Senility deaths in aged societies: The case of Japan.

Senility is now the third largest cause of death in Japan, comprising 11.4% of the total number of deaths in 2022. Although senility deaths were common in the period before the Second World War, they declined sharply from 1950 to 2000 and then increased up to the present. The recent increase is more than what we could expect from an increasing number of very old persons or the increasing number of deaths at facilities. The senility death description in the death certificate is becoming poorer, with 93.8% of them only with a single entry of "senility". If other diseases are mentioned, those are again vague diseases or conditions. Senility, dementia and Alzheimer's disease, sequelae of cerebrovascular disease, and heart failure are the largest causes of death in which senility is mentioned in the death certificate. The period from senility onset to death is often described within a few months, but it varies. In some cases, the deceased's age was written out of a conviction that the ageing process starts from birth. As senility is perceived differently among the certifying doctors, a standardised protocol to certify the senility death is needed. On the other hand, senility death is the preferred cause of death and many people do not wish to receive invasive medical examinations before dying peacefully. Together with other causes of death related to frailty, there would be a need to capture senility as a proper cause of death, not just as a garbage code, in the aged, low-mortality population.

HSP47 levels determine the degree of body adiposity.

Adiposity varies among individuals with the influence of diverse physiological, pathological, environmental, hormonal, and genetic factors, but a unified molecular basis remains elusive. Here, we identify HSP47, a collagen-specific chaperone, as a key determinant of body adiposity. HSP47 expression is abundant in adipose tissue; increased with feeding, overeating, and obesity; decreased with fasting, exercise, calorie restriction, bariatric surgery, and cachexia; and correlated with fat mass, BMI, waist, and hip circumferences. Insulin and glucocorticoids, respectively, up- and down-regulate HSP47 expression. In humans, the increase of HSP47 gene expression by its intron or synonymous variants is associated with higher body adiposity traits. In mice, the adipose-specific knockout or pharmacological inhibition of HSP47 leads to lower body adiposity compared to the control. Mechanistically, HSP47 promotes collagen dynamics in the folding, secretion, and interaction with integrin, which activates FAK signaling and preserves PPARγ protein from proteasomal degradation, partly related to MDM2. The study highlights the significance of HSP47 in determining the amount of body fat individually and under various circumstances.

Health of migrants and other vulnerable populations across Asian countries: Build Forward Better beyond the COVID-19 pandemic.

Global migration has been increasing since before the COVID-19 pandemic. The pandemic has clearly shown a lack of preparedness for the next public health emergency when it comes to vulnerable populations including migrants. To include the issues of migration and health in the current global health agenda, it is important to establish/strengthen a network for collaboration among various stakeholders from both the migrant-sending and host countries of migrants especially in the Asian-Pacific region. As the initial step for networking in Asia, in March 2023, a hybrid style international symposium was held in Japan and agreed on a goal and five pillars: surveillance and monitoring, risk communications, community engagement, access to health and social protection services, and supportive environments. Considering the transition of context from the COVID-19 crisis to 'Build Forward Better', through the Asian network, we will envisage the better world, where vulnerable populations including migrants will not be left behind from health security.

Basal Plasma Aldosterone Concentration Predicts Therapeutic Outcomes in Primary Aldosteronism.

PURPOSE: Normal basal plasma aldosterone concentration (PAC) reflects mild aldosterone excess compared to high basal PAC. We previously reported lower risk for cardiovascular and cerebrovascular events in patients with primary aldosteronism (PA) and normal basal PAC (nPA) than in those with high basal PAC (hPA). However, the differences in therapeutic outcomes between nPA and hPA are unclear. The aim of this multi-institutional, retrospective cohort study was to determine the clinical significance of nPA to therapeutic outcomes, including adrenalectomy (ADX) and treatment with mineralocorticoid receptor antagonists (MRAs). METHODS: A total of 1146 patients with PA who were diagnosed and underwent adrenal venous sampling (AVS) between January 2006 and October 2016 were enrolled. The clinical parameters at baseline and after ADX or treatment with MRA were compared between the nPA and hPA groups. RESULTS: Significantly higher rates of absent clinical success (36.6 vs. 21.9%, P = 0.01) and absent biochemical success (26.4 vs. 5.2%, P < 0.01) were found for the nPA group than for the hPA group, respectively. Logistic regression analysis identified baseline PAC as a significant independent predictor of absent clinical success of ADX and MRAs. CONCLUSIONS: Plasma aldosterone concentration at baseline was a significant and independent predictor of absent clinical success of ADX and MRA. Mineralocorticoid receptor antagonist treatment appeared to be a better therapeutic choice than ADX in the nPA group.

Glucocorticoid Replacement Affects Serum Adiponectin Levels and HDL-C in Patients With Secondary Adrenal Insufficiency.

CONTEXT: Low serum adiponectin and high-density lipoprotein-cholesterol (HDL-C) levels are risk factors for cardiovascular disease. Patients with primary adrenal insufficiency are at higher risk of cardiovascular complications compared with healthy subjects. However, there is no information on the relationship between adiponectin and glucocorticoid replacement therapy in patients with secondary adrenal insufficiency (SAI). OBJECTIVE: To determine the effects of intrinsic adrenal function and glucocorticoid replacement therapy on serum adiponectin levels and lipid profile in patients with SAI. DESIGN: Part 1: a cross-sectional study. Part 2: a randomized, double-blind, crossover study. SETTING: Osaka University Hospital, Osaka, Japan. PATIENTS: Part 1: 58 patients diagnosed with nonfunctioning pituitary adenoma who underwent insulin tolerance test (ITT) for assessment of adrenal function. Part 2: 12 SAI patients randomly received hydrocortisone replacement therapy at a dose of 10, 20, or 30 mg/d for 4 weeks per term for three terms. OUTCOME MEASUREMENTS: Part 1: we analyzed the relationship between serum cortisol levels during ITT and serum adiponectin levels and the lipid profile. Part 2: serum adiponectin levels and lipid profile were measured every 4 weeks. RESULTS: Serum levels of adiponectin and HDL-C correlated significantly with peak cortisol levels after ITT. Serum adiponectin and HDL-C levels were significantly lower in patients with SAI than non-SAI. Serum levels of adiponectin and HDL-C increased in a hydrocortisone dose-dependent manner. CONCLUSIONS: Glucocorticoid replacement therapy increased serum levels of adiponectin, an adipose-derived anti-atherogenic factor, and HDL-C in patients with SAI.

The number of positive confirmatory tests is associated with the clinical presentation and incidence of cardiovascular and cerebrovascular events in primary aldosteronism.

Primary aldosteronism (PA) is a major cause of secondary hypertension and presents a higher risk for cardio-cerebrovascular (CCV) events compared with essential hypertension. To diagnose PA after a positive screening test, at least one of three available confirmatory tests [the saline infusion test (SIT), the captopril challenge test (CCT) or the furosemide upright test (FUT)] should be performed. The aim of our study was to investigate the relationship between the number of positive confirmatory tests using SIT and CCT and the clinical presentation and prevalence of CCV events in 398 PA patients. The number of PA patients doubled when PA diagnosis was defined by positive results on either the SIT or CCT confirmatory tests (single positive) compared to positive results on both the SIT and CCT confirmatory tests (double positive). We also found a more typical clinical presentation of PA, such as the use of more antihypertensive drugs to control blood pressure and a higher incidence of hypokalemia, in PA patients with double positive confirmatory tests than in those with a single positive confirmatory test. The incidence of CCV events in PA patients with double positive confirmatory tests was significantly higher than that in those with a single positive confirmatory test. Our results demonstrated that the number of PA patients was doubled by the use of PA diagnostic criteria using a single positive confirmatory test compared to the use of double positive confirmatory tests. PA patients with double positive confirmatory tests were associated with a more typical clinical presentation and a higher incidence of CCV events than those with a single positive confirmatory test.

Adipocyte GR Inhibits Healthy Adipose Expansion Through Multiple Mechanisms in Cushing Syndrome.

In Cushing syndrome, excessive glucocorticoids lead to metabolic disturbances, such as insulin resistance, adipocyte hypertrophy, and liver steatosis. In vitro experiments have highlighted the importance of adipocyte glucocorticoid receptor (GR), but its metabolic roles in vivo have not been fully elucidated in Cushing syndrome. In this study, using clinical samples from patients with Cushing syndrome and adipocyte-specific GR knockout (AGRKO) mice, we investigated the roles of adipocyte GR and its clinical relevance in Cushing syndrome. Under chronic treatment with corticosterone, AGRKO mice underwent healthy adipose expansion with diminished ectopic lipid deposition and improved insulin sensitivity. These changes were associated with Atgl-mediated lipolysis through a novel intronic glucocorticoid-responsive element. Additionally, integrated analysis with RNA sequencing of AGRKO mice and clinical samples revealed that healthy adipose expansion was associated with dysregulation of tissue remodeling, preadipocyte proliferation, and expression of the circadian gene. Thus, our study revealed the roles of adipocyte GR on healthy adipose expansion and its multiple mechanisms in Cushing syndrome.

Clinical Characteristics of Acromegalic Patients With Paradoxical GH Response to Oral Glucose Load.

CONTEXT: A paradoxical GH response to oral glucose (OG) is often found in acromegaly. However, the clinical characteristics of patients with acromegaly and a paradoxical GH response to OG (OG responders) remain unclear. OBJECTIVE: The aim of the present study was to define the clinical characteristics of OG responders with acromegaly. DESIGN: Retrospective study. SETTING: Hospitalized care at Osaka University Hospital. PATIENTS AND METHODS: Of 63 patients with acromegaly admitted to our hospital from January 2006 to January 2017, 19 were classified as OG responders and 44 as nonresponders. The clinical characteristics of these groups were compared. RESULTS: Before surgery, OG responders had substantially greater IGF-1 SD scores than nonresponders (P < 0.05), although no difference was found in basal GH levels between the two groups (P = 0.46). Regarding glucose metabolism, 120-minute plasma glucose and immunoreactive insulin after OG administration and hemoglobin A1c were significantly greater in OG responders than in nonresponders (P < 0.01, P < 0.05, P < 0.05, respectively). GH levels during octreotide or bromocriptine testing were decreased more significantly in OG responders than in nonresponders (P < 0.05, P < 0.05, respectively). The proportion of pituitary tumors with hypointensity on T2-weighted MRI was significantly greater in OG responders than in nonresponders (P < 0.05). The difference in IGF-1 and parameters of glucose metabolism described disappeared between the two groups after surgery. CONCLUSIONS: The paradoxical GH response reflected the clinical characteristics, especially IGF-I level, glucose metabolism, and drug efficacy in acromegaly. A paradoxical GH response, in addition to the nadir GH levels, to OG load is potentially useful for evaluation of the clinical characteristics of acromegaly.

Evaluation of Hypothalamic-Pituitary-Adrenal Axis by the GHRP2 Test: Comparison With the Insulin Tolerance Test.

CONTEXT: GH-releasing peptide 2 (GHRP2) stimulates the hypothalamic-pituitary-adrenal axis (HPA) through the GH secretagogue receptor (GHSR) in the hypothalamus, in which ghrelin is a natural ligand. Therefore, the GHRP2 test (GHRP2T) could be used instead of the insulin tolerance test (ITT). OBJECTIVE: Can the GHRP2T replace the ITT for evaluation of HPA? DESIGN: The present retrospective study analyzed the clinical features and laboratory data from 254 patients admitted for evaluation of hypopituitarism who underwent both GHRP2T and ITT. We analyzed the association between the maximum cortisol level (Fmax) during both tests. Adrenocortical insufficiency was diagnosed by ITT. The suitability of GHRP2T was examined using the receiver operating characteristic curve. RESULTS: A strong correlation was found between Fmax measured using both tests (r = 0.777, P < 0.0001). However, the sensitivity (64%) and specificity (79%) showed that the GHRP2T was not suitable for clinical use. Various factors influenced the correlation, probably through their effects on ghrelin and/or GHSR, including functional adenoma (P < 0.05) and sex (P < 0.05). No substantial correlation was found between Fmax measured using both tests in patients with prolactinoma (n = 30). The exclusion of patients with functional adenoma revealed no factors that affected the association in male patients; however, age and menstruation significantly influenced it in female patients (P < 0.05). Analysis of the data from male subjects without functional adenoma (n = 104) showed high sensitivity (95%) and specificity (85%) for the GHRP2T. CONCLUSION: ITT can be substituted with GHRP2T for assessment of HPA in male patients free of functional adenoma.

Multiple Gouty Tophi with Bone Erosion and Destruction: A Report of an Early-onset Case in an Obese Patient.

A 27 year-old severely obese man (BMI, 35.1) had hyperuricemia and multiple gouty tophi with bone erosion and destruction, resulting in gait disturbance for 6 years after the early onset of gout at 21 years of age. His hyperuricemia was associated with hyperinsulinemia in obesity and a genetic variant of the ABCG2 gene. In addition, multiple gouty tophi with bone erosion and destruction might have been caused by hypoadiponectinemia and the elevation of the patient' s pro-inflammatory cytokine (IL-1ß) level with the accumulation of visceral fat. In this case, bone and Ga-67 scintigraphy were useful for detecting the location and magnitude of gouty tophi.

Saline Infusion Test highly associated with the incidence of cardio- and cerebrovascular events in primary aldosteronism.

Primary aldosteronism (PA) is caused by excess secretion of aldosterone and is an independent risk factor for cardio-cerebro-vascular (CCV) events. The goal of treatment of PA should include prevention of CCV events. A definitive diagnosis of PA is established by confirmatory tests [saline infusion test (SIT), furosemide upright test (FUT) and captopril challenge test (CCT)]. However, there is no information on whether the hormone levels measured by these confirmatory tests are associated with CCV events. The aim of this retrospective study was to elucidate the relationship between the results of the above confirmatory tests and prevalence of CCV disease in patients with PA. The study subjects were 292 PA patients who were assessed for past history of CCV events at the time of diagnosis of PA. CCV events were significantly higher in patients with positive than negative SIT (12.8% vs. 3.3%, p=0.04). There were no differences in the incidences of CCV events between patients with positive and negative CCT and FUT (CCT: 11.0% vs. 3.9%, p=0.13, FUT: 6.1% vs. 5.7%, p=0.93). Our results demonstrated a higher incidence of CCV disease in PA SIT-positive patients compared to those with negative test. SIT is a potentially useful test not only for the diagnosis of PA but also assessment of the risk of CCV events.

Plasma aldosterone level within the normal range is less associated with cardiovascular and cerebrovascular risk in primary aldosteronism.

BACKGROUND: Previous studies showed higher risk of cardiovascular and cerebrovascular (CCV) events in primary aldosteronism compared with essential hypertension, but the patients of these studies were limited to primary aldosteronism patients with high plasma aldosterone concentration (PAC). The introduction of the aldosterone-renin ratio as the screening test for primary aldosteronism led to the recognition of primary aldosteronism patients with normal PAC (nPA). However, there is no information on the risk of primary aldosteronism including nPA. METHOD: In this retrospectively and cross-sectional study, the clinical features and CCV event risk of primary aldosteronism at diagnosis including nPA were investigated and compared with essential hypertension. The study included 292 consecutive primary aldosteronism patients and 498 essential hypertension outpatients. All primary aldosteronism patients were diagnosed by autonomous aldosterone secretion using confirmatory tests, and then divided into nPA (n = 130) and primary aldosteronism patients with high PAC (hPA: n = 162) using a PAC cutoff level of less than 443 pmol/l (16 ng/dl), representing the normal upper limit of PAC. RESULTS: nPA patients were significantly older at diagnosis of primary aldosteronism and at onset of hypertension compared with hPA patients. They had milder hypokalemia and easier-to-control blood pressure. The results suggested that nPA could be considered a mild type of primary aldosteronism but not an early-stage hPA. Moreover, the risk of all CCV events in nPA was significantly lower than that in hPA (odds ratio 0.42, 95% confidence interval 0.18-0.90, P < 0.05) and not significantly higher than that in essential hypertension (odds ratio 0.95, 95% confidence interval 0.43-1.94, P = 0.899). CONCLUSION: This study suggests that aggressive diagnostic workout for nPA is less effective to prevent CCV events.

High efficient and cost-effective screening method for diabetic cardiovascular risk.

BACKGROUND: The vascular complications of outpatients with diabetes at ordinary hospitals vary. Ischemic heart disease is barely predictable after treatment using previously reported therapeutic indices. We developed a simple and noninvasive screening method to evaluate the possibility of ischemic heart disease in patients with diabetes. METHODS: Five years of clinical data from 337 outpatients (196 males and 141 females) with diabetes were analyzed. Twenty-three males and 14 females had ischemic heart disease. We examined the possibility of predicting ischemic heart disease after analyzing this population. The analyzed laboratory data included the following: minimum value of right or left ankle-brachial indices (ABI), maximum value of right or left pulse wave velocities (PWV), aortic calcification diagnosed on plain chest radiographs, plaque score (PS), maximum value of intima media thickness at the cervical artery (IMT), electrocardiographic (ECG) ischemic changes (including ST-T changes or abnormal Q waves, which were re-examined by a cardiologist), HbA1c, low-density lipoprotein cholesterol (LDL-C), uric acid (UA), urine albumin, age, sex, disease duration, and body mass index. All data were subjected to multivariate logistic regression analyses. RESULTS: The presence of ECG ischemic changes, aortic calcification, minimum ABI, maximum IMT, LDL-C, and UA were evaluated in multivariate logistic regression analysis with the onset of ischemic heart disease. The receiver operating characteristic curve indicated an area under the curve of 0.879 (0.820 - 0.938; P = 0.00). CONCLUSIONS: Ischemic heart disease could be predicted in patients with diabetes using a combination of results from conventional physical and laboratory tests.

Perceptions about disability among Ghanaian university students.

An exploratory/descriptive study was conducted on a sample of university students, including 305 social work and sociology majors, in Ghana to evaluate their attitudes toward disabilities. The findings indicate that the students in general agree with the idea of community integration and equal rights of persons with disabilities. At the same time, they are ambivalent about characteristics of persons with disabilities and feel uncomfortable interacting with them. Further, a substantive minority holds strong prejudices against persons with disabilities. Universities should provide their students with opportunities to improve knowledge and attitudes about disabilities.

The effect of exposure to a professor with a visible disability on students' attitudes toward disabilities.

An exploratory study was conducted on a small convenience sample of undergraduate social work students. The Modified Issues in Disability Scale was used to collect data on attitudes toward disability. There was no statistically significant difference in the attitudes scores among students who had different levels of contact with persons with disabilities. There was, however, a statistically significant difference between students who had a professor with a disability and those who did not. The former had more positive attitudes toward disability. These findings suggest that schools of social work should recruit more professors with disabilities.

Transcriptional co-factor CDCA4 participates in the regulation of JUN oncogene expression.

CDCA4, a member of the TRIP-Br transcriptional co-factor family, has been shown to possess a unique role in regulating the transcriptional activities of p53 as well as E2F1 transcription factors. In this study, we aimed to identify a pivotal transcriptional target gene regulated by CDCA4, so we suppressed CDCA4 expression by CDCA4-specific short interference RNA (siRNA) in HeLa cells, and then performed a DNA microarray analysis. Among the identified genes, we focused on JUN, 14-3-3eta, and IL6ST (gp130) mRNAs which were up-regulated in CDCA4-specific siRNA-transfected cells compared to control siRNA-transfected cells. We confirmed that JUN, 14-3-3eta, and IL6ST proteins were up-regulated when cells were transfected with CDCA4-specific siRNA. 14-3-3eta and IL6ST protein levels were unchanged upon on transfection of cells with JUN-specific siRNA, indicating that 14-3-3eta and IL6ST genes are not a direct target of JUN. Serine 63 and 73 phosphorylation of JUN was unchanged when cells were transfected with CDCA4-specific siRNA. In addition, JUN-driven reporter activity was unaffected by CDCA4 co-transfection, suggesting that CDCA4 affects solely JUN mRNA expression. Finally, by preparing various JUN promoter reporter constructs, we minimized the JUN promoter sequence that was affected by CDCA4 co-expression. Together, these results add an important role of CDCA4 in the context of transcriptional regulation and cell fate determination through the JUN oncogene.

Systemic glucocorticoid therapy reduces pain and the number of endoneurial tumor necrosis factor-alpha (TNFalpha)-positive mast cells in rats with a painful peripheral neuropathy.

Clinical and experimental evidence suggests that glucocorticoids may be effective in the treatment of neuropathic pain, but their mechanism of action is unknown. We gave triamcinolone (3 mg/kg) to rats with an experimental post-traumatic painful peripheral neuropathy, chronic constriction injury (CCI), five days after nerve injury, when the abnormal pain syndrome is known to be present; and pain sensitivity was measured on postoperative days 7 - 14, a period during which symptoms are known to be at approximately peak severity. Additional CCI rats were treated similarly; and then they were sacrificed five days after the injection for an immunocytochemical analysis of endoneurial tumor necrosis factor-alpha (TNFalpha), macrophages, and mast cells in the sciatic nerve proximal to the site of injury. Vehicle-injected CCI rats demonstrated the expected neuropathic pain symptoms. Triamcinolone-treated CCI rats had a statistically significant reduction in the magnitude of heat-hyperalgesia and mechano-allodynia, but there was no effect on cold-allodynia or mechano-hyperalgesia. On the nerve-injured side of vehicle-injected rats, TNFalpha was present in Schwann cells and mast cells. On the nerve-injured side of triamcinolone-treated rats, there was a significant (71.5%) reduction in the number of TNFalpha-positive mast cells. Our results suggest that glucocorticoid therapy for neuropathic pain may work via the reduced expression of TNFalpha in endoneurial mast cells.

Exploring trends: tracking evaluations data over several months by therapists and parents of children with cerebral palsy.

A pilot study was conducted at the outpatient rehabilitation unit of a children's hospital to explore the overall performance trends of children in daily life as perceived by their parents, compared to the evaluations of therapists. A performance goal was set for each child by his/her therapist and parent at an initial consultation. Over a six-month period, data were collected from the parents of children with cerebral palsy (N = 53), and therapists assessed children at each therapy session as well. The evaluations of both parents and therapists showed statistically significant upward trends in performance over several months.

Transcriptional regulation of human chromatin assembly factor ASF1.

Antisilencing function 1 (ASF1) is a conserved histone chaperone implicated in nucleosome assembly, transcriptional silencing, and the cellular response to DNA damage. Here, we report the identification of human ASF1B, but not ASF1A, as a direct transcriptional target of transcription factor E2F1. We demonstrated that overexpression of E2F1 by adenoviral-mediated gene transfer upregulated ASF1B mRNA expression in HeLa cells. Analysis of human ASF1B promoter constructs showed that an E2F-responsive sequence was necessary for E2F1-induced activation of the ASF1B gene transcription. Oligonucleotides including an E2F consensus sequence were specifically bound by E2F1 protein in vitro. Chromatin immunoprecipitation analysis demonstrated that E2F1 bound to an E2F-responsive sequence of the human ASF1B gene. Among the members of the E2F family, E2F1 to E2F5, but not E2F6, activated the ASF1B reporter construct. Sp1 and NFYA failed to induce the activity of the ASF1A and ASF1B promoter. ASF1A and ASF1B mRNA were upregulated by serum stimulation. Taken together, our results suggest that the expression of human ASF1A and ASF1B are upregulated followed by cell proliferation signal, but that of ASF1B is uniquely regulated by transcription factors E2F during cell cycle progression.

A combined computational and experimental study on the structure-regulation relationships of putative mammalian DNA replication initiator GINS.

GINS, a heterotetramer of SLD5, PSF1, PSF2, and PSF3 proteins, is an emerging chromatin factor recognized to be involved in the initiation and elongation step of DNA replication. Although the yeast and Xenopus GINS genes are well documented, their orthologous genes in higher eukaryotes are not fully characterized. In this study, we report the genomic structure and transcriptional regulation of mammalian GINS genes. Serum stimulation increased the GINS mRNA levels in human cells. Reporter gene assay using putative GINS promoter sequences revealed that the expression of mammalian GINS is regulated by 17beta-Estradiol-stimulated estrogen receptor alpha, and human PSF3 acts as a gene responsive to transcription factor E2F1. The goal of this study is to present the current data so as to encourage further work in the field of GINS gene regulation and functions in mammalian cells.