PubMed Health⌕ Search

Biomedical subjects

K Walker

Publications and source records attributed to K Walker.

At least 19 recordsLinked to original sources
PubMed2006

Multifactor dimensionality reduction reveals gene-gene interactions associated with multiple sclerosis susceptibility in African Americans.

Multiple sclerosis (MS) is a common disease of the central nervous system characterized by inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Multiple sclerosis exhibits many of the characteristics that distinguish complex genetic disorders including polygenic inheritance and environmental exposure risks. Here, we used a highly efficient multilocus genotyping assay representing variation in 34 genes associated with inflammatory pathways to explore gene-gene interactions and disease susceptibility in a well-characterized African-American case-control MS data set. We applied the multifactor dimensionality reduction (MDR) test to detect epistasis, and identified single-IL4R(Q576R)- and three-IL4R(Q576R), IL5RA(-80), CD14(-260)- locus association models that predict MS risk with 75-76% accuracy (P<0.01). These results demonstrate the importance of exploring both main effects and gene-gene interactions in the study of complex diseases.

Black or African American↗
PubMed2006

Benchmarking the current dispensing rate of Welsh hospital pharmacies.

BACKGROUND: There is a need to develop capacity measures for pharmacy services for strategic purposes, to provide guidance on safe working limits and to contribute to the target 40% reduction in serious medication errors by 2005. Attempts have been made to quantify workloads in the form of items/person/hour (i/p/h). However, much of these data are anecdotal, small scale or associated with vague methodology. OBJECTIVE: We estimate national average dispensing rates by collecting accurate data from secondary care dispensaries across Wales. METHOD: Seventeen sites collected hourly data relating to staff time and items dispensed over a 3-day period. The result showed a Welsh national average for non-specialist hospital pharmacy dispensing rates of 9.9 items/person/h (95% CI = 0.9, n = 17). There was a significant positive association between hospital size and telephone interruptions (r(s) = 0.83, P < 0.001) but no correlation between hospital size and dispensing rates (r(s) = 0.06, P = 0.822).

Benchmarking↗
PubMed2006

Detection of lysergic acid in ruminal fluid, urine, and in endophyte-infected tall fescue using high-performance liquid chromatography.

Ergot alkaloids present in endophyte-infected tall fescue induce fescue toxicosis in livestock consuming the plant. The lysergic acid (LA) ring structure is a common moiety among the ergot alkaloids. Little is known about the bioavailability of LA because of limitations in available analytical protocols. Thus, a high-performance liquid chromatography procedure was developed to analyze biological matrices for LA. The biological matrices of interest were tall fescue straw and seed, and ruminant feces, urine, and ruminal fluid. Lysergic acid was added to each matrix at a high (150 ng/ml) or low (30 ng/ml) level. Using the high-level addition, the greatest recovery of LA was obtained from ruminal fluid, feces, and urine (P < 0.05), with an average 85.1% recovered. At the low level, a greater recovery of added LA was observed in the ruminal fluid, urine, and feces (82.1%; P < 0.05) than that in the other 2 matrices (62.6%). The limit of quantitation (LOQ) in ruminal fluid and urine was 5.5 and 18.4 ng/ml, respectively. Seed, straw, and feces had higher LOQ (24.2, 14.5, and 36.0 ng/g, respectively). Limit of detection (LOD) was 1.64, 10.80, 4.35, 5.52, and 7.26 ng/g for ruminal fluid, feces, urine, seed, and straw, respectively. To test the assay in vivo, samples of ruminal fluid and urine were collected from steers consuming a diet containing 400 ng of ergovaline/g and 30 ng of LA/g. All matrices sampled resulted in levels above the LOD and LOQ for the assay, indicating that this assay is sufficiently sensitive for use in assessing the bioavailability of LA.

Animals↗
PubMed2006

Surface plasmon resonance investigations of human epidermal growth factor receptor 2.

This investigation utilizes surface plasmon resonance (SPR) spectroscopy to detect and quantify human epidermal growth factor receptor 2 (HER-2), an oncogene product that is over-expressed in some aggressive forms of breast cancer. Specifically, the HER-2 trans-membrane protein p185 and its extra cellular fragment p105 are analytes targeted in this work by using a gold-based biosensor slide on which an anti-HER-2 antibody has been immobilized by attachment to Protein G that is fixed to the gold film. A detection limit of > or =11 ng/mL for p185 resulted when trastuzumab was used as the anti-HER-2 antibody on the biosensor slide. Experiments with semi-purified p105 revealed that it binds weakly and reversibly to trastuzumab, therefore complicating its detection and quantification. Results of studies that reacted a 13-amino-acid peptide (PP13) from the HER-2 kinase domain with its specific antibody were critically different than p185 and p105 studies. Spectral analysis of the reflectivity at constant bulk buffer refractive index revealed a progressive negative SPR shift over time. A negative shift suggests that a loss of protein mass from the anti-PP13 antibody-Protein G biosensor is occurring. Several possibilities that may explain these negative SPR shifts are discussed.

