Biomedical subjects

Keith Wilson

Publications and source records attributed to Keith Wilson.

17 recordsLinked to original sources

PubMed2006

Iron and the anaemia of chronic disease: a review and strategic recommendations.

BACKGROUND: The incidence of anaemia is high in many chronic conditions, yet it often receives little attention. SCOPE/METHODS: A panel of international experts with experience in haematology, nephrology, oncology, rheumatology and pharmacy was convened to prepare strategic guidelines. A focused literature search was conducted after key issues had been identified. A series of recommendations was agreed, backed, wherever possible, by published evidence which is included in the annotations. RECOMMENDATIONS: Anaemia is a critical issue for patients with chronic diseases. Healthcare professionals need to recognise that anaemia is a frequent companion of cancer and chronic conditions such as rheumatoid arthritis and heart failure. It reduces patients' quality of life and can increase morbidity and mortality. Anaemia should be considered as a disordered process in which the rate of red cell production fails to match the rate of destruction which leads eventually to a reduction in haemoglobin concentration; this process is common to all chronic anaemias. The aim of anaemia management should be to restore patient functionality and quality of life by restoring effective red cell production. Blood transfusion can elevate haemoglobin concentration in the short term but does nothing to address the underlying disorder; red cell transfusion is, therefore, not an appropriate treatment for chronic anaemia. Patients with anaemia of chronic disease may benefit from iron therapy and/or erythropoiesis stimulating agents (ESAs). Intravenous iron should be considered since this can be given safely to patients with chronic diseases while intramuscular iron causes unacceptable adverse effects and oral iron has limited efficacy in chronic anaemia. CONCLUSION: The management of anaemia calls for the development of a specialist service together with education of all healthcare professionals and transfer of skills from areas of good practice. Improvement in the management of anaemia requires a fundamental change of attitude from healthcare professionals.

Anemia, Iron-Deficiency↗

PubMed2005

Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis.

RATIONALE: Many of the interstitial lung diseases represent a diagnostic and therapeutic challenge because their clinical and even histologic features are often nonspecific. Likewise, the transcriptional signatures of most of them are unknown. OBJECTIVE: To compare the gene expression patterns from patients with idiopathic pulmonary fibrosis (IPF) hypersensitivity pneumonitis (HP), and nonspecific interstitial pneumonia (NSIP) using custom oligonucleotide microarrays. METHODS: We profiled lung biopsies from 15 patients with IPF, 12 with HP, and eight with NSIP. Labeled complementary ribonucleic acid was hybridized to a custom Affymetrix oligonucleotide DNA microarray using standard Affymetrix protocols. The custom array, Hu03, contained 59,619 probe sets representing an estimated 46,000 gene clusters. RESULTS: We identified statistically significant gene expression signatures that characterize HP and IPF. The HP gene expression signature was enriched for genes that are functionally associated with inflammation, T-cell activation, and immune responses, whereas the IPF signature was characterized by the expression of tissue remodeling, epithelial, and myofibroblast genes. We then compared these gene expression signatures to classify NSIP, a histologic pattern that is often difficult to differentiate consistently from HP and IPF. Two cases exhibited an IPF-like gene expression, another one could be more properly classified as HP, whereas others did not resemble HP or IPF, suggesting that they may represent idiopathic NSIP. CONCLUSIONS: Our results underscore the value of gene expression signatures to classify the interstitial lung diseases and to understand pathogenic mechanisms, and suggest new ways to improve the diagnosis and treatment of patients with these diseases.

Alveolitis, Extrinsic Allergic↗

PubMed2005

Colon cancer secreted protein-2 (CCSP-2), a novel candidate serological marker of colon neoplasia.

Cancers of the colon and rectum are the second leading cause of cancer death among adult Americans. When detected at early stages, colon cancer is highly curable. Colonoscopy, an effective but invasive screening test, has been limited in its public acceptance. The goal of this study was to identify novel serum markers of colon cancers and precancerous colon adenomas as potential candidates for noninvasive detection of early colon neoplasms. Employing expression microarrays, we identified colon cancer secreted protein-2 (CCSP-2) as a novel transcript whose expression is generally absent in normal colon and other normal body tissues, but that is induced an average of 78-fold in Stage II, III, and IV colon cancers, as well as in colon adenomas and colon cancer cell lines. These findings were validated by real-time PCR analysis in an independent panel of colon cancer cases. Moreover, CCSP-2 was shown to encode a secreted protein that circulates stably and is detectable in the blood of mice bearing human cancer xenografts transfected with epitope-tagged CCSP-2. As a novel secreted protein that is markedly induced in colon adenomas and cancers, CCSP-2 is a novel candidate for development as a diagnostic serum marker of early stage colon cancer.

Amino Acid Sequence↗

PubMed2004

15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers.

