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Biomedical subjects

J Scott

Publications and source records attributed to J Scott.

At least 109 records · Page 6Linked to original sources
PubMed2000

Analysis of human immunodeficiency virus type 1 gp160 sequences from a patient with HIV dementia: evidence for monocyte trafficking into brain.

Towards understanding the pathogenesis of HIV dementia, we molecularly cloned and sequenced human immundeficiency virus type 1 (HIV-1) gp160 genes from uncultured post-mortem tissues collected from a patient with HIV dementia. Sequences from bone marrow, lymph node, lung, and four regions of brain - the deep white matter, head of caudate, choroid plexus and meninges - were compared. Also included were gp160 sequences recovered from blood monocytes collected 5 months prior to death. Phylogenetic analyses showed that the sequences from deep white matter were more closely related to those from bone marrow, than to those from the other tissues, and moreover, were most closely related to sequences from the blood monocytes. These findings suggest trafficking of bone marrow-derived monocytes into the deep white matter during this late stage of infection. Another cluster included sequences from choroid plexus, meninges and lymph node, and interestingly, identical patterns of four or nine stop codons were shared among these tissues. These mutations appear to be the consequence of G-->A hypermutation, and could reflect independent events, or the movement of virions or infected cells, from the choroid plexus into the cerebrospinal fluid and ultimately, into the lymph node. We propose that a critical step towards the development of HIV dementia is an increase in monocyte trafficking into the brain, and that this process is either initiated and/or accelerated during late-stage infection, which could explain why dementia occurs primarily during this time.

AIDS Dementia Complex↗
PubMed2000

Is it a different world to when you were growing up? Generational effects on social representations and child-rearing values.

In this paper, I explore the way in which people view how the world has changed since they were growing up. This is done both quantitatively and qualitatively, using open-ended responses from the British Household Panel Survey. The theoretical perspective draws on Mannheim's insight that generational location predisposes individuals to characteristic modes of thought and experience and Moscovici's contention that generations may have distinctive social representations. The data largely support the generational hypothesis. The ten most frequent changes mentioned are unemployment, lack of safety, lack of discipline, increased pressure, moral decline, increased crime, drugs, environmental problems, and family breakdown. These social representations of how the world has changed are significant predictors of child-rearing values, especially for women. More generally, I argue that despite the broad consensus concerning the problems facing children born today, the social representations of men and women who grew up in different epochs exacerbate the value clash between generations.

Adult↗
PubMed2000

Retirement planning and long-term risk.

Many defined contribution plan participants have available to them various measures of short-term risk. However, some of these participants don't understand that reducing short-term risk comes at the cost of increasing the risk of not reaching their retirement income goal. This article looks at the relationship between short- and long-term risk and their impact on retirement savings.

Humans↗
PubMed2000

Which clinical practice guidelines for depression? An overview for busy practitioners.

BACKGROUND: Many policy and research documents on the treatment of depression in primary care suggest that general practitioners (GPs) should make use of clinical guidelines. AIM: To describe the content of peer-reviewed guidelines for the detection and treatment of depression in primary care and help GPs identify the one most useful to their own needs. METHOD: Guidelines were evaluated by an explicit method using the Institute of Medicine assessment instrument and according to six key clinical management questions identified as important by GPs and psychiatrists. RESULTS: Only five (30%) of the published guidelines identified met all the pre-defined inclusion criteria. Total scores for development process and content ranged from 54% to 82%. Validity scores ranged from 52% to 88%. No guideline answered all the key questions identified by clinicians. CONCLUSIONS: Only two guidelines conform to the quality standard of a clinical practice guideline. One covers all aspects of detection and management of depression in primary care but gives no advice on first-line choice of antidepressant, while the other focuses only on medication and fails to explore problems of case detection or to consider non-pharmacological treatments. However, taken together they do cover most of the key clinical issues in a reliable and valid manner. The identified guidelines vary considerably in both utility and clinical applicability.

Depressive Disorder↗
PubMed1999

Intracellular localization of human cytidine deaminase. Identification of a functional nuclear localization signal.

The cytidine deaminases belong to the family of multisubunit enzymes that catalyze the hydrolytic deamination of their substrate to a corresponding uracil product. They play a major role in pyrimidine nucleoside and nucleotide salvage. The intracellular distribution of cytidine deaminase and related enzymes has previously been considered to be cytosolic. Here we show that human cytidine deaminase (HCDA) is present in the nucleus. A highly specific, affinity purified polyclonal antibody against HCDA was used to analyze the intracellular localization of native HCDA in a variety of mammalian cells by in situ immunochemistry. Native HCDA was found to be present in the nucleus as well as the cytoplasm in several cell types. Indirect immunofluorescence microscopy indicated a predominantly nuclear localization of FLAG-tagged HCDA overexpressed in these cells. We have identified an amino-terminal bipartite nuclear localization signal that is both necessary and sufficient to direct HCDA and a non-nuclear reporter protein to the nucleus. We also show HCDA binding to the nuclear import receptor, importin alpha. Similar putative bipartite nuclear localization sequences are found in other cytidine/deoxycytidylate deaminases. The results presented here suggest that the pyrimidine nucleotide salvage pathway may operate in the nucleus. This localization may have implications in the regulation of nucleoside and nucleotide metabolism and nucleic acid biosynthesis.

