Human cytomegalovirus (HCMV) is the most common cause of congenital infections in developed countries, with an incidence varying between 0.5 and 2.2% and consequences varying from asymptomatic infection to lethal conditions for the fetus. Infants that are asymptomatic at birth may still develop neurological sequelae, such as hearing loss and mental retardation, at a later age. Infection of neural stem and precursor cells by HCMV and consequent disruption of the proliferation, differentiation, and/or migration of these cells may be the primary mechanism underlying the development of brain abnormalities. In the present investigation, we demonstrate that human neural precursor cells (NPCs) are permissive for HCMV infection, by both the laboratory strain Towne and the clinical isolate TB40, resulting in 55% and 72% inhibition of induced differentiation of human NPCs into neurons, respectively, when infection occurred at the onset of differentiation. This repression of neuronal differentiation required active viral replication and involved the expression of late HCMV gene products. This capacity of HCMV to prevent neuronal differentiation declined within 24 h after initiation of differentiation. Furthermore, the rate of cell proliferation in infected cultures was attenuated. Surprisingly, HCMV-infected cells exhibited an elevated frequency of apoptosis at 7 days following the onset of differentiation, at which time approximately 50% of the cells were apoptotic at a multiplicity of infection of 10. These findings indicate that HCMV has the capacity to reduce the ability of human NPCs to differentiate into neurons, which may offer one explanation for the abnormalities in brain development associated with congenital HCMV infection.

Human cytomegalovirus (HCMV) is the most common cause of congenital infections in developed countries, with an incidence varying between 0.5-2.2%. Such infection may be the consequence of either a primary infection or reactivation of a latent infection in the mother and the outcome may vary from asymptomatic to severe brain disorders. Moreover, infants that are asymptomatic at the time of birth may still develop neurologic sequelae at a later age. Our hypothesis is that infection of stem cells of the central nervous system by HCMV alters the proliferation, differentiation or migration of these cells, and thereby gives rise to the brain abnormalities observed. We show that infection of human neural precursor cells (NPCs) with the laboratory strain Towne or the clinical isolate TB40 of HCMV suppresses the differentiation of these cells into astrocytes even at an multiplicity of infection (MOI) as low as 0.1 (by 33% and 67%, respectively). This inhibition required active viral replication and the expression of late HCMV proteins. Infection as late as 24 hr after the onset of differentiation, but not after 72 hr, also prevented the maturation of infected cultures. Furthermore, in cultures infected with TB40 (at an MOI of 1), approximately 54% of the cells were apoptotic and cell proliferation was significantly attenuated. Clearly, HCMV can reduce the capacity of NPCs to differentiate into astrocytes and this effect may provide part of the explanation for the abnormalities in brain development associated with congenital HCMV infection.

No abstract

Objective: To perform an evidence-based review of the literature on neuroimaging techniques utilized in spinal cord injury clinical practice and research.Methods: A search of the medical literature for articles on specific neuroimaging techniques used in SCI resulted in 2,302 published reports. Review at the abstract and full report level yielded 99 clinical and preclinical articles that were evaluated in detail. Sixty nine were clinical research studies subjected to quality of evidence grading. Twenty-three articles were drawn from the pre-clinical animal model literature and used for supportive evidence. Seven review articles were included to add an element of previous syntheses of current thinking on neuroimaging topics to the committee process (the review articles were not graded for quality of evidence). A list of clinical and research questions that might be answered on a variety of neuroimaging topics was created for use in article review. Recommendations on the use of neuroimaging in spinal cord injury treatment and research were made based on the quality of evidence.Results: Of the 69 original clinical research articles covering a range of neuroimaging questions, only one was judged to provide Class I evidence, 22 provided Class II evidence, 17 Class III evidence, and 29 Class IV evidence.Recommendations: MRI should be used as the imaging modality of choice for evaluation of the spinal cord after injury. CT and plain radiography should be used to assess the bony anatomy of the spine in patients with SCI. MRI may be used to identify the location of spinal cord injury. MRI may be used to demonstrate the degree of spinal cord compression after SCI. MRI findings of parenchymal hemorrhage/ contusion, edema, and spinal cord disruption in acute and subacute SCI may contribute to the understanding of severity of injury and prognosis for neurological improvement. MRI-Diffusion Weighted Imaging may be useful in quantifying the extent of axonal loss after spinal cord injury. Functional MRI may be useful in measuring the anatomic functional/metabolic correlates of sensory-motor activities in persons with SCI. MR Spectroscopy may be used to measure the biochemical characteristics of the brain and spinal cord following SCI. Intraoperative Spinal Sonography may be used to identify spinal and spinal cord anatomy and gross pathology during surgical procedures. Further research in these areas is warranted to improve the strength of evidence supporting the use of neuroimaging modalities. Positron Emission Tomography may be used to assess metabolic activity of CNS tissue (brain and spinal cord) in patients with SCI.

No abstract

No abstract

Object. Surgically created lesions of the spinal cord dorsal root entry zone (DREZ) to relieve central pain after spinal cord injury (SCI) have historically resulted in modest outcomes. A review of the literature indicates that fair to good relief of pain is achieved in approximately 50% of patients when an empirical procedure is performed. This study was undertaken to determine if intramedullary electrical guidance in DREZ lesioning could improve outcomes in patients with SCI-induced central pain. Additionally, electrical data were used to determine if the spinal cord could be somatotopically mapped with regard to this pain of central origin. Methods. Forty-one patients with traumatic SCI and intractable central pain underwent DREZ lesioning in which intramedullary electrical guidance was conducted. In nine patients, recording of DREZ-related spontaneous electrical hyperactivity guided the lesioning process. In 32 patients, recording of DREZ-induced evoked electrical hyperactivity during transcutaneous C-fiber stimulation (TCS) additionally guided lesioning. The follow-up period ranged from 1 to 7 years. The analyzed electrical data allowed for somatotopic mapping of the spinal cord. Conclusions. Intramedullary electrical guidance of DREZ lesioning substantially improves pain outcomes in patients with traumatic SCI—induced central pain, compared with an empiric technique. The best outcome occurs when DREZ-related spontaneous electrical hyperactivity and evoked hyperactivity during TCS are both used to guide the DREZ lesioning procedure. With such guidance, 100% relief of pain was achieved in 84% of patients and 50 to 100% relief of pain in 88%. Somatotopic mapping of the electrical data led to a proposed pain mechanism for below-level pain, implicating the sympathetic nervous system.

Studies in model organisms constitute the basis of our understanding of the principal molecular mechanisms of cell fate determination in the developing central nervous system. Considering the emergent applications in stem cell-based regenerative medicine, it is important to demonstrate conservation of subtype specific gene expression programs in human as compared to model vertebrates. We have examined the expression patterns of key regulatory genes in neural progenitor cells and their neuronal and glial descendants in the developing human spinal cord, hindbrain, and midbrain, and compared these with developing mouse and chicken embryos. As anticipated, gene expression patterns are highly conserved between these vertebrate species, but there are also features that appear unique to human development. In particular, we find that neither tyrosine hydroxylase nor Nurr1 are specific markers for mesencephalic dopamine neurons, as these genes also are expressed in other neuronal subtypes in the human ventral midbrain and in human embryonic stem cell cultures directed to differentiate towards a ventral mesencephalic identity. Moreover, somatic motor neurons in the ventral spinal cord appear to be produced by two molecularly distinct ventral progenitor populations in the human, raising the possibility that the acquisition of unique ventral progenitor identities may have contributed to the emergence of neural subtypes in higher vertebrates.