Obstetrical correlates and perinatal consequences of neonatal hypoglycemia in term infants.

OBJECTIVE: To determine independent perinatal and intrapartum factors associated with neonatal hypoglycemia. METHOD: Of singleton pregnancies delivered at term in 2013; 318 (3.8%) neonates diagnosed with hypoglycemia were compared to 7955 (96.2%) neonate controls with regression analysis. RESULTS: Regression analysis showed that independent prenatal factors were multiparity (odds-ratio [OR] = 1.61), gestational age (OR = 0.68), gestational diabetes (OR = 0.22), macrosomia (OR = 4.87), small for gestational age neonate [SGA] (OR = 6.83) and admission cervical dilation (OR = 0.79). For intrapartum factors, only cesarean section (OR = 1.57) and last cervical dilation (OR = 0.92) were independently significantly associated with neonatal hypoglycemia. For biologically plausible risk factors, independent factors were cesarean section (OR = 4.18), gentamycin/clindamycin in labor (OR = 5.35), gestational age (OR = 0.59) and macrosomia (OR = 5.62). Mothers of babies with neonatal hypoglycemia had more blood loss and longer hospital stays, while neonates with hypoglycemia had worse umbilical cord gases, more neonatal hypoxic conditions, neonatal morbidities and NICU admissions. CONCLUSION: Diabetes was protective of neonatal hypoglycemia, which may be explained by optimum maternal glucose management; nevertheless macrosomia was independently predictive of neonatal hypoglycemia. Cesarean section and decreasing gestational age were the most consistent independent risk factors followed by treatment for chorioamnionitis and SGA. Further studies to evaluate these observations and develop preventive strategies are warranted.

Outcome comparison of ABO-incompatible kidney transplantation with low-dose rituximab and ABO-compatible kidney transplantation: a single-center experience.

BACKGROUND: The development of immunosuppressive techniques has helped overcome the ABO incompatibility barrier. However, the outcomes of ABO-incompatible (ABOi) kidney transplantation remain a controversial issue with the advent of the anti-CD20 chimeric antibody rituximab. Herein, we report the outcomes of ABOi kidney transplantation with low-dose rituximab. PATIENTS AND METHODS: Between June 2006 and April 2013, 42 patients underwent living-related kidney transplantation at our hospital. The patients were divided into 2 groups: ABO-compatible (ABOc; n = 29) and ABOi kidney transplants using low-dose rituximab (100 mg/m(2)) without splenectomy (n = 13). The basic immunosuppression regimen (calcineurin inhibitor [CNI], mycophenolate mofetil [MMF], and steroids) was the same for both groups, except for the use of rituximab and therapeutic apheresis in the ABOi group. We compared post-transplantation renal function, incidents of virus infection, episodes of rejection, and graft survival between the 2 groups. RESULTS: In our hospital, 30% of recipients received ABOi kidney transplants. The estimated glomerular filtration rate (eGFR) did not differ between the groups. Rejection episodes confirmed by biopsy in the ABOc and ABOi groups were 8 (28%) and 4 (31%) patients (P = .833), acute antibody-mediated rejection was observed in 1 (3.5%) and 2 (15%) patients (P = .165), and virus infection was observed in 14 (48%) and 3 (23%) patients (P = .252), respectively. The 5-year patient survival rate was 100% in both groups, and the 5-year graft survival rates were 95% for ABOc and 100% for ABOi transplants (P = .527). CONCLUSIONS: These results suggest that the outcomes of ABOi kidney transplantation with low-dose rituximab are similar to those of ABOc kidney transplantation. Further study is necessary to address the efficacy and safety of ABOi kidney transplantation.

Involvement of estrogen receptor ß in maintenance of serotonergic neurons of the dorsal raphe.

