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Biomedical subjects

W Cole

Publications and source records attributed to W Cole.

At least 19 recordsLinked to original sources
PubMed2001

Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.

Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.

Animals↗
PubMed2000

MR imaging of simple bone cysts in children: not so simple.

OBJECTIVE: The unicameral bone cyst (UBC) is a common cystic bone lesion seen in children. We review and summarize its MR findings, focusing on their appearance following contrast enhancement, and correlating them to known histologic features of UBC. SUBJECTS AND METHODS: A retrospective review of 20 cases (13 boys, 7 girls; age range, 1-17 years; mean age, 8.9) diagnosed as UBC was conducted. Clinical histories, radiographic and MR features, follow-up data, and available pathologic findings were noted. RESULTS: At initial presentation 18 (90 %) of the patients with UBC had a history of acute or remote pathologic fracture. Cysts with history of fracture displayed heterogeneous fluid signals on T1-(n = 9, 50%), and T2-weighted (n = 15, 83 %) MR images. Gadolinium-enhanced images were obtained in 15 of the 18 UBC cases with history of previous fracture. All showed enhancement with focal, thick peripheral, heterogeneous, or subcortical patterns. Focal nodules of homogeneous enhancement (diameter > 1 cm) within the UBC (n = 5) correlated with areas of ground-glass opacification on plain film. Other interesting MR features were fluid-fluid levels (n = 11), "fallen-leaf" sign (n = 1), soft-tissue changes (n = 2), and detection of septations not seen on plain film (n = 2). CONCLUSION: UBCs frequently appear complicated on MR imaging, with heterogeneous fluid signals and regions of nodular and thick peripheral enhancement related to previous pathologic fracture and early healing.

Adolescent↗
PubMed2000

Periprosthetic bone remodelling around a prosthesis for distal femoral tumours. Measurement by dual-energy X-ray absorptiometry (DEXA).

We used dual-energy x-ray absorptiometry (DEXA) to evaluate the extent of periprosthetic bone remodelling around a prosthesis for distal femoral reconstruction, the Kotz modular femoral tibial replacement (KMFTR; Howmedica, Rutherford, New Jersey). A total of 23 patients was entered into the study which had four parts: 1) 17 patients were scanned three times on both the implant and contralateral legs to determine whether the precision of DEXA measurements was adequate to estimate bone loss surrounding the anchorage piece of the KMFTR; 2) in 23 patients the bone mineral density (BMD) in different regions of interest surrounding the diaphyseal anchorage was compared with that of the contralateral femur at the same location to test whether there was consistent evidence of loss of BMD adjacent to the prosthetic stem; 3) in 12 patients sequential studies were performed about one year apart to compare bone loss; and 4) bone loss was compared in ten patients with implants fixed by three screws and in 13 without screws. The mean coefficients of variation (SD/mean) for the 17 sets of repeated scans ranged from 2.9% to 7.8% at different regions of interest in the KMFTR leg and from 1.4% to 2.5% in the contralateral leg. BMD was decreased in the KMFTR leg relative to the contralateral limb and the percentage of BMD loss in general increased as the region of interest moved distally in the femur. Studies done after one year showed no consistent pattern of progressive bone loss between the two measurements. The ten patients with implants fixed by screws were found to have a mean loss of BMD of 42% in the most distal part of the femur, while the 13 without screw fixation had a mean loss of 11%. DEXA was shown to have adequate precision to evaluate loss of BMD around the KMFTR. This was evident relative to the contralateral leg in all patients and generally increased in the most distal part of the femur. In general, it stabilised between two measurements taken one year apart and was greater surrounding implants fixed by cross-locking screws.

Absorptiometry, Photon↗
PubMed1998

Brain contains inhibiting factors specific to the large T-antigen gene.

SV40 large T-antigen (LTa) gene-induced immortalized rat dopamine-producing nerve cells (IRB3AN27), which produce LTa protein and divide in vitro, do not divide and do not produce LTa protein when transplanted into striatum of adult rats. This suggests the presence of LTa gene-inhibiting factors in brain. Here we report that rat brain soluble fraction (SF) contains factors which specifically inhibit LTa gene activity in vitro. The brain SF inhibited LTa protein levels and the growth of IRB3AN27 cells and 2RSG cells (LTa gene-induced immortalized rat parotid acinar cells) in vitro, but it stimulated the growth of spontaneously immortalized human parotid acinar cells (2HPC8) and had no effect on the proliferation of murine neuroblastoma cells (NBP2) and rat glioma cells (C-6) in culture. In contrast, the liver SF inhibited the growth of all cell lines tested at varying degrees and thus lacked specificity with respect to LTa gene activity. The presence of specific LTa gene-inhibiting factors in the brain and general tumor growth-inhibiting factors in the liver may provide some of the mechanisms of protection against in vivo carcinogenesis.

Animals↗
PubMed1998

Cancer prevention studies: past, present, and future directions.

