[Hemochromatosis or hemosiderosis? Initial misinterpretation of clinical symptoms and laboratory findings in a 62-year-old patient]. / Hämochromatose oder Hämosiderose? Anfängliche Fehlbewertung der klinischen Symptomatik und der Laborwerte bei einem 62-jährigen Patienten.

The exact differential diagnosis of iron overload syndromes is mandatory as important therapeutic consequences may derive from a correct diagnosis, especially when hemochromatosis is present. To facilitate diagnostic and therapeutic decisions algorithms and probabilistic calculations based on different frequencies of clinical symptoms and typical laboratory findings of the diseases in question have been proposed. Overestimation and/or underestimation of clinical symptoms and/or laboratory findings in using such calculations, however, may lead to incorrect diagnosis and therapy as demonstrated in this case. We report on a 62-year-old patient with arthralgia, pathologic glucose metabolism, brown skin pigmentation and excessively elevated ferritin and transferrin saturation levels, which initially were interpreted as signs of the assumed underlying disease (hemo-chromatosis) based on a high initial suspicion level and further corroborated by Bayesian probability analysis yielding a probability 99.0 % for the presence of hemochromatosis. Because of this high probability and the patient's wish for treatment phlebotomy was started, but stopped after having obtained negative results of genetic testing and normal quantitative liver iron values. The diagnosis of hemochromatosis had to be revised and symptoms and laboratory findings of this patient were found to be compatible with chronic fatty liver and pathologically altered iron metabolism due to chronic alcohol intake which the patient has initially concealed. The joint pain was explained in terms of chronic degenerative bone destruction, the impaired glucose tolerance seen as the consequence of obesity and the skin pigmentation was ascribed to sun exposure due to the patient's outdoor activities as a hobby farmer not evaluated during initial presentation. The implications and importance of unbiased history taking, critical interpretation of clinical symptoms and laboratory findings in using probabilistic calculations and diagnostic decision analysis are emphasized and the different mechanisms of iron metabolism in hemochromatosis and hemosiderosis are discussed.

Tumors in rat kidney generated by initiation with trans-4-acetylaminostilbene and several promoting treatments.

trans-4-Acetylaminostilbene (AAS) is a complete carcinogen in rats and produces quite selectively tumors in Zymbal's glands. On the basis of DNA adduct formation, it has been proposed that this model arylamine initiates neoplastic transformation of cells in many tissues, particularly liver and kidney, which, in the classical sense are considered to be non-target tissues for this chemical. In the present study an initiating treatment with AAS was followed by unilateral nephrectomy and the application of two nephrotoxic substances, gentamycin or beta-cyclodextrin which, among other activities, stimulate cell proliferation specifically in kidney. The initiating dose of AAS, given alone, gave rise to Zymbal's gland and mammary tumors in female Wistar rats within 88 weeks but not to liver or kidney tumors. When the initiation treatment was followed by unilateral nephrectomy, alone or in combination with gentamycin, or by beta-cyclodextrin, four tumors in two out of ten animals, eight tumors in three/ten, and seven tumors in three/ten, respectively, were observed in the kidney. The administered dose of gentamycin was not sufficient to induce tumors on its own. The results support the view that the genotoxic effects of AAS produce promotable lesions in rat kidney. None of the animals that had been treated with AAS, with or without other treatments, developed tumors or the predominant types of preneoplastic lesions in the liver within 88 weeks; this supports the notion that liver, like kidney, is not a target for complete carcinogenesis for this chemical.

Intraglomerular proteinase activity in adriamycin-induced nephropathy.

Adriamycin (ADR)-induced nephropathy is characterized by focal and segmental glomerulosclerosis and is supposed to be an ideal model of chronic progressive renal disease. The aim of our study was to investigate whether there might be an altered activity of glomerular proteinases in ADR nephropathy, thereby aggravating glomerular protein accumulation as an important initiating hallmark of glomerulosclerosis. In fact, we could demonstrate significantly enhanced levels of intraglomerular protein and DNA content in the experimental animals at week 7, 12 and 22 after administration of ADR. When relating intraglomerular proteinase activity, which was measured in ultrasonically destroyed isolated glomeruli, obtained by differential sieving techniques, to the intraglomerular protein and DNA content, this enzyme activity was significantly reduced throughout the observation period. Based on these data, we suggest that this relatively decreased proteinase activity in glomeruli exposed to ADR might play a pathogenetic role in the development of glomerular hypertrophy, an important harbinger of glomerulosclerosis.

