A highly predictable animal model of retinoblastoma

Summary A new animal model of retinoblastoma was developed in newborn inbred CDF rats by intravitreous inoculation of retinal tumor cells (5×10⁴/5 l) derived from the cultured tumor cell line EXP-5. The retinal tumor from which the cell line originated was induced by a single intravitreous inoculation of human adenovirus serotype 12 (5 l of 10⁸ TCID 50/0.1 ml) in syngeneic rats. Within 1 month after intravitreous moculation of EXP-5 cells, a clinically recognizable ocular tumor was obtained in all 39 rats. Ad 12-specific T-antigens were demonstrated in the cultured tumor cells using immunofluorescent techniques. Morphologically these tumor cells closely resembled retinoblastuma, with poorly differentiated intracytoplasmic organelles, solitary cilia with a 9+0 tubule pattern, and abnormal nuclear membrane associated with a set of basal bodies. The significance of this highly manipulable retinal tumor cell line is the capability of providing a full-fledged intravitreous tumor in 1-month-old CDF rats, whose actual life span is known to be 42 months. Transplantable retinal tumors described to date are reviewed breifly and compared with the presently reported cell line.Supported by USPHS grants EY-CA01667, R01-EY-03171, and P30 EY-01784, by grants from the Retina Research Foundation, Houston, Texas, and by the Massachusetts Lions Eye Research Fund Inc.     

Diagnosis of cerebral Whipple's disease by cerebrospinal fluid cytology

Summary In a case of Whipple's disease the diagnosis was made by careful cytologic evaluation of the cerebrospinal fluid (CSF), identifying Sieracki cells. A basal granuloma invaded the hypothalamus, diencephalon, and rostral parts of the brainstem. An exploration in the initial stage led to misdiagnosis as a granular cell tumor. Diagnosis was then confirmed by intestinal biopsy.

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Zusammenfassung Es wird über einen Fall mit Morbus Whipple berichtet, der bei sorgfältiger Untersuchung des Liquor cerebrospinalis durch den Nachweis von Sieracki-Zellen diagnostiziert wurde. Die Exploration eines basalen Granuloms, das in den Hypothalamus, das Diencephalon und die rostralen Anteile des Hirnstamms eingewachsen war, hatte im Frühstadium zur Fehlinterpretation eines Granularzelltumors geführt. Die Diagnose wurde schließlich durch Dünndarmbiopsie bestätigt.

     

Hereditary neuropathy with liability to pressure palsies

Summary Clinical, neurophysiological and pathological investigations were carried out in 11 affected members of 2 families with hereditary neuropathy with liability to pressure palsies (HNPP). The observations were related to findings in 261 cases of 47 families published in the literature. It was concluded that HNPP is a nosological entity characterized by the following diagnostic criteria: (1) an autosomal dominant inheritance; (2) the clinical presentation of a recurrent mononeuropathy simplex or multiplex, frequently related to an inadequate trauma to peripheral nerves; (3) a significant slowing of motor and sensory conduction velocity in clinically affected, but also in clinically unaffected nerves; (4) characteristic morphological findings in sural nerve biopsy featuring tomaculous swellings of myelin sheaths, transnodal myelination and segmental demyelination. The pathogenesis of HNPP is not clear. Hypothetical explanations of the pathogenesis of HNPP are discussed.In memory of Albert Bischoff (1921–1981), Professor of Neurology, University of Berne     

Decrease in the number of lower affinity (type II) nerve growth factor receptors on embryonic sensory neurons does not affect fiber outgrowth

Nerve growth factor binds to two different specific receptors on responsive cells. The relationship of these two receptors is not fully understood at this time. We have studied the binding of labeled NGF to a different strain of white leghorn chicken embryo dorsal root ganglionic cells. The equilibrium dissociation constants for the two sites (K = 4.1 ± 1.8 × 10^?11M, K = 1.0 ± 0.8 × 10^?9M) are identical to those obtained previously. Also, the number of type I sites per cell (3.8 ± 1.3 × 10³) is the same as that previously determined. However, the number of type II sites per cell (1.9 ± 1.3 × 10⁴) is significantly different than that previously determined. This 2.5-fold decrease in the number of type II sites does not affect the concentration of NGF needed to obtain maximal fiber outgrowth from explanted sensory ganglia. The rate of association (1.2 ± 0.2 × 10⁷ M^?1 sec^?1 at 22°C) of labeled NGF with receptors on sensory neurons from this different strain of chickens is identical to that previously obtained. The rate of association of NGF with its receptors on sensory neurons was also determined at 4°C. This rate constant (2.1 ± 1.1 × 10⁶ M^?1 sec^?1) along with the rate constants obtained at 22° and 37°C were used to determine an activation energy for the binding of NGF to its receptors. The activation energy obtained (16.2 kcal/mole) suggests that binding is not a diffusion-controlled process.     

Bone involvement pattern in hypervascular lesions

The pattern of the focal bone lesion which consists partly or wholly of rounded holes with comparatively smooth edges is discussed.Twenty-two bone lesions were studied by angiography. The hypervascular pattern occurred in five cases of widely different histology, all with strong intraosseous hypervascularity. Different pathogenic mechanisms in the creation of this pattern are discussed. It is probably the result of both destructive and reparative processes in the bone.     

