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M V Johnston

Publications and source records attributed to M V Johnston.

At least 19 recordsLinked to original sources
PubMed2006

Temporal shift in methyl-CpG binding protein 2 expression in a mouse model of Rett syndrome.

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutations in methyl-CpG binding protein 2. Females with identical mutations in the methyl-CpG binding protein 2 gene can display varying severity of symptoms, suggesting that other factors such as X-chromosome inactivation affect phenotypic expression in Rett syndrome. Although X-chromosome inactivation is random and balanced in the blood and brain of the majority of girls with classic Rett syndrome, skewing in the ratio of expression of the mutant methyl-CpG binding protein 2-X to the wildtype-X affects the severity of symptoms. In this study, the pattern of immunostaining for methyl-CpG binding protein 2 was compared with that of neuronal nuclei specific protein, a pan-neuronal marker, to assess X-chromosome inactivation in a Rett syndrome mouse model. The number of cortical neurons and cortical volume were assessed by unbiased stereological measurements in younger adult (7-9 week old) wildtype (wildtype/methyl-CpG binding protein 2+/+), female heterozygous (heterozygous/methyl-CpG binding protein 2+/-), and null (methyl-CpG binding protein 2-/y) male mice and in older adult (24-95 week old) wildtype and heterozygous mice. The results showed that the number of neuronal nuclei specific protein-positive cells and cortical volume did not differ by genotype or age. However, younger adult heterozygous mice had significantly fewer methyl-CpG binding protein 2 cells and the pattern of methyl-CpG binding protein 2 staining was less distinct than in younger adult wildtype mice. However, in older adult heterozygous mice, the number and pattern of methyl-CpG binding protein 2-expressing neurons were similar to the wildtype. The ratio of methyl-CpG binding protein 2 to neuronal nuclei specific protein-stained neurons, a potential measure of X-chromosome inactivation, was close to 50% in the younger adult heterozygous mice, but nearly 70% in the older adult heterozygous mice. These results suggest that X-chromosome inactivation status changes with age. Such a change may underlie the more stable neurological function in older Rett syndrome patients.

Age Factors↗
PubMed2004

Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain.

The gene encoding methyl-CpG binding protein 2 (MeCP2) is mutated in the large majority of girls that have Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. To better understand the developmental role of MeCP2, we studied the ontogeny of MeCP2 expression in rat brain using MeCP2 immunostaining and Western blots. MeCP2 positive neurons were present throughout the brain at all ages examined, although expression varied by region and age. At early postnatal ages, regions having neurons that were generated early and more mature had the strongest MeCP2 expression. Late developing structures including cortex, hippocampus and cerebellum exhibited the most significant changes in MeCP2 expression. Of these regions, the cerebellum showed the most striking cell-specific changes in MeCP2 expression. For example, the early-generated Purkinje cells became MeCP2 positive by P6, while the late-generated granule cells did not express MeCP2 until the fourth postnatal week. The timing of MeCP2 expression in the granule cell layer is coincident with the onset of granule cell synapse formation. Although more subtle, the degree of MeCP2 expression in cortex and hippocampus was most closely correlated with synaptogenesis in both regions. Our finding that MeCP2 expression is correlated with synaptogenesis is consistent with the hypothesis that Rett Syndrome is caused by defects in the formation or maintenance of synapses.

Aging↗
PubMed2002

Diffusion tensor imaging of periventricular leukomalacia shows affected sensory cortex white matter pathways.

The authors used diffusion-tensor imaging to examine central white matter pathways in two children with spastic quadriplegic cerebral palsy. Corticospinal tracts projecting from cortex to brainstem resembled controls. In contrast, posterior regions of the corpus callosum, internal capsule, and corona radiata were markedly reduced, primarily in white matter fibers connected to sensory cortex. These findings suggest that the motor impairment in periventricular leukomalacia may, in part, reflect disruption of sensory connections outside classic pyramidal motor pathways.

Brain Mapping↗
PubMed2002

Determinants of health-related quality of life in multiple sderosis: the role of illness intrusiveness.

