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Biomedical subjects

C L White

Publications and source records attributed to C L White.

At least 19 recordsLinked to original sources
PubMed2006

Probing colloidal forces between a Si3N4 AFM tip and single nanoparticles of silica and alumina.

The atomic force microscope (AFM) has been used to measure surface forces between silicon nitride AFM tips and individual nanoparticles deposited on substrates in 10(-4) and 10(-2) M KCl solutions. Silica nanoparticles (10 nm diameter) were deposited on an alumina substrate and alumina particles (5 to 80 nm diameter) were deposited on a mica substrate using aqueous suspensions. Ionic concentrations and pH were used to manage attractive substrate-particle electrostatic forces. The AFM tip was located on deposited nanoparticles using an operator controlled offset to achieve stepwise tip movements. Nanoparticles were found to have a negligible effect on long-range tip-substrate interactions, however, the forces between the tip and nanoparticle were detectable at small separations. Exponentially increasing short-range repulsive forces, attributed to the hydration forces, were observed for silica nanoparticles. The effective range of hydration forces was found to be 2-3 nm with the decay length of 0.8-1.3 nm. These parameters are in a good agreement with the results reported for macroscopic surfaces of silica obtained using the surface force apparatus suggesting that hydration forces for the silica nanoparticles are similar to those for flat silica surfaces. Hydration forces were not observed for either alumina substrates or alumina nanoparticles in both 10(-4) M KCl solution at pH 6.5 and 10(-2) M KCl at pH 10.2. Instead, strong attractive forces between the silicon nitride tip and the alumina (nanoparticles and substrate) were observed.

Journal Article↗
PubMed2005

Effect of a selective OX1R antagonist on food intake and body weight in two strains of rats that differ in susceptibility to dietary-induced obesity.

An orexin-1 receptor antagonist decreases food intake whereas orexin-A selectively induces hyperphagia to a high-fat diet. In the present study, we evaluated the effect of an orexin antagonist in two strains of rats that differ in their sensitivity to becoming obese while eating a high-fat diet. Male Osborne-Mendel (OM) and S5B/Pl (S5B) rats were treated acutely with an orexin-1 receptor antagonist (SB-334867), after adaptation to either a high-fat (56% fat energy) diet or a low-fat (10% fat energy) diet that were equicaloric for protein (24% energy). Ad libitum fed rats were injected intraperitoneally with SB-334867 at doses of 3, 10 or 30 mg/kg, or vehicle at the beginning of the dark cycle, and food intake and body weight were measured. Hypothalamic prepro-orexin and orexin-1 receptor mRNA expression were analyzed in OM and S5B rats fed at a high-fat or low-fat diet for two weeks. SB-334867 significantly decreased food intake in both strains of rats eating the high-fat diet but only in the OM rats eating the low fat diet. The effect was greatest at 12 and 24 h. Body weight was also reduced in OM rats 1d after injection of SB-334867 but not in the S5B rats. Prepro-orexin and orexin-1 receptor expression levels did not differ between strains or diets. These experiments demonstrate that an orexin antagonist (SB-334867) reduces food intake and has a greater effect in a rat strain that is susceptible to dietary-induced obesity, than in a resistant strain.

Animals↗
PubMed2004

Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia.

Hippocampal sclerosis dementia (HSD) is a disease of unknown etiology and pathogenesis. To determine whether HSD cases could be reclassified as variants of frontotemporal dementia (FTD), a heterogeneous group of disorders, 18 brain autopsy cases previously diagnosed as HSD were re-evaluated. In 11 cases, ubiquitinated neuronal inclusions, similar to those of motor neuron disease inclusion dementia (MNDID), were found. Brain levels of soluble and insoluble tau were normal. Most patients with pathologic findings of HSD may actually have the MNDID variant of FTD.

Adult↗
PubMed2003

Frontotemporal and motor neurone degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS.

