Clinical outcomes in patients with native valve infective endocarditis and diabetes mellitus

BACKGROUNDThere is a lack of data on the clinical outcomes in patients with native valve infective endocarditis (NVIE) and diabetes mellitus (DM).AIMTo investigate (1) trends in the prevalence of DM among patients with NVIE; and (2) the impact of DM on NVIE outcomes. METHODSWe identified 76385 with NVIE from the 2004 to 2014 National Inpatient Sample, of which 22284 (28%) had DM. We assessed trends in DM from 2004 to 2014 using the Cochrane Armitage test. We compared baseline comorbidities, microorganisms, and in-patients procedures between those with vs without DM. Propensity match analysis and multivariate logistic regression were used to investigate study outcomes in in-hospital mortality, stroke, acute heart failure, cardiogenic shock, septic shock, and atrioventricular block.RESULTSCrude rates of DM increased from in 22% in 2004 to 30% in 2014. There were significant differences in demographics, comorbidities and NVIE risk factors between the two groups. Staphylococcus aureus was the most common organism identified with higher rates in patients with DM (33.1% vs 35.6%; P < 0.0001). After propensity matching, in-hospital mortality (11.1% vs 11.9%; P < 0.0001), stroke (2.3% vs 3.0%; P < 0.0001), acute heart failure (4.6% vs 6.5%; P = 0.001), cardiogenic shock (1.5% vs 1.9%; P < 0.0001), septic shock (7.2% vs 9.6%; P < 0.0001), and atrioventricular block (1.5% vs 2.4%; P < 0.0001), were significantly higher in patients with DM. Independent predictors of mortality in NVIE patients with DM include hemodialysis, congestive heart failure, atrial fibrillation, staphylococcus aureus, and older age.CONCLUSIONThere is an increasing prevalence of DM in NVIE and it is associated with poorer outcomes. Further studies are crucial to identify the clinical, and sociodemographic contributors to this trend and develop strategies to mitigate its attendant risk.     

A Re‐examination of the MDM2/p53 Interaction Leads to Revised Design Criteria for Novel Inhibitors

The general model of epitope‐type MDM2 inhibitor was developed based on the structural information on the complexes between MDM2 and various low molecular weight ligands found in the PDB database. Application of this model to our in‐house library has led us to a new scaffold capable of interrupting protein–protein interactions. A synthetic library based on this and related scaffolds resulted in new classes of compounds that possess biochemical and cellular activity and good pharmacokinetic properties. We assume that such general approach to PPI inhibitors design may be useful for the development of inhibitors of various PPI types, including Bcl/XL.     

Collagen/Chitosan Gels Cross-Linked with Genipin for Wound Healing in Mice with Induced Diabetes

Diabetes mellitus continues to be one of the most common diseases often associated with diabetic ulcers. Chitosan is an attractive biopolymer for wound healing due to its biodegradability, biocompatibility, mucoadhesiveness, low toxicity, and hemostatic effect. A panel of hydrogels based on chitosan, collagen, and silver nanoparticels were produced to treat diabetic wounds. The antibacterial activity, cytotoxicity, swelling, rheological properties, and longitudinal sections of hydrogels were studied. The ability of the gels for wound healing was studied in CD1 mice with alloxan-induced diabetes. Application of the gels resulted in an increase in VEGF, TGF-b1, IL-1b, and TIMP1 gene expression and earlier wound closure in a comparison with control untreated wounds. All gels increased collagen deposition, hair follicle repair, and sebaceous glands formation. The results of these tests show that the obtained hydrogels have good mechanical properties and biological activity and have potential applications in the field of wound healing. However, clinical studies are required to compare the efficacy of the gels as animal models do not reproduce full diabetes pathology.     

International trends in hepatocellular carcinoma incidence, 1978–2012

Primary liver cancer, the major histology of which is hepatocellular carcinoma (HCC), is the second leading cause of cancer death worldwide. We comprehensively examined recent international trends of primary liver cancer and HCC incidence using population-based cancer registry data. Incidence for all primary liver cancer and for HCC by calendar time and birth cohort was examined for selected countries between 1978 and 2012. For each successive 5-year period, age-standardized incidence rates were calculated from Volumes V to XI of the Cancer Incidence in Five Continents (CI5) series using the online electronic databases, CI5plus. Large variations persist in liver cancer incidence globally. Rates of liver cancer remain highest in Asian countries, specifically in the East and South-East, and Italy. However, rates in these high-risk countries have been decreasing in recent years. Rates in India and in most countries of Europe, the Americas and Oceania are rising. As the population seroprevalence of hepatitis B virus (HBV) continues to decline, we anticipate rates of HCC in many high-risk countries will continue to decrease. Treatment of hepatitis C virus (HCV) is likely to bring down rates further in some high-rate, as well as low-rate, countries with access to effective therapies. However, such gains in the control of liver cancer are at risk of being reversed by the growing obesity and diabetes epidemics, suggesting diabetes treatment and primary prevention of obesity will be key in reducing liver cancer in the longer-term.     

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

The PI3K/mTOR signaling cascade is fundamental in T‐cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T‐cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T‐cell activities. Substantial adverse effects in long‐term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T‐cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI‐103 and PKI‐587 inhibitors interfered IL‐2‐dependent responses in T‐cells. However, in contrast to the inhibitory effects in non‐Treg T‐cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI‐103, and PKI‐587 targeted different signaling events and induced different metabolic patterns in primary T‐cells. Similar to rapamycin, in vivo administration of PI‐103 and PKI‐587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T‐cells and support their potential as a novel therapeutic option in transplantation.