The serotonergic neurons of the dorsal raphe (DR) nucleus in the CNS are involved in fear, anxiety and depression. Depression and anxiety occur quite frequently in postmenopausal women, but estrogen replacement to correct these CNS disorders is at present not favored because estrogen carries with it an increased risk for breast cancer. Serotonin synthesis, release and reuptake in the DR are targets of pharmaceuticals in the treatment of depression. In the present study we have examined by immunohistochemistry, the expression of two nuclear receptors, that is, the estrogen receptors ERα and ERß. We found that ERß but not ERα is strongly expressed in the DR and there is no sex difference and no change with ageing in the number of tryptophan hydroxylase (TPH)-positive neurons in the DR of wild-type (WT) mice. However, in ovariectomized (OVX) WT and in ERß(-/-) mice, there was a marked reduction in the number of TPH-positive normal-looking neurons and a marked increase in TPH-positive spindle-shaped cells. These neuronal changes were prevented in mice 1-3 weeks (but not 10 weeks) after OVX by the selective ERß agonist, LY3201, given as continuous release pellets for 3 days. The ERß agonist had no effects on glucose homeostasis. Thus, the onset of action of the ERß agonist is rapid but there is a limited window in time after estrogen loss when the drug is useful. We conclude that, rather than estradiol, ERß agonists could be useful pharmaceuticals in maintaining functional DR neurons to treat postmenopausal depression.

Factors affecting assessment of severity of aggressive incidents: using the Staff Observation Aggression Scale - Revised (SOAS-R) in Japan.

The aim of this study is to investigate factors associated with overall judgements of aggression severity as provided by ward nurses, using the Japanese-language version of the Staff Observation Aggression Scale - Revised (SOAS-R). Nurses who observed 326 aggressive incidents involving psychiatric inpatients at five mental health facilities in Japan provided their assessments of the incident severity both on the established rating scale, the SOAS-R, and on a visual analogue scale (VAS), a one-item scale to indicate overall aggression severity. To evaluate the factors influencing the VAS severity scores, a multiple regression analysis was performed, in which consumer, nurse and ward characteristics were added consecutively, along with SOAS-R severity scores as independent variables. SOAS-R scores explained 17.6% of the VAS severity scores. Independently from the SOAS-R scores, the gender and age of the aggressive consumers (adjusted R(2) = 10.0%), as well as the gender of the nurses who reported the aggression (adjusted R(2) = 4.1%), each explained VAS severity score to a significant degree. Apart from the SOAS-R scores, consumer and nurse characteristics appeared to influence the overall judgements of severity of aggressive incidents, which may be connected to decisions about the use of coercive measures, such as seclusion/restraint or forced medication.

T cell-specific overexpression of interleukin-27 receptor α subunit (WSX-1) prevents spontaneous skin inflammation in MRL/lpr mice.

BACKGROUND: Interleukin (IL)-27 and WSX-1, the receptor α-specific subunit, have been shown to play important roles in initiating Th1 responses and in inducing immune modulation, and the immunosuppressive effect of IL-27 appears to be exerted via suppression of IL-10 and IL-17, which may participate in the pathogenesis of human systemic lupus erythematosus (SLE). OBJECTIVES: To examine the significance of IL-27/WSX-1 signalling in spontaneous skin inflammation of MRL/lpr mice, a model for SLE. METHODS: The severity and development of skin lesions, dermal inflammatory cells and epidermal-dermal depositions in the skin lesions of MRL/lpr mice with CD2-promoted WSX-1 overexpression (WSX-1 Tg mice) and those with globally disrupted WSX-1 (WSX-1 KO mice) were examined and compared with those of MRL/lpr mice. RESULTS: By 4 months of age, both WSX-1 KO mice and control MRL/lpr mice developed predominantly similar skin inflammation, while WSX-1 Tg mice hardly did so, demonstrating that intensifying IL-27/WSX-1 signalling on T cells prevents the spontaneous skin inflammation. WSX-1 KO mice showed Th2-type skin inflammation as evidenced by the Th2-prone dermal infiltrating cells and an absence of cutaneous Th1-type IgG deposition. Interestingly, there were significant IL-17+ dermal infiltrating cells in both WSX-1 KO and control MRL/lpr mice, which might potentially contribute to the formation of skin inflammation in these mice. CONCLUSIONS: These data indicate that IL-27/WSX-1 signalling may play a protective role in the development of SLE-like skin inflammation, and modulating IL-27/WSX-1 signalling might be an interesting therapeutic strategy in the treatment of SLE.

