Angiotensin-converting Enzyme Inhibitors in Pediatric Patients with Mitral Valve Regurgitation—Case-control Study and Review of the Literature

Objectives. To investigate the effectiveness of chronic administration of angiotensin-converting enzyme inhibitors in pediatric patients with mitral valve regurgitation. Design, Setting, Patients, Interventions. This was a case-control study of all echocardiograms of patients with moderate-to-severe mitral valve regurgitation, who underwent chronic administration of angiotensin-converting enzyme inhibitors between January 1990 and December 2006 at a single center. Outcome Measures. Echocardiographic parameters (left ventricular end-diastolic diameter, left ventricular posterior wall diameter, interventricular septum diameter, left atrium to aortic root diameter ratio, grade of mitral valve regurgitation, shortening fraction) were analyzed before and during therapy with angiotensin-converting enzyme inhibitors in 12 patients and compared with 12 patients without medications after one month and one year. Results. Twenty-four consecutive pediatric patients (median age of 7 years with a range 1 month–16 years) with moderate-to-severe mitral valve regurgitation were included. Data are given as standard deviation scores (z-scores) derived from body-surface-adjusted normal values. During angiotensin-converting enzyme inhibition left ventricular end-diastolic diameter decreased from mean z-score 2.04 to 1.66 (after 1 month) and to 1.73 (after 1 year), while left ventricular posterior wall diameter decreased from 0.25 to 0.12 (after 1 year), respectively. Shortening fraction, interventricular septum diameter, grade of mitral valve regurgitation, and left atrium to aortic root diameter ratio remained stable. Conclusions. In this case-control study of patients with moderate-to-severe mitral valve regurgitation effectiveness of angiotensin-converting enzyme inhibition on left ventricular dimensions and function after 1 month and 1 year is limited. Reviewing the literature, the lack of long-term follow-up studies with large patient cohorts and controversial study-results in adults require a prospective long-term multicenter follow-up study in pediatric patients.     

Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis

Background

Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.

Methods

SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between “number of risk alleles” and “age at diagnosis,” adjusted for sex and study site and stratified by tumor grade/histology where appropriate.

Results

Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10⁻²² and P = 9.5 × 10⁻⁷, respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10⁻⁴ and P = 2.5 × 10⁻⁴, respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.

Conclusions

Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).     

Application of loop analysis for the qualitative assessment of surveillance and control in veterinary epidemiology

Background

Systems for animal disease mitigation involve both surveillance activities and interventions to control the disease. They are complex organizations that are described by partial or imprecise data, making it difficult to evaluate them or make decisions to improve them. A mathematical method, called loop analysis, can be used to model qualitatively the structure and the behavior of dynamic systems; it relies on the study of the sign of the interactions between the components of the system. This method, currently widely used by ecologists, has to our knowledge never been applied in the context of animal disease mitigation systems. The objective of the study was to assess whether loop analysis could be applied to this new context. We first developed a generic model that restricted the applicability of the method to event-based surveillance systems of endemic diseases, excluding the emergence and eradication phases. Then we chose the mitigation system of highly pathogenic avian influenza (HPAI) H5N1 in Cambodia as an example of such system to study the application of loop analysis to a real disease mitigation system.

Results

Breaking down the generic model, we constructed a 6-variables model to represent the HPAI H5N1 mitigation system in Cambodia. This construction work improved our understanding of this system, highlighting the link between surveillance and control which is unclear in traditional representations of this system. Then we analyzed the effect of the perturbations to this HPAI H5N1 mitigation system that we interpreted in terms of investment in a given compartment. This study suggested that increasing intervention at a local level can optimize the system’s efficiency. Indeed, this perturbation both decreases surveillance and intervention costs and reduces the disease’s occurrence.

Conclusion

Loop analysis can be applied to disease mitigation systems. Its main strength is that it is easy to design, focusing on the signs of the interactions. It is a simple and flexible tool that could be used as a precursor to large-scale quantitative studies, to support reflection about disease mitigation systems structure and functioning.

