PubMed Health⌕ Search

Biomedical subjects

Brian Cox

Publications and source records attributed to Brian Cox.

At least 19 recordsLinked to original sources
PubMed2006

In quest of virtual tests for structural composites.

The difficult challenge of simulating diffuse and complex fracture patterns in tough structural composites is at last beginning to yield to conceptual and computational advances in fracture modeling. Contributing successes include the refinement of cohesive models of fracture and the formulation of hybrid stress-strain and traction-displacement models that combine continuum (spatially averaged) and discrete damage representations in a single calculation. Emerging hierarchical formulations add the potential of tracing the damage mechanisms down through all scales to the atomic. As the models near the fidelity required for their use as virtual experiments, opportunities arise for reducing the number of costly tests needed to certify safety and extending the design space to include material configurations that are too complex to certify by purely empirical methods.

Journal Article↗
PubMed2006

Risk factors for prostate cancer: A national case-control study.

Statutory notification of cancer in New Zealand provided an opportunity to investigate risk factors for prostate cancer in a large national population-based case-control study. We analyzed data obtained from telephone interviews with 923 cases and 1,224 controls. For inclusion in the study, all subjects had to have been married at some time. We found an increased risk of prostate cancer among those with a history of prostate cancer in first degree relatives (RR 2.6; 95% CI, 1.9-3.7) and an increased risk of prostate cancer with length of marriage among men married only once and still married at interview. For a consecutive subgroup of 550 cases and 819 controls, data on height and weight at age 20 and at 5 years before interview were collected. Men less than or equal to 1.7 m in height at age 20 years had a lower risk of prostate cancer than men taller at that age. There was no association between weight or body mass index and risk of prostate cancer.

Adult↗
PubMed2006

The control of melanoma in New Zealand.

AIMS: This study estimated the impact of prevention, screening, early diagnosis, and treatment on the burden of melanoma in New Zealand. METHODS: Cancer control plans and management guidelines were reviewed to identify activities that could reduce the burden of melanoma in New Zealand and an estimation was made of their effects on incidence and mortality. The base year for estimating changes in incidence and mortality was the published melanoma data for 2002. RESULTS: The registration of melanoma increased from 1037 new registrations in 1993 to 1487 in 1994 and peaked at 1759 in 1995. In 2002 a further increase occurred, to 1842 new registrations and 235 deaths from melanoma. It is likely that 328 of the 1842 new cases of melanoma in 2002 were directly attributable to severe sunburn. A reduction of 10% in the number of people getting severely sunburnt could prevent 28 melanoma cases per year. If 2% of melanoma deaths occur in high-risk individuals, approximately 4 deaths per year could be prevented by surveillance of high-risk groups. Thin melanoma has a very good prognosis: a 10% shift in the depth distribution into the thinnest depth category would result in about 29 deaths from melanoma prevented each year. CONCLUSIONS: The best avenues for reducing the burden of melanoma in New Zealand are prevention of excessive sun exposure and early diagnosis. Reducing severe sunburn and diagnosing a greater proportion of melanomas when they are thin would have the greatest impact on the incidence of and mortality from melanoma.

Adolescent↗
PubMed2006

Global survey of organ and organelle protein expression in mouse: combined proteomic and transcriptomic profiling.

Organs and organelles represent core biological systems in mammals, but the diversity in protein composition remains unclear. Here, we combine subcellular fractionation with exhaustive tandem mass spectrometry-based shotgun sequencing to examine the protein content of four major organellar compartments (cytosol, membranes [microsomes], mitochondria, and nuclei) in six organs (brain, heart, kidney, liver, lung, and placenta) of the laboratory mouse, Mus musculus. Using rigorous statistical filtering and machine-learning methods, the subcellular localization of 3274 of the 4768 proteins identified was determined with high confidence, including 1503 previously uncharacterized factors, while tissue selectivity was evaluated by comparison to previously reported mRNA expression patterns. This molecular compendium, fully accessible via a searchable web-browser interface, serves as a reliable reference of the expressed tissue and organelle proteomes of a leading model mammal.

