Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin

Tirapazamine (TPZ) is a new anticancer drug that is activated specifically at the low oxygen level typically found in solid tumours. It exhibits preferential cytotoxicity towards hypoxic cells and has been shown in preclinical studies with transplanted tumours and in phase II and III clinical trials to potentiate the anti-tumour efficacy of cisplatin without increasing its systemic toxicity. At present, the mechanism for this potentiation is unknown. Here we show that there is a schedule-dependent enhancement of cisplatin cytotoxicity by TPZ for cells in vitro that is similar to that seen with transplanted murine tumours. This cisplatin potentiation depends on the TPZ exposure being at oxygen concentrations below 1%, which are typical of many cells in tumours but not in normal tissues. Also, the interaction between TPZ and cisplatin does not occur in cells mutant in ERCC4, a protein essential for repair of DNA interstrand cross-links. Incubation of the cells with TPZ under hypoxia prior to cisplatin treatment increases cisplatin-induced DNA interstrand cross-links with kinetics suggesting that TPZ inhibits or delays repair of the DNA cross-links. In conclusion, we show that the tumour-specific potentiation of cisplatin cytotoxicity is likely the result of an interaction between TPZ and cisplatin at the cellular level that requires the low oxygen levels typical of those in solid tumours. The mechanism of the interaction appears to be through a potentiation of cisplatin-induced DNA interstrand cross-links, possibly as a result of a diminished or delayed repair of these lesion

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017

The overall aim of the guideline is to provide evidence-based recommendations on the use of biologic therapies (adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab) in adults, children and young people for the treatment of psoriasis; consideration is given to the specific needs of people with psoriasis and psoriatic arthritis. Biologic therapies have now been in use for over 10 years, and with accrued patient-years exposure and clinical experience, many areas that were covered in previous versions of the guideline are now part of the Summary of Product Characteristics (SPC) and/or routine care so that specific recommendations are redundant (see Toolkit A: Summary of licensed indications and posology for biologic therapy, in Supporting information 2). Therefore, in this update we focus on areas where there has been a major change in the evidence base or clinical practice, where practice is very varied and/or where clear consensus or guidelines are lacking (see section 3.1 in Supporting information 1)

Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria

In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 of 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p = 0.004) with a risk reduction of 69.2% (95% confidence interval (CI): 31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1-83.6%], p = 0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1-26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [-18.6-0.4%] per year in the captopril-treated group (p = 0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (-6.4 [-10.2--2.5] vs -1.4 [-5.3-2.6] ml . min(-1). 1.73 m(-2), p = 0.07). Baseline albumin excretion rate (p < 0.0001) and glycated haemoglobin (p = 0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p = 0.02) and serum cholesterol level (p = 0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects

Maternal malaria, birth size and blood pressure in Nigerian newborns:insights into the developmental origins of hypertension from the Ibadan growth cohort

Hypertension is an increasing health issue in sub-Saharan Africa where malaria remains common in pregnancy. We established a birth cohort in Nigeria to evaluate the early impact of maternal malaria on newborn blood pressure (BP).Anthropometric measurements, BP, blood films for malaria parasites and haematocrit were obtained in 436 mother-baby pairs. Women were grouped to distinguish between the timing of malaria parasitaemia as 'No Malaria', 'Malaria during pregnancy only' or 'Malaria at delivery', and parasite density as low (<1000 parasites/µl of blood) and high (≥ 1000/µl).Prevalence of maternal malaria parasitaemia was 48%, associated with younger maternal age (p<0.001), being primigravid (p = 0.022), lower haematocrit (p = 0.028). High parasite density through pregnancy had the largest effect on mean birth indices so that weight, length, head and mid-upper arm circumferences were smaller by 300 g, 1.1 cm, 0.7 cm and 0.4 cm respectively compared with 'No malaria' (all p ≤ 0.005). In babies of mothers who had 'malaria at delivery', their SBPs adjusted for other confounders were lower respectively by 4.3 and 5.7 mmHg/kg compared with 'malaria during pregnancy only' or 'none'. In contrast the mean newborn systolic (SBP) and diastolic BPs (DBP) adjusted for birth weight were higher by 1.7 and 1.4 mmHg/kg respectively in babies whose mothers had high compared with low parasitaemia.As expected, prenatal malarial exposure had a significant impact on fetal growth rates. Malaria at delivery was associated with the lowest newborn BPs while malaria through pregnancy, which may attenuate growth of the vascular network, generated higher newborn BPs adjusted for size. These neonatal findings have potential implications for cardiovascular health in sub-Saharan Africa