Lipoprotein(a)-associated atherothrombotic risk in hemodialysis patients

BACKGROUND: Hemodialysis patients show a considerably higher risk of atherothrombotic disease than the general population. We investigated both lipoprotein(a) [Lp(a)] plasma levels and apolipoprotein(a) [apo(a)] phenotypes in relation to occurrence of atherothrombotic events in hemodialysis patients compared with subjects showing a normal kidney function. Methods: Lp(a) levels and apo(a) isoforms were determined in 118 hemodialysis patients, including 59 with prior atherothrombotic events, and in 182 subjects with normal creatinine clearance, including 82 who experienced a prior atherothrombotic event. Results: Lp(a) levels in hemodialysis patients (median; 20 mg/dl) were higher (p < 0.01) than in age- and sex-matched subjects with normal renal function without a history of atherothrombosis (11.3 mg/dl). Among hemodialysis patients, median Lp(a) levels were higher in subjects with than in those without prior atherothrombosis (34 vs. 15 mg/dl, p < 0.05). In hemodialysis patients and in subjects without nephropathy, the percentage of low-molecular-weight apo(a) phenotypes were significantly higher in patients with than in those without a history of prior atherothrombotic events (56.9% vs. 33.9%, p < 0.05; 62.2% vs. 25%, p < 0.00001,respectively). Stepwise regression analysis indicated that the presence of at least one apo(a) isoform of low molecular weight was an independent predictor of atherothrombosis in hemodialysis patients (p < 0.05). Conclusions: Elevated Lp(a) plasma levels appear to be associated with atherothrombosis, independent of their origin due to genetic factors or related to the impaired kidney function. Low-molecular-weight apo(a) isoforms are reliable genetic markers of atherothrombosis both in patients with impaired kidney function and in subjects without nephropathy.     

Lichen sclerosus of the male genitalia and urethral stricture diseases

INTRODUCTION: The true incidence of urethral involvement in patients with genital lichen sclerosus (LS) is unknown. We review the epidemiology and discuss the pathogenesis of LS and urethral stricture diseases. MATERIALS AND METHODS: During the period 1991-2002, of 925 patients who underwent urethroplasty for anterior urethral stricture, 130 patients (14%) received the diagnosis of LS. In all patients with LS the histology was re-examined to confirm the clinical diagnosis. Retrograde and voiding urethrography was used to establish urethral involvement in the disease. RESULTS: In 106 patients (82%) the histology provided the classical features of LS, and 24 patients (18%) showed some histological variations. In 49 patients (37%) the LS involved the pendolous urethra (meatus-navicularis-penile), and in 53 cases (41%) a panurethral stricture was evident. CONCLUSIONS: LS urethral involvement appears to be a much more common and extensive disease than previously reported, and requires particular care in its early diagnosis.     

Octogenarians with contralateral carotid artery occlusion: a cohort at higher risk for carotid endarterectomy?

PURPOSE: Carotid angioplasty and stenting has been proposed as a treatment option for carotid occlusive disease in patients at high risk, including those 80 years of age or older or with contralateral carotid occlusion. We analyzed 30-day mortality and stroke risk rates of carotid endarterectomy (CEA) in patients aged 80 years or older with concurrent carotid occlusive disease. METHODS: From a retrospective review of 1000 patients undergoing 1150 CEA procedures to treat symptomatic and asymptomatic carotid lesions over 13 years, we identified 54 patients (5.4%) aged 80 years or older with concurrent contralateral carotid occlusion. These patients were compared with 38 patients (3.8%) aged 80 years or older with normal or diseased patent contralateral carotid artery and 81 patients (8.1%) younger than 80 years with contralateral carotid occlusion. All CEA procedures involved either standard CEA with patching or eversion CEA, and were performed by the same surgeon, with the patients under deep general anesthesia and cerebral protection involving continuous perioperative electroencephalographic monitoring for selective shunting. Shunting criteria were based exclusively on electroencephalographic abnormalities consistent with cerebral ischemia. RESULTS: The 30-day mortality and stroke rate in patients aged 80 years or older with concurrent contralateral carotid occlusion was zero. CONCLUSIONS: The concept of high-risk CEA needs to be revisited. Patients with two of the criteria considered high risk in the medical literature, that is, age 80 years or older and contralateral carotid occlusion, can undergo CEA with no greater risks or complications. Until prospective randomized trials designed to evaluate the role of carotid angioplasty and stenting have been completed, CEA should remain the standard treatment in such patients.     

