Biomedical subjects

C L White

Publications and source records attributed to C L White.

At least 37 records · Page 2Linked to original sources

PubMed2000

A glutaredoxin, encoded by the G4L gene of vaccinia virus, is essential for virion morphogenesis.

Vaccinia virus encodes two glutaredoxins, O2L and G4L, both of which exhibit thioltransferase and dehydroascorbate reductase activities in vitro. Although O2L was previously found to be dispensable for virus replication, we now show that G4L is necessary for virion morphogenesis. RNase protection and Western blotting assays indicated that G4L was expressed at late times after infection and was incorporated into mature virus particles. Attempts to isolate a mutant virus with a deleted G4L gene were unsuccessful, suggesting that the protein was required for virus replication. This interpretation was confirmed by the construction and characterization of a conditional lethal recombinant virus with an inducible copy of the G4L gene replacing the original one. Expression of G4L was proportional to the concentration of inducer, and the amount of glutaredoxin could be varied from barely detectable to greater than normal amounts of protein. Immunogold labeling revealed that the induced G4L protein was associated with immature and mature virions and adjacent cytoplasmic depots. In the absence of inducer, the production of infectious virus was severely inhibited, though viral late protein synthesis appeared unaffected except for decreased maturation-dependent proteolytic processing of certain core components. Electron microscopy of cells infected under nonpermissive conditions revealed an accumulation of crescent membranes on the periphery of electron-dense globular masses but few mature particles. We concluded that the two glutaredoxin homologs encoded by vaccinia virus have different functions and that G4L has a role in virion morphogenesis, perhaps by acting as a redox protein.

Gene Expression Regulation, Viral↗

PubMed2000

Recurrent (nonfamilial) hemangioblastomas involving spinal nerve roots: case report.

OBJECTIVE AND IMPORTANCE: Spinal nerve root hemangioblastomas are rare and are reported mainly in patients with von Hippel-Lindau (VHL) syndrome. The pathogenesis of so-called nonfamilial lesions is virtually unknown. We discuss, mainly from a molecular perspective, a unique patient with sporadic, recurrent hemangioblastomas restricted to spinal nerve roots. CLINICAL PRESENTATION: A 53-year-old man who had had a surgically corrected lumbosacral meningomyelocele presented on at least three occasions during a 17-year period with multifocal capillary hemangioblastomas involving spinal nerve roots. On each occasion, tumors appeared on a different nerve root, with the majority located in the midcervical segments. The patient had no clinical features or family history of VHL syndrome. TECHNIQUE: To obtain a clearer understanding of the pathogenesis of this unusual case and its relationship to VHL syndrome, molecular analysis of the VHL gene was performed by use of complete sequence analysis and loss of heterozygosity studies on deoxyribonucleic acid derived from the patient's blood leukocytes and three separately resected hemangioblastomas. CONCLUSION: Germ-line molecular analysis performed on all three exons in the VHL gene coding region did not indicate that any mutations were present. Loss of heterozygosity analysis of deoxyribonucleic acid from the three hemangioblastoma resections showed normal heterozygosity in the 3p25-26 region. Complete VHL gene sequence analysis did not demonstrate a somatic mutation in the coding region of the VHL gene in any of the three tumors, thereby supporting the loss of heterozygosity data that a molecular event directly involving the VHL gene may not be the causative factor in their tumorigenesis.

Base Sequence↗

PubMed1999

Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies.

Hyperphosphorylated forms of the neuronal microtubule (MT)-associated protein tau are major components of Alzheimer's disease paired helical filaments. Previously, we reported that ABalphaC, the dominant brain isoform of protein phosphatase 2A (PP2A), is localized on MTs, binds directly to tau, and is a major tau phosphatase in cells. We now describe direct interactions among tau, PP2A, and MTs at the submolecular level. Using tau deletion mutants, we found that ABalphaC binds a domain on tau that is indistinguishable from its MT-binding domain. ABalphaC binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and ABalphaC and tau bind to different domains on MTs. Specific PP2A isoforms bind to MTs with distinct affinities in vitro, and these interactions differentially inhibit the ability of PP2A to dephosphorylate various substrates, including tau and tubulin. Finally, tubulin assembly decreases PP2A activity in vitro, suggesting that PP2A activity can be modulated by MT dynamics in vivo. Taken together, these findings indicate how structural interactions among ABalphaC, tau, and MTs might control the phosphorylation state of tau. Disruption of these normal interactions could contribute significantly to development of tauopathies such as Alzheimer's disease.

