[Two rare cases of severe hyponatremia with consciousness disorder following bowel preparation and high fluid intake].

Symptomatic hyponatremia due to bowel preparation is extremely rare, but it can cause severe neurological symptoms and require hospitalization. We report our experience with two cases of symptomatic hyponatremia after bowel preparation. Our findings suggest that the cause of hyponatremia may be not only oral bowel cleansing agents but also high fluid intake. Adjusting the dose and pace of oral bowel cleansing agents and fluid intake;rehydration should be considered to prevent any recurrences.

Optimal candidates for early colonoscopy in the management of acute lower gastrointestinal bleeding.

BACKGROUND AND AIM: Early colonoscopy has not shown any advantages over elective colonoscopy in reducing the risk of early rebleeding (≤ 30 days) after acute lower gastrointestinal bleeding (ALGIB). Considering the heterogeneity among patients with ALGIB, we sought to evaluate appropriate candidates for early colonoscopy. METHODS: A total of 592 patients with ALGIB were enrolled, and the clinical outcomes of early colonoscopy were investigated. Thereafter, the participants were divided into two groups: the recent bleeding group (n = 445), with hematochezia 0-6 h before hospital arrival, and non-recent bleeding group (n = 147). The clinical outcomes yielded by early colonoscopy were assessed in each group. RESULTS: The multivariate analysis including the entire population revealed that early colonoscopy (< 24 h) did not reduce the risk of early rebleeding (adjusted odds ratio [AOR], 0.88; 95% confidence interval [CI], 0.55-1.39). However, in the subgroup analysis, early colonoscopy independently reduced the risk of early rebleeding in the recent bleeding group (AOR, 0.56; 95% CI, 0.33-0.94). Moreover, a reduction in the need for radiological or surgical intervention (AOR, 0.34), transfusion (AOR, 0.62), and prolonged hospitalization (AOR, 0.42), as well as improvement in diagnostic yield (AOR, 1.78) and endoscopic treatment rates (AOR, 1.66), were observed. Early colonoscopy did not improve the outcomes of the non-recent bleeding group. CONCLUSIONS: Early colonoscopy is not required for all patients with ALGIB. However, it may be suitable for those with hematochezia 0-6 h before hospital arrival, as it reduces early rebleeding and improves clinical outcomes.

Comparison of corneal irregular astigmatism by the type of corneal regular astigmatism.

We investigated the relation between corneal regular and irregular astigmatism in normal human eyes. In 951 eyes of 951 patients, corneal irregular astigmatism, such as asymmetry and higher-order irregularity components, was calculated using the Fourier harmonic analysis of corneal topography data within the central 3-mm zone of the anterior corneal surface. The eyes were classified by the type of corneal regular astigmatism into four groups; minimum (< 0.75 diopters), with-the-rule (WTR), against-the-rule (ATR), and oblique astigmatism. The mean age was significantly different among the four groups (P < 0.001); patients with WTR astigmatism were the youngest, followed by those with minimum, oblique, and ATR astigmatism. Significant inter-group differences were found among the four groups in asymmetry (P = 0.005) and higher-order irregularity components (P < 0.001); the largest was in eyes with oblique astigmatism, followed by ATR, WTR, and minimum astigmatism. The stepwise multiple regression analysis revealed that corneal regular astigmatism pattern significantly influenced the amount of corneal irregular astigmatism after controlling for confounding factors (P < 0.001). Corneal irregular astigmatism, such as asymmetry and higher order irregularity components, was the largest in eyes with oblique astigmatism, followed by those with ATR, WTR, and minimum astigmatism, even after adjustment for age of subjects.

Gonadal failure among female patients after hematopoietic stem cell transplantation for non-malignant diseases.

