RAD18 promotes DNA double-strand break repair during G1 phase through chromatin retention of 53BP1.

Recruitment of RAD18 to stalled replication forks facilitates monoubiquitination of PCNA during S-phase, promoting translesion synthesis at sites of UV irradiation-induced DNA damage. In this study, we show that RAD18 is also recruited to ionizing radiation (IR)-induced sites of DNA double-strand breaks (DSBs) forming foci which are co-localized with 53BP1, NBS1, phosphorylated ATM, BRCA1 and gamma-H2AX. RAD18 associates with 53BP1 and is recruited to DSB sites in a 53BP1-dependent manner specifically during G1-phase, RAD18 monoubiquitinates KBD domain of 53BP1 at lysine 1268 in vitro. A monoubiquitination-resistant 53BP1 mutant harboring a substitution at lysine 1268 is not retained efficiently at the chromatin in the vicinity of DSBs. In Rad18-null cells, retention of 53BP1 foci, efficiency of DSB repair and post-irradiation viability are impaired compared with wild-type cells. Taken together, these results suggest that RAD18 promotes 53BP1-directed DSB repair by enhancing retention of 53BP1, possibly through an interaction between RAD18 and 53BP1 and the modification of 53BP1.

Recognition of forked and single-stranded DNA structures by human RAD18 complexed with RAD6B protein triggers its recruitment to stalled replication forks.

Post-replication DNA repair facilitates the resumption of DNA synthesis upon replication fork stalling at DNA damage sites. Despite the importance of RAD18 and polymerase eta (Poleta) for post-replication repair (PRR), the molecular mechanisms by which these factors are recruited to stalled replication forks are not well understood. We present evidence that human RAD18 complexed with RAD6B protein preferentially binds to forked and single-stranded DNA (ssDNA) structures, which are known to be localized at stalled replication forks. The SAP domain of RAD18 (residues 248-282) is crucial for binding of RAD18 complexed with RAD6B to DNA substrates. RAD18 mutated in the SAP domain fails to accumulate at DNA damage sites in vivo and does not guide DNA Poleta to stalled replication forks. The SAP domain is also required for the efficient mono-ubiquitination of PCNA. The SAP domain mutant fails to suppress the ultraviolet (UV)-sensitivity of Rad18-knockout cells. These results suggest that RAD18 complexed with RAD6B is recruited to stalled replication forks via interactions with forked DNA or long ssDNA structures, a process that is required for initiating PRR.

Hospital dental hygienist intervention improves activities of daily living, home discharge and mortality in post-acute rehabilitation.

AIM: To examine the effects of oral management provided by dental hygienists (DH) on patient outcomes in post-acute rehabilitation. METHODS: We carried out a retrospective cohort study with 1056 patients newly admitted to a post-rehabilitation hospital in Japan. DH care was defined as two or more consecutive instances of oral management provided by a ward DH during hospitalization. The primary outcome was the motor domain of Functional Independence Measure score at discharge. Other outcomes included the rate of home discharge; length of stay, all-cause in-hospital mortality, and oral, swallowing and nutritional status at discharge. Propensity score matching was carried out to control and adjust for patients' backgrounds to compare outcomes between patients who did or did not receive DH care. RESULTS: Of 1056 patients enrolled (mean age 71 years; 52.0% women; 73.1% with oral problems), 415 (39.3%) received DH care. Multivariate analyses using pair-matched patients showed that DH care was significantly associated with higher motor domain of Functional Independence Measure score at discharge (ß = 0.281, P = 0.041), shorter length of stay (ß = 0.446, P = 0.044), higher rate of home discharge (odds ratio 1.202, 95% confidence interval 1.026-1.491, P = 0.037) and lower mortality (hazard ratio 0.818, 95% confidence interval 0.738-0.952, P = 0.037) after adjusting for potential covariates. CONCLUSIONS: DH oral management improves patient outcomes, including activities of daily living, home discharge and in-hospital mortality in post-acute rehabilitation. Early detection of oral problems, early oral treatment by dental professionals, and cooperation between medical and dental professionals should be implemented. Geriatr Gerontol Int 2019; 19: 189-196.

Impaired oral health status on admission is associated with poor clinical outcomes in post-acute inpatients: A prospective cohort study.

BACKGROUND & AIMS: Oral health is an integral part of nutrition and rehabilitation. The purpose of this study was to investigate the impact of impaired oral health status on clinical and functional outcomes in post-acute in-hospital rehabilitation. METHODS: We conducted a prospective cohort study of hospitalized patients undergoing rehabilitation at a 225-bed post-acute rehabilitation hospital in Japan. All newly admitted patients were eligible to enroll during the two-year research period. Oral health status was evaluated on admission using the Revised Oral Assessment Guide (ROAG). Nutritional status, assessed using the Mini Nutritional Assessment-Short Form; activities of daily living, assessed by Functional Independence Measure motor scores; home discharge; all-cause in-hospital mortality; and length of hospital stay were measured as clinical and rehabilitation outcomes. Multivariate analyses were used to determine whether the ROAG score on admission was associated with these outcomes at discharge. RESULTS: Of the 1066 patients enrolled, 1056 were included in the final analysis. The mean age was 70 ± 17 years. Fifty-two percent of patients were women. Stroke (21.7%) and musculoskeletal disorders (30.5%) were the most common reasons for admission. Slight or moderate to severe oral health problems were detected in 609 (57.7%) and 163 (15.4%) patients, respectively. Eighteen patients died during hospitalization. The ROAG score at admission was independently associated with Functional Independence Measure motor scores at discharge (P = 0.022), home discharge (P = 0.005), in-hospital mortality (P = 0.039), and length of hospital stay (P = 0.045), after adjusting for potential confounders. CONCLUSIONS: Impaired oral health status may be associated with rehabilitation outcomes in hospitalized patients. Early detection of oral health problems and treatment by dental professionals, or through cooperation between medical and dental professionals, should be implemented in these patients.

