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.

Growth hormone increase by luteinizing hormone-releasing hormone reflects gonadotroph-related characteristics in acromegaly.

PURPOSE: We previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly. METHODS: The clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared. RESULTS: No differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression. CONCLUSIONS: The increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors.

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.

Transforming growth factor ß1 signaling links extracellular matrix remodeling to intracellular lipogenesis upon physiological feeding events.

Adipose tissue dynamically changes its mass in response to external nutritional status, which plays an important role in maintaining the lipid homeostasis. Physiologically, feeding events are associated with the expansion of adipose tissue, but little is known about the detailed molecular mechanisms of this expansion. Here, using comprehensive transcriptome analysis, we found that levels of transforming growth factor ß1 (TGF-ß1), a key regulator of extracellular matrix (ECM) remodeling, were increased in adipose tissue under feeding conditions and associated with the lipogenic pathway. In addition, TGF-ß receptors are highly expressed in adipose tissue, and pharmacological inhibition of TGF-ß1 reduced adipose tissue mass and caused ectopic lipid accumulation in the liver. This reduced fat mass was associated with decreased gene expression in ECM remodeling and lipogenesis. Furthermore, similar results were observed in the adipose tissue of SMAD family member 3 knockout mice or upon systemic TGF-ß neutralization, with significant reductions in both ECM remodeling and lipogenesis-related genes. Mechanistically, we found that insulin-induced TGF-ß1 and cell-autonomous action remodels the ECM of adipocytes, which controls the downstream focal adhesion kinase-AKT signaling cascades and enhances the lipogenic pathway. Of note, destruction of collagens or matrix metalloproteinase/a disintegrin and metalloprotease activities, critical components of ECM remodeling, blocked TGF-ß1-mediated focal adhesion kinase-AKT signaling and the lipogenic pathway. Taken together, this study identifies a previously unknown lipogenic role of TGF-ß1 by which adipocytes can expand to adapt to physiological feeding 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.

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.

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.

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.

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.

Glutamine deficiency induces lipolysis in adipocytes.

Glutamine is the most abundant amino acid in the body, and adipose tissue is one of the glutamine-producing organs. Glutamine has important and unique metabolic functions; however, its effects in adipocytes are still unclear. 3T3-L1 adipocytes produced and secreted glutamine dependent on glutamine synthetase, but preadipocytes did not. The inhibition of glutamine synthetase by l-methionine sulfoximine (MSO) impaired the differentiation of preadipocytes to mature adipocytes, and this inhibitory effect of MSO was rescued by exogenous glutamine supplementation. Glutamine concentrations were low, and Atgl gene expression was high in epididymal white adipose tissues of fasting mice in vivo. In 3T3-L1 adipocytes, glutamine deprivation induced Atgl expression and increased glycerol concentration in culture medium. Atgl expression is regulated by FoxO1, and glutamine deprivation reduced FoxO1 phosphorylation (Ser256), indicating the activation of FoxO1. These results demonstrate that glutamine is necessary for the differentiation of preadipocytes and regulates lipolysis through FoxO1 in mature adipocytes.

Memory effect of external oscillation on residual stress in a paste.

We numerically investigate the stress distribution of a paste when an external oscillation is applied. The paste memorizes the oscillation through plastic deformation. Due to the plastic deformation, the residual stress remains after the oscillation, where the residual stress distribution depends on the number of cycles in the oscillation. As this number increases, the symmetry of the stress distribution is enhanced, which is consistent with the crack patterns observed in the experiments using a drying paste.

Shear modulus and reversible particle trajectories of frictional granular materials under oscillatory shear.

In this study, we numerically investigated the mechanical responses and trajectories of frictional granular particles under oscillatory shear in the reversible phase where particle trajectories form closed loops below the yielding point. When the friction coefficient is small, the storage modulus exhibits softening, and the loss modulus remains finite in the quasi-static limit. As the friction coefficient increases, the softening and residual loss modulus are suppressed. The storage and loss moduli satisfy scaling laws if they are plotted as functions of the areas of the loop trajectories divided by the strain amplitude and diameter of grains, at least for small values of the areas.

Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society.

Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism.

CONTEXT: The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature. OBJECTIVE: We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone. DESIGN AND PATIENTS: We retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35-40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS. MAIN OUTCOME MEASURE: Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years. RESULTS: Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35-40 years and 69% (198/289) in those aged ≥40 years (trend for P < .01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35-40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35-40 years. CONCLUSION: Primary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.

Relaxation Dynamics of a Granular Pile on a Vertically Vibrating Plate.

