Neprilysin Inhibition Promotes Skeletal Growth via the CNP/NPR-B Pathway.

C-type natriuretic peptide (CNP) plays a crucial role in enhancing endochondral bone growth and holds promise as a therapeutic agent for impaired skeletal growth. To overcome CNP's short half-life, we explored the potential of dampening its clearance system. Neprilysin (NEP) is an endopeptidase responsible for catalyzing the degradation of CNP. Thus, we investigated the effects of NEP inhibition on skeletal growth by administering sacubitril, a NEP inhibitor, to C57BL/6 mice. Remarkably, we observed a dose-dependent skeletal overgrowth phenotype in mice treated with sacubitril. Histological analysis of the growth plate revealed a thickening of the hypertrophic and proliferative zones, mirroring the changes induced by CNP administration. The promotion of skeletal growth observed in wild-type mice treated with sacubitril was nullified by the knockout of cartilage-specific natriuretic peptide receptor B (NPR-B). Notably, sacubitril promoted skeletal growth in mice only at 3 to 4 weeks of age, a period when endogenous CNP and NEP expression was higher in the lumbar vertebrae. Additionally, sacubitril facilitated endochondral bone growth in organ culture experiments using tibial explants from fetal mice. These findings suggest that NEP inhibition significantly promotes skeletal growth via the CNP/NPR-B pathway, warranting further investigations for potential applications in people with short stature.

Double somatic mutations in CTNNB1 and GNA11 in an aldosterone-producing adenoma.

Double somatic mutations in CTNNB1 and GNA11/Q have recently been identified in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis of APA due to these mutations, an association with pregnancy, menopause, or puberty has been proposed. However, because of its rarity, characteristics of APA with these mutations have not been well characterized. A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation and was diagnosed as having primary aldosteronism after endocrinologic examinations. Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling demonstrated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. The resected right adrenal tumor was histologically diagnosed as adrenocortical adenoma and subsequent immunohistochemistry (IHC) revealed diffuse immunoreactivity of aldosterone synthase (CYP11B2) and visinin like 1, a marker of the zona glomerulosa (ZG), whereas 11ß-hydroxylase, a steroidogenic enzyme for cortisol biosynthesis, was mostly negative. CYP11B2 IHC-guided targeted next-generation sequencing identified somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Immunofluorescence staining of the tumor also revealed the presence of activated ß-catenin, consistent with features of the normal ZG. The expression patterns of steroidogenic enzymes and related proteins indicated ZG features of the tumor cells. PA was clinically and biochemically cured after surgery. In conclusion, our study indicated that CTNNB1 and GNA11-mutated APA has characteristics of the ZG. The disease could occur in adults with no clear association with pregnancy or menopause.

Impact of smoking initiation age on nicotine dependency and cardiovascular risk factors: a retrospective cohort study in Japan.

Aims: Initiating smoking in early adolescence results in challenges with smoking cessation and is associated with high risk of cardiovascular disease. Recently, the initiation of smoking has transitioned from adolescence to young adulthood. However, there are few reports on the impact of initiating smoking at a later age. This study investigated the impact of the age of smoking initiation on nicotine dependency, smoking cessation rates, and cardiovascular risk factors, using a cut-off point of 20 years, within the Japanese population. Methods and results: This retrospective cohort study encompassed 1382 smokers who sought smoking cessation treatment at Kyoto Medical Centre Hospital between 2007 and 2019. Clinical indicators were evaluated by adjusting for age at the time of hospital visit and sex. The smoking cessation rate was further adjusted for treatment medication. The group with a smoking initiation age of <20 years reported a higher number of cigarettes/day (P = 0.002), higher respiratory carbon monoxide levels (P < 0.001), a higher Fagerström Test for Nicotine Dependence (FTND) score (P < 0.001), and a higher Self-rating Depression Scale score (P = 0.014). They also reported lower diastolic blood pressure (P = 0.020) and a lower successful smoking cessation rate [odds ratio: 0.736, 95% confidence interval (0.569, 0.951)] than the group with a smoking initiation age of ≥20 years. When smokers were divided into four groups based on the age they started smoking, the FTND score for those who started at 20-21 years was significantly higher than the score for those who started at 22 years or older. Conclusion: In young adulthood, initiating smoking later (beyond 20 years old) was associated with lower nicotine dependency and fewer depressive tendencies, as well as a higher success rate in smoking cessation among Japanese smokers. The results might suggest that raising the legal smoking initiation age from 20 to 22 years old or older could be effective in reducing nicotine dependency in smokers.

