Search PubMed⌕ Search

Biomedical subjects

S Saunders

Publications and source records attributed to S Saunders.

At least 19 recordsLinked to original sources
PubMed2001

Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition.

Simpson Golabi Behmel syndrome (SGBS) is a complex congenital overgrowth syndrome with features that include macroglossia, macrosomia, and renal and skeletal abnormalities as well as an increased risk of embryonal cancers. Most cases of SGBS appear to arise as a result of either deletions or point mutations within the glypican-3 (GPC3) gene at Xq26, one member of a multigene family encoding for at least six distinct glycosylphophatidylinositol-linked cell surface heparan sulfate proteoglycans. As a class of molecules, heparan sulfate proteoglycans have been found to play essential roles in development by modulating cellular responses to growth factors and morphogens. Specifically, mutations in both the murine GPC3 gene and the Drosophila glypican, dally, have been found to modify cellular responses to bone morphogenetic proteins, providing important clues to the molecular basis of SGBS in humans. Despite these advances, there remains a paucity of information about the natural history of SGBS and optimal medical management strategies, and whether select mutations influence the SGBS phenotype and risk of cancer. To this end, an International SGBS Registry has been created and is being maintained to improve the clinical care and understanding of the pathogenesis of SGBS. Using an integrated approach employing epidemiology, molecular genetic characterization of specific GPC3 mutations, and the use of model organisms should rapidly expand the understanding of this complex disorder.

Abnormalities, Multiple↗
PubMed2000

glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development.

Glypicans represent a family of six cell surface heparan sulfate proteoglycans in vertebrates. Although no specific in vivo functions have thus far been described for these proteoglycans, spontaneous mutations in the human and induced deletions in the mouse glypican-3 (Gpc3) gene result in severe malformations and both pre- and postnatal overgrowth, known clinically as the Simpson-Golabi-Behmel syndrome (SGBS). Mice carrying mutant alleles of Gpc3 created by either targeted gene disruption or gene trapping display a wide range of phenotypes associated with SGBS including renal cystic dysplasia, ventral wall defects, and skeletal abnormalities that are consistent with the pattern of Gpc3 expression in the mouse embryo. Previous studies in Drosophila have implicated glypicans in the signaling of decapentaplegic, a BMP homolog. Our experiments with mice show a significant relationship between vertebrate BMP signaling and glypican function; GPC3-deficient animals were mated with mice haploinsufficient for bone morphogenetic protein-4 (Bmp4) and their offspring displayed a high penetrance of postaxial polydactyly and rib malformations not observed in either parent strain. This previously unknown link between glypican-3 and BMP4 function provides evidence of a role for glypicans in vertebrate limb patterning and skeletal development and suggests a mechanism for the skeletal defects seen in SGBS.

Animals↗
PubMed1999

GPC6, a novel member of the glypican gene family, encodes a product structurally related to GPC4 and is colocalized with GPC5 on human chromosome 13.

Glypicans are a family of cell surface heparan sulfate proteoglycans that appear to play an important role in cellular growth control and differentiation, as is supported by the observation that mutations in GPC3 are responsible for Simpson-Golabi-Behmel syndrome (SGBS) in humans. Recently it has been shown that the GPC4 gene is tightly clustered with GPC3 on the X chromosome and that some patients with SGBS apparently have deletions affecting both genes. We report here the identification of a human cDNA encoding a novel glypican family member, glypican-6. This cDNA encodes a predicted protein of 554 amino acids and is structurally analogous to other members of the glypican gene family, but most highly related to glypican-4. A single GPC6 mRNA of 6.2 kb is detected most abundantly in the ovary, liver, and kidney, with lower levels of mRNA expression also detected in a wide range of other adult tissues. Radiation hybrid analysis mapped the GPC6 gene to human chromosome 13 very near the GPC5 gene, a member of the glypican family bearing strong similarity to GPC3.

Amino Acid Sequence↗
PubMed1999

Response to intradialytic parenteral nutrition.

