Search PubMed⌕ Search

Biomedical subjects

P Watson

Publications and source records attributed to P Watson.

At least 181 records · Page 10Linked to original sources
PubMed1994

Mismatch repair genes on chromosomes 2p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage.

Two susceptibility loci for hereditary nonpolyposis colorectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p. We studied the involvement of these loci in 13 large HNPCC kindreds originating from three different continents. Six families showed close linkage to the 2p locus, and a heritable mutation of the MSH2 gene was subsequently found in four. The 2p-linked kindreds included a family characterized by the lack of extracolonic manifestations (Lynch I syndrome), as well as two families with cutaneous manifestations typical of the Muir-Torre syndrome. Four families showed evidence for linkage to the 3p locus, and a heritable mutation of the MLH1 gene was later detected in three. One 3p-linked kindred was of Amerindian origin. Of the remaining three families studied for linkage, one showed lod scores compatible with exclusion of both MSH2 and MLH1, while lod scores obtained in the other two families suggested exclusion of one HNPCC locus (MSH2 or MLH1) but were uninformative for markers flanking the other locus. Our results suggest that mismatch repair genes on 2p and 3p account for a major share of HNPCC in kindreds that can be evaluated by linkage analysis.

Adult↗
PubMed1994

Reproducibility of computer-aided semen analysis: comparison of five different systems used in a practical workshop.

STUDY OBJECTIVES: To assess a single (donor) sample by the use of five computer-assisted semen analysis (CASA) systems. SETTING: British Andrology Society advanced course on computer-assisted semen analysis techniques, September 1992. PARTICIPANTS: Clinical, technical and scientific personnel with mixed experience of CASA techniques, but all interested in semen assessment technology. RESULTS: 22 sets of data, comprising 6 commonly derived parameters, from the same sample were obtained using five CASA systems. The coefficients of variation for sperm concentration (29%) and proportion motile (24%) were comparable to those previously reported for manual assessments. For all parameters, "within system" variability was considerably greater than "between system," indicating that differences in sample handling and operator expertise were more significant sources of variation than the CASA systems themselves. CONCLUSIONS: Emphasis on operator training and standardization of sample handling techniques would enhance the reproducibility of CASA measurements more than improvements in the CASA systems themselves. There was evidence, however, that the CASA measurements were more consistent than equivalent manual measures, and also provide information about the quality of sperm motility which cannot be obtained by alternative techniques.

Education, Medical, Continuing↗
PubMed1994

Pathology and heredity of breast cancer in younger women.

The pathology of early-age onset breast cancer is considered here from three perspectives: 1) benign proliferative disease, 2) the cancers themselves, and 3) familial and hereditary breast cancer. Hereditary breast cancer, a subset of familial breast cancer featuring a strong autosomal dominant pedigree pattern and multiple primary cancers, has a strong predilection for younger women, accounting for about one half of breast cancers under age 30. With respect to benign proliferative disease, the increased relative risk of breast cancer associated with proliferative disease with atypia, about fourfold to fivefold for all ages, is doubled by the presence of a family history of breast cancer and amplified by young age. With respect to the carcinomas, the relative incidences of medullary carcinoma and ductal carcinoma in situ are increased in young women, while lobular and tubular carcinomas are decreased. Invasive breast cancer is higher grade and more proliferative in younger women, as measured by thymidine-labeling index, DNA flow cytometric S-phase fraction, and proliferation-associated proteins. The increased fraction of ductal carcinoma in situ and higher grade invasive cancers may help to account, respectively, for increased recurrence rates with conservative therapy, and more aggressive natural history in younger women. Familial breast cancers show trends for increased medullary type, but the effect is not independent of age. Weak associations of family history with tubular carcinoma have been reported, but data for associations with lobular carcinoma in situ and invasive lobular carcinoma are conflicting. Hereditary breast cancer as a class has higher tumor proliferation rates, an effect independent of age. Knowledge of the pathology and biomarker characteristics of BRCA1 gene-linked hereditary breast cancers, which account for a substantial fraction of breast cancers in younger women, should shed light on the nature of the responsible gene(s) and guide approaches to therapy and prophylaxis.

Adult↗
PubMed1993

Genetic instability of microsatellites in endometrial carcinoma.

