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Biomedical subjects

R Hampson

Publications and source records attributed to R Hampson.

At least 19 recordsLinked to original sources
PubMed2004

Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial.

BACKGROUND: Evidence for disease modifying activity of low dose corticosteroid treatment in rheumatoid arthritis is contradictory. Studies showing radiological benefit suggest that continued treatment is required to sustain the effect. OBJECTIVE: To evaluate the effect of low dose oral prednisolone in early rheumatoid arthritis on disease activity over two years. DESIGN: Double blind placebo controlled trial. METHODS: Patients with rheumatoid arthritis, duration <3 years (n = 167), were started on a disease modifying antirheumatic drug (DMARD; sulphasalazine) and allocated by stratified randomisation to prednisolone 7 mg/day or placebo. Primary outcome measure was radiological damage, assessed by the modified Sharp method. Clinical benefit was a secondary outcome. A proactive approach to identifying and treating corticosteroid adverse events was adopted. Patients who discontinued sulphasalazine were offered an alternative DMARD. RESULTS: 90 of 257 patients eligible for the study refused to participate (more women than men). Of those enrolled, 84% were seropositive for rheumatoid factor, median age 56 years, median disease duration 12 months, female to male ratio 1.8:1. Prednisolone was given to 84 patients; of these 73% continued prednisolone and 70% sulphasalazine at 2 years. Of the 83 patients on placebo, 80% continued placebo and 64% sulphasalazine at 2 years. There were no significant differences in radiological score or clinical and laboratory measures at 0 and 2 years. CONCLUSIONS: Low dose prednisolone conferred no radiological or clinical benefit on patients maintained on a DMARD over two years. Low dose corticosteroids have no role in the routine management of rheumatoid arthritis treated with conventional disease modifying drugs.

Adult↗
PubMed2002

Illiteracy in rheumatoid arthritis patients as determined by the Rapid Estimate of Adult Literacy in Medicine (REALM) score.

OBJECTIVES: To determine the prevalence of illiteracy in a cohort of rheumatoid arthritis (RA) patients and the impact of illiteracy on disease severity and function. METHODS: We performed a prospective cross-sectional study with case record review of 127 consecutive patients with RA attending one centre. All patients completed the Rapid Estimate of Adult Literacy in Medicine (REALM) screening test. This 66-word recognition test provides an estimate of reading level in less than 3 min. Demographic data were collected by interview and case record review. Function was assessed with the Health Assessment Questionnaire (HAQ) and depression with the Hospital Anxiety and Depression (HAD) scale, both sent prior to clinic attendance. Social deprivation was assessed with the Carstairs index. RESULTS: Four patients refused to participate. Of these, three stated they were unable to read. Ninety-seven women and 26 men agreed to be interviewed. All but two were Caucasian. Median age was 56 yr (range 19-77 yr) and median disease duration was 10 yr (range 1-60 yr). Median number of previous disease-modifying anti-rheumatic drugs (DMARDs) was two. Eighteen (15%) patients were functionally illiterate, with a REALM score of less than 60. Sex, age, disease duration and numbers of joint replacements and previous DMARDs were not influenced by illiteracy. Illiteracy led to more anxiety (P=0.011), but did not affect HAQ score (P>0.5). Illiteracy was more common in the deprived (P=0.0064). Illiterate patients had three times more hospital visits compared with age- and sex-matched RA controls over the previous 12 months. CONCLUSIONS: One in six of our patient population are illiterate and would struggle to cope with patient education materials and prescription labels. These patients had significantly more hospital visits but equal function, suggesting that additional resources be directed towards these individuals. The REALM test is quick and easy to administer and allows us to identify patients who may require more appropriate literature.

Adult↗
PubMed2001

Muscular expressions: profiling genes in complex tissues.

Gene-expression profiling has yielded important information about simple systems, but complex tissues have not yet been widely profiled. Four recent studies of mammalian skeletal muscles have added to the catalogs of their gene expression differences, but have yet to lead to better understanding of the molecular processes underlying their physiological differences.

Animals↗
PubMed2001

Hedgehog signalling is required for maintenance of myf5 and myoD expression and timely terminal differentiation in zebrafish adaxial myogenesis.

