Cavin-2 promotes fibroblast-to-myofibroblast trans-differentiation and aggravates cardiac fibrosis.

AIMS: Transforming growth factor ß (TGF-ß) signalling is one of the critical pathways in fibroblast activation, and several drugs targeting the TGF-ß/Smad signalling pathway in heart failure with cardiac fibrosis are being tested in clinical trials. Some caveolins and cavins, which are components of caveolae on the plasma membrane, are known for their association with the regulation of TGF-ß signalling. Cavin-2 is particularly abundant in fibroblasts; however, the detailed association between Cavin-2 and cardiac fibrosis is still unclear. We tried to clarify the involvement and role of Cavin-2 in fibroblasts and cardiac fibrosis. METHODS AND RESULTS: To clarify the role of Cavin-2 in cardiac fibrosis, we performed transverse aortic constriction (TAC) operations on four types of mice: wild-type (WT), Cavin-2 null (Cavin-2 KO), Cavin-2flox/flox , and activated fibroblast-specific Cavin-2 conditional knockout (Postn-Cre/Cavin-2flox/flox , Cavin-2 cKO) mice. We collected mouse embryonic fibroblasts (MEFs) from WT and Cavin-2 KO mice and investigated the effect of Cavin-2 in fibroblast trans-differentiation into myofibroblasts and associated TGF-ß signalling. Four weeks after TAC, cardiac fibrotic areas in both the Cavin-2 KO and the Cavin-2 cKO mice were significantly decreased compared with each control group (WT 8.04 ± 1.58% vs. Cavin-2 KO 0.40 ± 0.03%, P < 0.01; Cavin-2flox/flox , 7.19 ± 0.50% vs. Cavin-2 cKO 0.88 ± 0.44%, P < 0.01). Fibrosis-associated mRNA expression (Col1a1, Ctgf, and Col3) was significantly attenuated in the Cavin-2 KO mice after TAC. α1 type I collagen deposition and non-vascular αSMA-positive cells (WT 43.5 ± 2.4% vs. Cavin-2 KO 25.4 ± 3.2%, P < 0.01) were reduced in the heart of the Cavin-2 cKO mice after TAC operation. The levels of αSMA protein (0.36-fold, P < 0.05) and fibrosis-associated mRNA expression (Col1a1, 0.69-fold, P < 0.01; Ctgf, 0.27-fold, P < 0.01; Col3, 0.60-fold, P < 0.01) were decreased in the Cavin-2 KO MEFs compared with the WT MEFs. On the other hand, αSMA protein levels were higher in the Cavin-2 overexpressed MEFs compared with the control MEFs (2.40-fold, P < 0.01). TGF-ß1-induced Smad2 phosphorylation was attenuated in the Cavin-2 KO MEFs compared with WT MEFs (0.60-fold, P < 0.01). Heat shock protein 90 protein levels were significantly reduced in the Cavin-2 KO MEFs compared with the WT MEFs (0.69-fold, P < 0.01). CONCLUSIONS: Cavin-2 loss suppressed fibroblast trans-differentiation into myofibroblasts through the TGF-ß/Smad signalling. The loss of Cavin-2 in cardiac fibroblasts suppresses cardiac fibrosis and may maintain cardiac function.

CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.

Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation. Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle. VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging. The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.

In-hospital mortality and cardiovascular treatment during hospitalization for heart failure among patients with schizophrenia: a nationwide cohort study.

