The Effects of Exercise on Dopamine Neurotransmission in Parkinson's Disease: Targeting Neuroplasticity to Modulate Basal Ganglia Circuitry.

Animal studies have been instrumental in providing evidence for exercise-induced neuroplasticity of corticostriatal circuits that are profoundly affected in Parkinson's disease. Exercise has been implicated in modulating dopamine and glutamate neurotransmission, altering synaptogenesis, and increasing cerebral blood flow. In addition, recent evidence supports that the type of exercise may have regional effects on brain circuitry, with skilled exercise differentially affecting frontal-striatal related circuits to a greater degree than pure aerobic exercise. Neuroplasticity in models of dopamine depletion will be reviewed with a focus on the influence of exercise on the dorsal lateral striatum and prefrontal related circuitry underlying motor and cognitive impairment in PD. Although clearly more research is needed to address major gaps in our knowledge, we hypothesize that the potential effects of exercise on inducing neuroplasticity in a circuit specific manner may occur through synergistic mechanisms that include the coupling of an increasing neuronal metabolic demand and increased blood flow. Elucidation of these mechanisms may provide important new targets for facilitating brain repair and modifying the course of disease in PD.

Elevated undercarboxylated and reduced carboxylated osteocalcin are associated with metabolic syndrome in middle age Asian females.

Accumulating data suggest that bone plays a role in energy metabolism through decarboxylation of osteocalcin. Thus, we aimed to study the association of circulating under--carboxylated osteocalcin (UC-OCN) and car-boxylated osteocalcin (C-OCN) with metabolic syndrome in middle aged Asian population.In this cross-sectional study, 131 middle aged Asian subjects were recruited. Circulating UC-OCN, C-OCN and parameters of metabolic phenotype were measured.Circulating UC-OCN was increased in subjects with metabolic syndrome (8.1±7.2 ng/ml vs. 5.9±4.6 ng/ml, p=0.036). In contrast, C-OCN showed a non-significant trend towards reduction in subjects with metabolic syndrome (3.6±2.2 ng/ml vs. 4.3±1.8 ng/ml, p=0.057). Further analysis revealed that changes in both UC-OCN and C-OCN occurred primarily among females with metabolic syndrome. Interestingly, neither forms of OCN differed significantly between individuals with and without metabolic syndrome in males. Logistic regression revealed that UC-OCN was independently associated with metabolic syndrome after adjusting for multiple covariates. However, association between metabolic syndrome and C-OCN was dependent on gender (i. e., amongst females only) in the fully adjusted regression model.Variation in OCN (including its sub-species) was associated with variation in metabolic parameters amongst Asian adults. Circulating UC-OCN was increased while C-OCN was decreased in treatment-naïve females with metabolic syndrome. Our preliminary observations further supported a potential link between bone and energy metabolism in humans.

Adipocytokine zinc α2 glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathy.

OBJECTIVE: A substantial proportion of diabetic nephropathy individuals are non-albuminuric. Using a proteomic approach, we searched for novel urinary biomarkers. METHODS: We studied three groups (n = 6 per group) of males with Type 2 diabetes: (1) normal renal function; (2) classical diabetic nephropathy (urinary albumin-creatinine ratio > 1000 mg/g and glomerular filtration rate < 60 ml/min.1.73 m(2) ) and (3) non-albuminuric diabetic nephropathy (glomerular filtration rate < 60 ml/min.1.73 m(2) and urinary albumin-creatinine ratio < 30 mg/g). We used two-dimensional fluorescence differential gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry peptide identification and western blot validation in the study. RESULTS: Sixty protein spots were differentially abundant between the non-albuminuric and macro-albuminuric subjects (> 2.5-fold, P < 0.05). In the non-albuminuric subjects, in addition to previously reported α(1) -microglobulin, the next most interesting spot (upregulated 3.44-fold, P = 0.0026) was human zinc-α(2) -glycoprotein, a novel adipose-cytokine associated with glomerular injury. This was confirmed by western blot and replicated in female diabetic nephropathy subjects. CONCLUSIONS: From our preliminary results, human zinc-α(2) -glycoprotein may be a novel urinary biomarker for non-albuminuric diabetic nephropathy.

Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease.