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain.

This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERalpha and ERbeta1 were widely distributed throughout the brain. Sucrose density gradient sedimentation followed by western blotting supported the histochemical evidence for high levels of both ERs at P7. Over the following 2 days, there was a rapid downregulation of ERs. At P9, ERalpha expression was visible only in the hypothalamic area. Decline in ERbeta1 expression was slower than that of ERalpha, and ERalpha-negative, ERbeta1-positive cells were observed in the dentate gyrus and walls of third ventricle. Between P14 and P35, ERs were undetectable except for the hypothalamic area. As before P7, the ovary does not produce estrogen but does produce 5alpha-androstane-3beta, 17beta-diol (3betaAdiol), an estrogenic metabolite of dihydrotestosterone, we examined the effects of high levels of 3betaAdiol in the postnatal period. We used CYP7B1 knockout mice which cannot hydroxylate and inactivate 3betaAdiol. The brains of these mice are abnormally large with reduced apoptosis. In the early postnatal period, there was 1-week delay in the timing of the reduction in ER expression in the brain. These data reveal that the time when ERs might be activated in the brain is limited to the first 8 postnatal days. In addition, the importance of aromatase has to be reconsidered as the alternative estrogen, 3betaAdiol, is important in neuronal function in the postnatal brain.

DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles.

BACKGROUND: Factor Xa (FXa), a key serine protease that converts prothrombin to thrombin in the coagulation cascade, is a promising target enzyme for the prophylaxis and treatment of thromboembolic diseases. DU-176b is a novel antithrombotic agent that directly inhibits FXa activity. OBJECTIVE: To evaluate the in vitro pharmacological profiles and in vivo effects of DU-176b in animal models of thrombosis and bleeding. METHODS: In vitro, FXa inhibition, specificity and anticoagulant activities were examined. Oral absorption was studied in rats and cynomolgus monkeys. In vivo effects were studied in rat and rabbit models of venous thrombosis and tail bleeding. RESULTS: DU-176b inhibited FXa with Ki values of 0.561 nm for free FXa, 2.98 nm for prothrombinase, and exhibited >10 000-fold selectivity for FXa. In human plasma, DU-176b doubled prothrombin time and activated partial thromboplastin time at concentrations of 0.256 and 0.508 microm, respectively. DU-176b did not impair platelet aggregation by ADP, collagen or U46619. DU-176b was highly absorbed in rats and monkeys, as demonstrated by more potent anti-Xa activity and higher drug concentration in plasma following oral administration than a prototype FXa inhibitor, DX-9065a. In vivo, DU-176b dose-dependently inhibited thrombus formation in rat and rabbit thrombosis models, although bleeding time in rats was not significantly prolonged at an antithrombotic dose. CONCLUSIONS: DU-176b is a more potent and selective FXa inhibitor with high oral bioavailability compared with its prototype, DX-9065a. DU-176b represents a promising new anticoagulant for the prophylaxis and treatment of thromboembolic diseases.

Monosomy and trisomy of 15q24-qter with cleft lip and palate.

Chromosome 15 aberrations clinically present as facial dysmorphisms such as a prominent nose, low-set ears, micrognathia and a short neck; a cleft lip and palate have not been reported. This is the first reported case of de-novo terminal deletion at 15q24 with a cleft lip and palate and low-set ears. The baby boy had a complete cleft lip and palate on the left side and incomplete cleft lip and palate on the right. A chromosomal study revealed partial monosomy and trisomy of the long arm of chromosome 15, with a karyotype of 46,XY,add(15)(24q) de novo. Surgery for lip plasty was performed at 6 months old and for palate plasty at 1 year and 9 months. Both operations were uneventful, although preoperative and postoperative examinations showed high creatinine phosphokinase values. At 3 years old, mild mental retardation was observed, but his physical development was normal.

