Dedifferentiation maintains melanocyte stem cells in a dynamic niche.

For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations1, which leads to hair greying in most humans and mice2,3. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli4-8. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.

Effects of Walking-Only Intervention on Physical Function, Fall-Related Outcomes, and Health-Related Quality of Life in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis.

This study aimed to determine the effects of walking-only intervention (walking was the only exercise in which people participated) on physical function, fall-related outcomes, and health-related quality of life in community-dwelling older adults. We conducted a systematic search across five electronic databases, assessing risk of bias using Minds Manual for Guideline Development. Meta-analyses were performed, and pooled standardized mean differences were calculated. Nine studies (a total of 1,309 participants) were included, showing that walking-only interventions improved walking endurance (standardized mean difference: 1.11, 95% confidence interval: [0.08, 2.15]) and health-related quality of life (standardized mean difference: 0.71, 95% confidence interval: [0.18, 1.25]). However, there were no significant improvements in other outcomes. The certainty of the evidence based on the Grading of Recommendations, Assessment, Development, and Evaluation approach for all outcomes was graded as very low, primarily due to significant inconsistency and imprecision. Our results suggest that walking-only intervention can be effective for enhancing walking endurance and health-related quality of life for community-dwelling older adults. Further studies are required to investigate the effects of walking-only intervention. This need stems from the limited number of randomized controlled trials, heterogeneous intervention settings and results, and the very low certainty of the evidence.

Efficacy of Therapeutic Exercise on Activities of Daily Living and Cognitive Function Among Older Residents in Long-term Care Facilities: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVES: This study aimed to systematically analyze the efficacy of therapeutic exercise on activities of daily living (ADL) and cognitive function among older residents in long-term care facilities. DATA SOURCES: PubMed, Cochrane Central of Register Trials, Physiotherapy Evidence Database, OTseeker, and Ichushi-Web were searched from inception until December 2018. STUDY SELECTION: Databases were searched to identify randomized controlled trials (RCTs) of therapeutic exercise for long-term care facility residents aged 60 years and older, focusing on ADL and cognitive function as outcomes. DATA EXTRACTION: Two independent reviewers extracted the key information from each eligible study. Two reviewers independently screened and assessed all studies for eligibility, extracting information on study participants, details of interventions, outcome characteristics, and significant outcomes. Any discrepancies were resolved by a third reviewer. DATA SYNTHESIS: A total of 11 RCTs with 1280 participants were eligible for analyses. Therapeutic exercise had a significant benefit on ADL (standard mean difference [SMD]=0. 22, 95% confidence interval [CI]: 0.02, 0.42, P=.03). Subgroup analyses indicated that interventions conducted ≥3 days per week [SMD=0.42, 95% CI 0.02, 0.82, P=.04] had a significant benefit on ADL. For cognitive function, group exercise and ≥3 days/week of intervention had a significant benefit (group exercise: mean difference [MD]=3.36, 95% CI 0.91, 5.80, P=.007; ≥3 days/week of intervention: MD=2.28, 95% CI 0.07, 4.49, P=.04). CONCLUSIONS: Therapeutic exercise conducted 3 or more days per week may be effective for improving ADL and cognitive function among older residents in long-term care facilities. This meta-analysis suggested that group exercise for cognitive functions was effective. However, the effective method of intervention delivery for ADL was unclear.

Shared decision-making in physiotherapy: a cross-sectional study of patient involvement factors and issues in Japan.

BACKGROUND: Evidence-based medicine education has not focused on how clinicians involve patients in decision-making. Although shared decision-making (SDM) has been investigated to address this issue, there are insufficient data on SDM in physiotherapy. This study aimed to clarify the issues concerning patient involvement in Japan, and to examine whether SDM is related to perceptions of patient involvement in decision-making. METHODS: The study participants were recruited from among acute and sub-acute inpatients and community residents receiving physiotherapy outpatient care, day care, and/or home rehabilitation. The Control Preference Scale (CPS) was used to measure the patients' involvement in decision-making. The nine-item Shared Decision-Making Questionnaire (SDM-Q-9) was used to measure SDM. In analysis I, we calculated the weighted kappa coefficient to examine the congruence in the CPS between the patients' actual and preferred roles. In analysis II, we conducted a logistic regression analysis using two models to examine the factors of patient involvement. RESULTS: Analysis I included 277 patients. The patients' actual roles were as follows: most active (4.0%), active (10.8%), collaborative (24.6%), passive (35.0%), and most passive (25.6%). Their preferred roles were: most active (3.3%), active (18.4%), collaborative (39.4%), passive (24.5%), and most passive (14.4%). The congruence between actual and preferred roles by the kappa coefficient was 0.38. Analysis II included 218 patients. The factors for patient involvement were the clinical environment, the patient's preferred role, and the SDM-Q-9 score. CONCLUSIONS: The patients in Japan indicated a low level of decision-making involvement in physiotherapy. The patients wanted more active involvement than that required in the actual decision-making methods. The physiotherapist's practice of SDM was revealed as one of the factors related to perceptions of patient involvement in decision-making. Our results demonstrated the importance of using SDM for patient involvement in physiotherapy.

