Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.

BACKGROUND: We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. METHODS: In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. RESULTS: Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. CONCLUSIONS: Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.     

Anesthetics Inhibit Acetylcholine-promoted Guanine Nucleotide Exchange of Heterotrimeric G Proteins of Airway Smooth Muscle

Background: Anesthetics inhibit airway smooth muscle contraction in part by a direct effect on the smooth muscle cell. This study tested the hypothesis that the anesthetics halothane and hexanol, which both relax airway smooth muscle in vitro, inhibit acetylcholine-promoted nucleotide exchange at the [alpha] subunit of the Gq/11 heterotrimeric G protein (G[alpha]q/11; i.e., they inhibit muscarinic receptor-G[alpha]q/11 coupling).

Methods: The effect of halothane (0.38 +/- 0.02 mm) and hexanol (10 mm) on basal and acetylcholine-stimulated G[alpha]q/11 guanosine nucleotide exchange was determined in membranes prepared from porcine tracheal smooth muscle. The nonhydrolyzable, radioactive form of guanosine-5'-triphosphate, [35S]GTP[gamma]S, was used as the reporter for G[alpha]q/11 subunit dissociation from the membrane to soluble fraction, which was immunoprecipitated with rabbit polyclonal anti-G[alpha]q/11 antiserum.

Results: Acetylcholine caused a significant time- and concentration-dependent increase in the magnitude of G[alpha]q/11 nucleotide exchange compared with basal values (i.e., without acetylcholine), reaching a maximal difference at 100 [mu]m (35.9 +/- 2.9 vs. 9.8 +/- 1.2 fmol/mg protein, respectively). Whereas neither anesthetic had an effect on basal G[alpha]q/11 nucleotide exchange, both halothane and hexanol significantly inhibited the increase in G[alpha]q/11 nucleotide exchange produced by 30 [mu]m acetylcholine (by 59% and 68%, respectively).     

Heart failure survival score continues to predict clinical outcomes in patients with heart failure receiving β-blockers

BACKGROUND: The Heart Failure Survival Score (HFSS) has been previously shown to effectively risk-stratify patients under evaluation for heart transplantation. However, this model was developed before broad use of beta blockade. We hypothesized that the prognostic tool would retain its ability to risk stratify patients treated with beta-blockers. METHODS: We collected clinical data on 524 consecutive patients referred for heart transplantation from 1994 to 2001. Kaplan-Meier survival analysis and multivariable Cox regression analysis were performed with events defined as death, left ventricular assist device placement, or United Network of Organ Sharing 1 heart transplantation. RESULTS: Kaplan-Meier analysis of the patient population revealed effective discrimination by the survival score both for beta-blocker treated and untreated patients (both p <0.0001). Two-year event-free survival was 94% +/- 2% and 84% +/- 4% for beta-blocker and no beta-blocker patients in the low-risk HFSS strata. Cox proportional hazard modeling showed that HFSS strata (medium risk: HR 2.65, 95% CI 1.75-4.02, p <0.001; high risk: HR 5.51, 95% CI 3.64-8.33, p <0.001) and beta-blocker treatment (HR 0.45, 95% CI 0.31-0.64, p <0.001) were significant predictors of event-free survival. Receiver operating curves (area under the curve) for HFSS strata used to predict 2-year events were similar for beta-blocker treated (0.78 +/- 0.04) and untreated (0.80 +/- 0.03) patients. CONCLUSIONS: The HFSS provides effective risk stratification with or without beta-blocker therapy. Consideration of beta-blocker therapy with survival score strata improves outcome prediction in patients evaluated for heart transplantation.     

Use of herbal supplements for chronic liver disease.

BACKGROUND & AIMS: Complementary and alternative medicine (CAM) is becoming popular among patients with liver disease. Although there is a growing body of evidence regarding potential mechanisms of action of these and other herbs, caution must be used to interpret the results of the few clinical trials available. Our goal was to discuss the biologic rationale for the use of specific herbs (silymarin, glycyrrhizin, sho-saiko-to, Phyllanthus amarus , Picrorrhiza kurroa , Compound 861, CH-100, and LIV.52) in the treatment of chronic liver diseases, as well as the evidence for their efficacy and adverse effects according to clinical trials. METHODS: Because of the relative paucity of clinical studies using herbs, every trial published in English was reviewed. RESULTS: Although many trials suggest that these herbs can decrease serum transaminase levels, the effects on hepatic histopathology and long-term survival are either poorly studied or conflicting. LIV.52 has been withdrawn from the market because of deleterious effects in patients with liver disease. CONCLUSIONS: Based on current evidence, we cannot recommend the use of herbal supplements for the routine treatment of any chronic liver disease and further well-designed clinical trials are necessary.     

