Inhibition of the CoREST Repressor Complex Promotes Wound Re-Epithelialization through the Regulation of Keratinocyte Migration.

Wound healing is a complex process involving phases of hemostasis, inflammation, proliferation, and remodeling. The regenerative process in the skin requires coordination between many regulators, including signaling molecules, transcription factors, and the epigenetic machinery. In this study, we show that chromatin regulators HDAC1 and LSD1, key components of the CoREST repressor complex, are upregulated in the regenerating epidermis during wound repair. We also show that corin, a synthetic dual inhibitor of the CoREST complex and HDAC1/LSD1 activities, significantly accelerates wound closure through enhanced re-epithelialization in a mouse tail wound model. Acetylated H3K9 (methylation of histone H3 at lysine 9) expression, a histone modification targeted by HDAC1, is increased in keratinocytes after topical treatment with 100 nM and 1 µM of corin. In vitro experiments demonstrate that corin promotes migration and inhibits the proliferation of human keratinocytes. Furthermore, expression levels of genes promoting keratinocyte migration, such as AREG, CD24, EPHB2, ITGAX, PTGS, SCT1, SERPINB2, SERPINE1, SLPI, SNAI2, and TWIST, increased in keratinocytes treated with corin. These data demonstrate that dual inhibition of class I histone deacetylases and LSD1 by corin may serve as a new approach for promoting wound re-epithelialization and provide a platform for further applications of corin for the treatment of chronic wounds.

Combination of delirium and coma predicts psychiatric symptoms at twelve months in critically ill patients: A longitudinal cohort study.

PURPOSE: We aimed to determine any associations between delirium and comas during intensive care unit (ICU) stay, and long-term psychiatric symptoms and disability affecting activity of daily living (ADL). MATERIALS AND METHODS: In this prospective observational study, we enrolled critically ill adult patients that were emergently admitted to an ICU. We assessed psychiatric symptoms and disability affecting ADL at three and twelve months after ICU discharge. RESULTS: Among the 81 and the 47 patients that responded to the questionnaires at three and twelve months, 22 (27%) and 13 (28%) patients experienced delirium, respectively. During their ICU stay, 28 (35%) and 21 (45%) had been in comas, respectively. At three and twelve months, 51 (63%) and 23 (49%) of patients experienced composite psychiatric symptoms or disability affecting ADL, respectively. After adjusting predefined confounders, the combination of delirium and comas was an independent risk factor for the presence of composite psychiatric symptoms or disability affecting ADL (adjusted odds ratio [aOR] 3.38; 1.10-10.38 at three months; aOR 8.28; 1.48-46.46 at twelve months). CONCLUSIONS: In critically ill adults, combination of delirium and comas during ICU stay is a predictor of psychiatric symptoms or ADL disability. TRIAL REGISTRATION: UMIN Clinical Trial Registry no. UMIN000023743, September 1, 2016.

Impaired Healing of a Cutaneous Wound in an Inducible Nitric Oxide Synthase-Knockout Mouse.

Background. We investigated the effects of loss of inducible nitric oxide synthase (iNOS) on the healing process of cutaneous excisional injury by using iNOS-null (KO) mice. Population of granulation tissue-related cell types, that is, myofibroblasts and macrophages, growth factor expression, and reepithelialization were evaluated. Methods. KO and wild type (WT) mice of C57BL/6 background were used. Under general anesthesia two round full-thickness excision wounds of 5.0 mm in diameter were produced in dorsal skin. After specific intervals of healing, macroscopic observation, histology, immunohistochemistry, and real-time reverse transcription-polymerase chain reaction (RT-PCR) were employed to evaluate the healing process. Results. The loss of iNOS retards granulation tissue formation and reepithelialization in excision wound model in mice. Detailed analyses showed that myofibroblast appearance, macrophage infiltration, and mRNA expression of transforming growth factor b and of collagen 1α2 were all suppressed by lacking iNOS. Conclusions. iNOS is required in the process of cutaneous wound healing. Lacking iNOS retards macrophage invasion and its expression of fibrogenic components that might further impair fibrogenic behaviors of fibroblasts.

Oxygenation improves during the first 8 h of extended-duration prone positioning in patients with respiratory failure: a retrospective study.

BACKGROUND: A recent multicenter trial demonstrated decreased mortality when patients with acute respiratory distress syndrome were treated with prone positioning (PP). However, the optimal duration of this treatment has not been established. METHODS: From May 2010 to August 2013, 15 patients with respiratory failure underwent extended-duration prone positioning (more than 40 h) in the medical-surgical intensive care unit of a university hospital. The records of each patient were retrospectively investigated to evaluate the impact of prone positioning on the PaO2/FiO2 ratio (PFR) during the first 40 h of therapy. RESULTS: The mean age of the patients was 72.2 ± 7.8 years, and the mean Acute Physiology and Chronic Health Evaluation II score was 19.0 ± 6.0. The hospital mortality rate was 47% (7/15), and the median duration of prone positioning was 47.5 h (46.5-67). The mean PFR before prone positioning was 193.8 ± 70.1, and it significantly improved to 274.7 ± 70.7 (p = 0.02) at 8 h after prone positioning initiation. Although PFR further improved to 294.1 ± 78.0 (p = 0.23) at 16 h, the change was not significant and PFR remained relatively constant at 289.0 ± 88.1, 294.6 ± 68.2, and 291.7 ± 72.7 at 24, 32, and 40 h, respectively. CONCLUSIONS: Extended-duration prone positioning resulted in a progressive improvement in oxygenation until 8 to 16 h after treatment initiation, after which there was no significant improvement. Further studies are warranted to clarify the optimal duration of prone positioning and the actual effectiveness of extended-duration PP for respiratory failure.

Out-of-hospital cardiac arrest and survival: an epidemiological analysis of emergency service reports in a large city in Japan.

BACKGROUND: The factors that influence survival of out-of-hospital cardiac arrest in Japan have not been fully investigated. METHODS AND RESULTS: The official emergency service record was used to investigate 1,600 patients for whom cardiopulmonary resuscitation was attempted by the city's emergency personnel. Only 45 (2.8%) patients survived for 1 month. The survival rate was 9.8% in the patients under 20 years of age, with a marked decreasing trend to 0.8% in the patients aged 80 years or older. The rate peaked at 4.8% on Sunday and bottomed out at 0.5% on Thursday, forming a distinct sine curve. The survival rate was 9.9% when an ambulance arrived at the scene within 4 min, with a steep drop to 2.5% when 4-7 min elapsed. However, the rate was not significantly different by the interval to hospital. Although bystander resuscitation did not significantly affect the survival, paramedics on board significantly improved the rate (3.5% vs 1.6%). Multivariate analysis confirmed that age, day of the week, place, interval to ambulance's arrival, and personnel on board were independently associated with the probability of survival. CONCLUSIONS: Quick arrival of a paramedic team would improve the survival after out-of-hospital cardiac arrest. General education of lifesaving techniques would be another key factor.