Saumya Sharma

Downregulation of peroxisome proliferator-activated receptor-α gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity

Background—The peroxisome proliferators–activated receptor-&agr; (PPAR&agr;), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPAR&agr; is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart. Methods and Results—Repetitive closed-chest I/R (15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPAR&agr; agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPAR&agr;-regulated genes and both myosin heavy chain isoform transcript levels, which was reversible on discontinuation of I/R. Overexpression of EC-SOD prevented the downregulation of PPAR&agr;-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPAR&agr; in mice exposed to repetitive I/R worsened contractile function, induced microinfarctions, and increased intramyocardial triglyceride deposition, features suggestive of cardiac lipotoxicity. Conclusions—Metabolic and myosin isoform gene expression in repetitive I/R is mediated by reactive oxygen species. Furthermore, we suggest that downregulation of PPAR&agr; in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.

Hypothyroidism and hyperthyroidism in anxiety disorders revisited: new data and literature review.

BACKGROUND The need for thyroid screening of patients presenting with panic disorder (PD), social phobia (SP) or generalized anxiety disorder (GAD) remains uncertain. METHODS We examined thyroid histories and serum testing in 169 patients, 92 with PD, 48 with SP, and 29 with GAD. Combined prevalence rates of hyperthyroidism and hypothyroidism were compared with expected rates (2.7%) derived from the population based Whickham Survey. Data from previously published studies were also compared with these expected rates. RESULTS In our sample, only 2/169 patients had thyroid dysfunction detected by serum testing, but 5/169 [1/92 (1%) with PD, 1/48 (2%) with SP, and 3/29 (10%) with GAD], all currently euthyroid, reported a history of thyroid disease. The rates were statistically significant only for GAD (10.4%; z = 2.56, p = 0.01). However, combining prior PD studies that examined both thyroid history and test results with our data also suggests significantly elevated rates of thyroid dysfunction (6.5%; z = 4.69, p < 0.0001). LIMITATIONS As with previous data, the 95% confidence interval for our findings is broad, reflecting the instability of low rates of illness in relatively small samples. Further, methods for obtaining thyroid histories and tests were not uniform. CONCLUSIONS Despite relatively low yields on serum testing, lifetime prevalence of thyroid dysfunction does appear elevated for GAD and PD, with minimal data addressing this issue for SP. The data support the need to query GAD and PD patients regarding thyroid history and perform serum testing in those without prior testing.

Longitudinal outcome with pharmacotherapy in a naturalistic study of panic disorder

BACKGROUND Current recommendations suggest that pharmacotherapy for patients with panic disorder should be continued for at least 1 year [Am. J. Psychiatry 155 (1998) 1], despite a paucity of data systematically examining outcome for periods greater than 3-6 months. It is critically important to obtain more information on the effectiveness of medications over time for patients who initially responded to pharmacotherapy for panic disorder. METHODS Long-term outcome was examined for 78 patients who attained a 2-month period of sustained remission on medication and received maintenance pharmacotherapy for up to 24 months during the Massachusetts General Hospital Longitudinal Study of Panic Disorder, a prospective, naturalistic study. Participants were categorized by their maintenance treatment condition at remission: benzodiazepine alone (N = 45, 58%), antidepressant alone (N = 12, 16%), and combined treatment with a benzodiazepine and an antidepressant (N = 21, 27%). RESULTS Approximately half (N = 36, 46%) of the patients who had achieved remission relapsed at some time over the 2-year naturalistic study period, despite continued and adequate pharmacotherapy. There was no difference in timing or frequency of relapse by type of maintenance pharmacotherapy. LIMITATIONS Interpretation of the data is limited by the naturalistic nature of the study, and by the relatively low sample size. CONCLUSIONS This data suggests that patients with panic disorder have a high rate of relapse even after acute response to pharmacotherapy, despite continued treatment. In addition, the use of combined pharmacotherapy with antidepressants and benzodiazepines does not appear to provide greater protection from relapse than monotherapy.

Mechanical Unloading of the Failing Human Heart Fails to Activate the Protein Kinase B/Akt/Glycogen Synthase Kinase-3β Survival Pathway

Background: Left ventricular assist device (LVAD) support of the failing human heart improves myocyte function and increases cell survival. One potential mechanism underlying this phenomenon is activation of the protein kinase B (PKB)/Akt/glycogen synthase kinase-3beta (GSK-3β) survival pathway. Methods and Results: Left ventricular tissue was obtained both at the time of implantation and explantation of the LVAD (n = 11). Six patients were diagnosed with idiopathic dilated cardiomyopathy, 4 patients with ischemic cardiomyopathy and 1 patient with peripartum cardiomyopathy. The mean duration of LVAD support was 205 ± 35 days. Myocyte diameter and phosphorylation of ERK were used as indices for reverse remodeling. Transcript levels of genes required for the activation of PKB/Akt (insulin-like growth factor-1, insulin receptor substrate-1) were measured by quantitative RT-PCR. In addition, we measured the relative activity of PKB/Akt and GSK-3β, and assayed for molecular and histological indices of PKB/Akt activation (cyclooxygenase mRNA levels and glycogen levels). Myocyte diameter and phosphorylation of ERK decreased with LVAD support. In contrast, none of the components of the PKB/Akt/GSK-3β pathway changed significantly with mechanical unloading. Conclusion: The PKB/Akt/GSK-3β pathway is not activated during LVAD support. Other signaling pathways must be responsible for the improvement of cellular function and cell survival during LVAD support.

Citalopram for social phobia: a clinical case series

Social anxiety disorder is a common illness with significant associated disability. Serotonin selective reuptake inhibitors (SSRIs) have become first-line treatment given their improved tolerability; however, there are few reports on the use of citalopram. Nine consecutive patients with a primary diagnosis of DSM-IV generalized social phobia were prospectively treated with citalopram. Citalopram was generally well-tolerated, and seven patients achieved responder status. This series of patients improved significantly on all measures. Results suggest that citalopram may be a safe and effective treatment for social anxiety disorder.