Biomedical subjects

Stephen H Kennedy

Publications and source records attributed to Stephen H Kennedy.

12 recordsLinked to original sources

PubMed2006

Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13-15.

BACKGROUND: Endometriosis is a common disease with a heritable component. The collaborative International Endogene Study consists of two data sets (Oxford and Australia) comprising 1176 families with multiple affected. The aim was to investigate whether the apparent concentration of cases in a proportion of families could be explained by one or more rare variants with (near-)Mendelian autosomal inheritance. METHODS AND RESULTS: Linkage analyses (aimed at finding chromosomal regions harbouring disease-predisposing genes) were conducted in families with three or more affected (Oxford: n = 52; Australia: n = 196). In the Oxford data set, a non-parametric linkage score (Kong & Cox (K&C) Log of ODds (LOD)) of 3.52 was observed on chromosome 7p (genome-wide significance P = 0.011). A parametric MOD score (equal to maximum LOD maximized over 357 possible inheritance models) of 3.89 was found at 65.72 cM (D7S510) for a dominant model with reduced penetrance. After including the Australian data set, the non-parametric K&C LOD of the combined data set was 1.46 at 57.3 cM; the parametric analysis found an MOD score of 3.30 at D7S484 (empirical significance: P = 0.035) for a recessive model with high penetrance. Critical recombinant analysis narrowed the probable region of linkage down to overlapping 6.4 Mb and 11 Mb intervals containing 48 and 96 genes, respectively. CONCLUSIONS: This is the first report to suggest that there may be one or more high-penetrance susceptibility loci for endometriosis with (near-)Mendelian inheritance.

Australia↗

PubMed2006

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer.

Histopathology and epidemiology studies have consistently demonstrated a strong link between endometriosis and endometriosis-associated ovarian cancers (EAOCs)--in particular, the endometrioid and clear cell subtypes. However, it is still unclear whether endometriosis is a precursor to EAOCs, or whether there is an indirect link because similar factors predispose to both diseases. In order to search for evidence of clonal progression, we analyzed 10 EAOCs (endometrioid=4; clear cell=6) with coexisting endometriosis for common molecular genetic alterations in both the carcinoma and corresponding endometriosis. We used 82 microsatellite markers spanning the genome to examine loss of heterozygosity (LOH) in the coexisting carcinoma and endometriosis samples. A total of 63 LOH events were detected in the carcinoma samples; twenty two of these were also detected in the corresponding endometriosis samples. In each case, the same allele was lost in the endometriosis and cancer samples. Interestingly, no marker showed LOH in the endometriosis alone. These data provide evidence that endometriosis is a precursor to EAOCs.

Adenocarcinoma, Clear Cell↗

PubMed2006

The impact of treatment for gynecological cancer on health-related quality of life (HRQoL): a systematic review.

Gynecologic cancers are major sources of mortality and morbidity. Although many review articles have reported on the impact of these diseases on health-related quality of life (HRQoL), none have reviewed the evidence in specific relation to the effect of treatment on HRQoL. Consequently, we systematically searched 4 electronic databases and hand-searched relevant reference lists and bibliographies to identify literature on this subject. Only 47 studies used a validated questionnaire to measure HRQoL. Although a meta-analysis was not possible, we found HRQoL rarely included as a treatment outcome, and when included assessment was often methodologically flawed. Seldom were pretreatment and posttreatment data collected or treatment regimes documented. Except for a few studies, analysis of HRQoL was conducted on small samples, excluding the cancer site and stage. Consequently, no definitive conclusions could be drawn and therefore we conclude with recommendations for the future reporting of HRQoL in gynecologic oncology studies.

Chemotherapy, Adjuvant↗

PubMed2006

Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity.

OBJECTIVE: To evaluate the phenotype, proliferative, and differentiation capacities in vitro of stromal cells derived from peritoneal, ovarian, and deeply infiltrating endometriosis. DESIGN: Experimental study using phase contrast microscopy, immunocytochemistry, and functional bioassays. SETTING: University-based laboratory. PATIENT(S): Women with and without endometriosis undergoing surgery for benign indications. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The stability in vitro of stromal cells derived from peritoneal (n = 18), ovarian (n = 29), and deeply infiltrating (n = 14) endometriotic lesions, as well as endometrium from women with (n = 5) and without endometriosis (n = 5) was evaluated by detection of endometrial markers. The proliferative and differentiation capacity of the cells was assessed by the use of cell doubling estimation and in vitro decidualization assays. RESULT(S): The expression of the progesterone receptor and CD10 in stromal cells derived from the three types of endometriotic lesions is retained in culture up to passage 10. The doubling time of stromal cells from deeply infiltrating lesions is lower than that of endometrial stromal cells. Levels of prolactin and insulin-like growth factor binding protein-1 (IGFBP-1) are reduced in supernatants from stromal cells derived from the three types of lesions and from the endometrium of women with endometriosis. CONCLUSION(S): The peritoneal, ovarian, and deeply infiltrating endometriotic stromal cell lines we describe retain in vivo tissue markers. Loss of differentiation capacity of the endometriotic cell lines and endometrial cells from women with endometriosis may influence the capacity for proliferation and survival of these cells in the ectopic environment.

Adult↗

PubMed2005

Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26.

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.

Australia↗

PubMed2005

Multivariate genetic analysis of chronic pelvic pain and associated phenotypes.

Chronic pelvic pain (CPP) is a common condition in women that is difficult to diagnose. Although heritability estimates have been published for some conditions potentially underlying pelvic pain, the heritability of CPP itself has never been investigated. Using data from 623 MZ and 377 DZ female twin pairs aged 29-50 from an Australian twin cohort, we found an increased CPP concordance among MZs compared to DZs, with tetrachoric correlations of 0.43 (95% CI: 0.26-0.58) and 0.11 (95% CI: -0.16-0.38), respectively. This corresponded to a heritability of 0.41 (95% CI: 0.25-0.56). Lack of correlations with environmental indicators suggested that violation of the equal environments assumption was not responsible for this effect. Multivariate Cholesky decomposition models incorporating CPP and significantly correlated phenotypes showed that the entire CPP heritability could be explained by genetic variance underlying endometriosis (38%), dysmenorrhoea (23%), fibroids (24%), and somatic distress (15%), the latter a possible indicator of increased nociception. CPP itself is unlikely to be a useful independent phenotype to conduct genetic aetiological studies; contributing conditions such as endometriosis and variation in nociception are likely to provide more useful phenotypes.

Adult↗

PubMed2005

Temporal calibration of freehand three-dimensional ultrasound using image alignment.

All freehand 3-D ultrasound systems have some latency between the acquisition of an image and its associated position. Previously, estimation of latency has been made by tracking a phantom in a sequence of images and correlating its motion to that recorded by the position sensor. However, tracking-based temporal calibration uses the assumption that latency is constant between scans. This paper presents a new method for temporal calibration that avoids this assumption. Temporal calibration is performed on the scan data by finding the latency at which the best alignment of the 2-D images within the reconstructed volume occurs. The mean voxel intensity variance is used as a global measure of the quality of alignment within the volume and is minimized with respect to latency for each scan. The new method is compared with previous methods using an ultrasound phantom. Finally, integration of temporal calibration with existing spatial calibration methods is discussed.

Calibration↗

PubMed2004

Polymorphism at codon 72 of the p53 gene is not associated with endometriosis in a Japanese population.

OBJECTIVE: Endometriosis is inherited as a complex trait, which means that multiple susceptibility genes interact with each other and the environment to produce the phenotype. Previous studies have implicated p53, a tumor suppressor gene, as a factor in the development of the disease. In a Japanese population, we investigated the frequency of the p53 polymorphism in women affected with endometriosis. METHODS: We compared the distribution of the p53 codon 72 polymorphism in endometriosis cases (n = 111) and population controls consisting of female neonates (n = 180) by using polymerase chain reaction restriction fragment-length polymorphism analysis in a Japanese population. RESULTS: The frequencies of the three p53 genotypes, Arginine (Arg)/Arg, Arg/Proline (Pro), and Pro/Pro in controls were 39.4%, 41.7%, and 18.9 %, respectively. The crude genotype frequencies in the endometriosis cases were similar to those of the controls (35.2%, 48.6%, and 16.2%, respectively). Using the Arg/Arg genotype as the reference, the odds ratios of the Arg/Pro and Pro/Pro genotypes were 1.30 (95% confidence interval [CI] 0.72-1.86, P =.33) and 0.96 (95% CI 0.47-1.94, P =.91), respectively. Thus, there were no significant differences in the frequency of the p53 codon 72 polymorphism between endometriosis cases and controls in this population. The endometriosis cases with severe disease only were also evaluated, but no significant difference was observed in the frequency of the polymorphism between this subgroup and the controls. CONCLUSION: Our findings suggest that the p53 codon 72 polymorphism is unlikely to be associated with endometriosis in Japanese women.

Codon↗

PubMed2004

Familial aggregation of endometriosis in a large pedigree of rhesus macaques.

