activation profile of endotoxin-stimulated lymphocytes were tested. LPS-pulsed lymphocytes enhanced OCL but inhibited OBL differentiation and increased the RANKL/OPG ratio, and, at the same time, upregulated chemotactic properties of bone cells, specifically CCL2, CCL5, and CXCL10 in OCL and CCL5 and CXCL13 in OBL. In parallel, bone cells had immunosuppressive effects by downregulating the lymphocyte expression of interleukin (IL)-1, IL-6, TNF-α and co-stimulatory molecules. OCL stimulated the production of osteoclastogenic cytokine RANKL in T lymphocytes. The anti-inflammatory effect, especially of OBL, suggests a possible compensatory mechanism to limit the inflammatory reaction during infection.     

Bleeding risk assessment using whole blood impedance aggregometry and rotational thromboelastometry in patients following cardiac surgery

Excessive bleeding after cardiopulmonary bypass (CPB) is risk factor for adverse outcomes after elective cardiac surgery (ECS). Differentiating between patients who bleed due to surgical issues and those whose excessive chest tube output (CTO) is due to coagulopathy, remains challenging. Bedside suitable tests to identify hemostatic disturbances and predict excessive bleeding are desirable. The study sought to evaluate prediction of excessive bleeding after ECS using two bedside suitable devices for platelet function and viscoelastic blood clot properties assessment. We enrolled 148 patients (105 male and 43 female) undergoing ECS in a prospective observational study. Patients were characterized as bleeders if their 24 h CTO exceeded the 75th percentile of distribution. Multiple electrode aggregometry (MEA, with ASPI, ADP and the TRAP test) and rotational thromboelastometry (TEM, with ExTEM, HepTEM and FibTEM test), were performed at three time points: preoperatively (T1), during CPB (T2), and after protamine administration (T3). The primary endpoint was CTO and the secondary endpoint was administration of blood products, 30-day and 1 year mortality. The best predictors of increased bleeding tendency were the tests performed after protamine administration (T3). At T3, patients characterized as bleeders had significantly lower MEA ASPI (median, 14 vs. 27 AUC, p = 0.004) and ADP test values (median, 22 vs. 41 AUC, p = 0.002) as well as TEM values expressed in maximum clot firmness after 30 min (MCF 30) for ExTEM (53 vs. 56 mm, p = 0.005), HepTEM (48 vs. 52 mm, p = 0.003) and FibTEM (8 vs. 11 mm, p < 0.001) test. 24 h CTO inversely correlated with both the MEA (ASPI test: r = ?0.236, p = 0.004; ADP test: r = ?0.299, p < 0.001), and TEM MCF 30 (ExTEM: r = ?0.295, p < 0.001; HepTEM: ?0.329, p < 0.001; FibTEM: ?0.377, p < 0.001) test values. Our study showed that MEA and TEM are useful methods for prediction of excessive bleeding after ECS. In order to prevent excessive postoperative CTO, hemostatic interventions with timely and targeted blood component therapy according to MEA and TEM results should be considered.     

Azo dyes, their environmental effects, and defining a strategy for their biodegradation and detoxification

Intense industrial development has been accompanied by the production of wastewaters of very complex content, which pose a serious hazard to the environment, put at risk sustainable development, and call for new treatment technologies that would more effectively address the issue. One particular challenge in terms of science and technology is how to biodegrade xenobiotics such as azo dyes, which practically do not degrade under natural environmental conditions. These compounds tend to bioaccumulate in the environment, and have allergenic, carcinogenic, mutagenic, and teratogenic properties for humans. Removal of azo dyes from effluents is mostly based on physical-chemical methods. These methods are often very costly and limited, as they accumulate concentrated sludge, which also poses a significant secondary disposal problem, or produce toxic end-products. Biotechnological approach may offer alternative, lowcost biological treatment systems that can completely biodegrade and detoxify even the hard-to-biodegrade azo dyes.     

Lipid and protein oxidation in female patients with chronic fatigue syndrome

Introduction

Chronic fatigue syndrome (CFS) is a widely recognized problem, characterized by prolonged, debilitating fatigue and a characteristic group of accompanying symptoms, that occurs four times more frequently in women than in men. The aim of the study was to determine the existence of oxidative stress and its possible consequences in female patients with CFS.