Malnutrition is a major clinical problem in patients receiving maintenance hemodialysis and has adverse effects on survival. Nutritional intervention is indicated, and there is evidence that intradialytic parenteral nutrition can be beneficial. We describe the application of a formal policy regarding the use of intradialytic parenteral nutrition and the beneficial effects on nutrition in the first four patients managed in this fashion. However, the fifth patient did not respond to parenteral nutrition, despite adequate dialysis. This prompted further investigation, and the patient was shown to have extensive gastric malignancy. This report shows that establishing a protocol for intradialytic parenteral nutrition is possible in a medium-sized hemodialysis unit. In these circumstances, nonresponse to this intervention should always be investigated to determine if there is another underlying cause of malnutrition unrelated to renal failure.

Adult↗
PubMed1999

Evaluation of risk assessment questions used to target blood lead screening in Illinois.

OBJECTIVE: Beginning in 1995, Illinois law permitted targeted-as opposed to universal-blood lead screening in low-risk areas, which were defined by ZIP code characteristics. State guidelines recommended specific lead risk assessment questions to use when targeting screening. This study was designed to evaluate the sensitivity and specificity of Illinois lead risk assessment questions. DESIGN: Parents bringing their 9- or 10- or 12-month and 24-month-old children for health supervision visits at 13 pediatric practices and parents of children (aged 6 through 25 months and who needed a blood lead test) receiving care at 5 local health departments completed a lead risk assessment questionnaire concerning their child. Children had venous or capillary blood lead testing. Venous confirmation results of children with a capillary level >/=10 micrograms/dL were used in analyses. CHILDREN: There were 460 children with both blood and questionnaire data recruited at the pediatric practices (58% of eligible) and 285 children (51% of eligible) recruited at local health departments. Of the 745 children studied, 738 provided a ZIP code that allowed their residence to be categorized as in a low-risk (n = 456) or high-risk (n = 282) area. RESULTS: Sixteen children (3.5%) living in low-risk areas versus 34 children (12.1%) living in high-risk areas had a venous blood lead level (BLL) >/=10 micrograms/dL; 1.8% and 5.3%, respectively, had a venous BLL >/=15 micrograms/dL. For children living in low-risk areas, Illinois mandated risk assessment questions (concerning ever resided in home built before 1960, exposure to renovation, and exposure to adult with a job or hobby involving lead) had a combined sensitivity of.75 for levels >/=10 micrograms/dL and.88 for levels >/=15 micrograms/dL; specificity was.39 and.39, respectively. The sensitivity of these questions was similar among children from high-risk areas; specificity decreased to.27 and.28, for BLLs >/=10 micrograms/dL and >/=15 micrograms/dL, respectively. The combination of items requiring respondents to list house age (built before 1950 considered high risk) and indicate exposure to renovation had a sensitivity among children from low-risk areas of.62 for BLLs >/=10 micrograms/dL with specificity of.57; sensitivity and specificity among high-risk area children were.82 and.36, respectively. For this strategy, similar sensitivities and specificities for low and high-risk areas were found for BLLs >/=15 micrograms/dL. CONCLUSIONS: The Illinois lead risk assessment questions identified most children with an elevated BLL. Using these questions, the majority of Illinois children in low-risk areas will continue to need a blood lead test. This first example of a statewide screening strategy using ZIP code risk designation and risk assessment questions will need further refinement to limit numbers of children tested. In the interim, this strategy is a logical next step after universal screening.

Child, Preschool↗
PubMed1998

Two quantitative methods for rib seriation in human skeletal remains.

Accurate rib sequencing is of importance to both forensic anthropologists and human osteologists, but until recently there have been few traits used to aid in the seriation of ribs within a human burial. This study examines two measurements (head to tubercle length and superior costotransverse ligament crest height) for the purpose of aiding rib identification and seriation in human skeletal remains. A sample of 344 ribs from 43 individuals from the 19th century Anglican Church cemetery of St. Thomas in Belleville, Ontario were used for the current study. While the head to tubercle length appeared unreliable for rib seriation, the superior costotransverse ligament crest height may provide an alternative technique for assessing rib sequence. More importantly though, the method provides a basis on which the identification of the central ribs can be made.

