Effects of Hypoxia and Transferrin on Toxicity and DNA Binding of Ruthenium Antitumor Agents in Hela Cells

Nuclear DNA binding and inhibition of growth of HeLa cells in culture were determined after 24 h incubation with the ruthenium anticancer agents cis-[Cl2(NH3)4Ru]Cl (CCR) and (ImH)trans-[(Im)2Cl4Ru] (ICR) as a function of [Ru], Po2, and added transferrin. Consistent with the “activation-by-reduction” hypothesis, cytotoxicity and DNA binding for both complexes increased under reduced oxygen conditions. Consistent with the “transferrin- transport” hypothesis, inhibition of cell growth also increased with added transferrin for both complexes. Despite their differences in charge, reduction potentials and substitution rates, both complexes behaved remarkably similarly indicating a common mechanism of action for both. Under atmospheric Conditions (Po2 = 159 torr), CCR inhibited HeLa cell growth with IC50 = 3.5 μM, while that for ICR was 2.0 μM. The binding of both complexes to DNA (RuDNA/PDNA) correlated with toxicity and was approximately linear in the concentration of the ruthenium complex in the culture medium, [Ru]. For both complexes, IC50 values decrease and DNA binding increases with decreasing log(Po2). In general, DNA binding at all oxygen pressures for both complexes is in the range of one Ru per 1000-2000 DNA base pairs at [Ru] = IC50

Comparison of usefulness of computer assisted continuous 48-h 3-lead with 12-lead ECG ischaemia monitoring for detection and quantitation of ischaemia in patients with unstable angina

AIMS: The selection of ECG leads used for ST monitoring may influence detection and quantitation of ischaemia. METHODS: We compared on-line continuous 48-h 12-lead against 3-lead ST monitoring in 130 unstable angina patients (Mortara. ELI-100). Onset and offset of ST episodes were defined by the lead with the first > or = 100 microV ST change relative to baseline and the lead with the latest return to baseline ST level, respectively. ST episodes were calculated for 12 leads and 3 leads (V2, V5, III) separately. RESULTS: ST episodes were detected in 88 patients (77%) by 12-lead and in 71 patients (62%) by 3-lead ST monitoring (P < 0.02). The median number (25.75%) of episodes/patient was 1 (0.3) for 3-lead and 2 (1.6) for 12-lead (P < 0.0001). The total duration of ischaemia detected during 12-lead far exceeded 3-lead monitoring: 12.3 (1, 58.2) and 1.7 (0, 23.3) min respectively (P < 0.0001). The probability of recurrent ischaemia declined most during the first 24 h of monitoring. After a period without ST changes of 1, 12, 24 and 36 h, the probabilities of recurrent ischaemia were 63, 31, 14 and 9%, respectively. CONCLUSIONS: Continuous 12-lead ST monitoring increases detection rate and duration of ST episodes compared to 3-lead ST monitoring. The use of continuous 12-lead ECG monitoring devices on emergency wards and coronary care units is recommended

Immediate and late outcome of excimer laser and balloon coronary angioplasty: A quantitative angiographic comparison based on matched lesions

Objectives.This study sought to compare acute lumen changes and late lumen narrowing during and after excimer laser-assisted balloon angioplasty, measured by quantitative coronary angiography, with the immediate and long-term outcome of balloon angioplasty alone.Background.Although excimer laser coronary angioplasty is used as an adjunct or alternative to balloon angioplasty, limited comparative data exist regarding the immediate and long-term efficacy of excimer laser-assisted balloon angioplasty versus balloon angioplasty alone.Methods.A series of 53 lesions in 47 consecutive patients successfully treated with excimer laser-assisted balloon angioplasty were individually matched after completion of 6-month follow-up angiography with 53 successfully treated balloon angioplasty lesions according to vessel location, preprocedural minimal lumen diameter and reference diameter. Immediate and long-term angiographic results were assessed by an automated lumen contour detection algorithm.Results.Before intervention in the laser and balloon angioplasty groups, respectively, minimal lumen diameter (mean ± SD) was 0.73 ± 0.47 and 0.74 ± 0.46 mm, and reference diameter was 2.71 ± 0.42 and 2.72 ± 0.41 mm. Laser angioplasty was followed by adjunctive balloon dilation in 50 lesions. Mean balloon diameter at maximal inflation was similar in both treatment groups (2.61 ± 0.32 and 2.65 ± 0.38 mm, respectively), resulting in similar minimal lumen diameters after intervention of 1.77 ± 0.41 and 1.78 ± 0.34 mm, respectively. At follow-up angiography, minimal lumen diameter after excimer laser-assisted balloon angioplasty was 1.17 ± 0.63 mm, and that after balloon angioplasty alone was 1.46 ± 0.67 mm (p = 0.02). The angiographic restenosis rates at follow-up using the 50% diameter stenosis cutoff criterion were 57% and 34%, respectively (p = 0.02).Conclusions.Quantitative angiographic analysis of a matched group of 106 successfully treated coronary lesions showed a similar immediate outcome but reduced long-term efficacy of excimer laser-assisted balloon angioplasty compared with that after balloon angioplasty alone

