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Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals
Background:
Use of fenfluramines for weight loss has been associated with the development of characteristic plaques on cardiac valves causing regurgitation. However, previously published studies of exposure to fenfluramines have been limited by relatively small sample size, short duration of follow-up, and the lack of any estimate of the frequency of subsequent valvular surgery. We performed an observational study of 5743 users of fenfluramines examined by echocardiography between July 1997 and February 2004 in a single large cardiology clinic.
Results:
The prevalence of at least mild aortic regurgitation (AR) or moderate mitral regurgitation (MR) was 19.6% in women and 11.8% in men (p < 0.0001 for gender difference). Duration of use was strongly predictive of mild or greater AR (p < 0.0001 for trend), MR (p = 0.002), and tricuspid regurgitation (TR) (p < 0.0001), as was earlier scan date (p < 0.0001 for those scanned prior to 1 January 2000 versus later). Increasing age was also independently associated with increased risk of AR and MR (both p < 0.0001). With mean follow-up of 30.3 months, AR worsened in 15.2%, remained the same in 63.1%, and improved in 21.7%. Corresponding values for MR were 24.8%, 47.4% and 27.9%. Pulmonary hypertension was strongly associated with MR but not AR. Valve surgery was performed on 38 patients (0.66% of 5743), 25 (0.44%) with clear evidence of fenfluramine-related etiology.
Conclusion:
Regurgitant valvulopathy was common in individuals exposed to fenfluramines, more frequent in females, and associated with duration of use in all valves assessed. Valve surgery was performed as frequently for aortic as mitral valves and some tricuspid valve surgeries were also performed. The incidence of surgery appeared to be substantially increased compared with limited general population data.
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LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, which affects about 2% of the population over age 60. In 2004 mutations in the LRRK2 gene were first described, that turned out to be the most frequent genetic cause of familial and sporadic PD and may account up to 40% of PD patients in distinct populations. Based on these findings Latourelle and colleagues show that the penetrance of the most common LRRK2 mutation is higher in familial compared to sporadic PD patients and identified a substantial number of affected relatives of mutation carriers not presenting with a LRRK2 mutation themselves. This commentary discusses the role of genetic and/or environmental susceptibility factors modulating the expressivity of the disease trait, how these factors may contribute to the phenomenon of phenocopies in genetically defined PD pedigrees, and how the findings of Latourelle and colleagues, published this month in BMC Medicine relate to current concepts of genetic counselling.
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The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's Disease: the GenePD study
Background:
We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2) related Parkinson's disease in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5-6% of familial PD cases and 1-2% of idiopathic cases making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including particularly differences between samples of familial PD versus sporadic PD.
Methods:
A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD affected members, 126 randomly ascertained PD patients and 197 controls, was screened for 5 different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.
Results:
Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while 2 had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the un-biased estimated penetrance was 67% for G2019S families, compared to a baseline PD risk of 17% seen in the non-LRRK2 related PD families.
Conclusions:
Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of 9 PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2 related PD. No differences in penetrance were found between men and women suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.
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25 years of HIV-1 research – progress and perspectives
Twenty-five years after the discovery and isolation of the human immunodeficiency virus by French and American scientists, much progress has been made in basic research, clinical treatment, and public health prevention measures for acquired immunodeficiency syndrome. Here, we summarize, in brief, advances that have been achieved and provide some perspectives on future challenges.
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Lack of association of two common polymorphisms on 9p21 with risk of coronary heart disease and myocardial infarction; results from a prospective cohort study
Background:
Recent genome wide association (GWA) studies identified two Single Nucleotide Polymorphisms (SNP) (rs10757278 and rs10757274) in the region of the CDK2NA and CDK2NB genes to be consistently associated with the risks of coronary heart disease (CHD) and myocardial infarction (MI). We examined the SNPs in relation to the risk of CHD and MI in a large population based study of elderly population.
Methods:
The Rotterdam Study is a population-based, prospective cohort study among 7983 participants aged 55 years and older. Associations of the polymorphisms with CHD and MI were assessed by use of Cox proportional hazards analyses.
Results:
In an additive model, the age and sex adjusted hazard ratios (HRs) (95% confidence interval) for CHD and MI were 1.03 (0.90, 1.18) and 0.94 (0.82, 1.08) per copy of the G allele of rs10757274. The corresponding HRs were 1.03 (0.90, 1.18) and 0.93 (0.81, 1.06) for the G allele of rs10757278. The association of the SNPs with CHD and MI was not significant in any of the subgroups of CHD risk factors.
Conclusion:
we were not able to show an association of the studied SNPs with risks of CHD and MI. This may be due to differences in genes involved in the occurrence of CHD in young and older people.
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The problems of meta-analysis for antibiotic treatment of chronic obstructive pulmonary disease, a heterogeneous disease: a commentary on Puhan et al
Exacerbations are a major cause of morbidity and mortality in chronic obstructive pulmonary disease. Exacerbations can be of bacterial, viral or mixed etiology, with bacteria involved in 50% of exacerbations. Consequently, current management of exacerbations frequently involves the use of antibiotics. The paper by Puhan et al published this month in BMC Medicine examines the benefit of antibiotics in placebo-controlled trials in mild to moderate outpatient exacerbations. The authors use a meta-analytic approach and rightly conclude that more trials are needed in this area. However, the heterogeneity of chronic obstructive pulmonary disease patients and exacerbations and the limited end-points in past trials do not allow firm conclusions to be drawn about antibiotic use in outpatient exacerbations based on this meta-analysis. Future trials need to take into account this heterogeneity as well as incorporate novel end-points to address this important issue.
