HIV stroke risk: evidence and implications.

An estimated 34 million men, women, and children are infected with human immunodeficiency virus type 1 (HIV-1), the virus that causes acquired immunodeficiency syndrome (AIDS). Current technology cannot eradicate HIV-1, and most patients with HIV-1-infection (HIV+) will require lifelong treatment with combined antiretroviral therapy (cART). Stroke was recognized as a complication of HIV-1 infection since the early days of the epidemic. Potential causes of stroke in HIV-1 include opportunistic infections, tumors, atherosclerosis, diabetes, hypertension, autoimmunity, coagulopathies, cardiovascular disease, and direct HIV-1 infection of the arterial wall. Ischemic stroke has emerged as a particularly significant neurological complication of HIV-1 and its treatment due to the aging of the HIV+ population, chronic HIV-1 infection, inflammation, and prolonged exposure to cART. New prevention and treatment strategies tailored to the needs of the HIV+ population are needed to address this issue.

The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment.

BACKGROUND: The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders. METHODS: Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the Affymetrix® array platform. RESULTS: With HIVE the HIV-1 RNA load in brain tissue was three log(10) units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits. INTERPRETATION: Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project).

Nuclear factor IA is expressed in astrocytomas and is associated with improved survival.

Nuclear factor IA (NFIA) is a transcription factor that specifies glial cell identity and promotes astrocyte differentiation during embryonic development. Its expression and function in gliomas are not known. Here, we examined NFIA protein expression in gliomas and its association with clinical outcome in pediatric malignant astrocytomas. We analyzed expression of NFIA by immunohistochemistry in 88 existing glioma specimens from Childrens Hospital Los Angeles and the University of Southern California. Association between NFIA expression and progression-free survival (PFS) was examined in high-grade astrocytomas for which clinical data were available (n = 23, all children). NFIA was highly expressed in astrocytomas of all grades, but only in a minority of cells in oligodendroglial tumors. NFIA was expressed on a higher percentage of tumor cells in low-grade astrocytomas (91 +/- 5% and 77 +/- 14% in World Health Organization [WHO] I and II, respectively) compared with high-grade astrocytomas (48 +/- 18% and 37 +/- 16% in WHO III and IV, respectively; P < .001, low- vs high-grade astrocytomas). There was a significant association between NFIA expression and PFS in children with astrocytoma WHO grade III or IV (Cox regression P = .019; logrank trend test for NFIA tertiles P = .0040 and NFIA quartiles P = .014). The association was not consistently significant in this small series of patients after adjustment was made for WHO grade III or IV. This is the first study to demonstrate expression of NFIA protein in astrocytomas and its association with grades of astrocytoma and PFS, suggesting that NFIA may play a role in astrocytoma biology.

An exploratory study of long-term neurocognitive outcomes following recovery from opportunistic brain infections in HIV+ adults.

Central nervous system opportunistic infections (CNS-OI) are a significant cause of morbidity and mortality in AIDS. While current interventions are increasingly successful in treating CNS-OI, little information exists regarding long-term behavioral outcomes among survivors. In this exploratory study we examined neurocognitive data among three groups of adults with different AIDS-related CNS-OI: 15 with past cryptococcal meningitis (CM), 8 with toxoplasmosis encephalitis (TE), and 8 with progressive multifocal leukoencephalopathy (PML). A group of 61 individuals with AIDS, but without CNS-OI, was used as a comparison group. A battery of standardized neuropsychological tests assessing a variety of cognitive domains was administered upon entry. Results indicate that individuals with a history of CNS-OI were most impaired on measures of cognitive and psychomotor speed relative to the HIV+ comparison group. Among the CNS-OI groups, individuals with history of TE had the most severe and varied deficits. The results are discussed in relation to what is known about the neuropathological consequences of the various CNS-OIs. While this is the first systematic group study of residual CNS-OI effects on neurocognitive function, future studies employing more participants, perhaps focusing on specific CNS-OIs, will further characterize the long-term outcomes in AIDS-related CNS-OI.

Review of meningioma histopathology.

The histological appearance of a meningioma is an important predictor of tumor behavior and is frequently a factor in decisions concerning therapy. The relationship between histological features and prognosis is formalized in grading schemes such as those published by the World Health Organization (WHO), most recently in 2007. Although the latest edition is an improvement over previous grading schemes, the WHO scheme still fails to fully address a variety of important issues regarding the relationship between meningioma histological characteristics and behavior. In particular, routine histological examination fails to identify the subset of Grade I tumors that behave aggressively. Because of this, many additional prognostic markers that require immunohistochemical, cytogenetic, or molecular techniques to evaluate are under investigation. Only one, immunohistochemistry for the proliferation marker, Ki 67 (MIB-1), is used routinely and it has only limited utility. It is hoped that an understanding of the genetic changes that underlie tumor progression will improve healthcare professionals' ability to predict the behavior of meningiomas.

Pathology of primary central nervous system lymphoma.

The understanding of primary central nervous system lymphoma (PCNSL) has lagged behind that of the much more common systemic, nodal lymphomas. Reasons for this include the relative rarity of PCNSL and the fact that these lesions differ in some ways from their histologically similar systemic counterparts. The purpose of this paper is twofold: first, the author provides concise descriptions of the pathological features of both common and uncommon types of PCNSL while discussing issues such as the confusion surrounding histological classification of PCNSLs, problems related to intraoperative diagnosis, and the appropriate diagnostic work up. Second, the author discusses a small number of molecular studies to demonstrate the great promise they offer. Such studies have already clarified some issues, including the category of lymphocyte from which the majority of PCNSLs are derived. Hopefully in the future these studies will help guide treatment decisions.

A rare case of periosteal osteoblastoma located in the frontal cranial bone.

Periosteal osteoblastoma is an extremely rare bone-forming neoplasm located on the surface of cortical bone. Of the fewer than 30 cases of periosteal osteoblastomas found in the literature, 2 have been reported to be located in cranial bone, and these have not been documented in detail with clinical history, radiographic findings, macroscopic features, and microscopic findings. Although the differential diagnoses of periosteal lesions include parosteal and periosteal osteosarcoma, periosteal chondroma and chondrosarcoma, osteochondroma, osteoid osteoma, periostitis ossificans, and myositis ossificans, an important differential diagnosis both radiologically and pathologically of such a lesion in the cranium is meningioma. We report an unusual case of periosteal osteoblastoma located in the frontal cranial bone that was radiologically consistent with a meningioma. The differential diagnosis of metaplastic meningioma with differentiation toward bone is discussed.