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P Watson

Publications and source records attributed to P Watson.

At least 37 records · Page 2Linked to original sources
PubMed2001

Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma.

BACKGROUND: Cells with deficient DNA mismatch repair develop microsatellite instability. Extensive microsatellite instability (MSI-high) is characteristic of colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) and in 10-% 15% of sporadic colorectal carcinomas. Microsatellite instability-high colorectal carcinomas differ from others in important clinical and pathologic features. However, MSI typing is expensive and not widely available. Microsatellite instability type may be predicted by tumor-infiltrating lymphocytes (TILs), which can be evaluated with ordinary light microscopy. METHODS: The authors evaluated TILs as a pathology screen for MSI-high status in 138 colorectal carcinomas that had been evaluated for MSI in a variety of studies. This case series was systematically enriched with HNPCC and other MSI-high cases to allow accurate sensitivity and specificity estimation. Tumor-infiltrating lymphocytes were quantitated as TILs per 10 high-power microscopic fields by an observer blinded to MSI status. RESULTS: Of the 138 carcinomas studied, 67 (48.6%) were MSI-high, 22 (15.9%) were MSI-low, and 49 (35.5%) were MSI-stable. All 25 HNPCC colorectal carcinomas were MSI-high. Tumor-infiltrating lymphocytes counts ranged from 0 to 300, with a markedly skewed distribution (median, 11; mean, 36). Sensitivity and specificity for selected cut points of TIL count were computed. Using a TIL count of 5 as a cut point yields a sensitivity of 93% and specificity of 62%. In a population in which 12% were MSI-high, consideration of TIL could reduce the number of colorectal carcinomas referred for MSI testing by greater than one-half, and still 93% of the MSI-high carcinomas would be identified. CONCLUSIONS: The presence of MSI defines a subset of colorectal carcinomas with special molecular etiology and characteristic clinical, pathologic features, inclusive of increased survival. The authors conclude that quantification of TILs may provide a simple, single criterion for choosing which colorectal carcinomas are candidates for MSI testing.

Colorectal Neoplasms↗
PubMed2001

Verifying the Kugo-Ojima confinement criterion in Landau gauge Yang-Mills theory.

Expanding the Landau gauge gluon and ghost two-point functions in a power series we investigate their infrared behavior. The corresponding powers are constrained through the ghost Dyson-Schwinger equation by exploiting multiplicative renormalizability. Without recourse to any specific truncation we demonstrate that the infrared powers of the gluon and ghost propagators are uniquely related to each other. Constraints for these powers are derived, and the resulting infrared enhancement of the ghost propagator signals that the Kugo-Ojima confinement criterion is fulfilled in Landau gauge Yang-Mills theory.

Journal Article↗
PubMed2001

Insulin-induced adipocyte differentiation. Activation of CREB rescues adipogenesis from the arrest caused by inhibition of prenylation.

Insulin is a potent adipogenic hormone that triggers an induction of a series of transcription factors governing differentiation of pre-adipocytes into mature adipocytes. However, the exact link between the insulin signaling cascade and the intrinsic cascade of adipogenesis remains incompletely understood. Herein we demonstrate that inhibition of prenylation of p21ras and Rho-A arrests insulin-stimulated adipogenesis. Inhibition of farnesylation of p21ras also blocked the ability of insulin to activate mitogen-activated protein (MAP) kinase and cyclic AMP response element-binding (CREB) protein. Expression of two structurally different inducible constitutively active CREB constructs rescued insulin-stimulated adipocyte differentiation from the inhibitory influence of prenylation inhibitors. Constitutively active CREB constructs induced expression of PPARgamma2, fatty acid synthase, GLUT-4, and leptin both in control and prenylation inhibitors-treated cells. It appears that insulin-stimulated prenylation of the Ras family GTPases assures normal phosphorylation and activation of CREB that, in turn, triggers the intrinsic cascade of adipogenesis.

Adipocytes↗
PubMed2001

SuperStar: improved knowledge-based interaction fields for protein binding sites.