[Two Cases of Transfusion-Free Hepatectomy Following Chemotherapy for H3 Grade of Simultaneous Liver Metastases].

We report 2 cases of transfusion-free treatment for H3 grade of simultaneous liver metastases of the colon which were treated with the chemotherapy followed by R0 liver resection. Case 1 was a 67-year-old woman bearing ascending colon cancer and a metastatic mass occupying the left lobe of the liver with 160 mm in diameter. Laparoscopic ileocecal resection and 30-day left hepatectomy were performed after the 7 courses of FOLFOX plus bevacizumab(BEV). Case 2 was a 72- year-old woman bearing transverse colon cancer with more than 10 foci of liver metastases ranging from 21 mm to 100 mm in diameter. After the transverse colon resection and 12 months of chemotherapy from FOLFOX plus BEV to FOLFIRI plus panitumumab, partial liver resection was performed for each of size-reduced foci. In both patients who declined blood transfusion, optimization of red cells and autologous transfusion with hemodilution contributed to the safe liver resection with no postoperative complications.

Concomitant Mitral Regurgitation in Severe Aortic Stenosis　- A Report From the CURRENT AS Registry.

BACKGROUND: The clinical significance of concomitant mitral regurgitation (MR) has not been well addressed in patients with severe aortic stenosis (AS).Methods and Results:We analyzed 3,815 patients from a retrospective multicenter registry of severe AS in Japan (CURRENT AS registry). We compared the clinical outcomes between patients with moderate/severe MR and with none/mild MR according to the initial treatment strategy (initial aortic valve replacement [AVR] or conservative strategy). The primary outcome measure was a composite of aortic valve-related death or heart failure hospitalization. At baseline, moderate/severe MR was present in 227/1,197 (19%) patients with initial AVR strategy and in 536/2,618 (20%) patients with a conservative strategy. The crude cumulative 5-year incidence of the primary outcome measure was significantly higher in patients with moderate/severe MR than in those with none/mild MR, regardless of the initial treatment strategy (25.2% vs. 14.4%, P<0.001 in the initial AVR strategy, and 63.3% vs. 40.7%, P<0.001 in the conservative strategy). After adjusting confounders, moderate/severe MR was not independently associated with higher risk for the primary outcome measure in the initial AVR strategy (hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.67-1.83, P=0.69), and in the conservative strategy (HR 1.13, 95% CI 0.93-1.37, P=0.22). CONCLUSIONS: Concomitant moderate/severe MR was not independently associated with higher risk for the primary outcome measure regardless of the initial treatment strategy.

NRF2 Augments Epidermal Antioxidant Defenses and Promotes Atopy.

Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2-related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1α. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.

Effect of education on physical and occupational therapists' perceptions of clinical practice guidelines and shared decision making: a randomized controlled trial.

[Purpose] This study aimed to investigate the influence of the evidence practice gap on physiotherapist and occupational therapists through shared decision making using the clinical practice guidelines. [Participants and Methods] A randomized controlled trial was used. The participants included 126 therapists from three institutions. The inclusion criteria was permanent employment in these institutions. Participants' characteristics were masked from the allocator, evaluator, and analyzer. For the intervention group, a workshop on shared decision making was conducted using clinical practice guidelines. Two control groups were set. One group received a lecture on the knowledge of clinical practice guidelines, and the other group received a lecture on the knowledge of shared decision making. The primary outcomes were "education, attitudes and beliefs, and interest and perceived role in evidence-based practice" scale. [Results] The primary outcomes showed a significant difference between the clinical practice guidelines with shared decision making group and the clinical practice guidelines group (mean ± standard deviation, pre/post; clinical practice guidelines with shared decision making group, 2.4 ± 0.9/4.4 ± 1.7; clinical practice guidelines group, 3.0 ± 1.5/3.5 ± 2.0; shared decision making group, 2.6 ± 1.2/ 3.3 ± 1.8). [Conclusion] Shared decision making education using the clinical practice guidelines improves evidence-based practice of self-efficacy in physiotherapists and occupational therapists.

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Regulates Epidermal Keratinization under Psoriatic Skin Inflammation.

Psoriasis is an autoinflammatory/autoimmune skin disease and the epitome of an exaggerated primary inflammatory response in the surface barrier tissue. Despite the efficacy of dimethyl fumarate, an electrophilic drug for psoriasis management, there is a paucity of mechanistic evidence in vivo. In response to electrophiles, the Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) system mediates a myriad of cytoprotective mechanisms, including the regulation of excessive inflammatory response and epidermal differentiation. Because the psoriasiform tissue reaction comprises neutrophil infiltration and parakeratotic scaling, it is hypothesized that Nrf2 not only regulates inflammatory responses but also maintains epidermal differentiation, a hallmark of epidermal homeostasis. By using the imiquimod-induced cutaneous inflammation model, an exaggerated inflammatory response and impaired epidermal differentiation in Nrf2-/- mice was detected. Dimethyl fumarate treatment in Nrf2+/+ mice attenuated a psoriasiform tissue reaction and rescued epidermal differentiation, which was not observed in Nrf2-/- mice. In accordance with the fact that psoriasis plaques form well-demarcated parakeratotic lesions in association with the psoriasiform tissue reaction, the lesional skin showed reduced expression levels of NRF2 and its downstream target genes compared with nonlesional skin. In conclusion, Nrf2 attenuates the psoriasiform tissue reaction and underscores the mechanistic legitimacy of the electrophile-based approach for the management of psoriasis.

Antihypertensive drug valsartan as a novel BDK inhibitor.

Catabolism of branched-chain amino acids (BCAAs) is affected by various physiological conditions and its abnormality is associated with glucose metabolism, heart disease, and neurological dysfunction. The first two steps of the BCAA metabolic pathway are common to the three BCAAs (leucine, isoleucine, and valine). The second step is an irreversible rate-limited reaction catalyzed by branched-chain α-keto acid dehydrogenase (BCKDH), which is bound to a specific kinase, BCKDH kinase (BDK), and inactivated by phosphorylation. Here, we investigated potential new BDK inhibitors and discovered valsartan, an angiotensin II type 1 receptor (AT1R) blocker, as a new BDK inhibitor. BCKDH phosphorylation and the BCKDH-BDK interaction were inhibited by valsartan in vitro. Valsartan administration in rats resulted in increased BCKDH activity by decreasing the dephosphorylated level of BCKDH complex, bound forms of BDK from BCKDH complex as well as decreased plasma BCAA concentrations. Valsartan is a novel BDK inhibitor that competes with ATP, via a different mechanism from allosteric inhibitors. The BDK inhibitor has been shown to preserve cardiac function in pressure overload-induced heart failure mice and to attenuate insulin resistance in obese mice. Our findings suggest that valsartan is a potent seed compound for developing a powerful BDK inhibitor and useful medication for treating heart failure and metabolic diseases with suppressed BCAA catabolism.

True Aneurysms of Foot Arteries: A Case Report of a Young Patient.

BACKGROUND: Reports of true aneurysms of the lower leg are rare. Among them, cases involving young patients are all the more rare, and there are many unexplored aspects to this pathological condition. CASE PRESENTATION: This is a case of a 30-year-old woman who was referred by an orthopedic surgeon with a chief complaint of severe pain during walking and landing. Angiography revealed multiple aneurysms and arteriovenous fistulas in the posterior tibial artery and lateral plantar artery. We anastomosed the lateral plantar artery and interposed the posterior tibial artery using the great saphenous vein. CONCLUSIONS: Although aneurysms in the arteries of the feet are rare, multiple true arterial aneurysms were observed in the lower leg of a juvenile patient in the present case. Dilation of arteries other than the aneurysm was also observed, suggesting that arteriovenous fistula and arterial occlusion may have been the causes of the true aneurysm of the lower leg. This is a valuable finding, suggesting a cause of aneurysm other than age-related atherosclerotic changes.

Anterior segment dysmorphogenesis of the eye and glaucoma in MG-W gerbils.

Unilaterally swollen eyes were histopathologically characterized in four MG-W gerbils. The primary lesions resided in the anterior segment of the eye where neural crest cells play a critical role in embryonic development. They included indistinct filtration angle, unformed canal of Schlemm, hypoplastic iris, and ciliary body. The findings noted in the retina, optic nerve, optic tract, and lateral geniculate nucleus were consistent with the lesions induced following the persistent elevation of intraocular pressure as a result of insufficient drainage of aqueous humor. Thus, the present cases observed in the eyes of MG-W gerbils exemplified the anterior segment dysmorphogenesis associated with inadequate neural crest migration or differentiation, leading to subsequent glaucoma.

