Novel non-apoptotic morphological changes in neurons of the mouse hippocampus following transient hypoxic-ischemia

Apoptosis has been recently implicated in the dying process of neurons under several pathological conditions including ischemia. However, although apoptosis was originally defined on the basis of its unique ultrastructural features (Kerr et al., 1972. Br. J. Cancer 26, 239-257; Wyllie et al., 1980. Int. Rev. Cytol. 68, 251-306), unambiguous ultrastructural evidence of apoptosis has been rarely demonstrated in the adult brain. In this study, we examined ultrastructural changes in mouse hippocampal neurons after transient hypoxic-ischemia. A small population of dentate granule cells showed typical apoptotic ultrastructures that could be used as internal morphological standards of apoptosis, whereas most other hippocampal neurons consistently showed a distinct form of cellular disintegration. Nuclei of the latter cells shrank and became TUNEL-positive but were distinguishable from apoptotic nuclei by both the presence of characteristic reticular-formed chromatin condensation and the absence of nuclear fragmentation. Perikarya of degenerating neurons also shrank as in apoptosis, but apoptotic bodies were not observed. Although organelles other than mitochondria disappeared almost completely from the perikarya, neither plasma nor mitochondrial membranes were disrupted, indicating that these changes were also different from typical necrosis. The presence of a novel form of cell death suggests the necessity of morphological re-examination of neuronal death, particularly in mature neurons in vivo.     

Relationships between Responsiveness of the Bronchi to Acetylcholine and Cyclic AMP Response of Lymphocytes to Beta1- and Beta2-Adrenergic Receptor Stimulation in Patients with Asthma

Decreased response of beta-adrenergic receptor has been considered to he one of the causes of increased responsiveness of the bronchi in asthma. Since beta-adrenergic receptor has two subtypes, beta₁ and beta₂, and the bronchodilating effect of beta stimulants is mediated by beta₂-receptor, responsiveness of the bronchi is expected to correlate to the cyclic AMP response of lymphocytes to a beta₂-stimulant. Responsiveness of the bronchi was expressed as respiratory threshold to acetylcholine (RT-Ach), which was the minimal concentration of acetylcholine solution to cause an initial decrease of FEV₁ of more than 20% of the baseline value. Beta₁ and heta₂-responses were expressed as the increments of cyclic AMP content of 10⁶ lymphocytes incubated with norepinephrine (beta₁-stimulant) and salbutamol (beta₂-stimulant).
RT-Ach showed a significant correlation with the beta₂-cyclic AMP response of lymphocytes, but not with the beta₁ -response among patients with asthma. Sixteen symptomatic patients on continuous beta-stimulants showed lower RT-Ach value and diminished beta₂-receptor activity of lymphocytes compared with 14 patients in remission. These results suggest that selective beta₂-adrenergic blockade may he one of the causes of bronchial hypersensitivity in asthma, though it should be noted that in this study beta-adrenergic responses were examined in lymphocytes and were compared with the responsiveneness of the bronchi. Possible beta-receptor subsensitivity induced by administration of beta-stimulants is discussed.     

Immune complex-mediated glomerulonephritis and interstitial pneumonia simulating Goodpasture's syndrome

An autopsy case of what was clinically considered to be Goodpasture's syndrome was investigated. The lung had hemorrhagic interstitial pneumonia, showing granular patterns of IgG and C3 along the alveoli by the immunofluorescent method and electron-dense subepithelial deposits by electron microscopy. The kidney had crescentic and segmental necrotizing glomerulonephritis associated with membranous nephropathy. Uneven, continuous patterns of immunofluorescent IgG and C3 along the GBM were noted. Electron microscopy showed numerous subepithelial deposits, and immunoelectron microscopy revealed that IgG was not present in the GBM itself but present in the subepithelial deposits. Anti-GBM antibody activity was not detected in the serum or the kidney eluate. It was suggested that renal and pulmonary lesions occurred through the same mechanism and in association with immune deposits. We propose that there is a disease having immune complex-mediated deposits. We propose that there is a disease having immune complex-mediated renal and pulmonary lesions which clinically resembles the conventional Goodpasture's syndrome.     

Effects of Bakumondo-to (Mai-Men-Dong-Tang) on cough sensitivity to capsaicin in asthmatic patients with cough hypersensitivity]

Some patients with bronchial asthma have increased cough sensitivity. In such patients coughing may be an inducer of wheeze. The aim of the present study was to investigate the effect of Bakumondo-to on the cough sensitivity and respiratory tract inflammation in asthmatic patients with increased cough sensitivity. In addition influences of intensity of respiratory tract inflammation, gender, type of asthma, and disease period on the effect of Bakumondo-to on the cough sensitivity were examined. Twenty-one bronchial asthmatics whose cough thresholds to capsaicin were less than 3.9 microM were examined. METHODS: Cough thresholds to capsaicin (concentration of inhaled capsaicin solution causing 5 or more coughs) was measured before and after 2 months or more treatment with Bakumondo-to (9 g/day, TJ-29). Number of eosinophils in peripheral blood, sputum eosinophil ratio, and ECP level in the serum were also measured before and after treatment. RESULTS: Bakumondo-to significantly increased the cough threshold. Although respiratory tract inflammation was not significantly improved, number of eosinophils in peripheral blood, sputum eosinophil ratio and ECP level in the serum were remarkably decreased more than the half. And Bakumondo-to was more effective in asthmatic subjects with severe airway inflammation. Furthermore, a greater effect of it was observed in women. A greater effect was also observed in patients having a disease duration of less than 1 year. CONCLUSION: Our results suggest that Bakumondo-to may be an effective therapeutic preparation for coughing in asthmatic patients with cough hypersensitivity.     

Chymase participates in chronic dermatitis by inducing eosinophil infiltration

An epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) to a mouse ear caused a transient skin swelling, and the repetition of the challenge enlarged the contact dermatitis. The repeated challenge with DNFB also induced eosinophil infiltration on the application site. Administration of a chymase inhibitor significantly inhibited the ear swelling as well as eosinophil accumulation. An intradermal injection of human chymase to the mouse ear also elicited transient skin swelling and eosinophil infiltration, both of which were augmented in proportion to the number of injections. Human serum albumin and heat-inactivated chymase failed to induce such skin reactions, suggesting the participation of proteolytic activity of the enzyme. In addition, chymase stimulated eosinophil migration in vitro in a concentration-dependent manner. Taken together, these observations suggest that mast cell chymase may contribute to development of the DNFB-induced dermatitis, probably by promoting eosinophil infiltration. It is therefore possible that chymase plays a role in pathogenesis of chronic dermatitis such as atopic dermatitis.     

Small round and spindle cell sarcoma with neuronal differentiation and oncocyte-like features of the thoracic wall: A case report with histological,immunohistochemical and ultrastructural examinations

A case of small round and spindle cell sarcoma with neuronal differentiation and oncocyte-like features is presented. The tumor was encountered in a 32 year old Japanese woman with an initial presentation of palpable tumor in the left lateral region of the thorax. The resected tumor was a partially well encapsulated whitish medullary one and consisted of small round and spindle tumor cells, together with so-called rhabdoid cells in the small round cell area. Although pseudorosettes were often observed, true rosette formation could not be detected anywhere. Ultrastructurally, despite a histologic variety of tumor cells, most tumor cells possessed numerous mitochondria, some of which occasionally contained abnormal filamentous or crystalloid structures. Various amounts of microfilaments were present in most tumor cells and microtubules were present in a few. A minority of small round cells possessed a small number of neurosecretory granules, especially in short cytoplasmic processes. A positive immunoreaction for neuron specific enolase was found by immunohistochemical examination in several small round tumor cells and for neurofilaments in lesser numbers. Despite the lack of S-100 protein, MB2 was detected in both small round and spindle cells. On the basis of these findings, the tumor of the present case corresponds to malignant peripheral nerve sheath tumor with neuronal differentiation and oncocytic features.     

Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma.

We report the results of reduced-intensity unrelated cord blood transplantation (RI-UCBT) in patients with advanced malignant lymphoma. Twenty patients (median age, 46.5 years; range, 27-66 years) underwent RI-UCBT with a preparative regimen consisting of fludarabine 125 mg/m2 , melphalan 80 mg/m 2 , and 4 Gy of total body irradiation. The median infused total cell dose was 2.75 x 10(7)/kg (range, 2.3-3.4 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Fifteen patients achieved primary neutrophil engraftment after a median of 20 days. Eight patients developed grade II to IV acute GVHD, and 2 developed chronic GVHD. Of the 16 patients with evaluable disease, 10 achieved a complete response. Primary disease recurred in 1 patient, and transplant-related mortality within 100 days occurred in 8 of 20 patients. The estimated 1-year probability of progression-free survival was 50%. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack an HLA-matched donor.     

Effects among healthy subjects of the duration of regularly practicing a guided imagery program

Background  

We examined a large number of healthy adults in the general community who had individually participated in a guided imagery (GI) program daily and for various durations, to examine the psychophysiological effects of a GI program within a healthy group.     

Synergism between interleukin-11 and bone morphogenetic protein-2 in the healing of segmental bone defects in a rabbit model.

Recombinant human interleukin-11 (rHuIL-11) and recombinant human bone morphogenetic protein-2 (rHuBMP-2) have been shown to act synergistically in the induction of osteoblast differentiation. To determine whether these two proteins can be used clinically in fracture healing and reconstructive surgery, we investigated whether rHuIL-11 and rHuBMP-2 act synergistically to heal segmental bone defects in a rabbit model. A 1.5-cm segmental defect was created in the right ulnar diaphysis of 20 Japanese white rabbits. Polylactic-co-glycolic acid (PLGA)-coated gelatin sponges (PGS) permeated with rHuBMP-2 (n = 8), rHuIL-11 plus rHuBMP-2 (n = 8), or rHuIL-11 (n = 4) were implanted into the bone defects. Radiographs were scored by two independent observers for bone formation and union rates after 2, 3, 4, and 8 weeks. Bone formation was higher in rabbits implanted with rHuBMP-2 plus rHuIL-11 than in those implanted with rHuBMP-2 alone, reaching statistical significance after 4 weeks. At early time points, the union rate in rabbits implanted with rHuBMP-2 plus rHuIL-11 was higher than in rabbits implanted with rHuBMP-2. At 2, 4, and 8 weeks, new bone volume was significantly higher in rabbits administered rHuIL-11 plus rHuBMP-2 than in those given rHuBMP-2 alone. In contrast, mechanical testing after 8 weeks showed that bone strength in the two groups of rabbits was equivalent. These findings show that rHuIL-11 and rHuBMP-2 act synergistically to accelerate bone formation without affecting bone strength. Treatment with a combination of rHuIL-11 and rHuBMP-2 may thus be of great benefit in fracture healing and for patients undergoing reconstructive surgery.