The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major.
We analyzed cardiac and liver T2* magnetic ...resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia.
Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.
Background Traumatic events are common globally; however, comprehensive population-based cross-national data on the epidemiology of posttraumatic stress disorder (PTSD), the paradigmatic ...trauma-related mental disorder, are lacking. Methods Data were analyzed from 26 population surveys in the World Health Organization World Mental Health Surveys. A total of 71 083 respondents ages 18+ participated. The Composite International Diagnostic Interview assessed exposure to traumatic events as well as 30-day, 12-month, and lifetime PTSD. Respondents were also assessed for treatment in the 12 months preceding the survey. Age of onset distributions were examined by country income level. Associations of PTSD were examined with country income, world region, and respondent demographics. Results The cross-national lifetime prevalence of PTSD was 3.9% in the total sample and 5.6% among the trauma exposed. Half of respondents with PTSD reported persistent symptoms. Treatment seeking in high-income countries (53.5%) was roughly double that in low-lower middle income (22.8%) and upper-middle income (28.7%) countries. Social disadvantage, including younger age, female sex, being unmarried, being less educated, having lower household income, and being unemployed, was associated with increased risk of lifetime PTSD among the trauma exposed. Conclusions PTSD is prevalent cross-nationally, with half of all global cases being persistent. Only half of those with severe PTSD report receiving any treatment and only a minority receive specialty mental health care. Striking disparities in PTSD treatment exist by country income level. Increasing access to effective treatment, especially in low- and middle-income countries, remains critical for reducing the population burden of PTSD.
Heart failure treatment depends partly on the underlying cause of the disease. We evaluated cardiovascular magnetic resonance (CMR) for the problem of differentiating dilated cardiomyopathy (DCM) ...from left ventricular (LV) dysfunction caused by coronary artery disease (CAD).
Late gadolinium enhancement with CMR was performed in 90 patients with heart failure and LV systolic dysfunction (63 patients with DCM and unobstructed coronary arteries and 27 with significant CAD at angiography). We also studied 15 control subjects with no coronary risk factors and/or unobstructed coronary arteries. None (0%) of the control subjects had myocardial gadolinium enhancement; however, all patients (100%) with LV dysfunction and CAD had enhancement, which was subendocardial or transmural. In patients with DCM, there were 3 findings: no enhancement (59%); myocardial enhancement indistinguishable from the patients with CAD (13%); and patchy or longitudinal striae of midwall enhancement clearly different from the distribution in patients with CAD (28%).
Gadolinium CMR is a powerful technique to distinguish DCM from LV dysfunction related to CAD and yields new insights in DCM. These data suggest that using the coronary angiogram as the arbiter for the presence of LV dysfunction caused by CAD could have lead to an incorrect assignment of DCM cause in 13% of patients, possibly because of coronary recanalization after infarction. The midwall myocardial enhancement in patients with DCM is similar to the fibrosis found at autopsy; it has not previously been visualized in vivo and warrants further investigation. CMR may become a useful alternative to routine coronary angiography in the diagnostic workup of DCM.
Cardiac complications secondary to iron overload are the leading cause of death in beta-thalassemia major. Approximately two thirds of patients maintained on the parenteral iron chelator deferoxamine ...have myocardial iron loading. The oral iron chelator deferiprone has been demonstrated to remove myocardial iron, and it has been proposed that in combination with deferoxamine it may have additional effect.
Myocardial iron loading was assessed with the use of myocardial T2* cardiovascular magnetic resonance in 167 patients with thalassemia major receiving standard maintenance chelation monotherapy with subcutaneous deferoxamine. Of these patients, 65 with mild to moderate myocardial iron loading (T2* 8 to 20 ms) entered the trial with continuation of subcutaneous deferoxamine and were randomized to receive additional oral placebo (deferoxamine group) or oral deferiprone 75 mg/kg per day (combined group). The primary end point was the change in myocardial T2* over 12 months. Secondary end points of endothelial function (flow-mediated dilatation of the brachial artery) and cardiac function were also measured with cardiovascular magnetic resonance. There were significant improvements in the combined treatment group compared with the deferoxamine group in myocardial T2* (ratio of change in geometric means 1.50 versus 1.24; P=0.02), absolute left ventricular ejection fraction (2.6% versus 0.6%; P=0.05), and absolute endothelial function (8.8% versus 3.3%; P=0.02). There was also a significantly greater improvement in serum ferritin in the combined group (-976 versus -233 microg/L; P<0.001).
