Effect of thyroxine treatment on pregnancy outcomes in infertile Japanese women with TSH levels between 2.5 µIU/mL and the upper reference limit: a retrospective study.

Recent randomized controlled studies have revealed that levothyroxine (LT4) treatment improves pregnancy outcomes only in infertile women with subclinical hypothyroidism who have thyroid autoantibodies (TAs), but not for those with high TSH levels within the normal range who have TAs. Here, we retrospectively investigated pregnancy outcomes in infertile Japanese women with 2.5 µIU/mL ≤ TSH < upper reference limit (URL). Between 2012 and 2018, 286 patients diagnosed with infertility were followed for more than 1 year at our institution. Among them, we included 106 patients with 2.5 µIU/mL ≤ TSH < URL. We divided these patients into four groups based on the combination of TA positivity and LT4 treatment status to assess the effects of LT4 treatment considering TA positivity on the incidence of pregnancy or miscarriage. In this study, we did not find any significant differences in the rates of pregnancy or miscarriage among the four groups (p = 0.81 and 0.52, respectively). In addition, logistic regression analysis showed that age and history of miscarriage were associated with the incidence of pregnancy, but presence of TAs and LT4 treatment status were not and that no variables examined were associated with the incidence of miscarriage. In summary, we were not able to demonstrate the benefit of LT4 treatment for pregnancy outcomes in Japanese euthyroid infertile women with 2.5 µIU/mL ≤ TSH < URL regardless of TA status in this study.

Defective autophagy in vascular smooth muscle cells enhances atherosclerotic plaque instability.

Autophagy is considered as an evolutionarily conserved cellular catabolic process. Defective autophagy has been implicated in various human diseases, including cardiovascular diseases. Recently, we and others demonstrated that defective autophagy in vascular smooth muscle cells (SMCs) promotes the progression of atherosclerosis. In this study, we investigated the role of autophagy in SMCs on plaque instability in vivo. We generated mice with a defect atg7in which is an essential gene for autophagy, in SMCs by crossing Atg7f/f mice with transgelin (Tagln) Cre+/0 mice (Atg7cKO). Then, Atg7cKO and apolipoprotein E (apoe)-deficient (apoeKO) mice were crossed to generate Atg7cKO:apoeKO mice. To generate a mouse model of plaque instability, we conducted to form a tandem stenosis in the carotid artery of Atg7cKO:apoeKO mice and their controls (apoeKO mice) at the age of 10 weeks. At 5 weeks after surgery, the percentage of cross-sectional stenosis area in the operated common carotid artery of Atg7cKO:apoeKO mice was significantly higher than that in apoeKO mice. In addition, thrombus, which was not observed in apoeKO mice, was frequently found in Atg7cKO:apoeKO mice. Furthermore, the number of Berlin blue staining-positive areas, which indicated intraplaque hemorrhage, was significantly higher in Atg7cKO:apoeKO mice than in control apoeKO mice. Taken together, our data suggest that defective autophagy in SMCs enhances plaque instability and the risk of plaque rupture.

Effects of linagliptin versus voglibose on treatment-related quality of life in patients with type 2 diabetes: sub-analysis of the L-STEP study.

Treatment-related quality of life (QOL) is an important aspect of diabetes management. However, no studies have compared the influence of dipeptidyl peptidase-4 inhibitors versus alpha-glucosidase inhibitors on treatment-related QOL. This prespecified sub-analysis of the Linagliptin Study of Effects on Postprandial blood glucose (L-STEP) compared the effects of linagliptin (5 mg once daily) and voglibose (0.2 mg/meal thrice daily) on treatment-related QOL in Japanese patients with type 2 diabetes (T2DM) inadequately controlled with diet and exercise therapy. Among 366 subjects in the original study, 182 in the linagliptin group and 173 in the voglibose group were included in this analysis. The outcome of this study was change in QOL as assessed by the Diabetes Therapy-Related Quality of Life 17 (DTR-QOL17) questionnaire from baseline to week 12. Compared with baseline data, total DTR-QOL17 scores were significantly higher after 12 weeks of linagliptin and voglibose treatment. The change in the total DTR-QOL17 score and the score of one domain, burden on social activities and daily activities, was significantly greater in the linagliptin group than in the voglibose group. In addition, only linagliptin treatment was identified as a factor associated with an increased total DTR-QOL17 score. Linagliptin is superior to voglibose in terms of improving treatment-related QOL in Japanese patients with T2DM.