Adult↗
PubMed1997

Expression of the cell surface proteoglycan glypican-5 is developmentally regulated in kidney, limb, and brain.

Heparan sulfate is ubiquitous at the cell surface, where it is expressed predominantly on proteoglycans of either the transmembrane syndecan family or the glycosylphosphatidylinositol (GPI)-anchored glypican family, and has been proposed to function as a "coreceptor" for a number of "heparin-binding" growth factors. Although little is known about functional differences between individual members of the glypican gene family, mutations in both the Drosophila gene dally and the human gene for glypican-3 strongly suggest that at least some glypicans do function in cellular growth control and morphogenesis. In particular, deletion of the human glypican-3 gene is responsible for Simpson-Golabi-Behmel syndrome, and its associated pre- and postnatal tissue overgrowth, increased risk of embryonal tumors during early childhood, and numerous visceral and skeletal anomalies. We have identified and characterized, by sequencing of EST clones and products of rapid amplification of cDNA ends (RACE), an mRNA that encodes a 572-amino-acid member of the glypican gene family (glypican-5) that is most related (50% amino acid similarity, 39% identity) to glypican-3. Glypican-5 mRNA is detected as a 3.9- and 4.4-kb transcript in adult and neonatal mouse brain total RNA, and in situ hybridization results localize transcript primarily to restricted regions of the developing central nervous system, limb, and kidney in patterns consistent with a role in the control of cell growth or differentiation. Interestingly, glypican-5 localizes to 13q31-32 of the human genome, deletions of which are associated with human 13q- syndrome, a developmental disorder with a pattern of defects that shows significant overlap with the pattern of glypican-5 expression.

Amino Acid Sequence↗
PubMed1995

Low-grade Papanicolaou smears and the Bethesda system: a prospective cytohistopathologic analysis.

OBJECTIVE: To examine the clinical usefulness of the Bethesda classification system of low-grade cervicovaginal cytology as it relates to predicting underlying histology and aiding in triage to colposcopy. METHODS: We evaluated 1454 women with abnormal cytologic screening results: 782 with atypical squamous cells of uncertain significance (atypia), 355 with low-grade squamous intraepithelial lesions (SIL) determined by the presence of human papillomavirus (HPV) alone, and 317 with low-grade SIL determined by the presence of cytologic evidence of mild dysplasia (cervical intraepithelial neoplasia [CIN] I) devoid of HPV cytopathologic features. All women underwent colposcopy, directed-punch biopsy or loop electrosurgical excision, and/or endocervical curettage (ECC), as indicated. RESULTS: Women from the low-grade SIL-CIN I referral cytology group were significantly more likely to harbor all grades of biopsy-proven dysplasia than were those from the atypical squamous cells of uncertain significance and low-grade SIL-HPV groups, which showed no statistical differences. CONCLUSIONS: Contrary to the Bethesda system, which combines CIN I and HPV changes because of cytomorphologic similarities, this study suggests that patients with HPV cytologic smears are similar to patients with atypical smears and are less likely to harbor any biopsy-proven CIN lesions than are patients with CIN I cervicovaginal smears. If excluded from colposcopic triage, approximately 5% of patients with atypical cytologic smears from a well-screened population similar to ours will harbor high-grade lesions that may progress during any waiting period. Triage of low-grade cervicovaginal smears based on histopathologic correlation is encouraged.

Adult↗
PubMed1995

Loss of cell surface syndecan-1 causes epithelia to transform into anchorage-independent mesenchyme-like cells.

