Low-grade monoclonal Epstein-Barr virus-associated lymphoproliferative disorder of the brain presenting as human immunodeficiency virus-associated encephalopathy in a child with acquired immunodeficiency syndrome.

The association of the Epstein-Barr virus with human immunodeficiency virus-associated primary central nervous system lymphomas is well known. We describe a pediatric patient infected with human immunodeficiency virus who developed a lesion in the central nervous system that appeared to be histologically reactive and that proved to be an Epstein-Barr virus-associated monoclonal B-cell lymphoproliferative disorder by molecular analysis. An 8-year-old girl was diagnosed with vertically transmitted human immunodeficiency virus infection at age 5, for which she was treated empirically with a combination of zidovudine and didanosine. At the age of 7 years, during evaluation for entry into an antiretroviral protocol, a single hypodense frontal lobe lesion was identified by computed tomography. After unsuccessful treatment for presumed toxoplasmosis and progressive neurologic deterioration, a stereotactic brain biopsy was performed. Although the biopsy contained a polymorphic lymphoid infiltrate that appeared to be cytologically reactive, polymerase chain reaction and in situ hybridization studies revealed a monoclonal Epstein-Barr virus-associated B-cell lymphoproliferative disorder, which was reminiscent of polymorphic B-cell hyperplasia observed in the setting of immunosuppression following organ transplantation. Postoperative therapy included steroids and antiretroviral therapy. The lesion decreased slightly in size, and the child's neurologic status was relatively unremarkable for 5 months. Subsequently, she developed cytomegalovirus retinitis, progressive encephalopathy, and died with pancytopenia. This case represents a newly described manifestation of Epstein-Barr virus-associated lymphoproliferative disorder, a diagnosis that should be considered in patients with neurologic symptoms and immunodeficiency. In addition, this case exhibited histologic features reminiscent of posttransplant lymphoproliferative disease, a histologic pattern that to our knowledge has not previously been reported in the setting of acquired immunodeficiency syndrome.

Thrombin-induced translocation of GLUT3 glucose transporters in human platelets.

Platelets derive most of their energy from anaerobic glycolysis; during activation this requirement rises approx. 3-fold. To accommodate the high glucose flux, platelets express extremely high concentrations (155+/-18 pmol/mg of membrane protein) of the most active glucose transporter isoform, GLUT3. Thrombin, a potent platelet activator, was found to stimulate 2-deoxyglucose transport activity 3-5-fold within 10 min at 25 degrees C, with a half-time of 1-2 min. To determine the mechanism underlying the increase in glucose transport activity, an impermeant photolabel, [2-3H]2N-4-(1-azi-2,2,2-trifluoethyl)benzoyl-1,3, -bis-(d-mannose-4-ylozy)-2-propylamine, was used to covalently bind glucose transporters accessible to the extracellular milieu. In response to thrombin, the level of transporter labelling increased 2.7-fold with a half-time of 1-2 min. This suggests a translocation of GLUT3 transporters from an intracellular site to the plasma membrane in a manner analogous to that seen for the translocation of GLUT4 in insulin-stimulated rat adipose cells. To investigate whether a similar signalling pathway was involved in both systems, platelets and adipose cells were exposed to staurosporin and wortmannin, two inhibitors of GLUT4 translocation in adipose cells. Thrombin stimulation of glucose transport activity in platelets was more sensitive to staurosporin inhibition than was insulin-stimulated transport activity in adipose cells, but it was totally insensitive to wortmannin. This indicates that the GLUT3 translocation in platelets is mediated by a protein kinase C not by a phosphatidylinositol 3-kinase mechanism. In support of this contention, the phorbol ester PMA, which specifically activates protein kinase C, fully stimulated glucose transport activity in platelets and was equally sensitive to inhibition by staurosporin. This study provides a cellular mechanism by which platelets enhance their capacity to import glucose to fulfil the increased energy demands associated with activation.

Human immunodeficiency virus type 1 infection of H9 cells induces increased glucose transporter expression.

A clone obtained from a differential display screen for cellular genes with altered expression during human immunodeficiency virus (HIV) infection matched the sequence for the human GLUT3 facilitative glucose transporter, a high-velocity-high-affinity facilitative transporter commonly expressed in neurons of the central nervous system. Northern (RNA) analysis showed that GLUT3 expression increased during infection. Flow cytometry showed that GLUT3 protein expression increased specifically in the HIV-infected cells; this increase correlated with increased 2-deoxyglucose transport in the HIV-infected culture. HIV infection therefore leads to increased expression of a glucose transporter normally expressed at high levels in other cell types and a corresponding increase in glucose transport activity. If HIV infection places increased metabolic demands on the host cell, changes in the expression of a cellular gene that plays an important role in cellular metabolism might provide a more favorable environment for viral replication.

Absence of insulin receptor gene mutations in three insulin-resistant women with the polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are markedly insulin-resistant, but the molecular mechanisms of these changes and their relationship to the hyperandrogenic state remain to be clarified. Mutations have recently been identified in the insulin receptor gene of patients with extreme forms of insulin resistance associated with hyperandrogenism (eg, type A insulin resistance), and these mutations account for the insulin resistance in such patients. We performed this study to determine whether mutations in the coding portion of the insulin receptor gene were responsible for insulin resistance in PCOS. Insulin binding studies using cultured skin fibroblasts of three obese (body mass index > 27 kg/m2) women with PCOS (ie, mild hyperandrogenemia and chronic anovulation of unknown etiology) and documented insulin resistance showed no apparent abnormalities in either the number or affinity of insulin binding sites. Direct sequencing of all 22 exons of the insulin receptor gene from two of the women with PCOS did not reveal any mutations. Furthermore, both alleles of the gene were expressed at equal levels. In a third insulin-resistant PCOS woman, there was no evidence for a mutation in the coding portion of the insulin receptor gene as determined by denaturing gradient gel electrophoresis (DGGE). We conclude that the insulin resistance in these PCOS women was caused by a defect extrinsic to the insulin receptor.