Rehospitalisation rates after long-term follow-up of patients with severe mental illness admitted for more than one year: a systematic review.

AIMS: This study aimed to conduct a systematic review of studies on the outcomes of long-term hospitalisation of individuals with severe mental illness, considering readmission rates as the primary outcome. METHODS: Studies considered were those in which participants were aged between 18 and 64 years with severe mental illness; exposure to psychiatric hospitals or wards was long-term (more than one year); primary outcomes were readmission rates; secondary outcomes were duration of readmission, employment, schooling, and social participation; and the study design was either observational or interventional with a randomised controlled trial (RCT) design. Relevant studies were searched using MEDLINE, PsycINFO, Web of Science, CINAHL, and the Japan Medical Abstract Society. The final search was conducted on 1 February 2022. The risk of bias in non-randomised studies of interventions was used to assess the methodological quality. A descriptive literature review is also conducted. RESULTS: Of the 11,999 studies initially searched, three cohort studies (2,293 participants) met the eligibility criteria. The risk of bias in these studies was rated as critical or serious. The 1-10 years readmission rate for patients with schizophrenia who had been hospitalised for more than one year ranged from 33 to 55%. The average of readmission durations described in the two studies was 70.5 ± 95.6 days per year (in the case of a 7.5-year follow-up) and 306 ± 399 days (in the case of a 3-8-year follow-up). None of the studies reported other outcomes defined in this study. CONCLUSIONS: The readmission rates in the included studies varied. Differences in the follow-up period or the intensity of community services may have contributed to this variability. In countries preparing to implement de-institutionalisation, highly individualised community support should be designed to avoid relocation to residential services under supervision. The length of stay for readmissions was shorter than that for index admissions. The results also imply that discharge to the community contributes to improved clinical outcomes such as improved social functioning. The validity of retaining patients admitted because of the risk of rehospitalisation was considered low. Future research directions have also been discussed.

Estimation of a Structural Equation Modeling of Quality of Life Mediated by Difficulty in Daily Life in Survivors of Breast Cancer.

BACKGROUND: The purpose of this study was to clarify the structural relationship of quality of life (QOL) in survivors of breast cancer, including difficulty in daily life and negative experiences in daily activities, as health-related indicators. METHODS: Participants were survivors of breast cancer for more than 2 years after primary breast cancer surgery and belonged to self-help groups. The assessment used FACT-B (QOL), HADS (anxiety and depression), SOC (sense of coherence), WHODAS 2.0 (difficulties in daily life), and CAOD (negative experiences in daily activities). Bayesian structural equation modeling (BSEM) was performed to analyze the hypothesized model. If the causal model was significant, multiplication of the path coefficient from emotional distress (anxiety and depression) to QOL, and from SOC to emotional distress, was considered a direct effect on QOL, and from SOC to difficulty in daily life, from difficulty in daily life to negative experiences in daily activities, and from negative experiences in daily activities to anxiety and depression were considered indirect effects on QOL. RESULTS: The participants comprised 73 survivors of breast cancer. The goodness of fit of the model in the BSEM was satisfactory. The direct effect was 0.274, and the indirect effect was 0.164. CONCLUSIONS: An additional finding of this study is that coping with difficulty in daily life and negative experiences in daily activities related to QOL may improve QOL.

Treatment Strategy of Fractured Osteochondroma in the Young Athlete's Knee.

Purpose: The main purpose of this study was to compare the clinical outcome of surgery versus observation in young athletes with fractured osteochondromas in the knee. The secondary aim was to evaluate displacement versus non-displacement fractures with regards to functional recovery. Methods: A retrospective analysis was performed in young athletes with fractures of osteochondromas in the knee. In the surgery group, resection of the osteochondromas was performed due to pain persisting at 4 weeks after injury. In contrast, patients with pain diminishing within 4 weeks after injury were observed without surgery. Displacement was defined as a gap widening of ≥1 mm between fragments, or translation of >50% of the distal fragment in relation to the proximal fragment. The time to return to the original sport was compared between groups. Results: The study sample was composed of 21 patients with a mean age of 12 years (range 9-16 years). There were 14 patients in the surgery group and 7 patients in the observation group. There were 10 patients (71%) with displacement and 4 patients (29%) with non-displacement fractures in the surgery group. Surgery was required more frequently in displacement than in non-displacement fracture patients (p = 0.01). The mean time to return to the original sport was 2.1 ± 1.1 and 7.2 ± 4.1 weeks in the surgery and observation groups, respectively (p < 0.01). Conclusions: Surgical excision is preferable in a young athlete's knee presenting with displacement of fractured osteochondromas due to disabling symptoms and in order to allow them to return faster to original sports activities.