Prevalence of stroke-related sarcopenia and its association with poor oral status in post-acute stroke patients: Implications for oral sarcopenia.

BACKGROUND & AIMS: The aim of the study was to investigate the prevalence of stroke-related sarcopenia and its association with poor oral status in post-acute stroke patients. METHODS: This cross-sectional study included 202 consecutive stroke patients who were admitted to convalescent rehabilitation wards in Japan. The Revised Oral Assessment Guide (ROAG) was used to assess oral status. Sarcopenia was defined as a loss of skeletal muscle mass index (SMI) with bioelectrical impedance and decreased muscle strength as measured by handgrip strength; cut-off values were adopted from the Asian Working Group for Sarcopenia. Univariate and multivariate analyses were applied to examine the associations between oral status, SMI, and HG. RESULTS: Study participants included 107 males and 95 females with a mean age of 72 ± 12 years. According to the ROAG, 82.2% of participants had slight to severe oral problems (median score: 11 [9-14]). The prevalence of stroke-related sarcopenia was 53.5%. Both SMI (mean: 6.1 ± 1.3) and handgrip strength (median: 15 [7-25]) were significantly lower in the group with oral problems (SMI = 5.8 ± 1.2, handgrip strength = 12 [6-20]) compared to individuals without oral problems (SMI = 7.4 ± .8, handgrip strength = 27 [23-34]) (p < .001). The ROAG score was independently associated with SMI and handgrip strength, after adjusting for sex, age, stroke severity, activities of daily living, cognitive level, nutritional status, comorbidities, and time from stroke onset. CONCLUSIONS: Poor oral status was associated with sarcopenia, reduced muscle mass and strength in post-acute stroke patients. Poor oral status and stroke-related sarcopenia were very common among the patients in this study, suggesting that healthcare providers should monitor for oral sarcopenia in post-acute stroke patients.

Poor oral status is associated with rehabilitation outcome in older people.

AIM: Poor oral status is associated with increased physical dependency and cognitive decline. Malnutrition, a potential result of poor oral status, is associated with poorer rehabilitation outcome and physical function. However, the association between oral status and rehabilitation outcome is not fully understood. The present study investigated the association of poor oral status with rehabilitation outcome in older patients. METHODS: A retrospective cohort study was carried out of 108 consecutive patients (mean age 80.5 ± 6.8 years; 50.9% men) who were admitted to convalescent rehabilitation wards. The Revised Oral Assessment Guide was used to evaluate oral status. Rehabilitation outcome was evaluated by the Functional Independence Measure (FIM) on discharge. Multivariate analyses were applied to examine the associations between poor oral status and motor-FIM on discharge. RESULTS: According to the Revised Oral Assessment Guide score, 14.8% of participants had normal oral status, 52.8% had slight to moderate oral problems and 32.4% had severe oral problems. The median scores of motor-FIM on admission and on discharge were 52 (interquartile range 25-70) and 75 (interquartile range 51-89), respectively. Multivariate analysis showed that the Revised Oral Assessment Guide score and the motor-/cognitive-FIM scores on admission were significant independent factors for motor-FIM on discharge, after adjusted for sex, age, length of stay, nutritional status, handgrip and causative diseases (P < 0.001). CONCLUSIONS: Poor oral status is associated with rehabilitation outcome in older people. Geriatr Gerontol Int 2017; 17: 598-604.

In vitro antifungal activity of luliconazole against clinical isolates from patients with dermatomycoses.

The in vitro antifungal activity of luliconazole, a novel topical imidazole, against pathogenic fungi implicated in dermatomycoses was studied. A total of 91 clinical isolates, consisting of 59 Trichophyton rubrum isolates, 26 T. mentagrophytes isolates, 1 Epidermophyton floccosum isolate, and 5 Candida albicans isolates were tested by the broth microdilution method, employing lanoconazole, terbinafine, and bifonazole as reference drugs. The minimum inhibitory concentrations (MICs) of luliconazole against T. rubrum and T. mentagrophytes were in the range of 0.00012-0.004 microg/ml and 0.00024-0.002 microg/ml, respectively. The MIC90 of luliconazole for these two species of dermatophytes was the same, at 0.001 microg/ml, and these values were 4 times, 30 times, and more than 1000 times lower than those of lanoconazole, terbinafine, and bifonazole, respectively. Similarly, the 1 isolate of E. floccosum tested was inhibited by luliconazole with an MIC of 0.001 microg/ml. Luliconazole also proved to be very potent against C. albicans (MIC range, 0.031-0.25 microg/ml), nearly on par, in terms of efficacy, with lanoconazole (0.063-0.25 microg/ml) and more potent than terbinafine (2->64 microg/ml) and bifonazole (0.5-4 microg/ml). These results showed that luliconazole was very potent in vitro against pathogenic fungi isolated from patients with dermatomycoses, and these findings emphasized the utility of luliconazole for the topical management of this condition.