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Biomedical subjects

A Magee

Publications and source records attributed to A Magee.

15 recordsLinked to original sources
PubMed2005

Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Adolescent↗
PubMed2003

A review of cochlear implantation in mitochondrial sensorineural hearing loss.

OBJECTIVE: Mitochondrial sensorineural hearing loss (SNHL) may be nonsyndromic (occurring in isolation), associated with the A1555G mutation in the MTRNR1 gene. Mitochondrial SNHL may also be syndromic, associated with the A3243G point mutation in the MTTL1 gene. In syndromic cases-mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS), maternally inherited diabetes and deafness, Kearns-Sayre syndrome, and chronic progressive external ophthalmoplegia-the SNHL compounds already existing disabilities. The genetic basis for mitochondrial SNHL and postulated sites of pathologic changes are discussed. DATA SOURCES: Sources used were relevant clinical and basic science publications. STUDY SELECTION: A search of the entire databases of Medline and Web of Science, using various subject headings and free-text terms, was used to identify patients with mitochondrial disease having cochlear implants. DATA EXTRACTION: The data from publications were critically reviewed and tabulated to assess implantation outcomes. DATA SYNTHESIS: The data were not amenable to formal meta-analysis or valid data summarization, other than descriptive statistics. CONCLUSIONS: There is an increasing awareness of the prevalence of mitochondrial SNHL and its progressive nature. High-risk candidates warrant genetic testing and family screening. Correlating the data for mitochondrial SNHL as a treatable entity is important, and the authors present an overview of these patients successfully rehabilitated by cochlear implantation.

Adult↗
PubMed2001

Comparison of two transcatheter closure methods of persistently patent arterial duct.

A randomized trial of arterial duct occlusion with a double umbrella (DU) or wire coil (WC) was undertaken for patients <18 years of age, weighing >10 kg with isolated ducts < or = 3 mm in diameter. Baseline, procedural, and outcome characteristics were compared in an intention-to-treat analysis according to randomization group. From 40 consecutively screened patients, 2 were not enrolled due to a ductal diameter of >3 mm on initial aortography, 38 patients were randomized to either the DU (n = 20) or WC (n = 18) groups. The groups did not differ significantly with respect to age, weight, gender, duct size, type, or branch pulmonary artery diameters. Crossover occurred only in the DU group, where 4 patients (20%) had a ductal diameter of < or = 1 mm and could not be entered for umbrella placement. All remaining DU group patients had ductal diameters of > or = 1.3 mm (p <0.0001). There were no embolizations or secondary implants in the DU group, but in the WC group there was 1 early and 1 late embolization, with 6 patients (33%) with > or = 2 coils. Mean times for the procedure (DU 68+/-19 minutes; WC 65+/-27 minutes; p = 0.70) and fluoroscopy (DU 14+/-4 minutes; WC 11+/-6 minutes; p = 0.22) did not differ significantly. Angiographic duct closure was documented in 4 of 13 patients (31%) of the DU group and 4 of 18 patients (22%) of the WC group (p = 0.69). Combined with an echocardiogram, closure in 11 of 17 patients with DU (65%) and 13 of 18 patients with WC (72%) (p = 0.64) was documented before hospital discharge. One WC group patient received thrombolytic therapy for a femoral artery thrombus. Follow-up at a median of 6.5 months (range 3.2 to 37) showed closure by Doppler echocardiography in 15 of 19 patients with DU (79%) versus 14 of 18 patients with WC (78%) (p = 1.0). Thus, with a tendency toward similar procedural characteristics and outcomes, the higher cost of the DU system compared with coil implants favors the use of coils for closure of the small arterial duct.

Analysis of Variance↗
PubMed2001

The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody.

