Biomedical subjects

C M Powell

Publications and source records attributed to C M Powell.

At least 19 recordsLinked to original sources

PubMed2000

Usefulness and limitations of FISH to characterize partially cryptic complex chromosome rearrangements.

Interpretation of a complex chromosome rearrangement (CCR) using only G-band analysis is difficult and potentially inaccurate. We present two patients with de novo, partially cryptic, CCRs that illustrate both the value and limitations of using fluorescence in situ hybridization (FISH) whole chromosome paint probes to characterize these types of rearrangements. In a patient referred because of features of Townes-Brocks syndrome, G-band analysis revealed an unbalanced CCR involving 3 chromosomes (2,11 and 16) and at least 4 breakpoints. A more complex rearrangement involving two cryptic insertions and at least 6 breakpoints, however, was detected using whole chromosome paint probes specific for the 3 chromosomes involved in the rearrangement. In this case, FISH studies were essential for accurate characterization of this patient's rearrangement. In a second patient, G-band analysis revealed that a 12-year-old male with obesity, small genitalia, attention deficit disorder, learning disabilities, and behavior problems, carried a CCR involving 4 chromosomes (3, 5, 10 and 13) with 6 breakpoints. This rearrangement seemed unbalanced, with missing terminal 3p26. 2-pter material. Our G-band interpretation of this karyotype was confirmed by FISH using whole chromosome paint probes specific for the involved chromosomes. Although no evidence of the "missing" 3pter material was observed using a chromosome 3 paint, FISH analysis using a chromosome 3p unique telomere probe identified telomeric 3p material on the distal long arm of the derivative 10 chromosome. This case illustrates the limited value of painting probes to detect small rearrangements, especially those involving terminal chromosome regions.

Abnormalities, Multiple↗

PubMed2000

Inhibition of the mammalian transcription factor LSF induces S-phase-dependent apoptosis by downregulating thymidylate synthase expression.

The thymidylate synthase (TS) gene, which is induced at the G(1)-S transition in growth-stimulated cells, encodes an enzyme that is essential for DNA replication and cell survival. Here we demonstrate that LSF (LBP-1c, CP2) binds to sites within the TS promoter and intronic regions that are required for this induction. Mutation of the LSF binding sites inhibits G(1)-S induction of mRNA derived from a TS minigene. Furthermore, expression of dominant-negative LSF (LSFdn) prevents the increase in TS enzyme levels during G(1)-S, and induces apoptosis in growth- stimulated mouse and human cell lines. Such apoptosis can be prevented either by circumventing the TS requirement through addition of low concentrations of thymidine, or by coexpression of the TS gene driven by a heterologous promoter. Induction of apoptosis by LSFdn parallels the process known as thymineless death, which is induced by the TS inhibitor and chemotherapeutic drug 5-fluorodeoxyuridine. Thus, LSF is a novel regulatory factor that supports progression through S-phase by targeting a single gene that is critical for cell survival.

Amino Acid Sequence↗

PubMed2000

Ophthalmic manifestations of Angelman syndrome.

In 1965, Angelman described 3 cases of what he called "Puppet" children, named for the characteristic signs associated with what is now known as Angelman syndrome, including mental retardation, speech impairment, easy excitability, and frequent spontaneous laughter.(1) Since that report, much progress has been made in defining the syndrome's clinical manifestations and understanding its molecular foundations, including identification of deletions of 15q11-13 in some patients. There are few reports in the ophthalmic literature regarding ocular manifestations of this syndrome. (2,3) We present the case of a child with strabismus associated with Angelman syndrome, and we review the ophthalmic and systemic findings, as well as recent advances in molecular genetics, in these patients.

Angelman Syndrome↗

PubMed1999

Genetic studies of autistic disorder and chromosome 7.

Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.

Adult↗

PubMed1999

Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder with multiple malformations and variable expression. Major findings include external ear anomalies, hearing loss, preaxial polydactyly and triphalangeal thumbs, imperforate anus, and renal malformations. Most patients with Townes-Brocks syndrome have normal intelligence, although mental retardation has been noted in a few.

Abnormalities, Multiple↗

PubMed1998

Prenatal diagnosis of mosaic trisomy 13: a case report.