Cross-sectional association of skeletal muscle mass and strength with dietary habits and physical activity among first-year university students in Japan: Results from the KEIJI-U study.

OBJECTIVE: Recently, the high prevalence of young Japanese individuals who are underweight has received attention because of the potential risk for sarcopenia. The aim of this study was to examine the prevalence and characteristics of sarcopenia in Japanese youth. METHODS: In 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 in 1264 first-year university students ages 18 to 20 y (838 men and 426 women). Sarcopenia was confirmed based on the presence of both low skeletal muscle mass and weak muscle strength. RESULTS: In all, 145 men (17%) and 69 women (16%) were diagnosed as underweight. Sarcopenia was diagnosed in 8 men (1%) and 5 women (1%). There was a significantly higher prevalence of low skeletal muscle mass index (SMI) and/or weak HGS in underweight individuals than in those in other body mass index (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 men, and SMI was significantly associated with energy intake in women. CONCLUSIONS: First-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. There may be sex differences in factors related to muscle mass and strength, but further research is needed to clarify this.

A case of osteogenesis imperfecta caused by a COL1A1 variant, coexisting with pituitary stalk interruption syndrome.

Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder that affects 6-7 per 100,000 populations, and pituitary stalk interruption syndrome (PSIS) is a rare congenital defect with varying degrees of pituitary hormone deficiency, affecting approximately 0.5 in every 100,000 births. Currently, only two cases of these complications have been reported. A 46-year-old male who had experienced more than 20 fractures (peripheral and vertebral) during adolescence visited our hospital for close examination. He presented with blue sclerae and long bone deformations. We suspected OI because his mother and sister, who were being treated for osteoporosis, also had blue sclerae. Genetic testing identified a heterozygous variant (c.757C > T, p.Arg253Ter) in the COL1A1 gene, leading to the diagnosis of OI. His mother and sister also had the same variant. Considering that he underwent GH replacement therapy for his short stature during his childhood, his pituitary hormone levels were also evaluated to know if GH deficiency impacted low bone density; hypopituitarism was then suspected. The pituitary function test results led to the diagnoses of hypothalamic GH deficiency, hypogonadism, hypothyroidism, and hypoadrenocorticism. Furthermore, magnetic resonance imaging showed anterior pituitary atrophy, pituitary stalk loss, and ectopic posterior pituitary, leading to the diagnosis of PSIS. The combination of OI and hypopituitarism may have caused further bone fragility. Therefore, although rare, clinicians should keep in mind that patients with OI can possibly have concomitant pituitary insufficiency, which can lead to developmental and growth retardation.

Randomized double-blind placebo-controlled multicenter trial for the effects of a polyherbal remedy, Yokukansan (YiganSan), in smokers with depressive tendencies.