BACKGROUND: Anti-CD11a (hu1124) is a humanized monoclonal antibody directed against the CD11a subunit of LFA-1. This study investigated whether treatment with anti-CD11a antibody provides clinical benefit to patients with moderate to severe plaque psoriasis. METHODS: This was a double-blind, placebo-controlled, phase II, multicenter study. In total, 145 patients with minimum Psoriasis Area and Severity Index scores of 12 and affected body surface area of 10% or more were sequentially enrolled into low-dose (0.1 mg/kg, n = 22) or high-dose (0.3 mg/kg, n = 75) groups. Within groups, patients were randomized to treatment or placebo (n = 48) in a 2:1 ratio. Drug was administered intravenously at weekly intervals for 8 weeks. RESULTS: The percentage of subjects achieving more than 50% improvement in physician's global assessment at day 56 (1 week after final dose) was 15% and 48% for placebo and 0.3 mg/kg of drug, respectively (P =.002). A physician's global assessment of excellent (>75% improvement) was greater in the 0.3 mg/kg group versus placebo (25% vs 2%, P =.0003). Average Psoriasis Area and Severity Index scores at day 56 were 13.9 +/- 7.5 (placebo) and 10.9 +/- 8.4 (0.3 mg/kg) (P <.0001). Epidermal thickness was reduced in the 0.3 mg/kg group compared with the placebo group (37% vs 19%, P =.004). Treatment was well tolerated; mild to moderate flu-like complaints were the most common adverse events. White blood cell counts and lymphocyte counts transiently increased. Depletion of circulating lymphocytes did not occur. CONCLUSIONS: Anti-CD11a antibody administered intravenously in 8 weekly doses of 0.3 mg/kg was well tolerated and induced clinical and histologic improvements in psoriasis.

Adult↗
PubMed2000

The genetics of amphibian declines: population substructure and molecular differentiation in the yosemite toad, Bufo canorus (Anura, bufonidae) based on single-strand conformation polymorphism analysis (SSCP) and mitochondrial DNA sequence data.

We present a comprehensive survey of genetic variation across the range of the narrowly distributed endemic Yosemite toad Bufo canorus, a declining amphibian restricted to the Sierra Nevada of California. Based on 322 bp of mitochondrial cytochrome b sequence data, we found limited support for the monophyly of B. canorus and its closely related congener B. exsul to the exclusion of the widespread western toad B. boreas. However, B. exsul was always phylogenetically nested within B. canorus, suggesting that the latter may not be monophyletic. SSCP (single-strand conformation polymorphism) analysis of 372 individual B. canorus from 28 localities in Yosemite and Kings Canyon National Parks revealed no shared haplotypes among these two regions and lead us to interpret these two parks as distinct management units for B. canorus. Within Yosemite, we found significant genetic substructure both at the level of major drainages and among breeding ponds. Kings Canyon samples show a different pattern, with substantial variation among breeding sites, but no substructure among drainages. Across the range of B. canorus as well as among Yosemite ponds, we found an isolation-by-distance pattern suggestive of a stepping stone model of migration. However, in Kings Canyon we found no hint of such a pattern, suggesting that movement patterns of toads may be quite different in these nearby parklands. Our data imply that management for B. canorus should focus at the individual pond level, and effective management may necessitate reintroductions if local extirpations occur. A brief review of other pond-breeding anurans suggests that highly structured populations are often the case, and thus that our results for B. canorus may be general for other species of frogs and toads.

Animals↗
PubMed2000

Expression of a single pair of desmosomal glycoproteins renders the corneal epithelium unique amongst stratified epithelia.

