Leuprolide causes pure red cell aplasia.
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Biomedical subjects
Publications and source records attributed to H Maeda.
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We report a case of sudden death following psychiatric electroconvulsive therapy (ECT). A schizophrenic patient with manic excitement (39-year-old male) in a mental hospital died while vomiting immediately after ECT. The cause of death was diagnosed as asphyxia due to aspiration of vomitus (choking). It is now considered that ECT is an effective treatment for a range of psychiatric disorders and the benefit-risk ratio is equal to or greater than that of psychoactive drugs. Recently, however, there have been 2 other forensic autopsy reports of death due to ECT in Japan. These cases suggest that more effort and careful management are necessary to prevent the accidental deaths.
We report a case of accidental infant death presumably due to exertional self-overheating in bed. On a winter morning, a 9-month-old female baby was found dead in her bed at home. She had been confined to the bed overnight by her father, totally covered with a blanket and a thick quilt, because her night crying disturbed his sleep. The clothing and bedclothes were extremely wet with sweat. Many petechial hemorrhages were observed in the upper chest and thoracic viscera. The blood was concentrated, indicative of dehydration. Histological and immunohistochemical investigation revealed findings of shock and myolysis in the cardiac and skeletal muscles. There was no evidence of natural diseases. The main cause of death was diagnosed as circulatory collapse from overheating (hyperpyrexia and dehydration; heat stroke/exhaustion) probably precipitated by struggling in the closed space. Although there was no apparent evidence of battering or any other repetitive physical violence, this case was regarded as an atypical type of fatal child abuse.
In recent years, accumulated evidence indicates that free radical species and nitric oxide (NO) or its derivatives are the key denominators in carcinogenesis. Our present topics discussed in this article will focus on the biological significance of free radical generation induced by viral and bacterial infections. In influenza virus infection in mice, the level of xanthine oxidase (XO) at the infected sites was elevated to a great extent. The timing of paralleled induction of XO with that of inducible NO synthase (iNOS) indicates efficient simultaneous reaction: NO + O2*- --> ONOO- (peroxynitrite). Peroxynitrite formation was identified by immunostaining of nitrotyrosine at the local site of infected organs. Peroxynitrite exhibits unique chemical reactivities such as protein nitration, DNA-strand breakage, guanine nitration, etc., which may then bring about not only cytotoxic effect but also mutagenesis. Numbers of evidence in vitro and in vivo show that treatment with chemical carcinogens such as carbon tetrachloride and heterocyclic amines also generated superoxide. The chronic inflammatory reactions, e.g., zymosan- and silica-induced granuloma, revealed very similar free radical generation in vivo. In addition, most experimental solid tumors have elevated levels of iNOS in the tumor tissue, and NO thus generated facilitates vascular permeability, which accelerates nutritional supply to the tumor tissue and hence sustains the rapid tumor growth. These circumstantial evidences suggest that inflammatory responses induced by various pathogens would accelerate mutagenesis as well as tissue damage, whereas NO also sustains more effectively solid tumor growth when normal cells are transformed to tumor or carcinoma cells by the host-derived free radical species.
Recent progress in the field of infectious diseases involving carcinogenesis has been striking. Extensive studies of Helicobacter pylori, and hepatitis type B and C virus showed that they are the primary cause of gastric cancer and hepatoma, respectively. Also some parasites such as Opistorchis viverrini and Schistosoma haematobium are also putative causes of cholangiocarcinoma and urinary bladder cancer, respectively. All of them require a chronic infection of more than 15 years. More than 50% of Japanese cancers are thus considered to be caused by chronic infection. The classic theory of carcinogenesis is radiation, chemicals and viral infection. Recent studies in free radical and biochemical research in our infectious diseases show all carcinogenesis involves free radical generation such as superoxide (O2.-), nitric oxide (NO), and their adducts peroxynitrite (ONOO-), H2O2 hydrooxyl radical (.OH), HClO, and NO2Cl as well as alkylperoxy radicals. All these molecular species are capable of modifying nucleic acid and DNA or RNA; furthermore a strand break is frequently observed, and hence potent mutagenicity and a probable cause of cancer. Thus, the unifying theory of carcinogenesis may most likely involve the mechanism of free radicals. This means a paradigm shift is needed in the public health policy for the tactics of cancer prevention.
This brief review discusses the diagnostic ability of prostate specific antigen adjusted for the transition zone volume (PSATZ) for the detection of prostate cancer in patients with intermediate prostate specific antigen (PSA) levels. PSATZ was defined as the quotient of the PSA value and the calculated transition zone volume. In comparison with standard parameters including PSA and prostate specific antigen density, PSATZ could be a useful indicator for the detection of prostate cancer in patients with PSA values between 4.1 and 10.0 ng/ml, especially in those with normal digital rectal examinations. Similar observations consistent with our results have been also reported by other investigators. PSATZ has some disadvantages including volumetry and expensive cost. Further study is necessary to discuss whether PSATZ is superior to other new modalities such as free-to-total PSA ratio with regard to diagnostic cost and efficacy.
Although systematic biopsy has increased the detection rate of prostate cancer, the optimal method of biopsy has not yet been fully established. The number and site of cores, and the biopsy route are controversial in terms of cancer detection and complication. We briefly review the advances in prostate biopsy, and present the results of our biopsy methods. Our study showed that the difference of cancer detection rate between 4 quadrant and 6 sextant biopsy was not significant. There was little value in systematic transition zone biopsies. However, such biopsies proved useful in patients whose first systematic biopsies was negative and who have persistently elevated PSA values. It is recommended that the biopsy protocol for routine prostate cancer detection be targeted to the peripheral zone.
In the past, radical prostatectomy commonly led to urinary incontinence and erectile dysfunction. In the last decade, new operative techniques have greatly reduced the complication rate and the operation has gained increasing popularity as treatment of choice for localized prostate cancer. Success or failure of radical prostatectomy has been reported not only in terms of disease-free survival, but in terms of patient attitudes to treatment and side effects. As physicians, we must remember that in presenting treatment options to patients it is important to emphasize both the quality and quantity of life that may result. With richer information on QOL in addition to duration of survival, patients will be able to make more informed decisions. Therefore, the QOL study will contribute patient self-report data to current treatment decision models that rely solely on physician estimates of patients' QOL and side effects following radical prostatectomy. We herein report the results of our recent QOL survey in men treated with radical prostatectomy, and briefly discuss QOL methodology.
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A 71-year-old man with inoperable intrathoracic esophageal cancer was treated by concurrent chemoradiation. A dose of 48 Gy (neck) and 60.6 Gy (mediastinum) and four courses of 5-FU (500 mg/day)-CDDP (50 mg/week) were delivered. The esophageal tumor and metastatic lymph nodes of the neck showed a complete response (CR) to the treatment, whereas paraaortic lymph nodes evidenced no change (NC). The patient is doing well without symptoms at 13 months after treatment. The chemoradiotherapy produced effective improvement and quality of life in this patient.
A diet high in fat and iron is known as a risk factor in cancer epidemiology. However, the details of the molecular mechanism remains to be elucidated. We examined the possible implication of lipid peroxyl radicals generated from fatty acids and heme-iron in DNA damage, and hence in the possibility of colon cancer. F344 female rats were given N-nitroso-N-methylurea six times during a 2-week period and then fed diets containing different amounts of safflower oil and hemoglobin (rich in iron) for 36 weeks; the occurrence of colon cancer was determined by H&E staining. In this animal model, simultaneous feeding of a fat diet and heme-iron produced a significant increase (P < 0.05) in the incidence of colon cancer compared with a diet without hemoglobin. Electron paramagnetic resonance and chemiluminescence studies revealed that oxidized refined vegetable oils, particularly safflower oil, readily generated lipid peroxyl radicals in the presence of various heme compounds, and the peroxyl radicals did effectively cleave DNA. Unpurified native vegetable oils contain a high amount of peroxyl radical scavengers, whereas conventional refining processes seem to reduce the levels of many valuable anti-peroxyl radical compounds abundant in plant seeds. In conclusion, lipid peroxides and heme components generate peroxyl radical species that exert DNA-cleaving activity. A plausible explanation is that lipid peroxyl radicals thus generated, which originated from routine dietary components such as fat and red meat, may contribute, at least in part, to the high incidence of colon cancer.
We studied the clinical significance of serum prostate specific antigen (PSA) ratio: free-PSA/total-PSA and free-PSA/complex-PSA to discriminate between prostate cancer (PC) and prostate benign disease (non-PCa) by using total-PSA, alpha 1-antichymotrypsin complexed (complex)-PSA and free-PSA enzyme-linked immunosorbent assay (ELISA) kits newly developed at EIKEN Chemical Co, Ltd. Fre-PSA and complex-PSA ELISA kits demonstrated high sensitivity and specificity. Total-PSA ELISA kit also demonstrated equimolarity for free-PSA and complex-PSA. On the total-PSA range of 4-10 ng/ml, free-PSA/total-PSA% (f/t%) and free-PSA/complex-PSA% (f/c%) were very useful to discriminate between PCa and non-PCa by receiver operating characteristic curve analysis as well as PSA density (PSA-D) but not free-PSA level. F/t% and f/c% were even useful to discriminate early stage PCa (i.e. A1 or B0) from non-PCa by the Mann-Whitney U-test.
Telomerase maintains telomere length and is considered to be necessary for the indefinite proliferation of human cells. Telomerase activity is detected not only in germline and immortal cancer cells, but also in stem/progenitor cells of renewal tissues and activated lymphocytes. While it is generally agreed that telomerase is a useful tumor marker, the utility of telomerase activity in non-cancerous cells should also be considered. In the present study, we quantitatively examined telomerase activity in 56 cytology samples and 106 bronchoalveolar lavage samples obtained from patients with various respiratory diseases. Fourteen of 34 samples obtained from lung cancer patients showed detectable telomerase activity, while only 7 of 128 samples obtained from patients without lung cancer did (p<0.001). Moreover, 12 of 14 telomerase-positive samples with lung cancer showed strong signals, while none without lung cancer did. Among 106 non-cancerous bronchoalveolar lavage samples, 4 telomerase positive samples had increased number of lymphocytes and increased disease progression. These findings indicate that evaluation of telomerase activity may not only be a useful diagnostic test for lung cancer, but may also be a marker of disease aggressiveness for immune-associated lung diseases.
A periodontal pathogen, Porphyromonas gingivalis possesses either a 53 kD (Ag53) or a 67 kD (Ag67) outer membrane protein (OMP). Almost all sera from patients with periodontal diseases reacted strongly with either Ag53 or Ag67. In previous work the cloning and sequencing of the 53 kD outer membrane protein gene designated pga53 from P. gingivalis FDC381, was reported and the presence of a gene homologous to pga53 in P. gingivalis ATCC 33277 demonstrated. In the present work this pga53-homologous gene from P. gingivalis ATCC 33277 was isolated and characterized. Nucleotide sequence analysis revealed that this gene encoded Ag67, and the gene was designated pga67. The deduced amino acid sequence and composition of pga67 was similar to the amino acid composition and N-terminal partial sequence of Ag67. An open reading frame of pga67 consisted of 1,692 nucleotides encoded as 564 amino acids, including a 49 amino acid signal sequence. The comparative analysis between pga67 and pga53 revealed that (1) the deduced amino acid sequence showed a 30.1% homology; (2) signal sequence and proline-rich regions at the C-terminus were the most conserved regions; (3) considerable differences were found mainly in the middle part of the OMPs; and (4) obvious differences in the two-dimensional models were evoked. These differences between pga67 and pga53 may explain the antigenic diversity between Ag67 and Ag53 OMPs.
We examined blood samples of 214 forensic autopsy cases, excluding fire victims, on a CO-oximeter system in order to evaluate post-mortem oxymetric profiles with reference to the causes of death. Oxyhemoglobin (O2-Hb) levels in the left and right heart blood, respectively, ranged from 0 to 97.7% and from 0 to 92.1%, showing no apparent correlation with the post-mortem intervals or rectal temperatures. In nearly 60% of the cases, O2-Hb was lower than 10%. A high O2-Hb level (over 50%) in the left heart blood was most frequently observed in death from cold exposure and occasionally in fatalities from blunt injuries and stab/incised wounds with or without medical care. O2-Hb in the heart blood was usually very low (under 10%) in fatalities from asphyxiation, drowning, poisoning and natural diseases. A greatest oxymetric variation was observed in death from injuries, probably due to varied causal mechanisms of death. In most cases, the differences between blood O2-Hb levels in the heart and iliac vessels were within 15%; whereas O2-Hb in the cerebral venous blood was usually evidently higher than that in the right heart blood. An inverse relation of O2-Hb levels to total hemoglobin contents was observed slightly for the blood in the heart and iliac vessels, and more obviously for the cerebral venous blood. The above post-mortem oxymetric profiles were considered to at least partially reflect the final balance of oxygen uptake and consumption in dying process, possibly also affected by the circulatory status, giving an objective index to the color of cadaveric blood (hypostasis), although it should be assessed in consideration of post-mortem interference and total hemoglobin contents. In any case, however, post-mortem oxymetry seemed to have a limited value owing to severe systemic hypoxia which would be a common final state before death from various fatal traumas and diseases, maybe except for those with extremely short agony.
