Outcome of childhood acute lymphoblastic leukaemia in resource-poor countries

The causes of treatment failure in childhood acute lymphoblastic leukaemia are thought to differ between resource-rich and resource-poor countries. We assessed the records of 168 patients treated for this disease in Honduras. Abandonment of treatment (n=38), the main cause of failure, was associated with prolonged travel time to the treatment facility (2-5 h: hazard ratio 3.1, 95% CI 1.2-8.1 vs >5 h: 3.7, 1.3-10.9) and age younger than 4.5 years (2.6, 1.1-6.3). 35 patients died of treatment-related effects. Outcome could be substantially improved by interventions that help to prevent abandonment of therapy (such as funding for transport, satellite clinics, and support groups), and by prompt treatment of infection.     

Cytokines,apoptosis and cachexia: the potential for TNF antagonism

The cachexia syndrome is characterised by progressive weight loss and depletion of lean body mass and has long been recognised as a poor prognostic sign. Whilst the clinical features of the wasting process are readily apparent, its pathogenesis is complex and poorly understood. There is increasing evidence that the immune system, in particular inflammatory cytokines, may play an important role in the development of cachexia. The cytokine considered to be the most relevant to this process is tumor necrosis factor alpha (TNF), although other mediators such as interleukin (IL) 1, IL-6 and interferon gamma have also been implicated. Apoptosis represents a potential pathway by which wasting can occur in chronic diseases. Cytokines and their corresponding receptors are known to be important regulators of cell death. Apoptosis has been demonstrated in the skeletal muscle of patients with chronic heart failure (CHF) and is thought to be partly responsible for the significant impairment of functional work capacity associated with this condition. An understanding of the mechanisms that regulate muscle protein breakdown is essential for the development of strategies for treating or even preventing muscle cachexia in patients. It is the aim of this article to review the role of inflammatory cytokines, particularly TNF, in the pathogenesis of wasting and also the potential for anti-cytokine therapy. Although this review will concentrate predominantly on the syndrome of CHF, other chronic illnesses such as liver disease, cancer, and sepsis will also be discussed.     

International nifedipine trial on antiatherosclerotic therapy (intact)

Summary A number of animal studies revealed an inhibition or retardation of the progression of atherosclerosis by calcium-antagonists. Encouraged by these studies, a multicenter trial on the progression of coronary artery disease (CAD) in man was initiated testing the antisclerotic effect of nifedipine against placebo in 426 patients with mild to moderate coronary disease over 3 years. All patients underwent coronary angiography before entering the trial and will be restudied after 3 years; changes of the coronary artery lumen size are quantitatively assessed by a computer-assisted system (CAAS). INTACT (International Trial on Antiatherosclerotic Coronary Therapy) is therefore the first randomized prospective study on the progression of CAD based on a quantitated anigraphic control of the coronary system.This report presents the design of this still-ongoing study as well as inclusion and exclusion criteria. The quantitative evaluation of the coronary angiograms and the mode of compliance test are described in detail. A number of baseline data as well as the preliminary results of the quantitative evaluation of the first coronary angiograms are presented.Beside the results on the effect of the calcium-antagonist nifedipine on the progression of CAD, INTACT might also supply information on the antiatherosclerotic potency of other drugs administered additionally (beta-blockers and nitrates) and of HDL-cholesterol.     

Non-invasive coronary computed tomographic angiography for patients with suspected coronary artery disease: the Coronary Angiography by Computed Tomography with the Use of a Submillimeter resolution (CACTUS) trial.

BACKGROUND: Non-invasive coronary angiography by multislice spiral computed tomography (MSCT) is a promising method for the diagnosis of coronary artery disease (CAD). However, the clinical role of this method has not been established for specific patient cohorts. Therefore, the objective of the current prospective, blinded study was to investigate the diagnostic value of coronary MSCT angiography in patients with an intermediate pre-test probability for having CAD when compared with invasive angiography. METHODS AND RESULTS: A total of 243 patients with an intermediate pre-test probability for having CAD were asked to undergo coronary 16- or 64-slice CT angiography before planned invasive angiography from 12 September 2003 to 13 July 2005. The primary end point was defined as the diagnostic accuracy in the detection of significant coronary stenosis (> or =50% lumen diameter reduction) on a per-patient and an 'intention-to-diagnose'-based analysis. Secondary end points comprised per-artery and per segment-based analyses as well as the comparison of diagnostic accuracy of 16- vs. 64-slice MSCT angiography. Of 243 enrolled patients, 129 and 114 patients were studied by 16- and 64-slice CT angiography, respectively. The overall sensitivity, negative predictive value, and specificity for CAD detection by MSCT were 99% (95% CI, 94-99%), 99% (95% CI, 94-99%), and 75% (95% CI, 67-82%), respectively. On a per-segment basis, the use of 64-slice CT was associated with significantly less inconclusive segments (7.4 vs. 11.3%, P < 0.01), resulting in a trend to an improved specificity (92 vs. 88%, P = 0.09). CONCLUSION: In patients with an intermediate pre-test probability for having CAD this large, prospective trial demonstrates that non-invasive coronary CT angiography is a very sensitive method for CAD detection. Furthermore, this method allows ruling out CAD very reliably and safely. Finally, 64-slice CT appears to be superior for CAD detection when compared with 16-slice CT.     

Trivalent Antimonials Induce Degradation of the PML-RARalpha Oncoprotein and Reorganization of the Promyelocytic Leukemia Nuclear Bodies in Acute Promyelocytic Leukemia NB4 Cells

Acute promyelocytic leukemia (APL) is characterized by a specifict(15;17) chromosomal translocation that fuses the genes encoding thepromyelocytic leukemia protein (PML) and the retinoic acid receptor (RAR). The resulting PML-RAR protein induces a block in thedifferentiation of the myeloid progenitor cells, which can be releasedby retinoic acid (RA) in vitro and in vivo. The RA-induceddifferentiation of APL blasts is paralleled by the degradation of thefusion protein and the relocation of wild-type PML from aberrantnuclear structures to its normal localization in nuclear bodies.Recently, arsenic trioxide (As₂O₃) treatment was proposed as an alternative therapy in APL, because it can inducecomplete remission in both RA-sensitive and -resistant APL patients.Intriguingly, As₂O₃ was also shown to inducedegradation of the PML-RAR chimera and to reorganize PML nuclearbodies. Here we show that trivalent antimonials also have strikingeffects on RA-sensitive and RA-resistant APL cells. Treatment of theAPL-derived NB4 cells and the RA-resistant subclone NB4R4 with antimonytrioxide or potassium antimonyl tartrat triggers the degradation of the fusion protein and the concomitant reorganization of the PML nuclear bodies. In addition, as reported for As₂O₃, theantimonials provoke apoptosis of NB4 and NB4R4 cells. The mechanism ofantimony action is likely to be similar to that ofAs₂O₃, notably both substances induce theattachment of the ubiquitin-like SUMO-1 molecule to the PML moiety ofPML-RAR. From these data, we propose that, in analogy toAs₂O₃, antimonials might have a beneficialtherapeutic effect on APL patients, perhaps with less toxicity thanarsenic.     

Influenza-Associated Hospitalizations,Singapore, 2004–2008 and 2010–2012

Studies of influenza-associated hospitalizations in tropical settings are lacking. To increase understanding of the effect of influenza in Singapore, we estimated the age-specific influenza-associated hospitalizations for pneumonia and influenza during 2004–2008 and 2010–2012. The rate of hospitalization was 28.3/100,000 person-years during 2004–2008 and 29.6/100,000 person-years during 2010–2012. The age-specific influenza-associated hospitalization rates followed a J-shaped pattern: rates in persons >75 years of age and in children <6 months of age were >47 times and >26 times higher, respectively, than those for persons 25–44 years of age. Across all ages during these 2 study periods, ≈12% of the hospitalizations for pneumonia and influenza were attributable to influenza. The rates and proportions of hospitalizations for influenza, particularly among the very young and the elderly, are considerable in Singapore and highlight the importance of vaccination in protecting populations at risk.     

A qualitative assessment of health seeking practices among and provision practices for men who have sex with men in Malawi

Background

In the context of a generalized epidemic and criminalization of homosexuality, men who have sex with men (MSM) in Malawi have a disproportionate burden of HIV compared to other adults. Past research has documented low uptake of HIV prevention and health services among MSM, self-reported fear of seeking health services, and concerns of disclosure of sexual orientation and discrimination in health settings. Qualitative research was conducted among MSM and health service providers in Blantyre, Malawi to understand underlying factors related to disclosure and health seeking behaviors and inform the development of a community-based comprehensive HIV prevention intervention.

Methods

Using peer recruitment, eight MSM participants representing a range of ages, orientations, and social and behavioral characteristics were enrolled for in-depth interviews. Five service providers were recruited from the district hospital, local health and STI clinics, and a HIV prevention service organization. We use the Health Belief Model as a framework to interpret the influential factors on 1) health seeking and uptake among MSM, and 2) influences on provision of services by healthcare providers for MSM.

Results

Results highlight disclosure fears among MSM and, among providers, a lack of awareness and self-efficacy to provide care in the face of limited information and political support. Service providers reported concerns of adverse repercussions related to the provision of services to men in same sex sexual relationships. Some MSM demonstrated awareness of HIV risk but believed that within the wider MSM community, there was a general lack of HIV information for MSM, low awareness of appropriate prevention, and low perception of risks related to HIV infection.

Conclusions

Qualitative research highlights the need for appropriate information on both HIV risks and acceptable, effective HIV prevention options for MSM. Information and educational opportunities should be available to the wider MSM community and the health sector. Health sector interventions may serve to increase cultural and clinical competency to address health problems experienced by MSM. To ensure availability and use of services in light of the criminalization and stigmatization of same sex practices, there is need to increase the safety of uptake and provision of these services for MSM.

     

Quantitative Validation of the n-Butanol Sniffin’ Sticks Threshold Pens

Odorant pens are used by medical practitioners and researchers to assess olfactory dysfunction. Despite their routine use, there are currently no data on the gas-phase odorant concentrations released from the pen tips or whether these concentrations scale linearly with the aqueous-phase concentrations inside the pens. The commercially available Sniffin’ Sticks odor threshold test containing n-butanol was chosen for evaluation. The gas-phase concentration of n-butanol at the tip of each pen was measured directly in a new set of pens via proton-transfer-reaction mass spectrometry (PTR-MS). Measurements were additionally made on the same pens after 6 months and two older pen sets, namely a 3-year-old (used) and 4-year-old (new) set. Furthermore, application-related tests were made to determine the performance of the pens during routine use and under stress. These data demonstrate that the gas-phase n-butanol concentrations of the threshold pens are linear over the entire set, both for brand-new pens and 6 months later; this reflects the expected performance that was previously only assumed. Furthermore, the application–simulation tests demonstrated a good performance of the pens when used according to their intended protocol. Measurements of the older pen sets suggest that storage conditions are more critical than usage for pen stability. The present findings confirm that the n-butanol odorant pens are an appropriate tool for threshold testing, provided they are stored and handled correctly.