Amelioration of human lupus-like phenotypes in MRL/lpr mice by overexpression of interleukin 27 receptor alpha (WSX-1).

OBJECTIVE: In the present work, we investigate the role of interleukin (IL)27/IL27 receptor alpha (Ralpha) (WSX-1) in the development of autoimmune disorders in the MRL/lpr mouse, which is considered as an experimental model of systemic lupus erythaematosus (SLE) in humans. METHODS: We generated two strains of WSX-1 transgenic mice in the MRL/lpr background with different expression levels of WSX-1, and investigated the effect of WSX-1 overexpression on survival, glomerulonephritis and immunological properties. RESULTS: In comparison with wild type (WT) MRL/lpr and transgenic (Tg) low (TgL) mice, Tg high (TgH) mice exhibited a prolonged lifespan and no apparent development of autoimmune nephritis. Production of anti-dsDNA antibody and total IgG and IgG2a were significantly lower in TgH mice than those of TgL and WT mice. The expressed amounts of interferon (IFN)gamma and IL4 mRNA by CD4+ T cells from Tg mice decreased in a dose-dependent fashion. CD4+ splenic lymphocytes in TgH mice were more subject to the IL27-mediated suppression of cytokine production. In vitro stimulation of CD4+ T cells by IL27 resulted in over phosphorylation of STAT3 in TgH cells than in WT cells. CONCLUSION: WSX-1 overexpression in the MRL/lpr background rendered the autoimmune prone mice protected from the development of autoimmune diseases. Our results suggest that IL27 signalling may be a therapeutic target against autoimmune diseases, including human SLE.

Complete nucleotide sequence of a Japanese isolate of Chrysanthemum virus B (genus Carlavirus).

The complete nucleotide sequence of a Chrysanthemum virus B isolate from Japan (CVB-S) has been determined. The genomic RNA of CVB-S is 8,990 nucleotides long, excluding the poly(A) tail and, like that of other carlaviruses, contains six open reading frames (ORFs). Multiple alignment and phylogenetic analyses indicated that the phylogenetic relationship among members of the genus Carlavirus is very diverse, with phlox virus S being the closest relative of CVB. In aphid transmission tests, CVB-S was transmitted at a very low rate by Aphis gossypii, a new vector of the virus.

Inhaling gas with different CT densities allows detection of abnormalities in the lung periphery of patients with smoking-induced COPD.

STUDY OBJECTIVES: To establish a novel method allowing detection of regional abnormalities in gas distribution at the acinar level by high-resolution CT (HRCT). PARTICIPANTS: Nonsmoking control subjects (n = 28) and patients with smoking-induced COPD (n = 47). MEASUREMENTS AND RESULTS: Changes in lung CT densities were examined by HRCT while the subjects inhaled a gas mixture consisting of 21% O(2) in SF(6) or 21% O(2) in He. HRCT images of the right upper and lower lung fields were obtained at the end of inspiration and expiration of the second and 60th breaths after the start of each gas. Introducing mean lung density (MLD) and relative area with low CT attenuation (%LAA), we analyzed the differences in acinar SF(6) and He distribution in the early phase (second breath) and in the equilibrium state (60th breath). We found that the differences in inspiratory MLD between the SF(6) and He images at the 60th breath were qualitatively consistent with the differences predicted from the physical properties of these gases. However, the differences in inspiratory MLD between the SF(6) and He images taken at the second breath were smaller than those at the 60th breath, especially in the smoking group with COPD. These differences in second-breath inspiratory MLD in the smoking group were smaller in the upper lung field than in the lower lung field. The differences in MLD between the two gases were not detected at end-expiration at the time of either the second or 60th breaths. The %LAA values did not differ between the SF(6) and He images in either the nonsmoking group or the smoking group. CONCLUSIONS: SF(6)/He-associated HRCT images obtained at end-inspiration, but not at end-expiration, in the early breathing phase are useful for predicting acinar gas distribution abnormalities in patients with COPD.

Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells.