Hedgehog proteins have been implicated in the control of myogenesis in the medial vertebrate somite. In the mouse, normal epaxial expression of the myogenic transcription factor gene myf5 is dependent on Sonic hedgehog. Here we examine in zebrafish the interaction between Hedgehog signals, the expression of myoD family genes, including the newly cloned zebrafish myf5, and slow myogenesis. We show that Sonic hedgehog is necessary for normal expression of both myf5 and myoD in adaxial slow muscle precursors, but not in lateral paraxial mesoderm. Expression of both genes is initiated normally in rostral presomitic mesoderm in sonic you mutants, which lack all Sonic hedgehog. Similar initiation continues during tailbud outgrowth when the cells forming caudal somites are generated. However, adaxial cells in sonic you embryos are delayed in terminal differentiation and caudal adaxial cells fail to maintain myogenic regulatory factor expression. Despite these defects, other signals are able to maintain, or reinitiate, some slow muscle development in sonic you mutants. In the cyclops mutant, the absence of floorplate-derived Tiggywinkle hedgehog and Sonic hedgehog has no discernible effect on slow adaxial myogenesis. Similarly, the absence of notochord-derived Sonic hedgehog and Echidna hedgehog in mutants lacking notochord delays, but does not prevent, adaxial slow muscle development. In contrast, removal of both Sonic hedgehog and a floorplate signal, probably Tiggywinkle hedgehog, from the embryonic midline in cyclops;sonic you double mutants essentially abolishes slow myogenesis. We conclude that several midline signals, likely to be various Hedgehogs, collaborate to maintain adaxial slow myogenesis in the zebrafish embryo. Moreover, the data demonstrate that, in the absence of this required Hedgehog signalling, expression of myf5 and myoD is insufficient to commit cells to adaxial myogenesis.

Amino Acid Sequence↗
PubMed2000

Large-scale analysis of gene expression changes during acute and chronic exposure to [Delta]9-THC in rats.

Large-scale cDNA microarrays were employed to assess transient changes in gene expression levels following acute and chronic exposure to cannabinoids in rats. A total of 24,456 cDNA clones were randomly selected from a rat brain cDNA library, amplified by PCR, and arrayed at high density to investigate differential gene expression profiles following acute (24 h), intermediate (7 days), and chronic (21 days) exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient of marijuana. Hippocampal mRNA probes labeled with (33)P obtained from both vehicle and Delta(9)-THC-treated animals were hybridized with identical cDNA microarrays. Results revealed a total of 49 different genes altered by Delta(9)-THC exposure; of these, 28 were identified, 10 had homologies to expressed sequence tags (ESTs), and 11 had no homology to known sequences in the GenBank database. Chronic or acute cannabinoid receptor activation altered expression of several genes (i.e., prostaglandin D synthase, calmodulin) involved in biochemical cascades of cannabinoid synthesis or cannabinoid effector systems. Other genes [i.e., neural cell adhesion molecule (NCAM), myelin basic protein], whose relation to cannabinoid system function was not immediately obvious, were also significantly altered. Verification of the changes obtained with the large-scale screen was determined by RNA dot blots in different groups of animals treated the same as those in the large-scale screen. Results are discussed in terms of the different types of genes affected at different times during chronic Delta(9)-THC exposure.

Animals↗
PubMed1999

Does social disadvantage contribute to the excess mortality in rheumatoid arthritis patients?

BACKGROUND: Socioeconomic deprivation is associated with increased mortality from cardiovascular causes and malignancy. The influence of disadvantage in patients with rheumatoid arthritis (RA), who are known to have premature mortality, has not been ascertained. AIM: To assess the relation between the level of patient deprivation and mortality in RA patients. METHODS: 200 RA patients, enrolled in a study comparing sulfasalazine and penicillamine in 1984-85, have been followed up prospectively for 12 years. Subjects were categorised into Carstairs groups with deprivation scores ranging from 1 (most affluent) to 7 (most deprived). Information about deaths was obtained from the Registrar General in Scotland, death certificates and GP/hospital records. RESULTS: There were more RA patients in the deprived areas then expected compared with the West of Scotland and England and Wales. Some 47.5% of the RA patients had died by 12 years-the majority of cardiorespiratory causes or malignancy. There were no differences in the median age or disease duration in the various Carstairs groups at study entry, but the percentage of deaths was higher in the more deprived groups after 12 years (36% dead in most affluent area compared with 61% in the most deprived, that is, in groups 6 and 7). CONCLUSION: In patients with RA increasing deprivation was associated with premature mortality. If confirmed elsewhere these findings have implications for rheumatological management strategies, for researchers involved in collaborative studies of patients from different socioeconomic backgrounds and for resource allocation.