RELATIONSHIP BETWEEN THE EFFECTIVENESS OF INORGANIC IODINE AND THE SEVERITY OF GRAVES THYROTOXICOSIS: A RETROSPECTIVE STUDY.

OBJECTIVE: Inorganic iodine is often used to treat patients with Graves thyrotoxicosis who do not tolerate thionamides due to adverse effects. However, predictors of continued inorganic iodine efficacy have not been fully elucidated. This study aimed to investigate the factors affecting the continued efficacy of potassium iodide (KI) in patients with Graves thyrotoxicosis. METHODS: In this study, among 1,197 patients with Graves disease who were initially treated with thionamides, we retrospectively studied 24 consecutive Japanese patients whose treatment was changed to KI alone due to the adverse effects of thionamides. We divided these patients into 2 groups: patients who had maintained euthyroid function for at least 180 days (nonrecurrence group, n = 11), and patients who had not maintained euthyroid function for 180 days (recurrence group, n = 13). RESULTS: Free triiodothyronine (FT3) and free thyroxine (FT4) levels on the day of changing from thionamides to KI were statistically higher in the recurrence group than in the nonrecurrence group (FT3, 9.3 [range, 5.2-11.6] vs. 3.7 [3.3-4.8] pg/mL, P = .02 and FT4, 3.6 [1.8-4.5] vs. 1.4 [1.2-1.9] ng/dL, P = .02). FT4 levels on the day of drug change were significantly higher in the recurrence group, even after adjusting for thionamide or KI dose. In the recurrence group, the duration of KI effect was inversed correlated with FT3 and FT4 levels on the day of drug change. CONCLUSION: Continued efficacy of KI after thionamides might be inversely correlated with thyrotoxicosis severity on the day of drug change. ABBREVIATIONS: ANOVA = analysis of variance eTV = estimated thyroid volume FT3 = free triiodothyronine FT4 = free thyroxine IQR = interquartile range KI = potassium iodide MMI = thiamazole PTU = propylthiouracil RAIT = radioactive iodine therapy TRAb = TSH receptor antibody TSH = thyroid stimulating hormone.

Cutoff value of thyroid uptake of (99m)Tc-pertechnetate to discriminate between Graves' disease and painless thyroiditis: a single center retrospective study.

Thyroid uptake of (99m)Tc-pertechnetate is a useful way to determine the cause of thyrotoxicosis. In daily clinical practice, (99m)Tc-pertechnetate uptake is used to discriminate between Graves' disease and painless thyroiditis when clinical information is not enough to make the distinction. However, since the optimal cutoff value of (99m)Tc-pertechnetate uptake has not yet been elucidated, our aim was to determine this value. We recruited patients with thyrotoxicosis in whom (99m)Tc-pertechnetate uptake was measured in clinical settings between 2009 and 2013. Three experienced endocrinologists (who were blinded to the value of (99m)Tc-pertechnetate uptake and initial treatment) diagnosed the cause of thyrotoxicosis based on thyrotropin, free triiodothyronine, free thyroxine, and thyrotropin receptor antibody levels, and by ultrasound findings and using images of thyroid uptake of (99m)Tc-pertechnetate without the actual values. Ninety-four patients diagnosed as having Graves' disease or painless thyroiditis were finally included. According to the diagnosis, the optimal cutoff value of (99m)Tc-pertechnetate uptake was determined by receiver operating characteristics analysis. A cutoff value of 1.0% provided optimal sensitivity and specificity of 96.6% and 97.1%, respectively. Then, its validity was confirmed in 78 patients with confirmed Graves' disease or painless thyroiditis diagnosed at another institute. Applying this cutoff value to the patients with thyrotoxicosis revealed positive and negative predictive values for Graves' disease of 100% and 88.9%, respectively. In conclusion, a cutoff value for (99m)Tc-pertechnetate uptake of 1.0% was useful to discriminate between Graves' disease and painless thyroiditis.

