ENERGI-F703 gel, as a new topical treatment for diabetic foot and leg ulcers: A multicenter, randomized, double-blind, phase II trial.

Background: Diabetic foot and leg ulcers are a major cause of disability among patients with diabetes mellitus. A topical gel called ENERGI-F703, applied twice daily and with adenine as its active pharmaceutical ingredient, accelerated wound healing in diabetic mice. The current study evaluated the safety and efficacy of ENERGI-F703 for patients with diabetic foot and leg ulcers. Methods: This randomized, double-blind, multicenter, phase II trial recruited patients from eight medical centers in Taiwan. Patients with intractable diabetic foot and leg ulcers (Wagner Grade 1-3 without active osteomyelitis) were randomly assigned (2:1) to receive topical ENERGI-F703 gel or vehicle gel twice daily for 12 weeks or until complete ulcer closure. The investigator, enrolled patients and site personnel were masked to treatment allocation. Intention to treat (ITT) population and safety population were patient to primary analyses and safety analyses, respectively. Primary outcome was complete ulcer closure rate at the end of treatment. This trial is registered with ClinicalTrials.gov, number NCT02672436. Findings: Starting from March 15th, 2017 to December 26th, 2019, 141 patients were enrolled as safety population and randomized into ENERGI-F703 gel (n = 95) group or vehicle gel (n = 46) group. In ITT population, ENERGI-F703 (n = 90) and vehicle group showed ulcer closure rates of 36.7% (95% CI = 26.75% - 47.49%) and 26.2% (95% CI = 13.86% - 42.04%) with difference of 9.74 % (95 % CI = -6.74% - 26.23%) and 25% quartiles of the time to complete ulcer closure of 69 days and 84 days, respectively. There were 25 (26.3%) patients in ENERGI-F703 group and 11 (23.9%) patients in vehicle group experiencing serious adverse events and five deaths occurred during the study period, none of them related to the treatment. Interpretation: Our study suggests that ENERGI-F703 gel is a safe and well-tolerated treatment for chronic diabetic foot and leg ulcers. Further studies are needed to corroborate our findings in light of limitations. Funding: Energenesis Biomedical Co., Ltd.

Survival and associated risk factors in patients with diabetes and amputations caused by infectious foot gangrene.

BACKGROUND: Infectious gangrene of the foot is a serious complication of diabetes that usually leads to a certain level of lower-extremity amputation (LEA). Nevertheless, the long-term survival and factors associated with mortality in such patients have yet to be elucidated. METHODS: A total of 157 patients with type 2 diabetes who received treatment for infectious foot gangrene at a major diabetic foot center in Taiwan from 2002 to 2009 were enrolled, of whom 90 had major LEAs (above the ankle) and 67 had minor LEAs (below the ankle). Clinical data during treatment were used for the analysis of survival and LEA, and survival was tracked after treatment until December 2012. RESULTS: Of the 157 patients, 109 died, with a median survival time of 3.12 years and 5-year survival rate of 40%. Age [hazard ratio 1.04 (95% confidence interval 1.01-1.06)], and major LEA [1.80 (1.05-3.09)] were independent factors associated with mortality. Patients with minor LEAs had a better median survival than those with major LEAs (5.5 and 1.9 years, respectively, P < 0.01). An abnormal ankle-brachial index was an independent risk factor [odds ratio 3.12 (95% CI 1.18-8.24)] for a poor outcome (major LEA) after adjusting for age, smoking status, hypertension, major adverse cardiac events, and renal function. CONCLUSIONS: Efforts to limit amputations below the ankle resulted in better survival of patients with infectious foot gangrene. An abnormal ankle-brachial index may guide physicians to make appropriate decisions with regards to the amputation level.

Garlic accelerates red blood cell turnover and splenic erythropoietic gene expression in mice: evidence for erythropoietin-independent erythropoiesis.