Adult↗
PubMed1998

N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea sensitivity in mismatch repair-defective human cells.

To determine whether loss of mismatch repair (MMR) confers sensitivity to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), the sensitivity of MMR-defective (MMR-) variants was compared to that of their parental cells. Loss of MMR confers between 2- and 5-fold hypersensitivity to CCNU on HeLa, Raji, or Chinese hamster ovary cells. We also examined whether the sensitivity to CCNU is a general feature of MMR-human tumor cells. The majority expressed O6-methylguanine-DNA-methyltransferase (MGMT; Mex+ phenotype) that confers resistance to CCNU independent of their MMR status. The single Mex- MMR- SW48 cells were 4-fold more sensitive to CCNU than the Mex- MMR+ SW620 cells. CCNU sensitivity of the Mex+ cells was analyzed after treatment with the MGMT inhibitor O6-benzylguanine. The MMR- AN3CA, LS174T, LoVo, and DU145 cells were 1.4-4.3-fold more sensitive to CCNU than the MMR+ HeLaS3, HT29, and A2780 cells. Hypersensitivity to CCNU was not seen in the MMR- cell lines DLD1, HEC1A, and HCT116, suggesting that other parameters, besides the MGMT and MMR defects, affect the cell's response to this drug. In contrast, loss of MMR was always associated with tolerance to the methylating agent N-methyl-N-nitrosourea. The sensitivity to CCNU in MMR- cells suggests a possible involvement of this repair pathway in repairing interstrand cross-links and may have implications for clinical treatment of MMR- tumors.

Animals↗
PubMed1998

Improved functional outcome in patients with early rheumatoid arthritis treated with intramuscular gold: results of a five year prospective study.

OBJECTIVE: To determine whether there is a relation between disease duration and functional outcome in patients with rheumatoid arthritis (RA) treated with intramuscular sodium aurothiomolate (gold) for five years. METHODS: 440 patients with RA were enrolled in a prospective trial of gold treatment. Initial demographic details were recorded. Disease activity was assessed at yearly intervals using a combination of clinical (pain score, Ritchie articular index, duration of morning stiffness) and laboratory (erythrocyte sedimentation rate, C reactive protein) parameters. Change in functional status was assessed using the health status questionnaire (HAQ). Patients were stratified according to disease duration at outset (group 1 = 0-2 years n = 106, group 2 = > 2-5 years n = 93, and group 3 = > 5 years n = 235). RESULTS: There were no significant differences between the groups at outset. A total of 160 patients completed five years of treatment (group 1 n = 44 (42%), group 2 n = 37 (40%), and group 3 n = 79 (34%)). Patients in group 1 had a significantly lower HAQ from year 1 to year 5 with a mean improvement of 30% at the end of the study (p < 0.001). Neither group 2 nor group 3 had a significant change in their HAQ at study end. There were significant improvements in all other variables (p < 0.05) in each group apart from pain in group 2. CONCLUSION: Patients with early RA have a larger reversible component to their HAQ. Only patients with disease duration of up to two years have a longlasting improvement in their functional ability after starting intramuscular gold treatment.

Adult↗
PubMed1998

Intention-to-treat analysis of 200 patients with rheumatoid arthritis 12 years after random allocation to either sulfasalazine or penicillamine.

OBJECTIVE: To assess existing disease modifying antirheumatic drugs (DMARD) using a strategy aiming for sustained suppression of inflammation. METHODS: We conducted intention-to-treat analysis of open randomized study [sulfasalazine (SASP) or penicillamine (PEN)], followup 12 years, conducted at specialist rheumatology clinics in Glasgow, Scotland. Subjects were 200 patients with rheumatoid arthritis (RA) with established disease. In this "true to life" approach, comorbidity was not an exclusion criterion unless it prejudiced assessment of drug toxicity. The main outcome measure was the Health Assessment Questionnaire (HAQ) functional score. RESULTS: Over 12 year followup 95 (47.5%) patients died; this was the commonest reason for study groups being unfulfilled. There was one drug related death (methotrexate). Patients who were socially disadvantaged were more likely to die prematurely. HAQ did not deteriorate significantly in those who continued taking their original DMARD, or in the SASP intention-to-treat group over 12 years. Sustained suppression of disease activity was possible in the entire group available for followup at 12 years. Most toxicity occurred early and no unexpected side effects were observed. CONCLUSION: High premature mortality in RA was confirmed and an association between mortality and deprivation was demonstrated. Sustained reduction in acute phase response was possible using sequential single DMARD. This study provides useful baseline and longterm information against which to evaluate combination therapy or new agents.