The relationship between the cognitive and physical aspects of multiple sclerosis (MS) and health-related quality of life (HRQL) was examined with particular focus on illness intrusiveness as a mediator of this relationship. Disease severity, cognitive functioning HRQL, depression, and illness intrusiveness were assessed in 90 patients with MS. Disease severity (Expanded Disability Status Scale [EDSS]) predicted physical aspects of HRQL (SF-36 Physical Component Summary [PCS], fatigue, and bladder control). Information-processing speed (Paced Auditory Serial Addition Test [PASAT]) predicted mental and emotional aspects of HRQL (SF-36 Mental Component Summary [MCS]). However, both the EDSS and the PASAT predicted depression. Illness intrusiveness was significantly correlated with all indicators of HRQL Illness intrusiveness also mediated the manner in which disease severity predicted: physical health, fatigue, and depression. Results underscore the need to assess MS and its impact more broadly rather than relying on traditional mobility-centered assessments. While in most cases physical indices of disease predict physical quality of life and cognitive assessments predict mental and emotional quality of life, the individuals perception of MS is also a major factor contributing to quality of life. MS dearly affects multiple aspects of life and activity, as illustrated by the broad and powerful network of relationships between illness intrusiveness and all aspects of HRQL Perceptions of illness intrusiveness appear to be a central and essential measure of the impact of MS on HRQL.

Activities of Daily Living↗
PubMed2001

Enhancing the detection of sulfate particles for laser ablation aerosol mass spectrometry.

A major limitation to the application of laser ablation aerosol mass spectrometry for the detection of particles less than 200 nm in diameter is a low ablation efficiency for sulfate particles. (Ablation efficiency is the probability that an ablated particle produces a detectable ion signal.) A method is described here to enhance the ablation efficiency of sulfate particles by coating them with a UV-absorbing compound. The method can be applied in-line with the aerosol mass spectrometer in a manner that does not significantly alter the aerosol size distribution. It is shown that a 12-nm coating of 1-naphthyl acetate increases the ablation efficiency of 136-nm ammonium sulfate particles by at least a factor of 20, while similar coatings on oleic acid and ammonium nitrate particles do not significantly alter the ablation efficiency. The results suggest that "undetected" particles, presumably sulfate, in ambient aerosol can be assessed.

Aerosols↗
PubMed2001

MK801 decreases glutamate release and oxidative metabolism during hypoglycemic coma in piglets.

Hypoglycemic coma increases extracellular excitatory amino acids, which mediate hypoglycemic neuronal degeneration. Cerebral oxygen consumption increases during hypoglycemic coma in piglets. We tested the hypothesis that the NMDA-receptor antagonist dizocilpine (MK801) attenuates the increase in cerebral oxygen consumption during hypoglycemia. We measured EEG, cerebral blood flow (CBF), cerebral oxygen consumption (CMRO(2)) and cortical microdialysate levels of glutamate, aspartate and glycine in pentobarbital-anesthetized piglets during 60 min of insulin-induced hypoglycemic coma. NMDA-receptor distribution was measured by autoradiography. MK801 (0.75 mg/kg i.v.) was given within 5 min after onset of isoelectric EEG. Saline- and MK801-treated normoglycemic control animals were also studied. Brain temperature was maintained at 38.5+/-0.5 degrees C. MK801 prevented the 5--10-fold increase in glutamate and aspartate occurring in saline-treated hypoglycemic animals, and attenuated the increase in CMRO(2). Increases in CBF of 200--400% during hypoglycemic coma were not affected by MK801. MK801 did not alter CBF, CMRO(2) or microdialysate amino acid levels in normoglycemic control animals. Parietal cortex corresponding to microdialysis sites was highly enriched in NMDA receptors, and the density and distribution overall of NMDA receptor binding sites were comparable to that reported in other species. We conclude that NMDA receptor activation plays a central role in hypoglycemia-induced glutamate release, and contributes to increased cerebral oxygen consumption. Neuroprotective effects of MK801 during hypoglycemia in piglets may involve inhibitory effects on glutamate release and oxidative metabolism.

Animals↗
PubMed2001

Application of the ART-2a algorithm to laser ablation aerosol mass spectrometry of particle standards.

Single-particle mass spectrometers are now commonly used to analyze atmospheric particles and generate tens of thousands of spectra from typical measurement campaigns. The ART-2a spectrum algorithm has been used to classify these spectra. In this work, we generate a range of particles that are models of those that are common in the atmosphere. A single-particle mass spectrometer is used to analyze these known particles, and the spectra are classified using ART-2a. The optimum vigilance parameter is approximately 0.5 while the optimum learning rate is approximately 0.05. The classifications elucidate limitations in generation of test particles, their analysis by single-particle techniques, and their classification by ART-2a.