Antibodies, Monoclonal↗
PubMed2005

Using a 360 degrees diagnostic screening tool to provide an evidence trail of junior doctor performance throughout their first postgraduate year.

New medical graduates in the UK are known as Preregistration House Officers (PRHOs). At the end of this first postgraduate year, the Postgraduate Dean is responsible for allowing the PRHO to be fully registered with the General Medical Council. During the period 1999-2002 Professor Miriam Friedman Ben-David designed a more robust approach to appraisal and assessment of PRHOs, which provided educational feedback to all trainees, allowed any poor performers to be detected at an early stage, and provided 'hard' observable evidence for certification decisions. This paper describes the more recent development of her work resulting from further piloting of her system. The key tool, a 360 degrees diagnostic questionnaire, is designed to identify strengths and weaknesses in individual performance. It is presently being used as a screening tool to identify any trainees needing additional support and further assessment. The tool also forms part of an evidence trail for all PRHOs and helps inform formative assessment as well as contributing, along with other evidence, to full registration decisions. The evaluation of this tool, also described in this paper, shows the feasibility of implementing such a system on a wider scale and illustrates the successful balance made between robustness and feasibility.

Attitude of Health Personnel↗
PubMed2005

Evaluation of a two dimensional analysis method as a screening and evaluation tool for anterior cruciate ligament injury.

BACKGROUND: Increased knee valgus predicts the risk of anterior cruciate ligament (ACL) injury, particularly in women. Reducing injury rates thus relies on detecting and continually evaluating people with relatively large valgus motions. OBJECTIVES: To examine the potential of a two dimensional (2D) video analysis method for screening for excessive valgus. METHODS: Ten female and 10 male National Collegiate Athletic Association basketball players had three dimensional (3D) knee valgus and two dimensional (2D) frontal plane knee angle quantified during side step, side jump, and shuttle run tasks. 3D valgus was quantified from external marker coordinates using standard techniques, and 2D data were obtained from both the frontal plane projections of these coordinates (2D-Mot) and manual digitization of digital video footage (2D-Cam). A root mean square (RMS) error was calculated between 2D-Mot and 2D-Cam data to evaluate the reliability of the latter. Correlations between 2D-Cam and 3D data (intersubject and intrasubject) were also conducted, and regression slope and r2 values obtained. RESULTS: 2D-Cam and 2D-Mot data were consistent for side step (RMS = 1.7 degrees) and side jump (RMS = 1.5 degrees) movements. Between subjects, 2D-Cam and 3D data correlated well for the side step (r2 = 0.58) and side jump (r2 = 0.64). Within subjects, 2D-Cam and 3D data correlated moderately for the side step (r2 = 0.25 (0.19)) and side jump (r2 = 0.36 (0.27)). CONCLUSIONS: The 2D-Cam method can be used to screen for excessive valgus in elite basketball players, particularly for movements occurring primarily in the frontal plane. This method may also be a useful training evaluation tool when large reductions in dynamic valgus motions are required.

Adult↗
PubMed2005

Patient stratification in the management of acute bacterial exacerbation of chronic bronchitis: the role of levofloxacin 750 mg.

This is the first prospective clinical trial in which patients with acute bacterial exacerbation of chronic bronchitis have been stratified by degree of underlying illness. Uncomplicated patients were randomised to levofloxacin 750 mg once daily (q.d.) for 3 days or azithromycin q.d. for 5 days. Complicated patients were randomised to levofloxacin 750 mg q.d. for 5 days or amoxicillin 875 mg/clavulanate 125 mg twice daily for 10 days. Regardless of therapy, complicated patients demonstrated lower clinical and microbiological success than uncomplicated patients. Clinical success for clinically evaluable patients was similar for levofloxacin and azithromycin (93.0 versus 90.1%, respectively), and levofloxacin and amoxicillin/clavulanate (79.2 versus 81.7%, respectively). For microbiologically evaluable patients, clinical response to levofloxacin for 3 days was superior to azithromycin for 5 days (96.3 versus 87.4%, respectively), and levofloxacin for 5 days was similar to amoxicillin/clavulanate for 10 days (81.4 versus 80.9%, respectively). Microbiological eradication was superior for levofloxacin for 3 days compared with azithromycin for 5 days (93.8 versus 82.8%, respectively), and similar for levofloxacin and amoxicillin/clavulanate for 10 days (81.4 versus 79.8%, respectively). In conclusion, levofloxacin 750 mg for 3 days was comparable to azithromycin for 5 days for uncomplicated patients with acute bacterial exacerbation of chronic bronchitis, while 5 days of 750 mg levofloxacin was comparable to 10 days of amoxicillin/clavulanate for complicated acute bacterial exacerbation of chronic bronchitis.

