External Fixation During the Acute Phase of Deep Burned Hands: Description of Saint Louis' Burn Center Technique.

Restoration of a good hand function and limitation of the sequelae are the main concerns in burns treatment. The intrinsic plus position is known as the safe position for hand splinting. This article aims at describing the technique of external fixation that have been developed in Saint Louis' Burn Center in management of burned hands during the acute phase. Since 2013, a technique of external fixation has been developed in our burn center using Hoffmann II External Fixation System from Stryker® and pins from Medicalex®. External fixation of a deep burned hand is an efficient and safe way to immobilize the hand in a correct intrinsic plus position, to secure the skin grafts to improve graft take and to permit changes of the dressings without removing the immobilization device.

A 10-Year Follow-Up Experience of 383 Patients with Bilateral Smooth Inflatable Breast Implants Filled with Saline Solution.

INTRODUCTION: In light of the concerns regarding the occurrence of anaplastic large-cell lymphoma, seromas, and scar capsules, there appears to be merit in analysis and presentation of the results of our series of inflatable smooth implants filled with saline solution, for which the follow-up was more than 10 years. PATIENTS AND METHOD: We carried out a retrospective study, including all of the patients who underwent a first breast implant for cosmetic reasons, between 2003 and 2006. RESULTS: A total of 383 patients with 766 smooth implants filled with saline solution were included in our study. No cases of lymphoma and seroma were diagnosed. Eleven patients exhibited a postoperative hematoma, and four went on to develop a capsule. Twenty-two patients (5.7%) developed a Baker Grade III or IV capsule that required revision surgery. Two patients (0.5%) opted for a bilateral prosthesis replacement due to visual rippling. In total, there were 26 (3.4%) early deflations of prostheses. DISCUSSION: There is not a statistically significant correlation between the occurrence of hematomas and the formation of a capsule. We found a lower shell rate with smooth-walled versus textured implants. The fact of having a decline of 10 years allows to be exhaustive. As for wrinkling and ripples, their occurrence has not been increased by the use of inflatable retropectoral implants. CONCLUSION: Smooth inflatable implants filled with saline solution have numerous advantages such as the possibility of a very small approach route and perioperative adaptability of the volume. In light of the lack of indication of anaplastic large-cell lymphoma with smooth implants, they are clearly an attractive alternative to textured implants filled with silicone gel. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Christmas, national holidays, sport events, and time factors as triggers of acute myocardial infarction: SWEDEHEART observational study 1998-2013.

OBJECTIVES: To study circadian rhythm aspects, national holidays, and major sports events as triggers of myocardial infarction. DESIGN: Retrospective observational study using the nationwide coronary care unit registry, SWEDEHEART. SETTING: Sweden. PARTICIPANTS: 283 014 cases of myocardial infarction reported to SWEDEHEART between 1998 and 2013. Symptom onset date was documented for all cases, and time to the nearest minute for 88%. INTERVENTIONS: Myocardial infarctions with symptom onset on Christmas/New Year, Easter, and Midsummer holiday were identified. Similarly, myocardial infarctions that occurred during a FIFA World Cup, UEFA European Championship, and winter and summer Olympic Games were identified. The two weeks before and after a holiday were set as a control period, and for sports events the control period was set to the same time one year before and after the tournament. Circadian and circaseptan analyses were performed with Sunday and 24:00 as the reference day and hour with which all other days and hours were compared. Incidence rate ratios were calculated using a count regression model. MAIN OUTCOME MEASURES: Daily count of myocardial infarction. RESULTS: Christmas and Midsummer holidays were associated with a higher risk of myocardial infarction (incidence rate ratio 1.15, 95% confidence interval 1.12 to 1.19, P<0.001, and 1.12, 1.07 to 1.18, P<0.001, respectively). The highest associated risk was observed for Christmas Eve (1.37, 1.29 to 1.46, P<0.001). No increased risk was observed during Easter holiday or sports events. A circaseptan and circadian variation in the risk of myocardial infarction was observed, with higher risk during early mornings and on Mondays. Results were more pronounced in patients aged over 75 and those with diabetes and a history of coronary artery disease. CONCLUSIONS: In this nationwide real world study covering 16 years of hospital admissions for myocardial infarction with symptom onset documented to the nearest minute, Christmas, and Midsummer holidays were associated with higher risk of myocardial infarction, particularly in older and sicker patients, suggesting a role of external triggers in vulnerable individuals.

Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis.

BACKGROUND: Sirtuins are a class of proteins with important physiologic roles in metabolism and inflammation. Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, activation is an unexplored therapeutic approach for the treatment of ulcerative colitis (UC). METHODS: Patients with mild to moderately active UC were blindly randomized to 50 mg or 500 mg daily of SRT2104, a selective activator of SIRT1, for 8 weeks. Colonic exposure and safety were assessed, as well as blinded endoscopic scoring and disease activity by Mayo score, Simple Clinical Colitis Activity Index and fecal calprotectin. RESULTS: Across both SRT2104 groups, only 3 of 26 evaluable subjects achieved remission on blinded endoscopic assessment. Clinical remission (Mayo score ≤2, no subscore >1) was achieved in 4 patients (2 of 13 evaluable patients in each dose group). Fecal calprotectin levels declined with treatment in both groups, but after 56 days of treatment subjects were still found to have levels approximately 4-fold elevated above normal. One subject experienced an SAE requiring study withdrawal and another was withdrawn for a severe UC flare; 19 subjects (61%) across both treatment groups experienced at least 1 treatment emergent adverse event. Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104, and colonic exposure was 140 to 160 times higher than plasma exposures. CONCLUSIONS: SRT2104 did not demonstrate significant clinical activity in mild to moderately active UC. This suggests that further evaluation of SRT2104 as a therapeutic strategy for the treatment of UC is not warranted.

A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis.

UNLABELLED: Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo. Across all SRT2104 groups, 35% of patients (p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84 but was not consistently in agreement with PASI. Improvement in histology was associated with modulation of IL-17 and TNF-α signaling pathways and keratinocyte differentiation target genes. 27 subjects (69%) across all treatment groups, including placebo, experienced at least one treatment emergent adverse event. The majority of AEs were either mild or moderate. Most common were headache (8%), dizziness (8%), upper respiratory tract infection (8%), and psoriatic arthropathy (8%). Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104 and had high intra-subject variability in exposure (AUC %CV: 51­89%). Given the interesting signals of clinical activity, impact on gene expression and the generally favorable safety profile seen in this study, further investigation of SIRT1 activators for the treatment of psoriasis is warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT01154101.

A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.

AIM: SRT2104 is a selective activator of SIRT1. In animal models, SRT2104 improves glucose homeostasis and increases insulin sensitivity. We evaluated the tolerability and pharmacokinetics of SRT2104, and its effects on glycaemic control, in adults with type 2 diabetes mellitus. METHOD: Type 2 diabetics with glycosylated haemoglobin (HbA1c) ≥ 7.5% and ≤10.5%, fasting glucose ≥160 and ≤240 mg dl(-1) , and on stable doses of metformin were evenly randomized to placebo or SRT2104 0.25 g, 0.5 g, 1.0 g or 2.0 g, administered orally once daily for 28 days. Changes in fasting and post-prandial glucose and insulin were analyzed. RESULTS: Safety evaluation found no major differences between groups in the frequency of adverse events. SRT2104 concentrations did not increase in a dose-proportional fashion. Significant variability in exposure was observed. Treatment with SRT2104 did not lead to any consistent, dose-related changes in glucose or insulin. Day 28 change from baseline (mean (SD)): fasting glucose (mmol l(-1) ) = -1.17 (2.42), -1.11 (3.45), -0.52 (2.60), -0.97 (2.83) and -0.15 (2.38) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively. Day 28 change from baseline (mean (SD)): fasting insulin (mmol l(-1) ) = 1.0 (51.66), 8.9 (95.04), -6.9 (41.45), 4.1 (57.16) and 15.2 (138.79) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively) Treatment with SRT2104 was associated with improvement in lipid profiles. CONCLUSION: Treatment with SRT2104 for 28 days did not result in improved glucose or insulin control which is likely due to the observed pharmacokinetics which were not dose proportional and had large between subject variability.

A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers.

BACKGROUND: SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD(+)-dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers. METHODS: Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity. RESULTS: SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2-4 hours with elimination half-life of 15-20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation. CONCLUSIONS: SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00964340.

Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma.

PURPOSE: Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma. PATIENTS AND METHODS: We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m(2) plus paclitaxel 80 mg/m(2) (E + P) or to paclitaxel 80 mg/m(2) alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc). RESULTS: At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated. CONCLUSION: E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.