Survival after gastric adenocarcinoma resection: Eighteen-year experience at a single institution

Gastric adenocarcinoma is the second leading cause of cancer death worldwide. In Western series, survival rates vary widely and are generally lower than those reported from Eastern series. We performed a retrospective analysis of cases operated on at the Johns Hopkins Hospital over the past 18 years and collected data on demographics, tumor characteristics, pathologic stage, treatment methods, complications, survival time, and other relevant factors. Survival according to stage of disease, Lauren tumor type, tumorlocation,time period, andadministration of adjuvant therapy wasanalyzed, andresultswerecompared with those of other Western series. During this period, 436 patients with gastric adenocarcinoma underwent resection. We have shown a statistically significant association between survival and margin status, stage of disease, and Lauren tumor type. Overall 5-year survival was 26%, and 5-year survival after R0 resection was 33%. No significant difference was detected between survival and tumor location, time period of treatment, or administration of adjuvant therapy. Analysis of various Western series reveals major differences between the cohorts under study, such as stage of disease, extent of resection, tumor type, and tumor location. Many of the reported differences among Western series may be due to cohort differences, such as stage of disease, extent of resection, tumor type, and tumor location.     

Long-Term Clinical Outcomes Following Treatment of Actinic Keratosis with Imiquimod 5% Cream

BACKGROUND: The results from four phase III, randomized, vehicle-controlled studies showed that imiquimod 5% cream (imiquimod) was safe and effective in the treatment of actinic keratosis (AK). Patients applied imiquimod or vehicle cream to AK lesions on the face or balding scalp, dosing three times per week or two times per week for 16 weeks. OBJECTIVE: To obtain long-term safety follow-up data and estimate AK recurrence in patients who completely cleared their AK lesions in the treatment area at the 8-week post-treatment visit in the phase III studies. METHODS: One hundred forty-six patients from 30 study centers in the United States were evaluated for clinical evidence of AK, and safety data were collected. RESULTS: After a median follow-up period of 16 months, 24.7% (19 of 77) of the patients administered imiquimod three times per week and 42.6% (23 of 54) of the patients administered imiquimod two times per week had a recurrence of AK (the appearance of at least one AK lesion) in the original treatment area. The median number of AK lesions present was one lesion for both patients receiving imiquimod three times and those receiving imiquimod two times per week compared with a median of six lesions at baseline in the combined three times per week and two times per week phase III studies. There were no long-term safety issues, and the skin quality seen in the imiquimod-treated patients at the end of the phase III studies was maintained. CONCLUSION: One and a half years following treatment, imiquimod continued to provide a long-term clinical benefit in a majority of patients who experienced complete clearance of their AK lesions.     

Comparison of a Chronotherapeutically Administered β Blocker vs. a Traditionally Administered β Blocker in Patients With Hypertension

Increasing systolic blood pressure and heart rate during the early morning results in increased myocardial oxygen demand. The use of β blockers during this period may decrease cardiac workload, particularly in β-blocker sensitive patients. The impact of a new chronotherapeutic β blocker was assessed in 44 hypertensive patients. Patients were randomized to delayed-release propranolol (INP) dosed at 10 p.m. or to traditionally dosed propranolol (ILA) dosed at 8 a.m. for 4 weeks, following which they were switched to the alternative formulation for 4 weeks. Thirty-four-hour ambulatory blood pressure monitoring and pharmacokinetic measurements were obtained. INP and ILA resulted in significant reductions in mean 24-hour blood pressure (−9.01-6.9 mm Hg and −10.41-7.7 mm Hg, respectively). The top 25% of responders to highdose propranolol (sensitive patients) were compared on each formulation. Mean trough reductions were −8.0/-6.7 mm Hg and −7.61-5.8 mm Hg, respectively. Mean blood pressure reductions in the β-blocker sensitive patients (n=11) between 6 a.m. and noon were −15.2/-11.9 mm Hg on INP and -8.0/-4.6 mm Hg on ILA. Heart rate reduction was −14.1 bpm and double product reduction was −3319 in the INP patients between 6 a.m. and 12 noon compared with −10.5 and −2209 in the ILA patients. This study suggests that INP and ILA are effective once-a-day β blockers, but the use of delayed-release propanolol results in a greater reduction in double product between 6 a.m. and noon in β-blocker sensitive patients than does traditionally dosed propranolol.     

Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial

While Ayurvedic medicine has touted the cognitive enhancing effects of Bacopa monniera for centuries, there is a need for double-blind placebo-controlled investigations. One hundred and seven healthy participants were recruited for this double-blind placebo-controlled independent group design investigation. Sixty-two participants completed the study with 80% treatment compliance. Neuropsychological testing using the Cognitive Drug Research cognitive assessment system was conducted at baseline and after 90 days of treatment with a special extract of Bacopa monniera (2 x 150 mg KeenMind) or placebo. The Bacopa monniera product significantly improved performance on the 'Working Memory' factor, more specifically spatial working memory accuracy. The number of false-positives recorded in the Rapid visual information processing task was also reduced for the Bacopa monniera group following the treatment period. The current study provides support for the two other published studies reporting cognitive enhancing effects in healthy humans after a 90 day administration of the Bacopa monniera extract. Further studies are required to ascertain the effective dosage range, the time required to attain therapeutic levels and the effects over a longer term of administration.