Evanescent Hyperechoic Changes After Fine-Needle Aspiration Biopsy of the Thyroid in a Series With a Low Overall Prevalence of Complications.

OBJECTIVES: The purpose of this study was to assess the frequency of and risk factors for fine-needle aspiration biopsy (FNAB)-related complications in Japanese patients with thyroid nodules evaluated by standard FNAB techniques. METHODS: Six hundred fifty-three consecutive Japanese patients with 742 nodules who had undergone FNAB were enrolled. Nodule characteristics were evaluated, and thyroid volumes were measured. Fine-needle aspiration biopsy-related complications were identified on the basis of sonographic findings and patients' conditions after undergoing FNAB. Comparisons of patients' backgrounds and nodule characteristics were made between those with and without complications. RESULTS: The prevalence rates for FNAB-related complications, including acute transient thyroid swelling after FNAB and appearance of anechoic lesions, were 0.13% and 0.94%. In this study, we could not identify risk factors for FNAB-related complications. The sudden appearance of bright hyperechoic foci within the thyroid immediately after biopsy was reported as an FNAB-related unfamiliar appearance in 5 cases. Experimental FNA using resected porcine thyroid tissue suggested that the etiology of the hyperechoic appearance may be artificial air bubbles or reversed flow of aspirated fluid. CONCLUSIONS: Fine-needle aspiration biopsy-related complications are rare if preventive measures are performed and are not specific to Japanese patients with thyroid nodules. The sudden appearance of bright hyperechoic foci may be cause by contamination from air or fluid.

Characteristics of patients with graves disease and intrathyroid hypovascularity compared to painless thyroiditis.

OBJECTIVES: The purpose of this study was to assess the frequency and sonographic and laboratory characteristics of Graves disease with intrathyroid hypovascularity in Japanese patients and to compare these characteristics in patients with painless thyroiditis. METHODS: A total of 194 consecutive patients with Graves disease and 21 patients with painless thyroiditis were enrolled. The patients underwent thyroid volume measurement, mean superior thyroid artery peak systolic velocity (PSV) measurement, power Doppler sonography, and proper blood testing to discriminate between Graves disease and painless thyroiditis. Based on the power Doppler sonographic findings, they were divided into 4 groups: from pattern 0 (most hypovascular thyroid) to pattern III (most hypervascular thyroid). Comparisons of multiple thyroid parameters were made among the groups. RESULTS: The prevalence of Graves disease with pattern 0 (n = 27) was 13.9% among the patients with Graves disease. The sonographic and laboratory data for patients with Graves disease and pattern 0 were compared to those of the 21 patients with painless thyroiditis, which typically shows intrathyroid hypovascularity. Free triiodothyronine and thyroxine levels and the superior thyroid artery PSV were significantly lower in patients with Graves disease and pattern 0 than those with patterns I, II, and III (P < .05). The thyroid volume and thyrotropin receptor antibody level were significantly lower in patients with Graves disease and pattern 0 than those with pattern III. In the comparison between patients with Graves disease and pattern 0 and those with painless thyroiditis and pattern 0, apart from thyrotropin receptor antibody, only the superior thyroid artery PSV was different. CONCLUSIONS: Although the clinical features of patients with Graves disease and intrathyroid hypovascularity were similar to those patients with painless thyroiditis, the superior thyroid artery PSV showed a moderate ability to discriminate these patients.

Optically Electroactive Polymer Synthesized in a Liquid Crystal with Cyclosporin A─Circularly Polarized Electron Spin Resonance.