Animals↗
PubMed2006

Hereditary diffuse gastric cancer: diagnosis and management.

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome defined by germline mutation of the E-cadherin gene (CDH-1). The cumulative risk for advanced gastric cancer in HDGC is 67% in men and 83% in women by 80 years of age. Early HDGC is characterized by multiple microscopic foci of intramucosal signet-ring cell carcinoma. The time to progression of these foci appears to be variable and currently is not predictable--the carcinoma foci may remain confined to the mucosa for many years. The management options for mutation carriers include prophylactic gastrectomy or surveillance gastroscopy. The only extensive published surveillance experience used chromogastroscopy, which detected early HDGC foci not visible on white-light endoscopy. The use of new techniques such as confocal microscopy, spectroscopy, or autofluorescence may prove useful, but have not been studied in HDGC. In patients up to 20 years of age, the risk for gastric cancer is less than 1%; this risk is outweighed by the mortality and morbidity associated with total gastrectomy. It is therefore recommended that genetic testing should occur at 16 years of age and that annual surveillance chromogastroscopy also should begin at age 16 in identified CDH-1 mutation carriers. After 20 years of age, delaying prophylactic gastrectomy carries significant risk, particularly if the alternative is surveillance by white-light gastroscopy. Surveillance chromogastroscopy (Congo red/methylene blue technique) should be considered for individuals younger than 20 years and patients unwilling to undergo prophylactic gastrectomy. Sufficient evidence for an increased risk for lobular breast cancer in CDH-1 carriers exists to justify breast screening in female carriers older than 35 years of age, however, evidence is insufficient to recommend prophylactic mastectomy.

Cadherins↗
PubMed2006

Use of alcohol and drugs to self-medicate anxiety disorders in a nationally representative sample.

This study examined the prevalence and correlates of self-medication of anxiety disorders with alcohol and drugs in a nationally representative sample (N = 5877). A modified version of the Composite International Diagnostic Interview was used to make DSM-III-R mental disorder diagnoses. Frequencies of self-medication ranged from 7.9% (social phobia, speaking subtype) to 35.6% (generalized anxiety disorder). Among respondents with an anxiety disorder, self-medication was significantly associated with an increased likelihood of comorbid mood disorders, substance use disorders, distress, suicidal ideation, and suicide attempts. Self-medication behavior remained significantly associated with an increased likelihood of suicidal ideation (adjusted odds ratio = 1.66; 1.17-2.36) as well as suicide attempts (adjusted odds ratio = 2.23; 1.50-3.31), even after adjusting for a number of sociodemographic and psychiatric variables. These results suggest that individuals with anxiety disorders who self-medicate their symptoms with alcohol or drugs may be at increased risk for mood and substance use disorders and suicidal behavior.

Adolescent↗
PubMed2006

The [PSI+] prion of Saccharomyces cerevisiae can be propagated by an Hsp104 orthologue from Candida albicans.

The molecular chaperone Hsp104 is not only a key component of the cellular machinery induced to disassemble aggregated proteins in stressed cells of Saccharomyces cerevisiae but also plays an essential role in the propagation of the [PSI+], [URE3], and [RNQ/PIN+] prions in this organism. Here we demonstrate that the fungal pathogen Candida albicans carries an 899-residue stress-inducible orthologue of Hsp104 (CaHsp104) that shows a high degree of amino acid identity to S. cerevisiae Hsp104 (ScHsp104). This identity is significantly lower in the N- and C-terminal regions implicated in substrate recognition and cofactor binding, respectively. CaHsp104 is able to provide all known functions of ScHsp104 in an S. cerevisiae hsp104 null mutant, i.e., tolerance to high-temperature stress, reactivation of heat-denatured proteins, and propagation of the [PSI+] prion. As also observed for ScHsp104, overexpression of CaHsp104 leads to a loss of the [PSI+] prion. However, unlike that of ScHsp104, CaHsp104 function is resistant to guanidine hydrochloride (GdnHCl), an inhibitor of the ATPase activity of this chaperone. These findings have implications both in terms of the mechanism of inhibition of Hsp104 by GdnHCl and in the evolution of the ability of fungal species to propagate prions.