Nonlinear relaxation dynamics of a vertically vibrated granular pile is experimentally studied. In the experiment, the flux and slope on the relaxing pile are measured by using a high-speed laser profiler. The relation of these quantities can be modeled by the nonlinear transport law assuming the uniform vibrofluidization of an entire pile. The fitting parameter in this model is only the relaxation efficiency, which characterizes the energy conversion rate from vertical vibration into horizontal transport. We demonstrate that this value is a constant independent of experimental conditions. The actual relaxation is successfully reproduced by the continuity equation with the proposed model. Finally, its specific applicability toward an astrophysical phenomenon is shown.

TSH ratio as a novel diagnostic method for Cushing's syndrome.

Circadian variations impact thyrotropin (TSH) secretion; in Cushing's syndrome (CS) patients, the nocturnal serum TSH surge is abolished. The aim of this prospective study is to examine whether serum TSH surge may be a useful diagnostic method for CS. This prospective study recruited 136 inpatients for differential diagnosis of CS or subclinical CS (SCS), and 21 inpatients with depression at Osaka University Hospital. Serum TSH surge was assessed by the midnight-to-morning serum TSH ratio (2300-2400 h to 0800-0900 h). The diagnostic accuracy (sensitivity and specificity) between TSH ratio and ordinary screening tests [low-dose dexamethasone suppression test (LDDST), late-night serum cortisol and urine free cortisol (UFC)] were compared. Twenty-two patients were diagnosed as CS (12 overt CS and 10 SCS) and the remaining 120 patients were excluded for CS. The diagnostic accuracy of TSH ratio (cutoff value 1.0) yielded sensitivity 90.9% [95% confidence interval (CI) 70.8-98.9], specificity 95.0% (95% CI 89.4-98.1), and a high positive and low negative likelihood ratio [18.2 (95% CI 8.2-40.1) and 0.096 (95% CI 0.026-0.359), respectively]. The specificity of TSH ratio was significantly higher than LDDST and midnight serum cortisol test. The sensitivity of TSH ratio was significantly higher than UFC. TSH ratio showed more than 1.0 in all patients with depression and CYP3A4 inducer users. TSH ratio is a novel supportive diagnostic method with higher specificity than the current diagnostic methods for CS.

New diagnostic criteria of adrenal subclinical Cushing's syndrome: opinion from the Japan Endocrine Society.

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 µg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 µg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 µg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 µg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 µg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 µg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging.

Collective Motion of Repulsive Brownian Particles in Single-File Diffusion with and without Overtaking.

Subdiffusion is commonly observed in liquids with high density or in restricted geometries, as the particles are constantly pushed back by their neighbors. Since this "cage effect" emerges from many-body dynamics involving spatiotemporally correlated motions, the slow diffusion should be understood not simply as a one-body problem but as a part of collective dynamics, described in terms of space-time correlations. Such collective dynamics are illustrated here by calculations of the two-particle displacement correlation in a system of repulsive Brownian particles confined in a (quasi-)one-dimensional channel, whose subdiffusive behavior is known as the single-file diffusion (SFD). The analytical calculation is formulated in terms of the Lagrangian correlation of density fluctuations. In addition, numerical solutions to the Langevin equation with large but finite interaction potential are studied to clarify the effect of overtaking. In the limiting case of the ideal SFD without overtaking, correlated motion with a diffusively growing length scale is observed. By allowing the particles to overtake each other, the short-range correlation is destroyed, but the long-range weak correlation remains almost intact. These results describe nested space-time structure of cages, whereby smaller cages are enclosed in larger cages with longer lifetimes.

Regulation of Dipeptidyl Peptidase-4, its Substrate Chemokines, and Their Receptors in Adipose Tissue of ob/ob Mice.

The physiological function of DPP-4 in proteolytic inactivation of incretins has been well established, however, there is limited information on the expression and the significance of DPP-4 in white adipose tissue with regard to obesity. The objective of the work was to reveal the expression and regulation of DPP-4 in adipocytes and compare the expression and activity of DPP-4 in white adipose tissue and several other organs such as the liver, muscle and kidney. We also investigated the gene expression levels of DPP-4 substrate chemokines, and their receptors in white adipose tissue. DPP-4 was mainly expressed in stromal vascular fraction (SVF), and downregulated in adipose tissue of ob/ob compared with C57BL6/J mice. Mimetic conditions of obese fat in vitro showed that differentiation of mouse primary preadipocytes into adipocytes was associated with marked downregulation of DPP-4 expression. Treatment with TNF-α or ROS even decreased DPP-4 expression in mouse primary adipocytes. Various DPP-4 substrate chemokines were expressed in white adipose tissue and regulated by obesity. The expression of receptors for DPP-4 substrate chemokines was markedly high and tightly regulated by obesity in white adipose tissue. Expression of DPP-4 was reduced in adipose tissues of ob/ob mice. Actions of several substrate chemokines might be potentiated by downregulation of DPP-4, synergistically with upregulation of chemokines and their receptors in adipose tissues of obese mice.