SuperStar is an empirical method for identifying interaction sites in proteins, based entirely on experimental information about non-bonded interactions occurring in small-molecule crystal structures, taken from the IsoStar database. We describe recent modifications and additions to SuperStar, validating the results on a test set of 122 X-ray structures of protein-ligand complexes. In this validation, propensity maps are generated for all the binding sites of these proteins, using four different probes: a charged NH(+)(3) nitrogen atom, a carbonyl oxygen atom, a hydroxyl oxygen atom and a methyl carbon atom. Next, the maps are compared with the experimentally observed positions of ligand atoms of these types. A peak-searching algorithm is introduced that highlights potential interaction hot spots. For the three hydrogen-bonding probes - NH(+)(3) nitrogen atom, carbonyl oxygen atom and hydroxyl oxygen atom - the average distance from the ligand atom to the nearest SuperStar peak is 1.0-1.2 A (0.8-1.0 A for solvent-inaccessible ligand atoms). For the methyl carbon atom probe, this distance is about 1.5 A, probably because interactions to methyl groups are much less directional. The most important addition to SuperStar is the enabling of propensity maps around metal centres - Ca(2+), Mg(2+) and Zn(2+) - in protein binding sites. The results are validated on a test set of 24 protein-ligand complexes that have a metal ion in their binding site. Coordination geometries are derived automatically, using only the protein atoms that coordinate to the metal ion. The correct coordination geometry is derived in approximately 75 % of the cases. If the derived geometry is assumed during the SuperStar calculation, the average distance from a ligand atom coordinating to the metal ion to the nearest peak in the propensity map for an oxygen probe is 0.87(7) A. If the correct coordination geometry is imposed, this distance reduces to 0.59(7)A. This indicates that the SuperStar predictions around metal-binding sites are at least as good as those around other protein groups. Using clustering techniques, a non-redundant set of probes is selected from the set of probes available in the IsoStar database. The performance in SuperStar of all these probes is tested on the test set of protein-ligand complexes. With the exception of the "ether oxygen" probe and the "any NH(+)" probe, all new probes perform as well as the four probes introduced first.

Algorithms↗
PubMed2001

Lunar influence?

Explore the source record for details and available documents.

Animals↗
PubMed2001

The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.

OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS: . Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage.

Adult↗
PubMed2001

A matrix metalloproteinase inhibitor, batimastat, retards the development of osteolytic bone metastases by MDA-MB-231 human breast cancer cells in Balb C nu/nu mice.

Bone resorption is a dominant feature of many bone metastases and releases factors from the bone matrix that can promote the expression of the metastatic phenotype in cancer cells. Since proteolytic enzymes, including matrix metalloproteinases (MMPs) contribute to bone destruction by metastatic tumour cells and host cells, we have examined the effect of a MMP inhibitor, batimastat, on the ability of MDA-MB-231 cells to degrade bone in vitro and to form bone metastases in BalbC nu/nu mice. In vitro, the neoplastic cells produced MMP-2 and MMP-9, degraded [3H]-proline-labelled osteoblast matrices, and formed resorption pits in cortical bone. These phenomena were inhibited by < or = 20 microM batimastat. To induce vertebral and long bone metastases in vivo, 1x10(5) MDA-MB-231 cells were injected into the arterial circulation of BalbC nu/nu mice. Test groups were also given 30 mg/kg batimastat intraperitoneally (i.p.). After 21 days, the long bone metastases were characterised by a 67% reduction of metaphyseal medullary bone and complete replacement of marrow by tumour. In tumour-bearing mice that had been treated with 30 mg/kg batimastat i.p., the tumour volume decreased 8-fold, osteolysis was inhibited by 35%, and replacement of the bone marrow by tumour was inhibited by 65%. Similar effects were observed in the vertebral metastases. These data provide evidence that MDA-MB-231 cells can degrade osteoblast matrices and mineralised bone in vitro and support the hypothesis that MMPs are involved in the pathogenesis of osteolytic bone metastases in vivo. They demonstrate that an agent which inhibits proteolysis can retard the development of osteolytic bone metastases in this model.

Animals↗
PubMed2001

Cancer risk in mismatch repair gene mutation carriers.

Optimally accurate and valid estimates of cancer risk in genetically- defined subgroups requires population-based research. For rare genetic traits, very large studies are needed. Such is the case in hereditary nonpolyposis colorectal cancer syndrome (HNPCC), caused by mutations in mismatch repair (MMR) genes. A potentially more efficient approach is genotyped-proband design (GPD), in which probands are genotyped and the phenotypes of their relatives are investigated. However, to date most information comes from registry-based studies, where ascertainment bias makes interpretation difficult. Development in testing technology will lead to more identified mutation carriers, producing a clinical imperative to estimate risk, despite these problems. We reviewed the available results, and concluded that male mutation carriers have a lifetime colorectal cancer risk of 74% or more; female mutation carriers have a lower risk which is still many times higher than the risk in the general population. Risk is highest between the ages of 40 and 60, but considerable even before age 40. Lifetime endometrial cancer risk is 42% or more; the highest incidence is between age 40 and 60, and diagnosis before the age of 35 is rare. MMR mutation carriers are at elevated risk for ovarian, gastric, urologic tract, small bowel, hepatobiliary tract cancer, and for brain tumors. The risk of these cancer types is much lower than the risk for colorectal and endometrial cancer, but accurate, especially age-related estimates of risk are not available. Prevention strategies depend on estimates of age-specific risk. Clearly, multicenter studies to obtain such estimates are needed.

Adult↗
PubMed2001

Calculating the knowledge-based similarity of functional groups using crystallographic data.