Amino Acid Sequence↗
PubMed2005

Formation of a distinctive complex between the inducible bacterial lysine decarboxylase and a novel AAA+ ATPase.

AAA+ ATPases are ubiquitous proteins that employ the energy obtained from ATP hydrolysis to remodel proteins, DNA, or RNA. The MoxR family of AAA+ proteins is widespread throughout bacteria and archaea but is largely uncharacterized. Limited work with specific members has suggested a potential role as molecular chaperones involved in the assembly of protein complexes. As part of an effort aimed at determining the function of novel AAA+ chaperones in Escherichia coli, we report the characterization of a representative member of the MoxR family, YieN, which we have renamed RavA (regulatory ATPase variant A). We show that the ravA gene exists on an operon with another gene encoding a protein, YieM, of unknown function containing a Von Willebrand Factor Type A domain. RavA expression is under the control of the sigmaS transcription factor, and its levels increase toward late log/early stationary phase, consistent with its possible role as a general stress-response protein. RavA functions as an ATPase and forms hexameric oligomers. Importantly, we demonstrate that RavA interacts strongly with inducible lysine decarboxylase (LdcI or CadA) forming a large cage-like structure consisting of two LdcI decamers linked by a maximum of five RavA oligomers. Surprisingly, the activity of LdcI does not appear to be affected by binding to RavA in a number of in vitro and in vivo assays, however, complex formation results in the stimulation of RavA ATPase activity. Data obtained suggest that the RavA-LdcI interaction may be important for the regulation of RavA activity against its targets.

Adenosine Triphosphatases↗
PubMed2005

Prospects for cancer control: colorectal cancer.

AIMS: The study assessed the contribution to the control of colorectal cancer achievable from primary prevention, screening, early diagnosis, and treatment in New Zealand. METHODS: Available estimates of the attributable risk or protection offered by significantly increasing consumption of fruit and vegetables were used to predict the number of cases of (and deaths from) colorectal cancer prevented if these activities were effective in 1999. The potential effect of screening was also estimated from published results. Estimates of the potential effect of improvements in early diagnosis and treatment available from cancer-control plans of other countries were used to estimate the likely impact of such improvements in New Zealand. RESULTS: Primary prevention could potentially prevent 81 deaths in men and 77 deaths in women from colorectal cancer each year. The potential impact of screening differed between screening methods, with the prevention of 44 deaths in men and 35 deaths in women from colorectal cancer by screening using faecal occult blood testing or 73 deaths in men and 53 deaths in women annually from colorectal cancer by screening using flexible sigmoidoscopy. Improvements in surgical practice and reorganisation of surgical services together with improved use of radiotherapy and chemotherapy could prevent about 82 deaths in men and 78 deaths in women from colorectal cancer each year. CONCLUSIONS: The most immediate control of colorectal cancer appeared to be achievable by improvements in surgical services and the introduction of screening while increased consumption of fruit and vegetables provided potential longer-term reductions in colorectal cancer incidence and mortality.

Adult↗
PubMed2005

Dissecting Wnt/beta-catenin signaling during gastrulation using RNA interference in mouse embryos.

