Citations

Nucleoside and nucleobase uptake is integral to mammalian cell function, and its disruption has significant effects on the cardiovasculature. The predominant transporters in this regard are the equilibrative nucleoside transporter subtypes 1 (ENT1) and 2 (ENT2). To examine the role of ENT1 in more detail, we have assessed the mechanisms by which microvascular endothelial cells (MVECs) from ENT1−/−mice transport and metabolize nucleosides and nucleobases. Wild-type murine MVECs express mainly the ENT1 subtype with only trace levels of ENT2. These cells also have a Na+-independent equilibrative nucleobase transport mechanism for hypoxanthine (ENBT1). In the ENT1−/−cells, there is no change in ENT2 or ENBT1, resulting in a very low level of nucleoside uptake in these cells, but a high capacity for nucleobase accumulation. Whereas there were no significant changes in nucleoside transporter subtype expression, there was a dramatic increase in adenosine deaminase and adenosine A2areceptors (both transcript and protein) in the ENT1−/−tissues compared with WT. These changes in adenosine deaminase and A2areceptors likely reflect adaptive cellular mechanisms in response to reduced adenosine flux across the membranes of ENT1−/−cells. Our study also revealed that mouse MVECs have a nucleoside/nucleobase transport profile that is more similar to human MVECs than to rat MVECs. Thus mouse MVECs from transgenic animals may prove to be a useful preclinical model for studies of the effects of purine metabolite modifiers on vascular function.

Background— When advanced, heart failure with preserved ejection fraction (HFpEF) is readily apparent. However, diagnosis of earlier disease may be challenging because exertional dyspnea is not specific for heart failure, and biomarkers and hemodynamic indicators of volume overload may be absent at rest. Methods and Results— Patients with exertional dyspnea and ejection fraction >50% were referred for hemodynamic catheterization. Those with no significant coronary disease, normal brain natriuretic peptide assay, and normal resting hemodynamics (mean pulmonary artery pressure <25 mm Hg and pulmonary capillary wedge pressure [PCWP] <15 mm Hg) (n=55) underwent exercise study. The exercise PCWP was used to classify patients as having HFpEF (PCWP ≥25 mm Hg) (n=32) or noncardiac dyspnea (PCWP <25 mm Hg) (n=23). At rest, patients with HFpEF had higher resting pulmonary artery pressure and PCWP, although all values fell within normal limits. Exercise-induced elevation in PCWP in HFpEF was confirmed by greater increases in left ventricular end-diastolic pressure and was associated with blunted increases in heart rate, systemic vasodilation, and cardiac output. Exercise-induced pulmonary hypertension was present in 88% of patients with HFpEF and was related principally to elevated PCWP, as pulmonary vascular resistances dropped similarly in both groups. Exercise PCWP and pulmonary artery systolic pressure were highly correlated. An exercise pulmonary artery systolic pressure ≥45 mm Hg identified HFpEF with 96% sensitivity and 95% specificity. Conclusions— Euvolemic patients with exertional dyspnea, normal brain natriuretic peptide, and normal cardiac filling pressures at rest may have markedly abnormal hemodynamic responses during exercise, suggesting that chronic symptoms are related to heart failure. Earlier and more accurate diagnosis using exercise hemodynamics may allow better targeting of interventions to treat and prevent HFpEF progression.

ABSTRACT Gastric and small intestinal circular smooth muscle layers have a transwall resting membrane potential (RMP) gradient that is dependent on release of carbon monoxide (CO) from interstitial cells of Cajal (ICCs). Our aim was to determine whether a RMP gradient exists in the mouse colon and whether the gradient is CO dependent. Microelectrodes were used to record RMPs from muscle cells at different depths of the circular muscle layer from wild‐type and heme oxygenase‐2‐knockout (HO‐2‐KO) mice. A transwall RMP gradient was present in wild‐type mice. The CO scavenger oxyhemoglobin (20 µM) and the heme oxygenase inhibitor chromium mesoporphyrin IX (CrMP, 5 µM) abolished the transwall gradient. The gradient was absent in HO‐2‐KO mice. Tetrodotoxin (1 µM) caused a significant depolarization in circular smooth muscle cells throughout the circular muscle layer and abolished the transwall gradient. Removal of the submucosal neurons abolished the gradient. The majority of submucosal neurons contained HO‐2 immunoreactivity (HO‐2‐IR), while ICCs did not. These data show for the first time that a transwall gradient exists across the circular smooth muscle layer of the mouse colon, that the gradient is due to CO, and that the source of CO is the submucosal neurons.—Sha, L., Farrugia, G., Linden, D. R., Szurszewski, J. H. The transwall gradient across the mouse colonic circular muscle layer is carbon monoxide dependent. FASEB J. 24, 3840–3849 (2010). www.fasebj.org