Administration, Oral↗
PubMed2004

Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers.

Lung cancer continues to be the leading cause of cancer death in developed countries. With smoking the major etiological factor for lung cancer, there is a great need for the development of chemopreventive treatments that inhibit the progression of initiated cells and premalignant lesions into overt lung cancer in smokers who quit. Although the major focus of chemoprevention research has been on agents that inhibit the metabolic activation of genotoxic chemicals contained in tobacco products, some of these agents may additionally modulate growth-regulating signal transduction. In turn, the function of such signaling pathways is highly cell type-specific, with a given pathway inhibiting the growth of one cell type while stimulating the growth of others. The current experiment has tested the hypothesis that green tea and the methylxanthine theophylline contained in tea inhibit the progression of neuroendocrine lung carcinogenesis in hamsters with hyperoxic lung injury and initiated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) while promoting the development of Clara cell-derived pulmonary adenocarcinomas initiated by NNK in healthy hamsters. This hypothesis is based on published evidence that human small cell lung cancer as well as the neuroendocrine hamster tumors are regulated via autocrine signaling pathways that activate Raf-1 and the mitogen-activated (MAP) kinase pathway whereas human pulmonary adenocarcinomas of Clara cell lineage and the hamster model of this cancer type are regulated by a beta-adrenergic pathway involving the activation of cyclic adenosine 3',5'-monophosphate (cAMP) and the arachidonic acid (AA) cascade. In turn, it was hypothesized that theophylline would inhibit Raf-1-dependent tumor progression while promoting cAMP-dependent tumor progression due to its documented ability to inhibit the enzyme cAMP-phophodiesterase. The experimental design simulated chemoprevention in former smokers in that treatments with tea or theophylline started after completion of a 10-week tumor induction period with NNK. Our data show that green tea as well as theophylline significantly inhibited lung tumor multiplicity in the neuroendocrine cancer model whereas identical chemopreventive treatments significantly promoted the lung tumor multiplicity in the adenocarcinoma model. These findings indicate that green tea and theophylline as well as other chemopreventive agents that modulate signal transduction may have opposite effects on cancers of different histolopathology and cell lineage. At the current state of knowledge such chemopreventive treatments should only be used as adjuvant to cancer therapy of cancers that have been fully characterized at the pathology and molecular level.

Adenocarcinoma↗
PubMed2002

The cyclooxygenase inhibitor ibuprofen and the FLAP inhibitor MK886 inhibit pancreatic carcinogenesis induced in hamsters by transplacental exposure to ethanol and the tobacco carcinogen NNK.

PURPOSE: Pancreatic cancer is the fourth leading cause of cancer death in men and women. Smoking is a documented risk factor for pancreatic cancer, and the risk is increased in smokers who also consume alcohol. Arachidonic acid (AA)-metabolizing enzymes have been implicated in aggressive clinical behavior of pancreatic cancer while mutations in the Ki- ras gene have been associated with prolonged survival and responsiveness to therapy. Using a hamster model of exocrine pancreatic cancer induced by transplacental exposure to ethanol and the tobacco-carcinogen NNK, we have analyzed these tumors for mutations in the ras and p53 genes and tested the modulating effects of the COX inhibitor, ibuprofen, and the FLAP inhibitor, MK886, on the development of pancreatic cancer in this animal model. METHODS: Hamsters were given 10% ethanol in the drinking water from the fifth to the last day of their pregnancy and a single dose of NNK on the last day. Starting at 4 weeks of age, groups of offspring were given either the COX inhibitor ibuprofen (infant Motrin oral suspension) or the FLAP-inhibitor MK886 (dissolved in carboxymethylcellulose orally) for life while a group of offspring not receiving any treatment served as positive controls. RESULTS: None of the induced pancreatic cancers demonstrated mutations in the Ki-, N-, or H- ras or p53 genes. The development of pancreatic cancer in offspring who had been given ibuprofen or MK886 was reduced by 50% or 30%, respectively. CONCLUSION: In conjunction with the documented over-expression of COX-2 and LOX in human pancreatic cancer, our findings suggest an important role of the AA-cascade in the genesis of this cancer type and indicate that pharmacological or dietary measures that reduce AA-metabolism may be useful for the prevention and clinical management of pancreatic cancer.