Fatty acids linked to cardiovascular mortality are associated with risk factors

Background. Although saturated fatty acids (FAs) have been linked to cardiovascular mortality, it is not clear whether this outcome is attributable solely to their effects on low-density lipoprotein cholesterol (LDL-C) or whether other risk factors are also associated with FAs. The Western Alaskan Native population, with its rapidly changing lifestyles, shift in diet from unsaturated to saturated fatty acids and dramatic increase in cardiovascular disease (CVD), presents an opportunity to elucidate any associations between specific FAs and known CVD risk factors. Objective. We tested the hypothesis that the specific FAs previously identified as related to CVD mortality are also associated with individual CVD risk factors. Methods. In this community-based, cross-sectional study, relative proportions of FAs in plasma and red blood cell membranes were compared with CVD risk factors in a sample of 758 men and women aged ]35 years. Linear regression analyses were used to analyze relations between specific FAs and CVD risk factors (LDL-C, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, fasting glucose and fasting insulin, 2-hour glucose and 2-hour insulin). Results. The specific saturated FAs previously identified as related to CVD mortality, the palmitic and myristic acids, were adversely associated with most CVD risk factors, whereas unsaturated linoleic acid (18:2n-6) and the marine n-3 FAs were not associated or were beneficially associated with CVD risk factors. Conclusions. The results suggest that CVD risk factors are more extensively affected by individual FAs than hitherto recognized, and that risk for CVD,MI and stroke can be reduced by reducing the intake of palmitate, myristic acid and simple carbohydrates and improved by greater intake of linoleic acid and marine n-3 FAs

Regions of very low H3K27me3 partition the Drosophila genome into topological domains

It is now well established that eukaryote genomes have a common architectural organization into topologically associated domains (TADs) and evidence is accumulating that this organization plays an important role in gene regulation. However, the mechanisms that partition the genome into TADs and the nature of domain boundaries are still poorly understood. We have investigated boundary regions in the Drosophila genome and find that they can be identified as domains of very low H3K27me3. The genome-wide H3K27me3 profile partitions into two states; very low H3K27me3 identifies Depleted (D) domains that contain housekeeping genes and their regulators such as the histone acetyltransferase-containing NSL complex, whereas domains containing moderate-to-high levels of H3K27me3 (Enriched or E domains) are associated with regulated genes, irrespective of whether they are active or inactive. The D domains correlate with the boundaries of TADs and are enriched in a subset of architectural proteins, particularly Chromator, BEAF-32, and Z4/Putzig. However, rather than being clustered at the borders of these domains, these proteins bind throughout the H3K27me3-depleted regions and are much more strongly associated with the transcription start sites of housekeeping genes than with the H3K27me3 domain boundaries. While we have not demonstrated causality, we suggest that the D domain chromatin state, characterised by very low or absent H3K27me3 and established by housekeeping gene regulators, acts to separate topological domains thereby setting up the domain architecture of the genome.This work was supported by the Wellcome Trust (https://wellcome.ac.uk/, grant 089834/Z/09/Z to RW, SR), by the University of Malaya High Impact Research (hir.um.edu.my, grant UM.C/625/HIR/MOHE/CHAN-08 to SWC) from the Ministry of Higher Education Malaysia, and by the BBSRC (www.bbsrc.ac.uk, grant BB/M007081/1 to RW, SR). BU was funded by a Cambridge Marshall Scholarship

