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Although excess production of androgens and glucocorticoids has often been observed in adrenocortical carcinomas, adrenocortical adenoma with such hormonal activity is rare. Herein, we report a 41-year-old woman who presented with hyperandrogenemia and mild autonomous cortisol secretion with an undetectable level of adrenocorticotropic hormone. Imaging demonstrated a 6 cm left adrenal tumor. The histologic diagnosis of the resected adrenal tumor was adrenocortical adenoma. Pre- and post-operative serum samples were used for steroid profiling with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis of pre-operative serum revealed an abnormal buildup of steroid precursors and androgens. Importantly, circulating levels of 11-oxygenated androgens, including 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), were highly elevated. Both androgen and glucocorticoid levels significantly decreased post-operatively. Immunohistochemical analysis of steroidogenic enzymes and cofactor protein supported the tumor's ability to directly produce 11OHT and 11KT. This study is the first to describe and characterize an adrenocortical adenoma that co-secretes glucocorticoids and 11-oxygenated androgens. Significance statement Due to its rarity, biochemical and histologic characteristics of androgen and glucocorticoid co-secreting adrenocortical adenomas are largely unknown. Herein, we report a case of adrenocortical adenoma that caused marked hyperandrogenemia and mild autonomous cortisol secretion. In this study, we investigated serum steroid profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and histologic characteristics of the resected tumor. LC-MS/MS revealed highly elevated levels of 11-oxygenated androgens which have not been well studied in adrenal tumors. The expression patterns of steroidogenic enzymes determined by immunohistochemistry supported the results of steroid profiling and suggested the capacity of the tumor cells to produce 11-oxygenated androgens. Measurement of 11-oxygenated steroids should facilitate a better understanding of androgen-producing adrenocortical neoplasms.

It is difficult to predict the development of carotid stenosis by means of the known risk factors. Using a computational fluid dynamics analysis, we examined the hemodynamic risks for carotid stenosis, focusing on wall shear stress (WSS) disturbances.In 59 patients with unilateral carotid stenosis, the plaque was removed from the original three-dimensional computed tomography angiographic images, and the vessel shape before stenosis was artificially reproduced. A multivariate regression analysis was performed to determine the associations between the degree of area stenosis and hemodynamic and morphologic factors after adjustment for 6 known risk factors.Metrics for WSS disturbances were higher at and distal to a bifurcation in the carotid arteries after plaque removal compared with the normal carotid arteries, and metrics for WSS magnitudes were lower. In the plaque-removed arteries, the degree of stenosis was significantly negatively correlated with the ratio of stenotic to distal values of metrics for WSS disturbances and the diameter ratio of the external to common carotid artery, and positively correlated with the ratio of proximal to stenotic values of metrics for WSS magnitudes.Rapid increases in WSS from the common carotid artery toward the bifurcation, rapid decreases in WSS disturbance from the bifurcation toward the internal carotid artery, and lower diameter ratio of the external to common carotid artery are more likely than other risk factors to cause future severe stenosis. In patients with these hemodynamic risks, underlying diseases should be controlled more strictly, with imaging examinations at shorter intervals.

Background Methods that facilitate muscle quality measurement may improve the diagnosis of sarcopenia. Current research has focused on the phase angle (PhA) obtained through bioelectrical impedance analysis (BIA) as an indicator of cellular health, particularly cell membrane integrity and cell function. The current study therefore aimed to evaluate the relationship between the PhA and muscle quality and muscle‐related parameters and to determine factors associated with the PhA. Moreover, we attempted to determine the cut‐off value of PhA for predicting sarcopenia. Methods First‐year university students (830 male students, 18.5 ± 0.6 years old; 422 female students, 18.3 ± 0.5 years old) and community‐dwelling elderly individuals (70 male individuals, 74.4 ± 5.5 years old; 97 female individuals, 73.1 ± 6.4 years old) were included. PhA and other body composition data were measured using BIA, while muscle quality was calculated by dividing handgrip strength by upper limbs muscle mass. The relationship between PhA and the aforementioned parameters were then analysed, after which the cut‐off value of PhA for predicting sarcopenia was examined. Results Multiple linear regression analysis revealed that age, skeletal muscle mass index (SMI), and muscle quality were independently associated with PhA in both sexes [male (age: standardized regression coefficient (β) = −0.43, P

