Absence of structural alterations of the multidrug resistance genes in transitional cell carcinoma

Summary Tumor DNA from 27 patients with treated or untreated transitional cell carcinomas of the urinary tract was screened for genomic alterations of the multidrug resistance genes in order to determine whether structural changes of these genes are important in primary urothelial tumors. None of the tumors showed evidence of amplification or rearrangements of either mdr1 or mdr2. The lack of amplification or rearrangements observed in these tumors suggests that structural alterations of the mdr1 and mdr2 genes are not important mediators of drug resistance in TCC.Supported in part by grant CA-34775 from the National Institutes of Health and by a grant from the Heckscher Foundation for ChildrenDr. Klein is a fellow of the American Cancer Society     

Frequent ongoing T-cell receptor rearrangements in childhood B- precursor acute lymphoblastic leukemia: implications for monitoring minimal residual disease

Crosslineage T-cell receptor delta (TCR delta) rearrangements are widely used as tumor markers for the follow up of minimal residual disease in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR). The major drawback of this approach is the risk of false-negative results due to clonal evolution. We investigated the stability of V delta 2D delta 3 rearrangements in a group of 56 childhood B-precursor ALL patients by PCR and Southern blot analysis. At the PCR level, V delta 2D delta 3-to-J alpha rearranged subclones (one pathway for secondary TCR delta recombination) were demonstrated in 85.2% of V delta 2D delta 3-positive patients tested, which showed that small subclones are present in the large majority of patients despite apparently monoclonal TCR delta Southern blot patterns. Sequence analysis of V delta 2D delta 3J alpha rearrangements showed a biased J alpha gene usage, with HAPO5 and J alpha F in 26 of 32 and 6 of 32 clones, respectively. Comparison of V delta 2D delta 3 rearrangement status between diagnosis and first relapse showed differences in seven of eight patients studied. In contrast, from first relapse onward, no clonal changes were observed in six patients studied. To investigate the occurrence of crosslineage TCR delta rearrangements in normal B and T cells, fluorescence-activated cell sorter-sorted peripheral blood CD19+/CD3- and CD19-/CD3+ cell populations from three healthy donors were analyzed. V delta 2D delta 3 rearrangements were detected at low frequencies in both B and T cells, which suggests that V delta 2-to-D delta 3 joining also occurs during normal B-cell differentiation. A model for crosslineage TCR delta rearrangements in B-precursor ALL is deduced that explains the observed clonal changes between diagnosis and relapse and is compatible with multistep leukemogenesis of B-precursor ALL.     

Biological and physical properties of autogenous vascularized fibular grafts in dogs

The biological and biomechanical properties of normal fibulae, fibulae that had had a sham operation, and both vascularized and non-vascularized autogenous grafts were studied in dogs at three months after the operation. The study was designed to quantify and correlate changes in these properties in orthotopic, stably fixed, weight-bearing grafts and to provide a baseline for additional studies of allografts. The grafts were eight centimeters long and internally fixed. The mechanical properties of the grafts were studied by torsional testing. Metabolic turnover of the grafts was evaluated by preoperative labeling of the dogs with 3H-tetracycline for resorption of bone mineral and with 3H-proline for turnover of collagen. Cortical bone area and porosity were measured. Postoperative formation of bone was evaluated by sequential labeling with fluorochrome. The vascularized grafts resembled the fibulae that had had a sham operation and those that had not had an operation with regard to the total number of osteons and the remodeling process, as measured both morphometrically and metabolically. The vascularized grafts were stronger and stiffer than the non-vascularized grafts and were not different from the bones that had had a sham operation. In contrast, the non-vascularized grafts were smaller, weaker, less stiff, and more porotic, had fewer osteons, and demonstrated increased turnover and resorption compared with the vascularized grafts, the bones that had had a sham operation, and the bones that had not been operated on.     

Case report: Concordant traumatic brainstem contusion delayed diagnosis in a young man with Wilson's disease

Wilson's disease is a hereditary autosomal recessive disorder of copper metabolism. The corresponding gene locus has been localized on the long arm of chromosome 13. Three different clinical variants of the disease can be distinguished: hepato-cerebral, abdominal/hepatic, and central nervous type. The heterogeneity of symptoms can cause problems in differential diagnosis, especially when another concordant disorder can also explain the pathogenesis of symptoms. The case report of a young man who suffered from brainstem contusion demonstrates the possibilities of misinterpretation because presenting symptoms could be attributed either to traumatic brain injury followed by adjustment disorder or Wilson's disease. Clinical signs included leftsided hemiparesis, bilateral gaze direction nystagmus, marked dysarthria with consecutive pervasive mutism, choreo-athetoid movements, spasmodic torticollis and diplopia dependent on gaze direction. Slit lamp examination showed Kayser-Fleischer's corneal ring. EEG- and computer assisted tomography investigations revealed non-specific findings. The patient was treated with D-Penicillamine. Alternative treatment with oral zinc preparations is discussed.