Simple epithelial cells are polygonal in shape, polarized in an apical-basal orientation, and organized into closely adherent sheets, characteristics that result from a variety of cellular specializations and adhesive proteins. These characteristics are lost when the epithelia transform during embryogenesis into mesenchymal cells or after neoplasia into invasive carcinoma cells. Of the syndecan family of transmembrane heparan sulfate proteoglycans, simple epithelia produce predominantly syndecan-1, which is found at basolateral surfaces and within adhesive junctions. To elucidate the function of this syndecan-1, normal murine mammary gland epithelia were made deficient in syndecan-1 by transfection with an expression vector containing the syndecan-1 cDNA in the antisense configuration. Several independently derived clones of stable transfectants contained the antisense cDNA in their genome and expressed the antisense transcript. These grew either as epithelial islands of closely adherent polygonal cells, identical to both the parental cells and the vector-only control transfectants, or as individual elongated fusiform cells that invaded and migrated within collagen gels, like mesenchymal cells, but were anchorage-independent for growth. The clones that retained epithelial characteristics were moderately deficient in cell surface syndecan-1 (greater than 48% of control levels) but did not differ from control cells in expression of beta 1-integrins and E-cadherin, or in F-actin organization. However, the clones of fusiform cells were severely deficient in cell surface syndecan-1 (less than 12% of control levels) and showed rearranged beta 1-integrins, markedly reduced E-cadherin expression, and disorganized F-actin filaments, but retained mammary epithelial markers. Therefore, depleting epithelia of cell surface syndecan-1 alters cell morphology and organization, the arrangement and expression of adhesion molecules, and anchorage-dependent growth controls. Thus, cell surface syndecan-1 is required to maintain the normal phenotype of simple epithelia.

Actins↗
PubMed1995

Effects of noise exposure, race, and years of service on hearing in U.S. Army soldiers.

Over the last two decades the U.S. Army has instituted a comprehensive hearing conservation program (HCP) to reduce the prevalence of hearing loss in soldiers and civilian employees. As a component of this program, hearing threshold levels (HTLs) are stored in a central computerized Army-wide hearing conservation data registry. The aim of this study was to analyze the hearing threshold data to compare the hearing loss among soldiers representing different (1) race groups, (2) noise exposure groups, and (3) duration of military service. HTLs were age-corrected using data base B values from ISO 1999 (1990). As may be expected, soldiers exposed to high noise levels had significantly poorer hearing than the group of soldiers with limited noise exposure. On the average, results indicated a significant difference in HTLs among the race groups with black soldiers having the most sensitive hearing and white soldiers having the poorest. Also, subjects with greater durations of military service had the least sensitive hearing. Finally, race and years of service factors were found to interact in their effect on HTL. The findings are discussed in terms of implications of race differences, normative data, and effectiveness of the U.S. Army HCP.

Adolescent↗
PubMed1994

Accuracy of sex determination using morphological traits of the human pelvis.

This study assesses the accuracy and reliability of 17 individual morphological traits of the pelvis frequently used to determine the sex of human skeletal remains. A sample of 49 right and left adult hip bones and sacra of documented individuals were available from an historic church cemetery dating from the 19th century. A hypothetical ranking of the accuracy of traits was drawn from the literature. Next, individual traits were evaluated for precision and accuracy of observations, and combinations of two and three traits were evaluated for their collective effectiveness as sex indicators. The effect of age on the accuracy of traits for sex determination was also examined. Precision of traits was generally good. Several combinations of three criteria produced higher levels of accuracy than the trait list as a whole. A total of six traits was judged to be most effective as sex discriminators because of low intraobserver error levels and better than 83% accuracy rats. There was no indication of an age effect on the precision or accuracy of these traits although sample sizes are small.

Adult↗
PubMed1993

Accuracy tests of tooth formation age estimations for human skeletal remains.