Early Surgery vs. Surgery After Watchful Waiting for Asymptomatic Severe Aortic Stenosis.

BACKGROUND: There is no large-scale study comparing postoperative mortality after aortic valve replacement (AVR) for asymptomatic severe aortic stenosis (AS) between initial treatment with AVR vs. eventual AVR after conservative management. Methods and Results: We analyzed data from a multicenter registry enrolling 3,815 consecutive patients with severe AS. Of 1,808 asymptomatic patients, 286 patients initially underwent AVR (initial AVR group), and 377 patients were initially managed conservatively and eventually underwent AVR (AVR after watchful waiting group). Mortality after AVR was compared between the 2 groups. Subgroup analysis according to peak aortic jet velocity (Vmax) at diagnosis was also conducted. There was no significant difference between the 2 groups in 5-year overall survival (OS; 86.0% vs. 84.1%, P=0.34) or cardiovascular death-free survival (DFS; 91.3% vs. 91.1%, P=0.61), but on subgroup analysis of patients with Vmax ≥4.5 m/s at diagnosis, the initial AVR group was superior to the AVR after watchful waiting group in both 5-year OS (88.4% vs. 70.6%, P=0.003) and cardiovascular DFS (91.9% vs. 81.7%, P=0.023). CONCLUSIONS: Asymptomatic severe AS patients who underwent AVR after watchful waiting had a postoperative survival rate similar to those who initially underwent AVR. In a subgroup of patients with Vmax ≥4.5 m/s at diagnosis, however, the AVR after watchful waiting group had worse postoperative survival rate than the initial AVR group.

Short-term effects of goal-setting focusing on the life goal concept on subjective well-being and treatment engagement in subacute inpatients: a quasi-randomized controlled trial.

OBJECTIVE: To investigate the short-term effects of the life goal concept on subjective well-being and treatment engagement, and to determine the sample size required for a larger trial. DESIGN: A quasi-randomized controlled trial that was not blinded. SETTING: A subacute rehabilitation ward. SUBJECTS: A total of 66 patients were randomized to a goal-setting intervention group with the life goal concept (Life Goal), a standard rehabilitation group with no goal-setting intervention (Control 1), or a goal-setting intervention group without the life goal concept (Control 2). INTERVENTIONS: The goal-setting intervention in the Life Goal and Control 2 was Goal Attainment Scaling. The Life Goal patients were assessed in terms of their life goals, and the hierarchy of goals was explained. The intervention duration was four weeks. MAIN MEASURES: Patients were assessed pre- and post-intervention. The outcome measures were the Hospital Anxiety and Depression Scale, 12-item General Health Questionnaire, Pittsburgh Rehabilitation Participation Scale, and Functional Independence Measure. RESULTS: Of the 296 potential participants, 66 were enrolled; Life Goal (n = 22), Control 1 (n = 22) and Control 2 (n = 22). Anxiety was significantly lower in the Life Goal (4.1 ±3.0) than in Control 1 (6.7 ±3.4), but treatment engagement was significantly higher in the Life Goal (5.3 ±0.4) compared with both the Control 1 (4.8 ±0.6) and Control 2 (4.9 ±0.5). CONCLUSIONS: The life goal concept had a short-term effect on treatment engagement. A sample of 31 patients per group would be required for a fully powered clinical trial.

Validity and reliability of the 2-min step test in individuals with stroke and lower-limb musculoskeletal disorders.

Introduction: We investigated the reliability and validity of the 2-min step test (2MST) for assessing the exercise endurance of individuals with stroke and lower-limb musculoskeletal disorders. Participants and methods: The participants were 39 individuals with stroke and 42 with lower-limb musculoskeletal disorders (mainly hip fractures) from the convalescent rehabilitation wards of four hospitals. The concurrent validity and congruence between the 2MST and the 6-min walk test (6MWT) and construct validity by hypotheses testing, including mobility and lower limb muscle strength, were also confirmed. A subset of participants (stroke-group, n = 15; musculoskeletal-group, n = 19) underwent a retest 2MST for our evaluation of relative and absolute reliability using the intraclass correlation coefficient (ICC1,1) and Bland-Altman plot. Results: Both groups showed a moderate correlation between the 2MST and 6MWT (ρ = 0.55-0.60), but the congruence was not sufficient. The 6MWT was correlated with mobility in both groups and with muscle strength in the stroke group, whereas the 2MST did not show a significant correlation with mobility. The relative reliability was excellent in both groups (ICC1,1 > 0.9). In terms of absolute reliability, the width of the limit of agreement was 18.8% for the stroke group and 15.4% for the musculoskeletal group, relative to their respective sample means of 2MST. A fixed bias was identified in the stroke group, in which step counts increased by 6.5 steps upon retesting. Discussion: Our analyses revealed that the 2MST is a valid and reliable tool for assessing the exercise endurance of individuals with stroke or lower-limb musculoskeletal disorders. However, it is necessary to validate the absolute reliability observed herein by using a larger sample size. In addition, when assessing the exercise endurance of individuals with stroke, it may be necessary to consider the potential bias of an increased step count during retesting.

