Longitudinal study of echocardiography-derived tricuspid regurgitant jet velocity in sickle cell disease.

Although echocardiography-derived tricuspid regurgitant jet velocity (TRV) is associated with increased mortality in sickle cell disease (SCD), its rate of increase and predictive markers of its progression are unknown. We evaluated 55 subjects (median age: 38 years, range: 20-65 years) with at least two measurable TRVs, followed for a median of 4·5 years (range: 1·0-10·5 years) in a single-centre, prospective study. Thirty-one subjects (56%) showed an increase in TRV, while 24 subjects (44%) showed no change or a decrease in TRV. A linear mixed effects model indicated an overall rate of increase in the TRV of 0·02 m/s per year (P = 0·023). The model showed that treatment with hydroxycarbamide was associated with an initial TRV that was 0·20 m/s lower than no such treatment (P = 0·033), while treatment with angiotensin converting enzyme inhibitors and angiotensin receptor blockers was associated with an increase in the TRV (P = 0·006). In summary, although some patients have clinically meaningful increases, the overall rate of TRV increase is slow. Treatment with hydroxycarbamide may decrease the progression of TRV. Additional studies are required to determine the optimal frequency of screening echocardiography and the effect of therapeutic interventions on the progression of TRV in SCD.

Predicting institutional violence in offenders with intellectual disabilities: the predictive efficacy of the VRAG and the HCR-20.

BACKGROUND: There is a developing evidence base to support the use of risk assessment instruments in offenders with intellectual disability (ID). The aim of this study was to try to develop this literature with the inclusion of a control group of mentally disordered offenders without an ID, using the HCR-20 and VRAG. MATERIALS AND METHODS: The VRAG and the HCR-20 were completed for a group of offenders with an ID (n = 25) and a control group (n = 45), in four medium-secure units across the UK. The outcome measure was physical aggression measured over 6 months. RESULTS: Both instruments consistently produced large effect sizes predicting any physical aggression and severe physical aggression. The structured clinical judgement based on the HCR-20 was especially good. CONCLUSIONS: The HCR-20 and the VRAG have excellent predictive efficacy in offenders with an ID. A structured clinical judgement based on the HCR-20 was especially predictive.

Placenta growth factor in sickle cell disease: association with hemolysis and inflammation.

Placenta growth factor (PlGF) is released by immature erythrocytes and is elevated in sickle cell disease (SCD). Previous data generated in vitro suggest that PlGF may play a role in the pathophysiology of SCD-associated pulmonary hypertension (PHT) by inducing the release of the vasoconstrictor, endothelin-1. In this cross-sectional study of 74 patients with SCD, we confirm that PlGF is significantly elevated in SCD compared with healthy control subjects. We found significantly higher levels of PlGF in SCD patients with PHT but observed no association of PlGF with the frequency of acute pain episodes or history of acute chest syndrome. The observed correlation between PlGF and various measures of red cell destruction suggests that hemolysis, and the resultant erythropoietic response, results in the up-regulation of PlGF. Although relatively specific, PlGF, as well as N-terminal pro-brain natriuretic peptide and soluble vascular cell adhesion molecule, has low predictive accuracy for the presence of PHT. Prospective studies are required to conclusively define the contribution of PlGF to the pathogenesis of PHT and other hemolytic complications in SCD.

Association of soluble fms-like tyrosine kinase-1 with pulmonary hypertension and haemolysis in sickle cell disease.

The pathophysiology of pulmonary hypertension (PHT) in sickle cell disease (SCD) is probably multifactorial. Soluble fms-like tyrosine kinase-1 (sFLT-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family. By adhering to and inhibiting VEGF and placenta growth factor, it induces endothelial dysfunction. We sought to evaluate the association of sFLT-1 with clinical complications of SCD. We confirmed that sFLT-1 was significantly elevated in SCD patients compared to healthy, race-matched control subjects. The level of sFLT-1 was significantly higher in patients with PHT, but no association was observed between sFLT-1 and the frequency of acute pain episodes or history of acute chest syndrome. sFLT-1 was correlated with various measures of haemolysis, erythropoietin and soluble vascular cell adhesion molecule-1. By inducing endothelial dysfunction, sFLT-1 may contribute to the pathogenesis of SCD-associated PHT, although this effect does not appear to be independent of haemolysis.