Amino Acid Sequence↗
PubMed1999

C-->U editing of apolipoprotein B mRNA in marsupials: identification and characterisation of APOBEC-1 from the American opossum Monodelphus domestica.

The C->U editing of RNA is widely found in plant and animal species. In mammals it is a discrete process confined to the editing of apolipoprotein B (apoB) mRNA in eutherians and the editing of the mitochondrial tRNA for glycine in marsupials. Here we have identified and characterised apoB mRNA editing in the American opossum Monodelphus domestica. The apoB mRNA editing site is highly conserved in the opossum and undergoes complete editing in the small intestine, but not in the liver or other tissues. Opossum APOBEC-1 cDNA was cloned, sequenced and expressed. The encoded protein is similar to APOBEC-1 of eutherians. Motifs previously identified as involved in zinc binding, RNA binding and catalysis, nuclear localisation and a C-terminal leucine-rich domain are all conserved. Opossum APOBEC-1 contains a seven amino acid C-terminal extension also found in humans and rabbits, but not present in rodents. The opossum APOBEC-1 gene has the same intron/exon organisation in the coding sequence as the eutherian gene. Northern blot and RT-PCR analyses and an editing assay indicate that no APOBEC-1 was expressed in the liver. Thus the far upstream promoter responsible for hepatic expression in rodents does not operate in the opossum. An APOBEC-1-like enzyme such as might be involved in C->U RNA editing of tRNA in marsupial mitochondria was not demonstrated. The activity of opossum APOBEC-1 in the presence of both chicken and rodent auxiliary editing proteins was comparable to that of other mammals. These studies extend the origins of APOBEC-1 back 170 000 000 years to marsupials and help bridge the gap in the origins of this RNA editing process between birds and eutherian mammals.

APOBEC-1 Deaminase↗
PubMed1999

Dental education and the European context.

Two hundred and sixteen additional dentists enter the Register from Europe annually [corrected]. Dental educational standards vary widely across Europe. Convergence is best promoted through exchanges (SOCRATES) and voluntary school visitations (DENTED). UK standards are set by the GDC and maintained by the schools. Consequently no school should be closed in response to current immigration levels by European dentists.

Clinical Competence↗
PubMed1999

Metastatic cardiac angiosarcoma of the cervical spine. Case report.

STUDY DESIGN: A case report of metastatic cardiac angiosarcoma of the cervical spine. OBJECTIVES: To show that this rare spine tumor behaves in the same manner as an arteriovenous malformation and embolization, which can allow for successful spine surgery, and to discuss the natural history and rarity of this tumor. SUMMARY OF BACKGROUND DATA: Primary angiosarcoma of the heart is a very rare tumor, with fewer than 200 reports in the English literature and nothing reported in the spine literature. RESULTS: The patient in this study initially sought treatment for neck pain, left arm pain, and weakness 17 months after cardiac surgery and subsequent chemotherapy. A cervical computed tomography scan demonstrated a C5 lytic vertebral body tumor with intracannilicular extension and cord compression. An anterior cervical approach was made, but the tumor was too vascular to resect, and surgery was aborted. The C5 vascular vertebral body metastasis subsequently was embolized successfully by an interventional neuroradiologist. Reoperation via an anterior approach with corpectomy, cadaveric fibula, and anterior locking plate internal fixation was successful, producing marked improvement in the patients' symptoms. CONCLUSION: Spinal involvement by primary cardiac angiosarcoma is very rare, and this is only the second operative case ever reported. The vascular nature of this tumor makes it behave in a manner similar to that of a high-flow arteriovenous malformation. Surgery should not be undertaken before preoperative angiography and embolization. The dismal prognosis for this rare malignancy is discussed.

Adult↗
PubMed1999

Baculovirus expression and biochemical characterization of the human microsomal triglyceride transfer protein.

