Incidence of menstrual cycle abnormalities and polycystic ovary syndrome in female Japanese patients with type 1 diabetes mellitus. The role of androgens.

Type 1 diabetes mellitus (T1DM) adversely affects gonadal function. This study aimed to define the characteristics and factors associated with menstrual cycle abnormalities and polycystic ovary syndrome (PCOS) in Japanese patients with T1DM. Our study enrolled 157 patients, including 55 with oligomenorrhea (prolonged menstrual cycle) and 102 without oligomenorrhea. LH/FSH ratio (p = 0.04) and total testosterone levels (p = 0.03) were significantly higher in the oligomenorrhea group than in the non-oligomenorrhea group. No significant differences were found between the two groups regarding age at menarche, age at T1DM diagnosis, treatment, glycated hemoglobin, or total daily insulin dose. Of the 55 patients in the oligomenorrhea group, 27 were diagnosed with PCOS based on the Rotterdam criteria. We concluded that female patients with T1DM, as well as abnormal menstrual cycles and hyperandrogenism, may suffer from undiagnosed PCOS and should be referred to a gynecologist for full assessment, diagnosis, and treatment.

Treatment strategy for maturity-onset diabetes of the young 3 (MODY3): Experience with two sisters and their mother.

Maturity onset diabetes of the young (MODY) is a relatively young-onset diabetes mellitus with an autosomal dominant inheritance. Among these phenotypes, MODY3, caused by mutations in HNF1A, is one of the most frequent. Although MODY3 is known to respond markedly to sulfonylureas (SU), many cases require insulin therapy. However, there are no clear guidelines for factors to consider when introducing antidiabetic drugs and insulin. This report describes a familial case in which an older sister was diagnosed with diabetes and subsequently with MODY3, followed by the onset of diabetes in the younger sister and mother. The elder sister initially denied insulin treatment and exhibited a suboptimal response to SU but finally agreed to insulin use. The mother initially selected insulin therapy because of the challenges associated with adherence to strict dietary therapy. Conversely, the younger sister responded positively to SU and maintained effective glycemic control. The management of MODY3, even though they have the same single-gene mutation and similar residual insulin secretion at diagnosis, should be flexibly individualized for each family member to ensure long-term adherence and appropriate glycemic control.

Perceptions of diabetes management among adolescents with type 1 diabetes and their caregivers: development and validation of the Japanese version of the diabetes family responsibility questionnaire.

The shift in diabetes management responsibility is critical for adolescents with type 1 diabetes (T1D). Currently, in Japan, there is insufficient progress in the development of scales for evaluating diabetes management responsibility. We developed the Japanese version of the Diabetes Family Responsibility Questionnaire (DFRQ), a scale to evaluate diabetes management responsibility, and verified its reliability and validity. We recruited 12-18-year-old adolescents with T1D and their caregivers. The DFRQ questionnaires (DFRQ-A for adolescents and DFRQ-C for caregivers) were distributed. The responses of 31 pairs were analyzed (adolescents: 9 males, 22 females; mean age: 14.8 ± 1.5 years). The median total DFRQ scores of adolescents (30.0) and caregivers (32.0) were not significantly different (p = 0.269). The internal consistencies (Cronbach's α) were 0.784 and 0.687 for DFRQ-A and DFRQ-C, respectively. DFRQ-A scores and adolescent age demonstrated a weak statistically significant negative correlation (r = - 0.397, p = 0.027), whereas DFRQ-C scores and adolescent age demonstrated a weak negative correlation not statistically significant (r = - 0.311, p = 0.089). Both scores were significantly negatively correlated with self-efficacy for diabetes self-management scores (r = - 0.390, p = 0.030; r = - 0.478, p = 0.006, respectively). Furthermore, a significantly moderate positive correlation was found between these scores (r = 0.624, p < 0.001). We confirmed the reliability and validity of the Japanese version of DFRQ. DFRQ is expected to be used as a dyadic scale to evaluate the status of diabetes management responsibility and its transition during adolescence in Japan.

Age at menarche in Japanese patients with type 1 diabetes mellitus: a look at changes since 1960s.

Menarche is delayed in patients with type 1 diabetic mellitus (T1DM) compared to non-diabetics. The purpose of this survey study was to define the age of onset of menarche in Japanese patients with T1DM, as well the secular trends in menarcheal age across the period of 1976-2020 and determine the effects of T1DM and disease management on that age. The study subjects (n = 155) were recruited from among Japanese T1DM patients who visited the outpatient clinic of the Department of Pediatrics, Osaka City University Hospital. The study subjects experienced menarche during 1976-2020. They were divided into the menarche-post-T1DM group (n = 117) and the menarche-pre-T1DM group (n = 38), in whom menarche occurred after or before the diagnosis of T1DM, respectively. The time of birth was also stratified into five decade/time bins extending from 1960s to 2000s. The subjects filled a questionnaire on menarche. Other clinical information was obtained from the medical records. The median age at menarche was 12.5 years (11.3-13.4) (25th-75th percentile) for the menarche-post-T1DM group and 11.8 years (10.9-13.0) for the menarche-pre-T1DM group (p = 0.024). Menarche occurred at a significantly younger age in recent years in the menarche-post-T1DM group (r = -0.209, p = 0.023), but no such trend was found in the control group. Analysis of data of subjects born after 1990 still showed significant delay associated with T1DM [post-T1DM group: 12.3 years (11.3-13.2), pre-T1DM group: 11.8 years (11.0-12.2), p = 0.045]. The results suggest that recent advances in insulin therapy seem to improve metabolism under T1DM but might have not enough impact on menarche in Japanese girls.