Urinary albumin excretion is associated with pulmonary hypertension in sickle cell disease: potential role of soluble fms-like tyrosine kinase-1.

BACKGROUND: Pulmonary hypertension (PHT) is reported to be associated with measures of renal function in patients with sickle cell disease (SCD). The purpose of this exploratory study was to determine the relationship between albuminuria and both clinical and laboratory variables in SCD. DESIGN AND METHODS: This cross-sectional study was performed using a cohort of adult patients with SCD and control subjects without SCD. Spot urine for microalbumin/creatinine ratio, measures of hemolysis, inflammation and other laboratory studies were obtained. Pulmonary artery systolic pressure was determined by Doppler echocardiography, and the diagnosis of PHT was defined using age-, sex- and body mass index-adjusted reference ranges. RESULTS: Seventy-three patients with SCD and 21 healthy, race-matched control subjects were evaluated. In patients with SCD, normoalbuminuria was observed in 34 patients (46.6%), microalbuminuria in 24 patients (32.9%) and macroalbuminuria in 15 patients (20.5%). There was a significant correlation between urine albumin excretion and age. In patients with HbSS and Sbeta(0) thalassemia, the levels of sFLT-1, soluble VCAM and NT pro-BNP were significantly higher in those with macroalbuminuria, compared to patients with microalbuminuria and normoalbuminura, but no significant differences were observed in the levels of laboratory measures of hemolysis. Urine albumin excretion was associated with PHT and a history of stroke. CONCLUSIONS: Our study confirms the high prevalence of albuminuria in SCD. The association of urine albumin excretion with sFLT-1 suggests that this vascular endothelial growth factor receptor family member may contribute to the development of albuminuria in SCD. By inducing endothelial activation and endothelial dysfunction, sFLT-1 appears to be a link between glomerulopathy and PHT in SCD.

Carbamate prodrugs of N-alkylfuramidines.

The synthesis and evaluation of 2,5-bis[4-(N-ethoxycarbonyl-N'-isopropyl)amidinophenyl]furan, 2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl-N'-isopropyl)amidinophenyl]furan and 2,5-bis[4-(N-cyclopentyl-N'-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan as prodrugs of bis-N-alkylamidines are reported. The results show that the bis-2,2,2-trichloroethyl carbamates function effectively in a rat model for Pneumocystis pneumonia.

Hyperglycemia and infections in pediatric trauma patients.

Hyperglycemia has been associated with poor outcome in children with head injuries and burns. However, there has not been a correlation noted between hyperglycemia and infections in severely injured children. The trauma registry of a Level I trauma center was queried for injured children <13 years admitted between July 1, 1999 and August 31, 2003. The records of severely injured children [Injury Severity Score (ISS) > 15] were examined for survival, age, weight, ISS, infection, length of stay (LOS), and maximum glucose levels within the first 24 hours of injury (D1G). Statistical analysis was performed using a t test, Fisher's exact test, a Mann-Whitney Rank Sum test, or Kendall's Tau where appropriate. Eight hundred and eighty eight children under 13 years of age were admitted. One hundred and nine had an ISS > 15, and 57 survived to discharge with measured D1G. Patients excluded were those who died in less than 72 hours or had an LOS less than 72 hours. The survivors were divided into high glucose (> or =130 mg/dL; n = 48) and normal glucose (<130 mg/dL; n = 9). There was no difference between the groups with respect to age, weight, incidence of head injury, and ISS. An elevated D1G correlated with an increased risk of infection (P = 0.05) and an increased LOS (P = 0.01). These data suggest that severely injured children are often hyperglycemic in the first 24 hours after injury. Hyperglycemia in this study population correlated with an increased incidence of infection and increased length of stay. This suggests that strict control of hyperglycemia in injured children may be beneficial.