Differential gene regulation integrated in time and space drives developmental programs during embryogenesis. To understand how the program of gastrulation is regulated by Wnt/beta-catenin signaling, we have used genome-wide expression profiling of conditional beta-catenin mutant embryos. Known Wnt/beta-catenin target genes, known components of other signaling pathways, as well as a number of uncharacterized genes were downregulated in these mutants. To further narrow down the set of differentially expressed genes, we used whole-mount in situ screening to associate gene expression with putative domains of Wnt activity. Several potential novel target genes were identified by this means and two, Grsf1 and Fragilis2, were functionally analyzed by RNA interference (RNAi) in completely embryonic stem (ES) cell-derived embryos. We show that the gene encoding the RNA-binding factor Grsf1 is important for axial elongation, mid/hindbrain development and axial mesoderm specification, and that Fragilis2, encoding a transmembrane protein, regulates epithelialization of the somites and paraxial mesoderm formation. Intriguingly, the knock-down phenotypes recapitulate several aspects of Wnt pathway mutants, suggesting that these genes are components of the downstream Wnt response. This functional genomic approach allows the rapid identification of functionally important components of embryonic development from large datasets of putative targets.

Alkaline Phosphatase↗
PubMed2005

The impact of breast cancer screening on breast cancer registrations in New Zealand.

AIMS: To investigate the impact of the national breast cancer screening programme, BreastScreen Aotearoa, on breast cancer registrations in New Zealand. METHODS: Age-specific breast cancer incidence rates for women aged 50-64 years were compared before and after the establishment of BreastScreen Aotearoa. The degree of spread of breast cancers diagnosed at screening was compared with the degree of spread of breast cancers registered before the introduction of population screening in New Zealand. RESULTS: As expected, there was a marked increase in the age-specific incidence of breast cancer in New Zealand women aged 50-64 years in the first year of screening. There was a shift towards earlier diagnosis in women diagnosed with breast cancer at screening, compared with the diagnosis of breast cancers in women aged 50-64 registered before the introduction of population screening for breast cancer in New Zealand. CONCLUSIONS: BreastScreen Aotearoa has had the expected impact on breast cancer registration for a screening programme that detects breast cancer early.

Age Distribution↗
PubMed2005

Therapeutic scope of modulation of non-voltage-gated cation channels.

Although widely regarded as attractive drug targets, less than a tenth of known ion channels are currently commercially exploited as therapeutic targets. Historically, drug discovery efforts on ion channel targets have been encumbered by a lack of molecular and structural information, sub-optimal screening technologies and a paucity of discriminating pharmacological tools. Although challenges remain, recent scientific and technological advances in the area of ion channel research and screening offer the exciting prospect of a new, more-predictive era of ion channel drug discovery. In this article, focusing primarily on non voltage gated cation channels, we describe the continuing evolution of approaches to ion channel drug discovery, highlight recent developments in the ion channel field and consider their potential impact on discovering and ascribing function to ion channel targets. We discuss the renaissance of known ion channel targets, such as nicotinic acetylcholine receptors and calcium-activated potassium channels, as well as the emergence of the transient receptor potential (TRP) channels as a gene family of cation channels with broad therapeutic potential.

Animals↗
PubMed2005

Integrating gene and protein expression data: pattern analysis and profile mining.

Proteomics and functional genomics are emerging new research fields devoted to the study of the entire collection of proteins and mRNA transcripts (collectively known as gene products) that define a biological system. DNA microarrays are now a popular platform for measuring changes in messenger RNA transcript levels on a genome-wide scale, while gel-free shotgun profiling methods based on tandem mass spectrometry are increasingly being used to determine the identity, modification states, and relative abundance of large numbers of proteins. By defining the behavior of entire biological pathways and networks under various physiological states, these studies aim to extend traditional reductionist molecular genetic approaches regarding the biological roles of the vast array of uncharacterized gene products. A key goal is to determine how the information encoded by the myriad of expressed gene products is integrated at the molecular, cellular, and even whole organism level to create the dynamic biochemical processes and complex physiological controls that sustain life. While comparison of the complementary information contained in proteomic and mRNA data sets poses considerable analytical challenges, these efforts should provide added insight into the fundamental mechanisms underlying physiology, development, and the emergence of disease. Here, we outline several analytical approaches, methods, and tools that have proven to be helpful in the face of this important challenge.

Algorithms↗
PubMed2004

Therapeutic scope of modulation of non-voltage-gated cation channels.