Smoking is associated with the deteriorating health of the gingiva and periodontium. The long-term beneficial effects of smoking cessation on oral health are well known. However, the effects of short-term smoking cessation on gingival bleeding and periodontal pocket depth are unknown. The purpose of the present study was to determine the effects of short-term smoking cessation on gingival bleeding and periodontal pocket depth.Dentate smokers with a mean age of 56.9 ± 14.4 years at an outpatient smoking cessation clinic participated in this study. A professional dentist checked the periodontal pocket depth and gingival bleeding. Patients visited the smoking cessation clinic on their first visit and 2, 4, 8, and 12 weeks (three months). The gingival assessment was re-performed in those who succeeded in smoking cessation 3 months after the baseline.The baseline data of 83 patients showed that an increase in pocket depth was associated with increasing age and the amount of smoking. A significant increase in gingival bleeding (Short-term smoking cessation increased periodontal pocket depth and gingival bleeding. These findings may reflect healing processes that occur in the healthy gingiva.Study findings will be useful to advise patients during smoking cessation programs. Dentists can inform patients that an initial increase in gingival bleeding and pocket depth could be associated with smoking cessation. Such advice will prevent patients from any apprehension that may cause them to recommence smoking.

Background and Objective Although older patients with coronavirus disease 2019 (COVID-19) are at the high risk of exacerbation that requires treatment with remdesivir, the safety of this medication is unclear in clinical practice, especially among older patients. We aimed to retrospectively evaluate the safety of remdesivir in older patients with COVID-19 who required hospitalization in our institute. Methods We reviewed patients with COVID-19 who were treated with remdesivir at our institute between July 2020 and May 2021. We defined older patients as those aged 80 years or older at admission; all other patients were defined as younger patients. We evaluated the safety of remdesivir by examining the incidence of discontinuation of remdesivir treatment because of adverse events and the incidence of any adverse events. Results A total of 80 patients were included in this study. Compared with younger patients, fewer older patients were treated with remdesivir for more than 5 days: 4 (15.4%) vs 23 (42.6%). Discontinuation of remdesivir because of adverse events occurred in one older patient (3.9%) and four younger patients (7.4%) [p > 0.99]. Remdesivir-induced liver dysfunction was the most frequent adverse event, which occurred in 29 (36.3%) patients. There were no significant differences in the incidence of remdesivir-induced liver dysfunction, renal dysfunction, and fatigue. Conclusions The safety of remdesivir was suggested to be comparable between patients older than 80 years of age and patients younger than 80 years of age. The results of this study may encourage the administration of remdesivir to this older patient group.

OBJECTIVE A unique clinical course was observed in a patient with resistance to thyroid hormone β (RTHβ) caused by a variant of the THRB gene leading to the replacement of glycine with arginine in codon 347 (p.G347R). He presented with the syndrome of inappropriate secretion of thyrotropin (TSH) (free T4 [fT4]: 32.43 pmol/L, TSH: 4.67 mIU/L), but slowly developed progressive hypothyroidism (fT4: 8.37 pmol/L, TSH: 100.90 mIU/L) that resolved after suspending bezafibrate (BZ) treatment (fT4: 32.18 pmol/L, TSH: 7.14 mIU/L). This study clinically and experimentally evaluated this interesting phenomenon. METHODS A retrospective cohort analysis of non-RTHβ patients was performed at Kyoto University Hospital. Data before BZ treatment were compared to the first data after treatment. Using reporter assays of iodothyronine deiodinases (DIO1, DIO2, DIO3) in HEK293T cells, we performed functional analyses of mutant thyroid hormone receptor β with p.G347R (G347R TRβ). Mice with G347R TRβ were generated by hydrodynamic gene delivery. RESULTS In non-RTHβ patients (n = 7), BZ treatment did not change serum free T3 and TSH but significantly increased fT4 (p = .008). BZ administration increased DIO3 reporter activity in the context of G347R TRβ, whereas did not change DIO1 and DIO2 reporter activity. In the livers of mice with G347R TRβ, BZ administration increased reverse T3 content, which corresponded to an increase in Dio3 messenger RNA. CONCLUSIONS While hypothyroidism associated with BZ treatment did not occur in non-RTHβ patients, it was observed in a patient with RTHβ due to the p.G347R variant. Liver DIO3 upregulation might involve this hypothyroidism.