The Arkansas aging initiative: an innovative approach for addressing the health of older rural Arkansans.

The Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences in Little Rock is addressing one of the most pressing policy issues facing the United States: how to care for the burgeoning number of older adults. In 2001, the Institute created the Arkansas Aging Initiative, which established seven satellite centers on aging across the state using $1.3 to $2 million dollars annually from the state's portion of the Master Tobacco Settlement. These centers on aging assist the state's population of older adults, many of whom reside in rural areas, live in poverty, and suffer from poor health. The centers provide multiple avenues of education for the community, health care providers, families, and caregivers. The Arkansas Aging Initiative, in partnership with local hospitals, also makes geriatric primary and specialty care more accessible through senior health clinics established across rural Arkansas. In 2005, older adults made more than 36,000 visits to these clinics. All sites have attracted at least one physician who holds a Certificate of Added Qualifications in geriatrics and one advanced practice nurse. Other team members include geriatric medical social workers, pharmacists, nutritionists, and neuropsychologists. This initiative also addresses other policy issues, including engaging communities in building partnerships and programs crucial to maximizing their limited resources and identifying opportunities to change reimbursement mechanisms for care provided to the growing number of older adults. We believe this type of program has the potential to create a novel paradigm for nationwide implementation.

Assessment of medication management by community-living elderly persons with two standardized assessment tools: a cross-sectional study.

BACKGROUND: The ability of patients to adhere to a medication regimen is imperative for achieving optimal outcomes. Elderly patients, especially those with memory loss, should be evaluated for their ability to manage medications to prevent significant drug-related problems. Assessment tools to determine the ability to manage medication therapy have not been tested in elderly patients with cognitive impairment. OBJECTIVES: This study compared the Medication Management Ability Assessment (M1V1AA) and the Drug Regimen Unassisted Grading Scale (DRUGS) as standardized tools to assess medication management skills in elderly patients with a range of cognitive function and evaluated the association between the results obtained from these scales and self-reported drug-related problems. METHODS: This was a cross-sectional study of older individuals living in the community. At a scheduled study visit, the research assistant (RA) questioned participants with a structured interview to document demographic information, medical history, prescription use, over-the-counter drug and dietary supplement use, health care resource use, medication management practices, and adverse drug events. Cognitive status was assessed with the Mini-Mental State Examination (MMSE) and functional status with the instrumental activities of daily living rating scale. The MMAA, which uses a fictitious medication regimen with labeled prescription bottles, and the DRUGS, which uses the patient's own prescription bottles, were administered. Three months after the visit, the RA telephoned participants to determine recent changes in living situation and drug-related problems. RESULTS: The study group comprised 52 people with a mean (SD) MMSE score of 28.3 (2.5). The participants had a mean (SD) age of 75.8 (6.2) years; 69% (36/52) were women, and 96% (50/52) were white. Participants reported an average of 4.1 medical conditions, and 88% (46/52) reported good to excellent health. Skipping doses or cutting them in half was reported by 25% (13/52) of participants who adjusted doses themselves. Almost half (44%) reported medication problems and/or medication ineffectiveness during the past 3 months at both the study visit and the 3-month follow-up (23/52 for both). The 49 participants who took the MMAA had a mean (SD) score of 19.4 (6.1), with a range of 0 to 25. Of the 49 participants with scores, 34 took less than the correct number of tablets and 13 took more. The 46 participants who took the DRUGS had a mean (SD) score of 91.6 (24.7), with a range of 0 to 100. Forty of 46 participants attempting the test attained the maximum score. Higher scores for both tests indicate better accuracy. Analysis revealed that the MMAA and the DRUGS correlated with one another (P = 0.000). We found no significant associations between these medication management assessment tools and selfreported adherence or drug-related events. CONCLUSIONS: The MMAA and DRUGS tools correlated positively with cognitive function in this population of community-living elderly persons but need further evaluation of their ability to predict who is at greatest risk for drug related problems due to nonadherence to medication regimens.