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by a familial predisposition to colorectal carcinoma and extracolonic cancers of the gastrointestinal, urological, and female reproductive tracts, notably the endometrium. A genetic locus for HPNCC was recently determined by linkage analysis to exist on chromosome 2p; both sporadic and HNPCC-associated colorectal carcinomas exhibit a "replication error" phenotype, characterized by instability of dinucleotide repeat sequences throughout the genome. Here, we address the hypothesis that the replication error phenotype would be evident in some fraction of sporadic endometrial carcinomas or in those associated with HNPCC. Microsatellite instability was observed in 17% of sporadic endometrial carcinomas and in 75% of those tumors associated with HNPCC. These data indicate that the HNPCC gene is also involved in heritable and somatic forms of endometrial carcinoma.

Adult↗
PubMed1993

DNA screening for breast/ovarian cancer susceptibility based on linked markers. A family study.

BACKGROUND: Linkage to chromosome 17q has been identified in hereditary breast cancer and hereditary breast/ovarian cancer syndrome. A hereditary breast/ovarian cancer syndrome kindred was identified that yielded a highly significant lod score (4.20) when 17q markers were studied, enabling us to identify those who probably carried the cancer-associated gene among the high-risk members of the family. METHODS: High-risk members of the hereditary breast/ovarian cancer syndrome kindred were offered counselling on the basis of 17q markers. Family members responding positively received one-to-one genetic counseling in a structured setting. Subjects were educated before disclosure, and the immediate impact of this information was assessed after disclosure. RESULTS: We provided genetic counseling on the basis of linkage findings to 32 relatives (four men and 28 women). Women who were told they were linkage positive expressed an increased motivation for surveillance and prophylactic surgery. Most women who were told they were linkage negative indicated that they would not proceed with prophylactic surgery but would continue careful surveillance. To date, there has been no evidence of serious emotional disturbances resulting from this disclosure. We believe that this experience can be used by cancer geneticists and physicians in developing protocols for genetic counseling in cancer-associated hereditary disorders. CONCLUSIONS: Physicians must understand current developments in cancer genetics and linkage so that they can be applied to genetic counseling and treatment of high-risk patients.

Adult↗
PubMed1993

Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability.

OBJECTIVE: To examine the evidence for using selective serotonin reuptake inhibitors instead of tricyclic antidepressants in the first line treatment of depression. DESIGN: Meta-analysis of 63 randomised controlled trials comparing the efficacy and acceptability of selective serotonin reuptake inhibitors with those of tricyclic and related antidepressants. MAIN OUTCOME MEASURES: Improvement in mean scores on Hamilton depression rating scale for 53 randomised controlled trials. Pooled drop out rates from the 58 trials which reported drop out by treatment group. RESULTS: Among the 20 studies reporting standard deviation for the Hamilton score no difference was found in efficacy between serotonin reuptake inhibitors and tricyclic and related antidepressants (standardised mean difference 0.004, 95% confidence interval -0.096 to 0.105). The difference remained insignificant when the remaining 33 studies that used the 17 item and 21 item Hamilton score were included by ascribing weighted standard deviations. The odds ratio for drop out rate in patients receiving serotonin reuptake inhibitors compared with those receiving tricyclic antidepressants was 0.95 (0.86 to 1.07). Similar proportions in both groups cited lack of efficacy as the reason for dropping out but slightly more patients in the tricyclic group cited side effects (18.8% v 15.4% in serotonin reuptake group). CONCLUSIONS: Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit.

Antidepressive Agents, Tricyclic↗
PubMed1993

Extracolonic cancer in hereditary nonpolyposis colorectal cancer.

BACKGROUND: It has been hypothesized that in some but not all families with hereditary nonpolyposis colorectal cancer (HNPCC) there is a high risk of certain cancers other than colon cancer. METHODS: The authors compared the observed frequency of cancer at specific sites in more than 1300 high-risk members of 23 kindreds with HNPCC with expectations based on general population incidence and evaluated the hypothesis that there was heterogeneity in cancer frequency among families. RESULTS: The authors observed significantly increased numbers of cancers of the stomach, small intestine, upper urologic tract (renal pelvis and ureter), and ovary. No excess was seen in other cancer types that have been associated previously with HNPCC, including cancer of the breast, pancreas, and urinary bladder. Significant heterogeneity among families was observed in the frequencies of endometrial, ovarian, and upper urologic system cancer. CONCLUSION: In addition to early onset cancers of the colorectum, HNPCC family members are at increased risk for cancers of other gastrointestinal tract organs, and, especially in some families, cancers of the upper urologic and female genital tract.