Marked increased expression of cyclooxygenase 2 (COX-2), a prostaglandin-synthesizing enzyme that is pharmacologically inhibited by nonsteroid anti-inflammatory-type drugs, is a major early oncogenic event in the genesis of human colon neoplasia. We report that, in addition to inducing expression of COX-2, colon cancers further target the prostaglandin biogenesis pathway by ubiquitously abrogating expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme that physiologically antagonizes COX-2. We find that 15-PGDH transcript and protein are both highly expressed by normal colonic epithelia but are nearly undetectable in colon cancers. Using gene transfection to restore 15-PGDH expression in colon cancer cells strongly inhibits the ability of these cells to form tumors in immune-deficient mice and demonstrates 15-PGDH to have functional colon cancer tumor suppressor activity. In interrogating the mechanism for 15-PGDH expression loss in colon cancer, we determined that colonic 15-PGDH expression is directly controlled and strongly induced by activation of the TGF-beta tumor suppressor pathway. These findings thus delineate an enzymatic pathway that induces colon cancer suppression, a pathway that is activated by TGF-beta and mediated by 15-PGDH.

Cell Proliferation↗

PubMed2004

C8orf4 is a transforming growth factor B induced transcript downregulated in metastatic colon cancer.

Transforming growth factor (TGF) beta mediates a tumor suppressor pathway in human colon epithelial cells. We were interested in identifying and characterizing novel genes regulated by the TGF beta pathway in the colon. We employed expression microarrays to identify transcripts induced by TGF beta in Vaco 330, a colon adenoma cell line. We then used expression microarrays to determine which of these TGF beta induced transcripts are down-regulated in metastatic colon cancer. Northern analysis and real-time reverse transcription PCR confirmed and quantified our findings from the microarrays. These analyses highlighted C8orf4 as induced by TGF beta in colon cells. Moreover, C8orf4 is expressed in most normal colon mucosa samples, and is not expressed in most colon cancer metastases or colon cancer cell lines. Colon cancer primary tumors showed reduced expression of C8orf4 relative to normal mucosa, possibly reflecting contributions of C8orf4 expression in stromal cells. C8orf4 is a gene regulated by TGF beta signaling and loss in advanced colon cancer suggests C8orf4 may play a role in colon cell differentiation or growth regulation.

Amino Acid Sequence↗

PubMed2004

Inhibitors of hepatitis C virus NS3.4A protease. Part 3: P2 proline variants.

We recently described the identification of an optimized alpha-ketoamide warhead for our series of HCV NS3.4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P(2). These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S(2) binding pocket as the defining pharmacophore for inhibition of the NS3.4A enzyme.

Carrier Proteins↗

PubMed2004

Larynx squamous cell carcinoma: concepts and future directions.

The larynx is one of the most important structures in the upper aerodigestive tract. Functional impairment of the larynx is a bur-den to patients who suffer from laryngeal carcinoma, the second most common cancer of the head and neck region after the oral cavity.

Carcinoma, Squamous Cell↗

PubMed2004

Australia needs a mental health commission.

OBJECTIVES: The present paper aims to: (i) describe how the Mental Health Commission in New Zealand works and has contributed to the substantial enhancement of mental health resources and services; (ii) determine whether mental health reform policies will ever be implemented properly without an independent monitor with official influence at the highest levels of government; and (iii) demonstrate how variants on this model work in other Western countries and how it can be adapted to the Federated system in Australia. CONCLUSIONS: It is recommended that the Australian National Mental Health Plan 2003-2008 should be complemented by a long-standing national mental health commission (or similarly constituted body), which is also able to report independently from and to the government, with direct access to the Prime Minister, Premiers and Australian Health Ministers. Its aims would be to monitor service effectiveness and identify gaps in service provision, training and performance of the work force, management and government. It would be informed by consumer, carer and provider experience, and by reviews of evidence-based research regarding health needs and cost-effective services. It should accurately cost such service gaps, and advise government on a strategy for implementing them. It could also promote and advise formally on enhancing community awareness, decreasing stigma and discrimination and improving workforce recruitment and retention.

Advisory Committees↗

PubMed2003

Older people. Rising SAP.

Single assessment is a complex process involving a variety of agencies, professions and functions. A key decision will be about the development or purchase of a standard assessment tool. A single assessment process lead needs to be appointed with support from senior management in all relevant organisations.

Aged↗

PubMed2003

PMEPA1, a transforming growth factor-beta-induced marker of terminal colonocyte differentiation whose expression is maintained in primary and metastatic colon cancer.