BACKGROUND: Smoking and depression are closely related and form a vicious cycle. Yokukansan (YiganSan) is a polyherbal remedy that has the effect of calming neuropsychiatric symptoms such as anger and irritation. To examine the efficacy of Yokukansan during smoking cessation (SC) therapy in smokers with depressive tendencies but without major depressive disorders requiring pharmacotherapy. METHODS: A multicenter, double-blind, randomized, placebo-controlled, parallel-group comparison trial was conducted between June 2016 and May 2020 at 12 centers of the National Hospital Organization, Japan. This trial targeted smokers who first visited the SC outpatient clinics, did not receive any pharmacological treatment at the psychiatric or psychosomatic department, and scored 39 or more on the self-rating depression scale (SDS). Participants (n = 198) were randomly assigned to either the Yokukansan or placebo groups. The trial drug was initiated with the start of the SC treatment and continued for 12 weeks. The primary outcome was the high success rate of the SC treatment, and the secondary outcomes included changes in scores of the SDS and the Profile of Mood States (POMS) instrument. RESULTS: The success rate of the SC treatment was similar between the placebo (63%) and Yokukansan (67%) groups (P = .649). The SDS scores (placebo: mean difference [MD] = -3.5, 95% confidence interval [CI][-5.8, -1.2], d = 0.42; Yokukansan: MD = -4.6, 95%CI[-6.8, -2.3], d = 0.55), and the "tension-anxiety" POMS-subscale scores (placebo: MD = -1.6, 95%CI[-2.5, -0.7], d = 0.52; Yokukansan: MD = -1.6, 95%CI[-2.9, -0.3], d = 0.36) showed significant improvement in both groups after the SC treatment. However, "depression-dejection" improved in the Yokukansan group (MD = -1.9, 95%CI[-3.1, -0.7], d = 0.44) but not in the placebo group (MD = -0.1, 95%CI[-1.0, 0.7], d = 0.04). Significant improvement in "fatigue" was noted in the Yokukansan group (MD = -2.1, 95%CI[-3.4, -0.9], d = 0.47) but not in the placebo group (MD = -0.5, 95%CI[-1.8, 0.8], d = 0.11). The time × group interaction on the improvement in "depression-dejection" was significant (P = .019). CONCLUSIONS: Yokukansan does not increase the SC treatment's success rate but has additional positive effects on the psychological states due to the SC treatment in smokers with depressive tendencies but without apparent mental disorders. TRIAL REGISTRATION: ID: UMIN000027036. Retrospectively registered at UMIN on April 18, 2017.

Psychological Effects of Aromatherapy on Smokers With Depressive Tendencies During Smoking Cessation Treatment: Protocol for a Pre-Post Single-Arm Clinical Trial.

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. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000043102; https://tinyurl.com/tn3hvt9w. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38626.

Impact of Chronic Kidney Disease on the Associations of Cardiovascular Biomarkers With Adverse Outcomes in Patients With Suspected or Known Coronary Artery Disease: The EXCEED-J Study.

Background The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high-risk patients remains unclear. Methods and Results We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms-like tyrosine kinase-1 (sFlt-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3-point MACE (3P-MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, cardiovascular death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt-1, NT-proBNP, and hs-cTnI, but not other biomarkers, were significantly associated with 3P-MACE, all-cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT-proBNP and hs-cTnI. NT-proBNP and hs-cTnI were also significantly associated with 5P-MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT-proBNP and hs-cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD. Conclusions NT-proBNP and hs-cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

C-type Natriuretic Peptide-induced PKA Activation Promotes Endochondral Bone Formation in Hypertrophic Chondrocytes.

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.

Gingival bleeding and pocket depth among smokers and the related changes after short-term smoking cessation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p = .031) and increase in pocket depth (p = .046) were observed 3 months after the baseline in patients who successfully quit smoking (n = 14). CONCLUSION: Short-term smoking cessation increased periodontal pocket depth and gingival bleeding. These findings may reflect healing processes that occur in the healthy gingiva. IMPLICATIONS: 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.

Phase angle from bioelectrical impedance analysis is a useful indicator of muscle quality.

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 (ß) = -0.43, P < 0.001, SMI: ß = 0.61, P < 0.001, muscle quality: ß = 0.13, P < 0.001) and female (age: ß = -0.56, P < 0.001, SMI: ß = 0.52, P < 0.001, muscle quality: ß = 0.09, P = 0.007)]. Participants with sarcopenia had a significantly lower PhA compared with those without it (sarcopenia vs. non-sarcopenia: young male participants, 5.51 ± 0.41° vs. 6.25 ± 0.50°, P < 0.001; young female participants, 4.88 ± 0.16° vs. 5.37 ± 0.44°, P = 0.005; elderly female participants: 4.14 ± 0.29° vs. 4.63 ± 0.42°, P = 0.009). Although no significant findings were observed in elderly male participants, the same tendency was noted. Receiver operating characteristic (ROC) curve analysis indicated that PhA had good predictive ability for sarcopenia in young male, elderly male, young female, and elderly female participants (area under the ROC curve of 0.882, 0.838, 0.865, and 0.850, with cut-off PhA values of 5.95°, 5.04°, 5.02°, and 4.20° for predicting sarcopenia, respectively). CONCLUSIONS: The PhA reflected muscle quality and exhibited good accuracy in detecting sarcopenia, suggesting its utility as an index for easily measuring muscle quality, which could improve the diagnosis of sarcopenia.