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Zusammenfassung Beim Morbus Wilson handelt es sich um eine autosomal rezessiv vererbte Störung des Kupferstoffwechsels. Der Genort konnte auf dem langen Arm des Chromosoms 13 lokalisiert werden. Klinisch können aufgrund ihrer Symptomatik drei Verlaufsformen (hepato-zerebraler, abdominalhepatischer und zerebraler Typ) unterschieden werden. Die Vielfalt der Symptome kann differentialdiagnostische Schwierigkeiten bereiten. Das Beispiel eines jungen Mannes mit einer traumatischen Hirnstammkontusion zeigt, wie die Diagnose der hepato-lentikulären Erkrankung dadurch erschwert wurde, daß die Pathogenese der Symptome durch die Hirnstammkontusion und darauf folgende Anpassungsstörungen erklärt worden war. Die Symptomatik bestand aus linksseitiger Hemiparese, lateralem Blickrichtungsnystagmus, Dysarthrie mit nachfolgendem universalem Mutismus, choreo-athetodischen Bewegungsstörungen, Torticollis spasmoidicus und blickrichtungsabhängigem Auftreten von Doppelbildern. Bei der Spaltlampenuntersuchung stellte sich der Kayser-Fleischer Ring dar. EEG- und computertomographische Untersuchungen erbrachten nur unspezifische Befunde. Die Behandlung erfolgte mit D-Penicillamin. Die alternative Behandlung mit oraler Gabe von Zinksalzen wird diskutiert.

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Résumé La maladie de Wilson est une affection héréditaire autosomale recessive concernant le métabolisme cuivré. Le locus du gène a été situé sur le bras long du chromosome 13. Du point de vue clinique on distingue trois formes symptomatologiques: le type hepato-cérébral, hepato-abdominal et cérébral. La diversité des signes cliniques peut poser des problèmes de diagnostic différentiel, car d'autres affections peuvent se présenter avec cette même Symptomatologie. Nous rapportons ici l'exemple d'un homme jeune, porteur d'une maladie de Wilson et victime d'une contusion traumatique du tronc cérébral, dont les signes cliniques ainsi que les troubles du comportement pouvaient été autant rapportés à la contusion du tronc cérébral qu'à l'affection métabolique.La Symptomatologie comprenait une hemiparesie gauche, un nystagmus lateralisé, une dysarthrie avec mutisme secondaire universel, des mouvements choréo-athétosiques, un torticolis spasmodique et une diplopie dépendante de la direction du regard. L'examen à la lampe à fente permettait à mettre en evidence un anneau de Kayser Fleischer. L'EEG et le scanner cérébral ne montraient pas d'anomalies specifique.Le traitement a consisté en l'administration de D-Penicillamine. Traitment alternative avec les sels de zinc est discuté.

     

La psychothérapie de l'enfant : la symbolisation accompagnée

The psychotherapy of children may be carried out by psychiatrists and psychologists, but also by psychomotricians, language therapists, etc. It varies according to age, pathology, context, expectancies. Symptoms, language use, introspection capacities, capacities in various domains such as language, body expression, etc. are taken into account. Treatment is indicated according to each individual situation. Psychotherapy is conceived as a method for accompanying symbolisation. It is meant to help children use playing and creativity as methods of symbolisation. It does not aim at searching unconscious significations. Art therapy may now be used in the field of social interventions or teaching, as a way to reduce the violence of contemporary society.     

Anti-mitochondrial antibodies in patients with dilated cardiomyopathy (anti-M7) are directed against flavoenzymes with covalently bound FAD

Anti-mitochondrial antibodies (anti-M7) in sera from patients with dilated cardiomyopathy and myocarditis recognize, besides mitochondrial antigens, bacterial sarcosine dehydrogenase. The common target antigen was identified as the covalently bound FAD of mitochondrial and bacterial flavoenzymes. Thus, anti-M7-positive serum reacted on Western blots exclusively with covalently flavinylated enzymes. The antigenic specificity of anti-M7 sera was reproduced by an antiserum raised in rabbits with 6-hydroxy- D -nicotine oxidase. The heart mitochondrial membrane antigen recognized by anti-M7 serum was identified as the flavoprotein subunit of succinate dehydrogenase, the antigens in rat liver mitochondrial matrix as the flavoenzymes dimethylglycine dehydrogenase and sarcosine dehydrogenase. Anti-M7 serum contained a specific anti-flavoenzyme antibody fraction. Nanomolar concentrations of FAD and riboflavin inhibited the immune reaction on Western blots and in ELISA, and incubation with FAD-agarose depleted the anti-M7 activity of the serum. N-terminally deleted dimethylglycine dehydrogenase proteins were only immunoprecipitated by anti-M7 sera when the FAD was covalently incorporated. An affinity constant (K_D) of 10^?8 M was established for the anti-flavoenzyme antibodies by competitive ELISA. Of patients with cardiomyopathy and myocarditis, 36% and 25%, respectively, were anti-flavoenzyme-positive by Western blot and ELISA, but only two of 15 patients with other heart diseases and none of 50 healthy controls.