Pharmacological Prevention of Ifosfamide- Induced Nephrotoxicity: From Bench to Bedside

Presently, substantially more children diagnosed with cancer survive than ever before. However, powerful cancer chemotherapy is associated with serious drug-induced organ damage, adversely affecting the health and the quality of life of these pediatric cancer survivors. This thesis focuses on a chemotherapeutic agent called ifosfamide, which is commonly used to treat pediatric solid tumours such as rhabdomyosarcoma, neuroblastoma, Wilm’s tumour and soft tissue sarcoma. It has been shown to cause serious renal damage substantially more in younger children (less than 3 years of age) than among older children or adults. This often leads to devastating consequences on the long-term health of children. Previous work from our lab has demonstrated that this agedependent nephrotoxicity is caused by a toxic ifosfamide metabolite produced in the kidney by CYP3A. We found that glutathione depletion enhances renal damage caused by ifosfamide in tubular cells. We sought to develop a therapeutic intervention to protect the kidney from ifosfamide-induced damage. We have selected N-acetylcysteine (NAC) as it has been used extensively and safely to treat acetaminophen overdose in children. Investigating its efficacy, we found that NAC prevents ifosfamide-induced nephrotoxicity in porcine renal proximal tubular cells and in a rat model. The use of NAC in children will be feasible only if it does not interfere with the antitumour effect of ifosfamide. To that end we demonstrated that in relevant cancer cell lines (rhabdomyosarcoma and neuroblastoma), NAC does not affect the cytotoxicity of ifosfamide mustard, the pharmacological active metabolite of ifosfamide. In parallel, we measured the plasma concentrations of NAC in children treated for acetaminophen overdose. The systemic exposure of NAC in these pediatric iii patients produced significantly higher levels as compared to our successful rat model. This indicates that the regular safe dosing schedule of NAC in these young patients may be used to prevent ifosfamide nephrotoxicity. In summary, NAC improves the risk-benefit ratio of ifosfamide, suggesting a novel therapeutic role in preventing nephrotoxicity in children treated with ifosfamide

Nets, Spray or Both? The Effectiveness of Insecticide-Treated Nets and Indoor Residual Spraying in Reducing Malaria Morbidity and Child Mortality in sub-Saharan Africa.

Malaria control programmes currently face the challenge of maintaining, as well as accelerating, the progress made against malaria with fewer resources and uncertain funding. There is a critical need to determine what combination of malaria interventions confers the greatest protection against malaria morbidity and child mortality under routine conditions. This study assesses intervention effectiveness experienced by children under the age of five exposed to both insecticide-treated nets (ITNs) and indoor residual spraying (IRS), as compared to each intervention alone, based on nationally representative survey data collected from 17 countries in sub-Saharan Africa. Living in households with both ITNs and IRS was associated with a significant risk reduction against parasitaemia in medium and high transmission areas, 53% (95% CI 37% to 67%) and 31% (95% CI 11% to 47%) respectively. For medium transmission areas, an additional 36% (95% CI 7% to 53%) protection was garnered by having both interventions compared with exposure to only ITNs or only IRS. Having both ITNs and IRS was not significantly more protective against parasitaemia than either intervention alone in low and high malaria transmission areas. In rural and urban areas, exposure to both interventions provided significant protection against parasitaemia, 57% (95% CI 48% to 65%) and 39% (95% CI 10% to 61%) respectively; however, this effect was not significantly greater than having a singular intervention. Statistically, risk for all-cause child mortality was not significantly reduced by having both ITNs and IRS, and no additional protectiveness was detected for having dual intervention coverage over a singular intervention. These findings suggest that greater reductions in malaria morbidity and health gains for children may be achieved with ITNs and IRS combined beyond the protection offered by IRS or ITNs alone

A Novel Statistical Algorithm for Gene Expression Analysis Helps Differentiate Pregnane X Receptor-Dependent and Independent Mechanisms of Toxicity

Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1) We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2) We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM) method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR+/+) and pregnane X receptor-knockout (PXR−/−) mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1). Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR+/+ animals. Comparison of concordant expression changes between PXR+/+ and PXR−/− mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport

Patterns of perceived barriers to medical care in older adults: a latent class analysis

<p>Abstract</p> <p>Background</p> <p>This study examined multiple dimensions of healthcare access in order to develop a typology of perceived barriers to healthcare access in community-dwelling elderly. Secondary aims were to define distinct classes of older adults with similar perceived healthcare access barriers and to examine predictors of class membership to identify risk factors for poor healthcare access.</p> <p>Methods</p> <p>A sample of 5,465 community-dwelling elderly was drawn from the 2004 wave of the Wisconsin Longitudinal Study. Perceived barriers to healthcare access were measured using items from the Group Health Association of America Consumer Satisfaction Survey. We used latent class analysis to assess the constellation of items measuring perceived barriers in access and multinomial logistic regression to estimate how risk factors affected the probability of membership in the latent barrier classes.</p> <p>Results</p> <p>Latent class analysis identified four classes of older adults. Class 1 (75% of sample) consisted of individuals with an overall low level of risk for perceived access problems (No Barriers). Class 2 (5%) perceived problems with the availability/accessibility of healthcare providers such as specialists or mental health providers (Availability/Accessibility Barriers). Class 3 (18%) perceived problems with how well their providers' operations arise organized to accommodate their needs and preferences (Accommodation Barriers). Class 4 (2%) perceived problems with all dimension of access (Severe Barriers). Results also revealed that healthcare affordability is a problem shared by members of all three barrier groups, suggesting that older adults with perceived barriers tend to face multiple, co-occurring problems. Compared to those classified into the No Barriers group, those in the Severe Barrier class were more likely to live in a rural county, have no health insurance, have depressive symptomatology, and speech limitations. Those classified into the Availability/Accessibility Barriers group were more likely to live in rural and micropolitan counties, have depressive symptomatology, more chronic conditions, and hearing limitations. Those in the Accommodation group were more likely to have depressive symptomatology and cognitive limitations.</p> <p>Conclusions</p> <p>The current study identified a typology of perceived barriers in healthcare access in older adults. The identified risk factors for membership in perceived barrier classes could potentially assist healthcare organizations and providers with targeting polices and interventions designed to improve access in their most vulnerable older adult populations, particularly those in rural areas, with functional disabilities, or in poor mental health.</p