Journal Article↗
PubMed2001

Cognitive impairment in Coffin-Lowry syndrome correlates with reduced RSK2 activation.

BACKGROUND: Gene expression and protein synthesis, mediated by the transcription factor CREB (cAMP response element binding protein), play an important role in learning and memory in several species, including Drosophila, snails, and mice. Patients with the X-linked disorder Coffin-Lowry syndrome (CLS) have cognitive disabilities, distinctive features, and bony abnormalities as well as mutations in RSK2 (ribosomal S6 kinase-2), a protein kinase that activates CREB by phosphorylation at serine 133. In fibroblasts from a single patient with CLS, epidermal growth factor (EGF)-stimulated CREB phosphorylation was reduced. METHODS: The authors assessed endogenous CREB phosphorylation in a CLS fibroblast line by Western blotting and found impaired CREB phosphorylation in response to stimulation by EGF and the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate (PMA). They studied RSK2 immunoprecipitated from fibroblasts and lymphoblasts from seven patients with CLS and found a wide range in RSK2's capacity to phosphorylate the synthetic CREB-like peptide, CREBtide, after cell stimulation by PMA. RESULTS: In lymphoblasts from patients with CLS, PMA-stimulated CREBtide phosphorylation was increased 1.2- to 2.7-fold over baseline, compared to an average fourfold increase in controls. Regression analysis suggested a linear relationship between the magnitude of in vitro RSK2-mediated CREBtide phosphorylation and CLS patient intelligence level (p < 0.05). CONCLUSIONS: This report suggests a correlation between human cognitive performance and cellular capacity to activate RSK2. It provides additional evidence that the CREB kinase, RSK2, and CREB phosphorylation may play important roles in human learning and memory, as they do in lower animals.

Abnormalities, Multiple↗
PubMed2001

Excitotoxicity in neonatal hypoxia.

Hypoxic-ischemic encephalopathy (HIE) in neonates is a disorder of excessive neuronal excitation that includes seizures, abnormal EEG activity, and delayed failure of oxidative metabolism with elevated levels of lactic acid in the brain. Evidence from experimental models and clinical investigation indicates that HIE is triggered by a profound disruption in the function of glutamate synapses so that re-uptake of glutamate from the synapse is impaired and post-synaptic membranes containing glutamate receptors are depolarized. Severe hypoxemia preferentially depolarizes neuronal membranes, while ischemia probably has greater impact on the activity of glial glutamate re-uptake. Together, severe hypoxia and ischemia trigger a delayed cascade of events that may result in cell death by necrosis and/or apoptosis. Apoptosis is far more prominent in the neonate than in the adult and activation of cysteine proteases such as caspase-3 is a very important pathway in excitotoxic neonatal injury. Understanding the complex molecular networks triggered by an excitotoxic insult in the neonate provides insight into patterns of selective neuronal vulnerability and potential therapeutic strategies.

Apoptosis↗
PubMed2001

Delayed increase in neuronal nitric oxide synthase immunoreactivity in thalamus and other brain regions after hypoxic-ischemic injury in neonatal rats.

We examined the response of neuronal nitric oxide synthase (nNOS)-containing CNS neurons in rats exposed to a unilateral hypoxic-ischemic insult at 7 days of age. Animals were sacrificed at several time points after the injury, up to and including 7 days (Postnatal Day 14). Brain regions ipsilateral to the injury (including cerebral cortex, caudate-putamen, and thalamus) exhibited delayed, focal increases in nNOS immunoreactivity. The increase in nNOS immunoreactive fiber staining was prominent in areas adjacent to severe neuronal damage, especially in the cortex and the thalamus, regions that are also heavily and focally injured in term human neonates with hypoxic-ischemic encephalopathy. In cerebral cortex, these increases occurred despite modest declines in nNOS catalytic activity and protein levels. Proliferation of surviving nNOS immunoreactive fibers highlights regions of selective vulnerability to hypoxic-ischemic insult in the neonatal brain and may also contribute to plasticity of neuronal circuitry during recovery.

Animals↗
PubMed2001

Developmental disorders of activity dependent neuronal plasticity.