Albuminuria Is Associated with Endothelial Dysfunction and Elevated Plasma Endothelin-1 in Sickle Cell Anemia.

BACKGROUND: The pathogenesis of albuminuria in SCD remains incompletely understood. We evaluated the association of albuminuria with measures of endothelial function, and explored associations of both albuminuria and measures of endothelial function with selected biological variables (vascular endothelial growth factor [VEGF], endothelin-1 [ET-1], soluble fms-like tyrosine kinase-1 [sFLT-1], soluble vascular cell adhesion molecule-1 [soluble VCAM-1] and plasma hemoglobin). METHODS: Spot urine measurements for albumin-creatinine ratio (UACR) and 24-hour urine protein were obtained. Endothelial function was assessed using brachial artery ultrasound with measurements of flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NTMD) and hyperemic velocity. RESULTS: Twenty three subjects with varying degrees of albuminuria were evaluated. UACR was significantly correlated with FMD (ρ = -0.45, p = 0.031). In univariate analysis, UACR was correlated with VEGF (ρ = -0.49; 95% CI: -0.75 --0.1, p = 0.015), plasma hemoglobin (ρ = 0.50; 95% CI: 0.11-0.75, p = 0.013) and ET-1 (ρ = 0.40; 95% CI: -0.03-0.69, p = 0.06). Multivariable analysis showed significant associations of ET-1 (estimate: 455.1 [SE: 198.3], p = 0.02), VEGF (estimate: -1.1 [SE: 0.53], p = 0.04) and sFLT-1 (estimate: -1.14 [SE: 0.49], p = 0.02) with UACR. Only ET-1 (estimate: -8.03 [SE: 3.87], p = 0.04) was significantly associated with FMD in multivariable analyses. Finally, UACR was correlated with both 24-hour urine protein (ρ = 0.90, p < 0.0001) and urine aliquots for albumin-creatinine ratio obtained from the 24-hour urine collection (ρ = 0.97, p < 0.0001). CONCLUSION: This study provides more definitive evidence for the association of albuminuria with endothelial dysfunction in SCD. Elevated circulating levels of ET-1 may contribute to SCD-related glomerulopathy by mediating endothelial dysfunction.

Chemotherapy of second stage human African trypanosomiasis: comparison between the parenteral diamidine DB829 and its oral prodrug DB868 in vervet monkeys.

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT.

Pentamidine Congeners 1: Synthesis of Cis- and Trans-Butamidine Analogues As Anti-Pneumocystis carinii Pneumonia Agents.

Butamidine analogues possessing unsaturation in the ether bridge between the bisamidinophenyl or bisimidazolinophenyl functionalities have been synthesized as semirigid congeners of pentamidine. These compounds demonstrated good anti-P. carinii pueumonia activity in a rat model of the disease.

Surgeon-directed ultrasound for trauma is a predictor of intra-abdominal injury in children.

This study investigated the efficacy of surgeon-directed focused assessment with sonography for trauma (FAST) in conjunction with physical exam (PEx) as a predictor of intra-abdominal injury in children. Injured children (ages < or = 17) presenting to a level I trauma center with abdominal trauma were evaluated in the emergency department (ED) by the trauma team of surgical attendings and residents. PEx and FAST were performed immediately upon arrival to the ED and results compared to CT, the standard exam for presence of intra-abdominal injury. Data was collected prospectively from July 1, 2000, until April 30, 2002. One hundred and twenty injured children underwent evaluation of abdominal trauma with PEx, FAST, and abdominal CT. Two patients had false-negative CT scans. Bayesian analysis was applied to the results of the remaining 118 patients. FAST compared with CT findings revealed sensitivity 70 per cent, specificity 100 per cent, positive predictive value 100 per cent, and negative predictive value 92 per cent. FAST results were combined with PEx findings such that either suggestive of intra-abdominal injury was regarded as a "positive exam." Sensitivity was 100 per cent, specificity 74 per cent, positive predictive value 53 per cent, and negative predictive value 100 per cent. Surgeon-directed FAST with consideration of PEx is a predictor of intra-abdominal injury in children.

