Is metformin poised for a second career as an antimicrobial?

Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may have a potential role in the therapy for multiple infectious diseases. Metformin, in addition to its traditional effects on glucose metabolism, provides anti-microbial benefits in patients with tuberculosis and in a very wide range of other infections encounters in vitro and in vivo.

Use of Team-Based Learning Pedagogy for Internal Medicine Ambulatory Resident Teaching.

BACKGROUND: Team-based learning (TBL) is used in undergraduate medical education to facilitate higher-order content learning, promote learner engagement and collaboration, and foster positive learner attitudes. There is a paucity of data on the use of TBL in graduate medical education. Our aim was to assess resident engagement, learning, and faculty/resident satisfaction with TBL in internal medicine residency ambulatory education. METHODS: Survey and nominal group technique methodologies were used to assess learner engagement and faculty/resident satisfaction. We assessed medical learning using individual (IRAT) and group (GRAT) readiness assurance tests. RESULTS: Residents (N = 111) involved in TBL sessions reported contributing to group discussions and actively discussing the subject material with other residents. Faculty echoed similar responses, and residents and faculty reported a preference for future teaching sessions to be offered using the TBL pedagogy. The average GRAT score was significantly higher than the average IRAT score by 22%. Feedback from our nominal group technique rank ordered the following TBL strengths by both residents and faculty: (1) interactive format, (2) content of sessions, and (3) competitive nature of sessions. CONCLUSIONS: We successfully implemented TBL pedagogy in the internal medicine ambulatory residency curriculum, with learning focused on the care of patients in the ambulatory setting. TBL resulted in active resident engagement, facilitated group learning, and increased satisfaction by residents and faculty. To our knowledge this is the first study that implemented a TBL program in an internal medicine residency curriculum.

Socioeconomic and demographic factors contributing to outcomes in patients with primary lymphoma of bone.

BACKGROUND: Primary lymphoma of bone (PLB) is a rare disease, comprising a malignant lymphoid infiltrate of bone. The goal of this study was to identify socioeconomic, demographic, and anatomic factors as prognostic indicators of survival for this disease using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The SEER database was used to identify a study population of 692 patients diagnosed with PLB in the United States from 1989 to 2003. Survival was analyzed using the Kaplan-Meier method, with effects of potential prognostic factors on survival analyzed using the log-rank test. Multivariable analysis was performed by Cox proportional hazards regression. RESULTS: The overall 5-year survival rate was 49.6%, with a 10-year survival rate of 30.2%. Median overall survival was 4.9 years (95% CI: 3.9, 6.1). In multivariable analysis, age (p<0.0001), marital status (p=0.006), and appendicular vs. axial tumor location (p=0.004) were found to be independent predictors of survival. CONCLUSIONS: This population-based study of PLB identified age, marital status, and tumor location as independent indicators of prognosis. This finding supports the clinical suspicion that an appendicular tumor location confers a better prognosis than an axial tumor location.

TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells.

Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone's Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9-induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone's BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated anomaly + del13q14) and negatively linked to a very high proportion of CD38(+) cells within the blood-derived B-CLL population. Furthermore, a clone's intrinsic potential for in vitro growth correlated directly with doubling time in blood, in the case of B-CLL with Ig H chain V region-unmutated BCR and <30% CD38(+) cells in blood. Finally, in vitro high-proliferator status was statistically linked to diminished patient survival. These findings, together with immunohistochemical evidence of apoptotic cells and IL-15-producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in vivo B-CLL growth.

Antithrombotic Therapy Practices in Older Adults Residing in the Long-Term Care Setting.

OBJECTIVES: To explore physician practice patterns with regard to antithrombotic therapy, including antiplatelets and anticoagulants, in long-term care residents and compare resulting embolic complications. METHODS: Conducted between August 2012 and March 2013, this study was a retrospective chart review of 400 residents of a long-term care facility. Electronic charts from October 2005 through January 2013 were selected using systematic random sampling. RESULTS: Approximately one-third of residents (29.6%) received anticoagulants, 27.3% received antiplatelets, 15.8% received both, and 27.3% did not receive any antithrombotic therapy. The most commonly prescribed antithrombotic drugs were aspirin (37.5%) and warfarin (22.1%). The type of antithrombotic therapy was significantly associated with medical history, including deep vein thrombosis (P = 0.03), the presence of atrial fibrillation (P = 0.001) and other nonsurgical medical conditions (P = 0.0001). Weight (P = 0.009) and body mass index (P = 0.007) also were significantly associated with type of antithrombotic therapy, indicating that heavier residents and those with a higher body mass index were more likely to receive both anticoagulants and antiplatelets. There was no difference in the number of embolic complications among groups. CONCLUSIONS: Physicians are more disposed to initiate and maintain residents on aspirin while being more cautious when prescribing anticoagulants such as warfarin, dabigatran, heparin, and enoxaparin. In some residents, anticoagulants were not used at all, even when residents had particular risk factors, demonstrating that at times physicians may err on the side of overcautiousness. Antithrombotic therapy should be individualized for each resident based on bleeding risk, comorbidities, and benefits of a particular therapy for our most vulnerable populations.

