Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality

<p>Abstract</p> <p>Objective</p> <p>Metformin has had a 'black box' contraindication in diabetic patients with heart failure (HF), but many believe it to be the treatment of choice in this setting. Therefore, we attempted to conduct a pilot study to evaluate the feasibility of undertaking a large randomized controlled trial with clinical endpoints.</p> <p>Study Design</p> <p>The pilot study was a randomized double blinded placebo controlled trial. Patients with HF and type 2 diabetes were screened in hospitals and HF clinics in Edmonton, Alberta, Canada (population ~1 million). Major exclusion criteria included the current use of insulin or high dose metformin, decreased renal function, or a glycosylated hemoglobin <7%. Patients were to be randomized to 1500 mg of metformin daily or matching placebo and followed for 6 months for a variety of functional outcomes, as well as clinical events.</p> <p>Results</p> <p>Fifty-eight patients were screened over a six month period and all were excluded. Because of futility with respect to enrollment, the pilot study was abandoned. The mean age of screened patients was 77 (SD 9) years and 57% were male. The main reasons for exclusion were: use of insulin therapy (n = 23; 40%), glycosylated hemoglobin <7% (n = 17; 29%) and current use of high dose metformin (n = 12; 21%). Overall, contraindicated metformin therapy was the most commonly prescribed oral antihyperglycemic agent (n = 27; 51%). On average, patients were receiving 1,706 mg (SD 488 mg) of metformin daily and 12 (44%) used only metformin.</p> <p>Conclusion</p> <p>Despite uncertainty in the scientific literature, there does not appear to be clinical uncertainty with regards to the safety or effectiveness of metformin in HF making a definitive randomized trial virtually impossible.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00325910</p

Nck2 promotes human melanoma cell proliferation, migration and invasion in vitro and primary melanoma-derived tumor growth in vivo

<p>Abstract</p> <p>Background</p> <p>Nck1 and Nck2 adaptor proteins are involved in signaling pathways mediating proliferation, cytoskeleton organization and integrated stress response. Overexpression of Nck1 in fibroblasts has been shown to be oncogenic. Through the years this concept has been challenged and the consensus is now that overexpression of either Nck cooperates with strong oncogenes to transform cells. Therefore, variations in Nck expression levels in transformed cells could endorse cancer progression.</p> <p>Methods</p> <p>Expression of Nck1 and Nck2 proteins in various cancer cell lines at different stages of progression were analyzed by western blots. We created human primary melanoma cell lines overexpressing GFP-Nck2 and investigated their ability to proliferate along with metastatic characteristics such as migration and invasion. By western blot analysis, we compared levels of proteins phosphorylated on tyrosine as well as cadherins and integrins in human melanoma cells overexpressing or not Nck2. Finally, in mice we assessed tumor growth rate of human melanoma cells expressing increasing levels of Nck2.</p> <p>Results</p> <p>We found that expression of Nck2 is consistently increased in various metastatic cancer cell lines compared with primary counterparts. Particularly, we observed significant higher levels of Nck2 protein and mRNA, as opposed to no change in Nck1, in human metastatic melanoma cell lines compared with non-metastatic melanoma and normal melanocytes. We demonstrated the involvement of Nck2 in proliferation, migration and invasion in human melanoma cells. Moreover, we discovered that Nck2 overexpression in human primary melanoma cells correlates with higher levels of proteins phosphorylated on tyrosine residues, assembly of Nck2-dependent pY-proteins-containing molecular complexes and downregulation of cadherins and integrins. Importantly, we uncovered that injection of Nck2-overexpressing human primary melanoma cells into mice increases melanoma-derived tumor growth rate.</p> <p>Conclusions</p> <p>Collectively, our data indicate that Nck2 effectively influences human melanoma phenotype progression. At the molecular level, we propose that Nck2 in human primary melanoma promotes the formation of molecular complexes regulating proliferation and actin cytoskeleton dynamics by modulating kinases or phosphatases activities that results in increased levels of proteins phosphorylated on tyrosine residues. This study provides new insights regarding cancer progression that could impact on the therapeutic strategies targeting cancer.</p

The effect of tetrahydrocannabinol on testosterone among men in the United States: results from the National Health and Nutrition Examination Survey