OBJECTIVE Primary aldosteronism has two main clinically and biologically distinct subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). We aimed to evaluate the changes of each subtype's clinical characteristics over a 13-year period. METHODS This retrospective study involved time-trend analyses to identify changes in the clinical features of APA and BAH at diagnosis (2006-2018). A nationwide database from 41 Japanese referral centers was searched, which identified 2804 primary aldosteronism patients with complete baseline information and adrenal venous sampling (AVS) data. RESULTS The proportion of patients with APA decreased from 51% in 2006-2009 to 22% in 2016-2018. Among the 1634 patients with BAH, trend analyses revealed decreases in hypertension duration (median 7--3 years; P

Context Adrenocorticotropin (ACTH) loading is used to increase the success rate of adrenal vein sampling (AVS). Objective We aimed to determine the effect of intraprocedural cortisol measurement (ICM) on ACTH-stimulated AVS (AS-AVS) owing to a lack of reliable data on this topic. Methods This multicenter, retrospective, observational study took place in 28 tertiary centers in Japan. Among 4057 patients enrolled, 2396 received both basal AVS (B-AVS) and AS-AVS and were divided into 2 groups according to whether ICM was used. The effect of ICM on AS-AVS was measured. Results In patients who underwent both AVS procedures, the ICM group had significantly higher success rates for both B-AVS and AS-AVS than the non-ICM group did. However, the probability of failure of AS-AVS after a successful B-AVS and the probability of success of AS-AVS after a failed B-AVS were not significantly different in the 2 groups. For subtype diagnosis, propensity-score matching revealed no significant difference between the 2 groups, and the discrepancy rate between B-AVS and AS-AVS for subtype diagnosis was also not significantly different. Conclusion ICM significantly increased the success rate of B-AVS and AS-AVS in protocols in which both AVS procedures were performed and had no effect on subtype diagnosis. However, in protocols in which both AVS procedures were performed, the results suggest ICM may not be necessary when performing AS-AVS if ICM is used only when B-AVS is performed. Our study suggests that ICM during AVS plays an important role and should be recommended.

Regulatory mechanisms of iodothyronine deiodinases (DIOs) require further elucidation, and conventional methods for evaluating DIOs are unsuitable for high-throughput screening (HTS). Here we explored factors of transcriptional regulation of 3 types of DIOs (DIO1, DIO2, and DIO3) from a chemical library using our designed HTS. We constructed HTS based on a promoter assay and performed a screen of 2480 bioactive compounds. For compounds that were clinically approved, we validated hit compounds through a retrospective cohort study in our department that evaluated changes in thyroid function in patients using the compounds as drug therapy. Furthermore, we verified the involvement of DIOs using mice treated with the compounds. Of the hit compounds, 6 and 7 compounds transcriptionally up- and downregulated DIO1, respectively; 34 transcriptionally upregulated DIO2; and 5 and 2 compounds transcriptionally up- and downregulated DIO3, respectively. The cohort study clarified the clinical effects of some hit compounds: ritodrine increased free triiodothyronine (fT3)/free thyroxine (fT4) ratio and decreased serum thyroid-stimulating hormone (TSH) levels, tadalafil increased serum fT3 levels, and tyrosine kinase inhibitors (TKIs) decreased serum fT3 and fT4 levels and increased serum TSH levels. Following in vivo experiments using treated mice, consistent results were observed in ritodrine, which upregulated DIO2 in the thyroid gland. In conclusion, we completed HTS for DIOs and obtained attractive hit compounds. Our cohort study revealed the clinical significance of ritodrine, sildenafil, and TKIs. We hope our unique method will contribute to analyzing various targets and lists of hit compounds will promote understanding of DIOs.

Aims Hypertension is a strong risk factor for heart failure with preserved ejection fraction. Curcumin has p300-specific histone acetyltransferase inhibitory activity, suppresses cardiomyocyte hypertrophy and fibrosis, and significantly reduces myocardial brain natriuretic peptide (BNP) expression without altering blood pressure in a rat model of hypertensive heart disease. This double-blind, placebo-controlled, randomized study, for the first time, aimed to examine the efficacy of a high-absorption curcumin for the prevention of hypertensive heart disease in humans. Methods and results Patients exhibiting initial signs of hypertensive heart disease with left ventricular ejection fraction ≥60% and stable blood pressure Conclusions A high-absorption curcumin agent did not affect the E/E′ ratio, rather it significantly inhibited the increase in plasma BNP levels in patients with initial signs of hypertensive heart disease.