Proteinase activity in isolated glomeruli of Goldblatt hypertensive rats.

In Goldblatt rats, the kidney exposed to high blood pressure reveals glomerulosclerosis. Moreover, in preexisting parenchymal renal disease, the development of glomerulosclerosis is accelerated in the unclipped kidney. Up to now, the pathogenetic mechanism underlying the development of glomerulosclerosis due to systemic hypertension has not completely been resolved. Traditionally, hemodynamic mechanisms have been discussed. This study was performed to investigate whether there might be a decreased activity of glomerular proteinases in the unclipped kidney of Goldblatt rats as a potential pathogenetic factor for glomerulosclerosis. 20 weeks after the surgical intervention, we found a reduced proteinase activity in ultrasonically destroyed isolated glomeruli obtained by differential sieving technique in comparison with the contralateral clipped kidney and the kidneys of sham-operated normotensive controls. This could be confirmed, when proteinase activity was related to DNA instead of protein. When investigating glomerular cathepsin B-content, a lysosomal enzyme, which is able to degrade glomerular structural as well as non-structural proteins, we found a decreased level in the kidney of Goldblatt rats exposed to systemic hypertension in comparison with normotensive control animals. Basing on these results we presume that glomerular protein accumulation and concomitant glomerulosclerosis due to systemic hypertension might be a result of a synergistical interaction between hemodynamic factors and biochemical ones; we suggest one of the latter to be a decreased glomerular proteinase activity.

[Sudden death caused by a heart tumor]. / Plötzlicher Tod infolge Herztumors.

Primary cardiac tumors in infancy and childhood are extremely rare. In the young age group the clinical symptoms often are variable and can make diagnosis difficult. Depending on the histological character and especially the localisation of the mass the clinical appearance may lead to the first diagnosis or at least to further investigation. While myocardial tumors (rhabdomyomas and fibromas) mainly cause rhythmic disturbances, the intracavitary tumors (like myxomas) frequently disturb hemodynamics. Echo-cardiography is the main diagnostic technique, followed by angiocardiography, computertomography and nuclearmagneticresonance imaging.

Ehlers-Danlos syndrome type IV (EDS IV) as model of a defective biopolymer composite material.

The connective tissue of a lethal EDS IV case was investigated for the reasons of the manifested disturbances of the arterial wall. This functional disorder was attributed to the mechanical decoupling of elastin and collagen, with the premise of a composite material consisting of cellular, fibrillar, lamellar and other matrix components. A conceivable relation between the manifested deficiency of type III collagen and a disturbed anchoring of elastin is shown. These findings are supported by biochemical, morphological, x-ray and mechanical data.

Nocardial endocarditis after aortic valve replacement. Reports of two cases.

Nocardial sepsis occurred after aortic valve replacement in two patients. A septic suture aneurysm of the aortotomy was resected and the prosthesis exchanged in one of them. The other received conservative treatment for sternal osteomyelitis and local mediastinitis. Clinical cure was followed by relapse and death from cerebral infarction, and necropsy revealed a septic suture aneurysm of the aortotomy. Radical surgical revision seems to be necessary for lasting cure in such infections.

Capillary rarefaction characteristic of the skeletal muscle of hypertensive patients.

There is evidence that the rarefaction of the capillary bed is typical for the skeletal muscle of spontaneously hypertensive rats. We were therefore interested to learn whether there is also a rarefaction in skeletal muscle of human hypertensives. The number of capillaries was morphometrically analysed and counted in the quadriceps and the pectoralis major muscles of human normotensives (n = 12) and hypertensives (n = 15). The clinical diagnosis and certain pathological criteria, such as blood pressure (with or without antihypertensive therapy), heart weight, left ventricular wall thickness, the state of kidney arterioles and brain, and heart vessels, were used to classify the patients into two groups. The dissected tissue samples were prepared according to the GMA method and the capillary numbers per area were counted using light microscopy (250 x). The quadriceps muscle had a capillary density (per 2.5 mm2) of 442 +/- 51 in normotensives and 277 +/- 41 in hypertensive patients; in the pectoralis major muscle we counted 477 +/- 30 in controls and 232 +/- 28 in hypertensives. The rarefaction in the quadriceps muscle ranged by about 37%, in the pectoralis major muscle by about 51%. It is suggested that the reduction of the capillary surface area caused by the capillary rarefaction reduces the transcapillary fluid exchange and in that way prevents an overperfusion of the terminal vascular bed.