We present the case of a patient who had clinical frontal lobe dementia without apparent motor neurone disease (MND), with pathologic findings not typical of any single currently classified frontotemporal degeneration (FTD). At autopsy, the brain had frontal and temporal atrophy with neuronal loss, gliosis, and superficial spongiosis, typical of all FTDs. There were at least three different morphologic types of intracytoplasmic neuronal inclusions in a variety of brain and brainstem regions, including the hippocampal dentate gyrus and pyramidal neurones, the neocortex (in particular, the motor cortex), basal ganglia, thalamus, subthalamic nucleus, basis pontis, and inferior olivary nuclei. Inclusions had the morphologies of Pick-like bodies, pleomorphic inclusions, and hyaline conglomerate (HC)-like inclusions. None of these were positive with tau immunostains. Pick-like bodies in the dentate gyrus were labelled with ubiquitin. The pleomorphic inclusions in the neocortex and dentate gyrus and the HC-like inclusions in the motor and parietal cortex were strongly positive with immunostains for neurofilament. We discuss the differential diagnosis and compare this case with those disorders to which it is most similar. In particular, we compare the unique neurofilament-positive inclusions to the inclusions of FTD-MND, to Pick bodies, and to the basophilic and HC inclusions that are occasionally seen in amytrophic lateral sclerosis (ALS). Although FTD-MND may be found in ALS, the findings in this case may have additional implications for a link between FTD and ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis.

In the past, 'Alzheimer disease' (AD) referred to pathologic AD with clinical onset of dementia in the presenium, while 'senile dementia of the Alzheimer type' (SDAT) referred to senile onset AD. Because AD appears clinically homogeneous regardless of age of onset, the two subtypes in more recent years have not been distinguished. Pathologic differences have been noted, but synapse loss has not previously been compared between the two groups. Hypothesizing that synapse loss would be greater in presenile onset than senile onset AD, we compared synapse loss, as well as Alzheimer pathology in presenile and senile onset AD, using an ELISA method to quantify synaptophysin. Synaptophysin was significantly lower in presenile than senile AD in right frontal and bilateral parietal lobes. Neuritic plaque counts were significantly higher in presenile than senile AD in bilateral frontal and parietal lobes. Semi-quantitative evaluation of neurofibrillary tangles revealed significantly more tangles in bilateral frontal and parietal lobes in presenile than senile AD. Brain weight was significantly lower in presenile than senile AD. The differences in synapse loss and Alzheimer-type pathology in presenile and senile onset AD support the hypothesis that 'cognitive reserve' protects the human brain from neurodegenerative disease.

Aged↗
PubMed2001

Structure of the yeast nucleosome core particle reveals fundamental changes in internucleosome interactions.

Chromatin is composed of nucleosomes, the universally repeating protein-DNA complex in eukaryotic cells. The crystal structure of the nucleosome core particle from Saccharomyces cerevisiae reveals that the structure and function of this fundamental complex is conserved between single-cell organisms and metazoans. Our results show that yeast nucleosomes are likely to be subtly destabilized as compared with nucleosomes from higher eukaryotes, consistent with the idea that much of the yeast genome remains constitutively open during much of its life cycle. Importantly, minor sequence variations lead to dramatic changes in the way in which nucleosomes pack against each other within the crystal lattice. This has important implications for our understanding of the formation of higher order chromatin structure and its modulation by post-translational modifications. Finally, the yeast nucleosome core particle provides a structural context by which to interpret genetic data obtained from yeast. Coordinates have been deposited with the Protein Data Bank under accession number 1ID3.

Amino Acid Sequence↗
PubMed2001

Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias.

BACKGROUND: Synapse loss has been found to be the major correlate of cognitive decline in Alzheimer disease (AD), and prefrontal synapse loss has been found in patients with frontotemporal dementia (FTD). OBJECTIVE: To see if our hypothesis that within each FTD case, regional synapse loss would correlate with lateralizing neuropsychologic and neurobehavioral deficits would be correct. DESIGN: We analyzed synaptophysin as a marker for synapse loss in snap-frozen brain samples, using an enzyme-linked immunosorbent assay technique. Quantitative results were obtained by comparing patient data with a standard curve made by analyzing serial dilutions of a recombinant synaptophysin protein fragment. A board-certified neuropsychologist and a board-certified neurologist, both unaware of the synaptophysin results, determined areas of primary neuropsychologic and neurobehavioral dysfunction. Relationships between areas of primary dysfunction and synapse loss were analyzed using the binomial test. PATIENTS: Six cases of FTD, 28 cases of AD, and 16 nondemented control subjects. RESULTS: Five of 6 FTD cases had regional synaptophysins correlating with lateralizing frontal or temporal deficits. Three of 6 correlated in 2 or more regions. Although our results were higher than that expected based on a pure-chance mechanism (50% vs 34%), statistical significance was not attained. CONCLUSIONS: We found a trend for an association between synapse loss and lateralizing neuropsychologic and neurobehavioral deficits in FTD. Studies in larger numbers of FTD cases are planned with the goal of attaining statistically significant conclusions.