Early splenectomy and polychemotherapy versus polychemotherapy alone in chronic myeloid leukemia

The effect of early splenectomy and of polychemotherapy with hydroxyurea, busulfan, and alternate bimonthly courses of arabinosyl cytosine and vincristine plus prednisone, was evaluated in 139 previously untreated patients with chronic myeloid leukemia (CML), consecutively admitted to 18 hospitals from March 1973 to October 1974. Fifty-six patients were splenectomized and 83 patients were not splenectomized. Splenectomy did not influence the duration of chronic and blastic phase, and did not prolong survival. The prognosis of high risk patients was not improved. During the chronic phase, high platelet counts were more frequent in splenectomy group, and five patients developed thrombotic or thromboembolic complications, 5 to 19 months after the operation. The median survival of the whole group was 50 months, with 32 of 139 patients (actuarial proportion 30%) remaining alive 72 months after diagnosis, but the slope of the survival curve was similar to that of historical controls. The results of this trial suggests that new strategies should be developed for the therapy of CML.     

Effects of 4-aminopyridine on the turnover of monoamines in the central nervous system of the rat

Summary The effects of 4-aminopyridine (4-AP) on the turnovers of 5-hydroxytryptamine, dopamine and noradrenaline in the central nervous system of rats were studied by means of amine disappearance following inhibition of tryptophan or tyrosine hydroxylase. 4-AP (3 mg/kg i.p.) did not change the utilizations of 5-hydroxytryptamine or dopamine but it markedly accelerated that of noradrenaline in the brain and in the spinal cord. This stimulatory effect of 4-AP was completely dependent on nerve impulses since no effect was observed following an acute section of the noradrenaline nerves to the spinal cord. The effect of 4-AP was blocked by the-adrenoreceptor stimulating agent clonidine. Pentylenetetrazole, at a dose producing similar behavioural changes as 4-AP, caused only a slight stimulation of the noradrenaline turnover. 4-AP might enhance the flux of calcium ions into nerve terminals during depolarization, and thus increase the release of noradrenaline, whereas this process might be of less importance in the dopamine and the 5-hydroxytryptamine nerves.     

Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats

The interaction of phenylbutazone with the enantiomers and racemic [ ³ H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 g/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(–), and R, S (±) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenyl-butazone. For racemic [ ³ H]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration-effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration-response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.This work was supported by the Deutsche Forschungsgemeinschaft.     

Dynamic aspects of peripheral nerve changes in progressive neural muscular atrophy

Summary Serial nerve biopsies were performed at an early, and at an advanced stage of the disease in 2 patients with progressive neural muscular atrophy. The early biopsy showed a complete loss of the large diameter and thickly myelinated fibres, as well as an expansion of the endoneurial interstitium in both cases. Myelinated and unmyelinated fibres exhibited axonal degeneration in all biopsies occasionally. Onion bulb formation, a typical feature of peripheral neuropathy in neural muscular atrophy, was found to be prominent only in the latter biopsies. As regards the formal pathogenesis of hypertrophic neuropathy in neural muscular atrophy, axonal dystrophy and interstitial changes of the endoneurium were regarded as primary phenomena, demyelination and onion bulb formation as secondary. A possible causal relation between axonal dystrophy and interstitial changes, observed in these cases, is discussed in the light of the present literature.

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Zusammenfassung Bei 2 Patienten mit progressiver neuraler Muskelatrophie wurden Nervenbiopsien jeweils in einem frühen und in einem fortgeschrittenerem Stadium der Erkrankung entnommen und verglichen. In beiden Fällen zeigten bereits die frühen Biopsien ein völliges Fehlen der großkalibrigen, dickbemarkten Axone. Ebenfalls als frühe Veränderung wurde eine Erweiterung des endoneuralen Interstitiums festgestellt. Eine geringe Anzahl der vorhandenen bemarkten und unbemarkten Axone in allen Biopsien wies degenerative Veränderungen auf. Die für die progressive neurale Muskelatrophie typische Zwiebelschalenbildung der Schwannschen Zellen — möglicherweise eine Reaktion auf wiederholte De-und Remyelinisierungsvorgänge um dystrophische Axone — trat erst in den späteren Biopsien deutlicher hervor. Hinsichtlich der formalen Genese der hypertrophischen Neuropathie bei neuraler Muskelatrophie sind nach diesen Beobachtungen axonale Dystrophie und interstitielle Veränderungen des Endoneuriums als primäre Entmarkung und Zwiebelschalenbildung als sekundäre Phänomene zu betrachten. Die Möglichkeit einer kausalen Beziehung zwischen axonaler Dystrophie und interstitiellen Veränderungen wird an Hand der vorliegenden Befunde und Literatur diskutiert.

     

Effect of short-term administration of lead to pregnant rats.

Lead was administred to adult female rats in drinking water (0;0.1:1 and 10 ppm) for 3 weeks before mating, during pregnancy and during 3 weeks after delivery. On day 21 after delivery the mothers and their newborns were sacrified and various parameters of blood -- lead concentration on (Pb-B), hematocrit (Htc), hemoglobin (Hb), free erythrocyte porphyrins (FEP), delta0aminolevulinate dehydratase (ALAD) -- and tissue -- ALAD, free tissue porphyrins (FTP), lead concentration (Pb-T) -- were determined. In mothers a significant increase in Pb-B and Pb concentration in kidney was found in the 10 ppm group, but this increase in lead concentration was not associated with any statistically significant modification of the biochemical parameters. In newborns, lead concentration in blood and in kidney was also significantly increased in the 10 ppm group and this lead exposure was associated with a decrease of the ALAD activity in blood and an increase of FTP in kidney. On the basis of the biochemical parameters investigated one can therefore conclude that the developing organism is more susceptible to the biological action of lead than the organism of adult animals and that the "no-effect" level of lead administered during pregnancy and in the neonatal period is around 1 ppm.