[Five simultaneous neoplasms]. / Bericht über ein Fünffachmalignom.

One case of five independent tumors is reported: Fibrosarcoma of the right thigh, bilateral carcinoma of breast, papillary carcinoma of thyroid, and basalioma below the left clavicula. A synopsis of literature containing the rare cases of more than three primary tumors is presented. The difficulties concerning localization, origin and registration of multiple primary malignancies and their differentiation to recurrencies and metastases are discussed.

[Mixed freeze preserved heterologous/autologous full-thickness transplants following 3d degree burns in animal experiments]. / Gemischt gefrierkonservierte heterolog/autologe Vollhauttransplantate nach drittgradigen Verbrennungen im Tierexperiment.

On five minipigs third-degree burns were applied. The surgical skin coverage was established after escharectomie by freeze-preserved heterological/autological intermingled full-thickness skin grafts. The freeze-preservation of the Makaka-skin (full-thickness skin) was achieved in a commercially available freezer at -27 degrees C. We could not observe a accelerated or even complete re-epithelialization as it is described in the Chinese papers. The burnwunds healt in form of scare areas covering about half of the previously burned area.

Syncarcinogenic effects on the initiation of rat liver tumors by trans-4-acetylaminostilbene and 2-acetylaminofluorene.

Two carcinogenic aromatic amines with different organotropism were tested for syncarcinogenic effects in rat liver in an initiation-promotion experiment. Trans-4-acetylaminostilbene (AAS) and 2-acetylaminofluorene (AAF) were administered as initiators in four doses each either alone or sequentially combined in both orders. The promotion phase was started by partial hepatectomy and continued by adding phenobarbital (250 p.p.m.) to the drinking water for 26 weeks. The number/cm2 of tissue section and average size of hyperplastic foci, glucose-6-phosphatase-deficient and gamma-glutamyl-transpeptidase-positive foci were determined and a total area of lesions calculated during the promotion phase after 18 and 31 weeks, and in the post-promotion phase after 42 and 47 weeks. The synergistic effects of AAS and AAF were clearly more than additive if compared with the sum of the effects exerted by each compound individually. The sequence in which both initiators were administered remarkably influenced the development of lesions. They developed more rapidly and persisted longer in the post-promotion phase when AAS was administered first and AAF second. In the final stage, enzyme altered foci increased in the livers of both combination groups, but to a greater extent in the AAS-AAF group. It is concluded that the two arylamides damage DNA independently. In addition, however, the results suggest that AAS acts predominantly as an initiator, and AAF as a weak initiator and a strong promoter in what is considered the initiation phase of this experiment.

Tissue specific, acute toxic effects of the carcinogen trans-4-dimethylaminostilbene.

The acute toxicity of the carcinogen trans-4-dimethylaminostilbene was studied in Wistar rats. The animals die after oral administration of 50 mg/kg (LD50) with a latency period of 11 days. Specific lesions of the stomach epithelium together with acute bone marrow incapacity and toxic effects on peripheral blood cells lead to acute anemia, which is considered to be the cause of death. Histological observations indicate that the stomach lesions develop in three phases. Firstly, necroses appear in the proliferative area predominantly in the antrum. This leads, secondly, to cystic transformation of the antrum, cardia, and Brunner's glands and further to peptic erosions and ulcerations. Thirdly, mitotic activity increases. With lethal doses, cell replacement remains incomplete. There ist a correlation between the proliferation rate of different cell types and their susceptibility; but this cannot entirely account for the tissue-specific, systemic effects of trans-4-dimethylaminostilbene. Metabolic activation is also involved, since enzyme induction with methylcholanthrene inhibits toxicity. The study disclosed a new target tissue which may now be used to investigate the mechanism of action of reactive metabolites of an aromatic amine in acute experiments. The same stomach lesions were also observed with adriamycin. With this compound, however, the intestine is also involved.

