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Background: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. Aims: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. Methods: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine's effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. Results: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. Conclusion: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level. [ABSTRACT FROM AUTHOR]

AIMS: Electrolyte imbalances caused by impaired ion transport are a frequent side effect of immunosuppressive treatment in renal transplant recipients. Clinical symptoms resemble features of hypoaldosteronism, although concentrations of aldosterone are in the normal range. Because immunosuppression might affect the hormone receptor status of cells, mineralocorticoid receptor (hMR) expression by peripheral blood leucocytes (PBL) was studied in these patients. METHODS: Twenty one renal transplant recipients being treated with cyclosporine A and 19 healthy controls were tested. hMR expression was quantified by means of competitive reverse transcription polymerase chain reaction (cRT-PCR) and compared with receptor binding studies with subsequent Scatchard plot analysis carried out previously on 20 renal transplant recipients and 25 controls. Advantages of PCR were summarised and compared with Scatchard plot analysis. RESULTS: Cyclosporine A caused a 37% decrease in hMR molecules on PBL in 75% of renal transplant recipients, and this effect was attributable to the downregulation of hMR transcription. PCR was 99% specific for the detection of hMR in PBL and highly reproducible. CONCLUSIONS: Decreases in hMR protein and RNA in PBL of transplant recipients revealed an inhibitory effect of cyclosporine A on hMR transcription. Because hMR acts as a transcription factor, the expression of several genes involved in electrolyte homeostasis is affected, leading to signs of nephrotoxicity that require therapeutic adjustments. Because of the small volume of blood, the assay can be repeated during treatment and is therefore useful for measuring treatment outcomes. Lower costs and the absence of radioactive challenge are further advantages of the PCR method. [ABSTRACT FROM AUTHOR]

OBJECTIVE. To examine whether apoptosis contributes to the pathogenesis of skin lesions in patients with cutaneous lupus erythematosus (CLE) after ultraviolet (UV) irradiation. METHODS: In situ nick translation and TUNEL were performed to detect apoptosis in 85 skin biopsy specimens from patients with various subtypes of CLE. Specimens from normal healthy donors and patients with polymorphous light eruption were used as controls. In addition to assessment of primary lesions, provocative phototesting was carried out to investigate events occurring secondary to UV irradiation during a very early stage of lesion formation. RESULTS: A significant increase in apoptotic nuclei was found in the upper epidermal layer of primary and UV light-induced skin lesions of CLE patients compared with controls. In tissue sections obtained from control subjects at 24 hours after a single exposure to UV light, a slight increase in the count of epidermal apoptotic nuclei was present as compared with skin tissue from CLE patients obtained under the same conditions before lesion formation. In sections obtained from controls at 72 hours after irradiation, a significant decrease in the apoptotic nuclei count was observed, consistent with a proper clearance of apoptotic cells in the period between 24 and 72 hours after irradiation. In striking contrast, the number of apoptotic nuclei increased significantly within this period in tissue sections from patients with CLE. CONCLUSION: These data support the hypothesis that apoptotic cells accumulate in the skin of patients with CLE after UV irradiation, as a result of impaired or delayed clearance. The nonengulfed cells may undergo secondary necrosis and release proinflammatory compounds and potential autoantigens, which may contribute to the inflammatory micromilieu that leads to formation of skin lesions in this disease. [ABSTRACT FROM AUTHOR]

Heering PJ, Kurschat C, Vo DT, Klein-Vehne N, Fehsel K, Ivens K. Aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression. Clin Transplant 2004: 18: 186–192. © Blackwell Munksgaard, 2004 After renal transplantation immunosuppressive drugs-like cyclosporin A (CsA) and FK506 induce either hypoaldosteronism or pseudo-hypoaldosteronism presenting with hyperkalemia and metabolic acidosis. We investigated the relationship between renal allograft function under CsA therapy and plasma aldosterone concentration, potassium- and water homeostasis and mineralocorticoid receptor (MR) expression level in peripheral leukocytes. We studied 21 renal transplant patients under CsA therapy and 12 healthy controls. Transplant recipients were studied before and under fludrocortisone treatment. Using quantitative reverse-phase polymerase chain reaction (RT-PCR) specific for the MR, we analyzed the level of expression of MR in peripheral leukocytes. In acidotic transplant recipients (HCO3 18.5 ± 1.2 mM) renal function was only slightly impaired with 2.0 ± 0.2 mg creatinine/dL when compared with 1.8 ± 0.3 mg/dL (ns) in non-acidotic patients (HCO3 23.0 ± 2.8 mM). Mean plasma aldosterone levels in renal transplant recipients did not differ from control levels (150 ± 33 pg/mL vs. 148 ± 33 pg/mL, ns). In contrast, the expression level of MR in peripheral leukocytes of renal transplant recipients treated with CsA was significantly decreased when compared with healthy controls without renal disease (120 ± 78 vs. 423 ± 73 RNA molecules/0.5 μg total RNA, p < 0.01). The level of expression of MR in renal transplant recipients did not differ between acidotic patients and non-acidotic patients (ns). The application of fludrocortisone reversed hyperkalemia and metabolic acidosis without significant effect on MR expression. The present data demonstrate that hyperkalemia and metabolic acidosis following CsA treatment in kidney transplantation might be associated with a down-regulation of MR expression on peripheral leukocytes. Electrolyte imbalance is reversible on application of fludrocortisone. This observation supports fludrocortisone treatment in transplant patients with severe electrolyte disturbances. [ABSTRACT FROM AUTHOR]

A letter to the editor about 'Clozapine enhances differentiation of adipocyte progenitor cells," by K. Hemmrich and others is presented in the journal of Molecular Psychiatry, issue of 2006 (11, 980-983).

Introduction In the brain, estrogen plays an important role in neural plasticity and its decline during menopause might result in cognitive impairment and predispose to the development of dementia. Two estrogen receptors – α and ß – mediate estrogen actions either as ligand-activated dimeric transcription factors or as membrane-embedded ER monomers. Objective To analyze ERß-variants and ApoE-genotype in the population-based SALIA cohort of 834 non-demented, elderly women. Aims We aimed to explore, whether ERß variants may impact on cognitive performance in interaction with air pollution and APOE. Methods DNA was isolated from lymphocytes. ApoE-epsilon-variants and ERß SNPs rs944045, rs1256062, rs10144225 and rs2274705 were determined by LCG /KBioscience (Hoddesdon, UK). All participants were assessed for cognitive impairment by the CERAD-Plus test battery. Subtests were merged to a total z-score, that corrected for gender, age and time of education. Long-term exposure to air pollution was backextrapolated from data collected by monitoring stations using a geographic information system. Results SNP analysis revealed that 3 ERß variants (rs1256062, rs10144225 and rs2274705) were significantly correlated with lower CERAD z total scores and especially with decline in episodic memory. These effects were strengthened in APOE-epsilon-E4 carriers. Air pollution (NO 2 , PM2,5) did not worsen the CERAD z total score of the women, but interacting with the ERß variants PM2,5 affected their visuoconstructive practice and NO 2 their semantic memory. Conclusion In this population-based, prospective study a gene-gene interaction effect of ApoE and ERß on cognitive performance appeared. Moreover, significant gene-environment interactions on cognition were found for air pollution. [ABSTRACT FROM AUTHOR]