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Hirayama disease is a rare neuromuscular disorder with peak age of onset at 15 to 17 years among young males. We report a male adolescent presenting with symmetric weakness and atrophy of bilateral upper extremities progressing for 2 years before stabilizing. Otherwise, he did not complain of any sensory disturbance. Electrophysiological findings revealed motor neuron damage at the C7-T1 spinal segments. Cervical magnetic resonance imaging revealed a high-signal mass of posterior dural sac at the C5-T5 vertebral level during neck flexion. Specifically, he had elevated serum total immunoglobulin E level, which had been postulated to be a precipitating factor in Hirayama disease. Early recognition and intervention of this unique neuromuscular disorder is important to avoid ongoing damage to motor neurons. Through this report, we would like to emphasize the crucial role of a pediatric neurologist in averting the progression of Hirayama disease at an early stage.

The expression of chemokines is critical in leukocyte recruitment and inflammation, but the regulatory mechanisms involved remain incompletely defined. While endocrine disrupter chemicals (EDCs) are known to be ubiquitous in the environment and often associated with altered inflammatory response, their potential impact on chemokine expression in monocytes is at present unknown. To this end, the effects of EDCs on the expression of Th1- and Th2-related chemokines in a human monocytic cell line, THP-1, were investigated. THP-1 cells were pre-treated with varying concentrations of EDCs (nonylphenol and 4-octylphenol) with or without the addition of an estrogen receptor (ER) antagonist, ICI 182,780 and then stimulated by lipopolysaccharide (LPS). The levels of chemokines, CXCL10/ IFN-alpha-inducible protein 10 (IP-10, a Th1 chemokine) and monocyte-derived chemokine (MDC)/CCL22, a Th2 chemokine) were measured by ELISA. EDC-mediated signaling events and histone modifications were examined by the use of Western blotting and chromatin immunoprecipitation (ChIP) assay. Nonylphenol and 4-octylphenol were able to suppress LPS-induced MDC and IP-10 expression. This suppressive effect was not reversed by the addition of ICI 182,780. Nonylphenol and 4-octylphenol reduced LPS-induced activation of MAPK signaling pathway, MKK1/2 and ERK, concomitant with decreased levels of LPS-induced acetylated histone 4 (H4) at the IP-10 and MDC gene loci. Nonylphenol and 4-octylphenol suppressed LPS-induced MDC expression in monocytes via, at least in part, the MKK1/2-ERK MAPK pathway and histone H4 acetylation, but not the estrogen receptor.

Background: Exposure to environmental endocrine-disrupting chemicals (EDCs) is often associated with dysregulated immune homeostasis, but the mechanisms of action remain unclear., Objectives: The aim of this study was to test a hypothesis that EDCs regulate the functions of human dendritic cells, a front-line, immunoregulatory cell type in contact with the environment., Methods: We investigated circulating myeloid dendritic cells (mDCs) from five subjects and measured their responses, with or without coculture with autologous T cells, to two common EDCs, nonylphenol (NP) and 4-octylphenol (4-OP). EDC-associated cytokine responses, signaling events, and histone modifications were examined using ELISA, Western blotting, and chromatin immunoprecipitation (ChIP) assays, respectively., Results: In all cases, mDCs treated with NP or 4-OP demonstrated increased expression of tumor necrosis factor-alpha (TNF-alpha) but decreased baseline and lipopolysaccharide (LPS)-induced (interleukin) (IL)-10 production; the increase in TNF-alpha was partially reversible by an estrogen receptor (ER) antagonist. Activation of the MKK3/6-p38 signaling pathway marked the effect of NP on TNF-alpha expression, concomitant with enhanced levels of methyltranferase complex [mixed-lineage leukemia (MLL) and tryptophan-aspartic acid repeat domain 5 (WDR5)] in the nucleus and of trimethylated H3K4, acetylated H3, and H4 at the TNFA gene locus. Further, up-regulated TNF-alpha expression was significantly suppressed in NP-treated mDCs by a histone acetyltransferase inhibitor. In the presence of NP-treated mDCs, T cells showed increased levels of IL-13 but decreased expression of interferon-gamma., Conclusions: These results suggest that NP and 4-OP may have functional effects on the response of mDCs via, in part, the ER, MKK3/6-p38 MAPK signaling pathway, and histone modifications, with subsequent influence on the T-cell cytokine responses.

Background: One of the most common complications in infants under parenteral nutrition treatment is parenteral nutrition-associated cholestasis (PNAC). The etiology of PNAC is thought to be multifactorial. The aims of this study were to evaluate the risk factors for PNAC in our neonatal intensive care unit and determine useful predictors., Methods: This study enrolled premature infants (gestational age <36 weeks) who were admitted to our neonatal intensive care unit and treated with parenteral nutrition infusion for at least 2 weeks between January 2004 and January 2007. Multiple possible risk factors were analyzed by a retrospective review study design. PNAC was defined as direct bilirubin greater than 1.5 mg/dL during parenteral nutrition., Results: A total of 62 premature infants with prolonged course of parenteral nutrition were eligible for this study; 11 (17.74%) of the infants developed PNAC. There were significant differences in terms of gestational age, birth body weight, duration of parenteral nutrition, septic episodes, and average energy intake during the 2nd and 3rd weeks of life between infants with cholestasis and those without cholestasis. Of these risk factors, the duration of parenteral nutrition was most significant after multivariate logistic regression analysis., Conclusion: Young gestational age, low birth body weight, more sepsis episodes, and long duration of parenteral nutrition were significant risk factors for PNAC in our study. Low energy intake during the 2nd and 3rd weeks of life is a predictor for PNAC.

Background: Multiple packed red blood cell (PRBC) transfusions in very low birth weight (VLBW) prematurity have been suggested to be a risk factor for the development of retinopathy of prematurity (ROP) or for chronic lung disease (CLD). The purpose of this study was to examine the effect of PRBC transfusions on the outcome of VLBW prematurity., Methods: In total, between July 2005 and June 2006, 36 VLBW preterm babies were admitted to our neonatal intensive care unit and were randomly allocated to the "restrictive" (n= 19) or "liberal" (n= 17) criteria for PRBC transfusion. Complete blood count (CBC) was examined at admission and 30 days later. Reticulocyte counts, serum iron and ferritin were examined and compared with the clinical outcomes., Results: Infants in the liberal group received a larger PRBC transfusion volume compared with the restrictive group over 30 days (41.7+/-20.1 vs. 27.2+/-15.9mL, p=0.029). There were no significant differences in the proportion of patients with respiratory distress syndrome, patent ductus arteriosus, severe intraventricular hemorrhage, ROP or CLD between the two groups. The laboratory data, except reticulocyte count, showed no significant difference on day 30. Further analysis of premature babies with and without CLD showed that total transfused blood volume greater than 30mL over 30 days was a risk factor for developing CLD in VLBW infants., Conclusion: Both criteria of PRBC transfusion had similar clinical outcomes, although liberal transfusion resulted in a greater amount of blood transfused and a low reticulocyte count at 30 days of age. We suggest restrictive criteria for minimizing the overall amount of transfusion to less than 30 mL may be a better way of preventing CLD in VLBW infants.

Background: Emerging evidence indicates that early adverse experiences result in the maladaptive development of the hypothalamic-pituitary-adrenal (HPA) axis and compromise the developing brain to subsequent neurological insults. Well known that mother-infant interaction plays an important role in early environment stimulation, neonatal isolation (NI) paradigm has been used as an early-life stress model in many relevant studies. Further, the effect of seizure on the developing brain is still not clarified despite more susceptibility to seizures of the developing brain. We had previously demonstrated that NI exacerbates cognitive deficit following early-life seizure. The aim of the current study was to investigate whether NI predisposes the brain to early-life seizure-induced long-term anxiety sequelae., Methods: Rats were assigned randomly to the following four groups: (1) normal rearing rats (NR); (2) NI rats that underwent daily separation from their dams from postnatal day 2 (P2) to P9; (3) NR rats suffering lithium-pilocarpine-induced status epilepticus (SE) at P10 (NR+SE); and (4) NI+SE rats. At P60, anxiety-related behavior was evaluated using elevated plus-maze (EPM) test., Results: SE induced in isolated rats rather than in NR rats produced a decrease in percentage of time spent in open arms, and all rats experiencing NI displayed reduced number of closed arm entries., Conclusion: Repetitive brief NI exacerbates anxiety-related behavior in EPM test following early-life SE.

