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Biomedical subjects

M Watson

Publications and source records attributed to M Watson.

At least 73 records · Page 4Linked to original sources
PubMed1999

XR3054, structurally related to limonene, is a novel inhibitor of farnesyl protein transferase.

In this report, a novel inhibitor of farnesyl protein transferase (FPTase) is described. The compound, XR3054, is structurally similar to farnesol, a component of the reaction in which FPTase catalyses transfer of farnesol pyrophosphate to the CAAX recognition motif on proteins. The compound was selected initially because of its ability to inhibit in vitro farnesylation of CAAX recognition peptides with an IC50 of 50 microM. The farnesylation of p21 ras was reduced in a dose-dependent manner in the presence of XR3054. Similarly XR3054 was able to reduce the anchorage-independent growth of V12 H-ras transformed NIH 3T3 cells in a focus formation assay in soft agar, with an IC50 value of 30 microM, whilst not affecting the anchorage-independent growth of v-raf transformed cells. XR3054 reduced the phosphorylation of p42 mitogen activated protein (MAP) kinase in parental NIH 3T3 cells and V12 H-ras transformed NIH 3T3 cells, but constitutively active v-raf transformed cells showed no reduction in phosphorylation of ERK2 in the presence of XR3054. XR3054 inhibited the proliferation of the prostatic cancer cell lines LnCAP and PC3 and the colon carcinoma SW480 and HT1080 (IC50 values of 12.4, 12.2, 21.4 and 8.8 microM, respectively) but was relatively inactive when tested against a panel of breast carcinoma cell lines. The activity did not relate to the presence of mutant or wild-type ras in the cell lines tested. In conclusion XR3054 inhibits ras farnesylation, MAP kinase activation and anchorage-independent growth in NIH 3T3 transformed with v12 H-ras. Since the antiproliferative effect of the compound is not related to the ras phenotype, XR3054 may also have effects on other cell signalling mechanisms.

Alkyl and Aryl Transferases↗
PubMed1999

Circuits with surface modifying additive alter the haemodynamic response to cardiopulmonary bypass.

OBJECTIVE: Blood contact with synthetic surfaces during cardiopulmonary bypass (CPB), inevitably results in the activation of a variety of interrelated pathways of inflammation and coagulation that may contribute to postoperative complications in cardiac surgery patients. The objective of this trial was to evaluate clinical events and complement activation related to the use of a novel biomaterial, into which a surface modifying additive had been incorporated into the polymer used to prepare the bypass circuit. METHODS: A prospective, double-blind trial was carried out with 34 patients randomized to surgery, with either a standard circuit or a circuit treated ('tip to tip') with the surface modifying additive. Variables recorded included perioperative haemodynamics, volume replacement, alpha-agonist and inotrope use. Terminal complement complex (SC5b-9) was measured using an ELISA. RESULTS: Upon initiation of bypass, there was a decrease in mean arterial pressure (MAP) in the control group, not seen in the test group (P = 0.0005, ANOVA). There was a decrease in the total volume of replacement fluid given intraoperatively in the test group as compared with the control group (total plus prime; control 5.3 +/- 1.2 L, test 4.4 +/- 1.9 L, P = 0.03, Mann-Whitney test). There was a trend to decreased need for inotrope infusion in the test group after CPB (test 1/17, control 6/17, Fisher exact test; P = 0.085). No difference was seen in the generation of terminal complement complex between the groups either during or after CPB. CONCLUSIONS: The decrease in blood pressure in the control group, upon the initiation of CPB, did not occur in patients undergoing CPB with the circuit prepared with the surface modifying additive. The decrease in blood pressure was likely associated with the increase in total administered fluids intraoperatively (approximately 1 l/patient) and perhaps the trend towards higher use of inotropes in the control patients as opposed to the test patients. These haemodynamic changes did not appear to be related to complement activation early in CPB.

Cardiac Output↗
PubMed1999

Hardy-Weinberg quality control.

An efficient test of deviation from Hardy-Weinberg frequencies with one degree of freedom was applied to 44 marker loci in a genome scan, and 7 loci had a significant excess of apparent homozygotes (chi2 (1) > 6) suggestive of typing error. In this example evidence for linkage did not increase when outliers were censored. Statistical quality control is an essential part of genotyping, and the effect of mistyping and map error should be considered in evaluating any genome scan.