[Application of mixed homologous/autologous full-thickness skin transplants preserved by freezing following 3d degree burns in animal experiments]. / Applikation gemischt homolog/autologer gefrierkonservierter Vollhauttransplantate nach drittgradigen Verbrennungen im Tierexperiment.

In 5 white piglets 3rd-degree burns were applied. After escharectomy the wound-dressing was done by intermingled homo/autografts. In variation of the Chinese method reported, in our experiments the homografts consisted of full-thickness skin preserved by freezing (-27 degrees C). In all piglets this procedure caused a perfect epithelialization and brought good cosmetic and clinical results.

Carcinogenicity of dichloroacetylene: an inhalation study.

Dichloroacetylene (DCA) is a by-product of the synthesis of certain chlorinated, aliphatic hydrocarbons (e.g., vinylidene chloride). In a long-term carcinogenicity inhalation study, groups of 30 male and 30 female rats and mice were exposed to DCA vapour under the following conditions: mice, group I: 9 p.p.m. 6 h/day, 1 day/week for 12 months; group II: 2 p.p.m. 6 h/day, 1 day/week for 18 months; group III: 2 p.p.m. 6 h/day, 2 days/week for 18 months; rats: 14 p.p.m. 6 h/day, 2 days/week for 18 months; controls: under identical conditions except for addition of DCA to breathing air. The most important result is a striking increase in the formation of kidney cystadenomas of the proximal tubuli in all DCA exposed animals. The median latency time of this tumor varied widely in both mice and rats. Renal cystic adenocarcinomas were found in statistically significant numbers in male mice. In addition to kidney tumors, the development of cystadenomas of the Harderian gland in mice and of liver cholangiomas in rats were highly significant findings. DCA failed to induce liver tumors in mice. Our results confirm that DCA possesses a high carcinogenic potential, pronounced organotropic properties and distinct species differences referring to the number and nature of the induced tumors. The risk associated with handling chlorinated aliphatic hydrocarbons is essentially increased by the decomposition product DCA.

[Irreversible renal failure following minimal change nephrosis]. / Irreversibles Nierenversagen nach Minimal-Changes-Nephrose.

A boy developed a nephrotic syndrome at the age of two years, and remained steroid sensitive for twelve years. In this time more than twenty relapses occurred. Two renal biopsies showed minimal changes. Renal function was normal all along. At an age of 14 years he developed an irreversible renal failure. Since this time he remained dependent to dialysis. A third renal biopsy now shows a perimembranous glomerulonephritis with a diffuse interstitial fibrosis.

Carcinogenicity study of trichloroethylene, with and without epoxide stabilizers, in mice.

Previous analytical studies of industrial samples of trichloroethylene (TRI) have revealed the presence of mutagenic and carcinogenic epoxides which, it was proposed, might be responsible for the carcinogenicity of such samples, as demonstrated with mice in other laboratories. To test this hypothesis, Swiss mice (ICR/HA) of both sexes, bred and kept in SPF conditions, were dosed daily with TRI in corn oil by gavage (males: 2.4 g/kg, females: 1.8 g/kg) with or without the addition of epichlorohydrin (EPC, 0.8%, w/w), 1,2-epoxybutane (BO, 0,8%), or EPC + BO (0.25% + 0,25%) for 18 months. The ensuing observation period terminated at 106 weeks (from start of experiment). Gross and microscopic examination of all organs revealed a statistically significant increase in the incidence of forestomach papillomas and carcinomas after EPC-, BO-, and (EPC + BO)-stabilized samples of TRI, but not after pure, amine base-stabilized TRI. This type of tumor is believed to be induced by the direct alkylating epoxides epichlorohydrin and epoxybutane, whose industrial use in stabilizing chlorinated aliphatic hydrocarbons should be discontinued. No other significant increase in tumor incidences was found. Again, this study does not support the suggestion that trichloroethylene itself is carcinogenic under realistic exposure conditions.