Acute complications of percutaneous transluminal coronary angioplasty for total occlusion

The incidence of major complications after percutaneous coronary angioplasty (PTCA) of a totally occluded artery was assessed retrospectively. A total of 1649 PTCA procedures were analyzed. After exclusion of procedures for acute myocardial infarction or total occlusion that resulted from restenosis, 90 patients wer

Role of Intrinsic Muscle Atrophy in the Etiology of Claw Toe Deformity in Diabetic Neuropathy May Not Be as Straightforward as Widely Believed

Objective: Clawing of the toes in the diabetic neuropathic foot is believed to be caused by muscle imbalance resulting from intrinsic muscle atrophy. However, experimental data that supports this mechanism is lacking. The aim of this study was to evaluate this hypothesis using magnetic resonance imaging (MRI). Research Design and Methods: In twenty neuropathic diabetic patients, ten with claw toe deformity and ten with normally aligned toes, multiple plane images of the foot and lower leg were acquired using T1-weighted spin-echo MRI. Atrophy of the intrinsic and extrinsic muscles controlling the toes were assessed using a semi-quantitative 5-point atrophy scale. An intrinsic-to-extrinsic foot muscle imbalance score was derived from these atrophy scores and correlation coefficients were established. Results: Mean (SD) intrinsic muscle atrophy score was 3.1 (1.1) for the toe deformity group and 2.6 (1.2) for the non-deformity group (not significantly different). Intrinsic muscle atrophy score was not correlated with degree of toe deformity (r = -0.18). Muscle imbalance score was not significantly different between study groups and not correlated with degree of toe deformity (r = -0.14). Conclusions: Neither intrinsic muscle atrophy nor muscle imbalance discriminated between neuropathic patients with or without claw toe deformity. This suggests that the role of these muscle factors in claw toe development may not be primary or as straightforward as previously believed. These findings shed new light on the etiology of foot deformity in diabetes and suggest a more complex nature of development, potentially involving anatomical and physiological predisposing factor

Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial

Background: Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. Methods: We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Results: Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Conclusions: Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy. Trial Registration: Clinical Trial Registration No: NCT00614445

Recurrence of idiopathic acute pancreatitis after cholecystectomy: systematic review and meta-analysis

Background: Occult biliary disease has been suggested as a frequent underlying cause of idiopathic acute pancreatitis (IAP). Cholecystectomy has been proposed as a strategy to prevent recurrent IAP. The aim of this systematic review was to determine the efficacy of cholecystectomy in reducing the risk of recurrent IAP. Methods: PubMed, Embase and Cochrane Library databases were searched systematically for studies including patients with IAP treated by cholecystectomy, with data on recurrence of pancreatitis. Studies published before 1980 or including chronic pancreatitis and case reports were excluded. The primary outcome was recurrence rate. Quality was assessed using the Newcastle–Ottawa Scale. Meta-analyses were undertaken to calculate risk ratios using a random-effects model with the inverse-variance method. Results: Overall, ten studies were included, of which nine were used in pooled analyses. The study population consisted of 524 patients with 126 cholecystectomies. Of these 524 patients, 154 (29·4 (95 per cent c.i. 25·5 to 33·3) per cent) had recurrent disease. The recurrence rate was significantly lower after cholecystectomy than after conservative management (14 of 126 (11·1 per cent) versus 140 of 398 (35·2 per cent); risk ratio 0·44, 95 per cent c.i. 0·27 to 0·71). Even in patients in whom IAP was diagnosed after more extensive diagnostic testing, including endoscopic ultrasonography or magnetic resonance cholangiopancreatography, the recurrence rate appeared to be lower after cholecystectomy (4 of 36 (11 per cent) versus 42 of 108 (38·9 per cent); risk ratio 0·41, 0·16 to 1·07). Conclusion: Cholecystectomy after an episode of IAP reduces the risk of recurrent pancreatitis. This implies that current diagnostics are insufficient to exclude a biliary cause