The last fossil primate in North America, new material of the enigmatic Ekgmowechashala from the Arikareean of Oregon.

OBJECTIVE: Primates were common in North America through most of the Eocene, but vanished in the Chadronian, about 35 million years ago. In the Arikareean, about 6 million years later, the enigmatic primate Ekgmowechashala appeared in the Great Plains and Oregon. This taxon shows little resemblance to other North American primates and its phylogenetic position has long been debated. New material of this taxon allows a revised assessment of its age and how it is related to other primates. METHODS: Recently collected Ekgmowechashala specimens from the Turtle Cove Member of the John Day Formation in Oregon are described. These specimens are compared to previously collected material from South Dakota and Nebraska, as well as other fossil primates from North America and Asia. RESULTS: Study of the John Day material allows diagnosis of a new, distinct species. Comparison of Ekgmowechashala to a pair of recently described Asian primates, Muangthanhinius and Bugtilemur, suggests that it is a strepsirrhine adapiform, rather than an omomyid. The well-defined stratigraphy and dated marker beds of the Turtle Cove Member provide a refined age for Ekgmowechashala occurrences in Oregon, during the Oligocene (early Arikareean). CONCLUSIONS: The age and morphology of these ekgmowechashaline taxa suggest that the group originated in Asia and dispersed to North America in the Oligocene, after the extinction of other primates in North America. Contemporaneous occurrences of Ekgmowechashala in Oregon and the Great Plains indicate the last non-human primates vanished in North America about 26 million years ago.

Clinical characteristics of women with familial pelvic floor disorders.

INTRODUCTION AND HYPOTHESIS: Understanding the clustering of pelvic floor disorders (PFDs) within families is important because it may suggest underlying risk factors that may be environmental, genetic or both. The objective of this study was to describe clinical characteristics observed in familial cases with PFDs and compare them with strictly defined controls. METHODS: Women evaluated and treated for PFDs were recruited as part of a larger genetic study. Here, we define familial cases as those with bothersome symptoms or treatment for a PFD (pelvic organ prolapse [POP], stress urinary incontinence [SUI], and overactive bladder [OAB]) and who had a first-degree relative with bothersome symptoms or treatment for the same pelvic floor defect. We assigned clinical characteristics to probands and their relatives using standardized symptom questions (PFDI), examination, and review of treatment records, if any. RESULTS: We identified 126 familial POP cases, 183 familial SUI cases, and 101 familial OAB cases. Familial cases were more likely to have bothersome symptoms for more than one PFD. Among familial POP cases, bothersome SUI (71 %), OAB (54 %), and a combination of all three disorders (48 %) were common. Among familial SUI cases, bothersome OAB (60 %), POP (59 %), and combinations of all disorders (40 %) were common. Among familial OAB cases, bothersome SUI (88 %), POP (66 %), and combinations of all three disorders (59 %) were common. CONCLUSIONS: Familial cases of POP, SUI, and OAB are more likely to have more than one pelvic floor defect. It is likely that underlying genetic factors contribute to more than one pelvic floor defect.

Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus.

Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4). To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5). Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.

The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.

Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.

A candidate prostate cancer susceptibility gene at chromosome 17p.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

A new North American therizinosaurid and the role of herbivory in 'predatory' dinosaur evolution.

Historically, ecomorphological inferences regarding theropod (i.e. 'predatory') dinosaurs were guided by an assumption that they were singularly hypercarnivorous. A recent plethora of maniraptoran discoveries has produced evidence challenging this notion. Here, we report on a new species of maniraptoran theropod, Nothronychus graffami sp. nov. Relative completeness of this specimen permits a phylogenetic reassessment of Therizinosauria-the theropod clade exhibiting the most substantial anatomical evidence of herbivory. In the most comprehensive phylogenetic study of the clade conducted to date, we recover Therizinosauria as the basalmost maniraptoran lineage. Using concentrated changes tests, we present evidence for correlated character evolution among herbivorous and hypercarnivorous taxa and propose ecomorphological indicators for future interpretations of diet among maniraptoran clades. Maximum parsimony optimizations of character evolution within our study indicate an ancestral origin for dietary plasticity and facultative herbivory (omnivory) within the clade. These findings suggest that hypercarnivory in paravian dinosaurs is a secondarily derived dietary specialization and provide a potential mechanism for the invasion of novel morpho- and ecospace early in coelurosaurian evolution-the loss of obligate carnivory and origin of dietary opportunism.

Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22.

