The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278

Summary The reversibility of cisplatin-protein interactions by the modulating agent WR2721, its active thiol-metabolite WR1065, and the symmetrical disulfide WR33278 was studied using the model compounds (Pt(diethylenetriammine) monofunctionally bound to the sulfur in glutathione (Pt(dien)SG) and Pt(diethylenetriammine) monofunctionally bound to the sulfur in S-methylglutathione (Pt(dien)SMeG). Both model compounds could be quantified by high-performance liquid chromatography (HPLC) with UV detection. The Pt-cysteine-like bond in Pt(dien)SG could not be reversed by any of the WR compounds or by the strong nucleophiles thiosulfate (TS) and diethyldithiocarbamate (DDTC). However, the Ptmethionine-like bond in Pt(dien)SMeG could be reversed by WR1065, although the reversal was slow (k₂=0.142m ^–1 s^–1) as compared with that obtained using the modulating agents TS (k₂=10.1m ^–1 s^–1) and DDTC (k₂=3.66m ^–1 s^–1). WR2721 was hardly able to reverse the Pt-S bond in Pt(dien)SMeG (k₂=0.00529m ^–1 s^–1), and WR33278 showed no capacity to do so. The activity ofcis-diamminedichloroplatinum(II) (CDDP)-inactivated fumarase was not appreciably restored by any of the WR compounds (16%, 7.7%, and 0 for 20mm WR1065, WR2721, and WR33278, respectively) in contrast to the strong nucleophile DDTC (61% for 2mm DDTC). These in vitro studies provide information at the molecular level that may explain why WR2721, in contrast to DDTC, does not provide protection against cisplatin-induced nephrotoxicity when it is given after platinum-containing chemotherapy. The results support the present clinical use of WR2721 prior to the administration of platinum compounds.This study was financially supported by the Netherlands Cancer Fund (grant IKA 87-12) and by US Bioscience     

Platelet aggregation,disc haemorrhage and progressive loss of visual fields in glaucoma

Platelet aggregationin vitro, deterioration of visual field defects (VFD) and the prevalence of disc haemorrhages (DH) were assessed in 49 patients with primary open angle glaucoma (POAG) and compared with the findings for 67 individuals with suspected glaucoma (GS) in a seven-year follow-up study (range 5.8 to 8.2 years). The percentage patients with spontaneous platelet aggregation (SPA) was higher for POAG patients with visual field deterioration (60%) than both POAG patients without progressive loss of visual fields (12.5%; P<0.005) and those with suspected glaucoma (22.4%; P<0.005). The occurrence of DH was higher among POAG patients with progressive loss of visual field (28%) compared to the GS group (8.4%; P<0.025) and the group of patients consisting of POAG patients without deterioration of VFD and GS (9.9%; P<0.05). DH also occurred more often in patients with low tension glaucoma (41.6%) than in the remaining POAG patients (13.5%; P<0.05). No relation between the patients with SPA and the patients with DH was observed.Abbreviations NPB normal platelet behavior - SPA spontaneous platelet aggregation - DH disc haemorrhage     

Effects of cadmium in freshwater clams. III. Interaction with energy metabolism inAnodonta cygnea

Freshwater clams,Anodonta cygnea, were exposed to cadmium, at 50 ppb (g/L), to investigate the effects of semi-chronic exposure on energy metabolism. Parameters examined included: adenylate energy charge (AEC), glycogen content, blood glucose and protein concentration, the accumulation of anaerobic metabolic end products,viz. lactate and succinate, and mitochondrial NADH-oxidase activity. In all tissues, AEC was significantly lowered after 12 weeks. Glycogen contents of the separate organs, except for the gills, were diminished to one half those of control animals. Hemolymph glucose increased between 4 and 8 weeks, whereas protein in hemolymph steadily decreased, to about one half the concentration of controls at 12 weeks. Lactate increased in mantle and midgut gland, whereas in gill only an initial accumulation was found after 2 weeks of exposure. Succinate concentrations increased in all organs between 4 and 8 weeks of Cd exposure. Thereafter, no further accumulation occurred. From the onset of exposure to cadmium there was a gradual reduction of NADH-oxidase activity of gill mitochondria, down to 60% of the control value after 12 weeks. The data indicate an impairment of oxidative carbohydrate metabolism that is brought about by a metabolic blockade, rather than by (partial) anaerobiosis as a consequence of shell closure.     

An exploration of the disease burden due to Cryptosporidium in consumed surface water for sub-Saharan Africa

The protozoan pathogen Cryptosporidium is an important cause of diarrhoeal disease, but in many contexts its burden remains uncertain. The Global Waterborne Pathogen model for Cryptosporidium (GloWPa-Crypto) predicts oocyst concentrations in surface water at 0.5 by 0.5° (longitude by latitude) resolution, allowing us to assess the burden specifically associated with the consumption of contaminated surface water at a large scale. In this study, data produced by the GloWPa-Crypto model were used in a quantitative microbial risk assessment (QMRA) for sub-Saharan Africa, one of the regions most severely affected by diarrhoeal disease. We first estimated the number of people consuming surface water in this region and assessed both direct consumption and consumption from a piped (treated) supply. The disease burden was expressed in disability adjusted life years (DALYs). We estimate an annual number of 4.3 × 10⁷ (95% uncertainty interval [UI] 7.4 × 10⁶–5.4 × 10⁷) cases which represent 1.6 × 10⁶ (95% UI 3.2 × 10⁵–2.3 × 10⁶) DALYs. Relative disease burden (DALYs per 100,000 persons) varies widely, ranging between 1.3 (95% UI 0.1–5.7) for Senegal and 1.0 × 10³ (95% UI 4.2 × 10²–1.4 × 10³) for Eswatini. Countries that carry the highest relative disease burden are primarily located in south and south-east sub-Saharan Africa and are characterised by a relatively high HIV/AIDS prevalence. Direct surface water consumption accounts for the vast majority of cases, but the results also point towards the importance of stable drinking water treatment performance. This is, to our knowledge, the first study to utilise modelled data on pathogen concentrations in a large scale QMRA. It demonstrates the potential value of such data in epidemiological research, particularly regarding disease aetiology.     

