Dimethyl Sulfoxide Induces Both Direct and Indirect Tau Hyperphosphorylation

Dimethyl sulfoxide (DMSO) is widely used as a solvent or vehicle for biological studies, and for treatment of specific disorders, including traumatic brain injury and several forms of amyloidosis. As Alzheimer’s disease (AD) brains are characterized by deposits of β-amyloid peptides, it has been suggested that DMSO could be used as a treatment for this devastating disease. AD brains are also characterized by aggregates of hyperphosphorylated tau protein, but the effect of DMSO on tau phosphorylation is unknown. We thus investigated the impact of DMSO on tau phosphorylation in vitro and in vivo. One hour following intraperitoneal administration of 1 or 2 ml/kg DMSO in mice, no change was observed in tau phosphorylation. However, at 4 ml/kg, tau was hyperphosphorylated at AT8 (Ser202/Thr205), PHF-1 (Ser396/Ser404) and AT180 (Thr231) epitopes. At this dose, we also noticed that the animals were hypothermic. When the mice were maintained normothermic, the effect of 4 ml/kg DMSO on tau hyperphosphorylation was prevented. On the other hand, in SH-SY5Y cells, 0.1% DMSO induced tau hyperphosphorylation at AT8 and AT180 phosphoepitopes in normothermic conditions. Globally, these findings demonstrate that DMSO can induce tau hyperphosphorylation indirectly via hypothermia in vivo, and directly in vitro. These data should caution researchers working with DMSO as it can induce artifactual results both in vivo and in vitro

Prospects, achievements, challenges and opportunities for scaling-up malaria chemoprevention in pregnancy in Tanzania: the perspective of national level officers

OBJECTIVES: To describe the prospects, achievements, challenges and opportunities for implementing intermittent preventive treatment for malaria in pregnancy (IPTp) in Tanzania in light of national antenatal care (ANC) guidelines and ability of service providers to comply with them. METHODS: In-depth interviews were made with national level malaria control officers in 2006 and 2007. Data was analysed manually using a qualitative content analysis approach. RESULTS: IPTp has been under implementation countrywide since 2001 and the 2005 evaluation report showed increased coverage of women taking two doses of IPTp from 29% to 65% between 2001 and 2007. This achievement was acknowledged, however, several challenges were noted including (i) the national antenatal care (ANC) guidelines emphasizing two IPTp doses during a woman's pregnancy, while other agencies operating at district level were recommending three doses, this confuses frontline health workers (HWs); (ii) focused ANC guidelines have been revised, but printing and distribution to districts has often been delayed; (iii) reports from district management teams demonstrate constraints related to women's late booking, understaffing, inadequate skills of most HWs and their poor motivation. Other problems were unreliable supply of free SP at private clinics, clean and safe water shortage at many government ANC clinics limiting direct observation treatment and occasionally pregnant women asked to pay for ANC services. Finally, supervision of peripheral health facilities has been inadequate and national guidelines on district budgeting for health services have been inflexible. IPTp coverage is generally low partly because IPTp is not systematically enforced like programmes on immunization, tuberculosis, leprosy and other infectious diseases. Necessary concerted efforts towards fostering uptake and coverage of two IPTp doses were emphasized by the national level officers, who called for further action including operational health systems research to understand challenges and suggest ways forward for effective implementation and high coverage of IPTp. CONCLUSION: The benefit of IPTp is appreciated by national level officers who are encouraged by trends in the coverage of IPTp doses. However, their appeal for concerted efforts towards IPTp scaling-up through rectifying the systemic constraints and operational research is important and supported by suggestions by other authors

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability