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Biomedical subjects

A Richardson

Publications and source records attributed to A Richardson.

At least 19 recordsLinked to original sources

Inferring thought and action in motor neurone disease.

The traditional assumption that classical motor neurone disease (MND) invariably spares cognitive function is now recognised to be incorrect. Deficits have most commonly been demonstrated on executive tasks suggesting impaired function of frontal systems. Yet, crucial aspects of frontal lobe function have not hitherto been explored. The study used tests of theory of mind (ToM) (interpretation of cartoons and stories) to examine the ability of 16 patients with MND to interpret social situations and ascribe mental states to others. Only minor differences were elicited in the MND group as a whole compared to controls, and performance was not differentially affected for cartoons and stories requiring inference of another's mental state (mental) compared to control (physical) cartoons and stories. However, abnormalities were elicited on both mental and physical tasks in a subgroup of patients with bulbar signs. Moreover, examination of individual patient scores revealed a spectrum of performance ranging from normal to severely impaired. Errors were qualitatively similar to those seen in frontotemporal dementia (FTD). Performance on the ToM tasks was significantly correlated with conventional, untimed measures of executive function, suggesting that ToM deficits in MND are likely to be linked to a more general executive failure. The findings contribute to the understanding of ToM performance in neurodegenerative disease and provide further evidence of the association between MND and FTD.

Aged↗

Genetic modification of the manganese superoxide dismutase/glutathione peroxidase 1 pathway influences intracellular ROS generation in quiescent, but not contracting, skeletal muscle cells.

Increased amounts of reactive oxygen species (ROS) are generated by skeletal muscle during contractile activity, but their intracellular source is unclear. The oxidation of 2',7'-dichlorodihydrofluorescein (DCFH) was examined as an intracellular probe for reactive oxygen species in skeletal muscle myotubes derived from muscles of wild-type mice and mice that were heterozygous knockout for manganese superoxide dismutase (Sod2(+/-)), homozygous knockout for glutathione peroxidase 1 (GPx1(-/-)), or MnSOD transgenic overexpressors (Sod2-Tg). Myoblasts were stimulated to fuse and loaded with DCFH 5-7 days later. Intracellular DCF epifluorescence was measured and myotubes were electrically stimulated to contract for 15 min. Quiescent myotubes with decreased MnSOD or GPx1 showed a significant increase in the rate of DCFH oxidation whereas those with increased MnSOD did not differ from wild type. Following contractions, myotubes from all groups showed an equivalent increase in DCF fluorescence. Thus the oxidation of DCFH in quiescent skeletal muscle myotubes is influenced by the content of enzymes that regulate mitochondrial superoxide and hydrogen peroxide content. In contrast, the increase in DCFH oxidation following contractions was unaffected by reduced or enhanced MnSOD or absent GPx1, indicating that reactive oxygen species produced by contractions were predominantly generated by nonmitochondrial sources.

Animals↗

The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus.

To date, three loci have been validated to confer susceptibility to inflammatory bowel disease (IBD): the CARD15/NOD2 gene, the discs large homolog 5 gene (DLG5), and the IBD5 locus on 5q31 (IBD5). We have explored the possibility that these loci may also be associated with susceptibility to two other chronic inflammatory diseases, multiple sclerosis (MS) and systemic lupus erythematosus (SLE). As the CARD15 risk alleles had previously been assessed in our collection of 496 MS trios, we focused our efforts on the DLG5 risk allele and the IBD5(risk) haplotype (IBD5(risk)) for MS. While there is no evidence of association within our MS sample with either of these polymorphisms, screening of 1027 subjects with SLE suggests that IBD5(risk) may have a modest contribution to disease risk in the subset of SLE subjects without lupus nephritis. In addition, a pooled analysis of existing published and unpublished data in 1305 cases of SLE genotyped for the CARD15 risk alleles suggests that only the CARD15(908R) IBD risk allele may have a strong effect on risk of SLE. Our data, therefore, suggest that both the CARD15 gene and the IBD5 locus may have a role as general susceptibility loci for certain common, genetically complex inflammatory diseases.