To identify potential effectors of transforming growth factor (TGF)-beta-mediated suppression of colon cancer, we used GeneChip expression microarrays to identify TGF-beta-induced genes in VACO 330, a nontransformed TGF-beta-sensitive cell line derived from a human adenomatous colon polyp. PMEPA1 was identified as a gene highly up-regulated by TGF-beta treatment of VACO 330. Northern blot analysis confirmed TGF-beta induction of PMEPA1 in VACO 330, as well as a panel of three other TGF-beta-sensitive colon cell lines. PMEPA1 induction could be detected as early as 2 h after TGF-beta treatment and was not inhibited by pretreatment of cells with cycloheximide, suggesting that PMEPA1 is a direct target of TGF-beta signaling. Wild-type PMEPA1 and an alternative splice variant lacking the putative transmembrane domain were encoded by the PMEPA1 locus and were shown by epitope tagging to encode proteins with differing subcellular localization. Both variants were found to be expressed in normal colonic epithelium, and both were shown to be induced by TGF-beta. Consistent with TGF-beta playing a role in terminal differentiation of colonocytes, in situ hybridization of normal colonic epithelium localized PMEPA1 expression to nonproliferating, terminally differentiated epithelium located at the top of colonic crypts. Intriguingly, in situ hybridization and Northern blot analysis showed that the expression of PMEPA1 was well maintained both in colon cancer primary tumors and in colon cancer liver metastases. PMEPA1 is thus a novel TGF-beta-induced marker of a differentiated crypt cell population. Moreover, as PMEPA1 expression is maintained, presumptively in a TGF-beta-independent manner after malignant transformation and metastasis, it demonstrates that even late colon cancers retain a strong capacity to execute many steps of the normal colonic differentiation program.

Alternative Splicing↗

PubMed2002

Primary care prescribing. Hard to swallow.

The Department of Health has invited applications from primary care trusts wishing to become pathfinder sites for repeat dispensing schemes. The NHS plan anticipated that a national scheme would be in operation by 2004 Research suggests repeat dispensing is welcomed by patients but does not save large amounts of money. Joint training for all those involved in a scheme is a key issue.

Drug Prescriptions↗

PubMed2002

Silence of chromosomal amplifications in colon cancer.

Oncogene activation by gene amplification is a major pathogenetic mechanism in human cancer. Using comparative genomic hybridization, we determined that metastatic human colon cancers commonly acquire numerous extra copies of chromosome arms 7p, 8q, 13q, and 20q. We then examined the consequence of these amplifications on gene expression using DNA microarrays. Of 55,000 transcripts profiled, 2,146 were determined to map to one of the four common colon cancer amplicons and to also be expressed in normal or malignant colon tissues. Of these, only 81 transcripts (3.8%) demonstrated a 2-fold increase over normal expression among cancers bearing the corresponding chromosomal amplification. Chromosomal amplifications are common in colon cancer metastasis, but increased expression of genes within these amplicons is rare.

Colonic Neoplasms↗

PubMed2002

The genesis of high-throughput structure-based drug discovery using protein crystallography.

Over the past 12 years, drugs have been developed using structure-based drug design relying upon traditional crystallographic methods. Established successes, such as the drugs designed against HIV-1 protease and neuraminidase, demonstrate the utility of a structure-based approach in the drug-discovery process. However, the approach has historically lacked throughput and reliability capabilities; these bottlenecks are being overcome by breakthroughs in high-throughput structural biology. Recent technological innovations such as submicroliter high-throughput crystallization, high-performance synchrotron beamlines and rapid binding-site analysis of de novo targets using virtual ligand screening and small molecule co-crystallization have resulted in a significant advance in structure-based drug discovery.

Crystallography, X-Ray↗

PubMed2002

A headache diagnosis project.

BACKGROUND: Despite the availability of objective criteria, the diagnosis of migraine is thought to be missed frequently in primary practice. OBJECTIVE: To determine the most important questions assisting in the clinical diagnosis of migraine headache. METHODS: A cohort of 461 patients referred to headache specialists in Canada was assessed using a pro-forma questionnaire that was completed by the patients alone or administered by the physicians themselves. A final clinical diagnosis was recorded after a complete clinical evaluation. In a subsequent validation study, three questions derived from the results of the first phase of the study were administered to a new cohort of 128 patients, and diagnoses of "migraine" or "not migraine" were recorded according to the decision generated in the first part of the study. The final clinical diagnosis was taken as the "gold standard" for diagnosis, and the results from the two independently derived diagnostic methods were compared. RESULTS: Statistical analysis of the responses from part 1 of the study yielded three questions (related to daily occurrence, unilaterally, and functional impairment) that distinguished between pure migraine and other headache diagnoses with high reliability and validity. The sensitivity and selectivity of the three-question protocol exceeded 91%. CONCLUSIONS: The use of three questions related to headache frequency, laterality, and impact on functioning may represent an attractive screening instrument in primary care practice, alerting physicians to the diagnosis of migraine in patients or to the possibility of a second or alternative headache diagnosis in patients in whom their diagnosis of migraine previously has been made. The presence of multiple headache syndromes in individual patients, as is common in tertiary referral practice, may reduce the discriminating power of the three-question protocol.