Background: Desmopressin orally disintegrating tablet (ODT) was approved in March 2012 in Japan; the post-market safety reports, which warned about adequate initial dose of desmopressin ODT, were published in 2014. However, it is unclear how the warning affected physician and patient behavior. Methods: We performed a retrospective single-center study to compare the clinical situation of Japanese central diabetes insipidus patients before and after the report. Results: Thirty-four patients before October 2014 and 16 patients after November 2014 switched from intranasal desmopressin to desmopressin ODT. The mean follow-up period after the switch to desmopressin ODT was 38 ± 3 months. Patients switching after November 2014 tended to have lower ratios of oral to nasal desmopressin dose at switching and 3 months after the switch (at switching; P = 0.20, 3 months; P = 0.42, respectively), and higher ratios from 6 to 12 months than before October 2014 (6 months; P = 0.93, 9 months; P = 0.52, 12 months; P = 0.80, respectively). Relative doses per initial desmopressin ODT at 9 and 12 months were significantly higher in patients switching after November 2014 than in patients switching before October 2014 (9 months; P = 0.02, 12 months; P = 0.04, respectively). Moreover, logistic regression analysis revealed that the incidence of hyponatremia was dependent on the ratio of nasal to oral desmopressin dose (P = 0.02). In addition, in four out of six patients who had serum sodium level reduced below 130 mEq/L, hyponatremia occurred within 1 month after the switch. Conclusions: A more gradual dose titration after the safety reports was performed, which involved the long-term safety of desmopressin ODT use. Vigilance of hyponatremia in early phase of desmopressin ODT use should be noted. J Clin Med Res. 2021;13(2):92-100 doi: https://doi.org/10.14740/jocmr4399

Acromegaly is characterized by autonomous excessive growth hormone (GH) secretion, generally due to GH-producing pituitary adenoma, and is associated with various systemic comorbidities including diabetes mellitus. Polycystic kidney disease (PKD) is characterized by the growth of numerous cysts in the kidneys that deteriorate renal function. While possible renal effects of excessive GH exposure have been a current issue in experimental medicine, only five cases of coexisting acromegaly and PKD have been reported previously, and little is known regarding the influence of acromegaly on renal disease. We treated a 50-year-old male with diabetes mellitus who showed a sudden and rapid decline of renal function along with increasing proteinuria, which led to diagnoses of PKD and acromegaly. His urinary protein levels were increased together with excessive GH secretion and worsening glycemic control. An increase of total kidney volume was also noted. Transsphenoidal surgery for the pituitary adenoma was successfully performed. Marked improvement of hyperglycemia and proteinuria were observed after the surgery, but renal function was unchanged. The patient's clinical course suggested common aspects of excessive GH secretion as an accelerating factor of the progression of diabetic nephropathy and PKD via direct and indirect pathways. Although coexisting acromegaly and PKD is clinically rare, vigilance for early diagnosis of acromegaly is appropriate in patients with diabetes and/or PKD, especially in those showing unexpected exacerbation of renal dysfunction.