Effects of a partially supervised conditioning programme in cystic fibrosis: an international multi-centre randomised controlled trial (ACTIVATE-CF): study protocol

Physical activity (PA) and exercise have become an accepted and valued component of cystic fibrosis (CF) care. Regular PA and exercise can positively impact pulmonary function, improve physical fitness, and enhance health-related quality of life (HRQoL). However, motivating people to be more active is challenging. Supervised exercise programs are expensive and labour intensive, and adherence falls off significantly once supervision ends. Unsupervised or partially supervised programs are less costly and more flexible, but compliance can be more problematic. The primary objective of this study is to evaluate the effects of a partially supervised exercise intervention along with regular motivation on forced expiratory volume in 1 s (FEV1) at 6 months in a large international group of CF patients. Secondary endpoints include patient reported HRQoL, as well as levels of anxiety and depression, and control of blood sugar.; It is planned that a total of 292 patients with CF 12 years and older with a FEV1 ≥ 35% predicted shall be randomised. Following baseline assessments (2 visits) patients are randomised into an intervention and a control group. Thereafter, they will be seen every 3 months for assessments in their centre for one year (4 follow-up visits). Along with individual counselling to increase vigorous PA by at least 3 h per week on each clinic visit, the intervention group documents daily PA and inactivity time and receives a step counter to record their progress within a web-based diary. They also receive monthly phone calls from the study staff during the first 6 months of the study. After 6 months, they continue with the step counter and web-based programme for a further 6 months. The control group receives standard care and keeps their PA level constant during the study period. Thereafter, they receive the intervention as well.; This is the first large, international multi-centre study to investigate the effects of a PA intervention in CF with motivational feedback on several health outcomes using modern technology. Should this relatively simple programme prove successful, it will be made available on a wider scale internationally.; ClinicalTrials.gov Identifier: NCT01744561 ; Registration date: December 6, 2012

Subjective Distresses of Nasogastric Tube Feeding

Health care professionals assume that tube feeding is an unpleasant, distressing experience for patients, which is only partially substantiated by experience. Thirty patients were interviewed via a tube feeding and hospital experience checklist (a 47–item interview schedule). Common experiences were operationally defined as those felt by at least 50%; subjectively distressful experiences were those identified by patients as causing distress. The most common and most distressful experiences of nasogastric tube feeding were: sensory irritations and sensory deprivation. The psychosensory irritation experiences were: thirst, sore nose or throat, dry mouth, runny nose, a tube in the nose, taking food through a tube, breathing through the mouth, breathing with a tube in the nose, taking food in a treatment type container, and taking food with a different texture and smell than usual. The psychosensory deprivation experiences were: an unsatisfied appetite for certain foods, deprivation of tasting, chewing, swallowing food, and drinking liquids, limited mobility, and deprivation of regular food. Except for burping, gastrointestinal symptoms were not common though they were usually distressful. This information has been used to develop teaching programs which are being tested for effectiveness in reducing distress associated with nasogastric tube feeding.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68702/2/10.1177_014860717900300204.pd

Immunogenicity and Efficacy of Single Antigen Gp63, Polytope and PolytopeHSP70 DNA Vaccines against Visceral Leishmaniasis in Experimental Mouse Model

Polytope approach of genetic immunization is a promising strategy for the prevention of infectious disease as it is capable of generating effective cell mediated immunity by delivering the T cell epitopes assembled in series. Leishmaniasis is a significant world wide health problem for which no vaccine exists. In this study we have compared immunogenicity and efficacy of three types of DNA vaccines: single antigen Gp63 (Gp63/pcDNA), polytope (Poly/pcDNA) and Polytope fused with hsp70 (Poly/hsp/pcDNA) against visceral leishmaniasis in susceptible BALB/c mice. Mice vaccinated with these plasmids generated strong Th1 immune response as seen by dominating IFN-γ over IL-10 cytokine. Interestingly, cytotoxic responses generated by polytope DNA plasmid fused with hsp70 of Leishmania donovani were significantly higher when compared to polytope and single antigen Gp63 vaccine. Challenge studies revealed that the parasite load in liver and spleen was significantly lower with Poly/hsp/pcDNA vaccination compared to other vaccines. Therefore, our study indicates that polytope DNA vaccine is a feasible, practical and effective approach for visceral leishmaniasis