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Biomedical subjects

M E Ross

Publications and source records attributed to M E Ross.

At least 37 records · Page 2Linked to original sources
PubMed1999

Age-dependent increase in ischemic brain injury in wild-type mice and in mice lacking the inducible nitric oxide synthase gene.

The authors investigated the influence of age on the outcome of cerebral ischemia in wild-type mice and in mice with a deletion of the inducible nitric oxide synthase (iNOS) gene. The middle cerebral artery was permanently occluded in iNOS-null mice and in wild-type (C57BL/6) controls aged 4, 8, 16, and 24 weeks. Infarct volume was determined in thionin-stained brain sections 4 days after permanent middle cerebral artery occlusion. No differences in forebrain volume were found among wild-type and iNOS-null mice at the ages studied (P > 0.05). In C57BL/6 mice (n = 5 to 6/group), neocortical infarct volume corrected for swelling was 28 +/- 5 mm3 in 4-week-old mice, 28 +/- 3 at 8 weeks, 35 +/- 4 at 16 weeks, and 37 +/- 6 at 24 weeks (mean +/- SD). iNOS-null mice (n = 5 to 6/group) had smaller infarcts than wild-type controls at all ages (P < 0.05). However, the magnitude of the reduction was greater in 4-week-old (-29% +/- 10%) or 8-week-old mice (-24% +/- 8%), than in 16-week-old (-14% +/- 10%) or 24-week-old mice (-11% +/- 6%). Neurologic deficit scores improved significantly between 24 and 96 hours in 4- and 8-week-old iNOS-null mice compared with age-matched wild-type mice (P < 0.05). However, in 16- or 24-week-old iNOS-null mice, neurologic deficits did not improve (P > 0.05). The authors conclude that in iNOS-/- and in wild-type mice, the size of the infarct produced by occlusion of the middle cerebral artery is larger in older than in younger mice. However, the reduction in infarct volume observed in iNOS-null mice is age-dependent and is greatest at 1 to 2 months of age. Therefore, age is a critical variable in studies of focal cerebral ischemic damage, both in wild-type mice and in mouse mutants.

Aging↗
PubMed1999

The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene.

The authors investigated the role of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) in the mechanisms of focal cerebral ischemia and its interaction with inducible nitric oxide synthase (iNOS). Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) in mice. Infarct volume was measured 96 hours later by computer-assisted planimetry in thionin-stained brain sections. The highly selective COX-2 inhibitor NS398 (20 mg/kg; intraperitoneally), administered twice a day starting 6 hours after MCA occlusion, reduced total infarct volume in C57BL/6 (-23%) and 129/SVeV mice (-21%), and ameliorated the motor deficits produced by MCA occlusion (P < .05). However, NS398 did not influence infarct volume in mice with deletion of the iNOS gene (P > .05). In contrast, the neuronal NOS inhibitor 7-NI (50 mg/kg; intraperitoneally), administered once 5 minutes after MCA occlusion, reduced neocortical infarct volume by 20% in iNOS -/- mice (P < .05). NS398 did not affect arterial pressure, resting CBF or the CBF reactivity to hypercapnia in anesthetized iNOS null mice (P > .05). The data suggest that COX-2 reaction products, in mouse as in rat, contribute to ischemic brain injury. However, the failure of NS398 to reduce infarct volume in iNOS null mice suggests that iNOS-derived NO is required for the deleterious effects of COX-2 to occur. Thus, COX-2 reaction products may be another mechanism by which iNOS-derived NO contributes to ischemic brain injury.

Animals↗
PubMed1999

Cerebellar histogenesis is disturbed in mice lacking cyclin D2.

Formation of brain requires deftly balancing primary genesis of neurons and glia, detection of when sufficient cells of each type have been produced, shutdown of proliferation and removal of excess cells. The region and cell type-specific expression of cell cycle regulatory proteins, such as demonstrated for cyclin D2, may contribute to these processes. If so, regional brain development should be affected by alteration of cyclin expression. To test this hypothesis, the representation of specific cell types was examined in the cerebellum of animals lacking cyclin D2. The loss of this cyclin primarily affected two neuronal populations: granule cell number was reduced and stellate interneurons were nearly absent. Differences between null and wild-type siblings were obvious by the second postnatal week. Decreases in granule cell number arose from both reduction in primary neurogenesis and increase in apoptosis of cells that fail to differentiate. The dearth of stellate cells in the molecular layer indicates that emergence of this subpopulation requires cyclin D2 expression. Surprisingly, Golgi and basket interneurons, thought to originate from the same precursor pool as stellate cells, appear unaffected. These results suggest that cyclin D2 is required in cerebellum not only for proliferation of the granule cell precursors but also for proper differentiation of granule and stellate interneurons.

Aging↗
PubMed1998

Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia.