Prediction of long-term biochemical cure in patients with unilateral primary hyperaldosteronism treated surgically based on the early post-operative plasma aldosterone value.

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.

ACTH-independent production of 11-oxygenated androgens and glucocorticoids in an adrenocortical adenoma.

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.

Safety of Remdesivir for Patients 80 Years of Age or Older with Coronavirus Disease 2019 (COVID-19).

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.

Subtype-specific trends in the clinical picture of primary aldosteronism over a 13-year period.

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 < 0.01) and hypokalemia prevalence (18--11%; P < 0.01). However, among the 952 patients with APA, there were no significant changes in hypertension duration (median 8 years) and hypokalemia prevalence (overall 70%). Furthermore, the APA group had a trend towards increased use of multiple hypertensive drugs at diagnosis (30--43%; P < 0.01). When subtypes were reclassified according to the precosyntropin stimulation AVS data, APA patients tended to be diagnosed earlier and at milder forms, consistent with the trend in overall primary aldosteronism patients. CONCLUSION: During 2006-2018, we identified marked subtype-specific trends in the clinical findings at the diagnosis of primary aldosteronism. Our results suggested that the emphasis on the implementing cosyntropin stimulation during AVS might lead to under-identification of APA, especially in patients with mild or early cases.

Parathyroid Carcinoma in a Patient With Secondary Hyperparathyroidism and Thyroid Hemiagenesis: A Case Report and Review of the Literature.

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.

Neutrophil/lymphocyte ratio is correlated with levels of inflammatory markers and is significantly reduced by smoking cessation.

Previous studies have reported that the neutrophil to lymphocyte ratio (NLR) is associated with onset and prognosis of cardiovascular disease (CVD). Smoking is a major risk factor for CVD and smoking cessation significantly reduces CVD risk. However, the effects of smoking cessation on the NLR remain unknown. Among smokers visiting our smoking cessation clinics, we examined changes in the NLR and CVD biomarkers before and after smoking cessation. A total of 389 individuals (301 men and 88 women) were enrolled in the study. The median NLR was significantly reduced after successful smoking cessation (before: 1.8, interquartile range [IQR] 1.5, 2.5; after: 1.7, IQR 1.3, 2.4). In a linear regression model adjusted for sex, percent change in NLR comparing before and after smoking cessation was significantly and positively correlated with percent changes in C-reactive protein (ß = 0.260), α1-antitrypsin-low density lipoprotein (ß = 0.151, p < 0.05), and serum amyloid A-low density lipoprotein (ß = 0.325). Our study demonstrated for the first time that smoking cessation significantly reduces the NLR in tandem with markers of inflammation and oxidative stress.

Short-term Changes in Self-rating Depression Scale Scores after Smoking Cessation in Neurotic Patients.

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.

Acromegaly accompanied by diabetes mellitus and polycystic kidney disease.

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.

Impact of Smoking Status on Growth Differentiation Factor 15 and Mortality in Patients With Suspected or Known Coronary Artery Disease: The ANOX Study.

Background Whether circulating growth differentiation factor 15 (GDF-15) levels differ according to smoking status and whether smoking modifies the relationship between GDF-15 and mortality in patients with coronary artery disease are unclear. Methods and Results Using data from a multicenter, prospective cohort of 2418 patients with suspected or known coronary artery disease, we assessed the association between smoking status and GDF-15 and the impact of smoking status on the association between GDF-15 and all-cause death. GDF-15 was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study (Development of Novel Biomarkers Related to Angiogenesis or Oxidative Stress to Predict Cardiovascular Events). Patients were followed up during 3 years. The age of the patients ranged from 19 to 94 years; 67.2% were men. Never smokers exhibited significantly lower levels of GDF-15 compared with former smokers and current smokers. Stepwise multiple linear regression analysis revealed that the log-transformed GDF-15 level was independently associated with both current smoking and former smoking. In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders. This association was still significant in never smokers, former smokers, and current smokers. However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in current smokers or in former smokers. Conclusions Not only current, but also former smoking was independently associated with higher levels of GDF-15. The prognostic value of GDF-15 on mortality was most pronounced in never smokers among patients with suspected or known coronary artery disease.