[Treatment of hemophagocytic lymphohistiocytosis, HLH, with bone marrow transplantation]. / Behandlung der Hämophagozytischen Lymphohistiozytose, HLH, mit Knochenmarktransplantation.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease of infancy and young childhood. The clinical presentation includes recurrent unexplained fever with hepatosplenomegaly. Cytopenia, hypofibrinogenemia and/or hypertriglyceridemia and hemophagocytosis in bone marrow, spleen and lymphnode confirm the diagnosis. Hemophagocytosis may not be present at the beginning. In these cases, diagnosis is facilitated by a positive family history, a relapsing course of the disease, the frequent involvement of the central nervous system and positive findings on immunological work-up. Treatment by chemotherapy and immunosuppressants can achieve sustained remissions in most patients and reinduction of remission after relapse is possible. Most children however, eventually die from progressive disease. At present, allogeneic bone marrow transplantation is the only curative therapeutic option. Between August 1992 and May 1997 eleven consecutive patients with HLH received bone marrow from unrelated (n = 7) or matched sibling donors (n = 4). The conditioning regimen consisted of busulfan, VP-16 and cyclophosphamide. Patients engrafted after a median time of 16 days (13-43). Only one patient developed grade III acute GVHD, another patient, grade II acute GVHD. Although regimen-related toxicity was extensive, all patients have survived without signs of HLH after a median follow up of 20 months (8-63). One patient suffers from chronic GVHD, three patients reveal psychomotoric retardation and one patient has severe impairment with spastic tetraparesis, amaurosis and seizures. Our experience shows that HLH can be successfully treated by allogeneic BMT from unrelated donors.

High-resolution CT in simple coal workers' pneumoconiosis. Lack of correlation with pulmonary function tests and arterial blood gas values.

We examined 21 miners by means of standard chest radiography, high-resolution computerized tomography (HRCT), pulmonary function tests, and resting arterial blood gas levels. Using the ILO/UC classification of pneumoconiosis, 7 miners had category 1/0 or 2/1 simple coal workers' pneumoconiosis (CWP). By HRCT, nodules were identified in 12 miners; 4 of 9 were classified as category 0/0 CWP; 2 of 5, 0/1 CWP; 5 of 6, 1/0 CWP; and 1 of 1, 2/1 CWP by chest radiograph. Focal emphysema was identified by HRCT in 7 miners; 4 of 9 were classified as 0/0 CWP; 2 of 5, 0/1 CWP; and 1 of 6, 1/0 CWP by standard chest radiography. Four miners with definite nodules confirmed by HRCT had focal emphysema, while three without nodules had focal emphysema. Pulmonary function testing was not different between miners with or without CWP by standard chest radiography, nor was it different between miners with or without definite nodules evidenced by HRCT. No difference in resting oxygenation was found between any group of miners. The presence of focal emphysema confirmed by HRCT did not significantly affect pulmonary function tests on resting arterial blood gas values. There was, however, a significantly lower FEV1 and mean forced expiratory flow during the middle half of forced vital capacity with lifetime nonsmoking miners. The presence of CWP on chest radiography was significantly correlated with smoking cigarettes but not the years of mining. The presence of nodules on HRCT approached a significant correlation with cigarette smoking, but focal emphysema did not. For detecting evidence of coal dust accumulation in lung parenchyma and identifying focal emphysema, HRCT was more sensitive than standard chest radiography. However, despite earlier detection of parenchymal abnormalities, abnormal pulmonary function attributable to coal dust could not be identified.

Classification of dangerous substances and pesticides in the European economic community directives: a proposed revision of criteria for inhalation toxicity.

Criteria for the classification of dangerous substances with respect to their inhalation toxicity were originally proposed by the European Economic Community (EEC) on the basis of a 1-hr LC50, as were the similar United Nations (UN) "transport" criteria. Both sets of criteria have since been amended for a 4-hr LC50, but whereas the UN criteria limits have been decreased to compensate for the increased exposure time, the EEC limits have not. This has introduced an anomaly into the EEC classification scheme whereby substances are classified more severely than they were previously. The EEC scheme is now out of line with the UN criteria and other international guidelines and gives a much more stringent toxicity classification for individual substances by inhalation than by the oral route, as well as causing an unjustifiable duplication of animal tests. This anomaly has led to a proposal by the Federal Republic of Germany for revised criteria. This paper examines the scientific basis for the relationship between inhalation exposure duration and toxicity, and for a comparison of the LD50 and LC50 classifications for individual substances. It is concluded that the proposed German revised classification scheme is more in line with the UN transport criteria and international guidelines and provides a rational basis for a classification scheme for inhalation toxicity. The classification criteria therefore should be harmonized by a revision of the EEC classification limits for inhalation toxicity.

Advances in the design and reporting of conventional carcinogenicity tests.

It is generally acknowledged that animal experiments provide the most important and best reliable service of information for assessing the possible carcinogenic activity of chemicals. In the past, experimental procedure has mainly concentrated on the choice of species, improved animal husbandry, the modes of exposure, test conditions and pathological examination. Although experience gained thereby indicated the necessity for further scientific exploitation of bioassay models, the rather rigid stereotyped procedures--proposed for convenience--were generally accepted and adopted. Nevertheless, continuous improvements have been made in the design of carcinogenicity tests in rodents. Current developments in test design tend to be primarily concerned with the predictive significance of carcinogenicity studies. Modern protocols call for optimum facility operation as much as for computerized support of study monitoring and data evaluation. Of particular significance are the automated handling of autopsy and histopathological data and their proper statistical evaluation. By the economical use of modern technology, cost-saving protocols can be designed for the production of the data which are essential for the reliable assessment of risk.

The self-association of ATP: thermodynamics and geometry.

The concentration and temperature dependence of the self-association of ademosin-5'-triphosphate (ATP) in aqueous solution was studied by means of ultraviolet absorption spectroscopy and circular dichroism (CD). Of several possible models, a model was indefinite linear self-association, in which each step has the same equilibrium constant, describes the data best. The two different methods lead within experimental error to the same thermodynamic parameters. At pH 8.7, IN 1 M Tris and 0.5 M 7gCl-2, we find deltaH-0 equals -5.1 kcal/mole and deltaS-0 equals -13.0 e.u. These values do not differ much from those found for the self-association of uncharged bases and nucleosides in aqueous solution. The CD spectrum that results from the self-association is conservative and quite similar in shape to that observed for some stacked dinucleotides: it is interpreted as a first approximation within the framework of the exciton model.