Biomedical subjects

Micheline McCarthy

Publications and source records attributed to Micheline McCarthy.

6 recordsLinked to original sources

PubMed2006

Neurotrophin-directed differentiation of human adult marrow stromal cells to dopaminergic-like neurons.

Marrow-isolated adult multilineage inducible (MIAMI) cells were differentiated in vitro to neuronal cells in a neurotrophin-dependent fashion. After induction, the cells revealed electrophysiological features similar to those observed in mature neurons. Primary early passage human MIAMI cells without any type of co-cultures with other cell types were used. The developmental program involved a multi-step process requiring the concerted action of brain-derived neurotrophic factor, nerve growth factor and depended on neurotrophin-3, after basic fibroblast growth factor withdrawal. MIAMI-derived neuron-like cells sequentially expressed the neuronal markers, developed a complex neurite outgrowth and arborization, and acquired electrophysiological characteristics similar to those observed in mature neurons. The young and old MIAMI-derived neuronal cells developed both inward and outward currents upon depolarization, similar to those observed in normal neurons. These results represent the earliest evidence that neurotrophin-3 can direct the differentiation of non-neural stem cells from human adult bone marrow stroma to neuron-like cells in vitro. Supplementing the aforementioned multi-step process with sonic hedgehog, fibroblast growth factor 8, and retinoic acid increased the expression of molecules involved in dopaminergic differentiation and of tyrosine hydroxylase, the rate limiting enzyme of dopamine synthesis. MIAMI cells from young and old individuals represent autologous human cell populations for the treatment of disorders of the skeletal and nervous systems and for applications in cell therapy and reparative medicine approaches.

Adolescent↗

PubMed2006

Brain CD8+ and cytotoxic T lymphocytes are associated with, and may be specific for, human immunodeficiency virus type 1 encephalitis in patients with acquired immunodeficiency syndrome.

CD8+ T cells infiltrate brains with human immunodeficiency virus type-1 (HIV-1) encephalitis (HIVE) and related animal models; their perineuronal localization suggests cytotoxic T cell (CTL)-mediated neuronal killing. Because CTLs have not been identified in acquired immunodeficiency syndrome (AIDS) brains, the authors identified their cytotoxic granules in autopsy AIDS brains with HIVE and without HIVE (HIVnE) plus controls (7 to 13 cases/group) and determined gene expression profiles of CTL-associated genes in a separate series of cases. CD3+ and CD8+ T cells were significantly increased (P < .01) in perivascular spaces and inflammatory nodules in HIVE but were rare or absent in brain parenchyma in HIVnE and control brains. Eight HIVE brains contained granzyme B+ T cells and five contained perforin+ T cells. Their T-cell origin was confirmed by colocalization of CD8 and granzyme B in the same cell and the absence of CD56+ natural killer cells. The CTLs directly contacted with neurons, as the authors showed previously for CD3+ and CD8+ T cells. CTLs were rare or absent in HIV nonencephalitis (HIVnE) and controls. Granzyme B and H precursor gene expression was up-regulated and interleukin (IL)-12A precursor, a maturation factor for natural killer cells and CTLs, was down-regulated in HIVE versus HIVnE brain. This study demonstrates, for the first time, CTLs in HIVE and shows that parenchymal T cells and CTLs are sensitive biomarkers for HIVE. Consequently, CD8+ T cells and CTLs could mediate brain injury in HIVE and may represent an important biomarker for productive brain infection by HIV-1.

AIDS Dementia Complex↗

PubMed2006

Maturing neurons are selectively sensitive to human immunodeficiency virus type 1 exposure in differentiating human neuroepithelial progenitor cell cultures.

