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Biomedical subjects

E Maher

Publications and source records attributed to E Maher.

At least 19 recordsLinked to original sources
PubMed2006

Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice.

BACKGROUND: Most Wilms tumours occur in otherwise healthy children, but a small proportion occur in children with genetic syndromes associated with increased risks of Wilms tumour. Surveillance for Wilms tumour has become widespread, despite a lack of clarity about which children are at increased risk of these tumours and limited evidence of the efficacy of screening or guidance as to how screening should be implemented. METHODS: The available literature was reviewed. RESULTS: The potential risks and benefits of Wilms tumour surveillance are finely balanced and there is no clear evidence that screening reduces mortality or morbidity. Prospective evidence-based data on the efficacy of Wilms tumour screening would be difficult and costly to generate and are unlikely to become available in the foreseeable future. CONCLUSIONS: The following pragmatic recommendations have been formulated for Wilms tumour surveillance in children at risk, based on our review: (1) Surveillance should be offered to children at >5% risk of Wilms tumour. (2) Surveillance should only be offered after review by a clinical geneticist. (3) Surveillance should be carried out by renal ultrasonography every 3-4 months. (4) Surveillance should continue until 5 years of age in all conditions except Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and some familial Wilms tumour pedigrees where it should continue until 7 years. (5) Surveillance can be undertaken at a local centre, but should be carried out by someone with experience in paediatric ultrasonography. (6) Screen-detected lesions should be managed at a specialist centre.

Chromosome Disorders↗
PubMed2005

Development of a condition-specific measure of quality of life for children with cerebral palsy: empirical thematic data reported by parents and children.

BACKGROUND: Although there is increasing recognition that quality of life (QOL) and health-related quality of life (HRQOL) are important outcome variables in clinical trials for children with cerebral palsy, there are substantial limitations in existing measures of QOL. This study identify themes of QOL for children with cerebral palsy and their parents to guide the development of a new condition-specific QOL scale. METHODS: A qualitative study of parent and child views on QOL composition was conducted, using a grounded theory framework. Families participated in semistructured interviews on QOL until thematic saturation was reached (n = 28 families). RESULTS: Overall, 13 themes emerged from the interviews: physical health, body pain and discomfort, daily living tasks, participation in regular physical and social activities, emotional well-being and self-esteem, interaction with the community, communication, family health, supportive physical environment, future QOL, provision of, and access to services, financial stability, and social well-being. CONCLUSIONS: Research with parents and children with cerebral palsy, representative of severity across the disease spectrum and socio-economic status, reinforced and expanded on the traditional themes that have underpinned QOL measurement development. This has implications not only for the development of a new QOL scale for children with cerebral palsy, but also for clinical interventions and community care management.

Activities of Daily Living↗
PubMed2005

Chromosome analysis: what and when to request.

Chromosome abnormalities have long been recognised as an important cause of learning disability and multiple malformation syndromes; 0.8% of live born infants have numerical or structural chromosomal anomalies resulting in an abnormal phenotype. The identification of such anomalies is important, both clinically and for accurate genetic counselling. Recently, the human genome sequence has enabled higher resolution screens for chromosome anomalies using both molecular cytogenetic and array based techniques. This review suggests a simple algorithm for the targeted use of diagnostic cytogenetic tools in specific patient groups commonly seen in paediatric practice.

Algorithms↗
PubMed1999

Third International Meeting on von Hippel-Lindau disease.

Five years after the identification of the von Hippel-Lindau (VHL) gene, physicians, scientists and concerned VHL family members met to review the current state of knowledge on the diagnosis and treatment of VHL and to summarize the latest information on the biochemistry of the VHL protein (pVHL). The NIH and University of Pennsylvania groups reported the detection of germ-line mutations in 100% (93 of 93) of VHL families studied. Several studies determined the frequency of VHL germ-line mutations in individuals with a single manifestation of VHL without a family history of VHL. National groups to improve the diagnosis and treatment of individuals with VHL disease have been established in Great Britain, Denmark, France, Holland, Italy, Japan, Poland, and the United States. Evidence for the existence of genes that modify the expression of VHL was presented. The VHL protein appears to have several distinct functions: (a) down-regulation of hypoxia-inducible mRNAs; (b) proper assembly of the extracellular fibronectin matrix; (c) regulation of exit from the cell cycle; and (d) regulation of expression of carbonic anhydrases 9 and 12.

