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.     

Personality of seasonal affective disorder analyzed by Tri-dimensional Personality Questionnaire

BACKGROUND: Although there have been numerous reports in personality of mood disorders, there have been few reports in regard with personality of winter seasonal affective disorder (SAD). Furthermore, no reports have been published concerning summer SAD personality characteristics. Thus, this study was conducted to assess the personality of winter and summer SAD using Tri-dimensional Personality Questionnaire (TPQ) that have been used in a variety of mental disorders. METHODS: A total of 6135 Japanese were evaluated with TPQ, the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Self-rating Depression Scale (SDS). Winter, summer and non-SAD groups were classified by SPAQ. We compared the difference of personality trait among these three groups in consideration of gender, age and SDS score influence. RESULTS: Winter SAD demonstrated higher "Novelty Seeking" and "Harm Avoidance"; summer SAD showed higher "Harm Avoidance" than the non-SAD group. "Harm Avoidance" in both SAD groups was re-analyzed using SDS score as a covariate, and "Novelty Seeking" in winter SAD using age as a covariate. As a result, the significance of high "Novelty Seeking" and high "Harm Avoidance" in winter SAD was excluded. However, "Harm Avoidance" remained the significant difference between summer and non-SAD. LIMITATION: SAD was diagnosed only by SPAQ and not by interview. The state-dependency of "Harm Avoidance" was not confirmed in identical patients over lapse of time. CONCLUSION: Patients with winter SAD have high "Harm Avoidance" dependent on the depressive state that is in accordance with non-seasonal depression. Patients with summer SAD have high "Harm Avoidance" possibly independent from the depressive state.     

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.     

Combination therapy of cyclosporine with steroid inhibits γ-interferon and interleukin-1 gene expression at the level of mRNA synthesisin vivo

The present study examined the effect of cyclosporine (CsA) administered with steroidin vivo on the capacity of peripheral blood mononuclear cells (PBMC) from kidney transplant recipients to generate cytokines and their gene expression at the level of messenger RNA (mRNA). PBMC from CsA-prednisolone (Pred)-treated recipients displayed 66.9% inhibition (54.3±12.4 IU/ml;N=42;P<0.01) of -interferon (-IFN) production compared with normal individuals (134.6±18.6 IU/ml;N=23). Azathioprine (Az)-Pred-treated recipients displayed significantly less inhibition of -IFN generation (96.0±16.1 IU/ml;N=22;P<0.05) than CsA-treated patients. Macrophages (m) from CsA-Pred-treated recipients displayed 60.0% inhibition (5.1±0.7 U/ml;N=20;P<0.01) of interleukin-1 (IL-1) production compared with normal individuals (13.0±2.9 U/ml;N=21). These results were confirmed by the experiments using cDNA probe for -IFN or IL-1 (, ). High levels of -IFN mRNA in phytohemagglutinin (PHA)-stimulated PBMC or IL-1() mRNA in lipopolysaccharide (LPS)-stimulated m were present in normal individuals but not in CsA-treated recipients as judged by hybridization to a cloned human -IFN or IL-1() cDNA probe. These studies demonstrated that combination therapy of CsA with steroid inhibits both -IFN and IL-1 gene expression at the level of mRNA at physiological concentrations.     

The therapeutic effects of aspoxicillin on various infectious diseases in children

Clinical application to ascertain the effects of aspoxicillin (ASPC), a new semisynthetic penicillin antibiotic, upon several infectious diseases of children was performed in 7 cases with pneumonia, 5 cases with acute bronchitis, each case with tonsillitis, enterocolitis, urinary tract infection and suspected sepsis. ASPC was injected by drip infusion and the dosage was 63-117 mg/kg/day in 3 and 4 times a day. Clinical efficacy obtained as "excellent" was in 7 cases, "good" in 8 cases "poor" in 1 case, and efficacy rate was 93.8%. From the bacteriological point of view, eliminated in each of H. influenzae, H. parainfluenzae, group A beta-Streptococcus and unchanged in a case of E. coli. There were transient thrombocytopenia in 2 cases and eosinophilia in 3 cases.     

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.     

Immunohistochemical demonstration of DNA polymerase alpha in human brain-tumor cells

The proliferative capacity of brain-tumor cells was analyzed in vitro and in situ using monoclonal antibody (MAb) against deoxyribonucleic acid (DNA) polymerase alpha. For the in vitro studies, two cultured human glioma cell lines were investigated using MAb against DNA polymerase alpha, the MAb Ki-67, a serum against proliferating cell nuclear antigen (PCNA/cyclin), bromodeoxyuridine (BUdR), and an anti-BUdR MAb. During exponential growth of the cells, the percentage of polymerase alpha-positive cells (the "polymerase alpha score") ranged from 72.0% to 77.1%, the Ki-67-positive cells (the "Ki-67 score") ranged from 43.4% to 59.4%, the PCNA/cyclin-positive cells from 30.9% to 41.4%, and the BUdR labeling index from 28.6% to 39.3%. For the in situ studies, tissue from 60 human brain tumors and from two normal human brains was investigated and the polymerase alpha scores and Ki-67 scores were compared. In normal brain tissue, no immunostaining was found by either method. In brain tumors, both the polymerase alpha scores and the Ki-67 scores correlated with the histological grade of malignancy. Polymerase alpha scores were generally higher than Ki-67 scores in the same specimen, especially in malignant brain tumors. These findings suggest that immunostaining of DNA polymerase alpha is a convenient and important new method by which to estimate the cellular proliferation rate of brain tumors. Polymerase alpha scores may be closer to the growth fraction of the individual tumor than the MAb Ki-67 or other scores.     

Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats

Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of -rat atrial natriuretic peptide (-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of -rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.     

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)