Chromosomes, Human, Pair 5↗

Sudden unexpected death in epilepsy (SUDEP): don't ask, don't tell?

BACKGROUND: The National Institute for Clinical Excellence in the UK has issued guidelines stating all individuals with epilepsy be given information about sudden unexpected death in epilepsy (SUDEP). METHODS: We conducted a survey of current practice among UK neurologists, using a questionnaire sent to all practising neurologists in the UK listed on the Association of British Neurologists database, asking under what circumstances they told patients about SUDEP. RESULTS: Of the validated respondents, 5% discussed SUDEP with all patients, 26% with a majority, 61% with a few, and 7.5% with none. The commonest reasons for SUDEP to be discussed were the patient asking about it and the neurologist counselling people with known risk factors for SUDEP. CONCLUSIONS: The variation we found, although not necessarily in tune with the guidelines, reflects the variation in patients' need for knowledge about their condition.

Adaptation, Psychological↗

Interobserver variation in sonography of the painful shoulder.

PURPOSE: This study was conducted as a prospective assessment of interobserver variability in the sonographic evaluation of the rotator cuff. METHODS: Three musculoskeletal radiologists who had different levels of scanning experience each performed shoulder sonography on 24 consecutive patients during 1 patient visit. The diagnostic criteria full-thickness rotator cuff tear, tendon calcification, tendinosis of the supraspinatus, subacromial fluid, subacromial synovial/bursal thickening, dynamic signs of impingement, and abnormality in the long head of biceps tendon were scored, with independent observers recording the data. Statistical analysis was performed using Cohen's kappa test, with significance assessed at p values of less than 0.05. RESULTS: There was good agreement (kappa >0.60, p <0.01) between the experienced operators for full-thickness rotator cuff tear, tendon calcification, dynamic signs of impingement, and abnormality of the long head of biceps tendon. There was no significant agreement between the experienced operators and the less experienced operator in several categories, including (and importantly) full-thickness rotator cuff tears (kappa=0.18-0.21). CONCLUSIONS: In experienced hands sonography of the rotator cuff is a reproducible diagnostic test, but agreement is poor when there is marked disparity between the operators' experience levels. Our findings suggest a need for a more clearly defined training curriculum for sonography of the shoulder in radiology training programs.

Adult↗

No association between interferon-gamma receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample.

BACKGROUND: Tuberculosis (TB) is a major global cause of mortality and morbidity, and host genetic factors influence disease susceptibility. Interferon-gamma mediates immunity to mycobacteria and rare mutations in the interferon-gamma receptor-1 gene (IFNGR1) result in increased susceptibility to mycobacterial infection, including TB, in affected families. The role of genetic variation in IFNGR1 in susceptibility to common mycobacterial diseases such as pulmonary TB in outbred populations has not previously been investigated. METHODS: The association between IFNGR1 and susceptibility to pulmonary TB was investigated in a Gambian adult population sample using a case-control study design. The coding and promoter regions of IFNGR1 were sequenced in 32 patients with pulmonary TB, and the frequencies of six common IFNGR1 polymorphisms were determined using PCR based methods in 320 smear positive TB cases and 320 matched controls. Haplotypes were estimated from the genotype data using the expectation-maximisation algorithm. RESULTS: There was no association between the IFNGR1 variants studied and TB in this Gambian population sample. Three common haplotypes were identified within the study population, none of which was associated with TB. CONCLUSIONS: These data represent an important negative finding and suggest that, while IFNGR1 is implicated in rare Mendelian susceptibility to mycobacterial disease, the common variants studied here do not have a major influence on susceptibility to pulmonary TB in The Gambian population.

Cohort Studies↗

Breast cancer detection rates, and standardised detection ratios for prevalence screening in the New Zealand breast cancer screening programme.