Animals↗
PubMed1999

The predictive value of findings of the common aneuploidies, trisomies 13, 18 and 21, and numerical sex chromosome abnormalities at CVS: experience from the ACC U.K. Collaborative Study. Association of Clinical Cytogeneticists Prenatal Diagnosis Working Party.

We report 611 non-mosaic and 91 mosaic findings of trisomies 13, 18 and 21, and numerical sex chromosome abnormalities in a series of 20,527 CVS, in the Association of Clinical Cytogeneticists U.K. Collaborative Study, the majority with analysis of both direct preparations and cultured cells. No false-positive results were encountered among the 611 non-mosaic cases, making these findings a very reliable indicator of the fetal karyotype. One false-negative case was reported. In contrast, the 91 mosaic abnormalities were unreliable predictors of fetal abnormality. Many were associated with normal outcomes, but a significant proportion of cases of each individual aneuploidy proved genuine. Mosaicism for 45,X, and trisomies 13 and 18 was disproportionately common. 17 of the mosaic cases showed complete discordance between the karyotype from direct preparations and that from cultured cells. All would have resulted in either a false-positive or a false-negative finding if only one technique had been used. Based on our experience, and that of others, we believe that the highest level of predictive accuracy using CVS can only be achieved if both direct preparation and cell culture are performed. In addition, we continue to recommend that all pregnancies demonstrating mosaicism for these aneuploidies at CVS undergo amniocentesis or fetal blood sampling to differentiate between confined placental mosaicism and true fetal karyotypic abnormality.

Aneuploidy↗
PubMed1997

Frequency of BCL-2/J(H) translocations in peripheral blood of follicular lymphoma patients.

Polymerase chain reaction (PCR) assays have been developed for follicular lymphoma-associated BCL-2/J(H) translocations. Few data are available on the quantitation by PCR of these translocations in peripheral blood mononuclear cells (PBM) of follicular lymphoma (FL) patients. We report that only one of five studied FL patients had a high level of these translocations in the circulation, namely, about 35,000 translocations per 5 x 10(6) PBM. This patient was stable with an excellent performance status at the time of this assay; however, he died of leukemia 1 month later.

Genes, Immunoglobulin↗
PubMed1997

Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations.

We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.

Adult↗
PubMed1997

The phenotypic effects of chromosome rearrangement involving bands 7q21.3 and 22q13.3.

We report a family in which the proband has a direct insertion of band 7q21.3 into chromosome 22 at 22q13.3, karyotype 46,XX,dir ins(22;7)(q13.3;q21.2q22.1). Two of her children have unbalanced chromosome rearrangements involving 7q21.3, with one girl monosomic for the region and a boy trisomic for the region. The child monosomic for band 7q21.3 has a split hand/split foot (SHSF) anomaly and her clinical features are consistent with the 7q21-q22 contiguous gene deletion syndrome. In situ hybridisation studies have shown that the proband and her son have a submicroscopic deletion of chromosome band 22q13.3. Interstitial deletions of this chromosome band have rarely been reported.

Adult↗
PubMed1997

Treatment of Kaposi's sarcoma after solid organ transplantation.

PURPOSE: This retrospective review of all patients who developed Kaposi's sarcoma (KS) after solid organ transplantation at a single institution was undertaken to define the clinical presentation of this malignancy in the setting of iatrogenic immunodeficiency, and to determine the most appropriate treatment for patients in this clinical setting. MATERIALS AND METHODS: The records of 2,099 patients who underwent heart, lung, liver, or kidney transplantation at The Toronto Hospital between January 1, 1981 and June 30, 1995, were reviewed. Twelve patients were identified who developed biopsy-proven KS in the posttransplantation period. Five patients who had disseminated KS who had not responded to either reduction or withdrawal of immunosuppression or to local radiotherapy were treated with combination chemotherapy consisting of doxorubicin 20 to 30 mg/m2, bleomycin 10 mg/m2, and vincristine 2 mg (ABV) administered intravenously every 3 weeks. RESULTS: Eight of 12 patients were male and nine were of Italian origin. KS was limited to a localized area of the skin for only six patients, all after kidney transplantation. Visceral KS was present in three patients. Four of five patients responded to ABV chemotherapy (two complete and two partial remissions). The fifth patient responded to second-line etoposide and cisplatin. The median duration of response was in excess of 13 months (range, 8+ to 45+ months). Toxicity was limited to grade 1 neurotoxicity and grade 1 skin toxicity. CONCLUSION: KS is an uncommon but recognized complication of solid organ transplantation. Combination chemotherapy is a safe and effective treatment for patients with disseminated or visceral KS that fails to respond to changes in immunosuppression.

Adult↗
PubMed1996

A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map.

Karyotypic analysis in a patient with Peutz-Jeghers' syndrome demonstrated a pericentric inversion on chromosome 6. Further investigation was undertaken using fluorescence in situ hybridisation (FISH) with yeast artificial chromosome clones selected to contain genetic markers from chromosome 6, and a probe for the centromeric alphoid repeat array. This analysis located one inversion breakpoint within the alphoid array, in a 1-cM interval between D6S257 and D6S402, and the other in a 4-cM interval between D6S403 and D6S311. The oestrogen receptor gene locus (ESR) is excluded from the latter interval.

Adult↗
PubMed1996

Vasoactive intestinal peptide and impotence in experimental diabetes mellitus.

OBJECTIVE: To determine whether a defect in vasoactive intestinal peptide (VIP)-mediated vasodilatation underlies diabetic impotence. MATERIALS AND METHODS: Rats treated with streptozotocin for 8 weeks developed diabetes, as shown by hyperglycaemia and glycosuria, and had significant impairment of sexual function, as determined by tests of sexual behavior. The VIP content of the penis and major pelvic ganglion, the VIP release by the penis in vitro and the responsiveness of the vasculature of the penis in vivo to intracavernous VIP injection were determined. RESULTS: In diabetic rats, the VIP content of the major pelvic ganglion and penis was markedly increased, while the acetylcholine content of the penis was normal. The amount of VIP released in vitro by high potassium concentration or veratridine was similar for penile tissue slices of normal and diabetic rats. Intracavernous injection of VIP induced erection in the control rats but not in diabetic rats, whereas intracavernous injection of the adenylate-cyclase activator forskolin produced erection in both control and diabetic rats. CONCLUSION: Because VIP induces vasodilatation by activating adenylate cyclase, and forskolin produced erection in the diabetic rats, the failure of VIP to produce erection in these rats is unlikely to be due to a defect in the second-messenger mechanism or in the properties of vascular smooth muscle. Thus, a defect at the level of the VIP receptor or of the associated G-protein possibly explains the failure of intracavernous VIP to produce erection in the diabetic rats. Hence, an abnormality in VIP is a component of sexual dysfunction in the diabetic rat and the defect is at the level of the VIP receptor or associated G-protein.

Acetylcholine↗
PubMed1995

Two new cases of FMR1 deletion associated with mental impairment.

Screening of families clinically ascertained for the fragile X syndrome phenotype revealed two mentally impaired males who were cytogenetically negative for the fragile X chromosome. In both cases, screening for the FMR1 trinucleotide expansion mutation revealed a rearrangement within the FMR1 gene. In the first case, a 660-bp deletion is present in 40% of peripheral lymphocytes. PCR and sequence analysis revealed it to include the CpG island and the CGG trinucleotide repeat, thus removing the FMR1 promoter region and putative mRNA start site. In the second case, PCR analysis demonstrated that a deletion extended from a point proximal to FMR1 to 25 kb into the gene, removing all the region 5' to exon 11. The distal breakpoint was confirmed by Southern blot analysis and localized to a 600-bp region, and FMR1-mRNA analysis in a cell line established from this individual confirmed the lack of a transcript. These deletion patients provide further confirmatory evidence that loss of FMR1 gene expression is indeed responsible for mental retardation. Additionally, these cases highlight the need for the careful examination of the FMR1 gene, even in the absence of cytogenetic expression, particularly when several fragile X-like clinical features are present.