Focal cerebral ischemia is associated with expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), enzymes whose reaction products contribute to the evolution of ischemic brain injury. We tested the hypothesis that, after cerebral ischemia, nitric oxide (NO) produced by iNOS enhances COX-2 activity, thereby increasing the toxic potential of this enzyme. Cerebral ischemia was produced by middle cerebral artery occlusion in rats or mice. Twenty-four hours after ischemia in rats, iNOS-immunoreactive neutrophils were observed in close proximity (<20 micrometer) to COX-2-positive cells at the periphery of the infarct. In the olfactory bulb, only COX-2 positive cells were observed. Cerebral ischemia increased the concentration of the COX-2 reaction product prostaglandin E2 (PGE2) in the ischemic area and in the ipsilateral olfactory bulb. The iNOS inhibitor aminoguanidine reduced PGE2 concentration in the infarct, where both iNOS and COX-2 were expressed, but not in the olfactory bulb, where only COX-2 was expressed. Postischemic PGE2 accumulation was reduced significantly in iNOS null mice compared with wild-type controls (C57BL/6 or SV129). The data provide evidence that NO produced by iNOS influences COX-2 activity after focal cerebral ischemia. Pro-inflammatory prostanoids and reactive oxygen species produced by COX-2 may be a previously unrecognized factor by which NO contributes to ischemic brain injury. The pathogenic effect of the interaction between NO, or a derived specie, and COX-2 is likely to play a role also in other brain diseases associated with inflammation.

Animals↗
PubMed1998

Differential expression and function of L-selectin on CD56bright and CD56dim natural killer cell subsets.

NK cells are the first line of defense against foreign cells, virally infected cells, and tumors. The mechanisms whereby NK cells accumulate in extralymphoid sites in response to pathogenic stimuli are not well understood. The L-selectin adhesion molecule (CD62L) plays a primary role in mediating the initial interaction of leukocytes with vascular endothelium, a crucial step in the extravasation of immune effector cells into tissues. In this report, we show L-selectin to be uniquely expressed on a subset of resting human NK cells (CD56bright). Notably, CD56bright NK cells expressed L-selectin at a higher density than all other peripheral blood leukocytes. NK activation by PMA, IL-2, IL-15, or TGF-beta down-regulated L-selectin on the CD56bright subset, while increased L-selectin levels were observed in both the CD56bright and CD56dim NK subsets in response to IL-12, IL-10, or IFN-alpha. Moreover, CD56bright NK cells bound with high efficiency to physiologic L-selectin ligands on peripheral lymph node high endothelial venules (HEV). In sharp contrast, CD56dim NK cells adhered poorly to HEV and were predominantly L-selectin- or expressed L-selectin only at low density. In CD56bright cells and a subpopulation of CD56dim cells, L-selectin ligation by mAb cross-linking activated lymphocyte function-associated Ag 1 (LFA-1), a second adhesion molecule required for leukocyte extravasation. LFA-1 was expressed on both NK subsets, although its density was constitutively higher on CD56dim cells. Taken together, evidence of differential expression of L-selectin and LFA-1 on CD56bright and CD56dim NK subsets strongly suggests unique migratory properties and functions of these cells during the early immune response to foreign pathogens.

3T3 Cells↗
PubMed1998

Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein.

X-linked lissencephaly and "double cortex" are allelic human disorders mapping to Xq22.3-Xq23 associated with arrest of migrating cerebral cortical neurons. We identified a novel 10 kb brain-specific cDNA interrupted by a balanced translocation in an XLIS patient that encodes a novel 40 kDa predicted protein named Doublecortin. Four double cortex/X-linked lissencephaly families and three sporadic double cortex patients show independent doublecortin mutations, at least one of them a de novo mutation. Doublecortin contains a consensus Abl phosphorylation site and other sites of potential phosphorylation. Although Doublecortin does not contain a kinase domain, it is homologous to the amino terminus of a predicted kinase protein, indicating a likely role in signal transduction. Doublecortin, along with the newly characterized mDab1, may define an Abl-dependent pathway regulating neuronal migration.

Amino Acid Sequence↗
PubMed1998

LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation.

Classical lissencephaly (LIS) is a neuronal migration disorder resulting in brain malformation, epilepsy and mental retardation. Deletions or mutations of LIS1 on 17p13.3 and mutations in XLIS ( DCX ) on Xq22.3-q23 produce LIS. Direct DNA sequencing of LIS1 and XLIS was performed in 25 children with sporadic LIS and no deletion of LIS1 by fluorescence in situ hybridization. Mutations of LIS1 were found by sequencing ( n = 8) and Southern blot ( n = 2) in a total of 10 patients (40%) of both sexes and mutations of XLIS in five males (20%). Combined with previous data, deletions or mutations of these two genes account for approximately 76% of isolated LIS. These data demonstrate that LIS1 and XLIS mutations cause the majority of, though not all, human LIS. The mutations in LIS1 were predicted to result in protein truncation in six of eight patients and splice site mutations in two, all of which disrupt one or more of the seven WD40 repeats contained in the LIS1 protein. Point mutations in XLIS identified the C-terminal serine/proline-rich region as potentially important for protein function. The patients with mutations were included in a genotype-phenotype analysis of 32 subjects with deletions or other mutations of these two genes. Whereas the brain malformation due to LIS1 mutations was more severe over the parietal and occipital regions, XLIS mutations produced the reverse gradient, which was more severe over the frontal cortex. The distinct LIS patterns suggest that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1998

Long-term care for elderly individuals and methods of financing.