The microsomal triglyceride transfer protein (MTP) complexed to protein disulphide isomerase (PDI) is obligatory for the assembly of chylomicrons and very-low-density lipoproteins. The determination of the atomic structure of the MTP-PDI heterodimer has important implications for the treatment of those forms of hyperlipidaemia associated with the overproduction of very-low-density lipoproteins, which predispose to premature coronary heart disease. To perform structural studies of the human MTP-PDI complex it was necessary to produce milligram quantities of pure protein. We chose the baculovirus expression system for this purpose. Insects cells were co-infected with recombinant viruses encoding FLAG-tagged MTP and His-tagged PDI; the resulting heterodimer was purified by affinity chromatography. From 5 litres of insect cells, 4-6 mg of more than 95% pure recombinant protein was obtained. CD and attenuated total reflection Fourier-transform infrared spectroscopy indicate that the purified protein has around 34% alpha-helical and 33% beta-structure content. The recombinant protein had a comparable triglyceride transfer activity to that of bovine MTP-PDI. The production of polyclonal antibodies raised against the MTP and PDI subunits of the purified protein is described. The present study demonstrates the feasibility of expressing two proteins at high levels in insect cells and describes a transferable methodology for the purification of the resulting protein complex.

Amino Acid Sequence↗
PubMed1999

A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase.

The assembly of triglyceride-rich lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein B (apoB), a microsomal triglyceride transfer protein (MTP), and protein disulfide isomerase (PDI). In the MTP complex, the amino-terminal region of MTP (residues 22-303) interacts with the amino-terminal region of apoB (residues 1-264). Here, we report the identification and characterization of a site on apoB between residues 512 and 721, which interacts with residues 517-603 of MTP. PDI binds in close proximity to this apoB binding site on MTP. The proximity of these binding sites on MTP for PDI and amino acids 512-721 of apoB was evident from studies carried out in a yeast two-hybrid system and by co-immunoprecipitation. The expression of PDI with MTP and apoB16 (residues 1-721) in the baculovirus expression system reduced the amount of MTP co-immunoprecipitated with apoB by 73%. The interaction of residues 512-721 of apoB with MTP facilitates lipoprotein production. Mutations of apoB that markedly reduced this interaction also reduced the level of apoB-containing lipoprotein secretion.

Amino Acid Sequence↗
PubMed1999

Identification of domains in apolipoprotein B100 that confer a high requirement for the microsomal triglyceride transfer protein.

The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apoB-containing lipoproteins. To investigate the role of MTP in lipoprotein assembly, we determined the ability of carboxyl-terminally truncated forms of apoB to be secreted from cells treated with the MTP inhibitor 4'-bromo-3'-methylmetaqualone (Benoist, F., Nicodeme, E., and Grand-Perret, T. (1996) Eur. J. Biochem. 240, 713-720). In Caco-2 and mhAT3F cells that produce apoB100 and apoB48, the inhibitor preferentially blocked apoB100 secretion. When the inhibitor was tested on McA-RH7777 cells stably transfected with cDNAs encoding human apoB100, apoB72, apoB53, apoB29, and apoB18, the secretion of apoB100, apoB72, and apoB53 was preferentially impaired relative to apoB48 and shorter forms. To delineate the region between apoB48 and apoB53 that has a high requirement for MTP, we used puromycin to generate a range of truncated forms of apoB in HepG2 cells. The secretion of apoB53 and longer forms of apoB was markedly affected by low concentrations of the MTP inhibitor (approximately 1 microM), whereas apoB51 and smaller forms of apoB were only affected at higher concentrations (> 10 microM). The size-related sensitivity to MTP inhibitor was not due to late processing or retention, since the same result was observed when nascent lipoproteins were isolated from the endoplasmic reticulum. The MTP inhibitor did not alter the density of the secreted lipoproteins, indicating that each apoB polypeptide requires a minimally defined amount of lipid to attain a secretable conformation. Our results suggest that the folding of the domain between apoB51 and apoB53 has a high requirement for lipid. This domain is predicted to form amphipathic alpha-helices and to bind lipid reversibly. It proceeds and is followed by rigid amphipathic beta-sheets that are predicted to associate with lipid irreversibly. We speculate that these domains enable apoB to switch from a stable lipid-poor conformation in apoB48 to another lipid-rich conformation in apoB100 during lipoprotein assembly.

Apolipoprotein B-100↗
PubMed1999

The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins.

The assembly of atherogenic lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein (apo)B, a microsomal triglyceride transfer protein (MTP) and protein disulphide isomerase (PDI). Here we show by molecular modelling and mutagenesis that the globular amino-terminal regions of apoB and MTP are closely related in structure to the ancient egg yolk storage protein, vitellogenin (VTG). In the MTP complex, conserved structural motifs that form the reciprocal homodimerization interfaces in VTG are re-utilized by MTP to form a stable heterodimer with PDI, which anchors MTP at the site of apoB translocation, and to associate with apoB and initiate lipid transfer. The structural and functional evolution of the VTGs provides a unifying scheme for the invertebrate origins of the major vertebrate lipid transport system.

Amino Acid Sequence↗