In vivo PET imaging of cardiac presynaptic sympathoneuronal mechanisms in the rat.

The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: (11)C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; (11)C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and (11)C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans. METHODS: We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart were recorded for 60 min after radiotracer injection. A myocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determined by monoexponential fitting of myocardial time-activity curves. RESULTS: At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (+/- SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% +/- 0.82%/min, 3.43% +/- 0.45%/min, and 4.24% +/- 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% +/- 0.23%/min, 1.13% +/- 0.35%/min, and 0.50% +/- 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%. CONCLUSION: Kinetic profiles of HED in the rat myocardium were similar to those of HED in humans, suggesting comparable neuronal transport density. Unlike in humans, however, significant washout of EPI and faster washout of PHEN were encountered, consistent with high intraneuronal metabolic activity, high catecholamine turnover, and reduced vesicular storage. This evidence of increased neuronal activity in rodents has implications for translational studies of cardiac neuronal biology in humans.     

Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort

Abstract   We evaluated the associations between glycemic therapies and prevalence of diabetic peripheral neuropathy (DPN) at baseline among participants in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial on medical and revascularization therapies for coronary artery disease (CAD) and on insulin-sensitizing vs. insulin-providing treatments for diabetes. A total of 2,368 patients with type 2 diabetes and CAD was evaluated. DPN was defined as clinical examination score >2 using the Michigan Neuropathy Screening Instrument (MNSI). DPN odds ratios across different groups of glycemic therapy were evaluated by multiple logistic regression adjusted for multiple covariates including age, sex, hemoglobin A1c (HbA1c), and diabetes duration. Fifty-one percent of BARI 2D subjects with valid baseline characteristics and MNSI scores had DPN. After adjusting for all variables, use of insulin was significantly associated with DPN (OR = 1.57, 95% CI: 1.15–2.13). Patients on sulfonylurea (SU) or combination of SU/metformin (Met)/thiazolidinediones (TZD) had marginally higher rates of DPN than the Met/TZD group. This cross-sectional study in a cohort of patients with type 2 diabetes and CAD showed association of insulin use with higher DPN prevalence, independent of disease duration, glycemic control, and other characteristics. The causality between a glycemic control strategy and DPN cannot be evaluated in this cross-sectional study, but continued assessment of DPN and randomized therapies in BARI 2D trial may provide further explanations on the development of DPN.     

A Preliminary Study of the Population-Adjusted Effectiveness of Substance Abuse Prevention Programming: Towards Making IOM Program Types Comparable

The Institute of Medicine distinguishes between programs based on who is targeted: the entire population (universal), those at risk (selective), or persons exhibiting the early stages of use or related problem behavior (indicated). Evaluations suggest that although universal programs can be effective in reducing and preventing substance use, selective and indicated programs are both more effective and have greater cost-benefit ratios. This paper tests these assumptions by comparing the impact of these program types in reducing and preventing substance use at the individual level (i.e., those exposed to intervention services) and in the population (i.e., those exposed and not exposed to intervention services). A meta-analysis was performed on 43 studies of 25 programs to examine program comparability across IOM categories. When examining unadjusted effect sizes at the individual level, universal programs were modestly more successful in reducing tobacco use, but selective and indicated programs were modestly more successful in reducing alcohol and marijuana use. When adjusted to the population level, the average effect sizes for selective and indicated programs were reduced by approximately half. At the population level, universal programs were more successful in reducing tobacco and marijuana use and selective and indicated programs were more successful in reducing alcohol use. Editors’ Strategic Implications: The authors’ focus on the public health value of a prevention strategy is compelling and provides a model for analyses of other strategies and content areas.     

Concomitant mitral valve surgery with aortic valve replacement: a 21-year experience with a single mechanical prosthesis

Background  

Long-term survival for combined aortic and mitral valve replacement appears to be determined by the mitral valve prosthesis from our previous studies. This 21-year retrospective study assess long-term outcome and durability of aortic valve replacement (AVR) with either concomitant mitral valve replacement (MVR) or mitral valve repair (MVrep). We consider only a single mechanical prosthesis.     

