The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

Employment status and work-related difficulties in stomach cancer survivors compared with the general population

Little was known about work situation and work-related difficulties, including housework after stomach cancer diagnosis. We aimed to compare employment status and work-related difficulties between stomach cancer survivors and the general population. We enrolled 408 stomach cancer survivors from two hospitals 28 months after diagnosis and 994 representative volunteers from the general population from 15 geographic districts. Working was defined as being employed (including self-employed) and nonworking as being retired or a homemaker. Nonworking was significantly higher among stomach cancer survivors (46.6%) than in the general population (36.5%). Compared with the general population, the survivors had more fatigue in performing both housework (adjusted odds ratio (aOR)=2.08; 95% confidence interval (95% CI)=1.01–4.29) and gainful work (aOR=4.02; 2.55–6.33). More cancer survivors had reduced working hours (aOR=1.42; 95% CI=4.60–28.35) and reduced work-related ability (aOR=6.11; 95% CI=3.64–10.27) than did the general population. The association of nonworking with older age and being female was significantly more positive for survivors than for the general population. Among survivors, poorer Eastern Cooperation Oncology Group Performance Status and receiving total gastrectomy were positively associated with nonworking. Stomach cancer survivors experienced more difficulties in both housework and gainful employment than did the general population. Our findings on stomach cancer survivors' work-related difficulties and the predictors of nonworking will help physicians guide patients towards more realistic postsurgical employment plans

Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

5,6-Dimethylxanthenone-4-acetic acid, synthesised in this laboratory, reduces tumour blood flow, both in mice and in patients on Phase I trial. We used TUNEL (TdT-mediated dUTP nick end labelling) assays to investigate whether apoptosis induction was involved in its antivascular effect. 5,6-Dimethylxanthenone-4-acetic acid induced dose-dependent apoptosis in vitro in HECPP murine endothelial cells in the absence of up-regulation of mRNA for tumour necrosis factor. Selective apoptosis of endothelial cells was detected in vivo in sections of Colon 38 tumours in mice within 30 min of administration of 5,6-Dimethylxanthenone-4-acetic acid (25 mg kg−1). TUNEL staining intensified with time and after 3 h, necrosis of adjacent tumour tissue was observed. Apoptosis of central vessels in splenic white pulp was also detected in tumour-bearing mice but not in mice without tumours. Apoptosis was not observed in liver tissue. No apoptosis was observed with the inactive analogue 8-methylxanthenone-4-acetic acid. Positive TUNEL staining of tumour vascular endothelium was evident in one patient in a Phase I clinical trial, from a breast tumour biopsy taken 3 and 24 h after infusion of 5,6-Dimethylxanthenone-4-acetic acid (3.1 mg m−2). Tumour necrosis and the production of tumour tumour necrosis factor were not observed. No apoptotic staining was seen in tumour biopsies taken from two other patients (doses of 3.7 and 4.9 mg m−2). We conclude that 5,6-Dimethylxanthenone-4-acetic acid can induce vascular endothelial cell apoptosis in some murine and human tumours. The action is rapid and appears to be independent of tumour necrosis factor induction

Outcome and quality of life after surgically treated ankle fractures in patients 65 years or older

<p>Abstract</p> <p>Background</p> <p>Despite high incidence of ankle fractures in the elderly, studies evaluating outcome and impact of quality of life in this age group specifically are sparse. The aim of this study was to evaluate outcome and quality of life 6 and 12 months after injury in patients 65 years or older who had been operated on due to an ankle fracture.</p> <p>Methods</p> <p>Sixty patients 65 years or older were invited to participate in the study. 6 and 12 months after the injury a questionnaire including inquiry to participate, the Olerud-Molander Ankle Score (OMAS), Short-Form 36 (SF-36), Linear Analogue Scale (LAS), Self-rated Ankle Function and some supplementary questions was sent home to the patients. The supplementary questions concerned subjective experience of ankle instability, sporting and physical activity level before injury and recaptured activity level at follow-ups, need of walking aid before injury, state of living before injury and at follow-ups and co-morbidities. After the 12-month follow-up the patients were also called for a radiological examination.</p> <p>Results</p> <p>Fifty patients (83%) answered the questionnaire at 6-month and 46 (77%) at the 12-month follow-up. Although, 45 (90%) fractures were low-energy trauma 44 (88%) were bi- or trimalleolar and post-operative reduction results were complete in 23 (46%) ankles. The median OMAS improved from 60 (Interquartile range (IQR) 36) at 6-month to 70 (IQR 35) at 12-month (p = 0.002), but at 12-month still sixty percent or more of the patients reported pain, swelling, problems when stair-climbing and reduced activities of daily life. Twenty (40%) rated their ankle function as 'good' or 'very good' at 6-month and 30 (60%) at 12-month. Forty-one (82%) were physically active before injury but still one year after only 18/41 had returned to their pre-injury physical activity level. According to SF-36 four dimensions differed from the age- and gender matched normative data of the Swedish population, 'physical function', 'role physical' and 'role emotional' were below norms at 6-month for women (p = 0.010, p = 0.024 and 0.031) and 'general health' was above norms at 12-month for men (p = 0.044).</p> <p>Conclusion</p> <p>One year after surgically treated ankle fractures a majority of patients continue to have symptoms and reported functional limitations. However, SF-36 scores indicate that only females had functional status below the age- and gender matched normative data of the Swedish population.</p

The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice

5,6-dimethylxanthenone-4-acetic acid, a novel antivascular anticancer drug, has completed Phase I clinical trial. Its actions in mice include tumour necrosis factor induction, serotonin release, tumour blood flow inhibition, and the induction of tumour haemorrhagic necrosis and regression. We have used mice with a targeted disruption of the tumour necrosis factor receptor-1 gene as recipients for the colon 38 carcinoma to determine the role of tumour necrosis factor signalling in the action of 5,6-dimethylxanthenone-4-acetic acid. The pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid, as well as the degree of induced plasma and tissue tumour necrosis factor, were similar in tumour necrosis factor receptor-1−/− and wild-type mice. However, the maximum tolerated dose of 5,6-dimethylxanthenone-4-acetic acid was considerably higher in tumour necrosis factor receptor-1−/− mice (>100 mg kg−1) than in wild-type mice (27.5 mg kg−1). The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (25 mg kg−1) was strongly attenuated in tumour necrosis factor receptor-1−/− mice. However, the reduced toxicity in tumour necrosis factor receptor-1−/− mice allowed the demonstration that at a higher dose (50 mg kg−1), 5,6-dimethylxanthenone-4-acetic acid was curative and comparable in effect to that of a lower dose (25 mg kg−1) in wild-type mice. The 5,6-dimethylxanthenone-4-acetic acid -induced rise in plasma 5-hydroxyindoleacetic acid, used to reflect serotonin production in a vascular response, was larger in colon 38 tumour bearing than in non-tumour bearing tumour necrosis factor receptor-1−/− mice, but in each case the response was smaller than the corresponding response in wild-type mice. The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour necrosis factor can be replaced by other vasoactive factors in its antitumour action, an observation of relevance to current clinical studies

Cytokines as mediators of chemotherapy-associated cognitive changes: Current evidence, limitations and directions for future research

10.1371/journal.pone.0081234PLoS ONE812-POLN