Adenocarcinoma↗
PubMed2002

A rat model of bone cancer pain.

This study describes the first known model of bone cancer pain in the rat. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) syngeneic MRMT-1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10-14 after inoculation of 3 x 10(3) MRMT-1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However, tartarate-resistant acid phosphatase staining revealed a large number of polykariotic cells, resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat-killed MRMT-1 cells. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) MRMT-1 cells, heat-killed cells or vehicle did not show changes in body weight and core temperature over 19-20 days. The general activity of animals after injection with live or heat-killed MRMT-1 cells was higher than that of the control group, however, the activity of the MRMT-1 treated group declined during the progress of the disease. Rats receiving intra-tibial injections of MRMT-1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12-14 or 10-12 following injection of 3 x 10(3) or 3 x 10(4) cells, respectively. These symptoms were not observed in rats receiving heat-killed cells or vehicle. Behavioural data suggest a reasonable time window for evaluation of anti-nociceptive agents between day 14 and 20 after cancer cell inoculation in this model. Acute treatment with morphine (1-3mg/kg, subcutanously (s.c.)) produced a dose-dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra-tibial injections of 3 x 10(3) MRMT-1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10-30 mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3 x 10(3) MRMT-1 cells. Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes. In summary, the induction of bone cancer in the rat by the syngeneic MRMT-1 mammary tumour cell line provides a valid pre-clinical model for pain associated with bone metastases. Significant mechanical hyperalgesia and allodynia develops in association with the progression of the tumour in the bone marrow cavity, while the general condition of the animal remains satisfactory. While acute treatment with morphine has some analgesic effect on hind limb sparing the selective COX-2 inhibitor, celebrex, has no influence on the pain-related behavioural changes in this model.

Analgesics, Opioid↗
PubMed2002

Interaction of group I mGlu and NMDA receptor agonists within the dorsal horn of the spinal cord of the juvenile rat.

1. The modulatory effects of mGlu receptors on NMDA-induced potential changes in spinal motoneurones were studied in vitro. 2. Selective activation of mGlu5 receptors by 10 microM (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG; EC(50)=280 +/- 24 microM) did not produce any change in the ventral root potential. However, the same concentration of CHPG (10 min perfusion) significantly attenuated the NMDA-induced ventral root depolarization (VRD). The effect persisted for 10 min after washout. NMDA-induced responses returned to control in 30 min. Brief co-application of CHPG and NMDA did not alter the NMDA-induced response indicating lack of direct receptor interaction. 3. The attenuating effect of CHPG on the NMDA-induced VRD was inhibited by the mGluR5 receptor antagonist, 2-methyl-6-phenyl-ethynylpyridine (MPEP). 4. In the presence of CGP56433A, a GABA(B) receptor antagonist, the NMDA-induced VRD was unchanged. However, NMDA-induced responses were potentiated after 10 min co-application of CHPG and CGP56433A. 5. (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), a group II mGlu receptor agonist did not attenuate the NMDA-induced response. 6. Under normal physiological conditions group I mGlu receptor agonists activate at least two populations of neurones: (1) GABA-ergic cells, which could release GABA and inhibit dorsal horn neurones, and (2) deep dorsal horn neurones/motoneurones which express NMDA receptors. Therefore, activation of mGlu5 receptors located on GABA-ergic interneurones could influence any direct potentiating interaction between mGlu5 and NMDA receptors in spinal cord and result in depression of the VRD. In the presence of a GABA(B) receptor antagonist, the direct synergistic interaction is unmasked. These data suggest that group I mGlu receptors provide a complex modulation of spinal synaptic processes.

Animals↗
PubMed2002

The resistance to heat of thermo-resistant streptococci attached to stainless steel in the presence of milk.

Skim milk residues had a significant impact on the sensitivity to heat of a dairy isolate of the thermo-resistant, Streptococcus thermophilus. Cells of S. thermophilus (H) suspended in water or in milk had D values at 60 degrees C of 2.0 and 14 min, respectively. Cells of S. thermophilus (H) attached to stainless steel in the presence of water or milk had D values at 60 degrees C of 2.2 and 8.1 min, respectively. The attached cells in both experiments were heat-treated in the presence of water. The increase in heat resistance could not be fully attributed to individual components (caseinate or whey) in the milk. The potential for thermo-resistant streptococci to survive heat treatment in a dairy manufacturing plant is therefore greater than may be expected for the organism in less complex environments.