To determine the association between tetrahydrocannabinol (THC) use and testosterone (T) levels among men in the United States. Using the National Health and Nutrition Examination Survey (NHANES) data from the years 2011-2016, we identified all men 18 years and older who answered the substance use questionnaire and underwent laboratory testing for T. Regular THC users were defined as those who use THC at least one time per month, every month for at least 1 year. Multivariable linear regressions controlling for confounders were then used to determine the relationship between THC use and T levels. Among the 5146 men who met inclusion, 3027 endorsed using THC at least once in their life (ever-user). Nearly half of the THC ever-users (49.3%) were considered regular THC users. Multivariate analysis controlling for age, comorbidities, tobacco use, alcohol use, body mass index (BMI), exercise level, and race revealed a small but statistically significant increase in T among regular THC users at any measured level of use, compared to non-regular THC users (non-users). This increase was characterized by an inverse U-shaped trend with Regular THC users using two-three times per month demonstrating the greatest increase in T (+ 66.77 ng/dL) over non-users. THC use is associated with small increases in testosterone. This increase in T appears to decline as THC use increases, but nevertheless, T is still higher with any amount of regular use when compared to T in non-users. Prospective work is needed to validate the observed increase and to better elucidate the mechanism of impact THC use has on T levels

Insulin and related factors in premenopausal breast cancer risk

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Decline in Serum Testosterone Levels Among Adolescent and Young Adult Men in the USA

Testosterone deficiency has a prevalence of 20% among adolescent and young adult (AYA) males. Although previous studies have shown that total testosterone (TT) levels are declining in the population compared to prior decades, no study has identified TT level trends for AYA males specifically. Using data from the National Health and Nutrition Examination Surveys, we investigated TT levels for 4045 men from 1999 to 2016. After controlling for confounders, we found that mean TT levels declined over time: TT levels were lower in the later (2011–2016) than in the earlier (1999–2000) cycles (all p < 0.001). Elevated body mass index (BMI) was associated with lower TT, but the trend remained significant even among men with normal BMI. Limitations include the influence of confounding variables such as environmental factors and the use of differing assays for TT measurement. Further studies using other data streams are needed to validate these findings. In this report we looked at data for adolescent and young adult men in a US national database on total testosterone (TT) levels. There has been a decline in mean TT levels over the past two decades and TT is lower with progressively higher body mass index. We conclude that TT levels have been declining in young adult men in recent decades. We report declining serum testosterone levels among adolescent and young adult men from 1999 to 2016. Our study has important clinical implications, as low serum testosterone has been associated with underlying comorbidities and potentially higher mortality risk

Characterizing re-triage guidelines: A scoping review of states\u27 rules and regulations

Background:State guidelines for re-triage, or emergency inter-facility transfer, have never been characterized across the United States. Methods: All 50 states\u27 Department of Health and/or Trauma System websites were reviewed for publicly available re-triage guidelines within their rules and regulations. Communication was made via phone or email to state agencies or trauma advisory committees to obtain or confirm the absence of guidelines where public data was unavailable. Guideline criteria were abstracted and grouped into domains of Center for Disease Control Field Triage Criteria: pattern/anatomy of injury, vital signs, special populations, and mechanisms of injury. Re-triage criteria were summarized across states using median and interquartile ranges for continuous data and frequencies for categorical data. Demographic data of states with and without re-triage guidelines were compared using the Wilcoxon rank sum test. Results: Re-triage guidelines were identified for 22 of 50 states (44%). Common anatomy of injury criteria included head trauma (91% of states with guidelines), spinal cord injury (82%), chest injury (77%), and pelvic injury (73%). Common vital signs criteria included Glasgow Coma Score (91% of states) ranging from 8 to 14, systolic blood pressure (36%) ranging from 90 to 100 mm Hg, and respiratory rate (23%) with all using 10 respirations/minute. Common special populations criteria included mechanical ventilation (73% of states), age (68%) ranging from60 years, cardiac disease (59%), and pregnancy (55%). No significant demographic differences were found between states with versus without re-triage guidelines. Conclusion: A minority of US states have re-triage guidelines. Characterizing existing criteria can inform future guideline development