Human immunodeficiency virus type 1 (HIV-1) infection of the brain is associated with neuronal injury manifested by dendritic pruning, aberrant neurofilament metabolism, and decreased synaptic density. The central nervous system (CNS) responds to neuronal injury by differentiating new neurons and astrocytes from resident populations of multipotent neuroepithelial progenitor cells (NEP) located in regions such as the subventricular zone or hippocampus. In vitro studies have demonstrated that the HIV-1 virion or envelope glycoprotein gp120 can injure differentiated human neurons and astrocytes, suggesting that HIV-1 proteins could similarly injure NEP or NEP-derived glial and neuronal lineage-committed precursor cells. To answer this question, human fetal brain-derived "neurospheres" containing NEP and NEP-derived precursor cells were cultured in low serum differentiation medium containing lymphotropic HIV-1(SF2), macrophage-tropic HIV-1(SF128A), or recombinant gp120SF2 from HIV-1(SF2). These experiments indicate that exposure to HIV-1 does not affect the ability of the NEP to differentiate into cells expressing either astrocyte-specific or neuron-specific cytoskeletal antigens. However prolonged exposure to HIV-1 does selectively decrease expression of neuronal antigens (microtubule beta-III-tubulin and intermediate filament neurofilament-L) but not astrocyte antigens (intermediate filament glial fibrillary acidic protein). The effects of continuous exposure to HIV-1 or gp120 may result from injury to developing neurons and/or impairment of the neuronal developmental process itself. By depressing neuronal microtubule and neurofilament protein expression, HIV-1 and gp120 exposure compromise the potential for postmitotic neuronal dendrite and axon development.

Caspase 3↗

PubMed2003

Newer viral encephalitides.

BACKGROUND: Viral encephalitis occurs in epidemic settings or is sporadic. New encephalitis patterns reflect the roles that biologic reservoirs and vectors play in determining virus-human interactions. "New" viral encephalitis can also result from human host modifications that increase susceptibility to neuroinvasive viral infection. REVIEW SUMMARY: Three human viruses, Nipah virus, Human Herpesvirus-6, and West Nile virus, present examples of how "new" viral encephalitides emerge in a specific geographic region or clinical setting. Nipah virus encephalitis emerged after the molecular evolution of a new zoonotic viral genus within the Paramyxovirinae family. Human herpesvirus-6 encephalitis has emerged in the immune suppressed human host harboring this ubiquitous but typically benign herpesvirus. West Nile virus encephalitis has emerged in the Western hemisphere after apparent abrupt translocation of this mosquito-borne virus to a distant geographic region with immunologically naive avian and human hosts. CONCLUSION: While the clinical features of these viral encephalitides are somewhat distinct, they each emerged as the result of human-derived factors that altered the biologic dynamic between humans and their viral pathogens.

Animals↗

PubMed2002

Cellular tropisms and co-receptor usage of HIV-1 isolates from vertically infected children with neurological abnormalities and rapid disease progression.

The longitudinal evolution of HIV-1 phenotypes was studied in a cohort of six vertically infected children with early onset and rapid progression of clinical disease. Among 30 viral isolates obtained from peripheral blood, tropisms for both human blood-derived cells (macrophages, T-lymphocytes), and for human neural (brain-derived) cells (microglia, astrocytes) were determined, as was chemokine co-receptor usage. All children harbored from birth macrophage-tropic isolates using the CCR5 co-receptor. Two children later developed T-cell tropic isolates with CXCR4 and CCR3 usage. While all six patients developed neurological abnormalities, only three produced neural cell tropic isolates, which used CCR5. However, early and persistent finding of both astrocyte- and microglia-tropic isolates in one patient did associate with the most rapid progression to brain atrophy among the six patients. Viral phenotypic properties determined in cell culture did not specifically predict clinical features or course, and the development of AIDS did not coincide with, or depend on, the appearance T-tropic, syncytia-inducing viruses.

Astrocytes↗

PubMed2001

St. Louis Encephalitis and West Nile Virus Encephalitis.

St. Louis encephalitis virus is a major cause of epidemic arboviral encephalitis in the US. Transmitted by a mosquito vector, this virus is an annual public health concern during the late summer and early fall in much of the midwest and southeast. The characteristic epidemic features of this viral encephalitis coupled with public health surveillance and vector monitoring programs have made the diagnosis readily accessible during the past decade. Recently, however, the arboviral landscape in the US changed dramatically with the emergence and persistence of West Nile virus and associated human neurologic illness in New York and the Northeast. In its New York presentation, West Nile virus encephalitis exhibited clinical and laboratory similarities to St. Louis encephalitis. Not surprisingly, this led to initial confusion in establishing the diagnosis. In anticipation of the potential geographic spread of West Nile virus beyond the northeastern US, neurologists must now consider West Nile virus along with St. Louis encephalitis when diagnosing patients with suspected epidemic mosquito-borne viral encephalitis or meningoencephalitis. Although no specific antiviral agents are yet available, patients will benefit from close monitoring during the initial phase of illness, supportive critical care, and appropriate rehabilitation.

Journal Article↗