Alzheimer Disease↗

PubMed1999

Radiation change versus recurrent astrocytoma: diagnostic utility of the proliferation index?

Differentiation of recurrent glioma from radiation damage can be a challenge to neurologists, neurosurgeons, neuroradiologists, and even neuropathologists. We hypothesized that by evaluating sections of recurrent lesions with proliferation markers we might objectively differentiate between radiation damage gliosis and recurrent astrocytoma. We compared the labeling indices of radiation damage and recurrent neoplasm immunohistochemically, using an antibody to MIB-1, a monoclonal antibody to the Ki-67 proliferation marker. Five of the six recurrent neoplasms were gliomas; four these were astrocytic tumors. In most cases, the MIB-1 LI of radiation damage was < 1% and the LI of recurrent neoplasm was > 3%, with pertinent exceptions. We discuss our findings and their possible interpretation.

Adult↗

PubMed1999

Prognostic value of proliferation index and expression of the RNA component of human telomerase (hTR) in papillary meningiomas.

Papillary meningioma is a rare subtype of meningioma that often behaves aggressively. In order to characterize factors that may influence this behavior, we chose to compare MIB-1 labeling index (LI) and telomerase RNA localization (hTR) in papillary meningiomas, meningiomas, and atypical meningiomas. LI is now often used to supplement histologic grade in the evaluation of these lesions. More recent studies indicate that increased expression of hTR is detected in many neoplastic cells, and may play an essential role in cell immortalization. The study group consisted of five papillary meningiomas (and a recurrence in one case), 11 conventional meningiomas, and eight atypical meningiomas. Conventional meningiomas showed either negative or 1 + hTR. Atypical meningiomas showed 1 + hTR. Papillary meningiomas showed the highest hTR (five of six, including recurrence, 2-3+ and one 1+). Generally, the LI was very low for conventional meningiomas (< 2%). The LI of atypical meningiomas ranged from 3-19%, mean 12%, and from 5.5-17.5%, mean 11.75% for papillary meningiomas. LI differentiated between meningiomas, and papillary or atypical meningiomas. hTR further delineated papillary (moderate to high) from atypical meningiomas (low). The combined variable of LI and hTR expression could be a useful independent prognostic indicator in patients with papillary meningioma.

Adolescent↗

PubMed1999

Changing pain management practice and impacting on patient outcomes.

Concerns about acute pain management prompted the development of a pain management program. The program, with assessment, intervention, and evaluation components, was introduced by the clinical nurse specialist (CNS) in collaboration with a multidisciplinary team. The assessment phase included a descriptive study of postoperative pain and a baseline audit of nursing documentation related to pain assessment and management. Interventions, including a focused educational program and new routes for postoperative analgesia, were then introduced. Evaluations at 3 months and 2 years indicated improvements in documentation of pain assessments and improved management of pain. Additionally, at each follow-up evaluation, patients reported decreased postoperative pain. The assessment and management of pain is an important domain of nursing practice. The CNS is in a unique position to influence nursing practice and to impact on patient outcomes in this area of pain management.

Acute Disease↗

PubMed1999

Progressive supranuclear palsy with dementia: cortical pathology.

Patients with progressive supranuclear palsy (PSP) often develop dementia, and cortical pathology has been documented in PSP. However, there are no reports correlating dementia in PSP with cortical pathology. We hypothesized that cases of PSP presenting with cognitive impairment would have more severe cortical tau pathology than those without. We compared 7 cases of PSP presenting with cognitive deficits (group 1) with 4 cases of PSP that did not (group 2). The subcortical tau pathology was almost identical in both groups. The cortical tau pathology was strikingly different in group 1, in which it was on average moderate, compared with group 2, in which it was minimal. The accumulation of cortical neuronoglial tau in PSP cases with dementia suggests that neurofibrillary pathology is central to the cause of dementia in PSP.

Aged↗

PubMed1998

The genomic sequence of defective interfering Semliki Forest virus (SFV) determines its ability to be replicated in mouse brain and to protect against a lethal SFV infection in vivo.