Background In peripheral tissues, triiodothyronine (T3) production and consequent thyroid hormone actions are mainly regulated by iodothyronine deiodinases (DIOs) classified into 3 types: D1, D2, and D3. Although thyroid hormone economy in the DIO-deficient mice and patients carrying genetic variants of DIOs was well clarified, a condition of DIOs upregulation was not enough elucidated. We aimed to investigate effects of peripheral DIOs on thyroid hormone economy and consequent thyroid hormone action using novel DIO-overexpressing mice that were not yet generated. Methods We cloned coding sequences of human DIOs with FLAG-tag and HiBiT-tag sequences into a pcDNA3.1 vector. To obtain full-length proteins, we modified these vectors by cloning selenocysteine insertion sequence of each DIO (SECIS vectors). Western blot analyses and HiBiT lytic assay using HEK293T cells revealed that SECIS vectors expressed full-length proteins with substantial activity. Subsequently, in vivo transfections of pLIVE-based SECIS vectors into male C57BL/6J mice were performed by hydrodynamic gene delivery to generate mice overexpressing DIOs (D1, D2, and D3 mice). Results First, we verified that DIOs were successfully overexpressed in the livers using HiBiT lytic assay as well as RT-PCR. Analyses of multiple organs of D3 mice assured that full-length protein was not significantly expressed in the heart, the kidney, and the skeletal muscle. RT-PCR analyses also suggested that the pituitary glands and the thyroid glands were not transfected. We evaluated thyroid hormone economy of DIO-overexpressing mice compared to Empty mice transfected with pLIVE-Empty vector. D1 mice did not have changes in serum thyroid hormone levels, whereas D2 mice had higher serum fT3 levels. Clearer changes were found in D3 mice. They had hypothyroidism with higher serum rT3 levels. Correspondingly, in their livers, rT3 concentration was higher and T3-responsive genes were downregulated. We elucidated by adding the cohort with levothyroxine (LT4) administration because DIO-overexpressing mice had liver T4 insufficiency probably due to consumption by DIOs. Comparisons between the DIO-overexpressing mice with and without LT4 administration revealed that D2 mice presented upregulation of T3-responsive genes by LT4 administration distinct from Empty mice. Conclusions We generated DIO-overexpressing mice that expressed human DIOs predominantly in the liver. They provided physiological evidence to integrate the phenotypes of the knockout mice and specific clinical situations. D2 mice seemed to recruit T3 into the circulation as well as in the liver. D3 mice had an overt phenotype characterized by consumptive hypothyroidism. In addition, D3 mice are expected to be a novel hypothyroidism model that does not involve disruption of thyroidal hormone secretion. DIO-overexpressing mice can be generated by single injections of plasmid vectors of interest and can contribute to progress in the field of thyroid hormone economy and action. Presentation: No date and time listed

BackgroundRecently, the high prevalence of young Japanese people who are underweight has received attention because of its potential impact on healthy life expectancy. Sarcopenia, defined as the presence of low muscle mass and function, is often observed in the underweight. However, few reports have described the prevalence and characteristics of sarcopenia in youth.MethodsIn this cross-sectional study, we measured skeletal muscle mass using a multifrequency bioelectrical impedance analysis device and handgrip strength (HGS) and administered questionnaires on dietary habits and physical activity to 1,264 first-year university students aged 18-20 years (838 males and 426 females). Sarcopenia was diagnosed based on the presence of both low skeletal muscle mass (SMI) and weak HGS according to the Asian Working Group for Sarcopenia.ResultsA total of 145 males (17.3%) and 69 females (16.2%) were diagnosed as underweight. Low SMI was diagnosed in 75 males (8.9%) and 18 females (4.2%), and weak HGS was diagnosed in 28 males (3.3%) and 10 females (2.3%). Then, sarcopenia was diagnosed in 8 males (1.0%) and 5 females (1.2%). There was a significantly higher prevalence of low SMI and/or weak HGS in underweight individuals compared with individuals in the other BMI ranges. The multivariate analyses indicated that SMI and HGS were significantly associated with BMI in both sexes. Furthermore, after adjusting for BMI, both SMI and HGS were significantly associated with physical activity in males, and SMI was significantly associated with energy intake and frequency of breakfast intake in females.ConclusionsFirst-year university students showed a high incidence of being underweight with low SMI and/or weak HGS, but the prevalence of sarcopenia was low in both sexes. BMI, energy intake, frequency of breakfast intake, and physical activity were independently associated with skeletal muscle mass and strength in youth.

BACKGROUND Cessation of smoking can markedly reduce the incidence of cardiovascular disease, improve health economics, and benefit society. Aromatherapy has the potential to be a novel option as an adjuvant therapy for smoking cessation that may alleviate depressive symptoms. However, research on the efficacy of aromatherapy as an adjuvant therapy for smoking cessation is scarce. OBJECTIVE The aim of this study was to examine the potential effects of aromatherapy on psychological states in smokers with depressive tendencies and to determine if it is reasonable to proceed to the next step (ie, a phase III trial). METHODS This is a pre-post single-arm clinical trial. Smokers with depression will be subjected to aromatherapy during smoking cessation treatment for 12 weeks. We will evaluate changes in scores on the Zung Self-Rating Depression Scale and the Profile of Mood States from pretreatment screening to 4 weeks and 12 weeks after the start of aromatherapy. Moreover, we will compare the group treated with aromatherapy with the group that received standard treatment in our previous randomized controlled trial (ie, the control group in that study). Furthermore, we will compare successful smoking cessation rates after 12 weeks. In addition, we will conduct an exploratory analysis of the efficacy of aromatherapy. The target sample size is 100, which is the number of subjects expected to be enrolled in this study during the 2-year study period. RESULTS This study was approved by the Kyoto Medical Center Institutional Review Board (IRB approval No. 19-016). Enrollment started on July 1, 2019. As of May 2022, 76 patients have been recruited. In the original plan, recruitment should have been finished on June 30, 2021. However, the number of subjects decreased due to the COVID-19 pandemic, and the study inclusion period was extended by 1 year (ie, until the end of June 2022) with the approval of the IRB on May 17, 2021. Analyses of the results will be completed subsequently. CONCLUSIONS This study has some limitations. This is not a rigorous validation study because it compares the same subjects who received standard treatment in a previous study. Moreover, the sample size and methods of statistical analysis were not fully set with prior consideration of statistical rigor. To address these limitations, we plan to conduct a phase III trial that will reflect the exploratory findings of this study. This is the first study to evaluate the psychological effects of aromatherapy during a smoking cessation program, and it may help improve the quality of treatment for smoking cessation in the future. CLINICALTRIAL UMIN Clinical Trials Registry UMIN000043102; https://tinyurl.com/tn3hvt9w INTERNATIONAL REGISTERED REPORT DERR1-10.2196/38626