In addition to malignant diseases, hematopoietic stem cell transplantation (HSCT) is also a vital option as a curative therapy for non-malignant diseases, such as immunodeficiency, and other hematological disorders. Not only for malignant diseases, but for non-malignant diseases, cytotoxic therapy of conditioning regimens are associated with high risks of adverse effects; however, clinical details regarding the long term outcomes of cytotoxic therapy for non-malignant diseases are not documented yet. To clarify the endocrinological consequences of pediatric HSCT for non-malignant disease patients, we conducted a retrospective analysis. From 1983 to 2014, 75 patients that underwent HSCT for non-malignant diseases were selected for this study. Of these, 23 patients (19 men, 4 women) were continuously followed up in our institute, with regular health check-ups for late effects. Based on a multiple linear regression analysis, the glucocorticoid treatment duration for chronic graft-versus-host disease (cGVHD) and the conditioning regimen were found to be independent predictors of growth retardation. All four female patients developed hypogonadism, and required hormone replacement therapy. The conditioning regimen for the four female patients with hypogonadism was based on the use of alkylating agents, and two female patients were treated with a reduced-intensity conditioning (RIC) regimen. Our study revealed that even the RIC regimen was toxic for the gonads in female patients, and that the survivors of both non-malignant and malignant diseases should be followed up carefully after pediatric HSCT.

Nr5a1 suppression during the murine fetal period optimizes ovarian development by fine-tuning Notch signaling.

The nuclear receptor NR5A1 is equally expressed and required for development of the gonadal primordia of both sexes, but, after sex determination, it is upregulated in XY testes and downregulated in XX ovaries. We have recently demonstrated, in mice, that this downregulation is mediated by forkhead box L2 (FOXL2) and hypothesized that adequate suppression of Nr5a1 is essential for normal ovarian development. Further, analysis of human patients with disorders/differences of sex development suggests that overexpression of NR5A1 can result in XX (ovo)testicular development. Here, we tested the role of Nr5a1 by overexpression in fetal gonads using a Wt1-BAC (bacterial artificial chromosome) transgene system. Enforced Nr5a1 expression compromised ovarian development in 46,XX mice, resulting in late-onset infertility, but did not induce (ovo)testis differentiation. The phenotype was similar to that of XX mice lacking Notch signaling. The expression level of Notch2 was significantly reduced in Nr5a1 transgenic mice, and the ovarian phenotype was almost completely rescued by in utero treatment with a NOTCH2 agonist. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by fine-tuning Notch signaling.

Peptidyl arginine deiminase 2 (Padi2) is expressed in Sertoli cells in a specific manner and regulated by SOX9 during testicular development.

Peptidyl arginine deiminases (PADIs) are enzymes that change the charge of proteins through citrullination. We recently found Padi2 was expressed exclusively in fetal Sertoli cells. In this study, we analyzed the transcriptional regulation of Padi2 and the role of PADI2 in testicular development. We showed SOX9 positively regulated Padi2 transcription and FOXL2 antagonized it in TM3 cells, a model of Sertoli cells. The responsive region to SOX9 and FOXL2 was identified within the Padi2 sequence by reporter assay. In fetal testes from Sox9 knockout (AMH-Cre:Sox9flox/flox) mice, Padi2 expression was greatly reduced, indicating SOX9 regulates Padi2 in vivo. In vitro analysis using siRNA suggested PADI2 modified transcriptional regulation by SOX9. However, Padi2-/- XY mice were fertile and showed no apparent reproductive anomalies. Although, PADI2 is known as an epigenetic transcriptional regulator through H3 citrullination, no significant difference in H3 citrullination between wildtype and Padi2-/- XY gonads was observed. These results suggest Padi2 is a novel gene involved in testis development that is specifically expressed in Sertoli cells through the regulation by SOX9 and FOXL2 and PADI2 supports regulation of target genes by SOX9. Analysis of the Padi2-/- XY phenotype suggested a redundant factor compensated for PADI2 function in testicular development.

Molecular mechanisms of insulin resistance in 2 cases of primary insulin receptor defect-associated diseases.