Clinical Utility of Bland Embolization Using Microspheres for Painful Malignant Musculoskeletal Tumors.

BACKGROUND/AIM: To evaluate retrospectively whether bland embolization using microspheres is safe and useful for relieving pain in patients with painful malignant musculoskeletal (MSK) tumors. PATIENTS AND METHODS: Bland embolization using microspheres was performed for 20 patients (11 women/9 men) with a median age of 69 years (range=40-89 years) who had 22 painful malignant MSK tumors. The maximum tumor diameters were 2.4-13.8 cm (median, 7.5 cm). Pain was evaluated using the visual analog scale. A decrease of this score by 2 or more after embolization was defined as clinically effective pain relief. Adverse events (AEs) were evaluated using CTCAE v5.0. Objective response, disease control rates, and overall survival were also evaluated. RESULTS: Effective pain relief was achieved in 18 patients (90.0%, 18/20). Grade-3 AEs developed in four patients (20.0%, 4/20): skin ulcer (n=2), skin ulcer and pain (n=1), and muscle weakness with dysesthesia (n=1). No grade-4 or grade-5 AEs developed. Objective response and disease control rates were 26.7% (4/15) and 86.7% (13/15), respectively. The 1-year survival rate was 43.8%, with median survival of 9.2 months (range=0.5-41.0 months). CONCLUSION: Although the survival benefit is equivocal, bland embolization is acceptably safe and useful for relieving pain by controlling tumor growth in patients with painful malignant MSK tumors.

Relationship between Lower Extremity Peripheral Arterial Disease and Mild Cognitive Impairment in Hemodialysis Patients.

BACKGROUND: The link between arterial stiffness and mild cognitive impairment (MCI) in patients on hemodialysis (HD) has been receiving increased attention. The purpose of this study was to investigate the relationship between cognitive function and ankle brachial index (ABI) and toe brachial index (TBI) values in patients on hemodialysis. Of the 100 participants (mean age: 67.9 years; average history of hemodialysis: 7.3 years). Of these, 46.0% had MCI. The MoCA-J scores were significantly higher in the ABI ≥ 1.06 group. However, the MoCA-J scores divided into the two groups according to the TBI cutoff value were not significantly different. In a multiple regression model with the MoCA-J scores as the objective variable, the ABI was a significantly associated factor. This study indicates that a low ABI might be associated with MCI.

Osteoscopic versus open surgery for the treatment of enchondroma in the foot.

INTRODUCTION: The conventional treatment of enchondromas is the open surgery with curettage of lesions. Osteoscopic surgery is a minimally invasive endoscopic approach for lesions inside bone. The aim of this study was to evaluate the feasibility of the osteoscopic surgery in comparison with the conventional open surgery for patients with foot enchondromas. MATERIALS AND METHODS: A retrospective cohort study comparing patients with foot enchondromas treated with osteoscopic or open surgery from 2000 to 2019. Functional evaluations were based on both the AOFAS score and the Musculoskeletal Tumor Society (MSTS) functional rate. Complication and local recurrence were evaluated. RESULTS: Seventeen patients underwent endoscopic surgery, and eight patients underwent open surgery. The AOFAS score was higher in the osteoscopic group than the open group at 1 and 2 weeks after surgery (mean, 89.18 vs 67.25 [p = 0.001], 93.88 vs 79.38 [p = 0.004]). The MSTS functional rate was also higher in the osteoscopic group than the open group at 1 and 2 weeks after surgery (mean, 81.96 vs 59.58% [p = 0.00], 90.98 vs 75.00% [p = 0.02]). No statistical differences were found after 1-month of surgery. The osteoscopic group had lower complication rate than the open group (12 vs 50%; p = 0.04). No local recurrence was found in any groups. CONCLUSION: The osteoscopic surgery is feasible to provide earlier functional recovery and fewer complications than the open surgery.