Adult↗
PubMed1997

Mismatch repair defects and O6-methylguanine-DNA methyltransferase expression in acquired resistance to methylating agents in human cells.

Fifteen variants with >/=30-fold resistance to N-methyl-N-nitrosourea were isolated from the Burkitt's lymphoma Raji cell line. Eight had received a single treatment with a highly cytotoxic dose. The remainder, including the previously described RajiF12 cell line, arose following multiple exposures to initially moderate but escalating doses. Surprisingly, methylation resistance arose in three clones by reactivation of a previously silent O6-methylguanine-DNA methyltransferase gene. Five clones, including RajiF12, displayed the microsatellite instability and increased spontaneous mutation rates at the hypoxanthine-guanine phosphoribosyltransferase locus, consistent with deficiencies in mismatch repair. Defects in either the hMutSalpha or hMutLalpha mismatch repair complexes were identified in extracts of these resistant clones by in vitro complementation using extracts from colorectal carcinoma cell lines. Defects in hMutLalpha were confirmed by Western blot analysis. Remarkably, five methylation-resistant clones in which mismatch repair defects were demonstrated by biochemical assays did not exhibit significant microsatellite instability.

Blotting, Western↗
PubMed1997

DNA mismatch repair in lymphoblastoid cells from hereditary non-polyposis colorectal cancer (HNPCC) patients is normal under conditions of rapid cell division and increased mutational load.

Patients with hereditary non-polyposis colorectal cancer (HNPCC) have germ-line mutations in one of four DNA mismatch repair genes (hMSH2, hMLH1, hPMS1 and hPMS2). It is supposed that a single functional copy of these genes is sufficient for normal mismatch repair, but it is not certain that this is the case under abnormal conditions such as rapid cell division or an increased tendency to DNA replication errors (RERs). We have analysed mismatch repair by examining replication errors in immortalised lymphoblastoid cells derived from two HNPCC patients heterozygous for mismatch repair defects (one hMSH2 mutant and one hMLH1 mutant), and from control individuals. Three conditions of cell culture have been used: (i) relatively slow cell growth and division; (ii) relatively fast growth and division; and (iii) chronic perturbation of the intracellular dNTP pool to promote a increased frequency of replication errors. No significant differences in microsatellite instability were found between HNPCC patients and controls in any of these environments. Lymphoblastoid cells from hMSH2 and hMLH1 mutant/wild-type heterozygotes appear, therefore, to have normal levels of mismatch repair, even under conditions that increase the requirement for repair. The pool bias cultures from the HNPCC patients and controls did, however, show similar, increased frequencies of RERs, suggesting that the mismatch repair capacity of the cells had been overloaded, but that the number of normal HNPCC alleles was not the limiting factor.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Selection for genome instability by DNA damage in human cells: unstable microsatellites and their consequences for tumourigenesis.

The emergence of tumour cells resistant to chemotherapeutic treatment is a major confounding factor in anticancer treatment. Many chemotherapeutic drugs are DNA damaging agents. Resistance to DNA damage can be acquired via a plethora of different mechanisms, including, surprisingly, loss of DNA mismatch repair activity. The DNA mismatch repair system acts after DNA replication and corrects non-Watson-Crick base pairs and other replication errors. Human cells lacking mismatch repair activity have high spontaneous mutation rates. Frequent frameshift mutations in repetitive DNA sequences are characteristically associated with the defect. This hypermutability at repetitive sequences is termed microsatellite instability. DNA mismatch repair defects underlie a predisposition to cancer and are associated with a significant fraction of apparently sporadic cancer cases. In contrast to many other neoplasms, gross genetic aberrations are rare in cells from tumours with microsatellite instability. In these mismatch repair-defective tumours, certain genes that would normally hinder tumour development are frequently found to be inactivated by frameshift mutations in repetitive DNA tracts within their coding sequences. This implies that the small-scale genome alterations characteristic of mismatch repair defects can act as a driving force in tumour development.

Antineoplastic Agents↗
PubMed1996

Selection for beta 2-microglobulin mutation in mismatch repair-defective colorectal carcinomas.