Cyclosporine A (CsA), a naturally derived biomaterial and physiologically active substance, is commonly used as an immunosuppressant. In this study, CsA was revealed to function as a chiral inducer of cholesteric liquid crystals (CLCs) with a high helical twisting power. CsA induced helical structures in 4-cyano-4'-pentylbiphenyl, a synthetic liquid crystal (LC) used for general purposes. Electrochemical polymerization in CLC with CsA was also performed. The polymer prepared in CLC showed electro-optical activity via chiral induction by CsA. Synchrotron X-ray diffraction measurements indicated that the polymer film prepared in the CLC formed in the manner of LC molecular arrangement through molecular form imprinting from the LC order, although the polymer exhibited no liquid crystallinity. The polymer showed structural color and laser light oscillation diffraction derived from its periodic structure. The anisotropy of the circularly polarized electron spin resonance signals for the resulting polymer with respect to the magnetic field was observed.

Adrenocortical Adenoma With Protrusion Into the Inferior Vena Cava Initially Suspected to Be Adrenocortical Carcinoma.

Adrenal tumors with invasion into the inferior vena cava (IVC) are typically malignant. Here, we present a case of adrenocortical adenoma with protrusion into the IVC. A 70-year-old man was referred to our hospital after his magnetic resonance imaging scan of the abdomen coincidently revealed a right adrenal tumor invading the IVC. We suspected an aggressive adrenal carcinoma and tumor resection was performed. However, all 3 existing pathological criteria (Weiss, modified Weiss, and Helsinki) suggested the tumor was benign. Immunohistochemistry for CD31 showed the tumor inside the central adrenal vein (CAV), right adrenal vein (RAV), and IVC was entirely covered with CD31-positive vascular endothelial cells. The CAV is known to sometimes lack smooth muscle in its walls and normal adrenocortical cells covered by endothelial cells sometimes protrude into the CAV from this gap. These findings suggest that this tumor likely protruded into the IVC by pushing against the CAV wall, rather than by invasion into the vascular wall. In the case with adrenal tumors protruding into the IVC, the fact that the tumor surface was covered by vascular endothelial cells was considered supportive of its benign nature.

Protocol of a Prospective Observational Study on Lifestyle and Quality of Life in Adults with Type 1 Diabetes in Japan.

INTRODUCTION: Recent studies have shown that the quality of life (QOL) of people living with type 1 diabetes (T1D) is poor and must be improved. However, the living situation and QOL of adults living with T1D in Japan have not been fully clarified. This study will examine their lifestyle, QOL, and clinical situation, as well as the relationships between them. METHODS: This is a prospective, 5-year follow-up observational study. Between December 2019 and September 2021, we enrolled adults in Japan who were living with T1D and receiving insulin therapy, and are acquiring longitudinal clinical data and the responses to seven questionnaires regarding lifestyle and QOL. The primary study outcomes are (1) the relationship between Problem Areas in Diabetes (PAID) scores and various factors including demographic data, clinical characteristics, medical history, lifestyle habits, treatment history, biochemical data, and the scores of questionnaires; and (2) the relationship between Beck Depression Inventory (BDI)-II scores and various factors aforementioned. The secondary outcomes are the relationships between various factors aforementioned and each of the following: (1) blood glucose control, (2) blood lipid control, (3) dietary patterns, (4) fear of hypoglycemia, (5) sleep patterns, and (6) physical activity. PLANNED OUTCOME: We registered 352 participants. The median age was 49 (41-63) years, and the median duration of T1D was 13 (8-20) years. All the results will be available in 2026. We expect to clarify the factors associated with decreased QOL, and that this knowledge will contribute to improving QOL in adults in Japan who are living with T1D and receiving insulin therapy. TRIAL REGISTRATION: Clinical Trials.gov identifier, UMIN000044088.

Diabetic ketoacidosis due to a sensor defect of FreeStyle Libre: A case report.

