The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals

Free radicals are involved in the pathogenesis and/or progression of Parkinson's disease (PD). Several ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and to show a neuroprotective effect in vivo. We investigated the in vitro free radical scavenging and antioxidant activities of cabergoline, a long-acting ergot DA agonist, as well as its ability to activate glutathione (GSH), catalase (Cat) and superoxide dismutase (SOD) activating effects and its in vivo neuroprotective properties against 6-hydroxydopamine (6-OHDA) intracerebroventricularly (i.c.v.) in mice. The striatal DA turnover induced by i.c.v. injection of 6-OHDA was completely normalized by pretreatment with cabergoline. Moreover, cabergoline scavenged free radicals in vitro and significantly reduced lipid peroxidation in vitro and in vivo. Furthermore, daily administration of cabergoline to mice significantly increased striatal GSH levels by activation of RNA expressions of GSH-related enzymes, although striatal Cat and SOD activities did not change. In addition, our present results suggest that repeated administration of cabergoline attenuates both 6-OHDA-induced nigrostriatal DAergic dysfunction and DA neuronal cell death, since cabergoline also had a neuroprotective effect in the immunohistochemical experiment. In conclusion, our findings indicate that the multiple antioxidant mechanisms of cabergoline, such as activation of the GSH system and the direct free radical scavenging activity, may explain the neuroprotective effect of this ergot DA agonist.     

Sotos syndrome associated with a de novo balanced reciprocal translocation t(5;8)(q35;q24.1).

We describe a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8 [46,XX,t(5;8)(q35;q24.1)] in a 15-month-old girl with a typical Sotos syndrome phenotype. Involvement of the 5q35 region was previously reported (Maroun et al. [1994: Am J Med Genet 50:291-293]) as one of translocation breakpoints in the present patient. We suggest that the gene responsible for Sotos syndrome is located to a distal long-arm region of chromosome 5.     

No evidence of PEG1/MEST gene mutations in Silver‐Russell syndrome patients

Silver‐Russell syndrome (SRS) is characterized by prenatal and postnatal growth retardation with morphologic anomalies. Maternal uniparental disomy 7 has been reported in some SRS patients. PEG1/MEST is an imprinted gene on chromosome 7q32 that is expressed only from the paternal allele and is a candidate gene for SRS. To clarify its biological function and role in SRS, we screened PEG1/MEST abnormalities in 15 SRS patients from various standpoints. In the lymphocytes of SRS patients, no aberrant expression patterns of two splice variants (α and β) of PEG1/MEST were detected when they were compared with normal samples. Direct sequence analysis failed to detect any mutations in the PEG1/MEST α coding region, and there were no significant mutations in the 5′‐flanking upstream region containing the predicted promoter and the highly conserved human/mouse genomic region. Differential methylation patterns of the CpG island for PEG1/MEST α were normally maintained and resulted in the same pattern as in the normal control, suggesting that there was no loss of imprinting. These findings suggest that PEG1/MEST can be excluded as a major determinant of SRS. © 2001 Wiley‐Liss, Inc.     

MULTIPLE PRIMARY MALIGNANT FIBROUS HISTIOCYTOMA OF THE STOMACH AND SMALL INTESTINE

A case of multicentric malignant fibrous histiocytoma of the stomach and small intestine is reported. The patient was a 60-year-old man who had total gastrectomy under an impression of a gastric carcinoma. The resected stomach revealed a large polypoid mass in the antral portion at the greater curvature. Three months later, he developed ileus and an 80 cm segment of the jejunum was removed. It contained two polypoid masses identical to that seen in the stomach. The tumors showed, in addition to the characteristic light microscopic appearances, strong positivity for alpha-1-antitrypsin by an immunoperoxidase technique, indicating the diagnosis of malignant fibrous histiocytoma (MFH). Electron microscopic findings were also consistent with MFH. We believe that this is the first well-documented case of MFH arising from the stomach and small intestine, to the best of our knowledge.     

Reduced NR2A expression and prolonged decay of NMDA receptor-mediated synaptic current in rat vagal motoneurons following axotomy

To elucidate characteristic changes in the N -methyl- d -aspartate (NMDA) receptor on neurons following axotomy, subunit expressions and functional features of the NMDA receptor were examined in the dorsal motor nucleus of vagus (DMV) of rats receiving vagal axotomy at the neck. Western blotting analysis demonstrated that the expression of NR2A decreased 2–3 days after in vivo axotomy, while expression of NR1 and NR2B, NR2C and NR2D subunits did not change significantly. To examine the functional changes, patch clamp recordings in whole-cell mode were employed on the axotomized DMV neurons identified by retrograde labelling with fluorescent dye. The amplitude ratios of ifenprodil-sensitive components of NMDA response and d , l -2-amino-5-phosphovaleric acid (APV)-sensitive evoked postsynaptic current increased after axotomy. In addition, APV-sensitive postsynaptic currents exhibited a longer decay time in identified axotomized vagal motoneurons than in control neurons. No significant differences in the current density of the NMDA response and the peak amplitude of APV-sensitive synaptic currents were observed between axotomized and intact DMV neurons. In conclusion, a decrease in NR2A expression results in the appearance of functional characteristics of the NMDA receptor predominantly containing the NR2B subunit. This might lead to a long-term increase of the susceptibility of neurons to excitotoxicity.     

Histological evidence of the altered distribution of osteocytes and bone matrix synthesis in klotho-deficient mice

Mice homozygous for klotho gene deletion are well established aging models as they mimic certain aspects of human senescence e.g. osteoporosis. Induced senescence may affect cellular functions and alter the histological properties of the extracellular matrices. The present study examined the histological and ultrastructural features of osteocytes and the surrounding bone matrix in klotho-deficient mice. As expected, osteoblasts showed a flattened shape with a weak immunoreactivity for alkaline phosphatase, and the bone matrix contained many empty osteocytic lacunae. The walls of both normal and empty lacunae were intensely immunopositive for osteopontin and dentin matrix protein-1, but featured an inconsistent immunoreactivity for osteocalcin and type I collagen. Not surprisingly, TUNEL-positivity, indicative of apoptosis, was found in many osteoblasts, osteocytes, and bone marrow cells of the klotho-deficient mice. In transmission electron microscopy, an amorphous matrix containing non-collagenous organic materials was recognizable around osteoblasts and in the osteocytic lacunae. Some osteoblasts on the bone surface featured these amorphous materials in vacuoles associated with their trans-Golgi network, indicating that, under klotho-deficient conditions, they synthesize and secrete the non-collagenous structures. Some osteocytes displayed pyknosis or degenerative traits. Thus, our findings provide histological evidence that klotho gene deletion influences the spatial distribution of osteocytes and the synthesis of bone matrix proteins in addition to the accelerated aging of bone cells.     

Analysis of acute-phase toxicities of intensity-modulated proton therapy using a model-based approach in pharyngeal cancer patients

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of these patients had a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% for mucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.     

P53 tumor-suppressor gene and cyclic adenosine-monophosphate in breast and esophageal cancer are regulated through high-concentration of epidermal growth-factor

To reveal the molecular mechanism of the growth-inhibitory effects of high concentrations of EGF, accumulations of p53 protein and p21ras expression in MX-1 and UM-1 breast cancer and ES-4 esophageal cancer transplanted into nude mice were investigated after local injections of 2 mug of EGF or 2 mug of TGF-beta. The accumulation of p53 protein and expression of p21ras were determined by using the methods of Western immunoblotting and p53 mutant selective quantitative ELISA assay. p53 mutation was investigated by using the PCR analysis and DNA sequencing. Contents of intra-cellular-cAMP of these tumors were also determined by radioimmunoassay. Results showed that the high concentration of EGF induced the accumulations not only of wild type p53 protein, but also of mutant p53 protein in these tumors growth-inhibited by EGF. In ES-4 esophageal cancer, 2 mug of EGF induced the up-regulation of p53 and the down-regulation of p21ras. On the contrary, 2 mug of TGF-beta induced the down-regulation of p53 and the up-regulation of p21ras in UM-1 human breast cancer. The point mutation of p53 gene was found at codon 181 contained C to T transversions (Amino acid switch: Arg --> Cys) in ES-4 esophageal cancer. The accumulations of p53 proteins were also associated with the down regulated intra-cellular-cAMP induced by high concentrations of EGF. These results indicate that p53 gene and ras gene are involved in the signal pathway of EGF and that the p53 gene may have some important role as a negative growth factor by suppressing ras oncogene in the mechanism of tumor growth inhibition through the high concentration of EGF.     

Dose-response relation and time course of

The dose-response relation of pipecuronium, the time course of its neuromuscular blocking effects, and the reversibility of the residual block by neostigmine have been investigated in patients under sevoflurane/N₂O Anesthesia using a neuromuscular transmission analyzer (Accelograph^®, Biometer, Denmark). After an initial dose of pipecuronium (0.04mg·kg^–1, i.v.), the maximum block rate, onset time, the time from administration until 25% recovery and 50% recovery of control twitch height of the first response to train-of-four nerve stimulation and the interval time of administration of maintenance dose (0.005mg·kg^–1, i.v.) were 93.7 ± 7.68%, 5.0 ± 1.84, 55.4 ± 23.92, 73.0 ± 29.44 and 38.7 ± 15.50 minutes, respectively. The average intubation score (excellent; 0, good; 1 fair; 2, poor; 3) was 0.63 ± 0.56 at the level of 95.88 ± 5.06% block. Neostigmine (1.5mg) promptly reversed the residual neuromuscular blockade induced by pipecuronium (reversal time: 10.1 ± 2.98 minutes). No side effects attributable to pipecuronium was seen in this study.In conclusion, pipecuronium is a very useful nondepolarizing neuromuscular blocking agent especially for moderately long surgical procedure over 4–5 hours.(Ueda N, Masuda Y, Muteki T, et al.: Does-response relation and time course of action of pipecuronium in patients anesthetized with nitrous oxide and sevoflurane. J Anesth 7: 151–156, 1993)     

Interleukin-6 and granulocytic elastase levels following laparoscopic cholecystectomy

Interleukin-6 (IL-6) levels have been shown to correlate well with the magnitude of surgical stress. Serum IL-6 and plasma granulocytic elastase levels, 24 h after surgery, were determined in 12 patients who underwent open major surgery [MS group; esophageal carcinoma (n=5), gastric carcinoma (n=3), colorectal carcinoma (n=4) 5 patients who had open cholecystectomy [OC group] and 17 patients who had laparoscopic cholecystectomy [LC group]. IL-6 levels correlated significantly with the duration of surgery (r=0.685,P < 0.01) and with intraoperative blood loss (r=0.583,P < 0.02). However, there was no significant correlation between granulocytic elastase and the duration of surgery or blood loss. Plasma IL-6 levels in the LC group (21±3 pg/ml) were significantly lower than those in the OC group (47±5 pg/ml) and the MS group (186±36pg/ml) (P<0.05;P<0.01). However, there was no significant difference in granulocytic elastase levels between the LC group (318±8g/l), the OC group (360±130 gmg/ml), and the MS group (701±344 g/l). Increased IL-6 levels correlated well with increased duration of surgery. The lower IL-6 levels following laparoscopic cholecystectomy may therefore be indicative of lower surgical stress associated with laparoscopic cholecystectomy.