Omeprazole: an exploration of its reported genotoxicity.

Because of its reported ability to induce unscheduled DNA synthesis in the gastric mucosa, the safety of omeprazole, a potentially clinically useful anti-ulcer drug, has been the subject of debate. We have undertaken a detailed computer-based study of structural basis of the putative mutagenicity, genotoxicity and carcinogenicity in rodents of omeprazole and of its sulphenimide, and we conclude that omeprazole is a potential 'genotoxic' carcinogen. The analysis is consistent with the possibility that these activities are associated with the unstable sulphenimide metabolite.     

Determination of the exposure concentration of propylene oxide to produce neuropathy in rats

Although propylene oxide, which is similar in chemical structure to ethylene oxide, is expected to produce neuropathy, there is no convincing evidence of the degeneration of the peripheral nervous system. To determine the exposure concentration of propylene oxide necessary to produce neuropathy in male Wistar rats, we subjected them to repeated exposures of propylene oxide at concentrations of 500, 750, 1000, 1500 and 2000 ppm. The test rats were subjected to a single 6 hour exposure of propylene oxide at a concentration of 1500 parts per million 5 times a week for 3 weeks. They developed a significant decrease in body weight, abnormal posture of the hindlegs and axonal degeneration of myelinated fibers in the peroneal and sural nerves, the nerves to the soleus muscle, and in the fasciculus gracilis of the spinal cord. Therefore, it was concluded that propylene oxide induces neuropathy in rats characterized by axonal degeneration, similar to that produced by ethylene oxide, and that the exposure to the higher concentration of propylene oxide is more necessary to produce neuropathy than in the case of ethylene oxide neuropathy in rats.     

Variations of activities in the segments of respiratory chain among tissues in a patient with mitochondrial encephalomyopathy

Enzymatic activities of NADH cytochrome c reductase and cytochrome c oxidase were determined in the mitochondria from various tissues of a patient with mitochondrial encephalomyopathy and compared with those of controls. NADH cytochrome c reductase in the present patient decreased significantly in the liver and spleen and to a less extent in the kidneys. On the other hand, cytochrome c oxidase of the patient decreased severely in the skeletal muscle and kidneys and partially in the heart. Difference spectrum of reduced-minus oxidized form of mitochondria from patient's skeletal muscle and heart showed a decrease of cytochrome aa3 peak in the alpha region at 605 nm. These results indicate that there are cryptic deficiencies in the segments of the respiratory chain in the mitochondria from several tissues of the present patient, such as liver, kidney, spleen without any clinical manifestation. The weakness and atrophy of skeletal muscle was, however, well correlated to the biochemical analysis.     

Maffucci’s syndrome associated with spindle cell hemangioendothelioma

 The case of a 49-year-old man with Maffucci’s syndrome, who developed multiple spindle cell hemangioendotheliomas, is presented. The case provides support for recent reports suggesting an association between this peculiar vascular lesion and skeletal enchondromatosis.     

Presenting symptoms and natural history of Wilson disease

The presenting symptoms of Wilson disease and its natural history as related to age are described based on 283 cases collected in Japan. The disease presented with a variety of signs and symptoms; the most frequent were in order of frequency jaundice, dysarthria, clumsiness, tremor, drooling, gait disturbance, malaise and arthralgia. The mean age at onset of the disease was 12.0 years. Hepatic and osteoarthral symptoms developed early and neurological symptoms late. Fifty-eight cases develolped neurological symptoms only, 28 cases had hepatic symptoms only, and in 26 cases hepatic mortality rate was observed in hepatic, hepato-haematological and hepato-renal cases mainly due to acute hepatic failure resulting in death only a few weeks after onset. Cases having only neurological symptoms showed a more favourable prognosis with a longer survival.     

Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.     

Overwork and its health effects--current status and future approach regarding Karoshi]

The word karoshi, i.e. death due to overwork, is not defined for medical diagnosis, but in Japan it means cases of compensation awarded by reason of fatal occupational diseases, particularly ischemic heart diseases and cerebrovascular diseases which are recognized as caused by a heavy workload. Current studies have shown that 1) almost definitely there is evidence of an association between overwork and cardiovascular diseases and the risk factors were found, 2) no reports have been published on evidence of a causal relationship between overwork and fatal effects even though the possibility remains, and 3) the adverse health effects can vary according to workers' characteristics such as gender, age, stress coping and perception. Recently there has been an increase in the proportion of compensated cases versus claims from 3.1% in the 1988 fiscal year to 20.7% in the 2001 fiscal year. This may be related to the deregulation of criteria for compensation, or nintei-kijun. The period of determination of overwork for victims has been extended to a maximum of six months in the newest criteria set in 2001, up from only one week in the criteria set in 1987. According to sociological analysis, long working hours in Japan are related not only to the structure of the working-time system but also the sociocultural background of labor. In 2002, the Japanese government provided the first countermeasures for the prevention of karoshi for all employees stating that they should not work more than 45 h overtime per month and that government intervention in the form of administrative guidance to employees and their employers should be conducted if overtime exceeds 100 h per month. It is a population strategy targeting all workers equally, not just a high-risk strategy targeting only those with some risk factors, and is expected to provide more fruitful results with flexibility, i.e. differentially reinforced management for older workers and those working under highly stressful conditions with harmonization of the production cycle in the workplace. Occupational health professionals such as occupational health physicians and nurses will play a key role in making break-throughs to solve various problems related to karoshi, which may then result in further investigations to provide scientific evidence for policy making.     

Availability of elements in leaded/unleaded automobile exhausts,a leaded paint,a soil,and some mixtures

The availabilities of elements in some dust proximal sources of urban pollution were investigated. The sources were: leaded and unleaded automobile exhaust; leaded dry paint; one soil; and mixtures that included the leaded exhaust as a common component. A miniaturized modified Tessier et al. leaching scheme was developed that showed little redistribution of the most available elements. Mn, Pb, S, and Sb were the most readily available in both the leaded and unleaded exhaust; C and Pb in the paint; and Mn and S in the soil. The available elements for the leaded exhaust predominated in its mixtures with evidence of redistributions for the three-component mixture. The environmental pollution (EP) toxicity procedure with five leachings was shown to be approximately equivalent to adding the water-soluble, exchangeable, carbonate, iron/manganese oxide, and part of the organic fractions. Simulated acid rainwater leached elements up to the iron/manganese oxide fraction. The results have application to storm runoff and acid rain leaching of dusts, aerosols, wastes, and soils.