BACKGROUND: Defects of the insulin receptor gene ( INSR ) cause wide spectra of congenital insulin resistance. Monoallelic defects result in milder insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN, type A). Whereas, leprechaunism (Donahue syndrome), the most severe condition with lethality during the infantile period is caused by biallelic defects of INSR . MATERIALS AND METHODS: We detected 2 missense mutations in 2 cases of leprechaunism and IRAN, type A, and reduced mRNA expression in the leprechaunism case. We performed an in vitro analysis to confirm that the 2 missense mutations are causative. RESULTS: The heterozygote mutations c.3436G>A (p.Gly1146Arg) and c.294C>A (p.Ser98Arg) were identified in a male patient with IRAN, type A and a female patient with leprechaunism, respectively. Gly1146Arg was previously reported in a diabetic case without precise functional analyses, and Ser98Arg is a novel mutation. Gly1146 and Ser98 are located on the tyrosine kinase domain and ligand-binding domain of INSR, respectively, and in vitro analyses (assay for insulin binding and phosphorylation) revealed that each mutation disrupted protein functions and properties. In the leprechaunism case, mutations in INSR other than Ser98Arg were not identified, and qRT-PCR analysis revealed that mRNA expression of INSR in lymphocytes was reduced in the leprechaunism case. CONCLUSION: Our study indicates that the 2 missense mutations of INSR , Gly1146Arg, and Ser98Arg, are responsible for insulin resistance, and, suggests that mutations not contained within INSR , but leading to decreased INSR expression should be considered for the patients who show insulin resistance without any mutations in the coding sequence of INSR.

Free T3 to free T4 ratio less than 2.0 suggests low T3 syndrome rather than central hypothyroidism from the age of two to eighteen years.

No serological cut-off exists to separate low T3 syndrome (LT) and central hypothyroidism (CH). The objective of this retrospective study was to propose such a cut-off. The first participant group comprised 52 patients from the age of six to twenty years. This group consisted of patients of 36 anorexia nervosa with LT and 16 CH. The second participant groups comprised 229 patients of all the same range of ages at the same hospital and included LT (n = 58) and CH (n = 4) patients, respectively. The third group of participants comprised 125 LT and 27 CH patients at the same hospital at all ages less than eighteen years. The last group of participants comprised 10 CH patients from the other two hospitals. The main outcome measure was fT3/fT4 ratio (pg/mL, ng/dL respectively). This ratio in the first group was significantly different (p < 0.05) between LT and CH. When the cut off value of fT3/fT4 was set as 2.0, the sensitivity of the LT and CH patients in the second group was 62% and 100%, respectively. This cut-off value of 2.0 was useful for distinguishing LT from CH only above the age of two years, as shown in the third group. The fT3/fT4 in 10 subjects with CH in the last group, aged 2 to 7 years, ranged from 2.55 to 7.71. In conclusion, fT3/fT4 less than 2.0 suggests LT rather than CH for patients from the age of two to eighteen years.

Lower body weight and BMI at birth were associated with early adiposity rebound in 21-hydroxylase deficiency patients.

21-hydroxylase deficiency (21-OHD) is the most common type of congenital adrenal hyperplasia. In addition to the clinical problems caused by adrenal insufficiency and androgen excess, a risk for obesity and metabolic syndrome during young adulthood is a major ramification of the disease. Although glucocorticoid therapy is very likely to be one of the contributory factors, the precise causes of the metabolic status of adult 21-OHD patients remain to be clarified. Previously we reported that 21-OHD patients developed early onset AR, a condition which might create a risk for obesity and metabolic syndrome in adulthood. In order to elucidate the association between the onset of AR and factors during the fetal period to early infancy, we conducted a retrospective longitudinal analysis of 29 21-OHD patients (male: 14 cases, female: 15 cases, salt wasting type: 16, simple virilizing type: 13), who were identified by newborn screening and followed up at least until the age 10 years. Body size at birth, lower body weight, and lower BMI were found to precipitate the timing of AR. On the other hand, no significant association was observed between the timing of AR and sex, gestational age, treatment regimen (including cumulative dose of HDC), and disease severity (the type of the disease, the value of DHEA-S and 17-OHP). There are two points to consider: first, in 21-OHD patients treated with glucocorticoid substitution therapy, the risk for early AR cannot be reduced by adjusting the dose of glucocorticoid; second, fetal factors might affect the metabolic status of 21-OHD patients.

A 45,X/46,XY DSD (Disorder of Sexual Development) case with an extremely uneven distribution of 46,XY cells between lymphocytes and gonads.

In 45,X/46,XY DSDs, the proportion of the two cell lineages is uneven in different organs and tissues, and 45,X and 46,XY cells can be found throughout the body. The gonadal development of 45,X/46,XY patients depends on the population of 46,XY cells in the gonads and the clinical features are variable. We had a 45,X/46,XY DSD patient whose 46,XY population in peripheral blood was extremely low, less than 0.2%, and was not detected by FISH analysis. However, the patient showed bilateral testicular development and more than 50% of the cells in the gonads had the 46,XY karyotype. This case suggests that a drastically imbalanced distribution could occur in 45,X/46,XY DSD cases.

