Minocycline prevents osmotic demyelination associated with aquaresis.

Overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome (ODS). Minocycline protects ODS associated with overly rapid correction of chronic hyponatremia with hypertonic saline infusion in rats. In clinical practice, inadvertent rapid correction frequently occurs due to water diuresis, when vasopressin action suddenly ceases. In addition, vasopressin receptor antagonists have been applied to treat hyponatremia. Here the susceptibility to and pathology of ODS were evaluated using rat models developed to represent rapid correction of chronic hyponatremia in the clinical setting. The protective effect of minocycline against ODS was assessed. Chronic hyponatremia was rapidly corrected by 1 (T1) or 10 mg/kg (T10) of tolvaptan, removal of desmopressin infusion pumps (RP), or administration of hypertonic saline. The severity of neurological impairment in the T1 group was significantly milder than in other groups and brain hemorrhage was found only in the T10 and desmopressin infusion removal groups. Minocycline inhibited demyelination in the T1 group. Further, immunohistochemistry showed loss of aquaporin-4 (AQP4) in astrocytes before demyelination developed. Interestingly, serum AQP4 levels were associated with neurological impairments. Thus, minocycline can prevent ODS caused by overly rapid correction of hyponatremia due to water diuresis associated with vasopressin action suppression. Increased serum AQP4 levels may be a predictive marker for ODS.

Effects of Switching From Another Sodium-Glucose Cotransporter 2 Inhibitor to Tofogliflozin on Nocturia in Patients With Type 2 Diabetes.

OBJECTIVE: We aimed to characterize the effects of a switch from another sodium-glucose cotransporter 2 (SGLT2) inhibitor to tofogliflozin, which has a shorter half-life, in Japanese patients with type 2 diabetes. In particular, we aimed to assess the changes in the frequency of nocturnal urination and other parameters after four months of treatment. METHODS: A cohort of 31 patients who were taking SGLT2 inhibitors other than tofogliflozin was selected for a switch to tofogliflozin. After four months, their clinical parameters were assessed. In addition, questionnaires were administered to evaluate changes in the frequency of urination during the day, the amount of water intake, and the quality of sleep of the participants at this time point. RESULTS: Data for 30 of the participants were analyzed. We documented the following comorbid conditions of the urinary system among the participants: prostatic hypertrophy (4, 13%) and prostate cancer (1, 3.3%). The SGLT2 inhibitors that the participants had been using before switching to tofogliflozin were empagliflozin (16, 53%), dapagliflozin (4, 13%), canagliflozin (8, 27%), luseogliflozin (1, 3.3%), and ipragliflozin (1, 3.3%). There was a significant decrease in the frequency of nocturnal urination, from 2.6 ± 0.83 to 2.1 ± 1.3 times (P = 0.014). However, there were no significant changes in any of the other measured parameters from baseline. The questionnaire survey showed that 10 (33%) participants experienced improvements in sleep quality. CONCLUSIONS: The switch from another SGLT2 inhibitor to tofogliflozin may reduce the frequency of nocturnal urination, implying that it may have a positive impact on the quality of life of patients with type 2 diabetes.

A Diabetic Patient with Prolonged Hyperammonemia Due to Urinary Tract Infection Caused by Urease-producing Bacteria.

Obstructive tract infection caused by urease-producing bacteria can lead to hyperammonemia. We herein report a 73-year-old woman with diabetes and compensated liver cirrhosis who developed obstructive pyelonephritis. Her consciousness level declined on day 3 of hospitalization. Blood tests revealed an elevated ammonia level of 140 µg/dL. Urine and blood cultures identified Proteus mirabilis as a urease-producing bacterium. The treatment included double J (WJ) catheter insertion and administration of antimicrobial agents. On day 7 of hospitalization, the ammonia level gradually decreased, and the patient's consciousness improved. However, despite these interventions, perinephric overflow of urine persisted, necessitating nephrectomy.