     

Cost Effectiveness of Romiplostim for the Treatment of Chronic Immune Thrombocytopenia in Ireland

Background

Romiplostim, a thrombopoietin receptor agonist (TPOra), is a second-line medical treatment option for adults with chronic immune thrombocytopenia (ITP). Clinical trials have shown that romiplostim increases platelet counts, while reducing the risk of bleeding and, in turn, the need for costly rescue medications.

Aims

The objective of this study was to assess the cost effectiveness of romiplostim in the treatment of adult ITP in Ireland, in comparison with eltrombopag and the medical standard of care (SoC).

Methods

A lifetime treatment-sequence cost-utility Markov model with embedded decision tree was developed from an Irish healthcare perspective to compare romiplostim with eltrombopag and SoC. The model was driven by platelet response (platelet count ≥50 × 10⁹/L), which determined effectiveness and progression along the treatment pathway, need for rescue therapy (e.g. intravenous immunoglobulin [IVIg] and steroids) and risk of bleeding. Probability of response, mean treatment duration, average time to initial response and utilities were derived from clinical trials and other published evidence. Treatment sequences and healthcare utilization practice were validated by Irish clinical experts. Costs were assessed in € for 2011 and included drug acquisition costs and costs associated with monitoring patients and management of bleeding, as available from published Irish reimbursement lists and other relevant sources. Deterministic and probabilistic sensitivity analyses were conducted.

Results

Romiplostim treatment resulted in an average of 20.2 fewer administrations of rescue medication (IVIg or intravenous steroids) over a patient lifetime than eltrombopag, and 29.3 fewer rescue medication administrations than SoC. Romiplostim was dominant, with cost savings of €13,258 and €22,673 and gains of 0.76 and 1.17 quality-adjusted life-years (QALYs), compared with eltrombopag and SoC, respectively. Romiplostim remained cost effective throughout a variety of potential scenarios, including short-term TPOra treatment duration (1 year). One-way sensitivity analysis showed that the model was most sensitive to variation in the cost of IVIg and use of romiplostim and IVIg. Probabilistic sensitivity analysis showed that romiplostim was likely to be cost effective in over 90 % of cases compared with eltrombopag, and 96 % compared with SoC at a willingness-to-pay threshold of €30,000 per QALY.

Conclusions

Use of romiplostim in the ITP treatment pathway, compared with eltrombopag or SoC, is likely to be cost effective in Ireland. Romiplostim improves clinical outcomes by increasing platelet counts, reducing bleeding events and the use of IVIg and steroids, resulting in both cost savings and additional QALYs when compared with current treatment practices.     

The natural cell-penetrating peptide crotamine targets tumor tissue in vivo and triggers a lethal calcium-dependent pathway in cultured cells

Our goal was to demonstrate the in vivo tumor specific accumulation of crotamine, a natural peptide from the venom of the South American rattlesnake Crotalus durissus terrificus, which has been characterized by our group as a cell penetrating peptide with a high specificity for actively proliferating cells and with a concentration-dependent cytotoxic effect. Crotamine cytotoxicity has been shown to be dependent on the disruption of lysosomes and subsequent activation of intracellular proteases. In this work, we show that the cytotoxic effect of crotamine also involves rapid intracellular calcium release and loss of mitochondrial membrane potential as observed in real time by confocal microscopy. The intracellular calcium overload induced by crotamine was almost completely blocked by thapsigargin. Microfluorimetry assays confirmed the importance of internal organelles, such as lysosomes and the endoplasmic reticulum, as contributors for the intracellular calcium increase, as well as the extracellular medium. Finally, we demonstrate here that crotamine injected intraperitoneally can efficiently target remote subcutaneous tumors engrafted in nude mice, as demonstrated by a noninvasive optical imaging procedure that permits in vivo real-time monitoring of crotamine uptake into tumor tissue. Taken together, our data indicate that the cytotoxic peptide crotamine can be used potentially for a dual purpose: to target and detect growing tumor tissues and to selectively trigger tumor cell death.