Cognitive vulnerability differentially predicts symptom dimensions of depression

Background

We examined the association of cognitive vulnerability to depression with changes in homogeneous measures of depressive symptoms.

Methods

Baseline and 1-year follow-up data were obtained from 2981 participants of the Netherlands study of depression and anxiety. Multivariate regression analyses were carried out on cognitive reactivity, locus of control and implicit and explicit self-depressive associations in combination with negative life events. The purpose of this analysis was to predict changes on the mood/cognition and anxiety/arousal subscales of the inventory of depressive symptomatology - self report.

Results

Cognitive reactivity, locus of control and explicit self-depressive associations were independently associated with changes in depressive symptoms after adjustment for covariates and baseline severity (all p<0.01). Negative life-events interacted with cognitive vulnerability to depression to predict depressive symptoms. Locus of control (b₁=0.16, SE=0.02, η²=0.01; b₂=0.10, SE=0.02, η²=0.004, F=8.69, p<0.01) and explicit self-depressive associations (b₁=0.10, SE=0.03, η²=0.02; b2=0.02, SE=0.04, F=7.50, p<0.01) were more strongly associated with the cognitive (b₁) than the somatic (b₂) symptom dimension of depression.

Limitations

The study sample is over-inclusive of depressed patients. Therefore it might be problematic generalizing the findings to the general population.

Conclusion

Cognitive etiological factors may play a role in a “cognitive” subtype of depression. The findings strengthen the notion that homogeneous measures of depressive symptoms enable a greater degree of discrimination between subtypes than a multidimensional conception of depression.     

Effect of shared care on blood pressure in patients with chronic kidney disease: a cluster randomised controlled trial

Background

Chronic kidney disease (CKD) is highly prevalent in patients with diabetes or hypertension in primary care. A shared care model could improve quality of care in these patients

Aim

To assess the effect of a shared care model in managing patients with CKD who also have diabetes or hypertension.

Design and setting

A cluster randomised controlled trial in nine general practices in The Netherlands.

Method

Five practices were allocated to the shared care model and four practices to usual care for 1 year. Primary outcome was the achievement of blood pressure targets (130/80 mmHg) and lowering of blood pressure in patients with diabetes mellitus or hypertension and an estimated glomerular filtration rate (eGFR)<60ml/min/1.73m².

Results

Data of 90 intervention and 74 control patients could be analysed. Blood pressure in the intervention group decreased with 8.1 (95% CI = 4.8 to 11.3)/1.1 (95% CI = −1.0 to 3.2) compared to −0.2 (95% CI = −3.8 to 3.3)/−0.5 (95% CI = −2.9 to 1.8) in the control group. Use of lipid-lowering drugs, angiotensin-system inhibitors and vitamin D was higher in the intervention group than in the control group (73% versus 51%, 81% versus 64%, and 15% versus 1%, respectively, [P = 0.004, P = 0.01, and P = 0.002]).

Conclusion

A shared care model between GP, nurse practitioner and nephrologist is beneficial in reducing systolic blood pressure in patients with CKD in primary care.     

Health outcomes measurement and organizational readiness support quality improvement: a systematic review

Background

Using outcome measures to advance healthcare continues to be of widespread interest. The goal is to summarize the results of studies which use outcome measures from clinical registries to implement and monitor QI initiatives. The second objective is to identify a) facilitators and/or barriers that contribute to the realization of QI efforts, and b) how outcomes are being used as a catalyst to change outcomes over time.

Methods

We searched the PubMed, EMBASE and Cochrane databases for relevant articles published between January 1995 and March 2017. We used a standardized data abstraction form. Studies were included when the following three criteria were fulfilled: 1) they relied on structural data collection, 2) when a structural and comprehensive QI intervention had been implemented and evaluated, and 3) impact on improving clinical and/or patient-reported outcomes was described. Data on QI strategies, QI initiatives and the impact on outcomes was extracted using standardized assessment tools.

Results

We included 21 articles, of which eight showed statistically significant improvements on outcomes using data from clinical registries. Out of these eight studies, the Chronic Care Model, IT application as feedback, benchmarking and the Collaborative Care Model were used as QI methods. Encouraging trends in realizing improved outcomes through QI initiatives were observed, ranging from improving teamwork, implementation of clinical guidelines, implementation of physician alerts and development of a decision support system. Facilitators for implementing QI initiatives included a high quality database, audits, frequent reporting and feedback, patient involvement, communication, standardization, engagement, and leadership.

Conclusion

This review suggests that outcomes collected in clinical registries are supportive to realize QI initiatives. Organizational readiness and an active approach are key in achieving improved outcomes.