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.     

Gender specific effects of ethanol in mice, lacking CCK2 receptors

Neuropeptide cholecystokinin (CCK) has been reported to suppress ethanol intake, but there is contradictory evidence about the role of CCK(2) receptors. In the present study anxiolytic, hypolocomotor and sedative effects of acute ethanol administration, but also voluntary ethanol consumption were studied in male and female mice, lacking CCK(2) receptors (-/-). Ethanol (1.0 and 2.0 g/kg) induced a significant reduction of anxiety-related behaviours in the elevated plus-maze, but this effect was statistically significant only in female homozygous mice (-/-). In male mice, lacking CCK(2) receptors (-/-), but not in their wild-type littermates (+/+), the suppression of vertical locomotor activity was caused by ethanol at a dose 0.5 g/kg. The highest dose of ethanol (2.0 g/kg) produced statistically significant reduction of horizontal locomotor activity only in female wild-type (+/+) mice, but this effect was related to increased basal activity when compared to female mutant (-/-) mice. Duration of the loss of righting reflex was not significantly affected by genotype or gender, but blood ethanol levels at regain of righting reflex were significantly lower in female homozygous mice (-/-) compared to their wild-type (+/+) littermates, indicating increased sensitivity to the sedative effect of ethanol. Ethanol intake, but not preference, at concentration 10% was significantly increased in female mice, lacking CCK(2) receptors (-/-). The present study revealed an altered response to the acute effects of ethanol in CCK(2) receptor deficient mice (-/-). These changes are gender-specific and could be attributed to the altered activity of dopaminergic system in male mice and increased activity of GABA-ergic system in female mice as established in our previous studies.     

The impact of postoperative infliximab maintenance therapy on preventing the surgical recurrence of Crohn’s disease: a single-center paired case–control study

Purpose

Preventing a recurrence of Crohn’s disease is a problem that remains to be solved. We evaluated the impact of using infliximab as a postoperative therapy on preventing the surgical recurrence of Crohn’s disease.

Methods

We performed a pair-matched study comparing 100 patients who had received postoperative infliximab maintenance therapy with those who had not between 1995 and 2010. The patients were matched by gender, Vienna classification and age at the time of the operation. Crohn’s disease-related reoperation was evaluated as surgical recurrence.

Results

In the postoperative infliximab maintenance therapy group, infliximab was administrated within 8 weeks after the operation. The median follow-up period was 36 months in the postoperative infliximab maintenance therapy group and 51 months in the control group. Surgical recurrences were recognized in 37 patients (three in the postoperative infliximab maintenance therapy group and 34 in the control group). A univariate analysis by the Kaplan–Meier method identified a body mass index >18 at the time of the operation (HR 0.19, p = 0.01) and postoperative infliximab maintenance therapy (HR 0.22, p = 0.0022) as factors related to the reduction of surgical recurrence. The multivariate analysis revealed that postoperative infliximab maintenance therapy was the only significant factor preventing surgical recurrence.

Conclusion

Postoperative infliximab maintenance therapy for Crohn’s disease prevents surgical recurrence, at least within 3 years after the operation.     

Reactivity of anti-AraC-resistant cell monoclonal antibody, YU-311, in formalin-fixed paraffin-embedded specimens of various hematopoietic disorders

YU-311 is a monoclonal antibody reacting with cytosine arabinoside (AraC)-resistant human leukemic cell line and identifies a 92 kDa membrane protein. We have examined YU-311 reactivity with various hematopoietic disorders by an immunohistochemical method and evaluated a correlation between YU-311 expression and refractoriness to chemotherapy, retrospectively. YU-311 reacted with AraC-resistant human leukemia cell lines, in which a 92 kDa membrane protein was identified by Western blotting, whereas drug-resistant cell lines to other than AraC failed to express YU-311 antigen. The frequency of YU-311 positivity was significantly increased in relapsed cases. Only five cases were positive for YU-311 at diagnosis and 24 cases at relapse. Unexpectedly, only eight cases of relapsed leukemia/lymphoma expressed YU-311 and P-glycoprotein simultaneously. Most of the YU-311-positive relapsed cases showed clinical refractoriness for chemotherapy and then failed to induct complete remission or relapsed at short periods with short disease-free duration. These findings indicate that YU-311 expression is closely associated with some aspects of drug resistance, especially with AraC resistance.     