AIMS: Schizophrenia is associated with cardiovascular disease (CVD) risk, and patients with schizophrenia are more likely to receive suboptimal care for CVD. However, there is limited knowledge regarding in-hospital prognosis and quality of care for patients with schizophrenia hospitalized for heart failure (HF). This study sought to elucidate the association between schizophrenia and in-hospital mortality, as well as cardiovascular treatment in patients hospitalized with HF. METHODS: Using the nationwide cardiovascular registry data in Japan, a total of 704,193 patients hospitalized with HF from 2012 to 2019 were included and stratified by age: young age, > 18 to 45 years (n = 20,289); middle age, >45 to 65 years (n = 114,947); and old age, >65 to 85 years (n = 568,957). All and 30-day in-hospital mortality as well as prescription of cardiovascular medications were assessed. After multiple imputation for missing values, mixed-effect multivariable logistic regression analysis was performed using patient and hospital characteristics with hospital identifier as a variable with random effects. RESULTS: Patients with schizophrenia were more likely to experience prolonged hospital stays, and incur higher hospitalization costs. In-hospital mortality for non-elderly patients with schizophrenia was significantly worse than for those without schizophrenia: the mortality rate was 7.6% vs 3.5% and the adjusted odds ratio (OR) was 1.96 (95% confidence interval (CI): 1.24-3.10, P = 0.0037) in young adult patients; 6.2% vs 4.0% and 1.49 (95% CI: 1.17-1.88, P < 0.001) in middle-aged patients. Thirty-day in-hospital mortality was significantly worse in middle-aged patients: the mortality rate was 4.7% vs 3.0% and an adjusted OR was 1.40 (95% CI: 1.07-1.83, P = 0.012). In-hospital mortality in elderly patients did not differ between those with and without schizophrenia. Prescriptions of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were significantly lower in patients with schizophrenia across all age groups. CONCLUSION: Schizophrenia was identified as a risk factor for in-hospital mortality and reduced prescription of cardioprotective medications in non-elderly patients hospitalized with HF. These findings highlight the necessity for differentiated care and management of HF in patients with severe mental illnesses.

Sex Differences in Process-of-Care and In-Hospital Prognosis Among Elderly Patients Hospitalized With Acute Myocardial Infarction.

BACKGROUND: Limited studies have demonstrated sex differences in the clinical outcomes and quality of care among elderly patients hospitalized with acute myocardial infarction (AMI).Methods and Results: Using nationwide cardiovascular registry data collected in Japan between 2012 and 2019, we enrolled patients aged ≥45 years. The 30-day and all in-hospital mortality rates, as well as process-of-care measures, were assessed, and mixed-effects logistic regression analysis was performed. A total 254,608 patients were included and stratified into 3 age groups: middle-aged, old and oldest old. The 30-day mortality rates for females and males were as follows: 3.0% vs. 2.7%, with an adjusted odds ratio (OR) of 1.17 (95% confidence interval (CI): 1.01-1.36, P=0.030) in middle-aged patients; 7.2% vs. 5.8%, with an OR of 1.14 (95% CI: 1.09-1.21, P<0.001) in old patients; and 19.6% vs. 15.5% with an OR of 1.17 (95% CI: 1.09-1.26, P<0.001) in the oldest old patients. Moreover, significantly higher numbers of female AMI patients across all age groups died in hospital, as well as having fewer invasive procedures and cardiovascular prescriptions, compared with their male counterparts. CONCLUSIONS: This nationwide cohort study revealed that female middle-aged and elderly patients experienced suboptimal quality of care and poorer in-hospital outcomes following AMI, compared with their male counterparts, highlighting the need for more effective management in consideration of sex-specific factors.

Renoprotective potential of concomittant medications with SGLT2 inhibitors and renin-angiotensin system inhibitors in diabetic nephropathy without albuminuria: a retrospective cohort study.

The renal protective effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors and renin-angiotensin system (RAS) inhibitors on diabetic nephropathy without albuminuria have not been fully investigated. This retrospective cohort study focused on patients with type 2 diabetes mellitus who had a baseline estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m2, and a urinary albumin-to-creatinine ratio < 30 mg/gCr. After propensity score matching, using covariates such as age, body mass index, systolic blood pressure, hemoglobin A1c levels, and prescription history of RAS inhibitors, we established a cohort of 58 patients: the SGLT2 inhibitor group (n = 28) and the control group (n = 28). In this cohort, we compared the annual eGFR decline rate between the two groups. The SGLT2 inhibitor group exhibited a significantly smaller eGFR change than the control group (- 1.15 vs. - 2.18 mL/min/1.73 m2/year). Within the SGLT2 inhibitor group, patients prescribed RAS inhibitors had demonstrated an even smaller eGFR change (- 0.70 mL/min/1.73 m2/year). In conclusion, SGLT2 inhibitors also have safeguarding effects in the stage of diabetic nephropathy without albuminuria, and the combined use of a SGLT2 inhibitor and a RAS inhibitor appears to be more effective than the single use of each.

Thyroid function, glycemic control, and diabetic nephropathy in patients with type 2 diabetes over 24 months: prospective observational study.