We report a 62-year-old Japanese man with familial frontotemporal dementia and a novel missense mutation (N296H) in exon 10 of the tau gene. The patient presented with frontal signs followed by temporal signs and parkinsonism. The brain showed localized frontotemporal lobe atrophy including the precentral gyrus and discoloration of the substantia nigra, and revealed severe neuronal loss with proliferation of tau-positive protoplasmic astroglia in the affected cerebral cortex, tau-positive coiled bodies and threads in the subcortical white matter, and tau-positive pretangle neurons in the subcortical and brain stem nuclei. There were no tau-positive neurofibrillary tangles, Pick bodies, tuft-shaped astrocytes or astrocytic plaques in the cerebral cortex. Immunoelectron microscopically, phosphorylated tau accumulated in both neurons and glial cells in different modalities, such as glial filaments in protoplasmic astroglia, straight tubules in coiled bodies, and free ribosomes in pretangle neurons. These findings suggest that tau proteins are not always assembled in abnormal filaments such as twisted ribbons, paired helical filaments and straight tubules in neurons and glial cells, which have been shown in previous cases with frontotemporal dementia and parkinsonism linked to chromosome 17. Immunoblotting of sarkosyl-insoluble tau exhibited accumulation of four-repeat tau isoforms in the brain. The N296H mutation may interfere with the ability of mutated tau to bind with microtubules and lead to tau aggregation. Further study is necessary to determine whether this mutation can account for the characteristic tau pathology of this case.

Enhanced proliferation and differentiation of rat hepatocytes cultured with bone marrow stromal cells.

Liver transplantation is the only clinically effective method of treating acute liver failure. However, wider application of this therapeutic modality is restricted primarily by shortage of donor organs. In the search for alternative methods of liver replacement therapy, investigators have focused on transplantation of normal allogeneic hepatocytes and on the development of liver support systems utilizing isolated hepatocytes. Since all human livers suitable for cell harvest are being used for transplantation, hepatocyte therapy using human tissue would require growing of cells in vitro. Unfortunately, although hepatocytes have tremendous capacity to proliferate in vivo, their ability to grow in culture is severely limited. Stromal cells from bone marrow and other blood-forming organs have been found to support hematopoiesis. In this paper, we show that bone marrow-derived stromal cells (BMSCs) enhance proliferation and support differentiation of rat hepatocytes in culture. Further, we demonstrate that in hepatocyte/BMSC co-cultures, clonal expansion of small hepatocytes (SH) is increased. Using semipermeable membrane cultures, we established that direct cell-cell contact is necessary for stimulation of cell proliferation. We also show that BMSCs which are in direct contact with hepatocytes and SH colonies express Jagged1. This suggests a potential role for Notch signaling in the observed effects. Finally, we present evidence that the expression and activity of liver specific transcription factors, CCAAT/enhancer binding proteins and liver specific key enzymes such as tryptophan 2,3-dioxygenase, are improved in hepatocyte/BMSC co-cultures. In conclusion, results of this study indicate that BMSCs could facilitate proliferation and differentiation of primary rat hepatocytes and their progenitors (SH) in vitro.

Light regulation of circadian clock-controlled gene expression in rice.

Using transgenic rice seedlings expressing a firefly luciferase (luc) gene under the control of a rice CAB (chlorophyll a/b binding protein) promoter, we demonstrated how light affects circadian clocks in the transcription of the CAB gene. Rhythmic luc expression was observed for more than 5 d under constant light and dark (DD) conditions after light/dark entrainment. After a light pulse was applied at different time points in DD various temporal patterns of CAB gene expression were individually observed. We first examined two distinct properties related to the entrainment mechanism of the circadian clock: fluence-rate dependence of free-running periods (FRPs) and phase resetting by a light pulse. Although fluence-rate dependent shortening of FRP was demonstrated, the FRP in DD was almost equal to that in constant light of a middle fluence-rate, indicating that this fluence-rate dependence may not fully describe the entrainment of the circadian clock in rice. Typical phase responses of the circadian clock by a single light pulse were also observed at the transcriptional level in rice seedlings. Thus, the phase resettings upon the light/dark transitions of daily cycles may be sufficient to explain the entrainment mechanisms of rice. We have further demonstrated that, in addition to having a gating effect to acute response, a light pulse can activate the circadian clock-controlled CAB1R gene expression at the first circadian peak in a phase-dependent manner. This suggests that light activates circadian clock activity in the diurnal CAB gene expression under daily light/dark cycles.

