Biomedical subjects
J Fergusson
Publications and source records attributed to J Fergusson.
Neurofibrillary tangles in progressive supranuclear palsy brains exhibit immunoreactivity to frameshift mutant ubiquitin-B protein.
In Alzheimer's disease (AD) neurofibrillary tangles (NFT) are strongly tau and ubiquitin immunopositive, and contain an aberrant form of ubiquitin derived from the ubiquitin-B gene denoted as UBB+1. We explored whether the tau-related NFT seen in another neurodegenerative disease, progressive supranuclear palsy (PSP), also showed an accumulation of UBB+1. Three cases of PSP were examined immunohistochemically for tau protein, ubiquitin-protein conjugates and UBB+1 using single and double labelling. We conclude that UBB+1 is associated with compact globose tangles rather than dispersed accumulations of tau in PSP, showing that its presence is not unique to AD. We propose that aggregation of ubiquitinated proteins into compact inclusions in PSP might be due to inhibition of the degradation of multiubiquitinated proteins by ubiquitin chains containing proximal UBB+1 rather than normal ubiquitin.
Ubiquitin and its role in neurodegeneration.
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Prion protein immunocytochemistry--UK five centre consensus report.
Creutzfeldt-Jakob disease (CJD) and other prion diseases are associated with the deposition of insoluble prion protein (PrPCJD) in the central nervous system (CNS). Antibodies raised against PrPCJD also react with its precursor protein, a soluble form of PrP (PrPC), which is widely distributed in the normal CNS. This cross-reactivity has in the past raised doubts as to the specificity and diagnostic reliability of PrP immunolocalization, especially in familial cases which are atypical clinically and which lack characteristic pathology findings. Following an MRC-funded workshop which focused on this problem, a multicentre prospective study was set up to identify a reliable protocol for PrPCJD immunocytochemistry. Five UK centres took part in this study and demonstrated consistent staining of plaques, vacuolar deposits in severe spongiform change, and perineuronal deposits using a variety of antibodies and enhancement procedures. A protocol using formic acid, guanidine thiocyanate, and hydrated autoclaving pre-treatment in conjunction with a monoclonal PrPCJD antibody produced the clearest immunochemical results and is presented as the consensus UK recommendation for PrPCJD immunocytochemical procedures.
Pathological lesions of Alzheimer's disease and dementia with Lewy bodies brains exhibit immunoreactivity to an ATPase that is a regulatory subunit of the 26S proteasome.
MS73 is one of a family of ATPases that act as regulatory subunits of the 26S proteasome. Localisation of this ATPase in histological sections of hippocampus from Alzheimer's disease (AD) and in cingulate gyrus sections of dementia with Lewy bodies (DLB) brains was examined immunohistochemically. In all cases of AD (n = 10) neurofibrillary tangles (NFT), plaque neurites and neuropil threads were immunoreactive for MS73. In seven out of the nine cases of DLB, distinctive MS73-positive structures were detected within cortical Lewy bodies. The association of MS73 with these neuronal abnormalities provides further evidence that proteolytic processing involving the 26S proteasome occurs in lesions of AD and DLB.
Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins.
The localisation of 14-3-3 proteins compared to that of tau and ubiquitin-protein conjugates in sections of hippocampus from Alzheimer's disease (AD) brains was examined by immunohistochemistry. In all cases (n = 10), anti-14-3-3 stained a proportion of neurofibrillary tangles (NFT). In general, NFT stained by anti-14-3-3 were smaller than those stained by anti-tau or anti-ubiquitin-protein conjugates and were more confined to the neuronal cell body. Occasionally, cortical Lewy bodies in cases of Lewy body dementia were also found to be 14-3-3-positive. Since 14-3-3 proteins are central to MAP kinase signalling, the results support the proposal that this pathway is in part responsible for the hyperphosphorylation of tau, which leads to the formation of the paired helical filaments seen in AD brains.
Concentrations and sources of cadmium, copper, lead and zinc in house dust in Christchurch, New Zealand.