Estimations of age from tooth formation standards for a large (n = 282) sample of subadult skeletal remains from a 19th century historic cemetery sample were analyzed. The standards of Moorrees et al. (1963a,b) for the permanent and deciduous teeth, and Anderson et al. (1976) for the formation of permanent dentition were employed in a variety of combinations to calculate mean dental ages. Tests of accuracy and bias were made on a small sample (n = 17) of personally identified individuals, and age of attainment scores were compared to age of prediction scores for each individual. The resulting dental age distributions for the skeletal sample were compared to documented burial records for the cemetery to determine the representativeness of the skeletal sample. These comparisons showed little difference between age of attainment versus age of prediction methodologies. The standards of Moorrees et al. (1963a,b) were observed to provide the most accurate estimates of age with a standard deviation of one-half year. The standards of Anderson et al. (1976), while easier to use and more extensive, are problematic in that the original reference sample begins at three years of age, while the sample used by Moorrees and colleagues begins at birth. The skeletal age distributions compare well to the overall chronological age distribution for the cemetery. These results affirm that tooth formation age estimates for subadult skeletal remains from archaeological or forensic samples provide accurate assessments of age at both the individual and population level.

Adolescent↗
PubMed1990

Cardioactive neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) and novel related peptides are encoded in multiple copies by a single gene in the snail Lymnaea stagnalis.

The neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) is a potent cardioactive neuropeptide in Lymnaea stagnalis. Isolation and sequencing of 2 cDNAs and a genomic clone shows that a single gene encodes a precursor protein which contains 9 copies of the FMRFamide peptide, 2 copies of the related peptide Phe-Leu-Arg-Phe-NH2 (FLRFamide), and single copies of the putative pentapeptides Gln-Phe-Tyr-Arg-lle-NH2 (posttranslationally modified to pQFYRlamide) and Glu-Phe-Leu-Arg-lle-NH2 (EFLRlamide). The gene is transcribed in the CNS and gives rise to a single RNA of 1.7 kb in size. The organization of the Lymnaea gene is significant with respect to the evolution of FMRFamide and related peptides in other organisms.

Animals↗
PubMed1989

Molecular cloning of syndecan, an integral membrane proteoglycan.

We describe cDNA clones for a cell surface proteoglycan that bears both heparan sulfate and chondroitin sulfate and that links the cytoskeleton to the interstitial matrix. The cDNA encodes a unique core protein of 32,868 D that contains several structural features consistent with its role as a glycosamino-glycan-containing matrix anchor. The sequence shows discrete cytoplasmic, transmembrane, and NH2-terminal extracellular domains, indicating that the molecule is a type I integral membrane protein. The cytoplasmic domain is small and similar in size but not in sequence to that of the beta-chain of various integrins. The extracellular domain contains a single dibasic sequence adjacent to the extracellular face of the transmembrane domain, potentially serving as the protease-susceptible site involved in release of this domain from the cell surface. The extracellular domain contains two distinct types of putative glycosaminoglycan attachment sites; one type shows sequence characteristics of the sites previously described for chondroitin sulfate attachment (Bourdon, M. A., T. Krusius, S. Campbell, N. B. Schwartz, and E. Ruoslahti. 1987. Proc. Natl. Acad. Sci. USA. 84:3194-3198), but the other type has newly identified sequence characteristics that potentially correspond to heparan sulfate attachment sites. The single N-linked sugar recognition sequence is within the putative chondroitin sulfate attachment sequence, suggesting asparagine glycosylation as a mechanism for regulating chondroitin sulfate chain addition. Both 5' and 3' regions of this cDNA have sequences substantially identical to analogous regions of the human insulin receptor cDNA: a 99-bp region spanning the 5' untranslated and initial coding sequences is 67% identical and a 35-bp region in the 3' untranslated region is 81% identical in sequence. mRNA expression is tissue specific; various epithelial tissues show the same two sizes of mRNA (2.6 and 3.4 kb); in the same relative abundance (3:1), the cerebrum shows a single 4.5-kb mRNA. This core protein cDNA describes a new class of molecule, an integral membrane proteoglycan, that we propose to name syndecan (from the Greek syndein, to bind together).

Amino Acid Sequence↗