Inhibition of cigarette smoke-related lipophilic DNA adducts in rat tissues by dietary oltipraz

The present study investigated the effects of dietary oltipraz on cigarette smoke-related lipophilic DNA adduct formation. Female Sprague- Dawley rats were exposed daily to sidestream cigarette smoke in a whole- body exposure chamber 6 h/day for 4 consecutive weeks. One group of rats was maintained on control diet while another group received the same diet supplemented with either a low (167 p.p.m.) or high (500 p.p.m.) dose of oltipraz, starting 1 week prior to initiation of smoke exposure until the end of the experiment. Analysis of lipophilic DNA adducts by the nuclease P1-mediated 32P-post-labeling showed up to five smoke-related adducts. Adduct no. 5 predominated in both the lung and the heart while adduct nos 3 and 2 predominated in the trachea and bladder, respectively. Quantitative analysis revealed that the total adduct level was the highest in lungs (270+/-68 adducts/10(10) nucleotides), followed by trachea (196+/-48 adducts/10(10) nucleotides), heart (141+/-22 adducts/10(10) nucleotides) and bladder (85+/-16 adducts/10(10) nucleotides). High dose oltipraz treatment reduced the adduct levels in lungs and bladder by >60%, while the reduction in lungs in the low-dose group was approximately 35%. In trachea, the effect of low and high dietary oltipraz on smoke DNA adduction was equivocal, while smoke-related DNA adducts in the heart were minimally inhibited by high-dose oltipraz. In a repeat experiment that employed a 3-fold lower dose of cigarette smoke, oltipraz (500 p.p.m.) was found to inhibit the formation of DNA adducts in rat lungs and trachea by 80 and 65%, respectively. These data clearly demonstrate a high efficacy of oltipraz in inhibiting the formation of cigarette smoke-induced DNA adducts in the target tissues.      

Genitalverstümmelung und Strafrecht

Some of the girls who live in Germany and have Muslim parents are threatened by female genital mutilation. This report describes the kinds and medical consequences of female genital mutilation as well as the criminal judgement. Female genital mutilation is considered as dangerous bodily harm, not as grievous bodily harm. Consent does not justify the infringement of rights. The argument that Islam justifies the infringement of rights is irrelevant by law. The human right of bodily intactness has priority over the right of religious freedom. Finally the legal regulations about dealing with personal data are presented. A legal compulsory registration still does not exist.     

Bone morphogenic protein-9 stimulates endothelin-1 release from human pulmonary microvascular endothelial cells: A potential mechanism for elevated ET-1 levels in pulmonary arterial hypertension

Abnormalities of signalling for the transforming growth factor beta (TGFβ) family of peptides, including bone morphogenic proteins (BMP), have been described in heritable pulmonary arterial hypertension (PAH). TGFβ can modulate synthesis of the vasoconstrictor and mitogen, endothelin-1 (ET-1), a mediator that contributes to the pathogenesis of PAH. BMP-9 is a circulating peptide recently recognized to affect endothelial function. The stimuli for increased microvascular endothelial production of ET-1 in PAH are unknown. We therefore studied the effects of BMP-9 on ET-1 production by human lung blood microvascular endothelial cells (HMVEC-LBl) in vitro. In vitro, BMP-9 increased ET-1 production by HMVEC-LBl. The effect was identical to TGFβ-1, but BMP-9 and TGFβ-1 combined further increased ET-1 levels by 29%. As compared to TGFβ-1, BMP-9 induced more potent and rapid phosphorylation of Smad 1/5, the downstream signalling molecules of the activin-like kinase 1 (ALK-1) receptor. Moreover, as has been previously shown for endothelial cells of other origin, BMP-9 also induced Smad 2 phosphorylation in HMVEC-LBl. In conclusion, BMP-9 stimulates ET-1 production by HMVEC-LBl in vitro. BMP-9 signals via several Smad pathways. These studies provide novel mechanisms for the potentiation of PAH.     

Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia

Seventy-five patients, 13 to 49 years of age, with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, fractionated total body irradiation, and marrow transplantation from an HLA-identical sibling and randomized to receive either cyclosporine (CSP) (n = 36) or methotrexate (MTX) (n = 39) as prophylaxis for graft-v-host disease (GVHD). All patients engrafted, and 22 who were given CSP and 21 who were given MTX, are alive at 20 to 47 (median, 35) months (P = .5). Engraftment as assessed by granulocyte recovery (P less than .0005) and platelet transfusion requirement (P = .01) was faster in patients on CSP. Twelve patients (33%) on CSP and 22 (56%) on MTX developed acute GVHD of grades II through IV (P = .07) and 15 of 30 on CSP and 14 of 32 on MTX that were at risk developed chronic GVHD. The most frequent causes of death were interstitial pneumonitis and marrow relapse of leukemia, which occurred with similar frequency in both groups. Beneficial effects observed in patients on CSP included less severe mucositis and shorter duration of hospitalization; adverse effects included renal function impairment and hypertension. These data confirm that CSP is a useful immunosuppressant in patients undergoing marrow transplantation but fail to show a significant improvement in survival as compared with the standard regimen of MTX.