The structure-function relationship of functionally distinct but structurally similar hexose transporters from Trypanosoma congolense.

We have previously characterized, in Trypanosoma brucei, a multigene family encoding two developmentally regulated glucose transporters that are 80% identical at the amino-acid level. We report here the characterization of the homologous glucose transporters (TcoHT1 and TcoHT2) in Trypanosoma congolense, an African trypanosome responsible for disease in domestic animals. Both TcoHT isoforms, which are 92.4% identical, are encoded by a single cluster of genes containing two copies of TcoHT1 and three copies of TcoHT2 arranged alternately. Northern blot analysis revealed that TcoHT2 is expressed in all of the adaptive forms, while mRNA encoding TcoHT1 is only present in the metacyclic and bloodstream forms of T. congolense. When transfected with the TcoHT2 gene, Chinese Hamster Ovary cells express a hexose transporter with properties similar to those of the T. congolense procyclic forms (Km D-glucose = 41 microM versus 64 microM). In contrast to TcoHT2, TcoHT1 expressed in the Chinese hamster ovary cells appeared to be a relatively low affinity glucose transporter (Ki D-glucose = 0.8 mM). To determine the region(s) involved in the different apparent affinities for glucose, a chimera analysis was undertaken on the TcoHT isoforms. This study shows that amino-acid residues important for D-glucose recognition are located in the central region (between transmembrane domains 3 and 7) and in the C-terminal intracellular domain of TcoHT2. Site directed mutagenesis identified Ser193 located within transmembrane helix 4 as a key residue in relaxing the apparent affinity of TcoHT1 for glucose.

Conserved organization of genes in trypanosomatids.

Trypanosomatids are unicellular protozoan parasites which constitute some of the most primitive eukaryotes. Leishmania spp, Trypanosoma cruzi and members of the Trypanosoma brucei group, which cause human diseases, are the most studied representatives of this large family. Here we report a comparative analysis of a large genomic region containing glucose transporter genes in three Salivarian trypanosomes (T. brucei, T. congolense and T. vivax), T. cruzi and Leishmania donovani. In T. brucei, the 8 kb (upstream) and 14 kb (downstream) regions flanking the glucose transporter genes cluster contain two and six new genes, respectively, six of them encoding proteins homologous to known eukaryotic proteins (phosphatidylinositol 3 kinase, ribosomal protein S12, DNAJ and three small G-proteins--Rab1, YPT6 and ARL3). This gene organization is identical in T. brucei, T. congolense and T. vivax suggesting that Salivarian trypanosomes have a high level of conservation in gene organization. In T. cruzi and Leishmania, the overall organization of this cluster is conserved, with insertion of additional genes when compared with T. brucei. Phylogenetic reconstitution based on glucose transporters is in accord with the monophyly of the genus Trypanosoma and the early separation of T. vivax within Salivarian trypanosomes. On the basis of gene organization, biochemical characteristics of isoforms and phylogeny, we discuss the genesis of the glucose transporter multigene family in Salivarian trypanosomes.

Tumor-like bone dystrophy and peripheral joint fusion in a patient with Paget's disease of bone.

The authors report an 80-year-old woman who was evaluated for pain in her left leg and ankle. Sixteen years earlier, she had received a diagnosis of monostotic Paget's disease at the same site, based on roentgenographic changes. The lesion was very unusual, with tumor-like lysis of the affected area and fusion of the tibia, fibula, and talus.

[Parsonage-Turner syndrome complicated by sympathetic dystrophy syndrome with adhesive capsulitis of the shoulder. Apropos of 2 cases]. / Syndrome de Parsonage et Turner compliqué d'algodystrophie avec rétraction capsulaire de l'épaule. A propos de deux observations.

Two typical cases of Parsonage-Turner syndrome with reflex sympathetic dystrophy syndrome and adhesive capsulitis of the shoulder are reported. The rarity of this combination is discussed.

[Rhabdomyolysis due to simvastin. Apropos of a case with review of the literature]. / Rhabdomyolyse à la simvastatine. A propos d'un cas avec revue de la littérature.

A new case of simvastatin-induced acute rhabdomyolysis with heart failure after initiation of treatment with fusidic acid is reported. In most reported instances, statin treatment was initially well tolerated with muscle toxicity developing only after addition of another drug. The mechanism of this muscle toxicity is unelucidated but involvement of a decrease in tissue Co enzyme Q is strongly suspected.