OBJECTIVES: To calculate breast cancer detection to expected incidence ratios and standardised detection ratios (SDRs) for the New Zealand breast cancer screening programme. METHOD: Breast cancer registrations for 1976-1999 were obtained from the New Zealand Cancer Registry. Using these registrations, the incidence in the absence of screening was projected for 1999 and 2000. These projections, and the invasive breast cancers detected in the New Zealand programme during 1999 and 2000, were used to calculate the detection to expected incidence ratios and SDRs. RESULTS: In 1999, the breast cancer detection rate was 5.6 per 1000 women screened. The expected incidence among these women in the absence of screening was 2.3 per 1000, a detection to expected incidence ratio of 2.4. The SDR was 0.84 (0.76-0.94). In 2000, the breast cancer detection rate was 6.0 per 1000 women screened. The expected incidence among these women in the absence of screening was 2.4 per 1000, a detection to expected incidence ratio of 2.5. The SDR was 0.90 (0.81 - 0.99). CONCLUSIONS: In the first two years of the national programme, detection to expected incidence ratios were less than 3.0, and the SDR results were below 1.0. It may be unrealistic to expect new screening programmes to achieve SDRs of 1.0 immediately. At a similar stage, the UK National Health Service Breast Cancer Screening Programme (NHSBSP) also reported SDRs of less than 1.0 and therefore lower than expected cancer detection rates compared with the Swedish Two-County trial. An encouraging finding was that SDRs in five of the six screening regions improved in the second year of the New Zealand screening programme.

Breast Neoplasms↗

Fatigue in adolescents with and following a cancer diagnosis: developing an evidence base for practice.

Although fatigue has been a focus for research in adult cancer care for some time, the same cannot be said for adolescent oncology practice. This paper summarises the literature concerning fatigue in adolescents with, and following, cancer diagnoses, drawing on data from four empirical studies. Fatigue is multidimensional, multifactorial and highly subjective, but can be managed to enhance self-caring and coping strategies. All of the studies reviewed within indicate that fatigue is a troublesome symptom, which impacts on quality of life. From this review, we set up a research study. This paper provides a brief report of preliminary data from this study drawn from a group of adolescents in late remission from childhood cancer. These data are used to evaluate the utility of focus groups as a method of data collection in exploring the concept of fatigue in adolescents. Concurring with the studies we reviewed, findings from the preliminary data suggest that fatigue is a highly subjective and 'abnormal' phenomenon that holds a variety of implied meanings and associated metaphors connected with past experiences of childhood cancer. The focus group proved to be a viable research method to facilitate mutual disclosure and provoke discussion. Recognition of the research challenges with adolescents, where there is the potential for a range of meanings for the experience of fatigue, is an important finding for future studies.

Adaptation, Psychological↗

Cancer-related fatigue--a difference of opinion? Results of a multicentre survey of healthcare professionals, patients and caregivers.

UNLABELLED: The objective of this study was to investigate the perceptions of patients with cancer, their caregivers and healthcare professionals (HCPs) about fatigue and its impact on quality of life. It was a cross-sectional survey, the respondents were patients with cancer attending three UK regional cancer centres (n = 1,370), their informal caregivers (n = 1,370) and a random selection of HCPs (oncologists/nurses/radiographers/haematologists; n = 1,098). The response rates for patients, caregivers and HCPs were 42%, 33% and 34% respectively. Fatigue was reported to affect 56% of patients and to have a considerable impact on quality of life. Caregivers also recognized that fatigue was a common problem, with significant effects on patients' quality of life and impact on themselves. Healthcare professionals recognized that fatigue was a common problem for their patients but overestimated its impact on some aspects of patients' daily lives. Although most HCPs reported that they prescribed/recommended treatment for over half of their patients, only 14% of patients reported receiving any such treatment. The most common advice was to take more rest and relaxation. CONCLUSIONS: patients with cancer report that fatigue is a common and distressing symptom and the importance of this symptom is generally recognized by both HCPs and lay-carers. Healthcare professionals need more information about the effectiveness of existing interventions for cancer-related fatigue and further research is required to improve the current management of this debilitating symptom.

