Biomedical subjects
Publications and source records attributed to Y Homma.
A 61-year-old woman with acute urinary retention was found to have a carcinosarcoma in the region of the urethra. Evaluation of the computed tomogram suggested a urethral tumor, which was resected by a transperineal approach. She received local radiotherapy after surgery, and is alive at 1-year follow-up with a tumor metastasis to the pelvis.
A 46-year-old Japanese woman has been followed up for 3 years due to interstitial pneumonia associated with progressive systemic sclerosis (PSS). During this follow-up period, chest roentgenogram revealed additional diffuse nodular shadows. She was diagnosed as having pulmonary sarcoidosis, which was confirmed by the presence of epitheloid granulomas within the alveolar septa. She was successfully treated with corticosteroids and recovered almost completely without worsening pulmonary abnormalities caused by her PSS. The independent clinical courses of these two diseases in the present case suggest that the complication of PSS and sarcoidosis in this patient may be coincidental.
We analyzed the effect of PLC inhibitor (PCI) peptides in their growth and cell cycle. N-Myristoylated PCI peptide, myr-PCI, originally developed based on the PCI sequence of PLC-gamma 2, inhibited activity of purified PLC isoforms in vitro. When myr-PCI was added to KMS-4 and KMS-8 cells, both derived from familial adenomatous polyposis patients, it suppressed the production of inositol trisphosphate, DNA synthesis, and cell growth, all of which were induced by serum in both KMS 4 and KMS 8 cells. Flow cytometry analysis with propidium iodide labelling revealed marked decreases in the percentage of KMS 8 cells in S phase and increases in G0, G1 by the addition of myr PCI. These results indicate that the activation of PLC is essential for growth and transformed properties of these colorectal carcinoma cells, and also that PLC inhibitors could be an anti-tumor drug for some cases.
We studied the relationship between the effectiveness of corticosteroid pulse treatment, clinical characteristics and outcomes in 17 patients with acute exacerbatin of idiopathic interstitial pneumonia. Acute exacerbation was defined as a decrease in PaO2 by more than 10 Torr, worsening of chest-radiographic findings, and deterioration of symptoms within 1 month. Effects of corticosteroid pulse treatment were judged 2 weeks and 3 months after the end of treatment. The change in AaD2 was computed and was used to determine whether the treatment had been effective, temporarily effective, or ineffective. The effects at three months were difficult to predict on the basis of those at two weeks. The treatment was often effective in patients who had not previously received steroids and in those with mild disease. Those in whom the treatment was effective at three months lived longer after the exacerbation than did those in whom it was ineffective, but the average lengths of survival through the whole clinical course were not significantly different among the three groups. We suggest that corticosteroid pulse treatment is effective in acute exacerbatins of idiopathic interstitial pneumonia and that effectiveness should be evaluated three months after treatment.
N-Myristoylated PCI peptide, myr-PCI, originally developed based on the PCI sequence of PLC- gamma 2, inhibited activity of purified PLC isoforms in vitro, and external stimuli-dependent IP3 formation in Swiss 3T3 cells. When myr-PCI was added to KMS-8 cells, derived from familial adenomatous polyposis patients, it also suppressed the serum-dependent IP3 formation, DNA synthesis, and cell growth. In order to develop PCI peptides with strong anti-PLC activity, we synthesized the peptides whose N- and/or C-termini were acylated by a variety of compounds, and examined their anti-PLC and anti-proliferative activities. Results would be quite helpful to determine the minimal structure required for PLC inhibition in vivo.
Using phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] prepared from phosphatidylinositol 4,5-bisphosphate and inositolphospholipid 3-kinase, we identified in bovine thymus extracts the enzyme activity which catalyzed dephosphorylation of PtdIns(3,4,5)P3, to produce phosphatidylinositol biphosphate. Since bovine thymus exhibited the highest level of activity among tissues screened, we tried to purify this enzyme PtdINs(3,4,5)P3 phosphatase from bovine thymus. After sequential chromatographies using S-Sepharose, heparin-Sepharose, blue Sepharose, and Toyopearl HW55, the enzyme was purified 1875-fold with a yield of 10%. SDS/PAGE analysis revealed that a 120-kDA protein band copurified with the enzyme activity. The apparent molecular mass of the active protein was 120 kDa on size-exclusion chromatography, suggesting that the 120-kDa band on SDS/PAGE is the PtdIns(3,4,5)P3 phosphatase. Since PtdIns(3,4,5)P3 phosphatase seemed to be the only activity that metabolized PtdIns(3,4,5)P3, and the enzyme did not hydrolyze phosphatidylinositol 4,5-biphosphate, the enzyme may play a critical role in the inositolphospholipid 3-kinase signalling.
The yeast two-hybrid system and in vitro binding assay were carried out to characterize the interaction between PKN and a small GTP-binding protein, RhoA. It was revealed that the region corresponding to the amino acid residues 33-111 in the amino-terminal region of PKN was sufficient to confer the ability to associate with RhoA. Each synthetic peptide fragment corresponding to the amino acid residues 74-93 and 94-113 of PKN inhibited the interaction between PKN and RhoA in the in vitro binding assay, suggesting that this region is important in the association with RhoA. The endogenous and the GAP-stimulated GTPase activity of RhoA was inhibited by the interaction with PKN, suggesting the presence of a regulatory mechanism that sustains the GTP-bound active form of RhoA.
A chicken B cell line DT40 and its syk-negative or lyn-negative mutants were used to investigate the roles of protein-tyrosine kinases in oxidant stress signaling. The data presented here for wild-type cells demonstrate that hydrogen peroxide stimulates p53/56lyn-dependent tyrosine phosphorylation and activation of p72syk, and induces a rapid and prolonged elevation of intracellular calcium, which consists of calcium release from intracellular stores and influx from the extracellular space. Hydrogen-peroxide-triggered calcium mobilization was impaired in both syk-negative and lyn-negative cells, which was mainly due to the loss of calcium release from intracellular stores. Further studies indicated that inositol trisphosphate production was also abolished in both syk-negative and lyn-negative cells, which is consistent with the loss of calcium release. Taken together, these observations suggest that the defect of p72syk or p53/56lyn was responsible for the abnormality of calcium mobilization in both lyn-negative and syk-negative cells, and that both p72syk and p53/56lyn might regulate calcium mobilization through the phosphatidylinositol pathway in B cell oxidant stress signaling.
We investigated the functional effects of epidermal growth factor (EGF) on guinea pig airways in vitro. EGF (3 ng/ml to 1 microgram/ml) induced a concentration-dependent contraction in epithelium-denuded strips. The average maximal contraction was 0.64 +/- 0.1 g (mean +/- S.E., for n = 27), which was 72.0 +/- 9.5% of the 100 mM KCl-induced contraction. The EC50 was 12.3 +/- 1.6 ng/ml. The presence of the epithelium significantly suppressed the EGF-induced contraction (P < 0.01). EGF-induced contraction was abolished by cyclooxygenase inhibitors (indomethacin and ibuprofen) and a 5-lipoxygenase inhibitor, 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4-benz oqu inone (AA-861). It was also inhibited by a leukotriene-receptor antagonist, 8-[p-(4-phenylbutyloxy)benzoyl]amino-2-(tetrazol-5-yl)-4-oxo -4H-1-benzopyran hemihydrate (ONO-1078) but not affected by a thromboxane A2-synthetase inhibitor, (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid (OKY-046) or a thromboxane A2-receptor antagonist, 9,11-epithio-11,12-methano-thromboxane A2 (ONO-3708). A phospholipase A2 inhibitor (mepacrine) inhibited the EGF-induced contraction but a diacylglycerol-lipase inhibitor, 1,6-di-(O-(carbamoyl)cyclohexanone oxime)hexane (U-57908) and a phospholipase D inhibitor (wortmannin) did not affect it. A tyrosine kinase inhibitor (genistein) abolished it. Measurement of prostanoids showed that EGF (300 ng/ml) did not increase the prostaglandin F2 alpha level in either epithelium-intact or epithelium-denuded strips. In epithelium-intact strips, EGF significantly increased the prostaglandin E2 concentration (P < 0.01). These results suggest that EGF causes contraction of guinea pig airway smooth muscle by activating tyrosine kinase followed by phospholipase A2 activation, and that arachidonic acid metabolites, especially leukotrienes, may have important roles in this contraction.
Mechanisms of relative potency in direct action of antiandrogens have not been fully elucidated. Using castrated rats, the effects of antiandrogens on the prostatic weight gain induced by exogenous testosterone (T), and on T uptake into prostatic cells were examined. Tested antiandrogens were cyproterone acetate, chlormadinone acetate, a new steroidal antiandrogen, 17acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione (TZP-4238), and one nonsteroidal type, flutamide (FL). Suppression of prostatic weight gain, T uptake and serum concentrations of compounds, correlated well each other among steroidal antiandrogens, while FL was five times more active in suppressing weight gain than TZP-4238, associated with a lower nuclear distribution of androgen. The results suggest that 1) suppression of T uptake is a major and common mechanism of steroidal antiandrogens and the relative potency is attributable to pharmacokinetic characteristics in vivo, and 2) FL suppress s nuclear T uptake more specifically than steroidal antiandrogens.
A 56-year-old male carpenter had a history of glass fiber inhalation for 41 years without any protective device. His chest radiograph showed small nodular opacities in lower lung fields and multiple cystic lesions and low attenuation areas in upper lung fields. Light and polarizing microscopic examinations of his transbronchial lung biopsy specimen revealed mild interstitial fibrosis and mononuclear cell infiltration in alveolar walls without birefringent substances. However, widespread depositions of small glass fibers (< 2.5 microns in length and 0.3 micron in diameter) were detected by analytical electron microscopy, which suggested their possible contribution to the development of his pulmonary fibrosis.
In corticobasal degeneration (CBD), cerebral cortical neuronal loss with achromasia and degeneration of the subcortical nuclei, particularly the substantia nigra, are common. Recent studies have suggested that the occurrence of argyrophilic nigral inclusions, resembling the neurofibrillary tangles found in progressive supranuclear palsy, and widespread tau abnormalities may be features of CBD. We studied brain tissues from two patients in whom CBD was suspected clinically. From the distribution of their cortical and subcortical lesions, the patients were diagnosed as having CBD. However, Gallyas/tau-positive neuronal and glial structures were not found, which suggests there may be a subgroup of CBD with neither argyrophilic inclusions nor tau abnormalities.
For imaging CNS 5-HT3 receptors by PET, a high affinity 5-HT3 receptor ligand, endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl 2-(n-propyloxy)-4-quinolinecarboxylate (KF17643), have been labeled with 11C. N-Methylation of the desmethyl compound with [11C]methyl iodide followed by HPLC separation produced [11C]KF17643 with the decay-corrected radiochemical yield of 19-28%, the specific activity of 7.5-49 GBq/mumol and the radiochemical purity of > 99% at 35-40 min from EOB. After i.v. injection of [11C]KF17643 into mice, it was taken by the brain at a high level and was stable for metabolism, but no sign for the 5-HT3 receptor selectivity was found in the brain tissues by the tissue sampling and autoradiography, probably because of large non-specific binding. The [11C]KF17643 was not suitable as a PET ligand for mapping the CNS 5-HT3 receptors.
Airway inflammation may cause alteration of airway responses in chronic airway diseases, such as bronchial asthma. The objective of this study was to examine whether interleukin-1beta (IL-1beta) [corrected], one of the pro-inflammatory cytokines, has a direct effect on airway functions. The effects of IL-1beta on carbachol, KCl and isoproterenol (ISO) responses of isolated guinea-pig tracheal strips were examined by measuring isometric tension in tissue bath. Responses of tracheal strips with or without epithelium to each agonist were compared before and after incubation with IL-1beta (25 ng or 250 ng/mL). Both 1 h and 5 h incubation of the strips with 250 ng/mL IL-1beta significantly decreased the sensitivity not only to KCl (P < 0.05; P < 0.01, respectively), but also to ISO (both P < 0.05) without affecting maximum contraction or relaxation. Response to carbachol was not affected by IL-1beta. Epithelial denudation abolished the effects of IL-1beta on KCl and ISO responses. Indomethacin (2 micromol/L) [corrected] reversed the effects of IL-1beta both on KCl and on ISO. These results suggest that IL-1 beta decreases the sensitivity of airway strips to KCl and ISO, possibly by stimulating prostaglandin production from the airway epithelium [corrected].