What outcomes in community mental health research are important to caregivers of people with schizophrenia? An exploratory qualitative analysis of an online survey.

AIMS: This study investigated outcomes in community mental health research that were important to caregivers of people with schizophrenia. METHODS: Using an online survey conducted from August 1 to 31, 2020, data were collected from caregivers belonging to the LINE Schizophrenia Family Association. Caregivers identified outcomes important in community mental health research. Two researchers categorized caregivers' statements into research outcomes. RESULTS: A total of 132 caregivers completed the online selfreported questionnaire, and 296 caregiver statements were identified. Qualitative analysis identified 17 outcome categories. The caregivers tended to value having more free time, maintaining an appropriate relationship with people with schizophrenia, and being able to cope with their symptoms. CONCLUSIONS: This exploratory study newly demonstrates the outcomes that caregivers of people with schizophrenia consider important in community mental health research. The findings may be useful in selecting outcomes for future studies of caregivers.

Discovery of Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors.

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1'-S2' sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.

Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor.

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.

Occupational Dysfunction as a Mediator between Recovery Process and Difficulties in Daily Life in Severe and Persistent Mental Illness: A Bayesian Structural Equation Modeling Approach.

Background: This study is aimed at verifying a hypothetical model of the structural relationship between the recovery process and difficulties in daily life mediated by occupational dysfunction in severe and persistent mental illness (SPMI). Methods: Community-dwelling participants with SPMI were enrolled in this multicenter cross-sectional study. The Recovery Assessment Scale (RAS), the World Health Organization Disability Assessment Schedule second edition (WHODAS 2.0), and the Classification and Assessment of Occupational Dysfunction (CAOD) were used for assessment. Confirmatory factor analysis, multiple regression analysis, and Bayesian structural equation modelling (BSEM) were determined to analyze the hypothesized model. If the mediation model was significant, the path coefficient from difficulty in daily life to recovery and the multiplication of the path coefficients mediated by occupational dysfunction were considered as each the direct effect and the indirect effect. The goodness of fit in the model was determined by the posterior predictive P value (PPP). Each path coefficient was validated with median and 95% confidence interval (CI). Results: The participants comprised 98 individuals with SPMI. The factor structures of RAS, WHODAS 2.0, and CAOD were confirmed by confirmatory factor analysis to be similar to those of their original studies. Multiple regression analysis showed that the independent variables of RAS were WHODAS 2.0 and CAOD, and that of CAOD was WHODAS 2.0. The goodness of fit of the model in the BSEM was satisfactory with a PPP = 0.27. The standardized path coefficients were, respectively, significant at -0.372 (95% CI: -0.586, -0.141) from "difficulty in daily life" to "recovery" as the direct effect and at -0.322 (95% CI: -0.477, -0.171) mediated by "occupational dysfunction" as the indirect effect. Conclusions: An approach for reducing not only difficulty in daily life but also occupational dysfunction may be an additional strategy of person-centered, recovery-oriented practice in SPMI.

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist.

Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, kidney disease, and heart failure. Thus, MR antagonists (MRAs) are expected to be beneficial to patients with these diseases. In order to identify novel nonsteroidal MRAs that overcome the issues of already marketed steroidal MRAs, we searched for new compounds guided by our hypothesis that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. We discovered that the novel 1,4-benzoxazin-3-one derivative 19 (apararenone: MT-3995) acted as a highly selective and potent nonsteroidal MRA. Apararenone exhibited a more potent antihypertensive and organ-protective activity than steroidal MRA eplerenone in a primary aldosteronism rat model obtained by infusing aldosterone in uninephrectomized rats.