The amounts (microgram m-2) and concentrations (microgram g-1) of cadmium, copper, lead and zinc have been measured in house dust in Christchurch, New Zealand. For 120 houses surveyed the geometric mean concentrations of the four metals are 4.24 micrograms g-1, 165 micrograms g-1, 573 micrograms g-1 and 10,400 micrograms g-1, respectively. In addition eleven variables, such as house age, carpet wear and traffic density, were recorded for each property and the results analysed with respect to their effects on the amounts and concentrations of the four elements. The amounts of all the metals were highly correlated with the overall dustiness of the houses, which was found to be predominantly determined by the degree of carpet wear. No one dominant source of cadmium was identified, although several minor sources including carpet wear, galvanized iron roofs and red/orange/yellow coloured carpets were implicated. Petrol lead and lead-based paints were identified as significant sources of lead in house dust. Rubber carpet underlays or backings were identified as a significant source of zinc, with some contribution from galvanized iron roofs. Road traffic and probably the existence of a fire place appear to contribute to the copper levels.
Immunoreactivity to ubiquitin-protein conjugates is present early in the disease process in the brains of scrapie-infected mice.
Brains from mice infected with either the 87V or the ME7 strains of mouse-passaged sheep scrapie were taken at stages during the disease process and immunostained to show the localization of ubiquitin-protein conjugates. In both models, conjugates were seen as fine, dot-like structures; as coarser, granular lesions within or adjacent to neurones; and in areas surrounding plaques. The dot-like structures were visible at 28 days post-ME7 infection and at 55 days in 87V-infected mice. In both models, the extent of immunoreactive changes increased as the disease progressed and terminal infection was as described earlier by us (Lowe et al., J. Pathol 1990; 162: 61-66). The patterns of development of these features were distinctive in two ways: progression from region to region was observable and the density of the pathological lesions grew exponentially as the clinical symptoms appeared. The earliest pathological dot-like structures corresponded temporally with the earliest detection of PrPSC by Western blotting, and immunogold electron microscopic investigation of the dot-like lesions indicated that they were the multi-vesicular, lysosome-related, dense bodies that we have described previously in terminal disease (Laszlo et al., J Pathol 1992; 166: 333-341). Until now, ubiquitin-protein conjugates were seen mainly in inclusion bodies associated with the terminal stages of a range of human degenerative diseases. This study establishes that ubiquitin-protein conjugates accumulate in lysosome-related bodies very early and appear to be intimately related to the pathological processes in the animal disorders that we have studied.
A role for lysosomes in scrapie pathogenesis.
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Properties of verapamil-hypersensitive multidrug-resistant Chinese hamster ovary cells.
Two vincristine-resistant Chinese hamster ovary cell lines have been shown previously to be hypersensitive to the calcium channel blocker, verapamil. They are now shown to be hypersensitive to the membrane-active agent quinidine sulfate and to the calcium channel blockers diltiazem and nicardipine. Hypersensitivity to quinidine sulfate implies that calcium channels are not the primary target for these drug effects on these cell lines and is consistent with our previous observation that their calcium accumulation is normal in the presence and absence of verapamil. The two cell lines have elevated levels of membrane P-glycoprotein and of two cytosolic proteins, Mr 27,000 and pI 6.0 and 6.4. Revertants have normal levels of these cytosolic proteins, suggesting that these proteins may play a role in conferring resistance. [3H]Verapamil accumulation by the two cell lines is lower than in controls. One of the cell lines has been hybridized to normal cells and the vincristine resistance and verapamil sensitivity of three hybrid clones has been determined. Vincristine resistance is semidominant but verapamil hypersensitivity is completely recessive.
Time required to assess children for the late effects of treatment. A report from the Childrens Cancer Study Group.
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Verapamil hypersensitivity of vincristine resistant Chinese hamster ovary cell lines.
Vincristine resistant CHO cell lines, obtained by prolonged selection in semi-inhibitory drug concentrations show considerable hypersensitivity to verapamil. Their D10 values are around 0.2 micrograms/ml compared to 23 micrograms/ml for unselected controls. Reversion of vincristine resistance during growth in vincristine free medium is correlated with reversal of verapamil sensitivity indicating that the two aspects of the cells' phenotype have a common underlying cause. The rate of uptake of calcium in the absence and presence of verapamil is similar in the vincristine resistant cells and the controls. The correlation of verapamil sensitivity with vincristine resistance is not a universal feature of CHO cell lines resistant to antimicrotubular drugs, since it was found that other resistant cell lines which have been selected by short term exposure to high drug concentrations were not verapamil hypersensitive.
