Effects of Three Months of Low Molecular Weight Heparin (dalteparin) Treatment After Bypass Surgery for Lower Limb Ischemia—A Randomised Placebo-controlled Double Blind Multicentre Trial

AbstractObjectivesTo test the hypothesis that long-term postoperative dalteparin (Fragmin®, Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment.DesignProspective randomised double blind multicenter study.Materials and methodsUsing a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000IU dalteparin or placebo injections once daily for 3 months. All patients received 75mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months.ResultsAt 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups.ConclusionsIn patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia

Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer

Anomalous self-assembly of the Aβ peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer's disease. Aβ fibril extension follows a template guided “dock and lock” mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon resonance (SPR) and quenched hydrogen-deuterium exchange NMR (H/D-exchange NMR), we have analysed the fibrillar structure and polymerisation properties of both the highly aggregation prone Aβ1–40 Glu22Gly (Aβ40Arc) and wild type Aβ1–40 (Aβ40WT). The solvent protection patterns from H/D exchange experiments suggest very similar structures of the fibrillar forms. However, through cross-seeding experiments monitored by SPR, we found that the monomeric form of Aβ40WT is significantly impaired to acquire the fibrillar architecture of Aβ40Arc. A detailed characterisation demonstrated that Aβ40WT has a restricted ability to dock and isomerise with high binding affinity onto Aβ40Arc fibrils. These results have general implications for the process of fibril assembly, where the rate of polymerisation, and consequently the architecture of the formed fibrils, is restricted by conformational constraints of the monomers. Interestingly, we also found that the kinetic rate of fibril formation rather than the thermodynamically lowest energy state determines the overall fibrillar structure

Ethnic differences in dissatisfaction with sexual life in patients with type 2 diabetes in a Swedish town

<p>Abstract</p> <p>Background</p> <p>The first aim of this study was to analyze whether self-reported satisfaction with one's sexual life was associated with ethnicity (Swedish and Assyrian/Syrian) in patients with type 2 diabetes. The second was to study whether the association between satisfaction with one's sexual life and ethnicity remained after controlling for possible confounders such as marital status, HbA1c, medication, and presence of other diseases.</p> <p>Methods</p> <p>This cross-sectional, questionnaire-based study was conducted at four primary health care centers in the Swedish town of Södertälje. A total of 354 persons (173 ethnic Assyrians/Syrians and 181 ethnic Swedes) participated.</p> <p>Results</p> <p>The total prevalence of self-reported dissatisfaction with one's sexual life in both groups was 49%. No significant ethnic differences were found in the outcome. In the final model, regardless of ethnicity, the odds ratio (OR) for self-reported dissatisfaction with one's sexual life in those ≥ 70 years old was 2.52 (95% CI 1.33-4.80). Among those living alone or with children, the OR was more than three times higher than for married or cohabiting individuals (OR = 3.10, 95% CI 1.60-6.00). Those with other diseases had an OR 1.89 times (95% CI 1.10-3.40) higher than those without other diseases.</p> <p>Conclusions</p> <p>The findings demonstrate that almost half of participants were dissatisfied with their sexual life and highlight the importance of sexual life to people with type 2 diabetes. This factor should not be ignored in clinical evaluations. Moreover, the findings demonstrate that it is possible to include questions on sexual life in investigations of patients with type 2 diabetes and even in other health-related, questionnaire studies, despite the sensitivity of the issue of sexuality.</p

Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance

Apoptotic cysteine–aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction

Ex Vivo Activity of Cardiac Glycosides in Acute Leukaemia

BACKGROUND: Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results. PRINCIPAL FINDINGS: In this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC(50) values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC(50) was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines. CONCLUSION: It is suggested that further investigation regarding CGs may be focused on diagnoses like T- and B-precursor ALL

Identification of a Novel Topoisomerase Inhibitor Effective in Cells Overexpressing Drug Efflux Transporters

BACKGROUND:Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS:A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS:The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids