Multiple pathways are involved in DNA degradation during keratinocyte terminal differentiation.

Loss of the nucleus is a critical step in keratinocyte terminal differentiation. To elucidate the mechanisms involved, we focused on two characteristic events: nuclear translocation of N-terminal fragment of profilaggrin and caspase-14-dependent degradation of the inhibitor of caspase-activated DNase (ICAD). First, we demonstrated that epidermal mesotrypsin liberated a 55-kDa N-terminal fragment of profilaggrin (FLG-N) and FLG-N was translocated into the nucleus. Interestingly, these cells became TUNEL positive. Mutation in the mesotrypsin-susceptible Arg-rich region between FLG-N and the first filaggrin domain abolished these changes. Furthermore, caspase-14 caused limited proteolysis of ICAD, followed by accumulation of caspase-activated DNase (CAD) in TUNEL-positive nuclei. Knockdown of both proteases resulted in a significant increase of remnant nuclei in a skin equivalent model. Immunohistochemical study revealed that both caspase-14 and mesotrypsin were markedly downregulated in parakeratotic areas of lesional skin from patients with atopic dermatitis and psoriasis. Collectively, our results indicate that at least two pathways are involved in the DNA degradation process during keratinocyte terminal differentiation.

[Achievement of causal inference in the social medicine in Japan].

As a condition to achieving an agreement of recognition on the causal relationship in medicine, we firstly explained Hume's problem and counterfactual model. We, however, emphasized that we believe in the existence of causality on medical issues in our daily lives. Therefore, we illustrated conditions when we usually believe in causality. On the other hand, we criticized two well-known key phrases, "lack of mechanism in epidemiology" and "black box in epidemiology", which have often been used in Japan for skeptic viewpoints against epidemiologic methods even if epidemiology is often used to elucidate a causal effect in medicine in the world. We emphasized that a priori determinations of levels for inference of mechanism is necessary. And, the level and feature of mechanism should be defined in concrete expressions. After explanation of these basic concepts, we mentioned a classic view on specific diseases and non-specific diseases which have not been sufficiently discussed enough yet in Japan. As an example, we used the statements in the Japanese Compensation Law for the Health Effect by Environmental Pollution. In Japan, the classification of these diseases has been confused with that between manifestational criteria of diseases and causal criteria of them. We described the basic concepts to illustrate the causal relationship between non-specific disease and its exposure by using attached figures. Actually, we cannot recognize disease occurrence as a specific disease for several reasons. We indicated that we can recognize the magnitude of effect by causal relationships in medicine as a quantitative continuous variable.

[An appraisal of the judgements of the Kumamoto Minamata Disease Certification Commission from May 1981 to July 1992 for applicants from December 1975 to April 1981].

The differences of the diagnosis from December 1975 to April 1981 and from May 1981 to July 1992 of the Committee on Certification of Minamata Disease based on the medical records of 3,870 applicants who had been examined from December 1975 to April 1981 by the Committee were compared and analyzed from a statistical point of view. Three hundred forty inhabitants from December 1975 to April 1981 and two hundred ninety eight inhabitants from May 1981 to July 1992, in total six hundred and thirty eight inhabitants, were certified to have Minamata disease by the Committee on Certification of Minamata Disease. One hundred and eleven inhabitants who were judged likely to have Minamata disease by application of the present criteria presented by the Japanese Environmental Agency in 1977 were certified by the committee from May 1981 to July 1992, and one hundred and thirty three inhabitants who were judged not likely to have Minamata disease by application of the present criteria were certified from May 1981 to July 1992. The author concluded that certification of the patients of Minamata disease by the Committee was inconsistent with the results of applying the present criteria to the data and that the prevalence of the symptoms of the inhabitants certified from December 1975 to April 1981 was inconsistent with that from May 1981 to July 1992.

A case of prostatic cancer metastasizing to the orbit.

PURPOSE: We report on a case of prostatic cancer with multiple bone metastases, including right orbital involvement. METHODS/RESULTS: Hormonal treatment and local irradiation to the right orbit were performed. Subjective symptoms with exophthalmos and pain disappeared. CONCLUSIONS: We report on a case of prostatic cancer metastasizing to the right orbital bone.

[Causal inference in medicine: a reaction to the report, "incidence of Minamata disease in communities along the Agano River, Niigata, Japan--patterns of the exposure and official diagnosis of patients"].

Kondo's "Incidence of Minamata Disease in Communities along the Agano River, Niigata, Japan (Jap. J. Hyg. 51:599-611;1996)" is critically reviewed. The data of the article were obtained from most of the residents living in the Agano river villages where Minamata disease was discovered in June, 1965. However, sampling proportions were much different between in the population base and in the cases. The method of identification of cases from the data and the reason for the difference were not clearly demonstrated. The citations of reference articles are insufficient despite the fact that other epidemiologic studies on methyl-mercury poisoning have been reported not only in Japan, but also around the world. His "analysis of the recognized patients" is erroneous. Both the sampling scheme of information of hair mercury and the modeling of the analysis are based on Kondo's arbitrary interpretation, not on epidemiologic theory. His "analysis of the rejected applicants" is also erroneous. His calculations of the attributable proportion are incorrect and self-induced in both the assignments of data and analysis of data. Kondo has failed to study the epidemiologic theories in light of changes in the field. Therefore, his article is lacking in epidemiologic theory, a logical base and scientific inference. In Japan, epidemiologic methodology has rarely been used in studies on Minamata Disease in either Kumamoto and Niigata. The government has used neurologically specific diagnosis based on combinations of symptoms to judge the causality between each of symptoms and methyl-mercury poisoning. Epidemiologic data obtained in Minamata, Kumamoto in 1971 indicate that the criteria set by the government in 1977 have produced much more false-negative patients than false-positive patients. As a result, a huge number of symptomatic patients, including those with peripheral neuropathy or with constriction of the visual field, did not receive any help or compensation until 1995. The authors emphasize that the causal relationship between each symptom and methyl-mercury exposure should be reevaluated epidemiologically in Japan.

[An appraisal on the judgements of the Kumamoto Minamata Disease Certification Commission].

Medical records of 3,870 applicants living near the Shiranui sea coast who had been examined from August 1975 to April 1981 by the Committee on Certification of Minamata Disease were analyzed from the statistical point of view. The author analyzed the pattern of signs and reevaluated the applicants' records. Three hundred forty applicants (8.8%) were certified to have Minamata disease by the Committee on Certification of Minamata Disease. By application of the present criteria presented by the Japanese Environmental Agency in 1977 to the records, 947 inhabitants (27.9%) were judged likely to have Minamata disease. The author concluded that the certification of the patients of Minamata disease by the Committee was inconsistent with the results of applying the present criteria to the data and that the number of patients certified by the Committee to have Minamata disease was too low.

Factors affecting the occurrence of urothelial tumors in dye workers exposed to aromatic amines.

BACKGROUND: Past studies have analyzed individual jobs in dyestuff factories, materials manufactured and handled, age at exposure, and the duration of exposure in factories as factors related to the occurrence of urothelial tumors. None of these studies was based on long-term observation, and the factors involved in the occurrence of urothelial tumors remain controversial. In this study, various factors that may affect the occurrence of urothelial tumors in dye workers were assessed by multivariate analysis. METHODS: Three hundred and sixty-three workers in nine member factories of the Dyestuff Industrial Cooperative Association were included the study. Factory A is a large dyestuff chemical factory in Wakayama City with 218 dye workers. The other eight smaller factories employ a total of 145 dye workers. Correlations of tumor occurrence with a variety of factors, such as dyestuff intermediates manufactured and handled, types of job in the factory, age at the beginning of occupational exposure, and the duration of exposure were examined by multivariate analysis using multiple logistic models. RESULTS: Urothelial tumors were found in 58 (16.0%) of the 363 dye workers in the nine member factories of the Cooperative Association examined in the present study. The incidence in workers in Factory A, 5.5% (12 patients), was significantly (P < 0.01) lower than the overall incidence, while that in the eight small factories, 31.7% (46 patients), was significantly (P < 0.01) higher than the overall incidence. The risk factors significantly related to tumor occurrence in the 363 dye workers were benzidine (odds ratio, 8.302) as a dyestuff intermediate, manufacturing work (odds ratio, 4.631), and a long period of exposure (odds ratio, 1.018). Correlations of the tumor occurrence with the various factors were examined by multivariate analysis using multiple logistic models. In the total of 363 workers, benzidine as an intermediate (P < 0.05), manufacturing work (P < 0.01) and the duration of exposure (P < 0.01) were found to have contributed to the urothelial tumor occurrence. In Factory A, benzidine as an intermediate (P < 0.01) and duration of exposure (P < 0.05) contributed significantly to tumor occurrence. CONCLUSIONS: 1) The manufacturing and handling of benzidine and duration of exposure contribute significantly to the occurrence of occupational urothelial tumor, the former more strongly than the latter; 2) the contribution of different job types to tumor occurrence may be dependent upon the industrial health and safety practices in each factory.

[A case of clear cell adenocarcinoma of the female urethra].

A case of clear cell adenocarcinoma arising from the female urethra is described. Histologically, solid and glandular areas consisted of clear cells. The tumor cells were stained positively with antibodies to prostate specific antigen (PSA) and prostatic acid phosphatase (PAP), suggesting that the clear cell adenocarcinoma arises from the female paraurethral duct, rather than embryonic remnant.

Clear cell adenocarcinoma of the female urethra showing positive staining with antibodies to prostate-specific antigen and prostatic acid phosphatase.

A case of clear cell adenocarcinoma arising from the female urethra is described. Histologically, solid and glandular areas consisted of clear cells. The tumor cells stained positively with antibodies to prostate-specific antigen and prostatic acid phosphatase, suggesting that the clear cell adenocarcinoma arises from the female paraurethral duct, rather than embryonic remnants.

[Prostate specific antigen in patients with prostatic cancer--clinical usefulness of its measurement with sensitive enzyme immunoassay, TOSOH II PA assay].