The FreeStyle Libre Flash Glucose Monitoring System allows users to obtain sensor glucose values by scanning with the reader or their mobile phone. We report a case of a 59-year-old man with type 1 diabetes mellitus who developed diabetic ketoacidosis due to a sensor defect. After replacing the sensor with a new one, the glucose value shown in the device was much lower than usual, which made him consider that he was hypoglycemic. Accordingly, he reduced his insulin dose and eventually developed diabetic ketoacidosis. He was unaware of the discrepancy due to the lack of self-monitoring of his blood glucose, although he was educated to do. In sum, glucose monitoring with the FreeStyle Libre is helpful; however, it is necessary to remind the patient that a sensor defect leading to a severe complication frequently happens.

Clinical characteristics of adrenal insufficiency induced by pembrolizumab in non-small-cell lung cancer.

BACKGROUND AND AIM: Immune checkpoint inhibitors have significantly improved the clinical outcomes of many cancer types, but they induce a range of immune-related adverse events (irAEs). Although adrenal insufficiency (AI) is a rare irAE, it can lead to serious consequences. This study aimed to determine the clinical features of patients with advanced non-small-cell lung cancer (NSCLC) who developed AI following pembrolizumab treatment. METHODS: We retrospectively reviewed and analyzed the clinical data of all patients with NSCLC treated with pembrolizumab at Juntendo University Hospital from February 2017 to December 2020. The diagnosis of AI was established based on the Endocrine Emergency Guidance for the acute management of endocrine complications of checkpoint inhibitor therapy in the UK and the clinical practice guidelines of the Japan Endocrine Society. RESULT: AI was clinically suspected in 59 out of 186 patients treated with pembrolizumab, and 10 (5.4%) cases were confirmed. The symptoms included hyponatremia (n = 9), fatigue (n = 8), and loss of appetite (n = 6). All patients had low adrenocorticotropic hormone (ACTH) levels, and five patients were diagnosed with isolated ACTH deficiency. All patients completely recovered with corticosteroid replacement. The median time to onset of AI was 8.0 (range 3.8-15.2) months. The median progression-free survival in these patients was 22.4 (95% confidence interval 11.2-not reached) months. CONCLUSION: The incidence of AI among patients treated with pembrolizumab is more frequent than previously reported. In addition, secondary AI, especially isolated ACTH deficiency, is a major form of AI induced by pembrolizumab.

Dynamically controllable emission of polymer nanofibers: electrofluorescence chromism and polarized emission of polycarbazole derivatives.

Electrochemical polymerization of a series of N-alkyl-2,7-di(2-thienyl)carbazoles in acetonitrile was performed to obtain conjugated polymers with fluorescence. Scanning electron and atomic force microscopies revealed that the surface morphology of the polymer films significantly depends on the alkyl chain lengths of the polymers. Particularly, a homopolymer bearing hexyl groups and copolymers with an average alkyl chain length of six carbon atoms show nanofiber morphology. The polymer nanofibers were stacked on a substrate electrode. The fluorescence of the polymer nanofiber film was tunable with application of voltage, with good repeatability. The X-ray diffraction pattern of the fibers showed the structural order. The polymer nanofibers thus prepared showed an electrochemically driven change in polarized photoluminescence.

IRS-2 deficiency in macrophages promotes their accumulation in the vascular wall.

The aim of this study was to investigate the role of insulin receptor substrate-2 (IRS-2) mediated signal in macrophages on the accumulation of macrophages in the vascular wall. Mice transplanted with IRS-2(-/-) bone marrow, a model of myeloid cell restricted defect of IRS-2, showed accumulation of monocyte chemoattractant protein-1-expressing macrophages in the vascular wall. Experiments using cultured peritoneal macrophages showed that IRS-2-mediated signal pathway stimulated by physiological concentrations of insulin, not by IL-4, contributed to the suppression of monocyte chemoattractant protein-1 expression induced by lipopolysaccharide. Our data indicated that IRS-2 deficiency in macrophages enhanced their accumulation in the vascular wall accompanied by increased expression of proinflammatory mediators in macrophages. These results suggest a role for insulin resistance in macrophages in early atherosclerogenesis.

Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury.

Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

Ultrasonic helical coil electrochemical reactor for simultaneous electrolysis-sonification-electrochemical polymerization, and applications for pollen cleaning.

Electrochemical polymerization of aniline by a combination of ultrasonic waves and electrolysis of water was performed. This method involves three processes: 1) creation of O2 micro bubbles produced by electrolysis of water on the anode side, 2) depolarization of the bubbles at the electrode surface via mechanical vibration using ultrasonic waves to diffuse ions in the electrolyte solution, and 3) progression of direct current (DC) electrochemical polymerization to yield a conductive polymer with fine pores on the surface. The diameter of the pores is on the micrometer scale and is similar in size to pollens. The combination of the electronic function of the conductive polymer and porous polymer surface can be applied as a method to collect allergens such as dust and flower pollens. Electrical adsorption and desorption of pollen was conducted with the porous polyaniline synthesized using a micro-bubble sonic-electrochemical preparation.

Conjugated Polymer Films Having a Uniaxial Molecular Orientation and Network Structure Prepared by Electrochemical Polymerization in Liquid Crystals.

A new method for fabricating conjugated polymer films was developed using electrochemical polymerization in liquid crystals and magnetic orientation. A uniaxial main chain orientation and a crosslinked network structure were achieved with this method. By employing eight types of monomers, the influence of the crosslinking for the film was investigated. The crosslinking was found to improve the solvent resistance of the conjugated polymer films. This new method is expected to be useful in various applications, such as high-powered organic electronic devices with durability.

Sequential micro-Maltese cross array in the ground beetle Carabus insulicola.

The exoskeleton of the ground beetle Carabus insulicola was observed using polarizing optical microscopy (POM) with simultaneous transmitted and reflected light. The surface showed iridescence owing to the periodic microstructure. A Maltese cross array of the inner layer of the elytra was observed. The matrix of the middle layer of the elytra is composed of protein with the arrangement of a cholesteric liquid crystal (CLC)-like helical structure. The scanning electron microscopy observations revealed the layers structure of the exoskeleton of the ground beetle. Synchrotron X-ray diffraction measurement evaluated crystallinity of the exoskeleton.　Morphology of the Maltese cross array of the beetle has similarity with synthetic chiral-CLC.

Defective autophagy in vascular smooth muscle cells enhances the healing of abdominal aortic aneurysm.

Autophagy is an evolutionarily conserved cellular catabolic process essential for cell homeostasis, and thus its failure is associated with several diseases. While autophagy has been reported to play a role in vascular smooth muscle cells (SMCs) in vascular disorders, its precise role in the pathogenesis of abdominal aortic aneurysm (AAA) has not yet been elucidated. In this study, we investigated the role of SMC autophagy in AAA formation. As a mouse model of AAA, we used control apolipoprotein E-deficient (apoeKO) mice and Atg7cKO (SMC-specific Atg7-deficient mice):apoeKO mice administered angiotensin II for 4 weeks. Intriguingly, Kaplan-Meier curves showed that the survival rates of Atg7cKO:apoeKO mice were significantly higher than those of apoeKO mice. The hematoma area in AAA of Atg7cKO:apoeKO mice was smaller than in apoeKO mice despite the lack of a significant difference in AAA incidence between the two groups. Furthermore, the amount of granulomatous tissues was significantly larger and the collagen-positive area within AAA was significantly larger in Atg7cKO:apoeKO mice than in apoeKO mice. In accordance with these findings, SMCs cultured from Atg7cKO mice showed increased expression of collagens, independent of angiotensin II action. Taken together, our data suggest that defective autophagy in SMCs elicits AAA healing that may underlie the better survival rate under dyslipidemia and angiotensin II infusion.