Attitude of Health Personnel↗

Oxidative damage to DNA and aging.

Oxidative damage to DNA increases with age in several tissues and animal models, and mitochondrial DNA has a higher level of oxidative damage than nuclear DNA. Dietary restriction extends lifespan and is associated with reduced levels of damage to mitochondrial and nuclear DNA. The effect of exercise on DNA damage appears to be related to the intensity of the exercise.

Aging↗

[Characteristic electrocardiographic procedures of isthmic-dependent atrial flutter; influence of clinical and echocardiographic procedures].

The appearance of the F waves on the ECG is considered to be related to the type of circuit of the anti-clockwise flutters and the clockwise isthmic-dependant flutters. In the authors' experience, the usual ECG description of these two types of flutter is not always observed. This study was undertaken to analyse the different appearances of anti-clockwise and clockwise flutters and to try and explain the reasons for these differences. Over a 4 year period, 139 patients with an ECG of atrial flutter required electro-physiological studies and echocardiography of the 156 flutters analysed: 130 were anti-clockwise and 26 clockwise. Three types of anti-clockwise flutter were observed: type 1 with exclusively negative F waves in the inferior leads: type 2 and 3 with negative F waves in the inferior leads and a small (type 2) or large (type 3) positive terminal components. The types 2 and 3 were associated with a higher incidence of left atrial dilatation, cardiac disease and atrial fibrillation than type 1. Two types of clockwise flutter were observed: type 1 with positive notched F waves in the inferior leads with a return to the iso-electric line and type 2 with wide F waves in the inferior leads with two components, predominantly positive and negative, without return to the iso-electric line. There are different ECG appearances of anti-clockwise and clockwise flutter which seem to be correlated with structural cardiac abnormalities. The anti-clockwise flutters with a positive terminal component of the F waves in the inferior leads corresponds to a subgroup with a high probability of cardiac disease and left atrial dilatation.

Atrial Flutter↗

Eliciting views of patients with head and neck cancer and carers on professionally derived standards for care.

OBJECTIVES: To examine views of patients and carers on the process of care for people with head and neck cancer; to assess whether focus groups are useful in this setting; to compare priorities and standards identified with those published by healthcare professionals; and to incorporate the expressed views into existing national standards. DESIGN: Multicentre study of nine regional focus groups. SETTING: Area covered by two regional health authorities. PARTICIPANTS: 40 patients who had had head and neck cancer and 18 carers. MAIN OUTCOME MEASURES: Views of individuals and groups on standards. Applicability of the method for patients whose appearance and ability to communicate was altered and for recently bereaved carers. Ease of incorporation of views into national and regional standards. RESULTS: Patients and carers participated in discussions on all the principal questions. Opinions were expressed on waiting times, information available to patients, coordination of care, and crisis management. Professionally derived standards were substantially improved by the incorporation of the views of patients and carers. There were no technical problems in carrying out this study on patients with communication difficulties or altered appearance nor with recently bereaved carers. Occasionally, participants said that the meetings were therapeutic. CONCLUSIONS: Professionally facilitated and analysed focus groups are effective in assessing views of patients with cancer and carers on professionally derived standards for care and can be applied in settings traditionally viewed as difficult. Views expressed by patients and carers are powerful motivators for change in the delivery of cancer care.

Caregivers↗

Expression of cyclins E1 and E2 during mouse development and in neoplasia.

Cyclin E1 (formerly called cyclin E) and the recently described cyclin E2 belong to the family of E-type cyclins that operate during the G(1)/S phase progression in mammalian cells. The two E-cyclins share a catalytic partner, cyclin-dependent kinase 2 (CDK2), and activate their associated kinase activities at similar times during cell cycle progression. Despite these similarities, it is unknown whether the two proteins perform distinct functions, or, alternatively, they control S-phase entry of different cell types in a tissue-specific fashion. To start addressing in vivo functions of E-cyclins, we determined the expression pattern of cyclins E1 and E2 during normal mouse development. We found that the two E-cyclins showed very similar patterns of expression; both were expressed within the proliferating compartment during embryo development. Analyses of cells and tissues lacking members of the retinoblastoma (pRB) family of proteins revealed that the expression of both cyclins is controlled in a pRB-dependent, but p107- and p130-independent fashion, likely through the pRB-dependent E2F transcription factors. We also found that cyclins E1 and E2 are expressed at high levels in mouse breast tumors driven by the Myc oncogene. Last, we found that cyclin E2 is overexpressed in approximately 24% of analyzed human mammary carcinomas. Collectively these findings suggest that the expression of cyclins E1 and E2 is governed by similar molecular circuitry.