Adult↗
PubMed1994

Fluorescence in situ hybridisation of multiple probes on a single microscope slide.

We report a method to analyse multiple samples by fluorescence in situ hybridisation on a single glass microscope slide. Wells were formed in which independent hybridisation reactions could proceed by sealing a silicon rubber gasket to the slide. In the largest format tested, different probes were hybridised simultaneously by applying them directly from a 96-well microtitre dish which was inverted on a glass plate. This technique will increase the rate of analysis of multiple probes against a standard set of chromosomes and could also be used to analyse different karyotypes using a panel of probes such as single chromosome paints during a single operation. It should be useful for both chromosomal mapping projects and screening for chromosome abnormalities in clinical diagnostic laboratories.

Chromosomes↗
PubMed1994

Role of neuron soma firing in the restoration of neurotensin store in sympathetic preganglionic neuron terminals after stimulus-evoked depletion.

We have previously shown that prolonged preganglionic stimulation (e.g. 40 Hz 20 min) depletes the neurotensin (NT) store of preganglionic axon terminals in the stellate ganglion (SG) of the cat and that replenishment of the store requires several days. The present study investigates the mechanisms which control turnover of the NT store in sympathetic preganglionic axon terminals. NT content of the SG and of the preganglionic axons which innervate it was determined by radioimmunoassay in the anesthetized cat. This study shows that, during the 24 h after 40-Hz 20-min stimulation of the preganglionic input to the SG, the rate of NT accumulation proximal to a ligature on the stimulated input is three times that observed in the control. The poststimulus increase in NT accumulation rate is prevented by treatment with protein-synthesis inhibitors. When the centripetal propagation of action potentials from the stimulus site on the preganglionic axons is prevented by a tetrodotoxin block applied locally during the stimulation period, the poststimulus increase in NT accumulation rate and the replenishment of the store are both prevented. These data suggest that the level of activity of the neuron regulates NT supply to the axon terminals, presumably by regulating NT synthesis. Thus, in the sympathetic preganglionic neuron, the action potential provides a mechanism for matching peptide synthesis to release.

Action Potentials↗
PubMed1994

In vitro and in vivo evidence of neurotensin release from preganglionic axon terminals in the stellate ganglion of the cat.

We have previously shown that the neurotensin (NT) store in preganglionic axon terminals of the cat stellate ganglion (SG) is reversibly depleted by prolonged preganglionic stimulation. The present study addresses the questions of whether the preganglionic axon terminals release NT in response to depolarizing stimuli in vitro and whether in vivo NT is released by the tonic firing of the sympathetic preganglionic neurons. Slices of the SG of the anaesthetized cat, maintained in oxygenated Ringer solution, released NT. The efflux increased when the K concentration was increased from 5 to 25 or 45 mM or when veratridine was added to the medium. In Ca-free medium, efflux was suppressed. The effect of veratridine was blocked by tetrodotoxin (TTX). In awake, freely moving cats, in which TTX was applied for 4 days to the preganglionic input of the right SG, the NT content of this ganglion doubled by comparison with the left SG. Since NT accumulates proximal to a ligature on the preganglionic input of the SG, the increased NT content is likely to result from suppression of action potential-dependent release while influx into the terminals persists. This result suggests that the steady state of the NT store in sympathetic preganglionic terminals is the result of a steady influx from the soma balanced by action potential-dependent loss, presumably release.

Action Potentials↗
PubMed1993

von Hippel-Lindau disease: identification of deletion mutations by pulsed-field gel electrophoresis.

Von Hippel-Lindau disease (VHL) is an inherited multisystem neoplastic disorder. We prepared a 2.5-megabase (Mb) restriction map of the region surrounding the VHL gene and identified and characterized overlapping deletions in three unrelated patients affected with VHL. The smallest nested deletion (100 kb) was located within a 510-kb NruI fragment detected by 19-63'. The rearrangements detected will be useful in isolating and evaluating candidate cDNAs for the VHL gene. The detailed physical map will be useful in studying the organization and structure of genes in the VHL region.

Adult↗