BACKGROUND: The LMNA gene, one of 6 autosomal disease genes implicated in familial dilated cardiomyopathy, encodes lamins A and C, alternatively spliced nuclear envelope proteins. Mutations in lamin A/C cause 4 diseases: Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, Dunnigan-type familial partial lipodystrophy, and dilated cardiomyopathy. METHODS AND RESULTS: Two 4-generation white families with autosomal dominant familial dilated cardiomyopathy and conduction system disease were found to have novel mutations in the rod segment of lamin A/C. In family A a missense mutation (nucleotide G607A, amino acid E203K) was identified in 14 adult subjects; disease was manifest as progressive conduction disease in the fourth and fifth decades. Death was caused by heart failure. In family B a nonsense mutation (nucleotide C673T, amino acid R225X) was identified in 10 adult subjects; disease was also manifest as progressive conduction disease but with earlier onset (third and fourth decades), ventricular dysrhythmias, left ventricular enlargement, and systolic dysfunction. Death was caused by heart failure and sudden cardiac death. Skeletal muscle disease was not observed in either family. CONCLUSIONS: Novel rod segment mutations in lamin A/C cause variable conduction system disease and dilated cardiomyopathy without skeletal myopathy.

Distribution and declines in cardiac allograft radionuclide left ventricular ejection fractions in relation to late mortality.

BACKGROUND: Cardiac allograft left ventricular ejection fraction (LVEF) is an important measure of left ventricular systolic function. Despite widespread use of LVEF after transplantation, its normal range and prognostic value in cardiac allografts has not been defined. METHODS: We conducted a retrospective cohort study among 292 consecutive adult heart transplant patients. Left ventricular ejection fractions were performed at 1, 3, 12, 24, and 48 months after transplantation using radionuclide ventriculography. Endomyocardial biopsies assessed rejection, right heart catheterization assessed loading conditions, and angiography assessed allograft coronary artery disease. We used Cox proportional hazards model to examine the predictive value of LVEF on late mortality. RESULTS: Of the patients who survived > or =4 years, the mean allograft LVEF decreased 4.7 units at 3 months, from 63.8 to 59.7; an additional 4.1 units at 12 months, from 59.7 to 55.6 (p < 0.001); and remained stable afterward. These changes were not associated with concurrent changes in loading conditions, episodes of rejection, or development of allograft coronary artery disease. Left ventricular ejection fraction lower than the 95% normal limit (<40%) at 12 months was inversely associated with risk for late cardiac mortality (relative risk = 3.5, 95% confidence interval = 1.0-12.2), while controlling for recipient age, sex, donor age, and rejection episodes. CONCLUSIONS: The cardiac-allograft LVEF frequently decreases in the first year after transplantation. The 95th percentile of allograft LVEF value (<40%) at Year 1 predicts late cardiac mortality among transplant recipients.

Prospective evaluation of an outpatient heart failure management program.

BACKGROUND: Although considerable effort has been devoted to the follow-up of hospitalized patients, the effectiveness and process of heart failure outpatient management have not been well demonstrated. METHODS AND RESULTS: All new patients referred to the program from April 1997 to September 1998 were followed and managed by comprehensive strategies including preemptive hospitalization. Quality of life (QOL) and patients' self-care adherence behaviors were measured at baseline, 3 months, and 6 months. Clinical outcomes were compared for the 6 months before and 6 months after referral. A total of 108 patients were recruited. Patients' self-care knowledge score was improved over time (difference score = 0.9, P <.01). The proportion of patients weighing themselves daily increased by 24% (P =.02). The proportion of patients with New York Heart Association (NYHA) class III to IV was 67.6% at baseline and 49.1% at 6 months (P =.01). Compared with 6 months before referral, the program intervention was accompanied by a 52% reduction in the risk of hospitalization for cardiovascular causes (56.1% v 27.2%, P <.001) and a 72% reduction in emergency room visits (53.6% v 14.5%, P <.01). The total hospital admissions for cardiovascular causes decreased by 59% from 94 to 39; the total emergency room visits decreased by 77% from 83 to 19. The patients' QOL was improved over time with a change score of 11.2 (P <.001) at 3 months and 10.7 (P <.001) at 6 months. CONCLUSION: Our study shows the effectiveness of this heart failure outpatient management program.

Comparative responsiveness of Short-Form 12 and Minnesota Living With Heart Failure Questionnaire in patients with heart failure.

BACKGROUND: The Short-Form 12 (SF-12) and Living With Heart Failure Questionnaire (LHFQ) are commonly used to measure quality of life (QOL) in heart failure outcomes research. Their comparative responsiveness, however, has not been documented. METHODS AND RESULTS: A prospective cohort study was conducted among patients attending a university-based heart failure clinic between April 1997 and September 1998. All patients received comprehensive heart failure care management. QOL of patients was assessed by the SF-12 and LHFQ at baseline and 3 months. Of 87 patients completing follow-up, the mean change score was 10.1 for the LHFQ and 5.8 for the SF-12 (both Ps < .001). The change scores of the instruments were correlated (r = 0.61; P < .001). The SF-12 had a greater ability than the LHFQ to statistically detect change in physical health but was less sensitive to changes in mental health. The LHFQ performed better than the SF-12 in the ability to distinguish the differences in perceived global health transition. CONCLUSION: The LHFQ is more responsive than the SF-12 to changes in QOL. The SF-12 should not be used alone to measure the changes in QOL of patients with heart failure.