[Neuropathology of the brain in 174 patients who died of AIDS in a Paris hospital 1982-1988]. / Etude neuropathologique de l'encéphale de 174 patients morts du SIDA dans un hôpital parisien, de 1982 à 1988.

Between 1982 and 1988, 174 brains were systematically collected from consecutive, autopsied AIDS patients in a Parisian general hospital without neurology and psychiatry departments. The data obtained under these conditions provide reliable information on the frequency of central nervous system (CNS) involvement in a non-selected population of AIDS patients, most of whom were homosexuals (75.9%). One or several lesions were observed in 148 cases (85%). HIV encephalitis and/or leucoencephalopathy with multinucleated giant cells was found in 33 cases (18.9%). Opportunistic infections were identified in 91 patients (52.3%): toxoplasmosis (65 cases; 37.3%), cytomegalovirus encephalitis (25 cases; 14.3%), cryptococcosis (9 cases; 5.8%), progressive multifocal leukoencephalitis (5 cases; 2.8%), candidosis (1 case) and tuberculosis (1 case). Neoplasias were observed in 23 patients: primary (16 cases; 17.9%) or secondary malignant non Hodgkin's large B-cell lymphoma (3 cas; 1.1%), Kaposi's sarcoma (1 case) and glioma (3 cases; 1.1%). Non-specific lesions (vasculitic, hemorrhagic, metabolic and especially microglial nodules) were common. During the 6 years of study, the rate of CNS involvement was constant. The number of toxoplasmosis cases per year was stable, however, evolutive forms were more prevalent between 1982 and 1986, whereas treated inactive lesions were seen most frequently thereafter. The opportunistic complications were often associated and it should be noted that HIV encephalitis was associated with one of several such infections in 85% of the patients. This high rate of association suggests that these opportunistic infections may play a role in the pathogenesis of HIV encephalitis.

Severe encephalitis resulting from coinfections with HIV and JC virus.

We observed 3 cases of progressive multifocal leukoencephalopathy (PML) among frozen CNS samples obtained at autopsy from 102 adult AIDS patients. In 2 patients, PML was associated with severe HIV encephalitis. In those 2 cases, the areas of extensive JC-induced demyelination were massively infiltrated by HIV infected macrophages/microglial cells with evidence for localized increase of HIV encephalitis in PML lesions. Using immunohistochemistry and in situ hybridization, we demonstrated that each virus infects, in a latent or productive fashion, different CNS cell populations. Therefore, the extension of HIV encephalitis could not be related to an intracellular transactivation of 1 virus by the other. However, the results are consistent with dissemination of viral infection by the recruitment of HIV-infected macrophages to damaged areas of the brain. This phenomenon might be generalized to other pathogens that are frequently associated with HIV CNS infection. Early detection and treatment of opportunistic CNS lesions could be important to prevent extension of HIV encephalitis.

[Medullomyoblastoma: immunohistochemical and ultrastructural study]. / Médullomyoblastome: étude immunohistochimique et ultrastructurale.

Medullomyoblastoma is a rare tumor of childhood, arising in the cerebellar vermis. In the case reported, the immunohistochemical study (desmin, myosin, myoglobin and actin) and the ultrastructural findings, confirm the presence of rhabdomyoblastic cells associated with a typical medulloblastic component. Differential diagnosis and histogenesis of this tumor are discussed.

MRI pattern of progressive multifocal leukoencephalopathy (PML) in AIDS. Pathological correlations.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease which occurs in immunodepressed subjects and is particularly frequent in AIDS. Some authors having drawn attention to the protean aspect of the disease and claimed that AIDS may lose its basic characteristics and affect the grey matter as well as the white matter, we reviewed a series of 8 patients who had been biopsied and/or autopsied and had been examined at least once by MRI. In this series, contrary to what is regularly observed in toxoplasmic abscesses we did not find any lesion of the grey matter or any mass effect. On the other hand, we confirmed that PLM is not multifocal in all cases and that it course may be interrupted by prolonged remissions. The MRI criteria for PML therefore are reliable, provided multiple T2-weighted slices in coronal plane are performed, clearly showing the anatomy of the white fibres affected. However, it must be borne in mind that HIV-infected patients often have other associated brain pathologies, especially when the immune deficiency increases.