A number of neurodevelopmental disorders are caused by defects in activity dependent neuronal plasticity, the process by which neuronal activity shapes developing neuronal circuits. These disorders are caused by genetic mutations or other factors that disrupt intracellular signaling pathways that link the cell surface with the nuclear machinery for gene expression. The signaling pathways disrupted by these disorders are involved in learning, memory and behavior as well as in the synaptic proliferation and pruning that occurs during normal development. Examples of neurodevelopmental disorders that target plasticity include X-linked disorders such as Rett, Fragile-X and Coffin-Lowry Syndromes as well as acquired disorders such as cretinism. Several other X-linked mental retardation syndromes as well as autosomal disorders including neurofibromatosis type 1 and tuberous sclerosis also involve signaling pathways involved in neuronal plasticity. Disruption of neuronal plasticity is a mechanism that may underlie a diverse group of neurodevelopmental disorders.

Brain Diseases↗
PubMed2001

Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection.

BACKGROUND: Ischemic preconditioning is an endogenous mechanism whereby brief periods of ischemia render neurons resistant to subsequent lethal insults. This protection appears to alter cellular apoptosis and can be induced by potassium channel openers acting on the inner membrane of the mitochondria (mitoK(ATP)). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoK(ATP) opener diazoxide was used in a canine model of brain injury induced by hypothermic circulatory arrest (HCA). METHODS: Seventeen dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. After 2 hours of HCA, animals were rewarmed and weaned from CPB. Six dogs received intravenous diazoxide (2.5 mg/kg bolus 15 minutes prior to CPB, then 0.5 mg/min until circulatory arrest, then restarted for the first hour of rewarming). Six animals received vehicle only. Five received diazoxide and the mitoK(ATP) blocker 5-hydroxydecanoate (5-HD). Using a modified Pittsburgh Canine Neurological Scoring System (0 = normal, 500 = brain death), animals were evaluated every 24 hours for 3 days. The brains were removed and histologic sections of four regions characteristically injured in this model were scored (0 = no injury, 4 = infarction) by a neuropathologist in a blinded fashion. RESULTS: Clinical scoring showed marked improvement in the diazoxide group at 48 hours (101 +/- 10.5 vs 165 +/- 14.8, p < 0.01) and 72 hours (54 +/- 9.3 vs 137 +/- 12.1, p < 0.01). This neuroprotection was attenuated when 5-HD was concomitantly administered. Three of four brain regions typically injured in this model (cortex, hippocampus, and entorhinal cortex) had significant neuron preservation in the diazoxide group. Likewise, combined region scores were significantly improved in the treatment group (1.18 +/- 0.2 vs 2.46 +/- 0.2, p < 0.01). CONCLUSIONS: Pretreatment with diazoxide resulted in significant improvement in both clinical neurologic scores and histopathology in our model of HCA. This suggests that pharmacologic preconditioning with the mitoK(ATP) channel opener diazoxide may offer effective neuroprotection during HCA.

Animals↗
PubMed2001

Prolonged suppression of brain nitric oxide synthase activity by 7-nitroindazole protects against cerebral hypoxic-ischemic injury in neonatal rat.

Nitric oxide mediates glutamate-induced excitotoxicity associated with cerebral hypoxia-ischemia through production in the brain by several isoforms of nitric oxide synthase (NOS). We examined the influence of the selective neuronal NOS inhibitor, 7-nitroindazole (7-NI), on brain NOS activity and its neuroprotective effects against cerebral hypoxic-ischemic injury in the postnatal day (PND) 7 rat. In the first set of experiments, 7-NI (50 mg/kg) administered intraperitoneally (i.p.) transiently inhibited NOS activity to 40% below the vehicle control level at 1 h after injection (P<0.001, analysis of variance (ANOVA)). In contrast, 7-NI (100 mg/kg, i.p.) inhibited NOS activity to 56% below the control level at 1 h with prolonged suppression of NOS activity at 3, 6, 9 and 12 h after injection. Two-factor ANOVA revealed an overall effect on NOS activity of 7-NI treatment (P<0.001) and time after injection (P<0.001). In the second set of experiments, 7-NI (50, 100 mg/kg) or an equal volume of vehicle was administered after unilateral carotid artery ligation, but 30 min before hypoxia in PND 7 rats. 7-NI (100 mg/kg) significantly protected against cerebral hypoxic-ischemic injury (100 mg/kg of 7-NI, 1.7+/-1.0% damage; control, 8.7+/-1.6%,P<0.05). 7-NI administered 15 min after cerebral hypoxia-ischemia was not neuroprotective. The data suggest that the protective effect of 7-NI is dose dependent, and is related to the duration of suppressed NOS activity.

Aging↗
PubMed2001

Neurobiology of Rett syndrome: a genetic disorder of synapse development.

