Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.

Assessing the Cushion Effect: A Systematic Review and Meta-Analysis of the Role of Obesity in Motor Vehicle Injuries and Fatalities.

PURPOSE: A systematic review and meta-analysis were done to evaluate the effect of obesity in injury and mortality due to motor vehicle accidents. MATERIALS & METHODS: The systematic review consisted of 20 studies meeting the inclusion criteria. The meta-analysis was conducted on these studies to analyze obesity as a risk factor for specific injuries, as well as overall injury and mortality compared to non-obese patients. RESULTS: The data revealed that obesity was associated with increased lower extremity injuries (odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.19-1.69, P ≤ 0.05), neck injuries (OR = 3.38, 95% CI = 1.58-5.19, P ≤ 0.05), and overall mortality (OR = 1.51, 95% CI = 1.40-1.61, P ≤ 0.05). When stratified for obesity class with class I as BMI >30.1-34.9, class II BMI 35-39.9, and class III BMI >40, only class II (OR = 1.20, 95% CI = 1.15-1.24, P ≤ 0.05) and class III (OR = 1.49, 95% CI = 1.30-1.68, P ≤ 0.05) were associated with increased mortality risk. No significant differences were seen with head, upper extremity, thoracic, abdominal, or pelvic injuries. CONCLUSION: Obesity is a risk factor in motor vehicle accidents for fatality and injury, specifically lower extremity and neck injuries.

Current Trends in the Use of Ultrasound Over Chest X-Ray to Identify Pneumothoraces in ICU, Trauma, and ARDS Patients.

Pneumothoraces are a common and potentially fatal complication for critically ill patients in the trauma and intensive care units. Since its use for pneumothorax detection was first reported in 1987, ultrasound has been increasingly used for the detection of thoracic injuries. As ultrasound imaging has improved and operators have potentially become more proficient, it is important to analyze more recent trends in the sensitivities and specificities of ultrasound for the detection of pneumothorax. This literature review and meta-analysis identifies 17 studies that directly compare the sensitivity and specificity of ultrasound and anterior-posterior chest x-ray in the identification of pneumothorax among 2955 patients who developed 793 pneumothoraces as detected by gold standard CT scanning. For the 17 articles analyzed, the pooled sensitivity of trans-thoracic ultrasound was 75.07% (64.92%-85.22%), and the pooled specificity was 98.36% (97.45%-99.26%). The pooled sensitivity of CXR was 45.65% (36.04%-55.26%), and pooled specificity was 99.62% (99.00%-100%). While this review demonstrates an improved sensitivity in the detection of pneumothorax with ultrasound over AP chest x-rays, it did not find a significant trend or improvement in the sensitivity or specificity of ultrasound for detecting pneumothorax over time.

The Role of Obesity in Motor Vehicle Injuries and Fatalities in the Pediatric Population: A Systematic Review.

PURPOSE: A systematic review done to evaluate obesity as a risk factor for injuries and mortality in motor vehicle accidents (MVAs) in the pediatric population, as there has not been a systematic review done in over 10 years. This study aims to update the literature regarding obesity as a risk factor for injuries in MVAs in the pediatric population. MATERIALS AND METHODS: A systematic review was conducted according to the PRISMA guidelines with strict inclusion and exclusion criteria, resulting in the use of 3 total articles to analyze obesity as a risk factor for overall injury and mortality in the pediatric population. RESULTS: Zaveri et al demonstrated a statistically significant, but weak, decrease in the odds of extremity injury in overweight patients ages 2 to 17 years old (odds ratio [OR] = 0.6, 95% confidence interval [CI] = 0.4-1.0, P ≤ 0.05). On the other hand, Pollack et al and Haricharan et al found an increase in extremity injury in the obese population, in ages 9 to 15 years (OR = 2.54, 95% CI = 1.15-5.59, P ≤ 0.05), and 10 to 17 years (Age 10-13: OR = 6.06, 95% CI = 2.23-16.44, P ≤ 0.05, Age 14-17 OR = 1.44, 95% CI = 1.04-2.00, P ≤ 0.05), respectively. Haricharan et al also found an increase in thoracic injuries in obese children, ages 2 to 13 and increased risk of head/face/neck injury in obese children ages 2 to 5 (OR = 3.67, 95% CI = 1.03-13.08, P ≤ 0.05), but a decreased risk of head injury in obese children ages 14 to 17 (OR = 0.33, 95% CI = 0.18-0.60, P ≤ 0.05). CONCLUSIONS: There are sparse data that are conflicting, regarding the effect of obesity on extremity injuries in the pediatric population. Obesity is not protective against thoracic, head, or abdominal injuries. However, it was found to be a risk factor for trunk injuries in ages 2 to 13, as well as head/face/neck injuries for ages 2 to 5. Since the literature is so sparse, further research is warranted in these areas.

A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss.

OBJECTIVE: This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity. METHODS: The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥  27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss. RESULTS: Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks. CONCLUSIONS: Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.

Effect of a nonsystemic, orally administered hydrogel, GS100, on metformin pharmacokinetics.

Overweight and obesity are major health concerns worldwide, and are major predisposing factors for type 2 diabetes. This single-centre, Phase I, randomised, open-label, single-dose, 4-arm crossover, device-drug interaction study on 24 healthy volunteers with a body mass index of 25-40 kg/m2 tested the effect of a novel, nonsystemic, orally administered hydrogel (GS100) on the pharmacokinetics of an oral antidiabetic drug, metformin. When administered in both the fed and fasted states, the effect of GS100 on metformin pharmacokinetic characteristics was found to be similar to that of food. The type, frequency, and intensity of adverse events observed when GS100 was co-administered with metformin were similar to those observed with metformin alone. This study demonstrates that GS100 can be taken by patients receiving metformin, without altering the administration of metformin.

Smarter Sole Survival: Will Neuropathic Patients at High Risk for Ulceration Use a Smart Insole-Based Foot Protection System?

OBJECTIVE: This study examined adherence to alert-based cues for plantar pressure offloading in patients with diabetic foot disease. METHOD AND DESIGN: Participants (n = 17) with in diabetic foot remission (history of neuropathic ulceration) were instructed to wear a smart insole system (the SurroSense Rx, Orpyx Medical Technologies Inc, Calgary, Canada) over a three-month period. This device is designed to cue offloading to manage unprotected sustained plantar pressures in an effort to prevent foot ulceration. A successful response to an alert was defined as pressure offloading, which occurred within 20 minutes of the alert onset. Patient adherence, defined as daily hours of device wear, was determined using sensor data and patient questionnaires. Changes in these parameters were assessed monthly. RESULTS: Patients demonstrating increased adherence over the course of the study received more alerts (0.82 ± 0.31 alerts/hour) than patients whose adherence did not improve (0.36 ± 0.46 alerts/hour, P = .156). By the final stages of the study, participants who had received at least one alert every two hours were more adherent with offloading than participants who received fewer alerts (52.5 ± 4.1% vs 24.7 ± 22.4%, P = .043). Furthermore, duration of time from alert generation to successful offloading was significantly greater in the group receiving fewer alerts. This was measured in the third month with an effect size Cohen's d = 1.739, P = .043. CONCLUSION: The results suggest a minimum number of alerts (one every two hours) is required for patients with diabetic neuropathy to optimally respond to offloading cues from a smart insole system.

L-Arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor.

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction.