Appearance of fluid content in Rathke's cleft cyst is associated with clinical features and postoperative recurrence rates.

PURPOSE: The contents of Rathke's cleft cysts (RCCs) vary from clear and slightly viscous to purulent. Surgical treatment of symptomatic RCCs involves removing the cyst contents, whereas additional cyst-wall opening to prevent reaccumulation is at the surgeon's discretion. The macroscopic findings of the cyst content can reflect the nature of RCCs and would aid in surgical method selection. METHODS: We retrospectively reviewed the records of 42 patients with symptomatic RCCs who underwent transsphenoidal surgery at our institute between January 2010 and March 2022. According to the intraoperative findings, cyst contents were classified into type A (purulent), type B (turbid white with mixed semisolids), or type C (clear and slightly viscous). Clinical and imaging findings and early recurrence rate (within two years) were compared according to the cyst content type. RESULTS: There were 42 patients classified into three types. Patients with type C were the oldest (65.4 ± 10.4 years), and type A included more females (92.9%). For magnetic resonance imaging, type-A patients showed contrast-enhanced cyst wall (92.9%), type-B patients had intracystic nodules (57.1%), and all type-C patients showed low T1 and high T2 intensities with larger cyst volumes. Fewer asymptomatic patients had type C. Preoperative pituitary dysfunction was most common in type A (71.4%). Early recurrence was observed in types A and C, which were considered candidates for cyst-wall opening. CONCLUSION: The clinical characteristics and surgical prognosis of RCCs depend on the nature of their contents.

Primary aldosteronism patients with previous cardiovascular and cerebrovascular events have high aldosterone responsiveness to ACTH stimulation.

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989-8.482; ΔPAC: OR, 2.344; 95% CI, 1.149-4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694-6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.Registration Number in UMIN-CTR is UMIN000032525.

Diagnosis and management of adrenal incidentaloma: use of clinical judgment and evidence in dialog with the patient.

The prevalence of adrenal incidentaloma (AI) in imaging studies, including those of the adrenal glands, is estimated to be 1-5%. Essential factors for the proper management of AI include a correct diagnosis, adequate surgical skills, appropriate perioperative management, and sound dialogue with the patient. Aside from the possibility of overdiagnosis, patients with apparent signs or symptoms attributable to adrenal hormone excess have reasonable indications for surgery. At the same time, milder patients may be candidates for active surveillance without intervention. Even individuals with nonfunctioning AI may benefit from surgery if imaging studies depict the tumor as suggestive of malignancy. However, a differential diagnosis of AI may not be easy for surgeons with little experience in seeing such patients.Furthermore, a patient without a correct diagnosis may miss the window of opportunity for a cure or incur a greater risk of developing complications, such as adrenal insufficiency or cardiovascular events during or after surgery, due to inadequate management. The clinical practice guidelines for AI from around the world may be helpful for shared decision-making; however, Japan lacks established guidelines. In this review article, we propose practical guidelines relevant to management by summarizing the evidence for five key questions that are often asked in dialog with patients with AI.

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.

A Rare Case of Placental Abruption and Postpartum Compression Fractures in Pregnancy With Cushing Syndrome.

Cushing syndrome (CS) is a disorder rarely found during pregnancy. Patients with CS usually receive treatment before pregnancy. In addition, hypercortisolism suppresses gonadotropins, leading to amenorrhea or irregular menstruation. Therefore, few reports have described cases of pregnancy with untreated CS. Here, we observed the changes in the cortisol level of a 38-year-old woman with adrenal CS before and throughout pregnancy and delivery. She also had primary aldosteronism, and we were able to follow her plasma aldosterone levels. Her symptoms of CS before pregnancy were submandibular acne and irregular menstruation, but after conception, "moon face" and fatigue appeared. Laboratory tests also revealed impaired glucose tolerance, hypokalemia, lymphocytopenia, and increased urinary free cortisol levels. After administration of metyrapone to ameliorate her general condition, laparoscopic adrenalectomy was performed in the nineteenth week of pregnancy. After the operation, the patient's symptoms improved, and the cortisol level was maintained with hydrocortisone supplementation. The patient's plasma aldosterone level and blood pressure did not deteriorate throughout the course. However, the delivery was complicated by placental abruption. One month after delivery, the mother presented with compression fractures. We review the literature and discuss the treatment and complications of pregnancy with CS.

Theory of rigidity and numerical analysis of density of states of two-dimensional amorphous solids with dispersed frictional grains in the linear response regime.

Using the Jacobian matrix, we obtain a theoretical expression of rigidity and the density of states of two-dimensional amorphous solids consisting of frictional grains in the linear response to an infinitesimal strain, in which we ignore the dynamical friction caused by the slip processes of contact points. The theoretical rigidity agrees with that obtained by molecular dynamics simulations. We confirm that the rigidity is smoothly connected to the value in the frictionless limit. We find that there are two modes in the density of states for sufficiently small k_{T}/k_{N}, which is the ratio of the tangential to normal stiffness. Rotational modes exist at low frequencies or small eigenvalues, whereas translational modes exist at high frequencies or large eigenvalues. The location of the rotational band shifts to the high-frequency region with an increase in k_{T}/k_{N} and becomes indistinguishable from the translational band for large k_{T}/k_{N}.

Eigenvalue analysis of stress-strain curve of two-dimensional amorphous solids of dispersed frictional grains with finite shear strain.

The stress-strain curve of two-dimensional frictional dispersed grains interacting with a harmonic potential without considering the dynamical slip under a finite strain is determined by using eigenvalue analysis of the Hessian matrix. After the configuration of grains is obtained, the stress-strain curve based on the eigenvalue analysis is in almost perfect agreement with that obtained by the simulation, even if there are plastic deformations caused by stress avalanches. Unlike the naive expectation, the eigenvalues in our model do not indicate any precursors to the stress-drop events.

An exact expression of three-body system for the complex shear modulus of frictional granular materials.

We propose a simple model comprising three particles to study the nonlinear mechanical response of jammed frictional granular materials under oscillatory shear. Owing to the introduction of the simple model, we obtain an exact analytical expression of the complex shear modulus for a system including many monodispersed disks, which satisfies a scaling law in the vicinity of the jamming point. These expressions perfectly reproduce the shear modulus of the many-body system with low strain amplitudes and friction coefficients. Even for disordered many-body systems, the model reproduces the results by introducing a single fitting parameter.

Static friction coefficient depends on the external pressure and block shape due to precursor slip.

Amontons' law states that the maximum static friction force on a solid object is proportional to the loading force and is independent of the apparent contact area. This law indicates that the static friction coefficient does not depend on the external pressure or object shape. Here, we numerically investigate the sliding motion of a 3D viscoelastic block on a rigid substrate using the finite element method (FEM). The macroscopic static friction coefficient decreases with an increase in the external pressure, length, or width of the object, which contradicts Amontons' law. Precursor slip occurs in the 2D interface between the block and substrate before bulk sliding. The decrease in the macroscopic static friction coefficient is scaled by the critical area of the precursor slip. A theoretical analysis of the simplified models reveals that bulk sliding results from the instability of the quasi-static precursor slip caused by velocity-weakening local friction. We also show that the critical slip area determines the macroscopic static friction coefficient, which explains the results of the FEM simulation.

Favine/CCDC3 deficiency accelerated atherosclerosis and thrombus formation is associated with decreased MEF2C-KLF2 pathway.

Currently, no mouse models manifest calcification and thrombus formation, which is frequently associated with human atherosclerosis. We demonstrated that lack of Favine/CCDC3 in apoE knockout mice accelerated atherosclerosis accompanied by large cholesterol crystals and calcification, and also promoted thrombus formation in the left ventricle and arteries. Circulating Favine was detectable in WT mouse plasma. RNA-sequencing analysis of aortae in DKO mice showed similar gene expression patterns of human atherosclerosis with unstable and vulnerable plaques. Importantly, human FAVINE mRNA expressions were lower in atheroma plaque than in adjacent intact aortic tissue and decreased with the progression of atherosclerosis. Pathway analysis of aortae in DKO mice suggested the decrease of the MEF2C-KLF2-mediated transcriptional pathway. Favine insufficiency and its attenuated downstream pathways may increase atherosclerosis progression with calcification and thrombus, which have not previously been fully modeled in experimental animals. Favine and its downstream pathways may have therapeutic potential for atherosclerosis.

Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision).

Congenital adrenal hyperplasia is a category of disorders characterized by impaired adrenocortical steroidogenesis. The most frequent disorder of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is caused by pathogenic variants of CAY21A2 and is prevalent between 1 in 18,000 and 20,000 in Japan. The clinical guidelines for 21-hydroxylase deficiency in Japan have been revised twice since a diagnostic handbook in Japan was published in 1989. On behalf of the Japanese Society for Pediatric Endocrinology, the Japanese Society for Mass Screening, the Japanese Society for Urology, and the Japan Endocrine Society, the working committee updated the guidelines for the diagnosis and treatment of 21-hydroxylase deficiency published in 2014, based on recent evidence and knowledge related to this disorder. The recommendations in the updated guidelines can be applied in clinical practice considering the risks and benefits to each patient.

ARMC5-CUL3 E3 ligase targets full-length SREBF in adrenocortical tumors.

Inactivating mutations of ARMC5 are responsible for the development of bilateral macronodular adrenal hyperplasia (BMAH). Although ARMC5 inhibits adrenocortical tumor growth and is considered a tumor-suppressor gene, its molecular function is poorly understood. In this study, through biochemical purification using SREBF (SREBP) as bait, we identified the interaction between SREBF and ARMC5 through its Armadillo repeat. We also found that ARMC5 interacted with CUL3 through its BTB domain and underwent self-ubiquitination. ARMC5 colocalized with SREBF1 in the cytosol and induced proteasome-dependent degradation of full-length SREBF through ubiquitination. Introduction of missense mutations in Armadillo repeat of ARMC5 attenuated the interaction between SREBF, and introduction of mutations found in BMAH completely abolished its ability to degrade full-length SREBF. In H295R adrenocortical cells, silencing of ARMC5 increased full-length SREBFs and upregulated SREBF2 target genes. siARMC5-mediated cell growth was abrogated by simultaneous knockdown of SREBF2 in H295R cells. Our results demonstrate that ARMC5 was a substrate adaptor protein between full-length SREBF and CUL3-based E3 ligase, and they suggest the involvement of the SREBF pathway in the development of BMAH.

Ketone body 3-hydroxybutyrate enhances adipocyte function.

Ketone bodies, including 3HBA, are endogenous products of fatty acid oxidation, and Hmgcs2 is the first rate-limiting enzyme of ketogenesis. From database analysis and in vivo and in vitro experiments, we found that adipose tissue and adipocytes express Hmgcs2, and that adipocytes produce and secrete 3HBA. Treatment with 3HBA enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors in adipose tissue in vivo and in adipocytes in vitro, accompanied by reduced ROS levels. Knockdown of endogenous Hmgcs2 in adipocytes markedly decreased 3HBA levels in adipocytes and decreased the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors with increased ROS levels. Conversely, overexpression of Hmgcs2 in adipocytes increased 3HBA secretion from adipocytes and enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors. These results demonstrate that 3HBA plays significant roles in enhancing the physiological function of adipocytes.

Association of cardiovascular disease risk and changes in renin levels by mineralocorticoid receptor antagonists in patients with primary aldosteronism.

A recent report stated that patients with primary aldosteronism who remain renin suppressed during mineralocorticoid receptor antagonist treatment might have a higher risk of developing cardiovascular disease than those with unsuppressed renin activity. We retrospectively investigated the incidence of composite cardiovascular disease and risk factors for cardiovascular disease in 1115 Japanese patients with primary aldosteronism treated with mineralocorticoid receptor antagonists. The median follow-up period was 3.0 years, and the incidence of cardiovascular events was very low (2.1%) throughout 5 years of follow-up. Changes in plasma renin activity from before to after mineralocorticoid receptor antagonist treatment were divided into three groups based on tertile, low, intermediate, and high plasma renin activity change groups, with incidences of cardiovascular disease events of 2.1%, 0.5%, and 3.7%, respectively. Multivariate Cox regression analysis revealed age (adjusted hazard ratio, 1.07; 95% confidence interval, [1.02-1.12]) and body mass index (adjusted hazard ratio, 1.13 [1.04-1.23]) as independent risk factors for cardiovascular disease. The high plasma renin activity change group had significantly higher cardiovascular disease risk with mineralocorticoid receptor antagonist treatment than the intermediate plasma renin activity change group (adjusted hazard ratio, 5.71 [1.28-25.5]). These data suggest that a high change in renin level after mineralocorticoid receptor antagonist treatment may not necessarily predict a better prognosis of cardiovascular disease in patients with primary aldosteronism.

Softening and Residual Loss Modulus of Jammed Grains under Oscillatory Shear in an Absorbing State.

From a theoretical study of the mechanical response of jammed materials comprising frictionless and overdamped particles under oscillatory shear, we find that the material becomes soft, and the loss modulus remains nonzero even in an absorbing state where any irreversible plastic deformation does not exist. The trajectories of the particles in this region exhibit hysteresis loops. We succeed in clarifying the origin of the softening of the material and the residual loss modulus with the aid of Fourier analysis. We also clarify the roles of the yielding point in the softening to distinguish the plastic deformation from reversible deformation in the absorbing state.

Lactate dehydrogenase regulates basal glucose uptake in adipocytes.

Plasma glucose levels are homeostatically regulated within strict boundaries and are maintained through a balance between peripheral glucose uptake and hepatic glucose production. However, little is known about the regulatory mechanism of glucose uptake in adipocytes during fasting. Under fasting conditions, the expression levels of 8 glycolytic enzymes were significantly reduced in adipose tissue. Among them, we focused on lactate dehydrogenase A (LDHA), the last enzyme of the glycolytic pathway. Under fasting conditions, both LDHA and Glut1 protein levels tended to decrease in adipose tissue. To elucidate the significance of LDHA in adipocytes, we generated adipocyte-specific LDHA knockout mice (AdLDHAKO) for the first time. AdLDHAKO mice showed no apparent changes in body weight or tissue weight. Under fasting conditions, AdLDHAKO mice exhibited a significant reduction in Glut1 protein levels and glucose uptake in adipose tissues compared with control mice. Similarly, siRNA of LDHA in 3T3-L1 adipocytes reduced Glut1 protein levels and basal glucose uptake. Moreover, treatment with bafilomycin A1, an inhibitor of lysosomal protein degradation, restored Glut1 protein levels by siRNA of LDHA. These results indicate that LDHA regulates Glut1 expression and basal glucose uptake in adipocytes.

Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

Plasma NfL is associated with mild cognitive decline in patients with diabetes.

BACKGROUND: Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes neural axons. Plasma NfL levels are elevated when neurodegeneration occurs. Here, we investigated whether plasma NfL levels were associated with cognitive decline in patients with type 2 diabetes. METHOD: This study included 183 patients with type 2 diabetes who visited Osaka University Hospital. All participants were tested for cognitive function using the Mini-Mental State Examination (MMSE) and the Rivermead Behavioural Memory Test (RBMT). NfL levels were analysed in the plasma and the relationship between NfL and cognitive function was examined. RESULTS: Lower RBMT-standardized profile scores (SPS) or MMSE scores correlated with higher plasma NfL levels (one-way analysis of variance: MMSE, P = 0.0237; RBMT-SPS, P = 0.0001). Furthermore, plasma NfL levels (ß = -0.34, P = 0.0005) and age (ß = -0.19, P = 0.016) were significantly associated with the RBMT score after multivariable regression adjustment. CONCLUSIONS: Plasma NfL levels were correlated with mild cognitive decline which is detected by the RBMT but not the MMSE in patients with type 2 diabetes. This suggests that plasma NfL levels may provide a valuable clinical tool for identifying mild cognitive decline in patients with diabetes.

Sex Difference in the Association of Osteoporosis and Osteopenia Prevalence in Patients with Adrenal Adenoma and Different Degrees of Cortisol Excess.

Objective: Osteoporosis and osteopenia (OS/OP) are frequent in patients with adrenal adenomas associated with cortisol excess (CE). However, the relationship between OS/OP and CE severity considering sex differences is unknown. Design: A cross-sectional observational study from January 2006 to December 2015. Patients. 237 patients with adrenal adenoma associated with CE, including Cushing's syndrome and mild autonomous cortisol secretion (MACS), diagnosed in 10 referral centers in Japan. MACS was defined by 1 mg overnight dexamethasone suppression test (DST) cortisol level >1.8 µg/dL. Measurements. Prevalence of fragility fractures, medication for osteoporosis, and bone mineral density. Results: In total, 112 of 237 patients, who were predominantly female (P < 0.001) and had lower BMI (P=0.013), had OS/OP. Patients with OS/OP was significantly affected by CE (P < 0.01) than those without. The adjusted odds ratio (OR) for predicting OS/OP was obtained in multivariate logistic regression analysis. Clinical measures of CE, 1 mg DST cortisol levels, were positively associated with OS/OP in total cases (OR 1.124, 95% CI: 1.070-1.181, P < 0.001) and the cases with MACS (OR 1.156, 95%CI: 1.046-1.278, P=0.005). A cutoff value of 1 mg DST cortisol level >5.0 µg/dL was associated with OS/OP differently between men and women. OS/OP risk in men with MACS was significantly affected only by 1 mg DST cortisol levels. However, OS/OP risk in women with MACS was significantly affected by 1 mg DST cortisol levels and age. Conclusions: CE severity in adrenal adenoma is positively associated with OS/OP. However, the associated factors of OS/OP in the patients with MACS are different between men and women.