In comparison to the standard chelation monotherapy of deferoxamine, combination treatment with additional deferiprone reduced myocardial iron and improved the ejection fraction and endothelial function in thalassemia major patients with mild to moderate cardiac iron loading.
To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug ...monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity.
A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency.
Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52).
These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.
The safety and pharmacokinetic (PK)/pharmacodynamic (PD) profile of the novel CCR1 antagonist CCX354 was evaluated in double‐blind, placebo‐controlled, single‐ and multiple‐dose phase I studies ...(1–300 mg/day oral doses). CCX354 was well tolerated and displayed a linear dose–exposure profile, with half‐life approaching 7 h at the 300‐mg dose. The extent of CCR1 receptor blockade on blood monocytes, which correlated well with plasma concentrations of the drug, was assessed using fluorescently labeled CCL3 binding in whole blood from phase I subjects. High levels of receptor coverage at the 12‐h time point were achieved after a single dose of 100 mg CCX354. Preclinical studies indicate that effective blockade of inflammatory cell infiltration into tissues requires ≥90% CCR1 inhibition on blood leukocytes at all times. The comparison of the properties of CCX354 with those published for other CCR1 antagonists has informed the dose selection for ongoing clinical development of CCX354 in rheumatoid arthritis (RA).
Clinical Pharmacology & Therapeutics (2011) 89 5, 726–734. doi:10.1038/clpt.2011.33
Recent advances in cardiovascular magnetic resonance (CMR) include improved image quality with steady-state free precession (SSFP) sequences and advanced post-processing of high temporal resolution ...ventricular function. We used these techniques to establish the reference values for right ventricular (RV) volumes and function.
We studied 120 healthy subjects (60 men, 60 women; from 20 to 80 years) after exclusion of cardiovascular abnormality. Data were generated from SSFP cines, with three-dimensional modelling. Gender, body surface area (BSA), and age were independent predictors of several RV parameters. Normalized RV mass (RVM) and absolute and normalized RV volumes decreased significantly with age, whereas ejection fraction increased. For diastolic variables, absolute and normalized early peak filling rate (PFR(E)) decreased and absolute and normalized active peak filling rate (PFR(A)) in males increased, with decreased PFR(E)/PFR(A). Increasing BSA was associated with increased RVM, volumes, and PFR(E). Gender significantly influenced absolute and normalized mass and volumes, and absolute and normalized PFR(A).
These data using state-of-the-art CMR show that normal values of RV systolic and diastolic parameters vary significantly by gender, BSA, and age. Appropriate reference ranges normalized to all three variables should be used in the determination of normality or severity of abnormality of RV dimensions and function.
Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies ...have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children.
The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children.
A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96-103) and nonbreastfed = 98 (95-101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups.
This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy.
We used state of the art CMR to define ranges for normal left ventricular volumes and systolic/diastolic function normalized to the influence of gender, body surface area and age. New CMR normalized ...ranges were modeled and displayed in graphical form for clinical use, with normalization for body surface area, gender, and age. The determination of normality, or the severity of abnormality, depends on the use of the appropriate reference ranges normalized to all 3 variables. These novel data have particular importance for clinical practice and clinical trials using CMR.
Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized ...controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2*) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral deferiprone monotherapy. The dose of deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% ± 5.3% and 93% ± 9.7% (P = .81), respectively. The improvement in myocardial T2* was significantly greater for deferiprone than deferoxamine (27% vs 13%; P = .023). Left ventricular ejection fraction increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P = .003). The changes in liver iron level (-0.93 mg/g dry weight vs -1.54 mg/g dry weight; P = .40) and serum ferritin level (-181 μg/L vs -466 μg/L; P = .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for deferiprone-treated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major.
PDF