Improvement in Overall Survival from Extremity Soft Tissue Sarcoma over Twenty Years.

Several patient demographic factors, including marital status, have been demonstrated to have prognostic significance for survival in extremity soft tissue sarcoma (ESTS). A study population of 12,546 adult patients diagnosed with ESTS from 1991 to 2010 was identified from the SEER database, a large population-based registry, in order to determine whether overall survival had changed over this recent 20-year period. The study population was divided into three groups by year of diagnosis: 1991-1996, 1997-2003, and 2004-2010. We used the Kaplan-Meier method and Cox proportional hazards regression to assess survival differences between different demographic groups and prognostic clinical characteristics. Over the course of time, the 5-year overall survival rates have increased from 28% in the earliest time period to 62% in the latest (P < 0.0001). On multivariate analysis, the mortality rate progressively declined from the 1991-1996 group (HR: 3.02, CI: 2.78-3.29) to the 1997-2003 group (HR: 2.21, CI: 2.06-2.37), with the 2004-2010 group having the best overall survival, despite increases in the proportion of patients with tumors greater than 5 cm in size (P < 0.0001), and those presenting with metastasis (P < 0.0001).

The brighter (and evolutionarily older) face of the metabolic syndrome: evidence from Trypanosoma cruzi infection in CD-1 mice.

BACKGROUND: Infection with Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, results in chronic infection that leads to cardiomyopathy with increased mortality and morbidity in endemic regions. In a companion study, our group found that a high-fat diet (HFD) protected mice from T. cruzi-induced myocardial damage and significantly reduced post-infection mortality during acute T. cruzi infection. METHODS: In the present study metabolic syndrome was induced prior to T. cruzi infection by feeding a high fat diet. Also, mice were treated with anti-diabetic drug metformin. RESULTS: In the present study, the lethality of T. cruzi (Brazil strain) infection in CD-1 mice was reduced from 55% to 20% by an 8-week pre-feeding of an HFD to induce obesity and metabolic syndrome. The addition of metformin reduced mortality to 3%. CONCLUSIONS: It is an interesting observation that both the high fat diet and the metformin, which are known to differentially attenuate host metabolism, effectively modified mortality in T. cruzi-infected mice. In humans, the metabolic syndrome, as presently construed, produces immune activation and metabolic alterations that promote complications of obesity and diseases of later life, such as myocardial infarction, stroke, diabetes, Alzheimer's disease and cancer. Using an evolutionary approach, we hypothesized that for millions of years, the channeling of host resources into immune defences starting early in life ameliorated the effects of infectious diseases, especially chronic infections, such as tuberculosis and Chagas disease. In economically developed countries in recent times, with control of the common devastating infections, epidemic obesity and lengthening of lifespan, the dwindling benefits of the immune activation in the first half of life have been overshadowed by the explosion of the syndrome's negative effects in later life.

P2Y12 platelet function assay for assessment of bleeding risk in coronary artery bypass grafting.

BACKGROUND: The use of platelet function testing has been advocated to individualize the time needed between discontinuation of P2Y12 inhibitors and coronary artery bypass grafting (CABG). However, the use of specific point-of-care assays to predict bleeding risk in patients on P2Y12 inhibitors prior to CABG has not been fully validated. METHODS: From September 2012 to May 2013, 81 patients on P2Y12 inhibitors underwent isolated CABG. Preoperative level of P2Y12 receptor blockade was measured using the VerifyNow P2Y12 assay. Packed red blood cell (pRBC) and platelet transfusions and postoperative chest tube output were correlated with preoperative P2Y12 reaction units (PRUs). RESULTS: Patients who stopped P2Y12 inhibitors for ≤3 days received significantly more platelet transfusions as compared to those whose inhibitors were stopped for longer (0.71 ± 1.05 units vs. 0.20 ± 0.71 units, p = 0.01). They also had increased postoperative chest tube output (552.5 ± 325.5 mL vs. 399.8 ± 146.5 mL, p = 0.03). There was no significant difference in platelet transfusions and chest tube output between patients whose preoperative PRU value was <250 compared to those whose values were ≥250. pRBC requirements were correlated with preoperative hematocrit and age but not with timing of discontinuation of P2Y12 inhibitors or with PRU levels. CONCLUSIONS: In patients on P2Y12 inhibitors undergoing CABG surgery, discontinuation of P2Y12 inhibitors three days prior to surgery rather than VerifyNow PRU values predicts postoperative bleeding and the need for platelet transfusions. Sole reliance on platelet function testing to determine the timing of surgery for patients on P2Y12 inhibitors should therefore be done with caution.