The involvement of nitric oxide (NO) and its reactive intermediates such as nitrogen dioxide (NO2) and peroxynitrite (ONOO-) in the activation of matrix metallo-proteinase was investigated. The human neutrophil procollagenase (matrix metalloproteinase-8) (M(r), 85 kDa) was purified to homogeneity from human neutrophils by using column chromatography. After incubation of human neutrophil procollagenase with various nitrogen oxide-generating systems, collagenolytic activity in each reaction system was measured. In addition, neutrophil collagenase activity was determined by assessment of proteolysis of human alpha 1-protease inhibitor. NO was formed by the propylamine NONOate, and NO2 was generated by oxidation of NO with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). NO2, formed by NONOate and carboxy-PTIO, and the synthetic ONOO- exhibited strong activation of the procollagenase at 1-20 microM. Significant activation of the procollagenase was observed with use of authentic NO2 gas as well. Constant flux infusion of ONOO- into the procollagenase solution resulted in stronger procollagenase activation than did a bolus addition of ONOO- to the reaction mixture. However, NO showed only weak activating potential under the aerobic (ambient) condition; an NO concentration of more than 10 mM was needed for appreciable activation of the procollagenase. Of considerable importance was the fact that NO participates in activation of the neutrophil collagenase through its conversion to NO2 or ONOO- in human neutrophils. These results suggest that NO2 and ONOO- may be potent activators of human neutrophil procollagenase.
Fas ligand (FasL) is a member of the tumor necrosis factor family and induces apoptosis in Fas (CD95)-bearing target cells. In this study, we generated several mAbs that react with mouse FasL (mFasL) and characterized their functional properties. One of these mAbs, K10, specifically reacted with mFasL derived from C57BL/6 (B6) mice, but not that from BALB/c mice as estimated by surface staining and blocking of cytotoxic activities of mFasL transfectants, suggesting a polymorphism of mFasL. Sequence analysis of mFasL cDNA from several strains revealed that BALB/c and DBA/2 mice have three nucleotide differences from the known B6 and C3H sequences, which result in two amino acid substitutions (Thr-184 --> Ala-184 and Glu-218 --> Gly-218) in the extracellular region. Analysis of the K10 reactivity and genotyping by PCR-restriction fragment length polymorphism revealed that inbred mice segregate into the following two allotypes: mFasL.1 (B6, C3H, MRL, SJL, NOD, NZB, NZW) and mFasL.2 (BALB/c, DBA/1, DBA/2). Interestingly, COS7 cells expressing BALB/c FasL lysed Fas-bearing target cells more efficiently than those expressing B6 FasL. Furthermore, BALB/c-derived CD8-FasL fusion protein, which is composed of the extracellular domains of human CD8alpha and mFasL, exhibited 9-fold higher specific activity than did B6-derived CD8-FasL. These results suggest that in mFasL.2 mice the Fas/FasL system works more effectively than in mFasL.1 mice.
CD40-mediated signals can induce cell aggregation, proliferation and rescue from apoptosis in WEHI231. To define which segment of cytoplasmic domain of CD40 and how signals are involved in those events, we generated mutant CD40 transfectants. We demonstrated the same 10 amino acid segment that could bind to tumor necrosis factor receptor associated factor-2 and -3 mediated all those responses. However, activation pattern of mitogen activated protein kinases was different. Immunoglobulin M-mediated apoptosis was inhibited by CD40-mediated signal that activated c-Jun aminoterminal kinase synergistically. While, CD40 stimulus through the 10 amino acid segment alone that induced cell aggregation and proliferation resulted in activation of extracellular signal-regulated protein kinase 2.