Y-29794--a non-peptide prolyl endopeptidase inhibitor that can penetrate into the brain.

A novel non-peptide prolyl endopeptidase (PPCE) inhibitor, Y-29794, has been identified. Y-29794 selectively and competitively inhibited rat brain PPCE (Ki = 0.95 nM) in a reversible manner. Ex vivo study demonstrated that Y-29794 could penetrate into brain to exhibit dose-dependent and long-lasting inhibition. Furthermore, Y-29794 was found to potentiate the effect of TRH on the release of ACh in the rat hippocampus. These results indicate that Y-29794 is an orally active, potent and specific PPCE inhibitor and should be of value in studies on the physiological role of the enzyme in neuropeptide metabolism especially in memory process.     

Membrane attack complex of complement and 20 kDa homologous restriction factor (CD59) in myocardial infarction

In order to investigate the mechanism of deposition of the complement membrane attack complex (MAC) in cardiomyocytes in areas of human myocardial infarction, the 20 kDA homologous restriction factor of complement (HRF20; CD59) and complement components (C1q, C3d and MAC) were analysed immunohistochemically using specific antibodies. Myocardial tissues obtained at autopsy from nine patients who died of acute myocardial infarction were fixed in acetone and embedded in paraffin. The ages of the infarcts ranged from about 3.5 h to 12 days. In cases of myocardial infarction of 20 h or less, MAC deposition was shown in the infarcted cardiomyocytes without loss of HRF20. Where the duration was 4 days or more, the cardiomyocytes with MAC deposition in the infarcted areas also showed complete loss of HRF20. Outside the infarcts, HRF20 in the cardiomyocytes was well preserved without MAC deposition. The present study suggests that the initial MAC deposition in dead cardiomyocytes can occur as a result of degradation of plasma-membrane by a mechanism independent of complement-mediated injury to the membrane. Loss of HRF20 from dead cardiomyocytes may not be the initial cause of MAC deposition, but may accelerate the deposition process of MAC in later stages of infarction.     

Differential IL-12 responsiveness of T cells but not of NK cells from tumor-bearing mice in IL-12-responsive versus -unresponsive tumor models

While IL-12 administration induces tumor regression through stimulating T cells in tumor-bearing mice, this IL-12 effect is observed in some but not all tumor models. The present study aimed to compare IL-12 responsiveness of T cells from tumor-bearing mice in IL-12-responsive (CSA1M and OV-HM) and -unresponsive (Meth A) tumor models. Tumor regression in IL-12-responsive tumor models required the participation of T cells, but not of NK1.1(+) cells. Because a NK1.1(+) cell population was the major producer of IFN-gamma, comparable levels of IFN-gamma production were induced in IL-12-responsive and -unresponsive tumor-bearing mice. This indicates that the amount of IFN-gamma produced in tumor-bearing individuals does not correlate with the anti-tumor efficacy of IL-12. In contrast, IL-12 responsiveness of T cells differed between the responsive and unresponsive models: purified T cells from CSA1M/OV-HM-bearing or Meth A-bearing mice exhibited high or low IL-12 responsiveness respectively, when evaluated by the amounts of IFN-gamma produced in response to IL-12. T cells from CSA1M- or OV-HM-bearing but not from Meth A-bearing mice exhibited enhanced levels of mRNA for the IL-12 receptor (IL-12R). These results indicate that a fundamental difference exists in IL-12 responsiveness of T cells between IL-12-responsive and -unresponsive tumor models, and that such a difference is associated with the expression of IL-12R on T cells.     

Survey of recognition and utilization of guidelines for the diagnosis and management of bronchial asthma in Japan

BACKGROUND: In Japan in 1993, the Japanese Society of Allergology (JSA) developed guidelines for diagnosis and management of asthma (JGL), which were based on the concept that asthma is a chronic inflammatory disorder of the airway. METHODS: This survey study was intended to investigate the recognition and utilization of JGL among physicians who had treated asthma. The survey comprised two methods: a quantitative mail survey and a qualitative door-to-door survey conducted by trained interviewers. RESULTS: In the mail survey, a total of 1028 physicians responded; 552 members of the JSA and 476 nonmembers. Ninety-four percent of JSA members were aware of adult asthma management guidelines, while 53% of nonmembers were aware of them. Although approximately half of the physicians, both members and nonmembers, found differences between the asthma management policies in JGL and their previous policies, most of them utilized JGL once they read it. In the qualitative door-to-door survey, 80-90% of physicians evaluated JGL as good after they read it. CONCLUSIONS: JGL was recognized and utilized by most JSA members, but only half of nonmember physicians were aware of JGL, although they utilized JGL after they read it. Further action to implement JGL among nonspecialist physicians is needed to improve management of asthma.     

Pigmentary degeneration indwed by N-methyl-N-nitrosourea and the fate of pigment epithelial cells in the rat retina

Pigmentary degeneration of the retina was induced by a single intraperitoneal Injection of 75mgkg of N-methyl-N-nitrosourea (MNU) In female Brown-Norway colored rats at 50 days of age, which were then observed at 24, 48 and 72 h and 7, 21,35 and 150 days after the treatment. MNU-treated rats showed selective destruction of the photoreceptor cells by an apoptotic mechanlsm 24 h after the treatment, and the destruction was completed by day 7. During the photoreceptor cell degeneration, proliferation of Miller cells and infiltratlon of macrophages was prominent 72h and 21 days aRttr the treatment, respectively. Müller cell proliferation and macrophage infiltratbn corresponded to degenerative photo-receptor cell phagocytosis, and prollferating Müller cell processes responded to stabilize the damaged retina. Pigment epithelial cell detachment from the Bruch's membrane was seen 72 h after the treatment, and migration within all layers of the retina was seen at day 7 when photoreceptor Cells were lost. At 21, 35 and 150 days after the treatment, lack of photoreceptor cells and deposition of pigment epithelial cells within the retina but not in contact to vascular endothe-lial cells were characteristic. MNU-induced photoreceptor apoptosis followed by Miiller cell and macrophage reaction then pigment epithellal cells deposition withln the retina partially resembles retinitis pigmentosa in humans.     

NECROTIZING MYOPATHY AS A REMOTE EFFECT OF GASTRIC CANCER ACCOMPANIED WITH HASHIMOTO'S THYROIDITIS

An autopsy case of a 74-year-old male who had shown clinically hypothyroidism due to chronic atrophic thyroiditis (Hashimoto's thyroiditis), and pathologically necrotizing myopathy as a remote effect of gastric cancer was reported.
Morphological features of this necrotizing myopathy was those of carcinomatous myopathy rather than those of hypothyroid or diabetic myopathy.
As for the pathogenesis of the necrotizing myopathy (as a Group IV of polymyositis of Walton and Adams), the malignancy might have played an important role as a trigger of the secondary immunological abnormality upon a pre-exizting longstanding immune disorder of Hashimoto's thyroiditis. Pseudomembranous colitis, which was thought to be related to antibiotics (Lincomycin), was also briefly discussed.     

Extrapleural solitary fibrous tumor: clinicopathologic study of 17 cases and molecular analysis of the p53 pathway

Solitary fibrous tumor (SFT) occurring at various extrapleural sites is sometimes difficult to diagnose because of its histologic variability. Although a solitary fibrous tumor is usually a slow-growing tumor with favorable prognosis, a small number of malignant cases have been reported. In the present study, we examined the clinical behavior, histologic, immunohistochemical and molecular features of 17 cases of extrapleural SFT. Four tumors were located in the pelvic cavity, two in the nasal cavity, two were confined to the pulmonary parenchyma, and there was one each in the meninges, kidney, mediastinum, retroperitoneum, temporal region, neck, groin, buttock and thigh. Histologically, all the tumors were characterized by the presence of areas consisting of a proliferation of bland spindle cells with variable amounts of thick, often hyalinized or keloid-like intercellular collagen bundles. Highly cellular areas were observed in three tumors, frequent mitoses in two, and cellular pleomorphism and tumor necrosis in one each. All 17 tumors showed immunoreactivity to CD34 and 15 (88%) to bcl-2 protein. The labeling indices of p53, mdm2 protein and Ki-67 were generally low. PCR-SSCP and a subsequent sequence analysis of the p53 gene disclosed point mutation at codon 161 in exon 5 in one of the 13 cases analyzed. According to follow-up information, none of the patients had developed local recurrence or distant metastasis. Our results suggest that most extrapleural SFTs behave in a benign fashion even in a higher histologic grade group, and it is difficult to predict their clinical outcome. Complete surgical excision in order to obtain clear margins and long-term follow-up is advisable for patients with an extrapleural SFT.     

Role of the common cytokine receptor gamma chain (gammac) in thymocyte selection

During thymocyte development, T-cell receptor (TCR) alphabeta-mediated intracellular signals can elicit two entirely different cellular responses: positive selection (resulting in rescue from death and maturation or differentiation) and negative selection (induction of apoptosis). Here, Hiroshi Nakajima and colleagues discuss how survival signals that are dependent on the common cytokine receptor gamma chain (gammac) might affect the TCR-driven selection process in thymocytes, underscoring the potential role of cytokines in this process.