Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas

Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis ( XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages ( P = 0.0002) and also with tumour dedifferentiation ( P = 0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early ( pT1) to advanced ( pT3) tumour stages. Moreover, RCCs confined within the organ capsule ( pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney ( pT3; P = 0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC.OncologySCI(E)46ARTICLE71349-13579

Female asylum seekers with musculoskeletal pain: the importance of diagnosis and treatment of hypovitaminosis D

BACKGROUND: Hypovitaminosis D is well known in different populations, but may be under diagnosed in certain populations. We aim to determine the first diagnosis considered, the duration and resolution of symptoms, and the predictors of response to treatment in female asylum seekers suffering from hypovitaminosis D. METHODS: Design: A pre- and post-intervention observational study. Setting: A network comprising an academic primary care centre and nurse practitioners. Participants: Consecutive records of 33 female asylum seekers with complaints compatible with osteomalacia and with hypovitaminosis D (serum 25-(OH) vitamin D <21 nmol/l). Treatment intervention: The patients received either two doses of 300,000 IU intramuscular cholecalciferol as well as 800 IU of cholecalciferol with 1000 mg of calcium orally, or the oral treatment only. Main outcome measures: We recorded the first diagnosis made by the physicians before the correct diagnosis of hypovitaminosis D, the duration of symptoms before diagnosis, the responders and non-responders to treatment, the duration of symptoms after treatment, and the number of medical visits and analgesic drugs prescribed 6 months before and 6 months after diagnosis. Tests: Two-sample t-tests, chi-squared tests, and logistic regression analyses were performed. Analyses were performed using SPSS 10.0. RESULTS: Prior to the discovery of hypovitaminosis D, diagnoses related to somatisation were evoked in 30 patients (90.9%). The mean duration of symptoms before diagnosis was 2.53 years (SD 3.20). Twenty-two patients (66.7%) responded completely to treatment; the remaining patients were considered to be non-responders. After treatment was initiated, the responders' symptoms disappeared completely after 2.84 months. The mean number of emergency medical visits fell from 0.88 (SD 1.08) six months before diagnosis to 0.39 (SD 0.83) after (P = 0.027). The mean number of analgesic drugs that were prescribed also decreased from 1.67 (SD 1.5) to 0.85 (SD 1) (P = 0.001). CONCLUSION: Hypovitaminosis D in female asylum seekers may remain undiagnosed, with a prolonged duration of chronic symptoms. The potential pitfall is a diagnosis of somatisation. Treatment leads to a rapid resolution of symptoms, a reduction in the use of medical services, and the prescription of analgesic drugs in this vulnerable population

Quality improvement cycles that reduced waiting times at Tshwane District Hospital Emergency Department

BACKGROUND: Tshwane District Hospital is a level-one hospital, delivering services in the centre of Pretoria since February 2006. It is unique in location, being only 100m away from the tertiary hospital, Pretoria Academic Hospital. In South Africa, public sector emergency units are under enormous pressure with large patient numbers, understaffing and poor resources. TDH Emergency Department (ED) is a typical example. An average of 3900 patients per month visited this ED in 2006. Recurrent complaints and dissatisfaction shown by the patients, about prolonged waiting times before consulting the medical practitioners in the ED was one of the initial challenges faced by the newly established hospital. It was decided to undertake a quality improvement study to analyse and improve the situation, using waiting time as a measure of improvement. METHODS: A quality improvement team was chosen. A total of 150 waiting times of stable and unstable patients were evaluated. There were 50 waiting times for each month; May, September and December 2006. Waiting time was defined as the time from arrival of the patient in the unit until the start of the consultation by the medical practitioner. Surveys were done in May and September to analyse the problems causing prolonged waiting times. The plan of action included instituting a functional triage system, improving the process of up- and down-referrals to and from the tertiary hospital, easy access to stock, reorganisation of doctors’ duty roster, re-organisation of the academic programme, announcement to patients of waiting time, nurses carrying out minor procedures, improvements in the registration, enhancing laboratory delays and availability of protocols. RESULSTS: The median waiting times for stable patients were; May 2006: 545 minutes, September 2006: 230 minutes and in December 2006: 89 minutes. There was a significant difference among these waiting times for May, September and December 2006 (p < 0.000; Kruskal-Wallis test).The median waiting times for unstable patients were; May 2006: zero minutes, September 2006: zero minutes and in December 2006: 0.5 minutes. There was no difference among the waiting times of unstable patients for May, September and December 2006 (p=0.906; Kruskal-Wallis test). CONCLUSION: This quality improvement exercise identified and rectified problems causing prolonged waiting time for stable patients in the Emergency Department. This was done without compromising the time taken to see unstable patients. Similar strategies might be used in other hospitals to reduce the waiting time