Receptor-independent infection by mutant viruses newly isolated from the neuropathogenic mouse hepatitis virus srr7 detected through a combination of spinoculation and ultraviolet radiation.

The mouse hepatitis virus (MHV) has a high mutation rate, leading to various neuropathologies after infection. The srr7 mutant was isolated from the MHV strain cl-2, which induces characteristic spongiform degeneration in the brain. To investigate outcomes of srr7 infection, we re-cloned srr7(H2) from the viral stock srr7(Mix). During this re-cloning, we obtained the mutant viruses, Mu-1, Mu-2, and Br-1 which was isolated from the mice brain infected with srr7(Mix). We examined mutant viruses for infectivity independent of the major MHV receptor (MHVR), because these mutants exhibited high virulence similar to cl-2, which is MHVR-independent. To confirm MHVR-independence in vitro, we used a combination of spinoculation and ultraviolet radiation to detect distinct plaque formation (SpinoPlaque(UV+)) afrer infection of BHK cells, which do not express MHVR. Using this technique, we found that the unique neuropathologies caused by infection with the mutant viruses result from infecting neurons, which do not express MHVR. Infection with the mutant viruses was 100% correlated with SpinoPlaque(UV+) formation. This is in contrast to infection with srr7, which does not from SpinoPlaque(UV+).

Spongiform degeneration induced by neuropathogenic murine coronavirus infection.

Soluble receptor-resistant mutant 7 (ssr7) is isolated from a highly neurovirulent mouse hepatitis virus (MHV) JHMV cl-2 strain (cl-2). srr7 exhibits lower virulence than its maternal strain in infected mice, which is typically manifested in a longer lifespan. In this study, during the course of infection with srr7, small spongiotic lesions became apparent at 2 days post-inoculation (pi), they spread out to form spongiform encephalopathy by 8 to 10 days pi. We recently reported that the initial expressions of viral antigens in the brain are detected in the infiltrating monocyte lineage and in ependymal cells. Here, we demonstrate that the next viral spread was observed in glial fibrillary acidic protein-positive cells or nestin-positive progenitor cells which take up positions in the subventricular zone (SVZ). From this restricted site of infection in the SVZ, a large area of gliosis extended deep into the brain parenchyma where no viral antigens were detected but vacuolar degeneration started at 48 h pi of the virus. The extremely short incubation period compared with other experimental models of infectious spongiform degeneration in the brain would provide a superior experimental model to investigate the mechanism of spongiotic lesions formation.

Cytopathy of an infiltrating monocyte lineage during the early phase of infection with murinecoronavirus in the brain.

Viral spread during the early stages after infection was compared between a highly neurovirulent mouse hepatitis virus (MHV), JHMV cl-2 strain (cl-2), and its low-virulent mutant, soluble-receptor-resistant (srr)7. The infection of cells with srr7 (soluble-receptor-resistant mutant 7) is dependent on a known MHV receptor (MHVR), carcinoembryonic cell adhesion molecule 1a, whereas cl-2 shows MHVR-independent infection. Initial viral antigens were detected between 12 and 24 h post-inoculation (p.i) in the infiltrating cells that appeared in the subarachnoidal space of mouse brains infected with viruses. There were no significant differences in the intensity or spread of viral antigens in the inflammatory cells between the two viruses. However, 48 h after infection with cl-2, viral antigen-positive cells in the grey matter with the shape of neurons, which do not express MHVR, were detected, while srr7 infection was observed primarily in the white matter. Some of the viral antigen-positive inflammatory cells found in the subarachnoidal space during the early phase of infection reacted with anti-F4/80 or anti-CD11b monoclonal antibodies. Syncytial giant cells (SGCs) expressing viral and CD11b antigens were also detected among these inflammatory cells. These antigen-positive cells appeared in the subarachnoidal space prior to viral antigen spread into the brain parenchyma, indicating that viral encephalitis starts with the infection of infiltrating monocytes which express MHVR. Furthermore, the observation indicates that viral infection has cytopathic effects on the monocyte lineage, which plays a critical role in innate immunity, leading to the rapid spread of viruses during the early stage of infection.