Multiple stakeholders' perspectives on patient and public involvement in community mental health services research: A qualitative analysis.

BACKGROUND: Patient and public involvement (PPI) has become essential in health research. However, little is known about multiple stakeholders' perspectives on the implementation of PPI in community mental health research settings. The present study aimed to qualitatively analyse multiple stakeholders' views on PPI, including potential concerns, barriers and approaches. METHODS: This study involved conducting focus group interviews and collecting qualitative data from 37 participants in multiple stakeholder groups (patients = 6, caregivers = 5, service providers = 7, government staff = 5 and researchers = 14) in the community mental health field. The data were qualitatively analysed using a data-driven approach that derived domains, themes and subthemes related to perspectives on PPI and to specific challenges and approaches for implementing PPI. RESULTS: The qualitative analysis identified four domains. The 'Positive views and expectations regarding PPI' domain consisted of themes related to supportive views of PPI in a mental health service research setting and improvements in the quality of research and service. The 'General concerns about PPI' domain included themes concerning the need for non-PPI research and tokenism, excessive expectations concerning social changes and use of evidence from PPI research, and heavy burdens resulting from PPI. The 'Specific issues regarding the implementation of PPI' domain consisted of four themes, including academic systems, selection methods (e.g., representativeness and conflict of interest issues), relationship building, and ambiguous PPI criteria. In particular, all stakeholder groups expressed concerns about relational equality during PPI implementation in Japan. The 'Approaches to PPI implementation' domain included themes such as facilitating mutual understanding, creating a tolerant atmosphere, establishing PPI support systems (e.g., training, ethics and human resource matching) and empowering patient organizations. CONCLUSION: The study replicated most of the barriers and approaches to PPI reported by qualitative research in Western counties. However, utilization of evidence produced by PPI research and partnership in the PPI process may be particularly serious issues in Japan. Future PPI studies should carefully address solutions that fit each culture. PATIENT OR PUBLIC CONTRIBUTION: A patient-researcher was involved in all stages of this project, from development of the research topic and the protocol to manuscript preparation.

Paramecium Polycomb repressive complex 2 physically interacts with the small RNA-binding PIWI protein to repress transposable elements.

Polycomb repressive complex 2 (PRC2) maintains transcriptionally silent genes in a repressed state via deposition of histone H3K27-trimethyl (me3) marks. PRC2 has also been implicated in silencing transposable elements (TEs), yet how PRC2 is targeted to TEs remains unclear. To address this question, we identified proteins that physically interact with the Paramecium enhancer-of-zeste Ezl1 enzyme, which catalyzes H3K9me3 and H3K27me3 deposition at TEs. We show that the Paramecium PRC2 core complex comprises four subunits, each required in vivo for catalytic activity. We also identify PRC2 cofactors, including the RNA interference (RNAi) effector Ptiwi09, which are necessary to target H3K9me3 and H3K27me3 to TEs. We find that the physical interaction between PRC2 and the RNAi pathway is mediated by a RING finger protein and that small RNA recruitment of PRC2 to TEs is analogous to the small RNA recruitment of H3K9 methylation SU(VAR)3-9 enzymes.

Outcomes frequently specified in Cochrane reviews of community-based psychosocial interventions for adults with severe mental illness: A systematic search and narrative synthesis.

BACKGROUND: Outcome selection in intervention studies is a critical issue for synthesizing evidence. This study is aimed to investigate outcomes used in Cochrane reviews assessing community-based psychosocial interventions for adults with severe mental illness. METHODS: Cochrane reviews that evaluated a community-based psychosocial intervention for adults with severe mental illness were searched electronically and manually. We extracted all outcomes specified in the Methods section in each Cochrane review. Outcomes that represent the same concept and context were synthesized into an outcome term. Outcome terms were categorized according to the existing taxonomy. RESULTS: We included 33 Cochrane reviews. Of the 216 outcome terms identified, 13 were used in more than half of the reviews: quality of life, mental state, admission to hospital, economic outcome, leaving the study early, social functioning, satisfaction, global state, relapse, adverse events/effects, carer satisfaction, employment, and duration of admission. Most outcome terms were categorized into the life impact core area (55%), followed by the resource use area (21%). CONCLUSIONS: Our study provides a candidate outcome list for developing a core outcome set for severe mental illness and offers a basis for comparison for future outcome investigation on mental health research.