Aged↗
PubMed2001

Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia.

We present a novel tauopathy in a patient with a 10-yr history of progressive frontal lobe dementia and a negative family history. Autopsy revealed mild atrophy of frontal and parietal lobes and severe atrophy of the temporal lobes. There were occasional filamentous tau-positive inclusions, but more interesting were numerous distinctive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex. Affected subcortical regions included substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus, in a distribution similar to progressive supranuclear palsy (PSP), but without significant accompanying neuronal loss or gliosis. Predominantly straight filaments were detected by electron microscopy (EM), while other inclusions were similar to fingerprint bodies. No twisted ribbons were detected. Immuno-EM studies revealed that only the filamentous inclusions were composed of tau. Immunoblotting of sarkosyl-insoluble tau revealed 2 major bands of 64 and 68 kDa. Blotting analysis after dephosphorylation revealed predominantly 4-repeat tau. Sequence analysis of tau revealed that there were no mutations in either exons 9-13 or the adjacent intronic sequences. The unique cortical tau pathology in this case of sporadic multiple system tauopathy with dementia adds a new pathologic profile to the spectrum of tauopathies.

Aged↗
PubMed2001

Cortical synapse loss in progressive supranuclear palsy.

Cortical synapse loss, the probable substrate of cognitive impairment in Alzheimer disease (AD), has not previously been evaluated in progressive supranuclear palsy (PSP). Hypothesizing that synapse loss would be greater in demented than non-demented PSP patients, we examined synaptophysin concentrations in 8 cases of PSP (5 demented and 3 nondemented cases). We found a decrease in mean synaptophysin concentration in these 8 cases in frontal, temporal, and parietal lobes, and in cerebellum, compared to the means in corresponding lobes of 16 controls. The decreases were similar to those in 28 cases of AD, but not as great. We determined synaptophysin concentration from motor cortex in only 4 of our PSP cases, 2 demented and 2 non-demented. The average concentrations in these 4 cases were lower than in AD motor cortex; both were lower than controls. When demented and non-demented PSP cases were compared, neocortical synaptophysin concentrations in non-demented PSP cases were lower than in demented cases. There appears to be a link between AD and PSP, in that synapse loss is found in both. However, the basis and significance of the prominent neocortical synapse loss in PSP, especially in non-demented subjects, remain to be explored.

Aged↗
PubMed2001

Continuity of care for short-stay neurosurgery patients: a quality improvement initiative.

Decreases in the length of hospital stay for patients undergoing spinal surgery prompted this evaluation of the post-discharge needs of patients and the strategies that patients and their families employ to meet these needs. The nature and extent of post-discharge problems experienced by newly discharged patients was required as a baseline for the evaluation and improvement of discharge planning. Forty patients were interviewed following discharge, 20 patients within the first week of discharge, and 20 different patients between three and four weeks after discharge. Most patients reported that they had been well-informed about pain management and the majority of patients reported that pain was well-controlled. There was a subset of patients, however, who continued to report high levels of pain, even at one month after discharge. Less than one in three patients stated that they had received information about wound care and the information received was not consistent among health professionals. Given the limited time to prepare patients for discharge, this project highlights the need for written materials and for systematic follow-up after discharge.

Adult↗
PubMed2000

A viral member of the ERV1/ALR protein family participates in a cytoplasmic pathway of disulfide bond formation.