While the clinical features associated with full trisomy 13 have been well characterized, the clinical outcome associated with mosaic trisomy 13 is much less clear. The medical literature reports a broad range of possible clinical outcomes from severe mental retardation and birth defects to normal intelligence. There is no consensus about the typical phenotype in these cases. This makes genetic counselling after prenatal diagnosis of mosaic trisomy 13 particularly difficult. Some of the medical literature attempts to correlate the percentage of trisomic cells in peripheral blood leukocytes or skin fibroblasts with clinical outcome. There have not been case reports correlating the percentage of trisomic amniocytes and clinical outcome. We report the prenatal diagnosis of mosaic trisomy 13 by amniocentesis in which no prenatal ultrasound abnormalities were noted, and autopsy was normal with the exception of the presence of a small ventricular septal defect.

Abortion, Induced↗

PubMed1997

A PET study of Turner's syndrome: effects of sex steroids and the X chromosome on brain.

Women with Turner's syndrome (TS) allow us to study the neurobiological associates of cognitive and behavioral abnormalities because they lack one/part of one X chromosome, and endogenous estrogen. We studied 13 healthy controls (mean age +/- SD, 28 +/- 6 years) and 16 TS subjects (mean age +/- SD, 26 +/- 6 years). We measured cognitive abilities using neuropsychological tests, and cerebral metabolic rates for glucose with positron emission tomography. Compared to controls, TS subjects had significant absolute hypermetabolism in most brain areas; however, normalized metabolism was significantly lower in TS subjects than controls in the insula and association neocortices bilaterally, and there were significant differences in functional metabolic associations of brain region pairs originating in occipital cortex bilaterally, and within the right hemisphere. There were significant correlations between right-left cognitive and metabolic asymmetries in the TS group. Also, within TS a preliminary analysis demonstrated "X chromosome dosage" effects in language ability and left temporal metabolism, asymmetry of right-left test scores, and parietal metabolism. We hypothesize that within TS: i) generalized brain hypermetabolism reflects global abnormalities in neuron packing; ii) neuronal abnormalities occur in association neocortex that differ in nature or extent from whole brain and are associated with significant differences in normalized metabolism; iii) cognitive deficits are related to brain metabolic abnormalities; and iv) social-behavioral problems may be related to abnormalities of brain metabolism. Moreover, in human brain the X chromosome involved in development of the association neocortices.

Adult↗

PubMed1997

Fibroadenomas: MR imaging appearances with radiologic-histopathologic correlation.

PURPOSE: To identify histopathologic correlates for the varied magnetic resonance (MR) imaging appearances of fibroadenomas. MATERIALS AND METHODS: Twenty-three fibroadenomas in 21 patients (aged 23-66 years) examined with gadolinium-enhanced MR imaging were graded for signal intensity on T2-weighted images, contrast material enhancement, shape, and internal septations and were correlated with histopathologic findings. RESULTS: Fibroadenomas demonstrated high T2 signal intensity with enhancement (n = 11), low T2 signal intensity with enhancement (n = 3), or low T2 signal intensity without enhancement (n = 9). Low T2 signal intensity and lack of enhancement were associated with more sclerotic stroma and older patient age. Lesion shape was lobular, oval, or round in 19 of 23 fibroadenomas (83%). Internal septations were identified within nine of 14 enhancing fibroadenomas (64%) and appeared to correlate with collagenous bands at histopathologic analysis. CONCLUSION: Fibroadenomas demonstrate marked histopathologic variability. The resultant variability in the MR appearance limits the ability to distinguish between benign and malignant masses on the basis of signal intensity and enhancement alone. Lobulation and internal septation, which appear to reflect intrinsic growth patterns of fibroadenomas, may provide a more reliable basis for distinction.

Adult↗

PubMed1997

Expression of prolactin and its receptor in human breast carcinoma.

The growth regulatory effects of PRL on the human breast are mediated by its receptor (PRLr), a member of the cytokine receptor family. Recent reverse transcriptase-PCR studies by our laboratory and others have shown PRL expression within breast tissues at the RNA level. To confirm the role of this growth factor-receptor complex in normal and malignant breast tissues, the expression of PRL and PRLr was examined in parallel with the estrogen receptor (ER) and progesterone receptor (PR). Sixty-nine cases of primary invasive breast carcinoma were examined for PRL and PRLr expression by in situ hybridization and immunohistochemical technique, respectively. These data revealed widespread expression of PRL and its receptor in the breast cancers studied (>95%) and in the normal breast tissues (>93%), with no association between the expression of PRL-PRLr and ER or PR. These findings stand in contrast to prior RIA-based studies that detected the PRLr in only 20-60% of breast carcinomas, most commonly in ER-PR-positive cells. These results confirm prior data indicating the presence of an autocrine/paracrine loop for the PRL-PRLr complex within human breast tissues. Given the widespread expression of PRL-PRLr in breast cancer, pharmacological interventions aimed at the inhibition of function of this growth regulatory receptor complex may be of considerable utility in the therapy of this disease.