In spite of extensive research on vitamins and diet, a consistent beneficial role of vitamin supplements, together with diet modification in human cancer prevention, has not been demonstrated. Published results of human intervention trials with vitamin supplements have been contradictory. This review critically, but briefly, evaluates (a) current concepts of human carcinogenesis, (b) effects of vitamins on biochemical parameters that are pertinent to cancer prevention, and (c) whether past or current protocols for intervention trials among high-risk populations adopt specific scientific rationales that are based on laboratory and human epidemiology studies. In addition, we propose a novel experimental design for intervention trials among high-risk human populations that is based on sound scientific principles derived from laboratory and human epidemiologic data on vitamins, diet, lifestyle, and cancer prevention. Such trials would answer a fundamental public health issue of today: Does supplementation with multiple vitamins, together with diet and lifestyle modifications, reduce the risk of cancer?

Animals↗
PubMed1998

Characterization of cartilage oligomeric matrix protein (COMP) in human normal and pseudoachondroplasia musculoskeletal tissues.

Cartilage oligomeric matrix protein (COMP), the fifth member of the -thrombospondin gene family, is an extracellular matrix calcium-binding protein. The importance of COMP is underscored by the finding that mutations in COMP cause the human dwarfing condition, pseudoachondroplasia (PSACH). Here, we report the results of human tissue distribution and cell secretion studies of human COMP. COMP is expressed and secreted by cultured monolayer chondrocyte, tendon and ligament cells, and COMP secretion is not restricted to a differentiated chondrocyte phenotype. Whereas COMP is retained in the endoplasmic reticulum that accumulates within PSACH chondrocytes in vivo, COMP is not retained intracellularly in the dedifferentiated PSACH chondrocytes in cultures. These results lend further support to the hypothesis that retention of COMP is related to the terminal PSACH chondrocyte phenotype, processing of proteins related to extracellular matrix formation, and maintenance in cartilage.

Achondroplasia↗
PubMed1998

Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.

The LIM-homeodomain protein Lmx1b plays a central role in dorso-ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects including hypoplastic nails, absent patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal malformation nail patella syndrome (NPS). We show that LMX1B maps to the NPS locus and that three independent NPS patients carry de novo heterozygous mutations in this gene. Functional studies show that one of these mutations disrupts sequence-specific DNA binding, while the other two mutations result in premature termination of translation. These data demonstrate a unique role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes. Furthermore, we provide evidence for the first described mutations in a LIM-homeodomain protein which account for an inherited form of abnormal skeletal patterning and renal failure.

Amino Acid Sequence↗
PubMed1992

Incest perpetrators. Their assessment and treatment.

The multitude of articles published in the last decade in the area of intrafamilial sexual abuse highlight the complexity of the issue--both its assessment and treatment. Although no unique profile of an incest perpetrator exists, a review of studies revealed problems in the areas of sexual satisfaction, psychological functioning, interpersonal relationships, and family of origin. As well, incest families have been reported to be dysfunctional, with power imbalances; control struggles; indirect, unclear communication; and inappropriate coalitions among family members. Based on these observations, a wide range of treatment interventions now exists, including offender-oriented cognitive/behavioral therapies and a family-focused multimodal systems approach. Although questions remain to be answered in regard to the effectiveness and process of treatment, efforts limited to the recognition of these problematic families are no longer adequate. The focus must move to prevention through the early identification of individuals at risk both for offending and being part of an incest family structure; the implementation of proven, cost-effective, proactive intervention strategies; and the continuing dissemination of information to the public.

Adolescent↗
PubMed1991

Repeated use of psychiatric emergency services by children.

In this study, the repeat utilization of child psychiatric emergency services was examined. There are patients who use psychiatric emergency services repeatedly, and these patients represent a significant proportion of child psychiatric emergencies seen in emergency rooms. Repeat patients were more likely to threaten to harm others, have a diagnosis of adjustment disorder, conduct or oppositional disorder and be under the care of a child welfare agency. They were significantly more likely than the one-time patients to be less compliant with outpatient follow-up, admitted to hospital more often, needed more social support and had greater difficulty remaining in a residential treatment setting. Intervention in the emergency room did not appear to change the way they used emergency services.

Adolescent↗
PubMed1989

Correlation of clinical and molecular biological abnormalities in osteogenesis imperfecta.

Substitution of a glycine residue in the triple helix of the alpha 1(I) chain by either arginine, valine or alanine was associated with the type II lethal perinatal osteogenesis imperfecta phenotype. This phenotype was also produced by a frameshift mutation that resulted in an abnormal amino acid sequence of the carboxy-terminal propeptide of the pro-alpha 1(I) chain. The latter baby, however, showed some clinical and radiographic differences from the other babies with type II OI. The severity of the clinical and radiographic phenotypes are likely to be determined by both the type and site of the mutation as well as by the intra-uterine environment.

Alanine↗
PubMed1988

Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene.

Substitutions of single glycine residues of alpha 1(I) collagen have previously been associated with the inherited disease osteogenesis imperfecta type II. Transgenic mice bearing a mutant alpha 1(I) collagen gene into which specific glycine substitutions have been engineered show a dominant lethal phenotype characteristic of the human disease, and demonstrate that as little as 10% mutant gene expression can disrupt normal collagen function.

Amino Acid Sequence↗