The effects of the treatment for cancer in childhood on growth and development.
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Home visits for the child with cancer.
Home visits for children with cancer has yet to become widely understood and accepted. However, health care planners and policy makers must be convinced of the numerous advantages and benefits of home visits for the child, his family, and the community.
Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation.
Intellectual and other neuropsychological dysfunctions have been observed in survivors of childhood acute lymphocytic leukaemia (ALL). The possible relationship of therapy to these dysfunctions was investigated in a prospective study of children with newly diagnosed ALL seen at the Children's Hospital of Philadelphia. They were evaluated with standardised intelligence tests during the first month of treatment and periodically thereafter. There were two therapy schedules--one using standard drugs for induction and maintenance, the other a more intensive schedule. Central-nervous-system prophylaxis (2400 rad cranial radiation and six doses of intrathecal methotrexate) was given to all. Significant reductions were found in overall IQ score for the majority of children, younger patients being most affected. More extensive testing of surviving children, with and without decline in IQ, all of whom were normal on the first test, revealed patterns of functional deficits and residual strengths that could not be characterised with IQ testing alone. These deficits, which could affect learning and academic performance, were not seen in six children studied years after receiving similar chemotherapy that included intrathecal and oral methotrexate but not cranial irradiation.
Parents' perceptions of randomization in pediatric clinical trials. Children Cancer Group.
OBJECTIVES: The purpose of this study was to investigate parents' knowledge and perceptions about randomization in clinical trials for children with cancer, and to determine whether parents' decisions were influenced by demographic factors, randomization circumstances, the clinical characteristics of the child with cancer, or a combination. MATERIALS AND METHODS: This study collected information from 192 parents of patients with various forms of childhood cancer who either accepted or refused randomization. A comparative case-control design was used. The Clinical Investigation Randomization Scale was administered to all participants. This scale included 32 questionnaire items (QIs) pertaining to randomization as well as a mixture of open-ended questions to obtain information about demographic and other factors. RESULTS: A predictor model was developed that accurately predicted acceptance or refusal of randomization 87% of the time. Demographic information was found to have less influence than expected on parents' decisions regarding randomization. Knowledge deficits were found among both groups of parents, those who accepted and those who refused randomization. CONCLUSIONS: What most distinguished parents who refused from those who accepted randomization was not their knowledge and information about randomized clinical trials. By far, the majority of QIs that accurately predicted acceptors and refusers involved parents' beliefs, values, and perceptions. Further research is needed to determine interventions that may enable the healthcare team to provide information and decisional support most effectively to improve the informed consent process.
A living legend in pediatric oncology nursing: Jean Fergusson. Interview by Kathy Ruccione.
Jean Fergusson is a true pioneer in pediatric oncology nursing. Her many professional accomplishments include working alongside Dr. Sidney Farber and others in the first pediatric Tumor Therapy Clinic in the United States, establishing a model pediatric nurse practitioner program that graduated an influential cadre of pediatric oncology nurse practitioners, publishing landmark papers about late sequelae of childhood cancer treatment, and serving as a role model and mentor to countless nurses over the past 50 years. Jean has brought all she is to her life as a nurse-she is gentle, funny, wise, easily moved, curious, generous, and, most of all, she truly loves children. An eyewitness to the dramatic changes in pediatric oncology over the decades, she herself is a survivor, having overcome dyslexia and other daunting life challenges. In this interview, Jean responds to questions about what shaped her interest in nursing and how she chose pediatric oncology, her impressions and recollections of the early days in pediatric oncology nursing, and her vision for the future of our specialty.
Describing the value of specialized distance education in pediatric oncology nursing.
Working as specialists in a changing environment, advanced practice nurses in pediatric oncology (APN-POs) benefit from specific pediatric oncology education. The graduates of a pediatric nurse practitioner program in pediatric oncology completed a survey about their educational experience and its impact on their current practice. This practitioner program included a subspecialty education in pediatric oncology and an early form of distance learning. The respondents' answers parallel a number of emerging themes in APN-PO practice and education. Employing distance learning methods in providing subspecialty education holds important implications for future APN-PO education and practice and for the health care of communities throughout the country.