BACKGROUND: Endometriosis occurs in several non-human primate species that have menstrual cycles. This study investigated the prevalence and familial aggregation of endometriosis in one of those species, the rhesus macaque. METHODS: Between 1978 and 2001, 142 animals with endometriosis were identified from necropsy and surgical records and through the use of magnetic resonance imaging (MRI) at the Wisconsin National Primate Research Center, Madison, USA. All cases were used to build one large multigenerational pedigree and nine nuclear families comprising 1602 females in total. By 2002, the pedigrees contained 124 cases diagnosed at necropsy; 17 at surgery and three at MRI. Female animals that had died aged > or = 10 years without endometriosis, had both ovaries until at least 1 year prior to death, and had a full necropsy, were considered unaffected. RESULTS: The prevalence of endometriosis among necropsied animals aged > or = 10 years in the colony was 31.4% [95% confidence interval (CI) 26.9-35.9%]; prevalence increased with rising age and calendar age at death. Familial aggregation of endometriosis was strongly suggested by a significantly higher average kinship coefficient among affecteds compared with unaffecteds (P < 0.001) and a higher recurrence risk for full sibs (0.75; 95% CI 0.45-1.0) compared with maternal half sibs (0.26; 95% CI 0.10-0.41) and paternal half sibs (0.18; 95% CI 0.02-0.34). The segregation ratio among affected mothers (44.2%) was not significantly higher compared with unaffected mothers (36.6%). CONCLUSIONS: The results support familial aggregation of endometriosis in the rhesus macaque, and indicate that this is a promising animal model for the investigation of mode of inheritance, the location of potential genetic susceptibility loci and the influence of environmental factors.

Age Factors↗

PubMed2002

Characteristics of patients with endometriosis in the United States and the United Kingdom.

OBJECTIVE: To investigate differences in characteristics of patients with endometriosis in the United States and the United Kingdom. DESIGN: Patient questionnaire. SETTING: Two university-based endometriosis referral centers. PATIENT(S): Women with surgically diagnosed endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patient demographics, menstrual and obstetric history, contraceptive use, medical history, risk factors, family history, endometriosis diagnosis, and current pain status and treatment. RESULT(S): Most demographic characteristics were similar between groups. However, patients in the United States were diagnosed at a younger age than were patients in the United Kingdom (25.6 +/- 6.7 years vs. 28.0 +/- 7.1 years) and more commonly presented with an ovarian mass. More U.K. women used oral contraceptives before diagnosis and were younger at first use. U.K. patients underwent fewer additional surgeries than U.S. patients but reported that surgery alone provided the best relief of symptoms, whereas most U.S. patients reported that surgical and medical therapy together provided the best relief of symptoms. CONCLUSION(S): The many similarities in demographics and symptoms among women with endometriosis in the U.S. and the U.K. support the universality of the disease process. Despite a variety of treatments, most patients from both groups still experienced pain from their endometriosis at the time of the survey.

Adult↗

PubMed2002

Health-related quality of life measurement in women with common benign gynecologic conditions: a systematic review.

Endometriosis, menorrhagia, chronic pelvic pain, and polycystic ovary syndrome are major sources of psychologic morbidity and can negatively affect quality of life. Although comparative studies have been published on the measurement of health-related quality of life for gynecologic malignancies, a similar review for these benign gynecologic conditions has not been conducted. Consequently, we searched the literature systematically to identify the impact of symptoms and treatments for these conditions on health status and to report on the types and psychometric properties of the instruments used. Papers were retrieved by systematically searching 6 electronic databases and hand-searching relevant reference lists and bibliographies. Forty-six studies used a questionnaire to measure health status: 34 studies (74%) used standardized instruments; of these, 23 studies (68%) used generic tools. Although a meta analysis was not possible, it appears that women with chronic pelvic pain and conditions that are associated with pelvic pain (such as endometriosis) report worse health-related quality of life. Despite the development of disease-specific questionnaires, only 2 questionnaires were generated from interviews of patients with the condition of interest, and few questionnaires are being used to evaluate the outcomes of treatment on subjective health status.

Endometriosis↗

PubMed2002

What makes a good case-control study? Design issues for complex traits such as endometriosis.

The combined investigation of environmental and genetic risk-factors in complex traits will refocus attention on the case-control study. Endometriosis is an example of a complex trait for which most case-control studies have not followed the basic criteria of epidemiological study design. Appropriate control selection has been a particular problem. This article reviews the principles underlying the design of case-control studies, and their application to the study of endometriosis. Only if it is designed well is the case-control study a suitable alternative to the prospective cohort study. Use of newly diagnosed over prevalent cases is preferable, as the latter may alter risk estimates and complicate the interpretation of findings. Controls should be selected from the source population from which cases arose. Potential confounding should be addressed both in studies of environmental and genetic factors. For endometriosis, a possible design would be to: (i) use newly diagnosed cases with 'endometriotic' disease; (ii) collect information predating symptom onset; and (iii) use at least one population-based female control group matched on unadjustable confounders and screened for pelvic symptoms. In conclusion, future studies of complex traits such as endometriosis will have to incorporate both environmental and genetic factors. Only adequately designed studies will allow reliable results to be obtained and any true aetiologic heterogeneity expected to underlie a complex trait to be detected.

Case-Control Studies↗