Adenocarcinoma↗
PubMed1993

Hereditary ovarian cancer. Heterogeneity in age at onset.

BACKGROUND: Hereditary ovarian cancer (HOC) is heterogeneous, with at least three distinctive syndromes, namely, hereditary site-specific ovarian cancer, hereditary breast-ovarian cancer (HBOC) syndrome, and Lynch syndrome II. Ovarian cancer, in accord with virtually all varieties of adult onset cancer, displays an increasing incidence with advancing age; however, it shows an earlier age of onset in hereditary settings. METHODS: Detailed medical and pathology studies were performed on extended ovarian cancer-prone pedigrees, with special attention given to age at ovarian cancer onset. RESULTS: The age of onset of ovarian cancer is heterogeneous, wherein the average age of onset in HBOC is 52 years, in hereditary site-specific ovarian cancer it is 49 years, and in the Lynch syndrome II it is 45 years, in contrast to its occurrence in the general population, at an average age of 59 years. CONCLUSIONS: These differences are important for the initiation of surveillance and management strategies. Age of onset of ovarian cancer differences in these several hereditary subsets are less striking than they are in the case of other integral forms of cancer in the respective syndromes, such as the breast in the HBOC syndrome. In addition, the phenomenon of extremely early age of onset of ovarian cancer occurs infrequently in HOC when compared to other forms of cancer, such as the breast in HBOC or the colon in Lynch syndrome II. Knowledge about age of onset heterogeneity in HOC may harbor important clues about etiology, pathogenesis, and cancer control.

Adult↗
PubMed1993

Blood-brain barrier penetration and in vivo activity of an NGF conjugate.

Nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons of the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant of dementia in these patients and may therefore suggest a therapeutic role for NGF. However, NGF does not significantly penetrate the blood-brain barrier, which makes its clinical utility dependent on invasive neurosurgical procedures. When conjugated to an antibody to the transferrin receptor, however, NGF crossed the blood-brain barrier after peripheral injection. This conjugated NGF increased the survival of both cholinergic and noncholinergic neurons of the medial septal nucleus that had been transplanted into the anterior chamber of the rat eye. This approach may prove useful for the treatment of Alzheimer's disease and other neurological disorders that are amenable to treatment by proteins that do not readily cross the blood-brain barrier.

Animals↗
PubMed1993

Surveillance in hereditary nonpolyposis colorectal cancer: an international cooperative study of 165 families. The International Collaborative Group on HNPCC.

During its second meeting at Amsterdam in 1990, the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) decided to carry out a pilot study on colorectal cancer surveillance in HNPCC. The objectives of the study were to ascertain in each of the participating centers the number of HNPCC families, the recommended screening procedures, the age at diagnosis of colorectal cancer (CRC), and the occurrence of interval cancers. Nine centers in seven countries including Denmark, Finland, Italy, Japan, The Netherlands, Switzerland, and the United States participated. Data were derived from a total of 165 families. With respect to screening, half of the centers advise colonoscopy as the only procedure. The interval between the consecutive examinations varies from one to three years. In the majority of the centers, screening begins at 20 to 25 years. Lifelong screening is recommended by three centers, while the rest advise discontinuation at age 60 to 75 years. The family material included 840 patients with colorectal cancer. The mean age at diagnosis was 45 years, and about 15 percent were diagnosed at age 60 or later. A total of 682 high-risk relatives are being followed. After the follow-up of 1 to 10 years in these families, only six cases of interval cancers were encountered.

Adolescent↗
PubMed1993

Cumulative incidence of metachronous colorectal cancer.

The incidence of metachronous colorectal cancer has most often been reported as a crude rate: second cancers/index cancers. The reported incidence varies between 0.5 percent and 3.6 percent. However, these calculations do not take into account factors such as length of survival and length of follow-up. The cumulative incidence more accurately reflects the risk for developing a metachronous cancer and was determined in a retrospective analysis of 5,476 patients who were diagnosed with colon or rectal cancer between 1965 and 1985. The cumulative probability was calculated by determining the number of patients developing a metachronous colon cancer vs. the number remaining at risk at that point in time. The calculated annual incidence for metachronous tumors was 0.35 percent per year. The cumulative incidence at 18 years was 6.3 percent. Analysis also demonstrated that metachronous cancers were diagnosed at earlier stages than were index cancers (P = 0.03). Subgroup analysis was performed on patients diagnosed with metachronous cancer before and after 1980. There was a difference in the incidence of metachronous cancers between these two groups (P = 0.04).