We have recently cloned and sequenced two genomes of defective interfering (DI) Semliki Forest virus (SFV), DI-6 (2146 nt), and DI-19 (1244 nt). These are similar in that both contain two large central deletions (encompassing the 5' part of the nsP1 gene and the 3' part of the nsP2 gene and all of the structural genes), and all the sequence of the latter is represented in the genome of SFV DI-6. RNA was transcribed from both and transfected into SFV-infected BHK-21 cells. RT-PCR analysis of tissue culture fluid harvested 18 h after transfection suggested that SFV DI virions had been rescued from the cloned genomes. Unlike the genomes of noncloned DI SFV, these genomes bred true for at least 7 serial passages. Cloned DI-6 and DI-19 viruses interfered to a similar extent with the multiplication of SFV in cultured cells, but only DI-19 protected mice from a lethal intranasal dose of SFV. Further investigation by RT-PCR analysis showed that DI-19 but not DI-6 genomes were replicated in mouse brain after direct intracerebral injection of DI virus together with an excess of infectious helper SFV. Thus the replication and hence antiviral activity of two closely related DI SFV genomes appears to be exquisitely sequence specific and cell specific. These findings mark a significant step on the way to using DI genomes as antivirals and also may explain why so few animal-protecting DI viruses have been identified.

Alphavirus Infections↗

PubMed1998

Dementia associated with cortical dysplasia.

Detailed neuropathologic examination was performed on a 47.5-year-old man with an unusual adult-onset dementing illness. His initial symptoms were those of depression, memory loss, and personality change. He developed progressive cognitive decline with prominent psychiatric symptoms. Seizures began approximately 11 months prior to death and he died 5.5 years after onset of symptoms. Pathologic examination of the brain at autopsy revealed organizing necrosis of the hippocampi, felt to be the result of his seizures. More significant was the finding of widespread microscopic nodular cortical dysplasia. The dysplastic nodules were composed of clusters of abnormal cells with enlarged, pleomorphic, vesicular nuclei, many of which contained nucleoli and had ballooned cytoplasm. There were no mitoses. Cortical dysplasia is most commonly associated with childhood-onset seizures. It has not, to our knowledge, been reported as a cause of dementia. Whether or not the dysplasia was the basis of the patient's dementia is difficult to say with certainty, but we discuss possible pathoetiologic mechanisms of dementia due to cortical dysplasia.

Brain↗

PubMed1998

Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease.

We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.

Aged↗

PubMed1998

Neocortical synapse density and Braak stage in the Lewy body variant of Alzheimer disease: a comparison with classic Alzheimer disease and normal aging.

Substantial numbers of cortical and subcortical Lewy bodies are seen in approximately one quarter of patients whose brains show sufficient histopathologic changes for a neuropathologic diagnosis of definite Alzheimer disease (AD). This subset of cases has been named the Lewy body variant of AD (LBV). Despite comparable dementia and the presence of neocortical senile plaques in LBV patients, the overall burden of neuropathologic changes, in particular neurofibrillary tangles (NFT), is less than in classic AD. While NFT frequency correlates with dementia severity in classic AD, the cognitive impairment in patients with LBV cannot be completely explained by such changes. Since several studies have suggested a role for synapse loss in relation to dementia severity in classic AD, we decided to investigate the role of synapse loss as a candidate for the cognitive impairment of LBV. The Braak staging method is based upon the distribution and severity of neurofibrillary changes, and one therefore would expect LBV cases to be assigned to lower Braak stages. In the present study we assigned a Braak stage to 14 LBV cases, 31 classic AD cases, and a group of 10 non-demented aged controls. We compared the severity of synapse loss as determined by ELISA immunoassay for synaptophysin and Braak stage among the three diagnostic groups. When compared to normal controls, synaptophysin concentrations were statistically significantly lower in both demented groups. There was comparable synapse loss in LBV and AD despite significantly lower Braak stages in the LBV cases. These results suggest a major role for loss of synapses as the substrate of cognitive impairment in LBV.

Aged↗

PubMed1998

An evaluation of the effectiveness of patient-controlled analgesia after spinal surgery.

The purpose of this study was to evaluate the effectiveness of patient-controlled analgesia (PCA) in patients undergoing spinal surgery. Sixty patients undergoing spinal surgery were randomly assigned to receive PCA or the standard approach to postoperative analgesia (intramuscular injections on an "as needed" basis). Information on pain intensity at rest and with activity, total daily amount of analgesia, presence of adverse effects, length of time to ambulation and length of hospital stay was collected on all patients. Patients in the PCA group reported lower levels of pain, both at rest and with activity, and were ambulating earlier than patients receiving standard analgesia. There were no differences between the groups in total daily analgesic intake, presence of adverse effects and length of hospital stay. These data suggest that PCA is a safe, effective approach to managing pain after spinal surgery.

Adolescent↗

PubMed1998

Molybdenum poisoning in feedlot cattle.