Consensus development of priority outcome domains for community mental health cares by multiple stakeholders: Protocol for an online Delphi study in Japan.

BACKGROUND: Treatment goals for mental illness have expanded from hospital discharge and improved functioning to employment, living alone, and personal realization. These changes in treatment goals have also influenced mental health research. Recent studies have addressed the development of core outcome sets focusing on clinical aspects of mental illness such as depression and anxiety. However, a well-developed framework of essential outcomes for people with mental illness (service users) who live in the community is lacking. In addition, recent worldwide trends suggest more patient and public involvement and the importance of considering multiple stakeholders' views in the area of mental health research. Purpose of this study is to explore consensus on high-priority outcome domains among multiple stakeholders in community mental healthcare fields in Japan. METHODS: A three-step approach to developing an outcome list will be used. First, we developed a long list of outcomes for community mental health through a literature review, focus group interviews with key stakeholders, and online questionnaire surveys of service users and caregivers. Second, the long list was checked and revised in a pilot study. Third, the long list will be shortened to the outcome list through the Delphi methodology with participation from multiple stakeholders. DISCUSSION: Identifying important common outcome domains through collaboration with multiple stakeholders appears to contribute to the development of evidence for community mental health research in Japan. In addition, the study process itself may help promote patient and public involvement in education, practice, and research in the field of community mental health.

Care difficulties and burden during COVID-19 pandemic lockdowns among caregivers of people with schizophrenia: A cross-sectional study.

AIMS: The purpose of this study was to retrospectively investigate care difficulties experienced by caregivers of people with schizophrenia during COVID-19 pandemic lockdowns in Japan (April 7-May 25, 2020) and examine associations between these care difficulties during lockdowns and daily caregiver burden. METHODS: Data were collected from 132 participants of the LINE Schizophrenia Family Association using an online survey. RESULTS: Caregivers were mostly concerned about who would care for people with schizophrenia if caregivers become infected with COVID-19. A significant association was found between higher daily caregiver burden and more difficult care experiences during COVID-19 pandemic lockdowns (B = 0.58, 95% confidence interval, 0.40-0.75, P < .01, adjusted R-squared = .34). CONCLUSIONS: Further studies and supports for caregivers of people with schizophrenia are needed.

Development of a New Daily Activities Scale for the Affected Hand after Stroke.

OBJECTIVES: There are few scales that reflect the function of the stroke-affected arm as it relates to the performance of daily activities while also indicating the difficulty of scale items. In this study, we developed the Activities Specific Upper-extremity Hemiparesis Scale (ASUHS) to evaluate daily activities performable by the affected arm after stroke. We also clarified the validity, reliability, and item difficulty of the scale. METHODS: The participants were 145 patients with stroke who were consecutively admitted to a convalescent rehabilitation ward. The unidimensionality of ASUHS was assessed by principal component analysis. Analyses of item discrimination and content validity were conducted to assess the overall validity. Reliability was evaluated by assessing internal consistency and inter-rater reliability. Item difficulties were determined by Rasch analysis. RESULTS: Unidimensionality, high discrimination, and good content validity were shown for all items. ASUHS consists of a dominant hand scale and non-dominant hand scale. Both scales showed good internal consistency (Cronbach's α coefficient = 0.99) and substantial inter-rater reliability (Cohen's Kappa coefficient = 0.74 and 0.75, respectively). Item difficulty was determined as being in the range -8.71 to +5.18 logit. CONCLUSIONS: This study suggested good validity and reliability of ASUHS. Furthermore, because the item difficulties of daily activities performed by the affected arm were clarified, therapists can use ASUHS to identify the process that should be the next focus for training. Consequently, therapists may be able to train patients in daily activities that match the affected arm's ability step by step rather than determining training activities empirically.