Adult↗
PubMed1993

Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review.

Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Warthin's description of family G, which he began studying in 1895. Warthin's observations were not fully appreciated until 1966 when two families with an autosomal dominant inheritance pattern of nonpolyposis colorectal cancer (CRC) and endometrial cancer were described. This condition was first termed the "cancer family syndrome" and was later renamed HNPCC. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome I, with hereditary predisposition for CRC having early (approximately 44 years) age of onset, a proclivity (70%) for the proximal colon, and an excess of synchronous and metachronous colonic cancers and Lynch syndrome II, featuring a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium. Transitional cell carcinoma of the ureter and renal pelvis and carcinomas of the stomach, small bowel, ovary, and pancreas also afflict some families. Current estimates indicate that HNPCC may account for as much as 6% of the total CRC burden. There are no known premonitory phenotypic signs or biomarkers of cancer susceptibility in the Lynch syndromes. This report will summarize current knowledge, with emphasis on the manner in which this knowledge can be employed effectively for diagnosis and management of HNPCC.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1993

Hypercholesterolaemia in briards in the United Kingdom.

Elevated fasting plasma cholesterol concentrations were identified in clinically healthy briards. Biochemical investigations revealed no other major abnormalities. Plasma lipoprotein electrophoresis demonstrated a marked increase in the intensity of the alpha 2 band (compared with control dogs) which was reduced by dextran sulphate-magnesium chloride or sodium phosphotungstate-magnesium chloride precipitation of apo B and apo E containing lipoproteins in the plasma. The study has identified a hyperlipidaemia in briards characterised by increased cholesterol but normal triglyceride concentrations. The absence of obvious metabolic changes associated with secondary hypercholesterolaemia, suggests the breed may have a primary abnormality in cholesterol metabolism. The increased density of the precipitable lipoprotein which migrates to the alpha 2 band suggests that the hypercholesterolaemia may be due to an abnormal accumulation of high density lipoprotein (HDL) possibly HDLc. The possibility that abnormality in lipid metabolism might play a role in the development of retinal pigment epithelial dystrophy in briards is currently being investigated.

Animals↗
PubMed1993

Pressurization of bone cement under standard, flanged and custom acetabular components for total hip replacement.

Custom acetabular components are proposed to achieve uniform cement mantles, even in irregular acetabula presented at revision, in order to enhance fixation. One aim of developing custom components was to permit pressurization of bone cement by the components at insertion and maintain the pressure during polymerization. A model acetabulum was set up for the insertion of standard, flanged and custom components under constant force. Cement pressure was measured at the floor of the acetabulum by means of a piezoelectric diaphragm transducer. Polythene tubes were inserted in the model acetabular walls to estimate penetration of cement into cancellous bone. Insertion of the standard and flanged components caused cement pressures up to 106 kPa which decayed to less than 21 kPa as cement escaped at the rim and the components came into contact with the acetabulum. The custom component maintained a pressure of over 60 kPa during polymerization from an initial pressure of 105 kPa and examination of cement mantles on removal showed no evidence of contact. The custom component also showed enhanced penetration of cement, especially around the rim of the acetabulum. It is concluded that the custom component design achieves higher cement pressures and that better fixation will result.

Bone Cements↗
PubMed1993

A breast-ovarian cancer susceptibility gene maps to chromosome 17q21.

Nineteen North American Caucasian families that contain a minimum of four confirmed cases of breast or ovarian cancer have been studied. Four polymorphisms (cLB17.1, D17S579, D17S588, and D17S74), which span a region of approximately 15 cM on chromosome 17q12, were typed. Our data confirm the location of a dominant gene conferring susceptibility to breast and ovarian cancer (maximum lod = 9.78) and suggest that the breast-ovarian cancer syndrome is genetically heterogeneous. Two recombinants in one large family suggest that the breast-ovarian cancer locus lies between D17S588 and D17S579.

Adult↗