As people age, there is an increase in chronic illness and disability and thus a growing need for long-term care. Unfortunately, the concept of long-term care can be very complex and confusing. Elderly individuals and their family members frequently have many questions, such as the following: What is long-term care, and who needs it? What long-term care services are available? Who will provide the services? Where will the services be provided? How much will the services cost, and who will pay for the expenses? Indeed, the cost of providing long-term care, whether in an institution or in one's own home, may represent an enormous burden for individuals and their families. Nurses, especially community health nurses, are in a prime position to address these questions and concerns to ensure appropriate care and services for their clients. This article addresses the questions clients frequently ask by defining long-term care and discussing long-term care services, settings, and providers. In addition, 4 methods of financing long-term care will be presented.

Aged↗
PubMed1997

Molecular pathology of cerebral ischemia: delayed gene expression and strategies for neuroprotection.

The evidence reviewed in this paper suggests that molecular and cellular events occurring in the late stages of cerebral ischemia (> 6 h) play an important role in the evolution of ischemic brain damage. We focused our inquiry on two inflammation-related genes iNOS and COX-2. iNOS is expressed in inflammatory and vascular cells in the post-ischemic brain. Pharmacological inhibition of iNOS activity ameliorates ischemic damage, whereas knockout mice lacking the iNOS gene are relatively protected from the consequences of cerebral ischemia. COX-2 is expressed in neurons at the infarct border and inhibition of COX-2 activity improves ischemic brain damage. These results indicate that expression of iNOS and COX-2 contributes to the late stages of ischemic brain damage. Consequently, inhibition of iNOS and COX-2 could be a valuable addition to treatment strategies for ischemic stroke. Most efforts to date have targeted the acute phase of cerebral ischemia. Inhibition of iNOS or COX-2 offers the prospect of treatments directed to the late stages of the damage. However, additional preclinical studies would be necessary before these new treatment strategies can be tested in human stroke.

Animals↗
PubMed1997

Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene.

Inducible nitric oxide synthase (iNOS), an enzyme that produces toxic amounts of nitric oxide, is expressed in a number of brain pathologies, including cerebral ischemia. We used mice with a null mutation of the iNOS gene to study the role of iNOS in ischemic brain damage. Focal cerebral ischemia was produced by occlusion of the middle cerebral artery (MCA). In wild-type mice, iNOS mRNA expression in the post-ischemic brain begun between 24 and 48 hr peaked at 96 hr and subsided 7 d after MCA occlusion. iNOS mRNA induction was associated with expression of iNOS protein and enzymatic activity. In contrast, mice lacking the iNOS gene did not express iNOS message or protein after MCA occlusion. The infarct and the motor deficits produced by MCA occlusion were smaller in iNOS knockouts than in wild-type mice (p < 0.05). Such reduction in ischemic damage and neurological deficits was observed 96 hr after ischemia but not at 24 hr, when iNOS is not yet expressed in wild-type mice. The decreased susceptibility to cerebral ischemia in iNOS knockouts could not be attributed to differences in the degree of ischemia or vascular reactivity between wild-type and knockout mice. These findings indicate that iNOS expression is one of the factors contributing to the expansion of the brain damage that occurs in the post-ischemic period. iNOS inhibition may provide a novel therapeutic strategy targeted specifically at the secondary progression of ischemic brain injury.

Animals↗
PubMed1997

Phenotypic and functional analysis of Fas (CD95) expression in primary central nervous system lymphoma of patients with acquired immunodeficiency syndrome.