An algorithm for train-of-four monitoring in patients receiving continuous neuromuscular blocking agents.

Neuromuscular blocking agents (NMBA) are increasingly being used in the management of critically ill patients. These medications are used to facilitate mechanical ventilation. Strange and colleagues estimated that only 4% of intensive care units utilize train-of-four (TOF) monitoring on a regular basis and that 70% never use this type of monitoring. The ease of use and low cost of the equipment lends itself to the increasingly frequent recommendations for this type of monitoring. Although unwilling to go so far as to establish this as a standard of care, the American College of Critical Care Medicine of the Society of Critical Care Medicine released an executive summary recommending train-of-four monitoring for patients receiving continuous or sustained NMBAs. This protocol and algorithm was developed to facilitate the objective monitoring of patients receiving continuous NMBAs.

A pilot study of eptifibatide for treatment of acute pain episodes in sickle cell disease.

INTRODUCTION: The contribution of platelet activation to the pathogenesis of sickle cell disease (SCD) remains uncertain. We evaluated the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the αIIbß3 receptor, in SCD patients during acute painful episodes. MATERIALS AND METHODS: In this single site, double-blind, placebo-controlled trial, eligible patients with SCD admitted for acute painful episodes were randomized to receive eptifibatide or placebo at a ratio of 2:1. RESULTS: Thirteen patients (SS - 10, Sß(0) - 2, SC - 1) were randomized to receive either eptifibatide (N=9; 6 females; median age - 25years) or placebo (N=4; 3 females; median age - 31years). In the intent-to-treat analysis, there were no major bleeding episodes in either the eptifibatide or placebo arms (point estimate of difference: 0.00, 95% CI; -0.604, 0.372). There was one minor bleeding episode in the eptifibatide arm (point estimate of difference for any bleeding: 0.11, 95% CI: -0.502, 0.494). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference: 0.11, 95% CI: -0.587, 0.495). There were no differences in the median times to discharge, median times to crisis resolution or the median total opioid use. CONCLUSIONS: In this small study, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Adequately powered studies are required to evaluate the safety and efficacy of eptifibatide in SCD. Clinicaltrials.gov Identifier: NCT00834899.

Hemodynamic characteristics and predictors of pulmonary hypertension in patients with sickle cell disease.

Pulmonary hypertension is a common co-morbidity of sickle cell disease with an associated increased mortality risk, but its etiology is not well-understood. To evaluate the hemodynamic characteristics, clinical predictors, and cardiovascular manifestations of elevated pulmonary arterial pressure in this population, we performed noninvasive hemodynamic assessments of 135 patients with sickle cell disease using Doppler echocardiography. A diagnosis of pulmonary hypertension was determined by gender-, age-, and body mass index-specific normal reference ranges for tricuspid regurgitation jet velocities (TRVs). A high TRV was noted in 34 patients (25%). Pulmonary vascular resistance was elevated in only 2 (6%) of the 34 patients with suspected pulmonary hypertension but was significantly greater than in those with normal TRV. On univariate regression, the TRV correlated with age, body mass index, left atrial pressure, and right ventricular stroke volume and was negatively associated with hemoglobin and glomerular filtration rate. The left atrial pressure, right ventricular stroke volume, and hemoglobin remained independent predictors of TRV in a multivariate model. A greater TRV was also associated with larger right ventricular and right atrial chamber sizes and greater N-terminal probrain natriuretic peptide levels. In conclusion, our results suggest that the mild elevation in TRV often observed in patients with sickle cell disease is rarely associated with a high pulmonary vascular resistance and that multiple factors-including the compensatory high output state associated with anemia, pulmonary venous hypertension, and pulmonary vasculopathy-can contribute to an elevated pulmonary arterial pressure in these patients.