Asthma↗
PubMed1999

The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer.

The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer 'frequently or constantly' and 18% that worry about breast cancer was 'a severe or definite problem'. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P = 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of cancer-related worry. Most clinic attenders were inaccurate in their estimates of the population risk of breast cancer with only 24% able to give the correct figure prior to genetic counselling and 36% over-estimating this risk. There was some improvement following genetic counselling with 62% able to give the correct figure, but this information was poorly retained and this figure had dropped to 34% by the 1-year follow-up. The study showed that women attending for genetic counselling are worried about breast cancer, with 34% indicating that they had initiated the referral to the genetic clinic themselves. This anxiety is not alleviated by genetic counselling, although women reported that it was less of a problem at follow-up. Women who continue to over-estimate their risk and worry about breast cancer are likely to go on seeking unnecessary screening if they are not reassured.

Adult↗
PubMed1999

Seven novel mutations of the PKD2 gene in families with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci accounting for the disease. Mutations in the PKD2 gene on the long arm of chromosome 4 are expected to be responsible for approximately 15% of cases of ADPKD. METHODS: We report a systematic screening for mutations covering the 15 exons of the PKD2 gene in eight unrelated families with ADPKD type 2, using the heteroduplex technique. RESULTS: Seven novel mutations were identified and characterized that, together with the previously described changes, amount to a detection rate of 85% in the population studied. The newly described mutations are two nonsense mutations, a 1 bp deletion, a 1 bp insertion, a mutation that involves both a substitution and a deletion (2511AG-->C), a complex mutation in exon 6 consisting of a simultaneous 7 bp inversion and a 4 bp deletion, and the last one is a G-->C transversion that may be a missense mutation. Most of these mutations are expected to lead to the formation of shorter truncated proteins lacking the carboxyl terminus of PKD2. We have also characterized a frequent polymorphism, Arg-Pro, at codon 28 in this gene. The clinical features of these PKD2 patients are similar to the previously described, with the mean age of end-stage renal disease being 75.5 years (SE +/- 3.8 years). CONCLUSIONS: Our results confirm that many different mutations are likely to be responsible for the disease and that most pathogenic defects probably are point or small changes in the coding region of the gene.

Amino Acid Sequence↗
PubMed1999

Consumption of fish oil leads to prompt incorporation of eicosapentaenoic acid into colonic mucosa of patients prior to surgery for colorectal cancer, but has no detectable effect on epithelial cytokinetics.

Fish oil (FO) was previously reported to partially normalize colorectal crypt cell cytokinetics in patients with colorectal neoplasms. We determined the effect of FO on the fatty acid composition of colonic mucosa and mesenteric adipose tissue and on rectal crypt cell proliferation in patients undergoing surgery for colonic carcinoma. Patients (49-28 males; 21 females) were randomly assigned to consume FO capsules (2 g b.d.; FO group) containing 1.4 g eicosapentaenoic acid (EPA) and 1.0 g docosahexaenoic acid per day, or safflower oil capsules (2 g b.d.; placebo group) for an average of 12.3 +/- 0.5 d prior to surgery. Rectal biopsies were obtained at entry, at surgery, and 8-12 wk postsurgery. Colonic biopsies and samples of mesenteric adipose tissue were analyzed for fatty acids by gas-liquid chromatography. Mitosis was determined in whole crypt mounts. The proportion of EPA (g/100 g total fatty acids) in mucosal lipids was significantly greater in FO patients compared to the placebo group, but there was no effect on mesenteric adipose tissue. However self-reported use of FO supplements prior to surgery was associated with higher levels of EPA in adipose tissue. There was no significant effect of FO on the frequency or spatial distribution of crypt cell mitosis. EPA from marine oil supplements is rapidly incorporated into the colonic mucosal lipids of humans, but the levels achieved in the present study did not modify colorectal cytokinetics.

Adipose Tissue↗
PubMed1999

Fentanyl does not increase brain injury after focal cerebral ischemia in rats.