Adult↗

PubMed1996

Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions in the short arm of chromosome 11.

A contiguous gene syndrome due to deletions of the proximal short arm of chromosome 11 is described in eight patients belonging to four families. The main clinical features are multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation. The patients have cytogenetic and/or molecular deletions of chromosome 11p11-p13. These deletions are located between the centromere and D11S914 in a region of approximately 20cM. The present study confirms the presence of a multiple exostoses gene on chromosome 11p. Furthermore, it suggests that the gene for isolated foramina parietalie permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region.

Abnormalities, Multiple↗

PubMed1995

Pseudoangiomatous stromal hyperplasia (PASH). A mammary stromal tumor with myofibroblastic differentiation.

Pseudoangiomatous stromal hyperplasia (PASH) is frequently a microscopic incidental finding in breast biopsies performed for benign or malignant disease. However, it may also produce a mass lesion. We reviewed PASH seen first as a tumor in 40 women aged 14 to 67 years (mean, 37 years). All but one lesion were clinically palpable. The exceptional tumor was found by mammography. The mass, typically unilateral, was usually diagnosed clinically as a fibroadenoma. Most specimens contained a well-circumscribed tumor with a firm white-gray cut surface. In six cases, there was no discrete gross lesion in the surgical specimen. Microscopically, there was a spectrum of pathological stromal changes ranging from classical PASH with anastomosing slit-shaped spaces outlined by flat, bland spindle cells to more proliferative lesions composed of bundles of plump spindle cells that obscured the underlying pseudoangiomatous architecture in the most florid lesions. The spindle cells were vimentin and CD34 positive and factor VIII negative. In more cellular fascicular lesions, the stromal cells acquired desmin and actin positivity. These immunohistochemical features were consistent with myofibroblastic histogenesis of PASH. Reactivity for progesterone receptor (PR) typically exceeded estrogen receptor (ER) in the nuclei of stromal and glandular cells. In most lesions, the nuclei of stromal spindle cells were ER negative. The majority of the patients were treated by excisional biopsy. One lesion, incompletely excised, spontaneously regressed. One patient had bilateral mastectomies. Follow-up was 0.6-11 years (mean, 4.5 years). Five patients had ipsilateral recurrences, and two had subsequent contralateral PASH. The morphological spectrum of cellular proliferation and staining qualities indicates that the myofibroblast plays a major role in the histogenesis of PASH. The pathogenesis of PASH remains uncertain, but aberrant reactivity of myofibroblasts to endogenous or exogenous hormones is likely to be an important factor. Simple excision is adequate treatment initially and for infrequent recurrences, Diffuse PASH occasionally presents a difficult management problem that may necessitate mastectomy.

Adolescent↗

PubMed1995

Staging of suspected breast cancer: effect of MR imaging and MR-guided biopsy.

PURPOSE: To investigate the effect of contrast material-enhanced magnetic resonance (MR) imaging on staging of breast cancer in patients with mammographically or clinically suspected tumor. MATERIALS AND METHODS: One hundred seventy-six patients underwent breast MR imaging at 1.5 T before excisional biopsy of a suspicious mammographic or palpable abnormality. Diagnostic imaging studies in patients with biopsy-proved or presumed breast carcinoma were reviewed. RESULTS: Sixty-four patients met the study criteria. MR imaging enabled detection of all 57 invasive breast cancers and nine of 15 in situ cancers. In 22 patients (34%), MR imaging depicted one or more cancers not visible at mammography, 13 (20%) of which were unsuspected multifocal or diffuse disease. As a result of the increased sensitivity of MR imaging compared with that of mammography, clinical staging and subsequent treatment were altered in seven patients (11%). CONCLUSION: MR imaging allows detection of mammographically and clinically occult foci of carcinoma in patients with suspected breast cancer.