Relationship Between Bedside Ketone Levels and Time to Resolution of Diabetic Ketoacidosis: A Retrospective Cohort Study.

INTRODUCTION: There is no information on the factors that influence the time required to induce resolution of diabetic ketoacidosis (DKA). New methods are currently available for bedside measurement of serum 3-hydroxybutyrate (3HB). The aim of this study was to determine the relationship between serum 3HB and the time to DKA resolution. METHODS: We reviewed the medical records of patients with type 1 diabetes (T1D) and a history of DKA who were admitted to the Department of Pediatrics, Osaka City University Hospital, between November 2008 and October 2018. DKA resolution was defined as 3HB below 1.0 mmol/L as measured by a bedside ketone meter. RESULTS: Data of 52 T1D-DKA episodes were analyzed (median age, 8.0 years; 20 male patients; 32 female patients; new T1D diagnosis, n = 13; established diagnosis, n = 39). In all cases, correction of serum 3HB was an important aspect of T1D management. The median time to DKA resolution (defined as the time from the start of insulin infusion until the fall of 3HB level to below 1.0 mmol/L) was 11 and 10 h in new and established T1D cases, respectively. 3HB on admission and the required insulin infusion dose per body weight, but not blood pH level on admission, correlated with time to DKA resolution. There was no relationship between blood pH level and 3HB on admission. CONCLUSIONS: Our results showed that DKA resolution could be achieved within 10-11 h when DKA treatment is guided by bedside 3HB monitoring without any severe complications. Blood 3HB level is a potentially suitable marker for the severity and resolution of DKA.

Plasma acrolein level in rheumatoid arthritis increases independently of the disease characteristics.

OBJECTIVE: This study aimed to clarify whether plasma acrolein level actually increases in rheumatoid arthritis (RA) patients, and to elucidate whether any relationship exists between the levels and the RA background variables. METHODS: Plasma levels of protein-conjugated acrolein (PC-Acro) in 84 patients (RA group) and 298 normal individuals (Control group) were measured by enzyme-linked immunosorbent assay procedures. The data were statistically analyzed with Wilcoxon rank-sum test, multiple logistic regression analyses and Spearman's rank correlation coefficient. RESULTS: The RA group showed significantly higher PC-Acro levels than the Control group (median [interquartile range]: 80.5 [63.2-105.2] and 65.9 [58.9-78.1] nmol/ml, respectively). Of background factors giving influence to PC-Acro level in the combination of the two groups, 'diagnosis of RA positive' indicated strong correlation to high PC-Acro level (odds ratio: 2.96; 95% confidence interval: 1.54-5.71). These increases of PC-Acro in the RA patients did not correlate to their disease duration and/or inflammatory variables: PC-Acro level could elevate even in early RA patients showing negative inflammatory findings. CONCLUSION: Plasma levels of PC-Acro increased with RA, but the levels did not correlate with RA background variables. This report provides the basis for further studies of early diagnosis of RA as well as its pathogenesis.

Expression of bone morphogenetic proteins in giant cell tumor of bone.

BACKGROUND: A giant cell tumor (GCT) of bone is a locally aggressive tumor with a propensity for local recurrence. A characteristic pattern of peripheral bone formation has been described in GCT recurrence in soft tissue, and in some pulmonary metastases from benign GCT. Although the bone formation in GCT in supposedly due to bone morphogenetic proteins (BMPs), the expression pattern of BMPs in GCT has not been well investigated. MATERIALS AND METHODS: The expression of BMPs in GCT tissues, cultured stromal cells from GCT, and osteoclast-like giant cells harvested by laser microdissection (LM), as well as from control osteosarcoma (NOS-1) cells was analyzed using reverse transcriptional-semiquantitative PCR. RESULTS: BMP 2, 3, 4, 5 and 6 were expressed in the GCT tissue. The cultured GCT cells expressed BMP 2, 4, 5 and 6. The osteoclast-like giant cells expressed BMP 2, 3, 5 and 6 and BMP 5 was expressed at the highest level. CONCLUSION: Both stromal cells and osteoclast-like cells in GCT expressed several kinds of BMPs.

Expression of coxsackievirus and adenovirus receptor in neointima of the rat carotid artery.