Garlic (Allium sativum) has been valued in many cultures both for its health effects and as a culinary flavor enhancer. Garlic's chemical complexity is widely thought to be the source of its many health benefits, which include, but are not limited to, anti-platelet, procirculatory, anti-inflammatory, anti-apoptotic, neuro-protective, and anti-cancer effects. While a growing body of scientific evidence strongly upholds the herb's broad and potent capacity to influence health, the common mechanisms underlying these diverse effects remain disjointed and relatively poorly understood. We adopted a phenotype-driven approach to investigate the effects of garlic in a mouse model. We examined RBC indices and morphologies, spleen histochemistry, RBC half-lives and gene expression profiles, followed up by qPCR and immunoblot validation. The RBCs of garlic-fed mice register shorter half-lives than the control. But they have normal blood chemistry and RBC indices. Their spleens manifest increased heme oxygenase 1, higher levels of iron and bilirubin, and presumably higher CO, a pleiotropic gasotransmitter. Heat shock genes and those critical for erythropoiesis are elevated in spleens but not in bone marrow. The garlic-fed mice have lower plasma erythropoietin than the controls, however. Chronic exposure to CO of mice on garlic-free diet was sufficient to cause increased RBC indices but again with a lower plasma erythropoietin level than air-treated controls. Furthermore, dietary garlic supplementation and CO treatment showed additive effects on reducing plasma erythropoietin levels in mice. Thus, garlic consumption not only causes increased energy demand from the faster RBC turnover but also increases the production of CO, which in turn stimulates splenic erythropoiesis by an erythropoietin-independent mechanism, thus completing the sequence of feedback regulation for RBC metabolism. Being a pleiotropic gasotransmitter, CO may be a second messenger for garlic's other physiological effects.

Human adenovirus 36 induces adiposity, increases insulin sensitivity, and alters hypothalamic monoamines in rats.

OBJECTIVE: Human adenovirus 36 (Ad-36) increases adiposity and reduces serum lipids in chicken, mouse, and non-human primate models, and it is linked to obesity in sero-epidemiological studies in humans. Involvement of the central nervous system (CNS) or adipose tissue in the mechanism of Ad-36-induced adiposity is unknown. The effects of Ad-36 on adiposity and on the neuroendocrine system were investigated in a rat model. RESEARCH METHODS AND PROCEDURES: Five-week-old male Wistar rats were inoculated intraperitoneally with Ad-36 or medium. RESULTS: Despite similar food intakes, infected rats attained significantly greater body weight and fat pad weight by 30 weeks post-inoculation. Epididymal-inguinal, retroperitoneal, and visceral fat pad weights of the infected group were greater by 60%, 46%, and 86%, respectively (p < 0.00001). The fasting serum insulin level and homeostasis model assessment index indicated greater insulin sensitivity in the infected group. Visceral adipose tissue expression of glycerol 3-phosphate dehydrogenase, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer-binding protein alpha and beta was markedly increased in the infected animals compared with controls. Ad-36 decreased norepinephrine levels significantly in the paraventricular nucleus in infected vs. control rats (mean +/- standard error, 8.9 +/- 1.1 vs. 12.8 +/- 1.2 pg/microg protein; p < 0.05). Ad-36 markedly decreased serum corticosterone in infected vs. control rats (mean +/- standard error, 97 +/- 41.0 vs. 221 +/- 111 ng/mL; p < 0.005). DISCUSSION: The results suggest that the pro-adipogenic effect of Ad-36 may involve peripheral as well as central effects. The male Wistar rat is a good model for the elucidation of metabolic and molecular mechanisms of Ad-36-induced adiposity.

Physical abuse against pregnant aborigines in Taiwan: prevalence and risk factors.

The purpose of this study was to estimate the prevalence of, and to investigate the risk factors for physical abuse against pregnant aborigines in Taiwan. A cross-sectional survey was conducted. Aboriginal women who had just given birth in hospitals were recruited from January to December 2003. The women were interviewed with a structured questionnaire about the physical abuse and substance use experiences. Participants were 1143 aboriginal women who had just given birth in hospitals. About 175/1143 of the women (15.3%) had ever experienced physical abuse from a husband or intimate partner, and 79/1143 of the women (6.9%) had experienced it during their recent pregnancy. Multiple logistic regression analysis revealed that the women who were more likely to have been physically abused during their pregnancy were: had fewer years of education, husbands who were unemployed, with a patriarchal family situation and had alcohol, cigarette and non-prescription drug use. Based on these results, we suggest that health care professionals provide adequate support and health education, develop interventions, and use referrals in concert with routine prenatal care in order to reduce and prevent the physical abuse of aboriginal women in Taiwan.