Hypothalamic Contribution to Pituitary Functions Is Recapitulated In Vitro Using 3D-Cultured Human iPS Cells.

The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.

Improved methods for the differentiation of hypothalamic vasopressin neurons using mouse induced pluripotent stem cells.

High differentiation efficiency is one of the most important factors in developing an in vitro model from pluripotent stem cells. In this report, we improved the handling technique applied to mouse-induced pluripotent stem (iPS) cells, resulting in better differentiation into hypothalamic vasopressin (AVP) neurons. We modified the culture procedure to make the maintenance of iPS cells in an undifferentiated state much easier. Three-dimensional floating culture was demonstrated to be effective for mouse iPS cells. We also improved the differentiation method with regards to embryology, resulting in a greater number of bigger colonies of AVP neurons differentiating from mouse iPS cells. Fgf8, which was not used in the original differentiation method, increased iPS differentiation into AVP neurons. These refinements will be useful as a valuable tool for the modeling of degenerative disease in AVP neurons in vitro using disease-specific iPS cells in future studies.

The effect of long-term sickness absence on coworkers in the same work unit.

After workers take long-term sickness absence due to mental disorders (LTSA-MD), the occupational stress of the coworkers in the same work unit might be affected. The aims of this study were to evaluate the effect of the incident of LTSA-MD on the coworkers' occupational stress. A retrospective cohort study of 16,032 public servants was conducted. The Brief Job Stress Questionnaire (BJSQ) was used, which was administered in 2011 and 2012. To analyze the amount of change in occupational stress, the difference between the scores of the BJSQ scales in 2011 and 2012 was calculated. After adjusting for the baseline BJSQ scales, sex, age, total number of workers, and social support, analysis of covariance of the difference between the BJSQ scales' scores showed that job stressors and stress responses worsened among the coworkers after the incident of LTSA-MD. Social support did not change among the coworkers. This study indicates that an incident of LTSA-MD in the same work unit adversely affects the coworkers' occupational stress. Focusing on the coworkers' mental state after an incident of LTSA-MD in the same work unit and an early intervention strategy are needed to prevent secondary mental illness and sickness absence in the coworkers.

Vasopressin-secreting neurons derived from human embryonic stem cells through specific induction of dorsal hypothalamic progenitors.

Arginine-vasopressin (AVP) neurons exist in the hypothalamus, a major region of the diencephalon, and play an essential role in water balance. Here, we established the differentiation method for AVP-secreting neurons from human embryonic stem cells (hESCs) by recapitulating in vitro the in vivo embryonic developmental processes of AVP neurons. At first, the differentiation efficiency was improved. That was achieved through the optimization of the culture condition for obtaining dorsal hypothalamic progenitors. Secondly, the induced AVP neurons were identified by immunohistochemistry and these neurons secreted AVP after potassium chloride stimulation. Additionally, other hypothalamic neuropeptides were also detected, such as oxytocin, corticotropin-releasing hormone, thyrotropin-releasing hormone, pro-opiomelanocortin, agouti-related peptide, orexin, and melanin-concentrating hormone. This is the first report describing the generation of secretory AVP neurons derived from hESCs. This method will be applicable to research using disease models and, potentially, for regenerative medicine of the hypothalamus.

Relationships between temperaments, occupational stress, and insomnia among Japanese workers.