Longitudinal bone growth is achieved by a tightly controlled process termed endochondral bone formation. C-type natriuretic peptide (CNP) stimulates endochondral bone formation through binding to its specific receptor, guanylyl cyclase (GC)-B. However, CNP/GC-B signaling dynamics in different stages of endochondral bone formation have not been fully clarified, especially in terms of the interaction between the cyclic guanine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) pathways. Here, we demonstrated that CNP activates the cAMP/protein kinase A (PKA) pathway and that this activation contributed to the elongation of the hypertrophic zone in the growth plate. Cells of the chondrogenic line ATDC5 were transfected with Förster resonance energy transfer (FRET)–based cGMP and PKA biosensors. Dual-FRET imaging revealed that CNP increased intracellular cGMP levels and PKA activities in chondrocytes. Further, CNP-induced PKA activation was enhanced following differentiation of ATDC5 cells. Live imaging of the fetal growth plate of transgenic mice, expressing a FRET biosensor for PKA, PKAchu mice, showed that CNP predominantly activates the PKA in the hypertrophic chondrocytes. Additionally, histological analysis of the growth plate of PKAchu mice demonstrated that CNP increased the length of the growth plate, but coadministration of a PKA inhibitor, H89, inhibited the growth-promoting effect of CNP only in the hypertrophic zone. In summary, we revealed that CNP-induced cGMP elevation activated the cAMP/PKA pathway, and clarified that this PKA activation contributed to the bone growth–promoting effect of CNP in hypertrophic chondrocytes. These results provide insights regarding the cross-talk between cGMP and cAMP signaling in endochondral bone formation and in the physiological role of the CNP/GC-B system.

The selective arterial calcium stimulation test (SACST) is one of the most useful localization tests for insulinoma but can cause false-positive and/or unexpected multi arterial positive results that hamper clinical decisions. There are also several adverse effects, such as nausea and hypoglycemia, at the conventional dose (0.025 mEq/kg) of calcium injection. We herein report five consecutive insulinoma cases in which low-dose (0.005-0.007 mEq/kg) calcium injection for SACST led to successful insulinoma localization. No adverse effects of SACST were observed. In conclusion, a low-dose SACST can be a favorable option as an insulinoma localization test in terms of accuracy and safety.

Objective The psychological status is a key factor in smoking continuance. However, details on short-term changes in mild depressive states after smoking cessation (SC) are still unknown. The purpose of the present study was to investigate these short-term changes. Methods A total of 989 patients who visited our SC Clinic were assessed using the Zung Self-Rating-Depression-Scale (SDS), an official instrument to measure depressive tendencies. The participants were classified into normal and neurotic groups based on their SDS scores during their initial visit; they were assessed again 2, 4, 8, and 12 weeks thereafter. Results The majority of patients in the neurotic group were women. These patients were also younger, with a higher nicotine dependence, and presented with a lower successful SC rate than the patients in the normal group. A decrease in SDS scores after starting the SC treatment was observed only in the neurotic group, especially during the first two weeks. In patients who continued to smoke, no improvement in depressive tendencies was noted in this period. Conclusion Depressive tendencies of patients with neurosis improve in the initial stages of the SC treatment (i.e., within two weeks after starting the treatment). This finding fills the mentioned knowledge gap regarding the effects of SC on mild depressive states in the short term.