[Intracranial localization of Hodgkin's disease. Apropos of 2 cases]. / Localisations intracrâniennes de la maladie de Hodgkin. A propos de deux cas.

Intracranial localizations of Hodgkin's disease (HD) are uncommon. We report on 2 patients with HD who presented with an intracranial relapse. We discuss 1) the pathogenesis of those rare recurrences; 2) the therapeutic strategy.

Late pleuropulmonary metastases of a cerebral ependymoma.

A patient with a 12-year history of occipital ependymoma was found to have late pleuropulmonary metastases without recurrence of the primary tumor. The pleural metastases were diagnosed by histologic, ultrastructural features and finally by glial fibrillary acidic protein (GFAP) labeling positive reaction. This case is unique because of the long interval between occurrence of the initial tumor and the metastases, and because of the apparent quiescence of the cerebral lesion when the pleuropulmonary metastases were discovered.

Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases.

This report concerns the clinicopathological features of 39 cases of a morphologically unique and surgically curable group of neuroepithelial tumors associated with medically intractable partial complex seizures. All were supratentorial and characterized by intracortical location, multinodular architecture, and heterogeneity in cellular composition. The constituent cells included astrocytes, oligodendrocytes, and neurons. Because neuronal atypia was often inapparent, the tumors superficially resembled mixed oligoastrocytomas. The term "dysembryoplastic neuroepithelial tumor" (DNT) is proposed for these distinctive lesions, the clinicopathological features of which suggest a dysembryoplastic origin. With the exception of the occurrence of headaches in 2 patients, partial complex seizures were the exclusive symptom. Age at onset of symptoms ranged from 1 to 19 years (mean 9 years). In addition to the chronic nature of the seizures (range, 2 to 18 years; mean, 9 years), one-third of the patients showed radiological features, such as focal cranial deformity, indicating that the tumors had an early onset and were of long standing. In most cases, computed tomography showed a "pseudocystic," well-demarcated, low density appearance associated in some cases with focal contrast enhancement (18%) or calcific hyperdensity (23%). The tumor involved the temporal lobe in 24 patients (62%), the frontal lobe in 12 (31%), and the parietal and/or occipital lobe in 3 cases. Although tumor removal was considered incomplete or subtotal in 17 patients (44%), long term follow-up (range, 1 to 18 years; mean, 9 years) showed neither clinical nor radiological evidence of recurrence in any patient. Comparison of the survival data of the 13 subjects who had undergone postoperative radiotherapy with 26 who had not indicated that radiation therapy was of no obvious benefit. The identification of DNT has therapeutic and prognostic implications because aggressive therapy can be avoided, thus sparing these young patients the deleterious long term effects of radio- or chemotherapy.

Cerebral astrocytoma in association with HIV infection.

Cerebral astrocytoma has been found in two patients with AIDS related conditions. The fortuity of this unusual association is discussed, insofar as immunosuppression could favour the growth of certain neoplasms.

Treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35 patients with the acquired immunodeficiency syndrome. Efficacy of long-term continuous therapy.

Thirty-five patients with the acquired immunodeficiency syndrome (AIDS) and central nervous system toxoplasmosis, seen over a 30-month period, were treated with the combination pyrimethamine/sulfadiazine. All patients had clinical and computed tomographic scan findings consistent with active neurotoxoplasmosis. Mean duration of total therapy was six months. During the first two months of therapy, four patients died of acute neurotoxoplasmosis and 31 showed improvement. Of the 24 patients evaluable for long-term therapy, 14 (58 percent) achieved complete resolution and 10 had late clinical (n = 7) and/or computed tomographic scan (n = 6) sequelae. Six patients experienced 10 relapses, which occurred within six weeks of treatment discontinuation in seven of 10. Reintroduction of the combination led to complete resolution of the relapse in eight cases. These clinical results were correlated with brain anatomic findings in the 15 autopsied cases. Side effects, noted in 25 of 35, were mainly hematologic toxicity (n = 21) and cutaneous rash (n = 12). However, the combination had to be definitively stopped in only two cases and sulfadiazine alone had to be withdrawn in eight other cases. These data suggest that pyrimethamine/sulfadiazine is highly efficacious in neurotoxoplasmosis and that life-long therapy is needed to prevent relapses in patients with AIDS.