Purpose. This study examined whether brief intervention strategies founded on the Behavior-Image Model and addressing positive images of college and career success could be potentially efficacious in impacting multiple health habits of high-risk adolescents transitioning into adulthood. Design. Participants were stratified by grade level and drug use and individually randomized to one of the three Plan for Success interventions, with baseline and 1 month postintervention data collections. Setting. A large, relatively diverse suburban school in northeast Florida. Subjects. A total of 375 11th and 12th grade students participated during the spring semester 2006. Intervention. Three interventions studied included: (1) Goal Survey, (2) Goal Survey plus Contract, or (3) Goal Survey plus Consult. Measures. Outcome measures included multiple health risk, health promotion, and personal development behaviors, as well as image and belief measures. Analysis. Repeated-measures MANOVAs and ANOVAs were used to examine intervention effects. Results. MANOVAs were significant for alcohol use, F (4,328) = 6.33, p = .001; marijuana use, F (4,317) = 3.72, p = .01; exercise, F (3,299) = 4.28, p = .01; college preparation, F (2,327) = 6.26, p = .001; and career preparation, F (2,329) = 6.17, p = .001, with most behaviors improving over time, whereas group-by-time interaction effects were found for nutrition habits, F (6,652) = 2.60, p = .02; and career preparation, F (4,658) = 3.26, p = .01, favoring the consultation. Conclusion. Brief interventions founded on the Behavior-Image Model may have potential to improve selected health and personal development habits among older adolescents.

Key elements for determining alveolar-capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) from the lung diffusing capacity (Dl) for carbon monoxide (DlCO) or for nitric oxide (DlNO) are the reaction rate of carbon monoxide with hemoglobin (θCO) and the DmCO/DlNOrelationship (α-ratio). Although a range of values have been reported, currently there is no consensus regarding these parameters. The study purpose was to define optimal parameters (θCO, α-ratio) that would experimentally substantiate calculations of Dm and Vc from the single-inspired O2tension [inspired fraction of O2(FiO2)] method relative to the multiple-FiO2method. Eight healthy men were studied at rest and during moderate exercise (80-W cycle). Dm and Vc were determined by the multiple-FiO2and single-FiO2methods (rebreathe technique) and were tabulated by applying previously reported θCOequations (both methods) and by varying the α-ratio (single-FiO2method) from 1.90 to 2.50. Values were then compared between methods throughout the examined α-ratios. Dm and Vc were critically dependent on the applied θCOequation. For the multiple-FiO2method, Dm was highly variable between θCOequations (rest and exercise); the range of Vc was less widespread. For the single-FiO2method, the θCOequation by Reeves and Park (1992) combined with an α-ratio between 2.08 and 2.26 gave values for Dm and Vc that most closely matched those from the multiple-FiO2method and were also physiologically plausible compared with predicted values. We conclude that the parameters used to calculate Dm and Vc values from the single-FiO2method (using DlCOand DlNO) can significantly influence results and should be evaluated within individual laboratories to obtain optimal values.

Objective: This 8-week, open-label trial assessed the efficacy of methylphenidate transdermal system (MTS) in 14 adult individuals diagnosed with ADHD and with a history of stimulant misuse, abuse, or dependence. Method: The primary efficacy endpoint was the Wender-Reimherr Adult ADHD Scale (WRAADS), and secondary efficacy endpoints included the Clinical Global Impression (CGI) ratings and substance abuse as quantified by urine drug screens and self-reported use. Results: Significant improvements from baseline were found on both the WRAADS and CGI measurements. No abuse of the study medication was observed. Conclusion: The findings suggested that MTS may improve ADHD symptoms in adults with a history of stimulant misuse; however, there were limitations. The study data showed the need for subsequent randomized studies that further explore findings made in this study.

Purpose Audiologists frequently encounter patients who complain of chronic dizziness or imbalance, in the absence of active vestibular or neurological deficits. Knowledge about conditions that cause this clinical presentation will allow audiologists to make important contributions to accurate diagnosis and effective management of these patients. This article reviews 2 such conditions, chronic subjective dizziness (CSD) and conversion disorder. Method A case of CSD and another of conversion disorder are presented, with a literature review of their clinical presentations, key diagnostic features, and treatment strategies. The role of the audiologist in assessing patients with these conditions and facilitating appropriate treatment referrals is discussed. Conclusions The audiologist is in a key position to identify individuals with CSD and conversion disorder, 2 conditions that can be effectively managed if properly recognized. The authors demonstrate an effective team approach program that includes the audiologist’s contribution to differential diagnosis, education of patients and other clinicians about these conditions, and development of recommendations for neurological, psychiatric, otologic, and physical therapy referrals.

SummaryClinical trials often include binary end points. In some cases, no successes are observed and the usual large sample estimates of relative risk are undefined. The paper proposes an estimator for relative risk based on the median unbiased estimator. The relative risk estimator proposed is well defined and performs satisfactorily for a wide range of data configurations. To facilitate the use of the estimator, a deterministic bootstrap confidence interval is also proposed, and an SAS macro is available to perform the necessary calculations. An on-going randomized clinical trial motivated the development of the estimator and is used to illustrate the approach.