Novel peptide antigens complexed with human leukocyte antigen (HLA) and beta 2-microglobulin (beta 2M) molecules are presented at the cell surface to cytotoxic T lymphocytes (CTLs), provoking lysis of the antigen-presenting cell [1]. In tumor cells, genetically altered or abnormally expressed proteins provide a source of peptides that can be presented to CTLs; the resulting anti-tumour CTL responses may provide part of the body's defence against cancer. Disabling mutations in the HLA and beta 2M proteins required for peptide presentation allow a tumour cell to escape destruction by CTLs. Cells with deficient DNA mismatch repair have high spontaneous mutation rates [2] and produce many altered proteins that are a potential source of numerous unique peptides. Mutator tumour cells might therefore be particularly vulnerable to immune surveillance and CTL attack. Mutator phenotypes [3,4] and loss of beta 2M (or HLA) expression [5,6] are both relatively common among sporadic colorectal tumours. We have compared the frequency of beta 2M mutations in sporadic colorectal and other tumours with and without a mutator phenotype. Mutations were more frequent among colorectal tumours with the microsatellite instability indicative of a defect in DNA mismatch repair. The inactivating beta 2M mutations were predominantly frameshifts, which is consistent with the underlying mismatch repair defects. Evasion of immune surveillance by acquiring beta 2M mutations therefore occurs at high frequency in tumour cells with a mutator phenotype due to defective DNA mismatch repair.

Colorectal Neoplasms↗
PubMed1996

Genomic instability and tolerance to alkylating agents.

Experimental models clearly indicate that the cytotoxic effects of the chemotherapeutic methylating agents are mediated by incomplete processing of one of the common DNA methylation products, O6-meGua. These attempts at processing persistent O6-meGua are by DNA mismatch repair, and resistance to methylating agents frequently arises through loss of this pathway. It is to be expected that mismatch repair defects will be found among cells that have developed clinical resistance to agents such as temozolomide and the methyltriazines. The selective sensitivity of mismatch repair defective cells to chloroethylating agents may have a direct applicability to clinical practice and offers real promise of effective chemotherapy for the substantial number of human tumours that show microsatellite instability. As for the mechanisms of human mismatch repair, the complexity of the early steps of the pathway(s) is underlined by the likely participation of multiple heterodimers in the mismatch recognition steps. just as different types of mismatch may be processed by distinct branches of the same pathway, the same may be true for different types of DNA damage.

Antineoplastic Agents, Alkylating↗
PubMed1995

DNA mismatch binding defects, DNA damage tolerance, and mutator phenotypes in human colorectal carcinoma cell lines.

DNA mismatch binding in vitro, resistance to DNA methylation damage, and spontaneous mutation rates were examined in human colorectal adenocarcinoma cell lines. Of 11 cell lines, 3 (DLD1, HCT15, and LoVo) were defective in mismatch binding. All three lines had a mutator phenotype. These properties indicate that DLD1 and HCT15 may, like LoVo, carry mutations in the mismatch recognition protein hMSH2. Mismatch binding was normal in the remaining eight lines, including HCT116 in which a second mismatch repair protein, hMLH1, is defective. Two lines, SW620 and SW48, did not express detectable levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. SW620 exhibited the expected sensitivity to N-methyl-N-nitrosourea. In contrast, SW48 cells were highly resistant to N-methyl-N-nitrosourea and also slightly to methyl methanesulfonate, indicating that they are tolerant to DNA methylation damage. SW48 exhibited the spontaneous mutator phenotype and microsatellite instability that are hallmarks of a defect in mismatch repair. This cell line provides evidence for the association between methylation tolerance and defective mismatch correction in human colorectal carcinoma cells. The properties of methylation-tolerant, mismatch repair-defective cells identify possible selective pressures that might facilitate the natural selection of mismatch repair-defective tumors.

Adenocarcinoma↗
PubMed1988

The psychosocial consequences of childhood infection with human immunodeficiency virus.

This article reviews the available medical literature on the psychosocial and neuropsychiatric implications of childhood infection by the human immunodeficiency virus. This information is supplemented by discussion of cases from our clinical experience. It is clear that different psychosocial issues are confronted by children of different ages (infants, young children or adolescents) and their families. The differences are due partly to the social correlates of different modes of transmission of the acquired immunodeficiency syndrome (AIDS), the psychosocial risk factors that are associated with certain family life-styles, whether other family members are infected, and the developmental stage and awareness of the child. Psychiatric assessments of these children and their families are recommended as a routine as they will identify potential ethical dilemmas, and will allow for the detection and management of the psychosocial and neuropsychiatric consequences of AIDS.

Acquired Immunodeficiency Syndrome↗