OBJECTIVE: To describe a case of acute, fatal molybdenum poisoning in feedlot cattle. DESCRIPTION OF THE HERD: In total, 831 Hereford, Hereford x Angus, and Hereford x Simmental steers, aged 8 to 10 months, with an average body weight of 310 kg were fed a diet, to which sodium molybdate at a rate of 1.9% of the total ration had been accidently added. INVESTIGATION: The steers lost appetite within 3 days and deaths commenced within 6 days of the diet being first offered. The error was rectified when deaths started to occur, but steers continued to die for up to 7 months afterwards. Of the 831 steers on the feedlot, 90 died and a further 5 remained in poor condition. The cause of death was periacinar to massive hepatic necrosis and acute renal tubular necrosis. Blood and tissue samples were taken from surviving steers for 76 days, by which time plasma molybdenum concentrations had returned to normal concentrations. CONCLUSION: Sodium molybdate when fed at a rate of 1.9% of the diet results in acute renal tubular necrosis and periacinar to massive hepatic necrosis.

Animal Feed↗

PubMed1998

Deletion analysis of a defective interfering Semliki Forest virus RNA genome defines a region in the nsP2 sequence that is required for efficient packaging of the genome into virus particles.

The 1,244-nucleotide genome of Semliki Forest virus (SFV) defective interfering (DI) RNA 19 (DI-19) is coterminal with the infectious genome and contains two major deletions. One deletion removes the end of the nsP1 gene and the beginning of the nsP2 gene, and the other removes the end of the nsP2 gene, the nsP3 and nsP4 genes, and all of the structural protein genes (M. Thomson and N. J. Dimmock, Virology 199:354-365, 1994). Like all DI SFV RNAs, DI-19 contains three regions that are conserved. Region a comprises the 5' terminus continuous with part of the nsP1 gene, region b comprises a central part of the nsP2 gene, and region c comprises the 3' terminus and the associated untranslated region. A deletion analysis of the 265-nucleotide b region (nucleotides 679 to 943, inclusive) was undertaken to determine its role in genome replication and packaging into DI virus particles. Deleted plasmids were constructed and transcribed, and the resulting DI RNAs were transfected into SFV-infected BHK cells. Putative progeny DI virus particles that had been released into the tissue culture fluid were then serially passaged in new monolayers together with added high-multiplicity SFV, and cells and tissue culture fluids were tested for the presence of DI RNA by reverse transcription-PCR. DI RNA that had all of the b region deleted was replicated well in BHK-21 cells, as shown by the presence of large amounts of negative-sense DI RNA and an increase in the amount of positive-sense RNA in the cytoplasm, but was packaged very inefficiently, as indicated by very low amounts of DI RNA in the tissue culture fluid. The genome of a deletion mutant that retained the 3' 224 nucleotides of region b was packaged successfully, but one that retained only the 5' 41 nucleotides was not detected in the tissue culture fluid. These and other data suggest that nucleotides 720 to 777 of region b are of particular importance in the packaging process. This finding agrees with data obtained with Ross River virus and contrasts with the well-studied Sindbis alphavirus major packaging signal that is located within the nsP1 gene.

Animals↗

PubMed1998

Hormone receptor immunoreactivity in hemangioblastomas and clear cell renal cell carcinomas.

Several primary central nervous system (CNS) neoplasms, including meningiomas, spinal cord ependymomas, and acoustic nerve schwannomas, express hormone receptors. In the present study, we investigated hormone receptor immunoreactivity in hemangioblastomas on the basis of recent reports of these tumors complicating pregnancy. We also evaluated cases of renal cell carcinoma (RCC) metastatic to the CNS, hypothesizing that estrogen receptor (ER), progesterone receptor (PR), or androgen receptor (AR) immunoreactivity might help to distinguish between these histologically similar neoplasms. Immunohistochemical analysis for ERs, PRs, and ARs was performed on paraffin-embedded sections of 27 hemangioblastomas, 12 primary clear cell RCCs, and 5 clear cell RCCs metastatic to the CNS. All of the hemangioblastomas demonstrated PR immunoreactivity, whereas 10 of 12 primary RCCs were negative. In addition, four of the five metastatic RCC were PR positive. All but one primary RCC were ER negative. AR immunoreactivity was seen in three hemangioblastomas, five primary RCCs, and one metastatic RCC. Although hormone receptor immunoreactivity was unable to distinguish between hemangioblastoma and clear cell RCC metastatic to the CNS, the identification of PR immunoreactivity in hemangioblastomas is a new finding that might have adjuvant therapy treatment implications.