Medication misadventures resulting in emergency department visits at and HMO medical center.

Medication misadventures resulting in visits to the emergency department of a health maintenance organization (HMO) were studied. The records of patients who visited the emergency department at a California HMO between August 1992 and August 1993 were evaluated for evidence of medication misadventures brought to the department. The definition of misadventure included noncompliance and inappropriate prescribing but excluded intentional overdoses and substance abuse. If it seemed probable that a misadventure occurred, a pharmacist interviewed the patient by telephone. During the 12-month study, 1,074 (1.7%) of 62,216 visits to the emergency department were due to medication misadventures. The patients who had had a misadventure were predominantly female (62%); 38% were 15-44 years of age and 33% were 65 or older. Interviews were possible with 962 patients. Only 30.6% of the patients had a good understanding of the potential adverse effects of their regimen, and only 29.0% had a good understanding of the potential interactions. Misadventures were most often due to allergies or medication underuse among patients < or = 14 years of age and to adverse effects and inappropriate dosage in elderly patients. Of the 1,074 misadventures, 152 (14.1%) resulted in hospital admission. Three areas of particular concern were identified (1) noncompliance with respiratory agents in the young, (2) nonsteroidal anti-inflammatory use leading to hospital admission, and (3) the frequency of problems in the elderly. Medication misadventures accounted for 1.7% of emergency department visits and 1.0% of hospital admissions at an HMO medical center.

Designing an advanced laparoscopic surgery training center.

The explosive development of minimally invasive surgery has had a staggering impact on the hospital, operating room, and surgeon, as well as on the medical equipment industry and insurance carriers. As a result of (1) the overwhelming demand by the public, (2) the potential of future developments of this modality, and (3) the progressive geometric influence that has spread to the various surgical subspecialties, unprecedented pressure has been placed on our systems for training, credentialing, developing, supplying, and evaluating changes in surgical technique.

Frequency and voltage-dependent effects of mono-N-dealkyldisopyramide, the major metabolite of disopyramide, in canine ventricular tissue.

Mono-N-dealkyldisopyramide (MND), the major metabolite of disopyramide, reaches significant concentrations in patients; however, the contribution of MND to the antiarrhythmic or toxic effects of disopyramide is not known. We assessed the kinetics and magnitude of interaction of MND with the sodium channel in canine ventricular tissue superfused in vitro using Vmax as an index of sodium channel block. At a basic cycle length of 1000 msec, MND (4-32 micrograms/ml) produced a concentration-dependent depression of both Vmax and amplitude of the action potential and accelerated all phases of repolarization in Purkinje fibers. To assess rate-dependent block, Purkinje fibers were stimulated with pulse trains at interstimulus intervals of 400 to 2000 msec. MND produced a concentration- and rate-dependent increase in the magnitude of rate-dependent block. There was also a concentration-dependent increase in the kinetics of onset of block (decrease in rate constant). The rate constant increased with faster stimulation rates. Minimal tonic block occurred at clinically relevant concentrations. Recovery from rate-dependent block followed a single exponential time course with time constants of 5.23 +/- 0.90 and 4.88 +/- 0.94 sec for Vmax and activation time, respectively. There was no shift of the normalized Vmax-membrane potential relationship except at the highest concentration, 32 micrograms/ml. At cycle lengths of 250 to 1000 msec, MND (4 micrograms/ml) shortened all phases of repolarization in Purkinje fibers, the greatest shortening occurring at the longest cycle length. Prolongation of effective refractory period occurred only at rapid heart rates. Both action potential duration and effective refractory period were prolonged in ventricular muscle which was independent of rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent advances in understanding the mechanisms of drug-induced torsades de pointes arrhythmias.

QTU prolongation and polymorphic ventricular tachycardia "torsades de pointes" have occurred in association with electrolyte abnormalities and during therapy with class IA and III antiarrhythmic drugs. Several recent studies have suggested that the arrhythmia may be due to bradycardia-dependent early afterdepolarizations and triggered activity. These drugs produce 2 types of triggered activity, each with a different frequency profile. The possible role of each type in arrhythmia generation is discussed. The existing evidence suggest that drug-induced triggered activity may originate in the Purkinje system. Triggered activity can be abolished or prevented by various interventions that are also effective clinically. The results of studies at the cellular level, when compared with recordings of monophasic action potentials in vivo, suggest a role for early afterdepolarizations in torsades de pointes arrhythmias.