A pediatric patient with classical citrullinemia who underwent living-related partial liver transplantation.

Patients with inborn errors of metabolism undergo liver transplantation, but the effect of transplanting the liver of healthy carriers of these conditions has not been fully clarified. A 6-year-old girl with classical citrullinemia, who repeatedly suffered from hyperammonemia, underwent living-related liver transplantation by using a segment of the liver of her mother, who was a heterozygote carrier for classical citrullinemia. Hyperammonemia alleviated in the patient after the transplantation, thereby dramatically improving her quality of life. Although the levels of plasma and urinary citrulline remained high postoperatively, there was no marked difference in the level of plasma citrulline up to 1 month after surgery when compared with that of previously reported orthotopic liver transplantation cases with classical citrullinemia.

The association of high jugular bulb venous oxygen saturation with cognitive decline after hypothermic cardiopulmonary bypass.

UNLABELLED: This study was conducted to investigate whether jugular bulb venous oxygen saturation (SjVO(2)) predicted cognitive decline after cardiac surgery with hypothermic cardiopulmonary bypass (CPB). We studied 35 patients undergoing cardiac surgery. After the induction of anesthesia, a 5.5F fiberoptic oximetry catheter was retrogradely inserted into the jugular bulb, and SjVO(2) and other cerebral oxygenation variables were analyzed before, during, and after CPB. At each point, an oxyhemoglobin dissociation curve was drawn, and the P(50) value of jugular bulb venous blood was calculated by computer analysis. Cognitive function was assessed with the revised version of Hasegawa's Dementia Scale and the Benton Revised Visual Retention Test before and early after the operation. In 15 patients (the Decline group), cognitive function was declined after surgery, whereas it remained unchanged in 20 patients (the Normal group). SjVO(2) was significantly higher and cerebral oxygen extraction was significantly lower before and during CPB in the Decline group than in the Normal group (P < 0.05). The oxygen pressure at an oxygen saturation of 50% was significantly lower before and after CPB in the Decline group than in the Normal group (P < 0.05). Logistic regression analysis showed that high SjVO(2) was a predictor of cognitive decline after cardiac surgery. We conclude that high SjVO(2) was associated with cognitive decline after cardiac surgery with hypothermic CPB. IMPLICATIONS: Jugular bulb venous oxygen desaturation has been suggested as a predictor of cognitive decline after cardiac surgery. However, the clinical value of jugular bulb venous oxygen saturation (SjVO(2)) may be limited during hypothermic cardiopulmonary bypass (CPB) when oxygen affinity to hemoglobin is increased. This study shows that high SjVO(2) before and during hypothermic CPB is a predictor of subsequent cognitive decline.

No evidence of an association between CYP2D6 polymorphisms among Japanese and dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most frequent degenerative dementia among the elderly, following Alzheimer-type dementia (ATD). An association of DLB with CYP2D6*4, one of the cytochrome P450IID6 (debrisoquine 4-hydroxylase; CYP2D6) gene polymorphisms, was reported previously, but this is controversial. Moreover, these reports have been restricted to Caucasian populations. Therefore, we compared frequencies of CYP2D6*3, *4, and *10 mutant alleles in 17 Japanese DLB patients to those among Alzheimer-type dementia (ATD) patients and healthy controls. Polymerase chain reaction amplification and restriction fragment length polymorphism analyses were used for genotyping. No significant difference of genotype or mutant allele frequencies was detected between DLB, ATD, and healthy controls. The present results do not support the suggestion that the CYP2D6 gene is related to DLB susceptibility, at least in the Japanese population.