UNLABELLED: Recent reports have indicated that large-dose opiate anesthesia can increase neuronal injury in rats subjected to forebrain ischemia. However, most episodes of cerebral ischemia in the operating room setting are focal in nature, and the influence of large-dose opioid administration on the tolerance of the brain to focal cerebral ischemia has not been studied. Accordingly, we undertook the present study to evaluate the effect of fentanyl administration on outcome after focal cerebral ischemia. Three groups of fasted Wistar-Kyoto rats (awake, fentanyl, and isoflurane groups; n = 20 per group) were anesthetized with isoflurane (2.5% end-tidal). Pericranial temperature was servocontrolled at 37.0 degrees C. After surgical preparation fentanyl 50 microg/kg was administered IV over 10 min in the fentanyl group. Thereafter, an infusion was established at a rate of 50 microg x kg(-1) x h(-1). The end-tidal concentration of isoflurane was then reduced to 1.1%, one minimum alveolar anesthetic concentration (1 MAC) in all groups. Occlusion of the middle cerebral artery was achieved by advancing a 0.25-mm filament into the anterior cerebral artery via the common carotid artery. In the fentanyl and awake groups, isoflurane administration was then discontinued. In the isoflurane group, isoflurane anesthesia was maintained at 1.0 MAC. After 90 min of focal ischemia, the filament was removed, and the animals were allowed to recover. Seven days later, the volume of cerebral infarction in the animals was determined by image analysis of hematoxylin and eosin-stained coronal brain sections. There was no difference in the infarct volume between the fentanyl and awake groups. The infarct volume was the least in the isoflurane group. The results confirm the ability of isoflurane to reduce brain injury caused by focal cerebral ischemia. Fentanyl neither increased nor decreased brain injury compared with the awake unanesthetized state. IMPLICATIONS: Fentanyl is commonly used in surgical procedures in which there is a substantial risk of focal cerebral ischemia. Fentanyl did not affect cerebral injury produced by focal ischemia in the rat. The data suggest that, in doses that produce respiratory depression and muscle rigidity, fentanyl does not reduce the tolerance of the brain to a focal ischemic insult.

Analgesics, Opioid↗
PubMed1999

The effect of information technology on the physician workforce and health care in isolated communities: the Canadian picture.

The ratio of physicians to population in Canada peaked in the mid-1990s and is now falling. The decrease in the number of family physicians has had a disproportionate effect on rural and remote communities, and surveys have indicated that the availability of physicians and services is likely to deteriorate in rural and remote communities. Telemedicine is increasingly evident in every Canadian province and territory, and it could assist in more effective use of workforce resources by linking appropriate experts at central sites to patients and practitioners at remote sites. Positive effects on recruitment and retention of health providers and morale of the local workforce can be expected. In spite of national interest, evidence for the effect of telemedicine on staff distribution, roles and recruitment, use of health resources, health management and system integration is very limited. Telephone interviews were therefore conducted to collect information from 12 telehealth projects in Canada, one from each province or territory. The responses confirmed observations in the literature that telemedicine has positive outcomes for the workforce.

Canada↗
PubMed1999

Development of the Royal Marsden Hospital paediatric oncology quality of life questionnaire.

Our objective was to develop a health-related quality of life measure for use in pediatric oncology. The development process followed the EORTC Quality of Life Study Group (QLSG) guidelines but utilized a parental proxy rating methodology developed within the framework of the EORTC QLSG. Data are reported on the preliminary stages of development, which include interviews in the target population, specialist review of questionnaire content and initial results on the psychometric structure of the measure. The questionnaire has been translated from English to Swedish and Dutch and is available for international field testing. Suggestions for further development of the new measure are described, including the need for parallel forms for use with children and adolescents as well as the parental proxy rating form described here.

Child↗
PubMed1998

Primary care groups. View to a skill.

Training is of critical importance to the successful development of PCGs. There are particular needs for developing strategic planning capacities. PCGs will need to understand and adopt many public health skills.

Group Practice↗
PubMed1998

Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer.