Proteins of the ERV1/ALR family are encoded by all eukaryotes and cytoplasmic DNA viruses for which substantial sequence information is available. Nevertheless, the roles of these proteins are imprecisely known. Multiple alignments of ERV1/ALR proteins indicated an invariant C-X-X-C motif, but no similarity to the thioredoxin fold was revealed by secondary structure predictions. We chose a virus model to investigate the role of these proteins as thiol oxidoreductases. When cells were infected with a mutant vaccinia virus in which the E10R gene encoding an ERV1/ALR family protein was repressed, the disulfide bonds of three other viral proteins-namely, the L1R and F9L proteins and the G4L glutaredoxin-were completely reduced. The same outcome occurred when Cys-43 or Cys-46, the putative redox cysteines of the E10R protein, was mutated to serine. These two cysteines were disulfide bonded during a normal virus infection but not if the synthesis of other viral late proteins was inhibited or the E10R protein was expressed by itself in uninfected cells, suggesting a requirement for an upstream viral thiol oxidoreductase. Remarkably, the cysteine-containing domains of the E10R and L1R viral membrane proteins and the glutaredoxin are in the cytoplasm, in which assembly of vaccinia virions occurs, rather than in the oxidizing environment of the endoplasmic reticulum. These data indicated a viral pathway of disulfide bond formation in which the E10R protein has a central role. By extension, the ERV1/ALR family may represent a ubiquitous class of cellular thiol oxidoreductases that interact with glutaredoxins or thioredoxins.

Amino Acid Sequence↗
PubMed2000

Effect of a serotonin 1-A agonist on food intake of Osborne-Mendel and S5B/P1 rats.

The effect on food intake of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a serotonin 1-A agonist, has been evaluated in two strains of rats that differ in their sensitivity to becoming obese while eating a high-fat diet. Male Osborne-Mendel (OM) and S5B/Pl rats were tested at 8 weeks and 16 weeks of age. Both strains were adapted to choose between two diets-a 56% fat energy diet, and a 10% fat energy diet-which were equicaloric for protein (24% energy). Daily food intake was measured for 2 weeks before injection of 8-OH-DPAT. The younger OM rats had no diet preference, while the older OM rats preferred the high-fat diet. The younger S5B/P1 rats preferred the low-fat diet, while the older S5B/P1 rats had no diet preference. Satiated rats were injected subcutaneously with 8-OH-DPAT at doses of 0.3, 1.0, or 3.0 mg/kg or vehicle. During the light phase, subcutaneous 8-OH-DPAT increased the intake of the high-fat diet in the 16-week-old OM rats but not the 8-week-old OM rats. 8-OH-DPAT had no effect on the low-fat diet intake in either age OM rat. The 8-week-old S5B/P1 rats showed a significant decrease in intake of the high-fat diet in response to 8-OH-DPAT, whereas an increase in the intake of the low-fat diet was observed in the older S5B/P1 rats. These data are consistent with the hypothesis that increased fat preference in Osborne-Mendel rats may result in part from altered serotonin activity of 5-HT(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Proliferative activity in craniopharyngiomas: clinicopathological correlations in adults and children.

BACKGROUND: Craniopharyngiomas are slow-growing, locally invasive intracranial tumors that can generate considerable morbidity, and recurrences are often difficult to manage. Because reliable morphologic criteria for accurately predicting the clinical outcome of these tumors are lacking, we evaluated the growth potential of craniopharyngiomas by measuring their proliferative activity based on MIB-1 immunostaining for the Ki-67 antigen, which is expressed during all phases of the cell cycle except G(0.) METHODS: Paraffin sections from 37 cases of craniopharyngiomas were immunostained with the monoclonal antibody MIB-1, and a labeling index was derived in each case from an the with the highest labeling. RESULTS: MIB-1 immunoreactivity was mainly confined to the peripheral palisaded epithelium of craniopharyngiomas. In adult craniopharyngiomas, MIB-1 labeling indices (MIB-LI) varied from 0.1% to 34.6% (mean 8.9%; SD 9. 8), and in pediatric tumors the indices ranged from 1.8% to 15.0% (mean 6.3%; SD 3.7). MIB-LI was not found to be an independent predictor of recurrence, although in all the pediatric cases that recurred, MIB-LI in the second specimen was greater. CONCLUSIONS: The actively proliferating compartment in craniopharyngiomas seems to be the peripheral palisaded epithelium. Low MIB-LI observed in the majority of tumors is in concordance with the slow growth and low-grade invasiveness associated with craniopharyngiomas. However, unlike other intracranial neoplasms, where Ki-67 labeling indices have been useful in predicting tumor behavior, a clear relationship could not be demonstrated between MIB-1 immunoreactivity, morphological features and clinical outcomes in adults or children with craniopharyngiomas.