Linkage analysis of ten Utah kindreds and one Texas kindred with multiple cases of cutaneous malignant melanoma (CMM) provided evidence that a locus for familial melanoma susceptibility is in the chromosomal region 9p13-p22. The genetic markers analyzed reside in a candidate region on chromosome 9p21, previously implicated by the presence of homozygous deletions in melanoma tumors and by the presence of a germline deletion in an individual with eight independent melanomas. Multipoint linkage analysis was performed between the familial melanoma susceptibility locus (MLM) and two short tandem repeat markers, D9S126 and the interferon-alpha (IFNA) gene, which reside in the region of somatic loss in melanoma tumors. An analysis incorporating a partially penetrant dominant melanoma susceptibility locus places MLM near IFNA and D9S126 with a maximum location score of 12.71. Therefore, the region frequently deleted in melanoma tumors on 9p21 presumably contains a locus that plays a critical role in predisposition to familial melanoma.

Inheritance of proliferative breast disease in breast cancer kindreds.

Previous studies have emphasized that genetic susceptibility to breast cancer is rare and is expressed primarily as premenopausal breast cancer, bilateral breast cancer, or both. Proliferative breast disease (PBD) is a significant risk factor for the development of breast cancer and appears to be a precursor lesion. PBD and breast cancer were studied in 103 women from 20 kindreds that were selected for the presence of two first degree relatives with breast cancer and in 31 control women. Physical examination, screening mammography, and four-quadrant fine-needle breast aspirates were performed. Cytologic analysis of breast aspirates revealed PBD in 35% of clinically normal female first degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggests that genetic susceptibility causes both PBD and breast cancer in these kindreds. This study supports the hypothesis that this susceptibility is responsible for a considerable portion of breast cancer, including unilateral and postmenopausal breast cancer.

Encephalocele--a single institution African experience.

OBJECTIVE: This study seeks to find out the presentation, management and complications of encephaloceles in an African setting. DESIGN: a retrospective study reviewing the age and sex of the patients, type and contents of encephaloceles, associated anomalies, preoperative evaluation and investigations, surgical approaches, intra- and post-operative complications as well as follow-up outcomes. SETTING: Bethany Crippled Children's centre and Bethanykids at Kijabe Hospital (BKKH), between January 1998 and August 2006. PATIENTS: Of the 53 patients seen, 23 were males and 30 females. The median age at presentation was four months. RESULTS: The follow-up period extended to eight years. Twenty nine patients had occipital encephaloceles, and 39 were operated using the direct external approach. Cererobrospinal fluid leak was the most common post-operative complication. Recurrence occurred in four patients and death in six. CONCLUSIONS: Most of the encephalocele patients manage d at BKKH had good outcomes and proceeded to live normal or near-normal lives. Our study confirms that even in resource-constrained areas, children with encephaloceles can be successfully managed with acceptable outcomes.

Familiality of diabetes mellitus.

The aims of this study were to estimate relative risk for type 1 and type 2 diabetes in relatives of diabetic patients, and to test for excess relatedness among diabetic patients. Additionally, the difference in parental transmission of diabetes was investigated. This study used a unique Utah genealogical resource, linked to electronic medical records of the largest health provider in Utah. We identified 19,640 patients with a diagnosis of type 1 or type 2 diabetes. Relative Risks (RRs) for type 1 and type 2 diabetes were assessed for first-, second- and third-degree relatives of diabetic patients. The observed average relatedness of diabetic patients was compared to the expected relatedness using the Genealogical Index of Familiality (GIF). We observed significantly elevated RRs for type 1 diabetes in first-degree (RR=8.68; P<0.0001), second-degree (RR=1.93; P<0.0001) and third-degree relatives (RR=1.74; P<0.0001) of type 1 diabetic patients. RRs for type 2 diabetes were significantly increased in first-degree (RR=2.24; P<0.0001), second-degree (RR=1.36; P<0.0001) and third-degree relatives (RR=1.14; P<0.0001) of type 2 diabetic patients. Significantly increased RRs for type 1 diabetes were observed in the relatives of type 2 diabetic patients, and vice versa. The GIF analysis showed significant excess relatedness for type 1 diabetes cases, and independently for type 2 diabetes cases. Offspring of diabetic fathers were at significantly higher risk for type 1 diabetes than offspring of diabetic mothers (RR=9.73; P<0.0001 compared to RR=4.99; P<0.0001). No significant difference in parental transmission was observed for type 2 diabetes. Our results strongly support the existence of a genetic contribution to both type 1 and type 2 diabetes, and additionally suggest a relationship between both types of diabetes. Furthermore, our results suggest a significant difference in parental transmission of type 1 diabetes.

Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands.