Material and methods

Twenty-four women aged 15-45 who fulfilled the diagnostic criteria for CFS with no comorbidities were recruited and were age matched to a control group of 19 healthy women. After conducting the routine laboratory tests, levels of the lipid oxidation product malondialdehyde (MDA) and protein oxidation protein carbonyl (CO) were determined.

Results

The CFS group had higher levels of triglycerides (p = 0.03), MDA (p = 0.03) and CO (p = 0.002) and lower levels of HDL cholesterol (p = 0.001) than the control group. There were no significant differences in the levels of total protein, total cholesterol or LDL cholesterol.

Conclusions

The CFS group had an unfavorable lipid profile and signs of oxidative stress induced damage to lipids and proteins. These results might be indicative of early proatherogenic processes in this group of patients who are otherwise at low risk for atherosclerosis. Antioxidant treatment and life style changes are indicated for women with CFS, as well as closer observation in order to assess the degree of atherosclerosis.     

Gastric Pentadecapeptide BPC 157 and Short Bowel Syndrome in Rats

The gastric pentadecapeptide BPC 157, which was shown to be safe as an antiulcer peptide in trials for inflammatory bowel disease (PL14736, Pliva), successfully healed intestinal anastomosis and fistula in rat. Therefore, we studied for 4 weeks rats with escalating short bowel syndrome and progressive weight loss after small bowel resection from fourth ileal artery cranially of ileocecal valve to 5 cm beneath pylorus. BPC 157 (10 μg/kg or 10 ng/kg) was given perorally, in drinking water (12 ml/rat/day) or intraperitoneally (once daily, first application 30 min following surgery, last 24 h before sacrifice). Postoperatively, features of increasingly exhausted presentation were: weight loss appearing immediately regardless of villus height, twofold increase in crypt depth and fourfold increase in muscle thickness within the first week, jejunal and ileal overdilation, and disturbed jejunum/ileum relation. In contrast, constant weight gain above preoperative values was observed immediately with BPC 157 therapy, both perorally and parenterally, and villus height, crypt depth, and muscle thickness [inner (circular) muscular layer] also increased, at 7, 14, 21, and 28 days. Moreover, rats treated with pentadecapeptide BPC 157 showed not different jejunal and ileal diameters, constant jejunum-to-ileum ratio, and increased anastomosis breaking strength. In conclusion, pentadecapeptide BPC 157 could be helpful to cure short bowel syndrome.     

Detection of residual tumor after radiofrequency ablation of liver metastasis with dual-modality PET/CT: initial results

The aim of this study was to determine the accuracy of dual-modality positron emission tomography(PET)/computed tomography (CT) in the detection of residual tumor after radiofrequency ablation (RFA) of liver metastasis of colorectal cancer. Eleven patients with 16 hepatic metastases (mean size 2.9 cm) from colorectal cancer were enrolled in this study, and 19 RFA procedures and 32 PET/CT examinations were performed. The patients had PET/CT before and after RFA using [¹⁸F]-2-fluoro-2-deoxy-D-glucose. CT images alone were read by two radiologists, PET images alone were evaluated by two nuclear physicians. Fused images were read by one physician of each speciality in consensus. The accuracy for detection of residual tumor by the different imaging modalities following RFA was assessed. Eleven patients with a mean age of 63 (range 55–71) years were evaluated. The mean follow-up period was 393 days. The overall procedure-based sensitivity for detection of residual tumor was 65% for PET and PET/CT and 44% for CT alone. The accuracies were 68% and 47%, respectively. Four patients had residual tumor after RFA, six patients total developed local recurrence. PET/CT therefore possibly proved superior to CT alone when assessing the liver for residual tumor after RFA.     

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139‐Ca have no influence on treatment outcome and its detection by diagnostic assays

The treatment of patients suffering from HBeAg‐positive chronic hepatitis B with REP 2139‐Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti‐HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139‐Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the “a” determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre‐S/S open reading frame (ORF) was sequenced and pre‐S1, pre‐S2 and S amino acid sequences were analysed. We found no major differences between pre‐S1, pre‐S2 and S sequences in responders and nonresponders correlated with low reduction in HBsAg. In addition, we found no mutations in the “a” determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre‐S/S ORF has no direct influence on response to REP 2139‐Ca therapy.