Adult↗

PubMed2002

Organ preservation with interstitial radiation for base of tongue cancer.

Management options for squamous cell carcinoma of the base of tongue include surgical resection (often with adjuvant radiation), definitive external radiation and external combined with interstitial radiation. The reported series is a single institution experience with interstitial radiation for base of tongue cancer. Twenty patients were treated definitively with interstitial radiation as a boost to external radiation, and four patients were treated palliatively with interstitial radiation alone for recurrent base of tongue cancers or disease arising in a previously irradiated base of tongue. Patient, tumor, and treatment details were analyzed relative to disease control and posttreatment patient function. The 5-year actuarial local control, locoregional control, distant metastasis-free survival, overall disease-free survival, and actuarial overall survival of the definitively treated patients were 86%, 84%, 57%, 41%, and 30%, respectively. The 5-year actuarial rate of tolerating a normal diet was 86%, and all long-term survivors had normal speech function. Of the four patients treated palliatively with interstitial implant alone for recurrent disease (three patients), or a second primary cancer in a previously irradiated site (one patient), local control was obtained in three and long-term disease-free survival was obtained in one. Interstitial implantation combined with external radiation is associated with a high rate of disease eradication with preservation of speech and swallow function. Interstitial radiation alone can achieve effective palliation.

Adult↗

PubMed2002

GRP78, a coreceptor for coxsackievirus A9, interacts with major histocompatibility complex class I molecules which mediate virus internalization.

It is becoming apparent that over the years cell infection by virus seems to have evolved into a multistep process in which many viruses employ distinct cell surface molecules for their attachment and cell entry. In this study the attachment and entry pathway of coxsackievirus A9 (CAV-9), a member of the Picornaviridae family, was investigated. It has been known that, although integrin alpha(v)beta3 is utilized as a receptor, its presence alone is insufficient for CAV-9 infection and that CAV-9 also requires a 70-kDa major histocompatibility complex class I (MHC-I)-associated protein (MAP-70) as a coreceptor molecule. We document by protein isolation and peptide sequencing that the 70-kDa protein is GRP78, a member of the heat shock protein 70 family of stress proteins. Furthermore we show by using fluorescence resonance energy transfer (FRET) that GRP78 is also expressed on the cell surface and associates with MHC-I molecules. In addition CAV-9 infection of permissive cells requires GRP78 and also MHC-I molecules, which are essential for virus internalization. The identification of GRP78 as a coreceptor for CAV-9 and the revelation of GRP78 and MHC-I associations have provided new insights into the life cycle of CAV-9, which utilizes integrin alpha(v)beta3 and GRP78 as receptor molecules whereas MHC-I molecules serve as the internalization pathway of this virus to mammalian cells.

Animals↗

PubMedDate not supplied

A clinical study of migraine evolution.

BACKGROUND: The buildup time of migraine headaches has not been well delineated in publications to date and we are aware of patients whose migraines last well over 72 hours. More concentration on these factors in the assessment of patients might lead to more appropriate therapeutic choices. METHOD: Prospective ascertainment of such data through a questionnaire completed by 253 informed and willing patients with IHS migraine with or without aura consulting Canadian headache specialists. Data were electronically sent to a central computer from each center, tabulated and analyzed using standard statistical parameters. RESULTS: In 253 patients with migraine ascertained using applied IHS criteria, nausea was a feature in over 90% of cases, especially in those with aura. This inhibited the ingestion of oral medications in about a quarter of all subjects. The time to build from no pain to moderate/severe pain was shorter in subjects with auras and was less than 2 hours in 97% of those with and 86% of those without auras. However, we also identified a group of subjects with migraine (over 10% of all) in whom the build time to maximum pain is delayed for over 2 hours. Nausea was experienced by 91.7% of subjects, slightly but significantly later in those without auras. While most headaches in each group lasted from 4 to 72 hours, 24.3% of those with and 20.6% of those without aura expected to experience pain for more than 72 hours, while in untreated cases disability due to pain, nausea, or malaise usually persisted for over 3 days in 24.3% and 16.7% of those with and without aura, respectively. One-fifth of migraineurs may be in pain and/or disabled by accompanying symptoms for over 3 days in a typical migraine attack. Over half of our subjects reported that their medications worked well or excellently. CONCLUSIONS: Attacks of migraine in real-life clinical situations vary somewhat from the IHS criteria in that they are more often associated with nausea that interferes with oral therapy; can persist for over 72 hours; may have slow (>2 hours) buildup to maximum pain in 10% of cases; and may cause disability for over 3 days. Nevertheless, current therapeutic regimens (including prescribed medications) work well for a substantial majority.

Adult↗