Synthesis and chemical-pharmacological characterization of the antimetastatic NAMI-A-type Ru(III) complexes (Hdmtp)[trans-RuCl4(dmso-S)(dmtp)], (Na)[trans-RuCl4(dmso-S)(dmtp)], and [mer-RuCl3(H2O)(dmso-S)(dmtp)] (dmtp = 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine)

Ruthenium compounds have gained large interest for their potential application as chemotherapeutic agents, and in particular the complexes of the type (X)[trans-RuCl4(dmso-S)L] (X = HL or Na, NAMI-A or NAMI, respectively, for L = imidazole) are under investigation for their antimetastatic properties. The NAMI(-A)-like compounds are prodrugs that hydrolyze in vivo, and the investigation of their hydrolytic properties is therefore important for determining the nature of the potential active species. The NAMI-A-type Ru(III) complex 1, (Hdmtp)[trans-RuCl4(dmso-S)(dmtp)] (dmtp is 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine), and the corresponding sodium analogue 2, (Na)[trans-RuCl4(dmso-S)(dmtp)], were synthesized. The hydrolyses of 1 and 2 in water as well as in buffered solutions were studied, and the first hydrolysis product, [mer-RuCl3(H2O)(dmso-S)(dmtp)].H2O (3), was isolated and characterized. The molecular structures of 1 and 3 were determined by single-crystal X-ray diffraction analyses and prove the importance of the hydrogen-bonding properties of dmtp to stabilize hydrolysis products. In vitro 1 (a) is not cytotoxic on tumor cells, following challenges from 1 to 72 h and concentrations up to 100 microM, (b) inhibits matrigel invasion at 0.1 mM and MMP-9 activity with an IC50 of about 1 mM, and (c) is devoid of pronounced effects on cell distribution among cell cycle phases. In vivo compound 1, similar to NAMI-A, significantly inhibits metastasis growth in mice bearing advanced MCa mammary carcinoma tumors. In the lungs, 1 is significantly less concentrated than NAMI-A, whereas no differences between these two compounds were found in other organs such as tumor, liver, and kidney. However, 1 caused edema and necrotic areas on liver parenchyma that are more pronounced than those caused by NAMI-A. Conversely, glomerular and tubular changes on kidney are less extensive than with NAMI-A. In conclusion, 1 confirms the excellent antimetastatic properties of this class of NAMI-A-type compounds and qualifies as an interesting alternative to NAMI-A for treating human cancers.     

DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system

The mammalian mismatch repair (MMR) system has been implicated in activation of the G(2) checkpoint induced by methylating agents. In an attempt to identify the signaling events accompanying this phenomenon, we studied the response of MMR-proficient and -deficient cells to treatment with the methylating agent temozolomide (TMZ). At low TMZ concentrations, MMR-proficient cells were growth-inhibited, arrested in G(2)/M, and proceeded to apoptosis after the second post-treatment cell cycle. These events were accompanied by activation of the ATM and ATR kinases, and phosphorylation of Chk1, Chk2, and p53. ATM was activated later than ATR and was dispensable for phosphorylation of Chk1, Chk2, and p53 on Ser15 and for triggering of the G(2)/M arrest. However, it conferred protection against cell growth inhibition induced by TMZ. ATR was activated earlier than ATM and was required for an efficient phosphorylation of Chk1 and p53 on Ser15. Moreover, abrogation of ATR function attenuated the TMZ-induced G(2)/M arrest and increased drug-induced cytotoxicity. Treatment of MMR-deficient cells with low TMZ concentrations failed to activate ATM and ATR and to cause phosphorylation of Chk1, Chk2, and p53, as well as G(2)/M arrest and apoptosis. However, all these events occurred in MMR-deficient cells exposed to high TMZ concentrations, albeit with faster kinetics. These results demonstrate that TMZ treatment activates ATM- and ATR-dependent signaling pathways and that this process is absolutely dependent on functional MMR only at low drug concentrations.     

Cytotoxic activity of Hypericum perforatum L. on K562 erythroleukemic cells: differential effects between methanolic extract and hypericin

The influence of a methanolic extract of Hypericum perforatum L. and of purified hypericin has been comparatively tested on the growth of a human erythroleukemic cell line (K562). After 1 h exposure to increasing concentrations (as hypericin content) of both agents in the dark, leukemic cells were grown for 24 h and 48 h. The effects on cell growth were determined by viable cell count, flow cytometry analysis and fluorescence microscopy. Our data show that purified hypericin has only a weak inhibitory effect on cell growth and no effect in inducing apoptotic cell death. In contrast, the Hypericum flower extract shows a significant concentration-dependent and long-lasting inhibition of cell growth, and induces apoptotic cell death. This work con fi rms the interesting role of Hypericum perforatum L. in cancer therapy and strongly supports the hypothesis that agents, other than hypericin, present in the total extract can impair tumor cell growth acting separately or in a combined manner.     

Identification of the antibacterial component of an ethanolic extract of the Australian medicinal plant, Eremophila duttonii

Activity-guided fractionation was used to determine the antibacterial component of an ethanolic extract of the leaves of an Australian native medicinal plant, Eremophila duttonii F. Muell. (Myoporaceae). The extract, previously shown to have activity against Gram positive bacteria, was shown to have activity against additional Gram positive bacteria, including Clostridium perfringens, C. sporogenes and Listeria monocytogenes. Thin layer chromatography (TLC) was used to separate the extract into seven coloured fractions in visible light, one of which was shown by bioautography to contain antibacterial activity. Recovery of the component from the TLC plate and testing for antibacterial activity using a plate-hole diffusion assay supported this result. The purity of the component was verified by high-performance liquid chromatography and a time-kill experiment indicated that the purified component showed identical bactericidal activity to the whole extract. TLC spray reagents indicated that the component was a sterol, terpene or sugar but not a flavonoid, while the pigmented nature suggested a carotenoid.