Adult↗

PubMed1994

Autonomously active protein kinase C in the maintenance phase of N-methyl-D-aspartate receptor-independent long term potentiation.

In area CA1 of the hippocampus, the induction of long term potentiation (LTP) requires activation of either N-methyl-D-aspartate receptors (NMDA receptor-dependent LTP) or voltage-gated Ca2+ channels (NMDA receptor-independent LTP). We have investigated biochemical sequelae of NMDA receptor-independent LTP induction. We find that a persistent increase in second messenger-independent protein kinase C activity is associated with the maintenance phase of NMDA receptor-independent LTP. This increase in protein kinase C activity is prevented by blocking LTP with nifedipine, a Ca2+ channel antagonist, or kynurenic acid, a nonselective glutamate receptor antagonist. Additionally, we find an increase in the catalytic fragment of protein kinase C (PKM) in the maintenance phase of NMDA receptor-independent LTP, indicating that proteolytic activation of protein kinase C may account for its autonomous activation. This increase in the catalytic fragment of protein kinase C is also prevented by blocking LTP induction. These results are the first to demonstrate that persistent protein kinase C activation is a possible mechanism for the maintenance of NMDA receptor-independent LTP.

Animals↗

PubMed1994

Molecular and cytogenetic studies of an X;autosome translocation in a patient with premature ovarian failure and review of the literature.

We have identified a patient with premature ovarian failure (POF) and a balanced X;autosome translocation: 46,X,t(X;6)(q13.3 or q21;p12) using high-resolution cytogenetic analysis and FISH. BrdU analysis showed that her normal X was late-replicating and translocated X earlier-replicating which is typical of balanced X;autosome rearrangements. Molecular studies were done to characterize the breakpoint on Xq and to determine the parental origin. PCR probes of tetranucleotide and dinucleotide repeat polymorphisms, and genomic probes were used to study DNA from the patient, her chromosomally normal parents and brother, and somatic cell hybrids containing each translocation chromosome. The translocation is paternally derived and is localized to Xq13.3-proximal Xq21.1, between PGK1 and DXS447 loci, a distance of 0.1 centimorgans. A "critical region" for normal ovarian function has been proposed for Xq13-q26 [Sarto et al., Am J Hum Genet 25:262-270, 1973; Phelan et al., Am J Obstet Gynecol 129:607-613, 1977; Summitt et al., BD:OAS XIV(6C):219-247, 1978] based on cytogenetic and clinical studies of patients with X;autosome translocations. Few cases have had molecular characterization of the breakpoints to further define the region. While translocations in the region may lead to ovarian dysfunction by disrupting normal meiosis or by a position effect, two recent reports of patients with premature ovarian failure and Xq deletions suggest that there is a gene (POF1) localized to Xq21.3-q27 [Krauss et al., N Engl J Med 317:125-131, 1987; Davies et al., Cytogenet Cell Genet 58:853-966, 1991] or within Xq26.1-q27 [Tharapel et al., Am J Hum Genet 52:463-471, 1993] responsible for POF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

The effects of sex steroids, and the X chromosome, on female brain function: a study of the neuropsychology of adult Turner syndrome.

Sex steroids and the X chromosome can independently affect cognitive abilities. Because subjects with Turner syndrome (TS) have gonadal aplasia, and various alterations in X chromosome structure and number, they provide a model to study the effects of sex steroids and of the X chromosome on human brain function. We used neuropsychological tests to study the cognitive abilities of 18 TS adults and 19 age/sex matched healthy controls. Nine TS subjects were mosaic for the 45,X karyotype, and 9 were non-mosaic 45,X (full TS). The TS group as a whole, compared to controls, had (i) significantly lower scores in tests of language and visual-spatial function, attention and memory, and (ii) a significantly greater discrepancy between verbal and performance scores. Mosaic TS subjects were intermediate between full TS and controls in some tests of verbal ability, but did not differ significantly from controls in others. Visuospatial ability was significantly lower than controls in both mosaic and full TS. Within the mosaic TS group, there was a significant negative correlation between visuospatial ability and % lymphocytes having a 45,X karyotype. Memory test scores were reduced independently of "X chromosome dosage" in all TS subjects. We conclude that in humans, the X chromosome is involved in development of both cerebral hemispheres, but moreso of the association neocortices. Also, sex steroids may modulate this effect--particularly in hippocampus.