BACKGROUND: Glutathione S-transferases (GSTs) are encoded by a superfamily of genes and play a role in the detoxification of potential carcinogens. In a nested case-control study, we investigated associations between genetic variability in specific GST genes (GSTM1, GSTT1, and GSTP1) and susceptibility to breast cancer. METHODS: In 1989, a total of 32 898 individuals donated blood samples to a research specimen bank established in Washington County, MD. Genotypes of blood specimen DNA were determined for 110 of 115 women with incident cases of breast cancer diagnosed during the period from 1990 through 1995 and up to 113 of 115 control subjects. Associations between specific genotypes and the development of breast cancer were examined by use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The GSTM1 homozygous null genotype was associated with an increased risk of developing breast cancer (OR = 2.10; 95% CI = 1.22-3.64), principally due to an association with postmenopausal breast cancer (OR = 2.50; 95% CI = 1.34-4.65). For GSTP1, the data were suggestive of a trend of increasing risk with higher numbers of codon 105 valine alleles (compared with isoleucine alleles); a 1.97-fold increased risk of breast cancer (95% CI = 0.77-5.02) was associated with valine/valine homozygosity. The risk of breast cancer associated with the GSTT1 homozygous null genotype was 1.50 (95 % CI = 0.76-2.95). The risk of breast cancer increased as the number of putative high-risk genotypes increased (P for trend <.001) (OR = 3.77; 95% CI = 1.10-12.88 for a combined genotype of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity). CONCLUSIONS: Our findings suggest that genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.

Breast Neoplasms↗
PubMed1998

Intrusive memories and depression in cancer patients.

Matched samples of depressed and nondepressed cancer patients were interviewed about past life events, particularly experiences of death and illness. They identified and described any spontaneous intrusive visual memories they had experienced in the past week corresponding to these events. About one quarter reported such memories and, as predicted, the majority of intrusive memories concerned illness, injury and death. The mean levels of intrusion and avoidance were equivalent to patients with post-traumatic stress disorder. Consistent with prediction, depressed patients reported significantly more intrusive memories than controls, and described the memories as typically beginning with or being exacerbated by the onset of depression. Greater numbers of intrusive memories were associated with more maladaptive coping, and greater avoidance with deficits in autobiographical memory functioning.

Adaptation, Psychological↗
PubMed1998

Predicting physical abuse against pregnant Hispanic women.

CONTEXT: Abuse during pregnancy is common and has adverse health effects on maternal and infant health. To prevent abuse to pregnant women, predictors must be identified and incorporated into routine screening and intervention protocols. OBJECTIVE: To investigate whether or not symbolic violence and threats of violence by a male intimate were associated with physical violence against pregnant Hispanic women. DESIGN: Cross-sectional interview survey questionnaire. SETTING: Urban, public health prenatal clinics. PARTICIPANTS: 329 pregnant, physically abused Hispanic women. MAIN OUTCOME MEASURE: Physical abuse against pregnant Hispanic women as measured on the Severity of Violence Against Women Scale. RESULTS: Regression analysis showed that symbolic violence and threats of violence by the perpetrator were jointly and independently significantly (P < .0005) associated with physical violence. CONCLUSIONS: Because symbolic violence is significantly associated with physical violence against pregnant women, screening and early intervention programs should focus on such behavior.

Adolescent↗
PubMed1998

Cost comparison between bilateral simultaneous, staged, and unilateral total joint arthroplasty.

A hospital-based computer system was used to compare the inpatient costs of performing bilateral simultaneous sequential, staged, and unilateral total hip and knee arthroplasties. Bilateral simultaneous sequential total knee arthroplasty was 36% less costly than 2 unilateral total knee arthroplasties. Bilateral simultaneous sequential total hip arthroplasty saved 25% over the costs of performing 2 unilateral hip arthroplasties. Prosthetic costs range between 28% and 43% of the total costs of hospitalization. There was a significant correlation between hospital length of stay, morbidity, and total costs, but no correlation with patient age and sex except in the unilateral knee patients. Bilateral simultaneous sequential joint arthroplasty can save more than $10,000 for each total knee patient and more than $8,000 for each total hip patient.

Adult↗
PubMed1998

Psychological factors predicting nausea and vomiting in breast cancer patients on chemotherapy.

