Background Numerous pre-clinical studies using bone marrow derived cells for the treatment of traumatic brain injury and stroke have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and other functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe TBI demonstrated safety and potentially a CNS structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Methods Adults (aged 18-55) with severe traumatic brain injury (GCS 5-8) and without signs of serious other injury or irreversible brain injury (see Table 1) were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6,9,12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest/infusion related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included MRI based measurements of supratentorial and corpus callosal volumes as well as DTI based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months post-injury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pre-treatment, post-treatment, and at 1 and 6 month follow-up. Results There were no serious adverse events related to harvest/infusion. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were down-regulated after BMMNC infusion. Conclusions Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by CNS structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are down-regulated after cell infusion. A Phase 2, prospective, randomized trial excluding the highest dose is warranted and can be powered based upon structural outcome variables.

BACKGROUND. Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS. Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS. Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS. Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION. NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074).

complications, even when performed in the subgroup of patients who have not had resolution of clinical symptoms and laboratory values. 4-7 In these studies, cholecystectomy was performed within 48-72 hours of admission. A recent randomized trial also showed that cholecystectomy within 48 hours of admission regardless of clinical and laboratory resolution led to shorter hospital LOS without increasing complications; however, this trial was terminated after interim analysis at 50% enrollment once the pre-specified effect size was detected, 8 and trials stopped early for benefit typically overestimate treatment effects. 9 Additional randomized trials are needed to confirm the safety and generalizability of early cholecystectomy for predicted mild acute gallstone pancreatitis. Furthermore, there are no prior randomized trials evaluating laparoscopic cholecystectomy within the first 24 hours of admission or in disadvantaged populations treated at safety-net hospitals. The objectives of this pilot randomized trial were: (1) to determine the feasibility of early cholecystectomy within 24 hours of presentation regardless of symptoms or laboratory values for patients mild gallstone pancreatitis predicted to be mild on admission, and (2) to obtain unbiased estimates of the effect of early cholecystectomy on hospital LOS, complications, and patient-reported outcomes (PROs) in order to determine the need for further evaluation. The hypothesis was that early cholecystectomy during index admission for predicted mild gallstone pancreatitis is feasible and results in shorter 30-day total hospital LOS without an increase in complications. Methods Design A single-center, parallel-group randomized trial () was performed comparing timing of laparoscopic cholecystectomy with intraoperative cholangiogram (IOC) during index admission among patients with predicted mild gallstone pancreatitis. 10 The trial compared cholecystectomy within 24 hours of presentation to cholecystectomy after clinical resolution on outcomes including 30-day hospital LOS, time to surgery, endoscopic retrograde cholangiopancreatography (ERCP) rates, complications, and PROs. Institutional Review Board approval was obtained. Setting The trial was conducted at Lyndon Baines Johnson General Hospital (LBJGH), a 207-bed safety-net hospital in Houston, Texas. LBJGH is a part of the safety-net system for Harris County, Texas, which is the third most populous county in the United States. Approximately 1300 elective and non-elective cholecystectomies are performed per year. Operative capabilities are available 24 hours a day, seven days a week. An on-call attending general surgeon is in house 24-hours a day along with a team of residents and operating room staff dedicated to perform around the clock non-elective general surgery procedures. Study population From June 2016 through June 2018, patients ≥ 18 years of age with predicted mild gallstone pancreatitis who were planned to undergo laparoscopic cholecystectomy prior to discharge Mueck et al.

Background: No treatment is available to reverse injury associated with traumatic brain injury (TBI). Progenitor cell therapies show promise in both pre-clinical and clinical studies. We conducted a meta-analysis of pre-clinical studies using progenitor cells to treat TBI. Methods: EMBASE, MEDLINE, Cochrane Review, Biosis, and Google Scholar were searched for articles using pre-specified search strategies. Studies meeting inclusion criteria underwent data extraction. Analysis was performed using Review Manager 5.3 according to a fixed-effects model, and all studies underwent quality scoring. Results: Of 430 abstracts identified, 38 met inclusion criteria and underwent analysis. Average quality score was 4.32 out of 8 possible points. No study achieved a perfect score. Lesion volume (LV) and Neurologic Severity Score (NSS) outcomes favored cell treatment with standard mean difference (SMD) of 0.86 (95%CI 0.64, 1.09) and 1.36 (95%CI 1.11, 1.60) respectively. Rotarod (RR) and Morris Water Maze (MWM) outcomes also favored treatment with improvements in SMD of 0.34 (95%CI 0.02, 0.65) and 0.46 (95%CI 0.17, 74) respectively. While LV and NSS were robust to publication bias assessments, RR and MWM were not. Heterogeneity (I2) ranged from 74% to 85% among the analyses, indicating a high amount of heterogeneity among studies. Precision as a function of quality score showed a statistically significant increase in the size of the confidence interval as quality improved. Conclusions: Our meta-analysis study reveals an overall positive effect of progenitor cell therapies on LV and NSS with a trend towards improved motor function and spatial learning in different TBI animal models.

BackgroundHuman multipotent adult progenitor cells (MAPC®) are an emerging therapy for traumatic brain injury (TBI); however, clinically translating a therapy involves overcoming many factors in vivo which are not present in pre-clinical testing. In this study we examined clinical parameters in vitro that may impact cell therapy efficacy.MethodsMAPC were infused through varying gauged needles and catheters with and without chlorhexidine, and their viability tested with trypan blue exclusion. MAPC were co-cultured with phenytoin and celecoxib at relevant clinical concentrations for 1 h and 24 h. Anti-inflammatory potency was tested using a stimulated rat splenocyte co-culture and ELISA for TNF-α production. MAPC were cultured under different osmolar concentrations and stained with propidium iodide for viability. Anti-inflammatory potency was tested by co-culture of MAPC with naïve lymphocytes activated by CD3/CD28 beads, and Click-iT® Plus EdU was used to quantify proliferation by flow cytometry.ResultsThe mean viability of the MAPC infused via needles was 95 ± 1%; no difference was seen with varying flow rate, but viability was notably reduced by chlorhexidine. MAPC function was not impaired by co-culture with phenytoin, celecoxib, or combination with both. Co-culture with phenytoin showed a decrease in TNF-α production as compared to the MAPC control. MAPC cultured at varying osmolar concentrations all had viabilities greater than 90% with no statistical difference between them. Co-culture of MAPC with CD3/CD28 activated PBMCs showed a significant reduction in proliferation as measured by EdU uptake.DiscussionNeedle diameter, phenytoin, celecoxib, and a relevant range of osmolarities do not impair MAPC viability or anti-inflammatory potency in vitro.