Changes of ground substance in the inner ear in Alloxan diabetic mice

Summary One of the important substances in the ground substance is acidic glycosaminoglycans (AGAGs). Changes of AGAGs in the inner ear and in other organs were investigated using alloxan diabetic mice in order to contribute to the understanding of diabetic hearing impairment. In the diabetic group, gradual increases of AGAGs were observed in each tissue. On the 60th day after alloxan injection, AGAG values were increased 3.5-fold in the cochlea, 2.5-fold in the brain, 13-fold in the liver, twofold in the kidney, and fivefold in the pancreas compared with the control values. It is interesting to note that both the cochlea and pancreas showed continuous increases of AGAGs.This research was supported by grant no. 757202 from the Ministry of Education. A part of this paper was read at the 16th workshop on Inner Ear Biology, Bern, Switzerland     

Case report of dysgerminoma in a patient with 46,XX pure gonadal dysgenesis

A clinicopathological study of a 42-year-old female with pure gonadal dysgenesis and dysgerminoma was made. At the age of 29, the patient with primary amenorrhea had been evaluated clinically and cytogenetically. (1) The results of cytogenetic studies were X-chromatin positive and revealed a karyotype in peripheral blood leukocytes of 46,XX. (2) Laboratory studies indicated hypergonadotropic hypogonadism and no response of the gonads to the human menopausal gonadotropin stumulation test. (3) At laparotomy, the gonads were streak-like. Pathological examinations of biopsy specimens from both gonads revealed dense, fibrous connective tissue resembling ovarian stroma and no primary follicles. Eleven years after the laparotomy, the patient complained of lower abdominal distention and severe pain, and laparotomy then revealed a 15 × 17-cm right solid adnexal mass occupying the pelvic cavity. The histological diagnosis of tissues from the partially removed tumor was pure dysgerminoma. Second-look operation after Linac X-ray irradiation showed complete remission of the residual tumor. Insofar as we are aware, the present patient represents the first case of dysgerminoma which occurred in the dysgenetic gonads of a phenotypic female with normal 46,XX sex-chromosomal constitutions in peripheral blood leukocytes and the skin fibroblasts although a possibility exists that mosaicism was possibly present but undetected, particularly since the streak gonads were not analyzed chromosomally.     

Multiple Ileal Diverticula Causing an Ileovesical Fistula: Report of a Case

We report a case of multiple ileal diverticula causing an ileovesical fistula in an 85-year-old man. The patient was admitted for investigation and treatment of intractable urethrocystitis, which he had suffered for 5 years. Cystography showed an ileovesical fistula, and contrast study of the small bowel revealed about 80 diverticula in the ileum. The segment involved by diverticula was resected and a pathological diagnosis of diverticulitis leading to ileovesical fistula was confirmed. His postoperative clinical course was uneventful. Received: September 13, 2001 / Accepted: March 5, 2002     

FDG-PET after radiotherapy is a good prognostic indicator of rectal cancer

In the management of rectal cancer after the combined therapy of the radiation and surgical operation, the evaluation of the prognosis is important. Although fluoro- 18-deoxyglucose positron emission tomography (FDG-PET) is considered as a useful tool for evaluation of therapeutic effect of this cancer as well as the other cancers, however, there are few articles that clearly describe the appropriate procedure of the FDG-PET in order to obtain the best prognostic value. The purpose of the present study is to compare several variations of a semi-quantification method, the Standardized Uptake Values (SUV) and to determine the most appropriate parameter, for the prognostic prediction and to propose the quantitative guideline of the FDG-PET. Especially, the authors focused on the SUV after radiotherapy, which had not been considered as a key quantitative value, as it was rather taken as a mere indicator of the therapeutic (radiotherapeutic) effect, not a direct indicator of the prognosis for the cancer itself. METHODS: Forty patients with rectal cancer in the lower rectal region underwent two series of FDG-PET study before and after pre-operative radiotherapy. Their SUVs were calculated from FDG-PET data and compared with the results of the long-term follow-up of the patients as well as with histopathological outcomes. Results: All 40 patients had high FDG uptake before radiotherapy. The mean value of SUV before radiotherapy (SUV1) was 7.6. After radiotherapy, the mean value of SUV (SUV2) decreased to 4.2. There was a significant difference in SUV2 between the groups with and without recurrence (p < 0.05), however, SUVI or SUV ratio (SUV2/SUV1) displayed no significant difference with the incidence of recurrence. CONCLUSION: SUV2 was considered to be a good prognostic indicator for long-term prognosis of rectal cancer patients. SUV1 nor SUV ratio SUV2/SUV1 did not have the equivalent prognostic usefulness. Subsets of patients with SUV2 greater than 3.2 should be observed closely.     

Molecular Cytogenetic Characterization of Drug-resistant Leukemia Cell Lines by Comparative Genomic Hybridization and Fluorescence in situ Hybridization

Resistance to chemotherapeutic drugs is one of the major difficulties encountered during cancer chemotherapy. To detect genomic aberrations underlying the acquired drug resistance, we examined three cultured human myelomonocytic leukemia cell sublines each resistant to adriamycin (ADR), 1-β–1- d -arabinofuranosylcytosine (ara-C), or vincristine (VCR), using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), RT-PCR, and western blot techniques. Chromosomes 7, 10 and 16 most conspicuously showed frequent aberrations among the resistant sublines as compared to the parental KY–821 cell line. In ADR-resistant cells, gains at 7q21, 16p12, 16p13.1–13.3, 16q11.1–q12.1, and losses at 7p22–pter, 7q36–qter, 10p12, 10p11.2–pter, 10q21–q25, 10q26–qter were notable. In ara-C-resistant cells, no remarkable gain or loss on chromosome 7, but losses at 10p14–pter, 10q26–qter and 16p11.2–p11.3 were observed. In VCR-resistant cells, gain at 7q21 and losses at 10p11–p13, 10p15 and 16p11.2–p13.3 were found. FISH identified amplified signals for the MDR–1 gene located at 7q21.1 in ADR-and VCR-but not ara-C-resistant cells, and for the MRP–1 gene located at 16pl3.1 in ADR-resistant cells. These findings were validated at the mRNA and protein levels. Overlapping of the amplified MRP–1 gene with MDR–1 gene may play a critical part in the acquisition of resistance to ADR. Resistance to ara-C excluded MDR–1 gene involvement and highlighted other key genes such as MXR gene. Several other genes putatively involved in the development of drug resistance might lie in other aberrated chromosomal regions.     

Table of contents of forthcoming issues

Human T-cell-leukemia-virus-type-1 (HTLV-I) infection is associated with adult T-cell leukemia/lymphoma (ATL) and HTLV-1 -associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The T-cell-targeting immunosuppressants, FK506 and cyclosporin A (CsA), suppressed proliferation of the HAM/TSP-derived T-cell lines, H89–59, H89–79 and H109. FK506 and CsA also reduced expression of the proto-oncogenes, c-myc and c-fos, but not c-jun and interleukin-2-receptor-α (IL-2Rα) gene in H109 cells. The growth-inhibitory effects of FKS06 and CsA were not abrogated by interleukin 2 (IL-2). These results suggest that the inhibitory effects of FK506 and CsA are independent of IL-2, and are associated with the reduction of c-myc and c-fos gene expression.