Adolescent↗
PubMed2000

Intragastric beta-casomorphin(1-7) attenuates the suppression of fat intake by enterostatin.

The current experiments were designed to compare the feeding response to enterostatin and beta-casomorphin(1-7) injected intragastrically. Sprague-Dawley rats with a gastric cannula were allowed to chose from high-fat diet (HF) or low-fat diet (LF) in separate jars. Enterostatin injected intragastrically into overnight fasted rats caused a U-shaped dose-dependent reduction in the intake of the HF diet for the first two hours after infusion but had no effect on the LF intake. beta-Casomorphin(1-7) stimulated the intake of the HF diet but had no effect on the LF diet. Finally, beta-casomorphin(1-7) blocked the inhibitory effect of enterostatin on HF intake in fasted rats.

Animals↗
PubMed2000

Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations.

Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We have previously reported that ABalphaC, a major form of protein phosphatase 2A (PP2A) in brain, binds tightly to tau protein in vitro and is a major tau phosphatase in vivo. Using in vitro assays, we show here that the FTDP-17 mutations G272V, DeltaK280, P301L, P301S, S305N, V337M, G389R, and R406W inhibit by approximately 20-95% the binding of recombinant three-repeat and four-repeat tau isoforms to the ABalphaC holoenzyme and the AC core enzyme of PP2A. Reduction in binding was maximal for tau proteins with the G272V, DeltaK280, and V337M mutations. We also show that tau protein can be specifically coimmunoprecipitated with endogenous PP2A from both rat brain and transfected cell extracts. It is significant that, by using similar coimmunoprecipitation assays, we show that all FTDP-17 mutations tested, including the N279K mutation, alter the ability of tau to associate with cellular PP2A. Taken together, these results indicate that FTDP-17 mutations induce a significant decrease in the binding affinity of tau for PP2A in vivo. We propose that altered protein-protein interactions between PP2A and tau may contribute to FTDP-17 pathogenesis.

3T3 Cells↗
PubMed2000

Alpha-synuclein expression in central nervous system tumors showing neuronal or mixed neuronal/glial differentiation.

Alpha-synuclein (alpha-synuclein) is a member of a family of cytoplasmic proteins found predominantly and abundantly in the brain, and concentrated in pre-synaptic nerve terminals, near vesicles. We hypothesized that an antibody to alpha-synuclein could be a useful marker of neuronal differentiation in central nervous system (CNS) tumors. Twenty tumors known to have neuronal or mixed neuronal/glial differentiation ( 11 gangliogliomas, 2 anaplastic gangliogliomas, 5 gangliocytomas, and 2 ganglioneuroblastomas), 5 central neurocytomas, and 1 dysembryoplastic neuroepithelial tumor (DNET) were immunostained with a mouse monoclonal antibody raised against human alpha-synuclein. Intense cytoplasmic staining, in some instances extending into the perikarya, was seen in 6 of 11 gangliogliomas, 2 of 2 anaplastic gangliogliomas, and 2 of 2 ganglioneuroblastomas. Alpha-synuclein-positive cells were usually large in size, resembled dysmorphic neurons, and were variably immunoreactive for anti-neurofilament and/or anti-synaptophysin antibodies. In contrast, central neurocytomas, gangliocytomas, and the DNET were negative for cytoplasmic alpha-synuclein expression. Our findings indicate that alpha-synuclein is expressed within the neuronal component of mixed tumors of the CNS displaying more than 1 histophenotype, and/or showing different degrees of anaplasia. Based on currently available data, we conclude that cytoplasmic alpha-synuclein expression is a marker of maturing neurons in these tumors.

Cell Differentiation↗