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Susan Holmes

Publications and source records attributed to Susan Holmes.

At least 19 recordsLinked to original sources
PubMed2025

Epistasis of ERAP1 With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia: A Genome-Wide Association Study Meta-Analysis.

IMPORTANCE: Frontal fibrosing alopecia (FFA) is an inflammatory and scarring form of hair loss of increasing prevalence that most commonly affects women. An improved understanding of the genetic basis of FFA will support the identification of pathogenic mechanisms and therapeutic targets. OBJECTIVE: To identify novel genomic loci at which common genetic variation affects FFA susceptibility and assess nonadditive effects on genetic risk between susceptibility loci. DESIGN, SETTING, AND PARTICIPANTS: Four genome-wide association studies were combined using an SE-weighted meta-analysis. Within the major histocompatibility complex (MHC) locus, stepwise conditional analysis was undertaken to determine independently associated classical MHC class I alleles. Statistical tests for epistatic interaction were performed between risk alleles at the MHC and endoplasmic reticulum aminopeptidase 1 (ERAP1) loci. MAIN OUTCOMES AND MEASURES: Genome-wide significant locus associated with FFA and nonadditive effects on genetic risk between susceptibility loci. RESULTS: Of 6668 included patients, there were 1585 European female individuals with FFA and 5083 controls. Genome-wide significant associations were identified at 4 genomic loci, including a novel susceptibility locus at 5q15, and the association signal could be fine-mapped to a single nucleotide substitution (rs10045403) in the 5' untranslated region of ERAP1 (rs10045403; odds ratio, 1.30; 95% CI, 1.19-1.43; P = 3.6 × 10-8). Within the MHC, FFA risk was statistically independently associated with HLA-A*11:01, HLA-A*33:01, HLA-B*07:02, and HLA-B*35:01. FFA risk was affected by genetic variation at the ERAP1 locus only in individuals who carried at least 1 of the MHC class I risk alleles. CONCLUSIONS AND RELEVANCE: In this genome-wide meta-analysis, a supra-additive effect of genetic variation was found that affected peptide trimming and antigen presentation on FFA susceptibility. Patients with FFA may benefit from emerging therapeutic approaches that modulate ERAP-mediated processes.

Female↗
PubMed2006

Parkinson's disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and genetic alterations in alpha-synuclein cause autosomal-dominant hereditary PD. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Here we investigated the effect of alpha-synuclein expression on cell susceptibility to proteasome inhibition, oxidative and nitrative stresses by using a PC 12-Tet-off regulatory system. We found that inducible expression of A30P or A53T mutant alpha-synuclein decreased the proteasome activity, increased intracellular ROS levels, and enhanced lactacystin- and H2O2-induced cell death. Furthermore, 3-nitrotyrosine levels increased in cells expressing alpha-synuclein, and further increased after Sin-1 (a NO donor) treatment compared with untreated or treated non-induced cells. Expression of alpha-synuclein (mutant more than wild type) significantly enhances Sin-1 toxicity. These results indicate that genetic mutations in alpha-synuclein may increase neuronal vulnerability to cellular stress in aging and PD pathogenesis.

Animals↗
PubMed2006

Fit for practice? An exploration of the development of newly qualified nurses using focus groups.

UNLABELLED: Previous research in the newly qualified has primarily focused upon their levels of competence at the time of registration rather than upon the way that this continues to develop over time. Though newly qualified nurses are expected to be competent and able to practice independently without direct supervision the reality is that, for most, their training has not equipped them with the knowledge, skills or confidence necessary for independent practice. This belief provided the foundations for this study designed to gain an understanding of the way that competence develops amongst nurses themselves and how this is seen by their managers and those working with them. It focused neither on what competencies nurses possessed nor on the level of overall competence but rather on the factors influencing the development of competence over time. RESEARCH DESIGN: This qualitative exploratory study relied upon a combination of focus groups and individual interviews to access information and perceptions not readily accessible through more quantitative means. DATA COLLECTION: Data was collected using focus groups involving newly qualified staff, including both those on a development programme and those in substantive posts, experienced qualified nurses (preceptors) and practice development nurses. A total of twelve focus groups were conducted yielding a purposive sample of 105 volunteer participants; groups were continued until no new data emerged and saturation was achieved. Ward managers (5) were interviewed individually and their data was added to that obtained from the focus groups. ANALYSIS: Content analysis of the transcripts enabled the material to be explored systematically to identify relevant themes and categories within the data thus helping to clarify descriptions of the major issues identified; these were returned to the participants to ensure validity in data interpretation. FINDINGS: Ward managers appear to have low expectations of the newly qualified while 'new' nurses themselves believe that they are expected to be able to fulfil tasks that they feel ill-equipped to undertake. This emphasises the need for appropriate support to enable them to develop their knowledge, skills and confidence and enable independent practice. While staff development programmes benefit some, others gain equal value from supportive preceptorship in helping them to develop the clinical and managerial skills necessary in today's healthcare climate.

Attitude of Health Personnel↗
PubMed2006

Nutrition and the prevention of cancer.

Many studies have shown an association between nutrition and cancer and, since one in three people in England will develop cancer and one in four will die from the disease, there is great interest in prevention through diet. The issues are complex and evidence is often limited or equivocal. This review considers the strength of the evidence and puts the risks of cancer in context. It concludes that although no dietary changes can be guaranteed to prevent cancer, on balance there is enough evidence to recommend the current official "healthy eating" guidelines as the best advice for reducing the risk of diet-associated cancers. The greatest protection against cancer coincides with eating more fruit, vegetables and wholegrain foods. Overindulgence in alcohol, smoking, obesity and lack of exercise may interact with dietary factors to increase the risk of some cancers. Healthy lifestyle measures such as regular exercise, avoiding overweight, not smoking and limiting the intake of alcohol can therefore also be recommended as helping to reduce the risk of cancer. When advising individuals, it is necessary to consider all aspects of the person's lifestyle and to bear in mind that there are some limitations to the current evidence. A summary of the practical recommendations for reducing cancer risk is included.

Diet↗
PubMed2005

Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer.

BACKGROUND: While lymph node metastasis is among the strongest predictors of disease-free and overall survival for patients with breast cancer, the immunological nature of tumor-draining lymph nodes is often ignored, and may provide additional prognostic information on clinical outcome. METHODS AND FINDINGS: We performed immunohistochemical analysis of 47 sentinel and 104 axillary (nonsentinel) nodes from 77 breast cancer patients with 5 y of follow-up to determine if alterations in CD4, CD8, and CD1a cell populations predict nodal metastasis or disease-free survival. Sentinel and axillary node CD4 and CD8 T cells were decreased in breast cancer patients compared to control nodes. CD1a dendritic cells were also diminished in sentinel and tumor-involved axillary nodes, but increased in tumor-free axillary nodes. Axillary node, but not sentinel node, CD4 T cell and dendritic cell populations were highly correlated with disease-free survival, independent of axillary metastasis. Immune profiling of ALN from a test set of 48 patients, applying CD4 T cell and CD1a dendritic cell population thresholds of CD4 > or = 7.0% and CD1a > or = 0.6%, determined from analysis of a learning set of 29 patients, provided significant risk stratification into favorable and unfavorable prognostic groups superior to clinicopathologic characteristics including tumor size, extent or size of nodal metastasis (CD4, p < 0.001 and CD1a, p < 0.001). Moreover, axillary node CD4 T cell and CD1a dendritic cell populations allowed more significant stratification of disease-free survival of patients with T1 (primary tumor size 2 cm or less) and T2 (5 cm or larger) tumors than all other patient characteristics. Finally, sentinel node immune profiles correlated primarily with the presence of infiltrating tumor cells, while axillary node immune profiles appeared largely independent of nodal metastases, raising the possibility that, within axillary lymph nodes, immune profile changes and nodal metastases represent independent processes. CONCLUSION: These findings demonstrate that the immune profile of tumor-draining lymph nodes is of novel biologic and clinical importance for patients with early stage breast cancer.

Adult↗
PubMed2005

Memory T cells have gene expression patterns intermediate between naive and effector.

The biological basis underlying differentiation of naive (NAI) T cells into effector (EFFE) and memory (MEM) cells is incompletely understood. Furthermore, whether NAI T cells serially differentiate into EFFE and then MEM cells (linear differentiation) or whether they concurrently differentiate into either EFFE or MEM cells (parallel differentiation) remains unresolved. We isolated NAI, EFFE, and MEM CD8(+) T cell subsets from human peripheral blood and analyzed their gene expression by using microarrays. We identified 156 genes that strongly differentiate NAI, EFFE, and MEM CD8(+) T cells; these genes provide previously unrecognized markers to help identify each cell type. Using several statistical approaches to analyze and group the data (standard heat-map and hierarchical clustering, a unique circular representation, multivariate analyses based on principal components, and a clustering method based on phylogenetic parsimony analysis), we assessed the lineage relationships between these subsets and showed that MEM cells have gene expression patterns intermediate between NAI and EFFE T cells. Our analysis suggests a common differentiation pathway to an intermediate state followed by a split into EFFE or MEM cells, hence supporting the parallel differentiation model. As such, conditions under which NAI T cells are activated may determine the magnitude of both EFFE and MEM cells, which arise subsequently. A better understanding of these conditions may be very useful in the design of future vaccine strategies to maximize MEM cell generation.

CD8-Positive T-Lymphocytes↗
PubMed2005

Assessing the quality of life--reality or impossible dream? A discussion paper.

Many now claim that maintaining or improving the quality of life is the essence of healthcare (i.e. care and/or treatment that improves the patients' quality of life). Interest in QL, however, stems from increasing recognition that individuals are an integrated whole rather than a series of disconnected parts or disease states. Though this represents a significant change from the past--when the emphasis lay solely on physical or medical condition--it is not, in itself, meaningful unless reliable and valid ways of evaluating the human aspects of the experience can be identified (i.e. quality of life). As quality of life (QL) is seen as a positive state, a desirable outcome of healthcare interventions, it has gained credence as an appropriate outcome measure and has intuitive appeal. Indeed, it is suggested that, because of its close relationship to mortality, self-perceived QL may be the most important outcome of both acute and, particularly, chronic disease. Lack of consensus about its meaning has, however, resulted in ambiguity and, therefore, difficulties in its measurement reflecting, in turn, the difficulty in identifying the components of this multifaceted concept. This paper explores these issues and questions whether we are, in fact, attempting to measure something that cannot truly be measured.

Outcome Assessment, Health Care↗
PubMed2005

Gene expression diversity among Mycobacterium tuberculosis clinical isolates.

Intraspecies genetic diversity has been demonstrated to be important in the pathogenesis and epidemiology of several pathogens, such as HIV, influenza, Helicobacter and Salmonella. It is also important to consider strain-to-strain variation when identifying drug targets and vaccine antigens and developing tools for molecular diagnostics. Here, the authors present a description of the variability in gene expression patterns among ten clinical isolates of Mycobacterium tuberculosis, plus the laboratory strains H37Rv and H37Ra, growing in liquid culture. They identified 527 genes (15 % of those tested) that are variably expressed among the isolates studied. The remaining genes were divided into three categories based on their expression levels: unexpressed (38 %), low to undetectable expression (31 %) and consistently expressed (16 %). The expression categories were compared with functional categories and three biologically interesting gene lists: genes that are deleted among clinical isolates, T-cell antigens and essential genes. There were significant associations between expression variability and the classification of genes as T-cell antigens, involved in lipid metabolism, PE/PPE, insertion sequences and phages, and deleted among clinical isolates. This survey of mRNA expression among clinical isolates of M. tuberculosis demonstrates that genes with important functions can vary in their expression levels between strains grown under identical conditions.

Bacterial Proteins↗
PubMed2004

What do we know about... nutrition and older people?

Nutrition is important to the health and functioning of elderly people. This paper summarises the evidence that many old people suffer from undernutrition and outlines the insidious effects of this form of malnutrition. It discusses the physiological and practical difficulties elderly people face in achieving good nutrition, and the challenge this poses to health workers. Given the UK's ageing population, undernutrition in older people is a significant public health issue as well as one that should concern all health professionals involved in individual or group contacts with elderly clients.

Aged↗
PubMed2003

An in vitro human cell-based assay to rank the relative immunogenicity of proteins.

A method to rank proteins based on their relative immunogenicity has been devised. A statistical analysis of peptide-specific responses in large human donor pools provides a structure index value metric that ranked four industrial enzymes in the order determined by both mouse and guinea pig exposure models. The ranking method also compared favorably with human sensitization rates measured in occupationally exposed workers. Structure index values for other proteins known to cause immune responses in humans were also determined and found to be higher than the value determined for human beta2-microglobulin. Using values from known immunogenic and putative nonimmunogenic proteins, a cut-off value was established. The structure index value calculation provides a comparative method to predict subsequent immunogenicity on a human population basis without the need to use animal models. Information provided by this assay can be used in the early development of protein therapies and other protein-based applications to select or create reduced immunogenicity variants.

Allergens↗
PubMed2003

Human population-based identification of CD4(+) T-cell peptide epitope determinants.

A human cell-based method to identify functional CD4(+) T-cell epitopes in any protein has been developed. Proteins are tested as synthetic 15-mer peptides offset by three amino acids. Percent responses within a large donor population are tabulated for each peptide in the set. Peptide epitope regions are designated by difference in response frequency from the overall background response rate for the compiled dataset. Epitope peptide responses are reproducible, with a median coefficient of variance of 21% when tested on multiple random-donor sets. The overall average response rate within the dataset increases with increasing putative human population antigenic exposure to a given protein. The background rate was high for HPV16 E6, and was low for human-derived cytokine proteins. The assay identified recall epitope regions within the donor population for the protein staphylokinase. For an industrial protease with minimal presumed population exposure, immunodominant epitope peptides were identified that were found to bind promiscuously to many HLA class II molecules in vitro. The peptide epitope regions identified in presumably unexposed donors represent a subset of the total recall epitopes. Finally, as a negative control, the assay found no peptide epitope regions in human beta2-microglobulin. This method identifies functional CD4(+) T-cell epitopes in any protein without pre-selection for HLA class II, suggests whether a donor population is pre-exposed to a protein of interest, and does not require sensitized donors for in vitro testing.

Blood Donors↗
PubMed2003

Statistics for phylogenetic trees.

This paper poses the problem of estimating and validating phylogenetic trees in statistical terms. The problem is hard enough to warrant several tacks: we reason by analogy to rounding real numbers, and dealing with ranking data. These are both cases where, as in phylogeny the parameters of interest are not real numbers. Then we pose the problem in geometrical terms, using distances and measures on a natural space of trees. We do not solve the problems of inference on tree space, but suggest some coherent ways of tackling them.

Animals↗
PubMed2003

Are probiotics and other functional foods the medicines of the future?

Many health benefits are being claimed on behalf of so-called 'functional foods', and they are becoming more popular among consumers. But do they really help to prevent and treat disease? This paper discusses their potential uses and looks at current research and opinion, focusing on probiotics, prebiotics and synbiotics, which can be added to foods such as yoghurt.

Animals↗
PubMed2003

Botulinum toxin: a deadly substance with great therapeutic effect.

Injections of botulinum toxin are commonly associated with cosmetic improvements. However, BTX is also used therapeutically to treat patients with neuromuscular and neurological disorders. Therapy is primarily carried out in outpatients as part of a wider management regimen, so it is vital for nurses to not only be aware of how BTX works but also of its deadly toxic properties.

Anti-Dyskinesia Agents↗
PubMed2002

A back migration from Asia to sub-Saharan Africa is supported by high-resolution analysis of human Y-chromosome haplotypes.

The variation of 77 biallelic sites located in the nonrecombining portion of the Y chromosome was examined in 608 male subjects from 22 African populations. This survey revealed a total of 37 binary haplotypes, which were combined with microsatellite polymorphism data to evaluate internal diversities and to estimate coalescence ages of the binary haplotypes. The majority of binary haplotypes showed a nonuniform distribution across the continent. Analysis of molecular variance detected a high level of interpopulation diversity (PhiST=0.342), which appears to be partially related to the geography (PhiCT=0.230). In sub-Saharan Africa, the recent spread of a set of haplotypes partially erased pre-existing diversity, but a high level of population (PhiST=0.332) and geographic (PhiCT=0.179) structuring persists. Correspondence analysis shows that three main clusters of populations can be identified: northern, eastern, and sub-Saharan Africans. Among the latter, the Khoisan, the Pygmies, and the northern Cameroonians are clearly distinct from a tight cluster formed by the Niger-Congo-speaking populations from western, central western, and southern Africa. Phylogeographic analyses suggest that a large component of the present Khoisan gene pool is eastern African in origin and that Asia was the source of a back migration to sub-Saharan Africa. Haplogroup IX Y chromosomes appear to have been involved in such a migration, the traces of which can now be observed mostly in northern Cameroon.

Africa↗