Animals↗
PubMed2002

Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease.

The complexity of recognizing the potential contribution of a number of possible predictors of complex disorders is increasingly challenging with the application of large-scale single nucleotide polymorphism (SNP) typing. In the search for putative genetic factors predisposing to coronary artery restenosis following balloon angioplasty, we determined genotypes for 94 SNPs representing 62 candidate genes, in a prospectively assembled cohort of 342 cases and 437 controls. Using a customized coupled-logistic regression procedure accounting for both additive and interactive effects, we identified seven SNPs in seven genes that, together, showed a statistically significant association with restenosis incidence (P <0.0001), accounting for 11.6% of overall variance observed. Among them are candidate genes for cardiovascular pathophysiology (apolipoprotein-species and NOS), inflammatory response (TNF receptor and CD14), and cell-cycle control (p53 and p53-associated protein). Our results emphasize the need to account for complex multi-gene influences and interactions when assessing the molecular pathology of multifactorial medical entities.

Angioplasty, Balloon, Coronary↗
PubMed2002

Hypercalcaemia in association with trisomy 21 (Down's syndrome).

The combination of hypercalcaemia, hypercalciuria, and nephrocalcinosis with and without renal impairment is rare in paediatric clinical practice. However, this constellation of findings has been reported in three children with trisomy 21, but the absence of detailed nutritional data has failed to clarify the underlying pathogenesis. This report describes a 4 year old girl with trisomy 21 who was found coincidentally to have hypercalcaemia, hypercalciuria, nephrocalcinosis, and renal impairment in the absence of metabolic alkalosis, following a prolonged period of excessive calcium intake.

Calcium, Dietary↗
PubMed2001

Outcome in patients with eating disorders: a 5-year study.

BACKGROUND: Eating disorders are disabling, unpredictable, and difficult to treat. We did a prospective 5-year investigation of a representative sample of patients with eating disorders. Our aim was to identify predictors of outcome and to assess effects of available treatments. METHODS: We prospectively investigated 95 patients with anorexia nervosa, 88 with bulimia nervosa, and 37 with eating disorders not otherwise specified (EDNOS), who sought treatment in Adelaide, South Australia. We divided patients into those who had, and had not, received treatment in specialist units and reached a safe body weight. Individuals were then further classified dependent on intensity of any treatment received. We assessed clinical symptoms, body-related attitudes, and psychosocial function. FINDINGS: 216 (98%) patients were available for follow-up after 5 years. Three patients with anorexia nervosa and two with EDNOS died. 65 (74%) bulimic, 29 (78%) EDNOS, and 53 (56%) anorexic patients had no diagnosable eating disorder. A small proportion of patients in every group had poor Morgan-Russell-Hayward scores at outcome. Final outcome was predicted by extent and intensity, but not duration, of initial symptoms in patients with anorexia nervosa, and by initial body-related attitudes and impaired psychosocial functioning in bulimia patients. We were unable to predict EDNOS outcome. Treatment did not affect outcome for any group. INTERPRETATION: Deaths in the study confirm the serious nature of eating disorders. However, our results suggest that the efficacy of existing interventions is questionable.

Adolescent↗
PubMed2001

Promoting sun safety among zoo visitors.

BACKGROUND: Each year, millions of children visit zoological parks, where they are exposed to long bouts of ultraviolet radiation (UVR). We conducted a study in the winter and replicated it in the summer to evaluate an intervention for reducing UVR exposure during the zoo visit. METHODS: Each study used a nonequivalent control group design: one zoological site received the intervention and a second received evaluation only. Key outcome measures consisted of observed prevalence of hat use by exiting children (N = 8,721 and 8,524, respectively, in winter and summer studies) and purchase rates of sunscreen and hats in zoo gift shops. Intervention consisted of tip sheets for parents, children's activities, prompts, and discounts off the price of sunscreen and sun-protective hats. RESULTS: In the summer study, sales of both sunscreen and target hats increased significantly at the intervention site relative to the control site, whereas in the winter study, only sunscreen sales at the intervention site had a significant (relative) increase. Children's hat use increased significantly at the intervention site, but only in the winter study. CONCLUSIONS: The multicomponent program was effective in promoting purchases of sun-safe items, but its impact on children's hat use was inconclusive.

California↗