db/db mice exhibit severe wound-healing impairments compared with other murine diabetic strains in a silicone-splinted excisional wound model

The pathophysiology of diabetic wound healing and the identification of new agents to improve clinical outcomes continue to be areas of intense research. There currently exist more than 10 different murine models of diabetes. The degree to which wound healing is impaired in these different mouse models has never been directly compared. We determined whether differences in wound impairment exist between diabetic models in order to elucidate which model would be the best to evaluate new treatment strategies. Three well-accepted mouse models of diabetes were used in this study: db/db, Akita, and streptozocin (STZ)-induced C57BL/6J. Using an excisional model of wound healing, we demonstrated that db/db mice exhibit severe impairments in wound healing compared with STZ and Akita mice. Excisional wounds in db/db mice show a statistically significant delay in wound closure, decreased granulation tissue formation, decreased wound bed vascularity, and markedly diminished proliferation compared with STZ, Akita, and control mice. There was no difference in the rate of epithelialization of the full-thickness wounds between the diabetic or control mice. Our results suggest that splinted db/db mice may be the most appropriate model for studying diabetic wound-healing interventions as they demonstrate the most significant impairment in wound healing. This study utilized a novel model of wound healing developed in our laboratory that stents wounds open using silicone splints to minimize the effects of wound contraction. As such, it was not possible to directly compare the results of this study with other studies that did not use this wound model.     

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.