An enriched environment can enhance brain recovery in animals with early-life status epilepticus (SE). The purpose of this study was to determine the effects of early-life SE on spatial memory and hippocampal extracellular signal-regulated kinase (ERK) level, and the possible therapeutic effects of the enriched environment. Rats were assigned randomly to four groups: (1) control rats (nonenriched control); (2) control rats housed in an enriched environment from Postnatal Day (P) 25 to P40 (enriched control); (3) rats in which SE was induced with lithium-pilocarpine (Li-PC) at P21 (nonenriched SE); and (4) rats in which SE was induced with Li-PC at P21 and then housed in an enriched environment from P25 to P40 (enriched SE). As adults, the rats underwent spatial learning and memory tests in the Morris water maze between P50 and P55. At P55, subsets of animals were evaluated for expression of hippocampal ERK1/2 phosphorylation immediately following completion of the Morris water maze. At ~P100, another set of animals was tested for seizure threshold. When studied as adults, only the nonenriched SE group had a spatial memory deficit. The nonenriched SE group also exhibited lower levels of phosphorylated ERK2 as compared with the nonenriched control, enriched control, and enriched SE groups. Both the nonenriched SE and enriched SE groups had reduced seizure thresholds as compared with the nonenriched control and enriched control groups. Results from this study demonstrate that an enriched environment improves spatial memory in rats subjected to early-life SE, possibly through upregulation of phosphorylated ERK2 in the hippocampus. However, an enriched environment has no effect on seizure threshold.

Perinatal hypoxia is an important cause of brain injury amongst the newborn, such injury often resulting in an increased risk of impaired performance as regards learning and memory in later life for the affected individual. The postsynaptic density 95 (PSD-95) protein is a cytoskeletal specialization involved in the anchoring of N-methyl-d-aspartate (NMDA) receptors in postsynaptic neurons and has been reported to serve several important functions (e.g., synaptogenesis, synaptic plasticity and learning and memory performance) for the mammalian brain. Herein we investigated the long-term effects of perinatal hypoxia upon the complex of PSD-95 with NMDAR subunits by means of downstream signalling cAMP response element binding protein (CREB) phosphorylation at the Serine-133 locus (CREB(Ser-133) phosphorylation) within the hippocampal CA1 area (an essential integration area for mammalian learning and memory) within test-rat brains, as well as the effects upon afflicted-individual long-term learning and memory performance. We also assessed the therapeutic efficacy of dopamine D1/D5 receptor (D1/D5R) activation for such study animals. Perinatal hypoxia on postnatal day ten (P10) led to impaired performance as regards long-term spatial learning and memory (as determined on P45) associated with decreases in the level of CREB(Ser-133) phosphorylation and decreases in the expression of the complex of PSD-95 with NMDAR subunits (NR1, NR2A, and NR2B). In addition, activation of the D1/D5R via A68930 (a selective, CNS-permeable agonist of D1/D5Rs) administration (2 mg/kg/day, P17-23 inclusively) markedly attenuated the hypoxia-induced deleterious effects, suggesting an effective therapeutic efficacy for A68930. Our results demonstrate the long-term effects of perinatal hypoxia upon the developing brain and provide additional insights into the relative vulnerability of postsynaptic density (PSD) proteins to such insult, as well as the impairment of downstream transcription signalling CREB(Ser-133) phosphorylation following perinatal hypoxia. More importantly, D1/D5R activation following perinatal hypoxia may be an alternative therapeutic strategy to that which is currently available and may offer significant clinical potential for hypoxia sufferers.

Emerging evidence indicates that early maternal care permanently modifies the activity of hypothalamic-pituitary-adrenal (HPA) axis and is a critical factor in determining the capacity of the brain to compensate for later encountered insults. The purpose of this study was to determine the role of corticosterone (CORT) in the detrimental effects of neonatal isolation (NI) on seizures. Rats were assigned randomly to the following five groups: (1) control (CONT) rats; (2) NI rats that underwent daily separation from their dams from postnatal day 2 (P2) to P9; (3) status epilepticus (SE) rats, induced by lithium-pilocarpine (Li-Pilo) model at P10; (4) NI plus SE (NIS) rats and (5) NISM rats, a subset of NIS rats receiving metyrapone (100 mg/kg), a CORT synthesis inhibitor, immediately after SE induction. At P10, plasma CORT levels were compared at baseline in CONT and NI rats and in response to Li-Pilo-induced SE among SE, NIS and NISM rats. We evaluated the spatial memory in the Morris water maze at P50 approximately 55, the expression of hippocampal cyclic adenosine monophosphate (cAMP)-responsive element-binding protein phosphorylation at serine-133 (pCREBSer-133) at P55, hippocampal neuronal damage at P80 and seizure threshold at P100. The isolated rats exhibited higher CORT release in response to SE than non-isolated rats, and the NIS rats had greater cognitive deficits and decreased seizure threshold compared to the CONT, NI and SE groups. By contrast, the NISM group, compared to the NIS group, showed a normal CORT response to SE and better spatial memory but no difference in seizure threshold. Compared to the CONT group, the hippocampal pCREBSer-133 level was significantly reduced in all experimental groups (NI, SE, NIS, NISM) with no differences between groups. All rats were free of spontaneous seizures later in life and had no discernible neuronal loss in the hippocampus. Results in this model demonstrate repetitive NI enhances response of plasma CORT to SE, and exacerbates the neurological consequences of neonatal SE. Amelioration of neurological sequelae following reduction of the SE-induced excessive rise in plasma CORT implicates CORT in the pathogenesis of NI increasing the vulnerability to seizures.

Malnutrition and/or seizure in the developing brain cause hippocampal damages. However, underlying mechanisms remain unclear. The malnutrition group (MN) subjected with malnutrition alone was culled to 20-22 rats per dam on postnatal day 1 (P1). The rats subjected to lithium-pilocarpine (Li/PC)-induced status epilepticus at P21 were grouped as the SE group. The rats subjected to malnutrition and subsequent status epilepticus were grouped as the MS group. Visual-spatial memory test using the Morris water maze task was performed at P80. Following behavioral tests, the hippocampus was evaluated for histological lesions and phosphorylated cAMP-responsive, element-binding protein at serine-133 (pCREB(Ser-133)), an important transcription factor underlying learning and memory in the mammalian brain. Here, the MN group exhibited decreased body weight at P21. There was no significant difference in the seizure duration and mortality between the SE and MS groups. In adulthood (P80), both the SE and MS groups showed the spatial learning deficit, hippocampal cell loss and decreased pCREB(Ser133) level within hippocampal CA1 region. Although the MN group demonstrated a decreased level of pCREB(Ser133), no distinguishable changes in the cognitive deficit and hippocampal neuronal loss were detected. Collectively, the present results suggest that early-life malnutrition led to a reduced phosphorylation of CREB(Ser133) in hippocampal CA1 in the absence of the long-term spatial learning deficit. This decreased phosphorylation of CREB(Ser133) could suggest that cascades of signal transduction responsible for the phosphorylation of CREB(Ser133) might be disturbed by early-life malnutrition. In addition, malnutrition caused no discernible synergistic effects on Li/PC-induced status epilepticus.

The applications of neural progenitor cells in clinical therapy for neural degeneration, such as Parkinson's disease, Huntington's disease, and cerebral infarction, have long been explored widely. It had been suggested that these cells may block the apoptosis of ischemia-induced neuronal damage and may themselves resist neurotoxic factors. In the present study, neural progenitor cells derived from the cortex of rodent embryos were cultured with the mitogenic agent epidermal growth factor. It was observed that these progenitor cells could self-renew and differentiate into a number of types of neurons and glial cells. By using sodium nitroprusside, glutamate, and N-methyl-D-aspartate, these neural progenitor cells were shown to have a higher resistance to neurotoxicity induced by these drugs compared with primary neuronal cells. However, the release of nitric oxide in response to glutamate by these neural progenitor cells was similar to the released by primary neuronal cells. Also, when the glutamate-stimulated increase in intracellular free Ca(2+) concentration was measured, stimulation of the glutamate receptors could not induce a significant influx of Ca(2+) into these progenitor cells until they differentiated. Our results suggest that the resistance of neural progenitor cells to neurotoxicity may be partially due to a lack of response to glutamate. In addition, some progenitor-generated neurotrophic factors may contribute to the resistance of these cells to nitric oxide-induced neurotoxicity., (Copyright 2002 Wiley-Liss, Inc.)

Nitric oxide (NO) induced by bacterial lipopolysaccharide (LPS) plays a critical role in various patho-physiological implications, such as atherosclerosis, vasculitis and septic shock. In addition, cAMP-responsive element binding protein (CREB), an important transcription factor for cell differentiation, has been shown to be involved in atherosclerogenesis in VSMCs. Here we investigated the possibility whether LPS-induced NO signaling led to phosphorylation of cAMP-responsive element binding protein on Serine-133 (CREBSer-133) in cultured vascular smooth muscle cells (VSMCs) from rats. Addition of LPS (1-10 microg/ml) for 48 hours increased not only the production NO, but also the phosphorylation of CREBSer-133. The use of NOS inhibitor (100-500 microM L-NAME) blocked the magnitudes of both LPS-induced NO production and CREBSer-133 phosphorylation. In addition, either a guanylyl cyclase (GC) inhibitor (30 microM ODQ) or a cGMP-dependent protein kinase (PKG) inhibitor (20 microM (Rp)-8-pCPT-cGMPs) significantly attenuated the magnitudes of LPS-induced CREBSer-133 phosphorylation, suggesting the involvement of NO-GC-PKG signaling. Thus, the present study suggests that NO-mediated signaling activated by bacterial LPS, at least in part, enhance CREBSer-133 phosphorylation in cultured VSMCs. The findings here may provide not only signaling pathway involved in VSMC differentiation during inflammatory response, but also new insight into possible therapeutic intervention.