Although widely regarded as attractive drug targets, less than a tenth of known ion channels are currently commercially exploited as therapeutic targets. Historically, drug discovery efforts on ion channel targets have been encumbered by a lack of molecular and structural information, sub-optimal screening technologies and a paucity of discriminating pharmacological tools. Although challenges remain, recent scientific and technological advances in the area of ion channel research and screening offer the exciting prospect of a new, more-predictive era of ion channel drug discovery. In this article, focusing primarily on non-voltage-gated cation channels, we describe the continuing evolution of approaches to ion channel drug discovery, highlight recent developments in the ion channel field and consider their potential impact on discovering and ascribing function to ion channel targets. We discuss the renaissance of known ion channel targets, such as nicotinic acetylcholine receptors and calcium-activated potassium channels, as well as the emergence of the transient receptor potential (TRP) channels as a gene family of cation channels with broad therapeutic potential.

Animals↗
PubMed2004

Does a U-shaped relationship exist between alcohol use and DSM-III-R mood and anxiety disorders?

BACKGROUND: In recent community surveys, abstainers and heavy drinkers of alcohol have reported more mood and anxiety symptoms than moderate drinkers (U-shaped relationship). The present study was aimed at extending this finding by investigating this potential U-shaped relationship using structured diagnostic interviews to assess mood and anxiety disorders. METHODS: Data came from two contemporaneous surveys, the National Comorbidity Survey (NCS; N=6780) and the Mental Health Supplement of the Ontario Health Survey (OHS-MHS; N=7001). The University of Michigan Revision of the Composite International Diagnostic Interview (UM-CIDI) was used to make DSM-III-R psychiatric diagnoses in both surveys. Three mutually exclusive lifetime alcohol use categories were compared: (1) Alcohol abstainers-individuals reporting no alcohol use or less than 12 drinks in any year throughout their life. (2) Moderate drinkers-individuals that did not meet criteria for alcohol abstainers or problem drinkers. (3) Problem drinkers-DSM-III-R lifetime alcohol abuse, dependence or hazardous levels of alcohol use. RESULTS: After controlling for demographic variables, alcohol abstainers were not found to have significantly higher rates of mood and anxiety disorders in comparison with moderate drinkers. However, problem drinking was significantly associated with mood and anxiety disorders. CONCLUSIONS: Across both surveys, there was no evidence of a U-shaped relationship between lifetime alcohol consumption and lifetime mood and anxiety disorders.

Adult↗
PubMed2004

TRP channels as drug targets.

Ca2+ channel antagonists acting on electrically-excitable cells have proved to be valuable therapeutic agents. The discovery of such agents and the identification of their molecular target resulted from the investigation of unexpected actions of known pharmacological agents. Ca2+ influx through receptor-operated channels in electrically non-excitable cells such as leukocytes is also functionally important, but to date the channels involved have not been successfully exploited as drug targets for anti-inflammatory therapy. Until recently, research in this area has been hindered by the lack of obvious molecular identity, but the emergence of the transient receptor potential (TRP) cation family has yielded promising candidates which may underpin the different receptor-operated Ca2+ influx pathways present in leukocytes. In addition, receptor-operated Ca2+ influx channels are also expressed in electrically-excitable cells suggesting that receptor-operated Ca2+ entry pathways are likely to be of wider significance and emphasizes the breadth of their potential as novel, and as yet, unexplored and unexploited drug targets.

Calcium↗
PubMed2003

Ritter-type reactions of N-chlorosaccharin: a method for the electrophilic diamination of alkenes.

[reaction: see text] N-Chlorosaccharin has been shown to undergo electrophilic Ritter-type reactions with alkenes in acetonitrile. The resulting labile beta-chloro sulfonylamidines can be ring-opened and cyclized to imidazolines. Overall this provides a one pot method for the electrophilic diamination of alkenes. Competing aziridine formation as well as allylic chlorination are also observed depending on the nature of the alkene used.

Acetonitriles↗