Significant efficiency findings while controlling for the frequent confounders of CAI research in the PlanAlyzer project's computer-based,self-paced,case-based programs in anemia and chest pain diagnosis

Richard E. Clark in his widely published comprehensive studies and meta-analyses of the literature on computer assisted instruction (CAI) has decried the lack of carefully controlled research, challenging almost every study which shows the computer-based intervention to result in significant post-test proficiency gains over a non-computer-based intervention. We report on a randomized study in a medical school setting where the usual confounders found by Clark to plague most research, were carefully controlled. PlanAlyzer is a microcomputer-based, self-paced, case-based, event-driven system for medical education which was developed and used in carefully controlled trials in a second year medical school curriculum to test the hypothesis that students with access to the interactive programs could integrate their didactic knowledge more effectively and/or efficiently than with access only to traditional textual “nonintelligent” materials. PlanAlyzer presents cases, elicits and critiques a student's approach to the diagnosis of two common medical disorders: anemias and chest pain. PlanAlyzer uses text, hypertext, images and critiquing theory. Students were randomized, one half becoming the experimental group who received the interactive PlanAlyzer cases in anemia, the other half becoming the controls who received the exact same content material in a text format. Later in each year there was a crossover, the controls becoming the experimentals for a similar intervention with the cardiology PlanAlyzer cases. Preliminary results at the end of the first two full trials shows that the programs have achieved most of the proposed instructional objectives, plus some significant efficiency and economy gains. 96 faculty hours of classroom time were saved by using PlanAlyzer in their place, while maintaining high student achievement. In terms of student proficiency and efficiency, the 328 students in the trials over two years were able to accomplish the project's instructional objectives, and the experimentals accomplished this in 43% less time than the controls, achieving the same level of mastery. However, in spite of these significant efficiency findings, there have been no significant proficiency differences (as measured by current factual and higher order multiple choice post-tests) between the experimental and control groups. Very careful controls were used to avoid what Clark has found to be the most common confounders of CAI research. Accordingly, this research proved Clark's rival hypothesis, that the computer, in itself, does not appear to contribute to proficiency gains, at least as measured by our limited post-testing. Clark's position is that the computer is primarily a vehicle—as is either a pill or a hypodermic needle for delivering a drug. The hypodermic needle can deliver the drug more efficiently than can the pill, (as can the computer deliver the subject matter content more efficiently, as our research indicates), but the same content is delivered. At the same time, we proved our own hypothesis, as far as efficiency gains resulting from the computer are concerned. However, going beyond Clark's research, we may be teaching processes both more effectively and efficiently with the computer (experience in problem-solving or clinical reasoning and pattern recognition) which our current post-tests do not adequately measure. Our on-going research suggests additional inquiry in several areas: better evaluation instruments to measure the clinical reasoning skills PlanAlyzer was designed to teach; the addition of more advanced cases to determine if this might transform efficiency gains of the computer group into proficiency gains; the addition of enhanced graphic decision support tools and other pedagogical enhancements including cognitive feedback to strengthen PlanAlyzer's power to teach complex concepts of medical decision-making.     

Regional cerebral glucose transport in insulin-dependent diabetic patients studied using [11C]3-O-methyl-D-glucose and positron emission tomography

Regional cerebral [11C]3-O-methyl-D-glucose ([11C]MeG) uptake kinetics have been measured in five insulin-dependent diabetic patients and four normal controls using positron emission tomography (PET). Concomitant measurement of regional cerebral blood volume and CBF enabled corrections for the presence of intravascular [11C]MeG signal in cerebral regions of interest to be carried out, and regional cerebral [11C]MeG unidirectional extraction fractions to be computed. Four of the five diabetic subjects were studied with their fasting plasma glucose level clamped at a normoglycaemic level (4 mM), and four were studied at hyperglycaemic plasma glucose levels (mean 13 mM). The four diabetic subjects whose fasting plasma glucose levels were clamped at a normoglycaemic level of 4 mM had mean fasting whole-brain, cortical, and white matter [11C]MeG extraction fractions of 15, 15, and 16%, respectively, values similar to those found for the four normal controls (whole brain, 14%; cortex, 13%; white matter, 17%). Mean regional cerebral [11C]MeG extraction fractions were significantly reduced in diabetic subjects during hyperglycaemia whether their plasma insulin levels were undetectable or whether they were raised by continuous intravenous insulin infusion. Such a reduction in [11C]MeG extraction under hyperglycaemic conditions can be explained entirely in terms of increased competition between [11C]MeG and D-glucose for the passive facilitated transport carrier system for hexoses across the blood-brain barrier (BBB). It is concluded that the number and affinity of D-glucose carriers present in the BBB are within normal limits in treated insulin-dependent diabetic subjects. In addition, insulin appears to have no effect on the transport of D-glucose across the BBB.