Hypothermia attenuates apoptosis and protects contact between myelin basic protein‐expressing oligodendroglial‐lineage cells and neurons against hypoxia–Ischemia

Periventricular leukomalacia (PVL) is a major form of brain injury among preterm infants, which is characterized by extensive loss and dysfunction of premyelinating oligodendrocytes (pre‐OLs) induced by hypoxia–ischemia (HI). Therapeutic hypothermia, which is a standard treatment for term infants with HI encephalopathy, is not indicated for preterm infants because its safety and effect have not been established. Here we investigate the effectiveness and mechanism of hypothermia for the inhibition of pre‐OLs damage in PVL. For in vivo studies, 6‐day‐old rats underwent left carotid artery ligation, followed by exposure to 6% oxygen for 1 hr under hypothermic or normothermic conditions. The loss of myelin basic protein (MBP) was inhibited by hypothermia. For in vitro studies, primary pre‐OLs cultures were subjected to oxygen–glucose deprivation (OGD) under normothermic or hypothermic conditions, and dorsal root ganglion neurons were subsequently added. Hypothermia inhibited apoptosis of pre‐OLs, and, despite specific downregulation of 21.5‐ and 17‐kDa MBP mRNA expression during hypothermia, recovery of the expression after OGD was superior compared with normothermia. OGD caused disarrangement of MBP distribution, decreased the levels of phosphorylated 21.5‐kDa MBP, and disturbed the capacity to contact with neurons, all of which were restored by hypothermia. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 during and after OGD significantly reduced the protective effects of hypothermia on apoptosis and myelination, respectively. These data suggest that phosphorylated exon 2‐containing (21.5‐ and possibly 17‐kDa) MBP isoforms may play critical roles in myelination and that hypothermia attenuates apoptosis and preserves the contact between OLs and neurons via ERK1/2 phosphorylation. © 2014 Wiley Periodicals, Inc.     

Maximum standardized uptake value change rate before and after neoadjuvant chemotherapy can predict early recurrence in patients with locally advanced esophageal cancer: a multi-institutional cohort study of 220 patients in Japan

Esophagus - Neoadjuvant chemotherapy (NAC) followed by esophagectomy can improve the prognosis of locally advanced esophageal cancer (LAEC). However, LAEC reportedly recurred in 17–21% of...     

Eye movement and random number in NP lupus evaluation

We evaluated the vulnerability of central nervous system (CNS) in patients with systemic lupus erythematosus (SLE) using exploratory eye movement analysis and random number generation (RNG), and compared the tests in evaluating CNS vulnerability. Nineteen patients received the tests more than a month after SLE onset in nonpsychotic status. Exploratory eye movements were analyzed using an eye-mark recorder that detects corneal reflection of infrared light, and numbers of eye fixations were counted to calculate responsive search score (RSS). Using digits 0 through 9, 100 numbers were vocally generated at a random fashion. “Seriality score” was calculated from the recorded 100 numbers. RSS of SLE patients was similar to that of normal individuals, irrespective of neuropsychiatric lupus history. Seriality score of patients having a history of neuropsychiatric lupus was higher than that of never having it (p < 0.05). No relations were confirmed between RSS and seriality score. The current study suggested heterogeneous nature of SLE in CNS vulnerability when evaluating with seriality score, but not with RSS. There seemed to be a difference between exploratory eye movement analysis and RNG in evaluating CNS vulnerability. Each test seemed to evaluate different aspects of brain function.     

Glucocorticoid receptor and serum‐ and glucocorticoid‐induced kinase‐1 in esophageal adenocarcinoma and adjacent Barrett's esophagus

Barrett's esophagus (BE) is a consequence of gastroesophageal reflux disease and is predisposed to esophageal adenocarcinoma (EAC). EAC is an exemplar model of inflammation‐associated cancer. Glucocorticoids suppress inflammation through glucocorticoid receptor (GR) and serum‐ and glucocorticoid‐induced kinase‐1 (Sgk1) expressions. Therefore, we immunolocalized GR and Sgk1 in EAC and the adjacent BE tissues and studied their association with clinical disease course in 87 patients with EAC who underwent surgical resection (N = 58) or endoscopic submucosal dissection (N = 29). Low GR and Sgk1 expressions in adjacent BE tissues were associated with adverse clinical outcomes (P = 0.0008 and 0.034, respectively). Patients with low Sgk1 expression in EAC cells exhibited worse overall survival (P = 0.0018). In multivariate Cox regression analysis, low GR expression in the adjacent nonmalignant BE tissues was significantly associated with worse overall survival (P = 0.023). The present study indicated that evaluation of GR and Sgk1 expressions in both the EAC cells and adjacent nonmalignant BE tissues could help to predict clinical outcomes following endoscopic and surgical treatments. In particular, the GR status in BE tissues adjacent to EAC was an independent prognostic factor.     

Acute kidney injury after acute gastroenteritis in an infant with hereditary hypouricemia

Hereditary hypouricemia is a rare disorder characterized by extremely low serum uric acid levels caused by excessive urinary excretion due to an inherited tubular defect in urate handling. Exercise-induced acute kidney injury (AKI) is the main complication of this disorder, though AKI may also be induced by other factors. A 7-month-old boy with hereditary hypouricemia developed AKI associated with severe dehydration caused by rotavirus gastroenteritis. He also showed severe hypernatremia and metabolic acidosis and received continuous renal replacement therapy for 3 days. He showed no signs of hydronephrosis or urolithiasis. However, hypouricemia was noted when his renal function recovered (serum uric acid <0.6 mg/dl). Analysis of the urate transporter 1 gene revealed a homozygous nonsense mutation in exon 4 (c.774G > A, p.W258X). Both parents were heterozygous for the mutation and his younger brother was later determined to have severe hypouricemia (0.6 mg/dl). Conclusion: Uric acid is an essential factor for scavenging oxidative stressors. In this patient, severe dehydration may have directly caused pre-renal AKI, but susceptibility to oxidative stressors under severe dehydration, as well as exercise, may also contribute to AKI. Careful attention should be paid to dehydration, especially in young children, to avoid the development of AKI in patients with hereditary hypouricemia.     

Immunological studies on delayed hypersensitivity to phenytoin--I. A new method for preparing phenytoin antiserum

The present study was initiated to produce an antiserum to phenytoin with high specificity and sensitivity which would be suitable not only for determination of blood phenytoin concentration but also for induction of a hypersensitivity reaction to phenytoin in experimental animals. p-Aminophenytoin was synthesized and identified by means of IR, 1H-NMR and mass spectroscopy. BSA-phenytoin conjugate was prepared by using p-aminophenytoin, BSA and, as a coupling reagent, glutaraldehyde. Satisfactory response to immunization was achieved at a 9.8:1 molar ratio of p-aminophenytoin to BSA. The antiserum obtained from rabbits immunized with BSA-phenytoin conjugate exhibited practically no cross-reactivity with either phenytoin metabolites or other anti-epileptic drugs, indicating that this antiserum provides sufficiently high specificity. In our experiments, the lower limit for detecting phenytoin was 2 ng using RIA, whereas 200 ng was the minimum amount detectable by HPLC. Thus, by a difference of two orders of magnitude, the present RIA method shows a much higher sensitivity than that of HPLC, though we found a good correlation of simultaneous determinations of serum phenytoin between the two methods. Reproducibility of phenytoin determination in plasma was confirmed by calculating the coefficient of variance. The values were less than 10%.     

Immunological studies on delayed hypersensitivity to phenytoin--II. The delayed skin reaction induced by BSA-phenytoin conjugate

Remarkable swelling of the foot pad was induced in guinea pigs sensitized with BSA-phenytoin by challenging with BSA-phenytoin or EA-phenytoin. Forty-eight hours after local injection of a mixture of exudate cells obtained from the abdominal cavity of sensitized guinea pigs. and BSA (EA)-phenytoin, both erythema and induration developed at the injection sites in normal guinea pigs. At the sites exhibiting these skin reactions, an exudation of mononuclear leukocytes was noted. In addition, macrophages obtained from the abdominal cavity of phenytoin-sensitized animals showed a low migration index in the presence of phenytoin. When phenytoin was administered to rats (p.o.), large amounts of the compound were detected in the gingiva and there was a good correlation between the tissue and serum phenytoin concentrations. These findings indicate that the etiology of gingival hyperplasia produced by chronic administration of phenytoin may be related in some way to a delayed-type hypersensitivity induced by the drug.     

Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist.

J-104132 [(+)-(5S,6R, 7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3, 4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation protocols, the inhibition of ET receptors with J-104132 is reversible and competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephrine or KCl in the vascular preparations. The in vivo potency of J-104132 was assessed using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1 causes death. Pretreatment with J-104132 prevents the lethal response to ET-1 when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35 mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET-1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg) administration. In anesthetized dogs, ET-1 was administered directly into the renal artery or brachial artery to generate dose-response (blood flow) curves, and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132 produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antagonist of both ETA and ETB receptors and is an excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB receptor antagonist.