A series of 100 breast cancer patients were included in a study to test the hypothesis that incidence of anticipatory nausea and vomiting during chemotherapy and towards the end of a patient's course of treatment is influenced by patient expectation, anxiety level and coping response. The role of psychological factors in postinfusional nausea and vomiting was also examined. Incidence of postinfusional and anticipatory nausea was high overall, with vomiting less frequently reported; 43% of patients reported nausea or vomiting before treatment at some stage over their chemotherapy cycles and 77% reported post-treatment symptoms. Anticipatory nausea was described by 47% of those experiencing it as being of moderate or severe intensity at some point throughout chemotherapy. Postinfusional side-effects were more intense; 21 and 10 patients, respectively, described severe or very severe levels as occurring at some point during their treatment. The majority of patients experiencing postinfusional symptoms indicated that these persisted for more than 24 h and were worse a day or two after chemotherapy administration. Incidence of anticipatory nausea or vomiting was found to relate directly to experience of nausea or vomiting during preceding cycles. Psychological variables were associated with symptoms of anticipatory nausea mid-treatment, but not with postinfusional symptoms. In particular, trait anxiety and a baseline expectation that nausea would be experienced during treatment were predictive in a multivariate model. Despite this, the overwhelming factor influencing ANV and PNV both mid- and towards the end of treatment was that of previous experience of the symptoms at earlier courses.

Adult↗
PubMed1998

Chylothorax following oesophagogastrectomy for malignant disease.

OBJECTIVE: To define the incidence, causes, management and impact of Chylothorax after oesophagogastrectomy for malignant disease in Nottingham Thoracic Surgery unit. PATIENTS AND METHODS: Retrospective analysis of 523 patients with cancer of the oesophagus or the gastro-oesophageal junction who underwent oesophageal resection between January 1987 and November 1997 in a single unit using similar techniques and uniform routine perioperative management. RESULTS: Chylothorax occurred in 21 patients (4.0%). There were 12 males and 9 females with a mean age of 64.7 years (SD 7.5). Age, sex, tumour site, length, histological type, depth of wall penetration, nodal status and type of operative approach were not significant predisposing factors on univariate and multivariate analysis. Seventeen patients were treated conservatively (four deaths, 23.5%) and four surgically (one death, 25.0%), effective control of the chylous leak being achieved in all four cases. Eleven patients with a chylous drainage of up to 2.2 l/day, diminishing within 1 week of conservative treatment had an uneventful recovery. However, a chylous drainage of more than 2.5 l/day in the remaining ten patients was associated with increased morbidity, hospital stay, operative mortality and the need for surgical intervention. In comparison with the remaining patients (n = 502), those who developed chylothorax (n = 21) had more respiratory complications (42.8%, P = 0.008), longer mean hospital stay (23.8 days, P = 0.004), higher operative mortality (23.1%, P = 0.004) and, unexpectedly, reduced 5 year survival rate (P < 0.0001). CONCLUSIONS: There appeared to be no clear predisposing factor in the development of a chylous leak other than the routine extensive dissection. Although definitive conclusions can not be drawn, where there is early reduction of the initial amount (in this series up to 2.2 l/day) of drainage, there may be a place for successful non-surgical management; in cases of high output chylothorax, persisting after a few days of conservative treatment, however, early re-operation and ligation of the thoracic duct, seems to be advisable.

Aged↗
PubMed1998

Memory processes and the course of anxiety and depression in cancer patients.

BACKGROUND: Intrusive memories of stressful events, many involving illness and death, are found in a minority of depressed cancer patients, and may predict the course of anxiety and depression. METHOD: Matched samples of mild to moderately depressed and non-depressed cancer patients were followed up after 6 months. Anxiety and depression at follow-up were related to measures of intrusive memories of stressful life events and autobiographical memory functioning that had been assessed at baseline. RESULTS: Levels of anxiety and depression remained fairly constant over time in the two groups, and the depressed group continued to experience high levels of intrusive memories. The presence of intrusive memories at baseline, and the extent to which these memories were consciously avoided, predicted greater anxiety at follow-up, even after controlling for initial severity of physical and psychiatric symptoms. None of the measures of memory functioning predicted levels of depression at follow-up. CONCLUSIONS: Intrusive memories appear to be a marker of more prolonged psychopathology in cancer patients and may respond to direct therapeutic intervention.

Adult↗