Insomnia among workers reduces the quality of life, contributes toward the economic burden of healthcare costs and losses in work performance. The relationship between occupational stress and insomnia has been reported in previous studies, but there has been little attention to temperament in occupational safety and health research. The aim of this study was to clarify the relationships between temperament, occupational stress, and insomnia. The subjects were 133 Japanese daytime local government employees. Temperament was assessed using the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire (TEMPS-A). Occupational stress was assessed using the Generic Job Stress Questionnaire (GJSQ). Insomnia was assessed using the Athens Insomnia Scale (AIS). Stepwise multiple logistic regression analyses were conducted. In a stepwise multivariate logistic regression analysis, it was found that the higher subdivided stress group by "role conflict" (OR = 5.29, 95% CI, 1.61-17.32) and anxious temperament score (OR = 1.33; 95% CI, 1.19-1.49) was associated with the presence of insomnia using an adjusted model, whereas other factors were excluded from the model. The study limitations were the sample size and the fact that only Japanese local government employees were surveyed. This study demonstrated the relationships between workers' anxious temperament, role conflict, and insomnia. Recognizing one's own anxious temperament would lead to self-insight, and the recognition of anxious temperament and reduction of role conflict by their supervisors or coworkers would reduce the prevalence of insomnia among workers in the workplace.

The Usefulness of Assessing and Identifying Workers' Temperaments and Their Effects on Occupational Stress in the Workplace.

The relationship between temperaments and mental disorders has been reported in previous studies, but there has been little attention to temperaments in the occupational safety and health research. The aim of this study was to clarify the effects of temperaments on occupational stress among local government employees. The subjects were 145 Japanese daytime workers in local government. Temperaments were assessed by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire (TEMPS-A). Occupational stress was assessed using the Generic Job Stress Questionnaire (GJSQ). Hierarchical multiple linear regression analysis was used. Hyperthymic temperament predicted a higher level of job control, and a lower level of role ambiguity and job future ambiguity. Irritable temperament predicted a lower level of social support from supervisors and a higher level of role conflict, variance in workload and intragroup conflict. Anxious temperament predicted a lower level of social support from coworkers and a higher level of job future ambiguity. The sample size was small. Only Japanese local government employees were surveyed. Hyperthymic temperament played a protective role, and irritable, anxious temperament played a vulnerable role against one's own occupational stress and recognizing the roles they play in work life would lead to self-insight. Additionally, recognition of the temperaments and temperament-related stressors by one's supervisors or coworkers would facilitate provision of social support.

BMP4 and FGF strongly induce differentiation of mouse ES cells into oral ectoderm.

During embryonic development, oral ectoderm differentiates into the adenohypophysis, dental epithelia, salivary glands, and nasal pit. Few reports exist concerning the induction of oral ectoderm from embryonic stem (ES) cells. Generally, any lot differences in fetal bovine serum (FBS) and serum replacer may affect the induction of ES cell-differentiation. Using a previously established culture strategy for differentiation, the proportion of cell aggregates containing Pitx1+ oral ectoderm varied widely between 9-36% when several different lots of FBS or serum replacer were used. We therefore tried to enhance the differentiation method. We found that bone morphogenetic protein (BMP) 4 and fibroblast growth factor (FGF) treatments improved oral ectoderm induction. Such treatment also improved the differentiation of oral ectoderm into the adenohypophysis. Furthermore, increased BMP4 treatment induced dental epithelium and mesenchyme. Such differentiation suggests that the Pitx1+ layer displays similar properties to oral ectoderm, as found in vivo. Differentiation of ES cells into oral ectoderm using different lots of FBS and serum replacer increased 78-90% after treatment with BMP4 and FGF. In summary, we have established a robust strategy for the induction of oral ectoderm differentiation from mouse ES cells.

Eplerenone improved hypokalemia in a patient with Gitelman's syndrome.

A 47-year-old woman presented with hypokalemia (2.4 mmol/L). She also had hypomagnesemia, hypocalciuria, and hyperreninemic hyperaldosteronism. Sequence analysis revealed a compound heterozygous mutation, R655C and R955Q, in the SLC12A3 gene. These findings were compatible with Gitelman's syndrome (GS). Eplerenone, a selective aldosterone blocker, in combination with oral potassium chloride improved serum potassium level (3.6 mmol/L) with no apparent adverse effect. Although eplerenone has an advantage over spironolactone for its selective affinity for the aldosterone receptor, the efficacy and safety of eplerenone for GS is little understood. Our observation suggests that eplerenone is a useful treatment option for GS.