BACKGROUND: Cancer has long been recognized to have a familial component. Elevated risks for cancers at the same site for relatives of cancer probands have been reported for both common cancers and a number of the rarer cancer sites. For a particular cancer site, however, the estimated risks to relatives have varied considerably depending on criteria for selection of probands, how cancers were determined in relatives, and overall study design. Not surprisingly, the estimated risks of other cancers in relatives of probands with cancer at a given site have been subject to even more variation. PURPOSE: The aim of this study was to use the Utah Population Database resource to systematically study familial clustering of 28 distinct cancer site definitions among first-degree relatives (parents, siblings, and off-spring) of cancer probands. METHODS: We estimated familial relative risks from the Utah Population Database by identifying all cases of cancer in these first-degree relatives. These observed values were compared with those expected based on cohort-specific internal rates calculated from 399,786 relatives of all individuals in the Utah Population Database known to have died in Utah. RESULTS: All sites showed an excess of cancers of the same site among relatives, with thyroid and colon cancers and lymphocytic leukemia showing the highest familial risks. When the analyses were restricted to cases with early ages at diagnosis, increased familial components for most cancer sites became evident. A significant difference in familial relative risk (FRR) between male (FRR = 4.04; 95% confidence interval [CI] = 3.13-5.07) and female (FRR = 2.24; 95% CI = 1.54-3.08) probands was found for colon cancer. Highly significant familial associations (one-sided; P < .001) were found among breast, colon, and prostate cancers and between breast and thyroid cancers. Statistically significant (one-sided, P < .01) associations were also found between tobacco-associated sites (lung, larynx, lip, and cervix). CONCLUSIONS: This study represents a unique comprehensive population-based study of familial cancer. The familial associations reported here will be useful in generating hypotheses about specific genetic and environmental factors that can be tested in genetic linkage and case-control studies.

Inheritance of nevus number and size in melanoma and dysplastic nevus syndrome kindreds.

Previous studies of the genetics of melanoma have focused on the dysplastic nevus syndrome (DNS). The variability in clinical and histopathological expression of affected individuals, however, has made definition and diagnosis of the syndrome difficult and subjective. Independent of the DNS, case-control studies have demonstrated the total number of nevi to be a significant risk factor for melanoma. In this article, we report results of genetic analyses of two quantitative nevus phenotypes that can be measured objectively in all subjects: the total number of nevi on an individual (TNN) and total nevus density (TND), a derived phenotype which incorporates both number and size of nevi. Ten kindreds ascertained for multiple cases of DNS-melanoma (multiplex ascertainment) and 16 kindreds and 19 solitary cases ascertained from a sequential list of melanoma cases without regard for family history (simplex ascertainment) were studied. Both phenotypes exhibited increased levels in relatives of probands compared with those in spouse controls. While neither TNN nor TND exhibited evidence for a major factor in the simplex pedigrees, a major factor was strongly indicated in the multiplex kindreds for TND. When both phenotypes were examined in more detail in the multiplex kindreds, the phenotype incorporating nevus size, TND, fit a mendelian pattern of inheritance better than the TNN. Significant residual familial correlations were found for both phenotypes. Parameter estimates from the best fitting genetic model indicated that a major gene may be responsible for 55% of the phenotypic variability of TND in the multiplex kindreds.

A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis.

BACKGROUND: Mutation of a specific, but as yet unidentified, gene BRCA1 on chromosome 17q results in increased susceptibility to breast and ovarian cancer. It is important to know the effects of this gene in terms of the age-specific risks of these cancers and the potential interaction of this gene with other known risk factors. PURPOSE: We performed detailed studies on a large multigenerational family, in which there is known 17q-linked breast and ovarian cancer, in order to characterize the effects of the BRCA1 mutation on development of breast and ovarian cancer. METHODS: Data from the Utah Population Database were used to identify a family (identified as K2082) with a cluster of premenopausal breast cancer and ovarian cancer at any age. Blood samples from 195 members of the family were obtained and these individuals were genotyped for a series of four chromosome 17q polymorphic markers. Information on reproductive history, cancer incidence and treatment, and lifestyle factors was collected on 72 women in the family by questionnaire or through contact with living relatives. RESULTS: Odds in favor of linkage of breast and ovarian cancer in this family to the BRCA1 region of chromosome 17q are greater than 10(8) to 1. The estimated risks for breast or ovarian cancer because of the BRCA1 mutation in this family are 40% by age 50 years and 90% by age 70. No differences between affected and unaffected older BRCA1 gene carriers were observed for a number of known epidemiologic risk factors for these cancers. The gender of the parent from whom the mutant BRCA1 allele was inherited was significantly associated with phenotypic expression (P = .04). A recombinant which places BRCA1 distal to the marker Mfd191 was observed. CONCLUSIONS: Women with the BRCA1 mutation are at increased risk of developing breast and ovarian cancer. In our study population, the mutation appears to confer a lower risk of cancer at younger ages than found in previous studies. Continued interaction with family K2082 will be useful in longitudinal follow-up studies and in studies of the psychosocial implications of providing DNA diagnosis of BRCA1.

Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers.

BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. METHODS: We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. RESULTS: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. CONCLUSIONS: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.

Therapy in an intracerebral murine glioma model, using Bacillus Calmette-Guérin, neuraminidase-treated tumor cells, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

The s.c.-propagated murine glioma, GL-26, was established in tissue culture. The tissue culture line, with a doubling time of 36 hr, was used as the common source for all tumor cells. Suspensions of the tumor cells were transplanted intracerebrally in mice to produce an anaplastic ependymoblastoma. In vitro 51-Cr cytotoxicity assays did not detect any cellular immunity against GL-26 tumor cells in animals bearing either s.c. or i.c. tumors, indicating that the tumor itself is not highly immunogenic. Howeveer,significant cellular cytotoxicity was elicited in non-tumor-bearing animals by immunization with Vibrio cholerae neuramini-animals by immunization with Vibrio cholerae neuraminidase and mitomycin C-treated tumor cells plus complete Freund's adjuvant. In vivo therapy studies revealed significant increases in survival of animals preimmunized with V. cholerae neuraminidase- and mitomycin C-treated cells plus complete Freund's adjuvant. 1(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, when given i.p. on Day 3 or 12 after tumor challenge, also resulted in significant increases in survival. Furthermore, the effects of 1-(2-chloroethyl)- 3-cyclohexyl-1-nitrosourea and preimmunization were additive, with significanchloroethyl)-3-cyclohexyl-1-nitrosourea. In contrast to results reported for several extracranial tumor systems, immunotherapy, using either V.cholerae neuraminidase- and mitomycin-treated tumor cells, Bacillus Calmette-Guerin, or both, beginning 3 0r 4 days after tumor challenge, did not produce any significant increases in survival.

Familiality of cancer in Utah.

The Utah Population Database allows examination of the genetic relationships among the 35.7% of all cancer cases in the state that have genealogical records. Familial clustering of cancer is measured by the Genealogical Index of Familiality and is examined by site, and within site by age of onset, histology, and gender. Most cancer sites examined show excess familiality for all cases considered together. Subsets of individuals with certain characteristics showed unusually high levels of familial clustering, specifically lymphocytic leukemias and especially chronic lymphocytic leukemia, lobular breast cancer, early lip cancer, early melanoma, and female lung cancers of alveolar/adenoma histology. These may represent characteristics of the most penetrant forms of inherited susceptibilities, those which are enhanced by environmental factors, chance aggregations, rare inherited syndromes, or a combination of these factors.

Genetic heterogeneity and unmapped genes for colorectal cancer.

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.

Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM).

A susceptibility locus for familial melanoma has been localized to the short arm of chromosome 9. Penetrance of melanoma was estimated by calculating the Kaplan-Meier function and fitting a log normal hazard function in 124 gene carriers in three 9p-linked kindreds. The penetrance of the gene for melanoma was estimated to be 53% by age 80. Additionally, nevus counts, skin type, and sun exposure histories were gathered for 119 individuals in two kindreds. Gene carriers were found to have higher nevus counts and nevus densities than non-gene carriers. Among gene carriers, individuals with melanoma were found to have more sun exposure within each skin type than gene carriers without melanoma. These analyses suggest that the 9p melanoma susceptibility is related to total number of nevi and that it interacts with other genetic and environmental factors to produce melanoma.

Genomic structure, expression and mutational analysis of the P15 (MTS2) gene.

The P15 gene (MTS2) encodes a cyclin-dependent kinase (CDK) inhibitor with considerable sequence identity and biochemical similarity to the CDK inhibitor p16. It is closely linked to the P16 gene (MTS1) and is homozygously deleted in many tumor cell lines. These features suggest that p15 may be a tumor suppressor. We have determined the genomic structure of P15 and examined its pattern of mRNA expression. In addition, we have shown that ectopic expression of p15 inhibits growth of tumor-derived cell lines. We have also searched for P15 mutations in tumor cell lines and in 9p21-linked melanoma kindreds. Other than the previously described homozygous deletions, no mutations of P15 were found. Collectively, these observations suggest a role for p15 in growth regulation, but a limited role for p15 in tumor progression.