The TOSOH II PA (AIA-PACK PA in the U.S.A.) monoclonal immunoenzyme assay was used and the clinical usefulness of prostate specific antigen (PSA) was evaluated in 39 men with prostatic cancer and 32 men with benign prostatic hyperplasia (BPH) confirmed pathologically. We evaluated the lower limit of detection in this assay by the mean PSA level plue 3 standard deviations in 5 separate experiments with a zero control sera as well as the mean PSA level minus 3 standard deviations in 5 separate experiments with serial dilutions of a known concentration of PSA. PSA concentrations of 0 to 0.25 ng/ml could not be distinguished from the zero control. Therefore, we set the lower limit of detection for the assay as 0.25 ng/ml. At our laboratory, the normal standard value was determined by the mean PSA level plus 3 standard deviations in 79 healthy men as 2.3 ng/ml. Of patients that underwent radical cystoprostatectomy for bladder cancer, all had PSA levels less than 0.25 ng/ml, while only 6% had PAP levels less than 0.11 ng/ml, the lower limit of detection in the TOSOH II PAP assay. We compared TOSOH II PA with Markit PA, a commonly used assay in Japan. Although there was a close linear correlation (r = 0.90) between the TOSOH II PA and Markit PA, the difference of slope in the linear regression lines was great, it was thought due to anti-PSA antibodies in each assay recognizing different epitopes of PSA in the blood.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of Klebsiella pneumoniae endophthalmitis metastasized from prostatitis.

A case of Klebsiella pneumoniae endophthalmitis metastasized from prostatitis is reported. A 58-year-old alcoholismic man with diabetic diathesis suffered from endophthalmitis which required enucleation of his left eye, when he interrupted the treatment of prostatitis. Metastatic bacterial endophthalmitis from urinary tract infection is rare.

Determination of aspoxicillin in broncho-alveolar lavage fluid by high-performance liquid chromatography with photolysis and electrochemical detection.

A determination method for the penicillin antibiotic aspoxicillin in broncho-alveolar lavage fluid has been developed, involving high-performance liquid chromatography and post-column photolysis. The method enabled the determination of aspoxicillin at concentrations below 100 ng/ml, with a linear calibration curve at concentrations of 1-1000 ng/ml for 100 microliters of lavage fluid. The detection limit was 1 ng/ml at a signal-to-noise ratio of 3:1.

[A case of deoxycorticosterone-producing adrenal tumor].

We present a case of a 11-deoxycorticosterone (DOC)-producing adrenocortical tumor. A 55-year-old female was admitted to our hospital with the chief complaints of sustained hypertension and weakness of lower extremities. A laboratory study revealed a decrease in the serum potassium level and plasma renin activity, a normal level of plasma aldosterone and a significant elevation of plasma DOC and 18-OH-DOC levels. The plasma DOC level was increased by ACTH stimulation and was not suppressed by dexamethasone. The tumor appeared at a low intensity of the T1 weighted image of magnetic resonance imaging (MRI) and at a high intensity on the T2 weighted image. Left adrenalectomy was performed and histological examination revealed a benign adrenal adenoma. Postoperatively, the abnormal blood pressure, serum potassium level and plasma level of DOC and 18-OH-DOC became normal.

[A clinical review of 19 patients with pheochromocytoma].

Nineteen cases of pheochromocytoma were experienced at our department between 1979 and 1990. Nine patients were males and 10 females with an average of 42.4 years old. In 18 patients the tumor was located in the adrenal gland (9 in right, 5 in left and 4 in bilateral adrenal gland), while in one patient whose original tumor had been resected 15 years earlier, the tumor had recurred in the extra-adrenal gland and was surgically extirpated revealing a malignant pheochromocytoma by histological examination. Hypertension was seen in 16 patients; 14 had paroxysmal and 2 had sustained hypertension. In 3 patients, hypertension was not observed. Familial pheochromocytoma was seen in 5 patients. Three patients had Sipple syndrome. Computed tomographic scan and magnetic resonance imaging were very useful techniques in preoperatively localizing the tumor. Even in the cases treated with alpha- or beta-blocker agents preoperatively, significant hypotension was observed immediately after resection of the tumor and treatment with norepinephrine or rapid blood transfusion or both was needed. Although meticulous care with alpha- and beta-blockers is important, surgical treatment of pheochromocytoma should spare the surgeon of unnecessary anxiety.

[Evaluation of beta-glucuronidase activity for the isolation of diarrhea-causing Escherichia coli].

To compare the isolating efficiency of diarrhea-causing Escherichia coli between Fluorocult agar plates, which reveal the beta-glucuronidase activity of E. coli, and a combination of SS and DHL agar plates, a total of 330 fecal specimens collected from outpatients were examined. Diarrhea-causing E. coli, identified by serological and toxigenic characters, were demonstrated in 52 samples. Among these specimens, 35 samples tested were positive on the Fluorocult agar plates, and 26 samples on the combination of SS and DHL agar plates. However, only 10 samples were positive on both the Fluorocult agar plates and the combination of SS and DHL agar plates. Thus, using Fluorocult agar plates for the isolation of diarrhea-causing E. coli in addition to the conventional SS and DHL agar plates will improve isolating efficacy.