Our previous study revealed that the coxsackievirus and adenovirus receptor (CAR) is a homophilic cell adhesion molecule and may function as a sensor of cell-cell interactions in the brain and damaged heart. In this study, we investigated if CAR expression is involved in the formation of neointimal hyperplasia using a balloon injury model of rat carotid artery. Cultured vascular smooth muscle cells (SMCs) from rat aorta were also studied. CAR antigen was constitutively detected in the endothelial cells (ECs) but not in SMCs before injury. On Day 5 after balloon injury, CAR was expressed strongly in the first layer of medial SMCs. Neointimal hyperplasia was observed on Day 7, and strong expressions of CAR concomitantly with proliferating cell nuclear antigen (PCNA) were obvious in the neointimal SMCs, while CAR in medial SMCs disappeared. The expression of CAR mRNA reached a peak on Day 7 and declined gradually to the basal levels. When the ECs regenerated on Day 14, CAR antigen was observed in the ECs but disappeared in the neointima. CAR together with PCNA was expressed abundantly in the proliferating SMCs in vitro and diminished in cells grown to a confluent state. The abundant expression of CAR in the neointima may facilitate an adenoviral gene therapy.

Spatiotemporal changes of coxsackievirus and adenovirus receptor in rat hearts during postnatal development and in cultured cardiomyocytes of neonatal rat.

Coxsackievirus B is the most common cause of viral myocarditis and is particularly virulent in neonates and children. Adenovirus is also a leading cause of the disease. The determinant of tropism for both viruses is considered to be the expression of coxsackievirus and adenovirus receptor (CAR) in target organs. However, developmental change and physiological localization of CAR in the heart are unknown. We examined expression levels of CAR in rat hearts by quantitative real-time polymerase chain reaction and Western blot analysis and found that CAR decreased gradually during postnatal development, although CAR was detectable, even in adults. Immunohistochemistry revealed CAR on the whole surface of cardiomyocytes in immature rat hearts. In contrast, CAR was detected predominantly on intercalated disks in the adult heart and was accumulated especially at the contact point between the cultured cardiomyocytes, even though they were prepared from the neonatal rat heart. In conclusion, CAR was expressed abundantly on the whole surface of cardiomyocytes in immature rat hearts. Both the expression level and the localization of CAR are possible determinants of the susceptibility to viral myocarditis of neonates and children.

Developmental distribution of coxsackie virus and adenovirus receptor localized in the nervous system.

Mouse coxsackie virus and adenovirus receptor (mCAR), which was isolated from the nerve growth cone-enriched fraction of newborn mouse brains, is a member of immunoglobulin-super family, and functions as a homophilic adhesion molecule. We observed the expression of mCAR in embryos to adult tissues by means of immunohistochemical analysis with a peptide antibody. mCAR expression was first detected in the embryonic ectoderm in the uterus on embryonic day 6.5 (E6.5). Then it was strongly expressed in the neuroepithelium of the neural tube, the developing brain and the spinal cord from E8.5 to postnatal day 7 (P7), in the cranial motor nerves from E9.5 to E11.5, and in the optic nerve from E13.5 to P7, which agrees with periods of their respective morphogenetic peaks. This expression of mCAR decreased postnatally and was absent in adult tissues. We found that mCAR occurred in a few proliferating cells of the hippocampal dentate gyrus, the subventricular zone (SVZ) of the lateral ventricles, and the rostral migratory stream (RMS) over P21. These observations demonstrate that mCAR was expressed characteristically in the immature neuroepithelium including progenitor cells or radial cells derived from the neural tube and in immature cells in a selected germinal zone of the mature brain. Based on our findings, we propose that mCAR is involved in migration and fasciculation during a restricted period as an adhesion molecule.

Expression of the coxsackievirus and adenovirus receptor in musculoskeletal tumors and mesenchymal tissues: efficacy of adenoviral gene therapy for osteosarcoma.

Recombinant adenovirus is used as a competent vector in a wide spectrum of cancer gene therapies. Adenovirus infection depends on coxsackievirus and adenovirus receptor (CAR)-mediated virus attachment to the cell surface. However, the expression levels of CAR and the efficiency of adenoviral gene transduction in musculoskeletal tumors have not been systematically investigated. To study the feasibility of gene therapy in musculoskeletal tumors, the expression levels of CAR and the antiproliferative effect of an adenovirally transduced wild-type p53 tumor suppressor gene were examined in 15 distinct musculoskeletal tumor cell lines, 19 tumor tissue samples, and the corresponding pathologically unremarkable mesenchymal tissues. The expression levels of the CAR gene were significantly higher in six of seven osteosarcoma cell lines and two of five osteosarcoma tissue samples than in the other cell lines, musculoskeletal tumors, and mesenchymal tissues. CAR expression levels were closely correlated with adenoviral gene transduction efficiency and the antiproliferative effect of a transduced adenoviral p53 gene in the tested cell lines. In addition, an immunocytochemical study confirmed that transfected green fluorescent protein (GFP) borne by Ad-CAG-GFP was expressed at the cell surface of CAR-positive cells. These results indicate that CAR expression is a critical determinant of transduction efficiency in adenovirus-based gene therapy. Most osteosarcomas appeared to express high levels of CAR, and thus adenovirus-mediated p53 gene therapy is likely to be suitable for the treatment of such tumors.