Animals↗

Does oxidative damage to DNA increase with age?

The levels of 8-oxo-2-deoxyguanosine (oxo8dG) in DNA isolated from tissues of rodents (male F344 rats, male B6D2F1 mice, male C57BL/6 mice, and female C57BL/6 mice) of various ages were measured using sodium iodide to prevent oxidative damage to DNA during DNA isolation. Oxo8dG was measured in nuclear DNA (nDNA) isolated from liver, heart, brain, kidney, skeletal muscle, and spleen and in mitochondrial DNA (mtDNA) isolated from liver. We observed a significant increase in oxo8dG levels in nDNA with age in all tissues and strains of rodents studied. The age-related increase in oxo8dG in nDNA from old mice was shown not to the result of the tissue's reduced ability to remove the oxo8dG lesion. Rather, the increase in oxo8dG levels appears to arise from an age-related increase in the sensitivity of these tissues to oxidative stress. We also observed an age-related increase in oxo8dG in mtDNA isolated from the livers of the rats and mice. Dietary restriction, which is known to retard aging and increase the lifespan of rodents, was shown to significantly reduce the age-related accumulation of oxo8dG levels in nDNA in all tissues of male B6D23F1 mice and in most tissues of male F344 rats. Our study also showed that dietary restriction prevented the age-related increase in oxo8dG levels in mtDNA isolated from the livers of both rats and mice.

8-Hydroxy-2'-Deoxyguanosine↗

Effect of overexpression of human Cu/Zn-SOD on activation-induced lymphocyte proliferation and apoptosis.

The process of lymphocyte proliferation and apoptosis is known to be linked to oxidative stress. In the present study, we have used a new transgenic mouse model to investigate the effect of human Cu/Zn superoxide dismutase (Cu/Zn-SOD) overexpression on activation-induced lymphocytes proliferation and apoptosis. Cu/Zn-SOD activity was 3.5-fold higher in the spleen of the transgenic mice overexpressing Cu/Zn-SOD (Tg-Cu/Zn-SOD) compared to the wild-type littermates. Proliferative response of lymphocytes to lipopolysaccharide (LPS), Concanavalin A (Con A), and anti-CD3 was measured by [3H]-thymidine incorporation. Activation-induced apoptosis was determined by incubating the T cells with anti-CD3 (primary stimulus) for 72 h, followed by restimulation with Con A (secondary stimulus) for various times. Apoptosis was assessed by measuring DNA fragmentation using a spectrofluorimetric assay and monitoring the expression of the specific apoptotic markers (Fas/CD95 receptor and Fas/CD95 ligand (Fas-L) using flow cytometry. There was no significant difference in proliferative response of lymphocytes to LPS, Con A, or anti-CD3 in transgenic mice overexpressing human Cu/Zn superoxide dismutase (Tg-Cu/Zn-SOD) compared to wild-type littermates. In addition, no significant difference was observed in lymphocyte populations and subsets between Tg-Cu/Zn-SOD mice and wild-type littermates. However, splenic T cells from Tg-Cu/Zn-SOD mice exhibited a significantly (p <.05) higher level of activation-induced DNA fragmentation than T cells from wild-type littermates. The increase in DNA fragmentation was paralleled with an increase in the proportion of T cells expressing Fas and Fas-L molecules. The possible consequences of Cu/Zn-SOD overproduction on activation-induced apoptosis are discussed.

Animals↗