BACKGROUND: Glutaraldehyde cross-linked (GAX) collagen has recently become available as injection material for treatment of urinary incontinence and should be evaluated for its long-term efficacy. METHODS: The subjects included 78 females with genuine stress incontinence (GSI) and 19 male or female patients with intrinsic sphincter deficiency (ISD: urinary incontinence due to urethral sphincter damage). GAX collagen was injected transperineally or transurethrally through an injection needle under direct endoscopic observation. The efficacy was evaluated by the patients' overall assessment at two years post-treatment. RESULTS: Under local or regional anesthesia, GAX collagen was injected 1.9 times on average (total injection volume: 23.5 mL) in GSI patients and 2.2 times (40.1 mL) in ISD patients. Improvement at two years post-treatment by patients' assessment was observed in 71.7% of GSI patients and 53.3% in ISD patients. Side effects were urinary retention and difficulty in voiding after 48 of the total of 188 injections (25.5%), a large amount of residual urine in four (2.1%) and miscellaneous in 19 (10.1%), for a short period after injection and were not serious. CONCLUSION: Our study indicates that GAX collagen injection is an effective, safe and easy non-medical treatment for urinary incontinent patients.
BACKGROUND: Standard severity criteria for benign prostatic hyperplasia (BPH) are needed to facilitate clinical and epidemiologic investigations in the common terminology. PATIENTS AND METHODS: A total of 692 BPH patients from 8 institutions were judged by specialized physicians for their overall disease severity and severity in 4 domains: symptom, function, anatomy, and quality of life (QOL). The items measuring severity in these 4 domains were the International Prostate Symptom Score (I-PSS) questionnaire, uroflowmetry, transrectal ultrasonography (TRUS), and questionnaires on bother and I-PSS QOL index, respectively. By Spearman's rank correlation and multiple regression analysis using physicians' judgement as the criterion variable (gold standard) the items and their cut-off levels were selected so that high predictivity, practicality and clinical significance were maintained, while the number of items in use was minimized. RESULTS: The item(s) and their ranges of values for each severity grade were summarized as follows; the evaluation domain (the selected item(s): range of mild, moderate, severe): symptom (I-PSS: 0-7, 8-19, 20-35), function (maximum flow rate and residual urine volume: > or = 15 mL/s and < 50 mL, > or = 5 mL/s and < 100 mL, < 5 mL/s or > or = 100 mL), anatomy (prostate volume on TRUS: < 20 mL, < 50 mL, > or = 50 mL), QOL (QOL index: 0 and 1, 2 to 4, 5 and 6). The overall severity was efficiently predicted when defined according to the combinations of severity grades of the 4 domains. These criteria predicted physicians' judgement with accuracy of about 80% for overall severity and severity of individual domains. CONCLUSION: The proposed criteria are valid, practical, and would be useful for the common scale of the BPH severity in clinical and epidemiologic studies.
BACKGROUND: Various treatment modalities for benign prostatic hyperplasia (BPH) have emerged and are now in use or await evaluation of clinical usefulness. It is difficult, however, to compare their efficacies on a single scale, because standardized criteria for therapeutic efficacy of BPH treatments have not been established. PATIENTS AND METHODS: A total of 692 BPH patients from 8 institutions in Japan received various treatments, and were judged by specialized physicians for overall efficacy, and for efficacy in 4 domains: symptom, function, anatomy, and quality of life (QOL). Efficacy of treatment was graded as excellent, good, fair or poor, and assessed using items based on conventional clinical measurements. These items included 1) the difference (post-pretreatment value), 2) relative ratio (post/pre) and, 3) the individual values of pre- or posttreatment measurements. The cut off levels for each grade were heuristically selected by Spearman's rank correlation and multiple regression analysis so that the results accurately predicted physicians' judgement, while the feasibility was maintained. RESULTS: The results for each efficacy grade (range of excellent, range of good, range of fair, range of poor) were summarized as follows: Symptom: (post/pre treatment ratio of I-PSS) < or = 0.25, < or = 0.5, < or = 0.75, > 0.75. Function: (post-pre of Qmax) > or = 10 mL/s, > or = 5 mL/s, > or = 0.25 mL/s, < 0.25 mL/s. Anatomy: (post/pre ratio of prostate volume) < or = 0.5, < or = 0.75, < or = 0.9, > 0.9. QOL: (pre-post of QOL index) > or = 4, 3, 2 and 1, < or = 0. The overall efficacy grade was defined as the median of efficacy grades of 3 domains: symptom, function and QOL. The agreement rates between the criteria and physicians' judgement on the dichotomous efficacy (either excellent plus good, or fair plus poor) were approximately 80% in individual domains and overall estimate, and consistent among various treatments. CONCLUSION: The proposed criteria are fairly accurate, simple, and practical, and thus may be useful as a standard method for assessing the clinical efficacy of BPH treatments.
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