BACKGROUND: The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in type 2 diabetes patients. This study was conducted to reveal whether higher prevalence of thyroid dysfunction is observed in patients with type 2 diabetes. METHODS: We examined thyroid functions and thyroid autoantibodies in 200 patients with type 2 diabetes and 225 controls, with 24 months follow up for those with type 2 diabetes. RESULTS: Serum free triiodothyronine (fT3) levels and fT3/free thyroxine (fT4) ratio were significantly lower, while fT4 levels were significantly higher in patients with type 2 diabetes. The number of patients with thyroid dysfunction or patients positive for thyroid autoantibodies were not different between the two groups. The fT3/fT4 ratio was positively and negatively correlated with serum c-peptide and HbA1c levels, respectively, suggesting that the difference can be attributable to insulin resistance and diabetic control. In the follow-up observation, we found no significant correlation between basal thyrotropin (TSH), fT3, fT4 or fT3/fT4 ratio with the amounts of changes of HbA1c levels at 12 or 24 months after the basal measurements. There was a negative relationship between TSH levels and eGFR at baseline measurements, but TSH levels did not seem to predict future decline of eGFR levels. No relationship was observed between urine albumin/ g‧cre levels and thyroid function. CONCLUSION: Thyroid dysfunction and thyroid autoantibodies were not different in prevalence between patients with type 2 diabetes and controls, although in patients with type 2 diabetes, the fT3/fT4 ratio was decreased. Basal thyroid function did not predict future diabetes control or renal function within 24 months of follow-up.

Development of a Prediction Model for Healthy Life Years Without Activity Limitation: National Cross-sectional Study.

BACKGROUND: In some countries, including Japan-the leading country in terms of longevity, life expectancy has been increasing; meanwhile, healthy life years have not kept pace, necessitating an effective health policy to narrow the gap. OBJECTIVE: The aim of this study is to develop a prediction model for healthy life years without activity limitations and deploy the model in a health policy to prolong healthy life years. METHODS: The Comprehensive Survey of Living Conditions, a cross-sectional national survey of Japan, was conducted by the Japanese Ministry of Health, Labour and Welfare in 2013, 2016, and 2019. The data from 1,537,773 responders were used for modelling using machine learning. All participants were randomly split into training (n=1,383,995, 90%,) and test (n=153,778, 10%) subsets. Extreme gradient boosting classifier was implemented. Activity limitations were set as the target. Age, sex, and 40 types of diseases or injuries were included as features. Healthy life years without activity limitations were calculated by incorporating the predicted prevalence rate of activity limitations in a life table. For the wide utility of the model in individuals, we developed an application tool for the model. RESULTS: In the groups without (n=1,329,901) and with (n=207,872) activity limitations, the median age was 47 (IQR 30-64) and 69 (IQR 54-80) years, respectively (P<.001); female sex comprised 51.3% (n=681,794) in the group without activity limitations and 56.9% (n=118,339) in the group with activity limitations (P<.001). A total of 42 features were included in the feature set. Age had the highest impact on model accuracy, followed by depression or other mental diseases; back pain; bone fracture; other neurological disorders, pain, or paralysis; stroke, cerebral hemorrhage, or infarction; arthritis; Parkinson disease; dementia; and other injuries or burns. The model exhibited high performance with an area under the receiver operating characteristic curve of 0.846 (95% CI 0.842-0.849) with exact calibration for the average probability and fraction of positives. The prediction results were consistent with the observed values of healthy life years for both sexes in each year (range of difference between predictive and observed values: -0.89 to 0.16 in male and 0.61 to 1.23 in female respondents). We applied the prediction model to a regional health policy to prolong healthy life years by adjusting the representative predictors to a target prevalence rate. Additionally, we presented the health condition without activity limitations index, followed by the application development for individual health promotion. CONCLUSIONS: The prediction model will enable national or regional governments to establish an effective health promotion policy for risk prevention at the population and individual levels to prolong healthy life years. Further investigation is needed to validate the model's adaptability to various ethnicities and, in particular, to countries where the population exhibits a short life span.

Association between patient volume to cardiologist, process of care, and clinical outcomes in heart failure.

AIMS: The impact of hospital volume on clinical performance has been investigated by many researchers to date and thought that it is associated with quality of care and outcome for patients with heart failure (HF). This study sought to determine whether annual admissions of HF per cardiologist are associated with process of care, mortality, and readmission. METHODS AND RESULTS: Among the nationwide registry 'Japanese registry of all cardiac and vascular diseases - diagnostics procedure combination' data collected from 2012 to 2019, a total of 1 127 113 adult patients with HF and 1046 hospitals were included in the study. Primary outcome was in-hospital mortality, and secondary outcome was 30 day in-hospital mortality and readmission at 30 days and 6 months. Hospital and patient characteristics and process of care measures were also assessed. Mixed-effect logistic regression and Cox proportional-hazards model was used for multivariable analysis, and adjusted odds ratio and hazard ratio were evaluated. Process of care measures had inverse trends for annual admissions of HF per cardiologist (P < 0.01 for all measures: prescription rate of beta-blocker, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, mineralocorticoid receptor antagonist, and anticoagulant for atrial fibrillation). Adjusted odds ratio for in-hospital mortality was 1.04 (95% confidence interval (CI): 1.04-1.08, P = 0.04) and 30 day in-hospital mortality was 1.05 (95% CI: 1.01-1.09, P = 0.01) for interval of 50 annual admissions of HF per cardiologist. Adjusted hazard ratio for 30 day readmission was 1.05 (95% CI: 1.02-1.08, P < 0.01) and 6 month readmission was 1.07 (95% CI: 1.03-1.11, P < 0.01). Plots of the adjusted odds indicated 300 as the threshold of annual admissions of HF per cardiologist for substantial increase of in-hospital mortality risk. CONCLUSIONS: Our findings demonstrated that annual admissions of HF per cardiologist are associated with worse process of care, mortality, and readmission with the threshold for mortality risk increased, emphasizing the optimal proportion of patients admitted with HF to cardiologist for better clinical performance.

Effect of SARS-CoV-2 BNT162b2 mRNA vaccine on thyroid autoimmunity: A twelve-month follow-up study.

Objectives: Graves' disease (GD) has been highlighted as a possible adverse effect of the respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. However, it is unknown if the SARS-CoV-2 vaccine disrupts thyroid autoimmunity. We aimed to present long-term follow-up of thyroid autoimmunity after the SARS-CoV-2 BNT162b2 mRNA vaccine. Methods: Serum samples collected from seventy Japanese healthcare workers at baseline, 32 weeks after the second dose (pre-third dose), and 4 weeks after the third dose of the vaccine were analyzed. The time courses of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibody, thyroid-stimulating hormone receptor antibody (TRAb), and thyroid function were evaluated. Anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were additionally evaluated in thirty-three participants. Results: The median age was 50 (IQR, 38-54) years and 69% were female. The median anti-spike IgG antibody titer was 17627 (IQR, 10898-24175) U/mL 4 weeks after the third dose. The mean TRAb was significantly increased from 0.81 (SD, 0.05) IU/L at baseline to 0.97 (SD, 0.30) IU/L 4 weeks after the third dose without functional changes. An increase in TRAb was positively associated with female sex (ß = 0.32, P = 0.008) and low basal FT4 (ß = -0.29, P = 0.02) and FT3 (ß = -0.33, P = 0.004). TgAb was increased by the third dose. Increase in TgAb was associated with history of the thyroid diseases (ß = 0.55, P <0.001). Conclusions: SARS-CoV-2 BNT162b2 mRNA vaccine can disrupt thyroid autoimmunity. Clinicians should consider the possibility that the SARS-CoV-2 vaccine may disrupt thyroid autoimmunity.

Robust prognostic prediction model developed with integrated biological markers for acute myocardial infarction.

Commonly used prediction methods for acute myocardial infarction (AMI) were created before contemporary percutaneous coronary intervention was recognized as the primary therapy. Although several studies have used machine learning techniques for prognostic prediction of patients with AMI, its clinical application has not been achieved. Here, we developed an online application tool using a machine learning model to predict in-hospital mortality in patients with AMI. A total of 2,553 cases of ST-elevation AMI were assigned to 80% training subset for cross validation and 20% test subset for model performance evaluation. We implemented random forest classifier for the binary classification of in-hospital mortality. The selected best feature set consisted of ten clinical and biological markers including max creatine phosphokinase, hemoglobin, heart rate, creatinine, systolic blood pressure, blood sugar, age, Killip class, white blood cells, and c-reactive protein. Our model achieved high performance: the area under the curve of the receiver operating characteristic curve for the test subset, 0.95: sensitivity, 0.89: specificity, 0.91: precision, 0.43: accuracy, 0.91 respectively, which outperformed common scoring methods. The freely available application tool for prognostic prediction can contribute to risk triage and decision-making in patient-centered modern clinical practice for AMI.

Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report.

BACKGROUND: The global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19. CASE PRESENTATION: A healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH < 1.5 pg/ml, cortisol 1.6 µg/dl). He was diagnosed with adrenal crisis and was emergently treated with hydrocortisone. The symptoms responded well and he recovered within a few days. Magnetic resonance images after the replacement with hydrocortisone revealed an atrophic pituitary gland. The patient was referred to our tertiary hospital for further endocrinological examination. Pituitary endocrine load tests revealed isolated adrenocortical response deficiency. After other clinical assessments, he was diagnosed as having isolated ACTH deficiency. After initiation of hydrocortisone replacement, there has been no recurrence of symptoms related to adrenocortical insufficiency nor involvement of other pituitary functions. CONCLUSION: This is the first reported case of IAD potentially associated with COVID-19 immunization. Recent reports have emphasized the importance of adjuvants in the mRNA vaccine that induce the endocrinological adverse effects through disturbance of the autoimmune system, but details are still unclear. Given the broad and rapid spread of vaccinations against COVID-19, it is clinically important to consider that there could be cases with a rare but emergent adrenal crisis even among those who present common symptoms of adverse effects following inactive SARS-CoV-2 mRNA vaccination.

Hypopituitarism and cranial nerve involvement mimicking Tolosa-Hunt syndrome as the initially presenting feature of diffuse large B-cell lymphoma: a case report.

BACKGROUND: Early diagnosis of lymphoma involving the central nervous system is sometimes difficult but emergent to avoid the delay of therapeutic initiation. Pituitary insufficiencies are usually associated with lymphoma in the pituitary gland. There have been no cases of lymphoma originating from extra pituitary gland with hypopituitarism that simultaneously presenting unilateral upper cranial nerve palsies and ophthalmalgia. These symptoms are mostly caused by neoplastic involvement of the skull base or benign diseases such as Tolosa-Hunt syndrome (THS). We report a case of lymphoma with unique clinical courses initially presenting hypopituitarism and symptoms mimicking THS with a mass in sphenoidal and cavernous sinuses accompanying sphenoidal bone erosion. CASE PRESENTATION: A 71-year-old woman visited our hospital with left ophthalmalgia, ptosis, and diplopia. Neurological findings revealed left oculomotor, trochlear and abducent nerve palsies. Endocrine tests indicated partial hypopituitarism. Initial CT and MRI revealed that a mass in sphenoidal and cavernous sinuses had invaded the sella with osteolysis of the sphenoid bone. At around four weeks, almost all the symptoms of cranial nerve palsies were relieved. Seven weeks later, she had a high fever and cervical lymph node (CLN) swellings. CLN biopsy revealed CD20-positive B-cells. She was diagnosed with diffuse large B-cell lymphoma (DLBCL). 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) revealed elevated uptake at the erosion lesion of the sphenoidal bone, but not the pituitary gland. After chemotherapy, all the symptoms related to systemic lymphoma were relieved, but partial hypopituitarism remained. The mass in sphenoidal and cavernous sinuses and elevated uptake by PET/CT were dissolved. CONCLUSION: This case of DLBCL had a unique clinical course; initial presentation of hypopituitarism and symptoms mimicking THS. There was also rare demonstration of mass lesions related to DLBCL in the sphenoidal and cavernous sinuses compressing the pituitary gland through an eroded area of the sphenoidal bone. It should be clinically cautioned that DLBCL can be associated with erosion of the sphenoidal bone and cause both hypopituitarism and THS-mimicking symptoms.

Laparoscopic sleeve gastrectomy for morbid obesity improves gut microbiota balance, increases colonic mucosal-associated invariant T cells and decreases circulating regulatory T cells.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) for morbid obesity may improve gut microbiota balance and decrease chronic inflammation. This study examines the changes in gut microbiota and immune environment, including mucosal-associated invariant T cells (MAIT cells) and regulatory T cells (Treg cells) caused by LSG. METHODS: Ten morbidly obese patients underwent LSG at our institution between December 2018 and March 2020. Flow cytometry for Th1/Th2/Th17 cells, Treg cells and MAIT cells in peripheral blood and colonic mucosa and 16S rRNA analysis of gut microbiota were performed preoperatively and then 12 months postoperatively. RESULTS: Twelve months after LSG, the median percent total weight loss was 30.3% and the median percent excess weight loss was 66.9%. According to laboratory data, adiponectin increased, leptin decreased, and chronic inflammation improved after LSG. In the gut microbiota, Bacteroidetes and Fusobacteria increased after LSG, and indices of alpha diversity increased after LSG. In colonic mucosa, the frequency of MAIT cells increased after LSG. In peripheral blood, the frequency of Th1 cells and effector Treg cells decreased after LSG. CONCLUSIONS: After LSG for morbid obesity, improvement in chronic inflammation in obesity is suggested by change in the constituent bacterial species, increase in the diversity of gut microbiota, increase in MAIT cells in the colonic mucosa, and decrease in effector Treg cells in the peripheral blood.

Reduced Fat Taste Sensitivity in Obese Japanese Patients and Its Recovery after a Short-Term Weight Loss Program.

Fat taste has recently attracted attention as the 'sixth taste.' However, the relationship between fat and sweet taste in Japanese obesity has not yet been examined, and no reports have ascertained whether improvement of fat taste can be obtained by weight loss. Patients were recruited into obesity group (BMI≥30 kg/m2; n=15) or control group (BMI<25 kg/m2; n=11). They answered a questionnaire on smoking, eating behavior, lifestyle, and food frequency, and their taste thresholds were measured (fat, umami, and sweet). The obesity group was tested twice (on admission and before discharge). They showed several eating behavior abnormalities, higher total energy intake, and less physical activity. There were some gender differences: physical inactivity was more prominent in females, and high total energy intake in males, which correlates with fat taste rank. Fat taste rank was significantly higher in obesity group, whereas taste rank of umami and sweet were not significantly different. Gender-specific analysis of fat taste rank revealed only male obesity showed significant difference. Reduced sensitivity of fat may be specific to male gender or obesity by overeating, but not by physical inactivity. Multiple logistic regression analysis revealed that fat taste was a factor relevant to obesity. Fat taste significantly improved after a weight loss program, with average duration of 11.3 d. Japanese obese people, especially males and those who are obese by overeating, have reduced sensitivity to fat taste. This can be recovered by even a short-term weight loss program.

Energy-sparing by 2-methyl-2-thiazoline protects heart from ischaemia/reperfusion injury.

AIMS: Cardiac ischaemia/reperfusion (I/R) injury remains a critical issue in the therapeutic management of ischaemic heart failure. Although mild hypothermia has a protective effect on cardiac I/R injury, more rapid and safe methods that can obtain similar results to hypothermia therapy are required. 2-Methyl-2-thiazoline (2MT), an innate fear inducer, causes mild hypothermia resulting in resistance to critical hypoxia in cutaneous or cerebral I/R injury. The aim of this study is to demonstrate the protective effect of systemically administered 2MT on cardiac I/R injury and to elucidate the mechanism underlying this effect. METHODS AND RESULTS: A single subcutaneous injection of 2MT (50 mg/kg) was given prior to reperfusion of the I/R injured 10 week-old male mouse heart and its efficacy was evaluated 24 h after the ligation of the left anterior descending coronary artery. 2MT preserved left ventricular systolic function following I/R injury (ejection fraction, %: control 37.9 ± 6.7, 2MT 54.1 ± 6.4, P < 0.01). 2MT also decreased infarct size (infarct size/ischaemic area at risk, %: control 48.3 ± 12.1, 2MT 25.6 ± 4.2, P < 0.05) and serum cardiac troponin levels (ng/mL: control 8.9 ± 1.1, 2MT 1.9 ± 0.1, P < 0.01) after I/R. Moreover, 2MT reduced the oxidative stress-exposed area within the heart (%: control 25.3 ± 4.7, 2MT 10.8 ± 1.4, P < 0.01). These results were supported by microarray analysis of the mouse hearts. 2MT induced a transient, mild decrease in core body temperature (°C: -2.4 ± 1.4), which gradually recovered over several hours. Metabolome analysis of the mouse hearts suggested that 2MT minimized energy metabolism towards suppressing oxidative stress. Furthermore, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography imaging revealed that 2MT reduced the activity of brown adipose tissue (standardized uptake value: control 24.3 ± 6.4, 2MT 18.4 ± 5.8, P < 0.05). 2MT also inhibited mitochondrial respiration and glycolysis in rat cardiomyoblasts. CONCLUSIONS: We identified the cardioprotective effect of systemically administered 2MT on cardiac I/R injury by sparing energy metabolism with reversible hypothermia. Our results highlight the potential of drug-induced hypothermia therapy as an adjunct to coronary intervention in severe ischaemic heart disease.

Requirement of Cavin-2 for the expression and stability of IRß in adequate adipocyte differentiation.

OBJECTIVE: Adipogenesis plays an essential role in maintaining energy and hormonal balance. Cavin-2, one of the caveolae-related proteins, is abundant in adipocytes, the leading site of adipogenesis. However, the details of the roles of Cavin-2 in adipogenesis remain unknown. Here, we demonstrate the requirement of Cavin-2 for the expression and stability of IRß in adequate adipocyte differentiation. METHODS: Cavin-2 knockout (Cavin-2 KO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 8 weeks. We evaluated body weight, food intake, and several tissues. Glucose homeostasis was assessed by glucose and insulin tolerance tests. Insulin signaling in epididymal white adipose tissue (eWAT) was determined by Akt phosphorylation. In vitro study, we evaluated adipocyte differentiation, adipogenesis-related genes, and insulin signaling to clarify the relationship between Cavin-2 and adipogenesis under the manipulation of Cavin-2 expression. RESULTS: Caveolae structure decreased in eWAT of Cavin-2 KO mice and Cavin-2 knockdown 3T3-L1 cells. Cavin-2 enhanced the stability of insulin receptor (IR) through direct association at the plasma membrane in adipocytes, resulting in accelerated insulin/IR/Akt signaling-induced adipogenic gene expression in insulin-containing solution-stimulated 3T3-L1 adipocytes. IR-mediated Akt activation also enhanced Cavin-2 and IR expression. Cavin-2 knockout mice showed insulin resistance with dyslipidemia and pathological hypertrophic adipocytes after a HFD. CONCLUSIONS: Cavin-2 enhances IR stability through binding IR and regulates insulin signaling, promoting adequate adipocyte differentiation. Our findings highlight the pivotal role of Cavin-2 in adipogenesis and lipid metabolism, which may help to develop novel therapies for pathological obesity and adipogenic disorders.

Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy.

Significant progress has been made in developing new treatments and refining the use of preexisting ones against cancer. Their successful use and the longer survival of cancer patients have been associated with reports of new cardiotoxicities and the better characterization of the previously known cardiac complications. Immunotherapies with monoclonal antibodies against specific cancer-promoting genes, chimeric antigen receptor T cells, and immune checkpoint inhibitors have been developed to fight cancer cells, but they can also show off-target effects on the heart. Some of these cardiotoxicities are thought to be due to nonspecific immune activation and inflammatory damage. Unlike immunotherapy-associated cardiotoxicities which are relatively new entities, there is extensive literature on anthracycline-induced cardiomyopathy. Here, we provide a brief overview of the cardiotoxicities of immunotherapies for the purpose of distinguishing them from anthracycline cardiomyopathy. This is especially relevant as the expansion of oncological treatments presents greater diagnostic challenges in determining the cause of cardiac dysfunction in cancer survivors with a history of multiple cancer treatments including anthracyclines and immunotherapies administered concurrently or serially over time. We then provide a focused review of the mechanisms proposed to underlie the development of anthracycline cardiomyopathy based on experimental data mostly in mouse models. Insights into its pathogenesis may stimulate the development of new strategies to identify patients who are susceptible to anthracycline cardiomyopathy while permitting low cardiac risk patients to receive optimal treatment for their cancer.

Deterioration of pituitary function without relapse after steroid therapy for IgG4-related hypophysitis.

SUMMARY: IgG4-related hypophysitis is an autoimmune hypophysitis associated with IgG4-related disease. Swelling of the pituitary gland is responsive to steroid therapy, but the prognosis of pituitary function after the treatment remains unclear. The present case implies that transiently improved pituitary function can re-worsen during long-term follow-up in IgG4-related hypophysitis. A 71-year-old male patient with IgG4-related hypophysitis visited a nearby hospital with malaise, anorexia, and polyuria. Pituitary dysfunction was suspected, so he was referred to our hospital for further examination. Imaging studies and laboratory data showed swelling of the pituitary gland and panhypopituitarism, which dramatically improved following steroid therapy. There was no evidence of relapsing IgG4-related disease during prednisolone tapering. Pituitary function was examined after 4 years under treatment with low-dose prednisolone; surprisingly, anterior pituitary function had worsened again. Our case suggests a need for continuous monitoring of pituitary function after steroid therapy for IgG4-related hypophysitis. This report illustrates the natural course of pituitary function in IgG4-related hypophysitis and may be informative when considering the introduction of steroid therapy. LEARNING POINTS: Steroid therapy is an effective first-line therapy for pituitary dysfunction and pituitary swelling in IgG4-related hypophysitis. Pituitary function can worsen again during follow-up, despite transient improvement after steroid therapy in IgG4-related hypophysitis. Continuous monitoring of pituitary function is necessary for IgG4-related hypophysitis, regardless of disease activity.

Prediction of well-being and insight into work-life integration among physicians using machine learning approach.

There has been increasing interest in examining physician well-being and its predictive factors. However, few studies have revealed the characteristics associated with physician well-being and work-life integration using a machine learning approach. To investigate predictive factors of well-being and obtain insights into work-life integration, the survey was conducted by letter mail in a sample of Japanese physicians. A total of 422 responses were collected from 846 physicians. The mean age was 47.9 years, males constituted 83.3% of the physicians, and 88.6% were considered to be well. The most accurate machine learning model showed a mean area under the curve of 0.72. The mean permutation importance of career satisfaction, work hours per week, existence of family support, gender, and existence of power harassment were 0.057, 0.022, 0.009, 0.01, and 0.006, respectively. Using a machine learning model, physician well-being could be predicted. It seems to be influenced by multiple factors, such as career satisfaction, work hours per week, family support, gender, and power harassment. Career satisfaction has the highest impact, while long work hours have a negative effect on well-being. These findings support the need for organizational interventions to promote physician well-being and improve the quality of medical care.

Autosomal Dominant Hypocalcemia With Atypical Urine Findings Accompanied by Novel CaSR Gene Mutation and VitD Deficiency.

INTRODUCTION: Autosomal dominant hypocalcemia (ADH) is caused by gain-of-function mutations of the calcium sensing receptor (CaSR). It is characterized by hypercalciuria in spite of hypocalcemia. Vitamin D deficiency increases calcium reabsorption in the distal tubules of the kidneys, resulting in hypocalciuria. MATERIALS AND METHODS: A 38-year-old female proband had hypocalcemia, hypocalciuria, and vitamin D deficiency. Her father and brother also had hypocalcemia, but her mother was normocalcemic. We analyzed the CaSR gene abnormality in this family. Polymerase chain reaction (PCR) and sequence analysis were performed to explore the CaSR gene mutation. Mutagenesis, transfection, and functional analysis were performed on the discovered genetic abnormalities. RESULT: PCR and sequence analysis revealed that the proband, her father, and brother had a novel heterozygous mutation of the CaSR genes that causes threonine to asparagine substitution at codon 186 (T186N). Using HEK293 cells transfected with wild-type or T186N CaSR complementary DNA, we assessed the intracellular Ca2+ concentration in response to changes in the extracellular Ca2+ concentration. The cells transfected mutant CaSR gene had higher activity than that of wild-type. Therefore, we determined our patient had ADH with a novel mutation of the CaSR gene and hypocalciuria resulting from a vitamin D deficiency. We administered vitamin D to the proband, which caused elevation of her urinary calcium level, a typical finding of ADH. CONCLUSION: Vitamin D deficiency was suggested to potentially mask hypercalciuria in ADH. Hypocalcemia with vitamin D deficiency should be diagnosed with care.