A knowledge-based method for calculating the similarity of functional groups is described and validated. The method is based on experimental information derived from small molecule crystal structures. These data are used in the form of scatterplots that show the likelihood of a non-bonded interaction being formed between functional group A (the 'central group') and functional group B (the 'contact group' or 'probe'). The scatterplots are converted into three-dimensional maps that show the propensity of the probe at different positions around the central group. Here we describe how to calculate the similarity of a pair of central groups based on these maps. The similarity method is validated using bioisosteric functional group pairs identified in the Bioster database and Relibase. The Bioster database is a critical compilation of thousands of bioisosteric molecule pairs, including drugs, enzyme inhibitors and agrochemicals. Relibase is an object-oriented database containing structural data about protein-ligand interactions. The distributions of the similarities of the bioisosteric functional group pairs are compared with similarities for all the possible pairs in IsoStar, and are found to be significantly different. Enrichment factors are also calculated showing the similarity method is statistically significantly better than random in predicting bioisosteric functional group pairs.

Artificial Intelligence↗
PubMed2001

Assessment of chronic pain behaviour: reliability of the method and its relationship with perceived disability, physical impairment and function.

The aim of the present study was to develop a reliable assessment of pain behaviour performed during the execution of a range of functional assessment measures. For the initial reliability study 18 subjects (consecutive referrals) were assessed. Subjects were observed and videotaped during a variety of physical tasks and demonstrations of pain behaviour were recorded; the videotapes were scored by two independent observers on two occasions. The relationships between pain behaviour, distress and physical function and impairment were also investigated in a group of 51 patients with chronic back pain. Self-report of disability and pain intensity were assessed using the Finnish version of Oswestry disability questionnaire and the pain visual analogue scale (VAS). Depression and somatic perception were assessed using the modified Zung and modified somatic perception questionnaire. The Tampa scale for kinesiophobia was used to evaluate fear of movement and (re)injury. The results of the intra- and interobserver reliability study demonstrate good to excellent levels of agreement. The exception was facial expression (kappa 0.29), which was excluded from the final instrument. There was a strong correlation between pain behaviour and subjective pain report and disability (p < 0.01). The correlations between total pain behaviour and performance of physical function tasks is striking (p < 0.01). Subjective disability was analysed by means of multiple regression analysis. Pain measured on the VAS was the most important variable explaining 36% of the variance, pain behaviour and pain combined explained 48% of the variance for self reported disability. In conclusion, this functional videobased assessment of pain behaviour is a reliable measure of pain behaviour. The total scores for pain behaviour correlate with tasks that involve the back; tests involving upper limbs were not affected. This test is suitable for the assessment of those with pain problems specifically involving the back. Furthermore, in the group studied pain and pain behaviour were the two most important determinants of self-reported disability.

Adult↗
PubMed2001

Phenotypic and genetic analysis of diarrhea-associated Escherichia coli isolated from children in the United Kingdom.

BACKGROUND: A hospital-based study was performed to (1) compare phenotypic and genotypic diagnostic tests for enteropathogenic Escherichia coli, enteroaggregative E. coli, and diffuse-adhering E. coli (collectively termed adherent E. coli) and (2) to assess the importance of these different classes of adherent E. coli as causes of infant diarrhea in the United Kingdom in comparison with other enteropathogens. METHODS: E. coli isolated from 1,496 infants with diarrheal disease and from 546 age-related controls were screened for enteropathogenic E. coli, enteroaggregative E. coli, and diffuse-adhering E. coli using HEp-2 cell adherence assays and DNA probes. RESULTS: Marked discrepancies between the phenotype and genotype of isolates indicate significant heterogeneity among enteroaggregative E. coli and diffuse-adhering E. coli strains. Depending on the assay used, adherent E. coli were isolated as the only putative pathogen in 23% to 27% of diarrhea cases, a significantly higher incidence than in the control group. Individually, enteroaggregative E. coli (8.5-8.6% of cases) and diffuse-adhering E. coli (10.4-11.3% of cases), but not enteropathogenic E. coli (4.5-7.5% of cases), were significantly associated with diarrhea. CONCLUSIONS: These studies indicate that adherent E. coli may be an important cause of diarrhea in infants in the United Kingdom; they also emphasize the need for more specific virulence-based tests for these putative classes of "diarrheagenic" (diarrhea causing) E. coli.

Bacterial Adhesion↗
PubMed2001

Gastric corpus atrophy following eradication of Helicobacter pylori.

BACKGROUND: Atrophic gastritis can develop in patients with Helicobacter pylori infection leading to a reduction in basal acid output. Whether the atrophy that develops is reversible is controversial. OBJECTIVE: To investigate the effect of H. pylori eradication in infected subjects who had developed atrophy of the corpus mucosa. METHOD: Ten H. pylori positive patients with corpus atrophy were identified at oesophagogastroduodenoscopy (OGD). They received eradication therapy with amoxicillin, clarithromycin and omeprazole. Repeat OGD with biopsy was performed at least 3 months later. Fasting plasma gastrin was measured at baseline and at re-endoscopy. H. pylori eradication was confirmed by 13C urea breath testing. RESULTS: Median time to re-endoscopy was 5 months. There was improvement in corpus atrophy in 50% of patients after H. pylori eradication, and a significant reduction in plasma gastrin (P = 0.03). The index patients had a significant diminution of basal acid output compared to controls. CONCLUSION: Corpus atrophy as defined by the Sydney System is reversible in some patients after H. pylori eradication. Improvement in atrophy is associated with a fall in fasting plasma gastrin levels. This may have implications in the prevention of gastric carcinoma.

Adult↗
PubMed2001

The differential assessment of children's attention: the Test of Everyday Attention for Children (TEA-Ch), normative sample and ADHD performance.

"Attention" is not a unitary brain process. Evidence from adult studies indicates that distinct neuroanatomical networks perform specific attentional operations and that these are vulnerable to selective damage. Accordingly, characterising attentional disorders requires the use of a variety of tasks that differentially challenge these systems. Here we describe a novel battery, the Test of Everyday Attention for Children (TEA-Ch), comprising nine subtests adapted from the adult literature. The performance of 293 healthy children between the ages of 6 and 16 is described together with the relationships to IQ, existing measures of attention, and scholastic attainment. This large normative sample also allows us to test the fit of the adult model of functionally separable attention systems to the observed patterns of variance in children's performance. A Structural Equation Modelling approach supports this view. A three-factor model of sustained and selective attention and higher-level "executive" control formed a good fit to the data, even in the youngest children. A single factor model was rejected. There are behavioural and anatomical grounds to believe that Attention Deficit Disorder (ADD) is particularly associated with poor self-sustained attention and behavioural control. The TEA-Ch performance of 24 boys diagnosed with ADD presented here is consistent with this view. When performance levels on WISC-III subtests were taken into account, specific deficits in sustained attention were apparent while selective attention performance was within the normal range.

Activities of Daily Living↗
PubMed2001

Fluoridation--what the public know and what they want.

OBJECTIVE: To describe the knowledge and beliefs on fluoridation of a community served by an unfluoridated water supply prior to consultation on implementing fluoridation. METHODS: Telephone survey of a sample of residents and businesses utilising semi-structured questionnaires. Comparisons were made among responses of ethnic and age groups. RESULTS: Residents were more conversant concerning fluoridation than business users. Knowledge and beliefs among ethnic groups differed significantly. Younger persons and those who had never been married were less knowledgeable. Pamphlets supplied by water-provider organisations or health professionals were the preferred methods of acquiring fluoridation information. The majority of respondents wished the opportunity to express their views via a referendum. Health authorities were the favoured decision-makers. CONCLUSIONS AND IMPLICATIONS: Gaps were identified in this community's knowledge on fluoridation with important differences based on ethnicity and age. Strategies to inform the public on water fluoridation need to address these subgroup differences.

Adolescent↗
PubMed2001

Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein.

Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe mental retardation, absent speech, ataxia, sociable affect, and dysmorphic facial features. Eighty five percent of patients with AS have an identifiable genetic abnormality of chromosome 15q11-13. Mutations within the X linked MECP2 gene have been identified in patients with Rett syndrome (RTT), a neurodevelopmental disorder which affects females almost exclusively and which shares phenotypic overlap with AS. RTT is usually associated with normal development in infancy followed by loss of acquired skills and evolution of characteristic hand wringing movements and episodes of hyperventilation.A panel of 25 female and 22 male patients with a clinical diagnosis of AS and no molecular abnormality of 15q11-13 were screened for MECP2 mutations and these were identified in four females and one male. Following the diagnosis, it was possible to elicit a history of regression in three of these patients, who by then were showing features suggestive of Rett syndrome. In the remaining two subjects the clinical phenotype was still considered to be Angelman-like. These findings illustrate the phenotypic overlap between the two conditions and suggest that screening for MECP2 mutations should be considered in AS patients without a demonstrable molecular or cytogenetic abnormality of 15q11-13. Since MECP2 mutations almost always occur de novo, their identification will substantially affect genetic counselling for the families concerned.

Angelman Syndrome↗
PubMed2001

Managing diversity in the environment of care.

In this report, the authors delineate the experience of Lakeland Regional Medical Center Inc. with redeployed services over the last 10 years. They provide a brief history of the restructuring, then focus on their experience with the management of redeployed services. In addition to the perspectives of the authors, they include information gathered through interviews with staff and managers in both the operating and business centers. The article concludes with a summary of the challenges and opportunities of managing a department with redeployed services and cross-trained staff.

Financial Management, Hospital↗