The poor prognosis associated with patients afflicted with the acquired immunodeficiency syndrome and primary central nervous system lymphoma (AIDS-PCNSL) is due in part to the intrinsic resistance of this Epstein-Barr virus (EBV)-associated tumor to conventional antineoplastic therapy. Fas (CD95) is a transmembrane protein receptor that transmits an intracellular signal leading to rapid programmed cell death following ligation with its natural ligand or anti-Fas antibodies. Fas expression and function were assessed in AIDS-PCNSL biopsy samples and in EBV+ human B-cell tumors that spontaneously developed in severe combined immune deficient (SCID) mice engrafted with human lymphocytes (hu-PBL-SCID mice). All tumors samples showed high-density surface expression of Fas by flow cytometry or immunohistochemical staining. Cells from two AIDS-PCNSL biopsy samples that did not express pan B-cell markers did not express Fas antigen. All tumors examined were susceptible to Fas-mediated apoptosis, as measured by standard assays for endonucleolytic cleavage of DNA. The response to Fas-mediated apoptosis was dependent on log-fold increases in the concentration of immobilized anti-Fas antibody, but could also be induced with a mobilized anti-Fas antibody. No evidence for intrinsic resistance to Fas-mediated apoptosis (ie, secreted or truncated forms of Fas) could be shown. Radiation-induced apoptosis of neoplastic EBV+ B cells was enhanced by activation of Fas, and prolonged exposure to interleukin-2 increased both Fas expression and Fas-induced apoptosis. As the normal brain parenchyma appears to have either low-density or absent expression of Fas, and antineoplastic therapy can be selectively delivered to the CNS with little systemic toxicity, local delivery of Fas-activating molecules could prove to be a useful component in the multimodal treatment of AIDS-PCNSL.

Animals↗
PubMed1997

Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage.

Cyclo-oxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, is induced during inflammation and participates in inflammation-mediated cytotoxicity. Cerebral ischemia is followed by an inflammatory reaction that plays a role in the evolution of the tissue damage. We studied whether COX-2 is induced after cerebral ischemia and if so, whether such expression contributes to ischemic brain damage. The middle cerebral artery was occluded in rats, and the ischemic area was sampled for analysis 3-96 hr later. COX-2 mRNA was determined by the competitive reverse-transcription PCR. COX-2 mRNA was upregulated in the ischemic hemisphere, but not contralaterally, beginning 6 hr after ischemia. The upregulation reached a maximum at 12 hr, at which time a fivefold induction of the message occurred. Twenty-four hours after ischemia, the concentration of prostaglandin E2 was elevated in the injured brain by 292 +/- 57% (n = 6). COX-2 immunoreactivity was observed in neurons at the medial edge of the ischemic area. Administration of the COX-2 inhibitor NS-398 attenuated the elevation in prostaglandin E2 in the postischemic brain and reduced the volume of the infarct by 29 +/- 6% (p < 0.05). Thus, cerebral ischemia leads to upregulation of COX-2 message, protein, and reaction products in the injured hemisphere. The data implicate COX-2 in the mechanisms of delayed neuronal death at the infarct border and provide the rationale for neuroprotective strategies employing COX-2 inhibitors.

Animals↗
PubMed1997

Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response.

Interferon-gamma (IFN-gamma) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-gamma from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-gamma is unknown. Here we show that the same cytokines that induce human NK cell IFN-gamma production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha (TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming growth factor-beta, which inhibits cytokine-induced NK cell production of IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3-CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma production, followed by NK cell apoptosis and a decline in IFN-gamma production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.

Apoptosis↗
PubMed1997

Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): a gene causing neuronal migration defects in human brain.

While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.

Cerebral Cortex↗
PubMed1997

Lack of effect of thyroid hormone on late fetal rat brain development.

Studies were undertaken to test whether alterations in fetal brain thyroid hormone levels during the final week of gestation can prematurely induce gene expression in brain or affect cerebellar morphogenesis. Pregnant dams were treated either by administration of 0.025% methimazole (MMI) in the drinking water from day 14 post conception (PC14) or administration of 2.5 mg T4/100 g BW on PC15. On PC21, treatment with MMI resulted in a 53% fall in fetal brain T3 levels and excess T4 resulted in a 2- to 3-fold increase to concentrations observed in adult brains. Neither excess nor reduced levels of T3 caused alterations in the expression of the myelin basic protein, Pcp-2 or calmodulin kinase IV genes. Cerebella of control brains showed early evidence of foliation and the presence of a several cell thick Purkinje cell layer and an external granule layer. No treatment induced effects were evident. Thus, at the late fetal stage in the rat, the developing brain appears to be unresponsive to thyroid hormone despite the presence of thyroid hormone receptors. We infer the presence of as yet unidentified factors that suppress precocious response to thyroid hormone or the absence of cofactors essential for such a response.

Animals↗
PubMed1996

Cell division and the nervous system: regulating the cycle from neural differentiation to death.

It has long been recognized that the balance between cellular proliferation and cell death during embryogenesis is a key factor in formation of the CNS. The recent definition of molecular mechanisms that drive the cell-division cycle and programmed cell death provides an opportunity to investigate the molecular interactions that co-ordinate cell-cycle regulation with CNS-pattern formation, neural differentiation and histogenesis. It is proposed that not only is the cell-division cycle regulated by developmentally controlled molecular signals to halt or proceed, but gene products that drive the cycle can also influence the course of neural differentiation and apoptosis.

Animals↗