Adolescent↗

PubMed1994

Adipose differentiation in cystosarcoma phyllodes. A study of 14 cases.

Adipose differentiation is an uncommon stromal alteration in cystosarcoma phyllodes (CP). We have studied 14 lesions to define the structural variation and prognostic significance of these rare forms of CP. All patients were women between 17 and 71 years of age (mean 40 years; median 42 years). Most were first seen with a mass; three were pregnant. Grossly, the lesions were circumscribed with lobulated cut surfaces. Microscopically, the mesenchymal component showed adipose differentiation that ranged from mature fat to liposarcoma with well-differentiated, myxoid, or pleomorphic components. Six lesions were high-grade malignant CP with immature cellular mesenchyme, abundant mitoses, and areas of pleomorphic liposarcoma. Seven tumors were low-grade malignant CP with few mitoses, relatively low cellularity, and myxoliposarcoma. One tumor with slight periductal condensation and mature adipose tissue was a benign CP, which we named lipophyllodes tumor. Two patients had concurrent breast carcinoma, and two others subsequently had carcinoma. The follow-up was 8-90 months (mean 46 months; median 39 months). There was one recurrence among eight patients treated with simple excision and no recurrences in six treated with mastectomy. One woman died of metastatic breast carcinoma. All others are alive and free of disease. CP with adipose differentiation can be graded histologically on the basis of this component. Despite the high-grade histology in some instances, the patients had an excellent prognosis when the tumors were completely excised.

Adipose Tissue↗

PubMed1994

MR imaging-guided localization and biopsy of breast lesions: initial experience.

PURPOSE: To evaluate the usefulness of a magnetic resonance (MR) imaging-guided system for localization and biopsy of mammographically and clinically occult breast lesions. MATERIALS AND METHODS: The 11 needle localizations and one cyst aspiration were performed with MR imaging guidance in 11 patients with breast lesions. Two MR systems were tested; both required the patient to lie prone with the breast compressed between medial and lateral plates. One system used a grid with 18-gauge holes placed at 5-mm intervals and two reference markers to position the needle; the other, a stereotaxic external needle guide and a software system to calculate coordinates. RESULTS: Fibroadenoma, ductal carcinoma in situ, invasive ductal carcinoma, atypical ductal hyperplasia, fat necrosis, and sclerosing adenosis were found at histologic examination. In two cases, biopsies revealed multi-focal breast cancer where mammographic and clinical findings had indicated a single lesion. CONCLUSION: MR imaging-guided needle localizations may be performed in a clinical setting with the systems described. Accurate localization of mammographically and clinically occult lesions will allow MR imaging to achieve a clinically significant role.

Biopsy, Needle↗

PubMed1994

Multinucleated stromal giant cells in mammary fibroepithelial neoplasms. A study of 11 patients.

Multinucleated stromal giant cells (MSGCs) found in otherwise-banal breast tissue have only rarely been mentioned in specific lesions. We describe unilateral fibroepithelial tumors with MSGCs in 11 women who were 23 to 60 years old (mean age, 42 years). The tumors ranged from 1.7 to 9.0 cm in greatest dimension (mean, 3.7 cm) and were classified on the basis of stromal cellularity, infiltration at the margin, cellular pleomorphism, and mitoses independently of MSGCs. Using these criteria, there were four fibroadenomas, one benign cystosarcoma, and four low-grade and two high-grade malignant cystosarcomas. The MSGCs had hyperchromatic or vesicular nuclei, many with clear nuclear inclusions. The nuclei were often arranged in a semicircular or florette pattern. The MSGCs, although widely distributed, tended to cluster. They accounted for most of the stromal cellularity in the fibroadenomas, numbering focally up to 10 per high-power field. The benign and low-grade malignant cystosarcomas had fewer MSGCs. The MSGCs contributed least to the cellularity in the high-grade cystosarcomas. Five patients had no further therapy. Five patients underwent wide excision and one patient had a mastectomy. Follow-up extended to 8 years (median follow-up, 4 years). There were no recurrences, and all patients were alive with no evidence of disease. The results of this study lead us to conclude that the diagnosis and grading of fibroepithelial tumors of the breast depend on the cellularity and pleomorphism of the stroma, exclusive of MSGCs. Cystosarcomas that have MSGCs do not have an especially malignant clinical course.

Adult↗