Adolescent↗

PubMed1998

Correlation of bcl-2, p53, and MIB-1 expression with ependymoma grade and subtype.

In this study, we report our results on the proliferative activity of ependymomas as determined by MIB-1 (also known as Ki-67) immunohistochemical analysis, and we compare our results with those obtained by immunolabeling with monoclonal antibodies to p53 and bcl-2 proteins to assess whether expression correlated with ependymoma subtype or tumor grade. The study included 4 myxopapillary ependymomas (Grade I of the World Health Organization [WHO] scale), 10 subependymomas (WHO Grade I), 17 ependymomas (WHO Grade II), 2 papillary ependymomas (WHO grade II), and 4 anaplastic ependymomas (WHO Grade III). The MIB-1 proliferation index was significantly higher in tumors diagnosed as anaplastic ependymoma (P < .001), with a moderate level of correlation (Kendall's tau-b = 0.557, asymptotic standard error = 108). In addition, one ependymoma (WHO Grade II) not considered overtly anaplastic by routine histologic criteria showed a high MIB-1 labeling index, suggesting that the MIB-1 proliferation index might be a more objective indicator of tumor grade. The remaining WHO Grade I and Grade II ependymomas showed low proliferative activity. bcl-2 oncoprotein expression was identified in all of the four myxopapillary and in both papillary ependymomas. An additional observation was the correlation of p53 expression with increasing WHO grade. These data suggest that high MIB-1 and p53 immunolabeling might be objective indicators of high grade in ependymomas that do not otherwise meet routine histologic criteria for high-grade ependymoma. Subsequent clinicopathologic analyses will be important in assessing whether these markers are useful as independent predictors of survival.

Adolescent↗

PubMed1997

Community-based urine screening for Chlamydia trachomatis with a ligase chain reaction assay.

BACKGROUND: Urine tests for Chlamydia trachomatis permit expansion of screening beyond traditional clinic environments. Prevention of infection in teenagers is a high priority. OBJECTIVE: To define the prevalence of C. trachomatis among teenagers by using the ligase chain reaction assay on urine specimens and to evaluate leukocyte esterase testing of urine specimens as an indicator of infection. DESIGN: Cross-sectional study. SETTING: An adolescent clinic, a juvenile detention facility, seven school-based clinics, and three community-based youth organizations in Seattle, Washington. PARTICIPANTS: 10,118 sexually active teenagers and young adults. MEASUREMENTS: Chlamydia trachomatis infection detected in urine specimens by ligase chain reaction assay and leukocyturia detected by leukocyte esterase testing. RESULTS: The prevalence of chlamydial infection among female participants was 8.6% and declined with increasing age; among male participants, it was 5.4% and increased with increasing age. In female participants, independent predictors of infection were being 17 years of age or younger (odds ratio [OR], 1.49), having had two or more sex partners in the previous 2 months (OR, 1.61), and having genitourinary symptoms (OR, 1.46). In male participants, independent predictors were being of nonwhite race or ethnicity (OR, 2.00 to 3.08), having had two or more sex partners in the previous 2 months (OR, 1.57), and having used a condom during the most recent sexual encounter (OR, 0.67). For identifying infection in male participants, the sensitivity of leukocyte esterase testing was 58.9%, the specificity was 94.9%, the positive predictive value was 38.4%, and the negative predictive value was 97.7%. CONCLUSIONS: Chlamydial infection is common in teenagers and young adults in community settings. The urine ligase chain reaction assay will permit widespread screening for C. trachomatis, but leukocyte esterase testing had low sensitivity for selecting persons for screening with this assay. Indicators of chlamydial infection differed substantially in male and female participants.

Adolescent↗

PubMed1997

Predictors of the development of chronic pain.

The purpose of this secondary analysis was to explore the role of potential risk factors in predicting the development of chronic pain. Linear discriminant function analysis was used to derive a prediction equation that maximized the differences between a group of hospitalized patients experiencing acute pain who developed chronic pain (n = 171) and a group whose pain resolved (n = 200). Patients who developed chronic pain reported a higher pain intensity, higher anxiety and distress, less certainty that their pain would resolve, longer hospitalization, less independence in ambulation, a diagnosis of trauma, and less need for surgery. Recognition of these factors could lead to early identification of those individuals with acute pain who are at risk for developing chronic pain.

Activities of Daily Living↗