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Where is the supporting evidence for treating mild to moderate chronic obstructive pulmonary disease exacerbations with antibiotics? A systematic review
Background:
Randomised trials comparing different drugs head-to-head are extremely valuable for clinical decision-making. However, it is scientifically and ethically sensible to demand strong evidence that a drug is effective by showing superiority over a placebo before embarking on head-to-head comparisons of potentially ineffective drugs. Our aim was to study the evolvement of evidence from placebo-controlled and head-to-head trials on the effects of antibiotics for the treatment of mild to moderate exacerbations of chronic obstructive pulmonary disease.
Methods:
We conducted a historical systematic review. Through electronic databases and hand-searches, we identified placebo-controlled and head-to-head antibiotic trials for the treatment of mild to moderate chronic obstructive pulmonary disease exacerbations. We compared the numbers of patients recruited in placebo-controlled and head-to-head trials between 1957 and 2005. Using cumulative meta-analysis of placebo-controlled trials, we determined when, if ever, placebo-controlled trials had shown convincing evidence that antibiotics are effective in preventing treatment failure in patients with mild to moderate chronic obstructive pulmonary disease exacerbations.
Results:
The first head-to-head trial was published in 1963. It was followed by another 100 trials comparing different antibiotics in a total of 34,029 patients with mild to moderate chronic obstructive pulmonary disease exacerbations. Over time, the cumulative odds ratio in placebo-controlled trials remained inconclusive throughout with odds ratios ranging from 0.39 (95% confidence intervals 0.04–4.22) to the most recent estimate (1995) of 0.81 (95% confidence intervals 0.52–1.28, P = 0.37).
Conclusion:
Placebo-controlled trials do not support the use of antibiotics in chronic obstructive pulmonary disease patients with mild to moderate exacerbations. Conducting head-to-head trials is, therefore, scientifically and ethically questionable. This underscores the requirement to perform or study systematic reviews of placebo-controlled trials before conducting head-to-head trials.
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Germline polymorphisms as modulators of cancer phenotypes
Identifying the complete repertoire of genes and genetic variants that regulate the pathogenesis and progression of human disease is a central goal of post-genomic biomedical research. In cancer, recent studies have shown that genome-wide association studies can be successfully used to identify germline polymorphisms associated with an individual's susceptibility to malignancy. In parallel to these reports, substantial work has also shown that patterns of somatic alterations in human tumors can be successfully employed to predict disease prognosis and treatment response. A paper by Van Ness et al. published this month in BMC Medicine reports the initial results of a multi-institutional consortium for multiple myeloma designed to evaluate the role of germline polymorphisms in influencing multiple myeloma clinical outcome. Applying a custom-designed single nucleotide polymorphism microarray to two separate patient cohorts, the investigators successfully identified specific combinations of germline polymorphisms significantly associated with early clinical relapse. These results raise the exciting possibility that besides somatically acquired alterations, germline genetic background may also exert an important influence on cancer patient prognosis and outcome. Future 'personalized medicine' strategies for cancer may thus require incorporating genomic information from both tumor cells and the non-malignant patient genome.
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Genomic variation in myeloma: design, content, and initial application of the Bank On A Cure SNP Panel to detect associations with progression-free survival
Background:
We have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma.We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials.
Results:
Quality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes.
Conclusion:
A targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS.
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Association between umbilical cord glucocorticoids and blood pressure at age 3 years
Background:
Animal data show that decreased activity of placental 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which potently inactivates glucocorticoids (e.g. cortisol) to inert forms (cortisone), allows increased access of maternal glucocorticoids to the fetus and 'programs' hypertension. Data in humans are limited. We examined in humans the association between venous umbilical cord blood glucocorticoids, a potential marker for placental 11β-HSD2 enzyme activity, and blood pressure at age 3 years.
Methods:
Among 286 newborns in Project Viva, a prospective pre-birth cohort study based in eastern Massachusetts, we measured cortisol (F) and cortisone (E) in venous cord blood and used the ratio of F/E as a marker for placental 11β-HSD2 activity. We measured blood pressure (BP) when the offspring reached age 3 years. Using mixed effects regression models to control for BP measurement conditions, maternal and child characteristics, we examined the association between the F/E ratio and child BP.
Results:
At age 3 years, each unit increase in the F/E ratio was associated with a 1.6 mm Hg increase in systolic BP (95% CI 0.0 to 3.1). The F/E ratio was not associated with diastolic blood pressure or birth weight for gestational age z-score.
Conclusion:
A higher F/E ratio in umbilical venous cord blood, likely reflecting reduced placental 11β-HSD2 activity, was associated with higher systolic blood pressure at age 3 years. Our data suggest that increased fetal exposure to active maternal glucocorticoids may program later systolic blood pressure.
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