Prognostic significance of baseline low-density lipoprotein cholesterol in patients undergoing coronary revascularization; a report from the CREDO-Kyoto registry.

BACKGROUND: The impact of very low baseline levels of low-density lipoprotein cholesterol (LDL-C) on patients with coronary artery disease remains unclear. METHOD: We enrolled 39,439 patients of the pooled population from the CREDO-Kyoto registries Cohorts 1, 2, and 3. The study population consisted of 33,133 patients who had undergone their first coronary revascularization. We assessed the risk for mortality and cardiovascular events according to quintiles of the baseline LDL-C levels. RESULTS: Patients in the very low LDL-C quintile (<85 mg/dL) had more comorbidities than those in the other quintiles. Lower LDL-C levels were strongly associated with anemia, thrombocytopenia, and end-stage renal disease. The cumulative 4-year incidence of all-cause death increased as LDL-C levels decreased (very low: 19.4 %, low: 14.5 %, intermediate: 11.1 %, high: 10.0 %, and very high: 9.2 %; p < 0.001), which was driven by both the early and late events. After adjusting for baseline characteristics, the adjusted risks of the very low and low LDL-C quintiles relative to the intermediate LDL-C quintile remained significant for all-cause death (very low: HR 1.29, 95 % CI 1.16-1.44, p < 0.001; low: HR 1.15, 95 % CI 1.03-1.29, p = 0.01). The excess adjusted risks of the lowest LDL-C quintile relative to the intermediate LDL-C quintile were significant for clinical outcomes such as cardiovascular death (HR 1.17, 95 % CI 1.01-1.35), non-cardiovascular death (HR 1.35, 95 % CI 1.15-1.60), sudden death (HR 1.44, 95 % CI 1.01-2.06), and heart failure admission (HR 1.11 95 % CI 1.01-1.22), while there was no excess risk for the lowest LDL-C quintile relative to the intermediate LDL-C quintile for myocardial infarction and stroke. CONCLUSIONS: Lower baseline LDL-C levels were associated with more comorbidities and a significantly higher risk of death, regardless of cardiovascular or non-cardiovascular causes, in patients who underwent coronary revascularization.

Pseudoaneurysm at the cannulation site of the ascending aorta arising 8 days postoperatively: report of a case.

A postoperative pseudoaneurysm is a rare complication that is difficult to diagnose. Computed tomography (CT) revealed a pseudoaneurysm in the ascending aorta of a 68-year-old female 8 days after mitral valve replacement and tricuspid annuloplasty. The defect was simply repaired during emergency surgery without cardiopulmonary bypass (CPB). The early detection of a postoperative pseudoaneurysm is important to avoid a second operation complicated by adhesions. Enhanced CT was useful for early detection in this patient. Pseudoaneurysm of the ascending aorta at the cannulation site can occur soon after surgery, and early recognition might allow simpler surgery without CPB.

CFD simulation of CVD reactors in the CH3SiCl3(MTS)/H2 system using a two-step MTS decomposition and one-step SiC growth models.

In this study, we report on a computational fluid dynamics (CFD) simulation of the chemical vapor deposition reactor of silicon carbide (SiC) in the methyltrichlorosilane (MTS, CH3SiCl3)/H2 system. The formation of SiC thin film is controlled by various process parameters, such as temperature and pressure. In this study, we propose a reaction mechanism of MTS decomposition to SiC growth on a substrate surface for CVD reactors in the CH3SiCl3(MTS)/H2 system. The reaction mechanism has two gas-phase pyrolysis reactions and one SiC film formation reaction. However, we individually build and validate MTS decomposition and SiC growth models to reduce uncertainty. An in-house version of reactingFoam, a reactive flow solver within OpenFOAM v2006, was used as the simulation tool. Our model accurately reproduced MTS decomposition for T = 1100-1350 K and [H2]/[MTS] = 2.65-14 at p = 101,325 Pa. Then, the MTS decomposition model was coupled with the SiC growth model, and the coupled model was applied to the SiC deposition data. The model could reproduce multiple datasets through validation studies.