The Polycomb protein Ezl1 mediates H3K9 and H3K27 methylation to repress transposable elements in Paramecium.

In animals and plants, the H3K9me3 and H3K27me3 chromatin silencing marks are deposited by different protein machineries. H3K9me3 is catalyzed by the SET-domain SU(VAR)3-9 enzymes, while H3K27me3 is catalyzed by the SET-domain Enhancer-of-zeste enzymes, which are the catalytic subunits of Polycomb Repressive Complex 2 (PRC2). Here, we show that the Enhancer-of-zeste-like protein Ezl1 from the unicellular eukaryote Paramecium tetraurelia, which exhibits significant sequence and structural similarities with human EZH2, catalyzes methylation of histone H3 in vitro and in vivo with an apparent specificity toward K9 and K27. We find that H3K9me3 and H3K27me3 co-occur at multiple families of transposable elements in an Ezl1-dependent manner. We demonstrate that loss of these histone marks results in global transcriptional hyperactivation of transposable elements with modest effects on protein-coding gene expression. Our study suggests that although often considered functionally distinct, H3K9me3 and H3K27me3 may share a common evolutionary history as well as a common ancestral role in silencing transposable elements.

The binding of Chp2's chromodomain to methylated H3K9 is essential for Chp2's role in heterochromatin assembly in fission yeast.

The binding of heterochromatin protein 1 (HP1) to lysine 9-methylated histone H3 (H3K9me) is an essential step in heterochromatin assembly. Chp2, an HP1-family protein in the fission yeast Schizosaccharomyces pombe, is required for heterochromatic silencing. Chp2 recruits SHREC, a multifunctional protein complex containing the nucleosome remodeler Mit1 and the histone deacetylase Clr3. Although the targeting of SHREC to chromatin is thought to occur via two distinct modules regulated by the SHREC components Chp2 and Clr2, it is not clear how Chp2's chromatin binding regulates SHREC function. Here, we show that H3K9me binding by Chp2's chromodomain (CD) is essential for Chp2's silencing function and for SHREC's targeting to chromatin. Cells expressing a Chp2 mutant with defective H3K9me binding (Chp2-W199A) have a silencing defect, with a phenotype similar to that of chp2-null cells. Genetic analysis using a synthetic silencing system revealed that a Chp2 mutant and SHREC-component mutants had similar phenotypes, suggesting that Chp2's function also affects SHREC's chromatin binding. Size-exclusion chromatography of native protein complexes showed that Chp2-CD's binding of H3K9me3 ensures Clr3's chromatin binding, and suggested that SHREC's chromatin binding is mediated by separable functional modules. Interestingly, we found that the stability of the Chp2 protein depended on the Clr3 protein's histone deacetylase activity. Our findings demonstrate that Chp2's H3K9me binding is critical for SHREC function and that the two modules within the SHREC complex are interdependent.

Induction of hibernation-like hypothermia by central activation of the A1 adenosine receptor in a non-hibernator, the rat.

Central adenosine A1-receptor (A1AR)-mediated signals play a role in the induction of hibernation. We determined whether activation of the central A1AR enables rats to maintain normal sinus rhythm even after their body temperature has decreased to less than 20 °C. Intracerebroventricular injection of an adenosine A1 agonist, N6-cyclohexyladenosine (CHA), followed by cooling decreased the body temperature of rats to less than 20 °C. Normal sinus rhythm was fundamentally maintained during the extreme hypothermia. In contrast, forced induction of hypothermia by cooling anesthetized rats caused cardiac arrest. Additional administration of pentobarbital to rats in which hypothermia was induced by CHA also caused cardiac arrest, suggesting that the operation of some beneficial mechanisms that are not activated under anesthesia may be essential to keep heart beat under the hypothermia. These results suggest that central A1AR-mediated signals in the absence of anesthetics would provide an appropriate condition for maintaining normal sinus rhythm during extreme hypothermia.