In peripheral tissues, triiodothyronine (T3) production and consequent thyroid hormone actions are mainly regulated by iodothyronine deiodinases (DIOs) classified into 3 types: D1, D2, and D3. We aimed to investigate the effects of peripheral DIOs on thyroid hormone economy independent of the hypothalamus-pituitary-thyroid axis. We cloned coding sequences of human DIOs with FLAG-tag and HiBiT-tag sequences into a pcDNA3.1 vector. To obtain full-length proteins, we modified these vectors by cloning the selenocysteine insertion sequence of each DIO (SECIS vectors). Western blot analyses and HiBiT lytic assay using HEK293T cells revealed that SECIS vectors expressed full-length proteins with substantial activity. Subsequently, in vivo transfections of pLIVE-based SECIS vectors into male C57BL/6J mice were performed by hydrodynamic gene delivery to generate mice overexpressing DIOs predominantly in the liver (D1, D2, and D3 mice). After 7 days from transfections, mice were analyzed to clarify phenotypes. To summarize, serum thyroid hormone levels did not change in D1 mice but D2 mice had higher serum free T3 levels. D3 mice developed hypothyroidism with higher serum reverse T3 (rT3) levels. Transfections with levothyroxine administration suggested that thyroid hormone action was upregulated in D2 mice. Our DIO-overexpressing mice provided insights on the physiological properties of upregulated DIOs: D2 augments local thyroid hormone action and recruits T3 into the circulation: D3 decreases circulating T3 and T4 levels with elevated rT3, leading to consumptive hypothyroidism. As D3 mice are expected to be a novel hypothyroidism model, they can contribute to progress in the field of thyroid hormone economy and action.

In 2017, the Primary Aldosteronism Surgical Outcome (PASO) investigators proposed consensus criteria for clinical and biochemical outcomes. However, 6 to 12 months need to pass in order to assess for the outcome in patients who have undergone surgery for the management of primary hyperaldosteronism. This study aims to evaluate the post-operative biochemical and clinical outcomes of primary aldosteronism (PA) on the basis of the laboratory findings obtained within 10 days after surgery. We retrospectively studied 59 consecutive patients with unilateral PA who underwent adrenalectomy and were assessed for plasma aldosterone concentration (PAC) and plasma renin activity both at the initial assessment (1-10 days after surgery) and the final assessment (6-12 months after surgery). When comparing the complete biochemical success group (n = 51) and the partial or absent biochemical success group (n = 8), the median post-operative PAC at the initial assessment was significantly greater in the partial or absent biochemical success group (12.7 ng/dL; interquartile range [IQR], 10.6-14.5) than that in the complete biochemical success group (6.3 ng/dL; IQR, 5.0-7.9) (p < 0.001), while no significant differences were observed in other factors. The receiver operating characteristic curves of post-operative PAC at the initial assessment, which was used to predict biochemical outcomes, indicated that 8.1 ng/dL is the optimal PAC cut-off for biochemical success (sensitivity, 76.5%; specificity, 100%). Low post-operative PAC at the initial assessment may predict the biochemical cure of PA.

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.

Natriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury.

Parathyroid carcinoma is a rare endocrine tumor. Parathyroid carcinoma in patients with secondary hyperparathyroidism due to chronic kidney disease is also rare. In addition, thyroid hemiagenesis is a rare congenital anomaly. We report an extremely rare case of parathyroid carcinoma in a patient with secondary hyperparathyroidism and thyroid hemiagenesis. We also present a review of the literature of this rare entity. We also discuss the surgical procedure performed for this patient. Our review of the literature found 34 case reports of parathyroid carcinoma in patients undergoing dialysis due to chronic renal failure; 14 reports of thyroid hemiagenesis with parathyroid disease; and no previous reports of thyroid hemiagenesis with secondary hyperparathyroidism and parathyroid carcinoma. Although surgical treatment of parathyroid carcinoma requires combined resection with the thyroid, peritracheal dissection with total parathyroidectomy, and monitoring intact parathyroid hormone as a tumor marker, our procedure preserved the patient’s thyroid function. There has been no evidence of recurrence for over 8 years.

