Search

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

Within hibernating myocardium, it is uncertain whether a normal energetic state is present at baseline and whether maintaining that energy state during a catecholamine challenge is dependent on ATP-dependent potassium channel opening. In this study, 16 swine underwent a thoracotomy with placement of an external constrictor on the left anterior descending coronary artery (LAD) (hibernation model). Seven additional swine underwent a sham operation. At 10 wk, the myocardial energetic state in the LAD region was assessed by [sup.31]P-NMR spectroscopy, and the ratio of phosphocreatine to ATP (PCr/ATP) was determined at baseline, during glibenclamide treatment (0.5 mg/kg bolus with 50 [micro]g/min iv), and during addition of dobutamine (40 [micro]g x [kg.sup.-1] x [min.sup.-1] iv). At baseline, transmural blood flow in the LAD and remote region was 0.75 [+ or -] 0.11 and 0.88 [+ or -] 0.09 ml x [min.sup.-1] x [g.sup.-1], respectively (P < 0.01), in hibernating hearts and 0.83 [+ or -] 0.12 and 0.88 [+ or -] 0.15 ml x [min.sup.-1] x [g.sup.-1], respectively (not significant), in sham-operated hearts. Under basal conditions, PCr/ATP in the LAD region of hibernating and sham pigs was 2.15 [+ or -] 0.04 and 2.11 [+ or -] 0.05, respectively (not significant). In sham pigs, addition of dobutamine to glibenclamide increased the double product from 10.4 [+ or -] 0.8 to 23.9 [+ or -] 4.0 mmHg x beats x [min.sup.-1] x 1,000 (P < 0.05) and decreased transmural PCr/ATP from 2.06 [+ or -] 0.06 to 1.69 [+ or -] 0.06 (P < 0.05). Dobutamine increased the double product in hibernating pigs in a similar fashion and, despite a 40% lower blood flow response, induced an equivalent decrease in PCr/ATP from 2.04 [+ or -] 0.04 to 1.73 [+ or -] 0.08 (P < 0.05). In conclusion, we found that, in chronic hibernating swine myocardium with reduced basal blood flow and perfusion reserve, the transmural energetic state, defined by PCr/ATP, is normal during addition of dobutamine, despite inhibition of ATP-dependent potassium channel opening with glibenclamide. These data suggest that important adaptations other than the ATP-dependent potassium channel opening allow hibernating myocardium to operate over a lower range of the oxygen supply-demand relationship to protect against myocardial ischemia. myocardial ischemia; high-energy phosphates; preconditioning; hibernation; mitochondrial adaptations

The benefit of coronary-artery revascularization before elective major vascular surgery is assessed. Findings reveal that a strategy of coronary-artery revascularization before elective vascular among patients with stable cardiac symptoms cannot be recommended.

In preconditioned myocardium, activation of the mitogen-activated protein kinase (MAPK) p38 leads to increased glucose uptake via enhanced GLUT-4 translocation. Glucose uptake is also increased in chronic hibernating myocardium, but the role of p38 MAPK and GLUT-4 translocation has not been studied. Nine swine underwent instrumentation of the proximal left anterior descending coronary artery (LAD) with a small, external constrictor. At 3 mo after instrumentation, myocardial glucose uptake by PET imaging was higher in the LAD than in the remote region under basal, fasted conditions (0.08 [+ or -] 0.02 vs. 0.04 [+ or -] 0.01 [micro]mol x [min.sup.-1] x [g.sup.-1], P < 0.05). Compared with the remote region, the LAD region demonstrated increased membrane-bound GLUT-4 relative to total content (61 [+ or -] 04 vs. 45 [+ or -] 06%, P < 0.05), higher glycogen (28.37 [+ or -] 4.41 vs. 19.26 [+ or -] 1.87 mg/g wet wt, P < 0.05), and increased inducible nitric oxide synthase (NOS) activity (1.43 [+ or -] 0.34 vs. 0.51 [+ or -] 0.21 activity/mg protein, P < 0.05). p38 MAPK was 47 [+ or -] 14% higher in the LAD than in the remote region (P < 0.05) and correlated well with the absolute degree of GLUT-4 membrane-bound translocation (r = 0.81, P < 0.01), relative increase in glycogen (r = 0.70, P < 0.05), and total NOS activity (r = 0.68, P < 0.05). In chronic hibernating myocardial tissue, p38 MAPK activation is increased under basal fasted conditions and correlates well with the increased degree of GLUT-4 translocation, glycogen accumulation, and NOS activity. As in preconditioned myocardium, activation of p38 MAPK may play an important role in the metabolic adaptations that characterize chronic hibernating myocardium. GLUT-4; glucose uptake; preconditioned myocardium; inducible nitric oxide synthase

Glucose uptake and glycogen levels are increased in pig heart after repetitive ischemia. Am J Physiol Heart Circ Physiol 282: H205-H211, 2002.--Repetitive myocardial ischemia increases glucose uptake, but the effect on glycogen is unclear. Thirteen swine instrumented with a hydraulic occluder on the circumflex (Cx) artery underwent 10-min occlusions twice per day for 4 days. After 24 h postfinal ischemia and in the fasted state, echocardiogram and positron emission tomography imaging for blood flow ([sup.13]N]-ammonia) and 2-[[sup.18]F]fluoro-2-deoxy-D-glucose (FDG) uptake were obtained. Tissue was then collected for ATP, creatine phosphate (CP), glycogen, and glucose transporter-4 content, and hexokinase activity. After reperfusion, regional function and CP-to-ATP ratios in the Cx and remote regions were similar. Despite the absence of stunning, the Cx region demonstrated higher glycogen levels (33 [+ or -] 11 vs. 24 [+ or -] 11 [micro]mol/g; P < 0.05), and this increase correlated well with the increase in FDG uptake ([r.sup.2] = 0.78; P < 0.01). Hexokinase activity was also increased relative to remote regions (0.62 [+ or -] 0.29 vs. 0.37 [+ or -] 0.19 IU/g; P < 0.05), with no difference in GLUT-4 content. In summary, 24 h after repetitive ischemia, glucose uptake and glycogen levels are increased at a time that functional and bioenergetic markers of stunning have recovered. The significant correlation between glycogen content and FDG accumulation in the postischemic region suggests that increased rates of glucose transport and/or phosphorylation are linked to increased glycogen levels in hearts subjected to repetitive bouts of ischemia. myocardial ischemia; stunning; glucose transporter-4; 2-[[sup.18]F]fluoro-2-deoxy-D-glucose; hexokinase