[Thoracic metastases of ependymoma. Apropos of a case and review of the literature]. / Les métastases thoraciques des épendymomes. A propos d'un cas, revue de la littérature.

A 27-year old woman with occipital ependymoma treated by surgery and radiotherapy for multiple recurrences developed a right lymphocytic pleural effusion. After 3 inconclusive needle biopsies of the pleura, pleurectomy was performed. Pathological examination with a specific immunohistochemical marker provided a diagnosis of pleuro-pulmonary metastases from the ependymoma. This rare case of extraneuraxial metastasis from a cerebral ependymoma is discussed in the light of published data. Its originality lies in that a positive diagnosis of pleural metastases was obtained with an immunohistochemical marker, the gliofibrillary antiprotein serum (anti-GFAP) specific of glial tissue.

AIDS subacute encephalitis. Identification of HIV-infected cells.

Human immunodeficiency virus (HIV) RNA and proteins were detected in the brains of several AIDS patients with subacute encephalitis, by in situ hybridization and immunohistology. The majority of infected cells were mononucleated and bore processes. Using single and double immunohistologic procedures, the authors identified these cells as macrophages. The majority of them had the phenotype of microglial cells (Leu-M3-, CD4-), others were labeled with markers of circulating macrophages (Leu-M3+, CD4+/-). The presence of HIV RNA and proteins in CD4- cells could be explained by depressed CD4 antigen expression, as a result of infection or macrophage tissue differentiation.

Leucoencephalopathy with multinucleated giant cells containing human immune deficiency virus-like particles and multiple opportunistic cerebral infections in one patient with AIDS.

A 29-year-old homosexual male with AIDS presented with progressive encephalopathy and cytomegalovirus (CMV) pneumonia. Neuropathological examination revealed toxoplasma abscesses in corpus callosum, basal ganglia and cerebellar white matter; demyelinating foci in the parietal white matter, with microscopic changes typical of progressive multifocal leucoencephalopathy and intranuclear papovavirus inclusions in oligodendrocytes; and lesions of subacute encephalitis in the periventricular regions with large cells positive by immunostaining for CMV. Diffuse myelin loss was observed in the cerebral white matter. Multinucleated giant cells were numerous in the demyelinated areas, they were also observed in close relationship with papova, CMV and Toxoplasma lesions. Immunostaining of these cells was positive for histiocyte markers and negative with the leucocyte common antigen monoclonal antibody. Some of them contained virus-like particles measuring around 100 nm similar to human immune deficiency virus (HIV) as observed in human brain.

Localization of H blood group antigen in ectoblastic derivatives of murine teratocarcinoma.

Ectoblastic derivatives (ectodermal and neuroectodermal components) constitute more than 90% of all structures in the murine teratocarcinoma derived from the PCC4-aza-1 line. This tumor was labeled immunocytochemically with fluoresceinated antibodies to A, B and H blood groups. A and B antigens were always noted to be absent from all structures of the three germ layers. With anti-H, however, embryonic and fetal endodermal components, e.g. alimentary or respiratory duct-like structures, gave positive staining. Mesodermal components, i.e. bone and cartilage structures, fibroblasts and myocytes of mature or embryonal type, were negative. Immature and mature ectodermal components, viz. epidermoid cysts or islets, were always positive. Neuroectodermal components, neuroblastic cysts and differentiated neuronal, glial and ependymal elements were always negative. Ectoblastic and/or neuroectoblastic individual cells or cell clusters, observed in the vicinity of positive differentiating ectodermal and neuroectodermal structures, were positive. Similar cells or clusters were negative when located close to negative neuroectodermal components. The undifferentiated, embryonal carcinoma cells and structures were always negative. These observations are compared to the staining patterns of H antigen in murine embryos and adult mice and in human teratocarcinomas. It is suggested that poorly differentiated, morphologically similar ectoblastic and/or neuroectoblastic structures are positive, if they concern ectodermal components, and negative, if they belong to neuroectodermal components, with the exception of some primary sensory cells that are positive. These last cells are also positive in normal fetal and adult tissues.