Growth retardation is an important side effect of glucocorticoid (GC)-based drugs, which are widely used in various preparations to treat many pediatric diseases. We investigated the therapeutic effect of exogenous CNP-53, a stable molecular form of intrinsic CNP, on a mouse model of GC-induced growth retardation. We found that CNP-53 successfully restored GC-induced growth retardation when both dexamethasone (DEX) and CNP-53 were injected from 4 to 8 weeks old. Notably, CNP-53 was not effective during the first week. From 4 to 5 weeks old, neither CNP-53 in advance of DEX, nor high-dose CNP-53 improved the effect of CNP. Conversely, when CNP-53 was started at 5 weeks old, final body length at 8 weeks old was comparable to that when CNP-53 was started at 4 weeks old. As for the mechanism of resistance to the CNP effect, DEX did not impair the production of cGMP induced by CNP. CNP reduced Erk phosphorylation even under treatment with DEX, while CNP did not changed that of p38 or GSK3β. Collectively, the effect of CNP-53 on GC-induced growth retardation is dependent on age in a mouse model, suggesting adequate and deliberate use of CNP would be effective for GC-induced growth retardation in clinical settings.

Background Osteocrin (OSTN), a bone-derived humoral factor, was reported to act on heart and bone by potentiating the natriuretic peptide (NP) system. Ostn gene polymorphisms have been associated with renal function decline, but its pathophysiological role in the kidney remains unclear. Methods The role of endogenous OSTN was investigated using systemic Ostn-knockout (KO) mice. As a model for OSTN administration, liver-specific Ostn-overexpressing mice crossed with KO (KO-Tg) were generated. These mice were subjected to unilateral ischemia–reperfusion injury (IRI) and renal lesions after 21 days of insult were evaluated. A comprehensive analysis of the Wnt/β-catenin pathway was performed using a polymerase chain reaction (PCR) array. Reporter plasmid-transfected proximal tubular cells (NRK52E) were used to investigate the mechanism by which OSTN affects the pathway. Results After injury, KO mice showed marginal worsening of renal fibrosis compared with wild-type mice, with comparable renal atrophy. KO-Tg mice showed significantly ameliorated renal atrophy, fibrosis and tubular injury, together with reduced expressions of fibrosis- and inflammation-related genes. The PCR array showed that the activation of the Wnt/β-catenin pathway was attenuated in KO-Tg mice. The downstream targets Mmp7, Myc and Axin2 showed similar results. MMP7 and Wnt2 were induced in corticomedullary proximal tubules after injury, but not in KO-Tg. In NRK52E, OSTN significantly potentiated the inhibitory effects of NP on transforming growth factor β1–induced activation of the Wnt/β-catenin pathway, which was reproduced by a cyclic guanosine monophosphate analog. Conclusions Ectopic Ostn overexpression ameliorated subsequent renal injury following ischemia–reperfusion. OSTN could represent possible renoprotection in acute to chronic kidney disease transition, thus serving as a potential therapeutic strategy.

AimsProgrammed cell death-1 (PD-1) blockade therapy frequently results in immune-related adverse events involving the thyroid gland (thyroid irAEs). Although clinical features of thyroid irAEs are known, the mechanisms remain unclear. Here, we conducted a pilot study to investigate mechanisms of thyroid irAE development from the perspective of autoantibodies.MethodsWe performed immunoprecipitation-based assays using sera of 3 patients who developed thyroid irAEs with PD-1 blockade therapy by nivolumab and HEK293T cell lysates, including overexpressed proteins of interest (NKX2-1, PAX8, FOXE1, and HHEX; thyroid-specific transcriptional factors). The pellets were analyzed by western blot to detect the HiBit tag attached to the C-terminus of the proteins.ResultsRelevant changes to NKX2-1 bands were not seen in all 3 patients, but PAX8 bands were augmented in patient 2 with lung cancer and patient 3 with renal cell carcinoma. In addition, FOXE1 bands were augmented in patient 1 with malignant melanoma and patient 3, and a HHEX band was augmented in patient 3. Thus, we revealed novel thyroid-specific autoantibodies, PAX8Ab, FOXE1Ab, and HHEXAb. Expression patterns of the antigens recognized by these antibodies were not identical to the primary sites, so autoimmune responses in thyroid irAE may originate from the thyroid gland, and not the malignancy. Considering that TPOAb rather than TgAb is often negative in patients with thyroid irAEs, other mechanisms such as cytotoxic T cell and antigenicity of thyroglobulin may be involved.ConclusionsAlthough the significance of these novel autoantibodies needs further examination, the present study provides new insights for thyroid autoimmunity.