Rett syndrome is a developmental disorder that restricts brain growth beginning in the first year of life and evidence from neuropathology and neuroimaging indicates that axonodendritic connections are especially vulnerable. In a study of amino acid neurotransmitter receptors using receptor autoradiography in tissue slices of frontal cortex and the basal ganglia, we found a biphasic age-related pattern with relatively high receptor densities in young RS girls and lower densities at later time. Using microarray analysis of gene expression in frontal cortex, we found that some of the most prominent alterations occurred in gene products related to synapses, including the NMDA receptor NR1 subunit, the cytoskeletal protein MAP-2 and synaptic vesicle proteins. Using a new antibody that recognizes MeCP2, the transcription factor mutated in RS, we established that most neurons in the rodent brain express this transcription factor. We hypothesize that a major effect of mutations in the MeCP2 protein is to cause age-related disruption of synaptic proliferation and pruning in the first decade of life.

Adolescent↗
PubMed2001

Neuroimaging studies in Rett syndrome.

Neuroimaging is a key instrument for determining structural and in vivo functional status of the brain, non-invasively. Multiple approaches can now determine aspects of anatomic and neurochemical changes in brain, and have been utilized effectively in Rett Syndrome patients to understand the biological basis of this neurodevelopmental disorder. Studies performed at our institute include volumetric analyses of MRI, magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), cerebral blood flow measurements with MRI, and positron emission tomography scans (PET). These studies have provided considerable insight into mechanisms underlying the clinical features of this disease. Volumetric analyses suggest that decreased brain volume in RS results from global reductions in both gray and white matter of the brain. A selective vulnerability of the frontal lobes is evidenced by the preferential reduction of blood flow, increased choline and reduced n-acetyl aspartate (NAA) by MRS, and increased glucose uptake in these same regions as shown by ((18)F)-fluorodeoxyglucose (FDG) PET scans. We hypothesize that the increased glucose uptake relates to increased glutamate cycling in synapses. The resulting neuroexcitotoxic injury to the developing brain contributes to the seizures, behavioral disturbance and respiratory irregularities commonly seen in phases 1 and 2 of this disorder.

Adolescent↗
PubMed2001

Age-dependent effects of trihexyphenidyl in extrapyramidal cerebral palsy.

Trihexyphenidyl (Artane) is a centrally active muscarinic antagonist commonly used to treat patients with generalized dystonia. In a retrospective survey of 22 consecutive children with extrapyramidal cerebral palsy, we evaluated trihexyphenidyl on upper extremity and lower extremity function, expressive language, and drooling. Functional changes were assessed using a parental questionnaire (rating scale 1-5: from 1 = little or no change to 5 = tremendous change, with scores in either a positive or negative direction). Improvements of +4 or +5 were reported in eight children for upper extremity function, in eight children for verbal expressive language, in five for drooling, and in none for lower extremity function. Using bivariate linear regression modeling to investigate variables associated with treatment effects, there was a significant inverse relationship between age at initiation of medication and therapeutic response. Furthermore, beneficial responses were specific to upper-extremity function and expressive language. These results suggest that younger children are more likely to respond to trihexyphenidyl and that primary functional benefits include improved fine motor abilities and expressive language. A prospective masked study with a standardized clinical instrument is needed to confirm these findings.

Age Factors↗
PubMed2001

Mental practice combined with physical practice for upper-limb motor deficit in subacute stroke.

BACKGROUND AND PURPOSE: This case report describes a patient with upper-limb hemiparesis (ULH) who received a program combining physical therapy for the affected side with mental practice. CASE DESCRIPTION: The patient was a 56-year-old man with stable motor deficits, including ULH, on his dominant side resulting from a right parietal infarct that occurred 5 months previously. He received physical therapy for an hour 3 times a week for 6 weeks. In addition, 2 times a week the patient listened to an audiotape instructing him to imagine himself functionally using the affected limb. The patient also listened to the audiotape at home 2 times a week. Pretreatment and posttreatment measures were the upper-extremity scale of the Fugl-Meyer Assessment of Sensorimotor Impairment (Fugl-Meyer Scale), the Action Research Arm Test (ARA), and the Stroke Rehabilitation Assessment of Movement (STREAM). OUTCOMES: The patient exhibited reduction in impairment (Fugl-Meyer Scale) and improvement in arm function, as measured by the ARA and STREAM. DISCUSSION: Mental practice may complement physical therapy to improve motor function after stroke.

Activities of Daily Living↗