PURPOSE: To determine desmosomal glycoprotein isoform expression in bovine corneal, limbal, and conjunctival epithelium and desmosomal profile and distribution during corneal re-epithelialization. METHODS: Immunofluorescence (IF) for desmosomal components on cryostat sections of fresh epithelia was supported by immunoblot analysis of tissue lysates. Wounded corneas maintained in organ culture were examined by IF at times up to full re-epithelialization (96 hours). RESULT: Immunofluorescence for desmoplakin confirmed desmosome presence throughout all three epithelia. Plakoglobin was also ubiquitous. Of the desmosomal glycoproteins, desmocollin 2 (Dsc2) and desmoglein 2 (Dsg2) were expressed throughout, but Dsc3 and Dsg3 were confined to the limbus and conjunctiva, and Dscl and Dsgl were absent. Dsc2 and Dsg2 IFs were stronger in superficial layers, but Dsc3 and Dsg3 were stronger basally, fading suprabasally. Glycoprotein expression in cornea and conjunctiva was confirmed by immunoblot analysis. No change in glycoprotein expression occurred during re-epithelialization. CONCLUSIONS: Uniquely among stratified epithelia, cornea expresses only a single pair of desmosomal glycoproteins, Dsc2 and Dsg2. Expression of Dsc3 and Dsg3 in limbus and conjunctiva coincides with their association with cell proliferation in other epithelia, but corneal epithelial cells did not express Dsc3 or Dsg3 during re-epithelialization. Absence of Dscl and Dsgl correlates with lack of keratinization in ocular epithelia. These expression patterns may have significance for the specific properties and differentiation patterns of the epithelia. Presence of desmosomes throughout re-epithelialization raises the question of how migrating cells mutually re-position.

Animals↗
PubMed1999

The epidemiology of myotonic dystrophy in Northern Ireland.

Multiple sources of ascertainment were used to identify families with myotonic dystrophy in Northern Ireland. A total of 59 families with 188 living affected members were identified. The prevalence rate was 119.5 x 10(-6) in a total population of 1.5 million, a rate similar to neighbouring communities. Information about the natural history of the disease in these families enabled analysis of age of onset, fertility, fitness and age at death.

Journal Article↗
PubMed1997

Macrocephaly with cutis marmorata, haemangioma and syndactyly--a distinctive overgrowth syndrome.

We describe nine children with a similar pattern of features including macrocephaly and cutis marmorata telangiectatica congenita. All were large at birth and had a distinctive capillary haemangioma involving the philtrum and upper lip. The seven who survived all developed hydrocephalus and had developmental delay. Six developed body asymmetry and three had internal arteriovenous malformations. Syndactyly of the second and third toes and/or the third and fourth fingers or toes was commonly seen. All of the cases were sporadic. This condition is easily recognizable and should be considered in the differential diagnosis of patients presenting with overgrowth and macrocephaly.

Abnormalities, Multiple↗
PubMed1997

Fractures and phenylketonuria.

Parent or self-reported history of fractures in a group of patients aged from 0.3 to 33.6 years on dietary treatment for phenylketonuria was studied by means of a questionnaire. Twenty-one of 85 patients had a history of fracture compared with 18/98 sibling controls. There was no significant difference in the lifetime risk of fracture between patients and controls (chi 2 = 1.43, df = 1, p = 0.23), but a significantly higher risk of fracture was reported over the age of 8 y (chi 2 = 5.11, df = 1, p = 0.024), with a relative risk of 2.6 (95% confidence interval 1.1.6.1). We suggest this may be related either to deterioration in dietary control in this age group or to a cumulative disease-related or diet-related reduction in bone mass.

Adolescent↗
PubMed1996

Augmentation of pulmonary blood flow with an axillary arteriovenous fistula after a cavopulmonary shunt.

Of 320 children with cyanotic congenital heart malformations who had previously undergone cavopulmonary shunt operations, 11 had increasing cyanosis and exercise intolerance and were considered unsuitable for definitive repair, a Fontan procedure, or other palliation. Eight had a previous Glenn shunt and three had a previous bidirectional cavopulmonary connection. To augment pulmonary blood flow, 10 patients underwent creation of an ipsilateral axillary arteriovenous fistula. Mean oxygen saturations were 80% +/- 2% before operation, 85% +/- 2% immediately after operation, and 84% +/- 3% at a mean follow-up interval of 7.4 years (range 0.1 to 15.5 years). Mean hemoglobin values were 202 +/- 10 gm/L before operation, 177 +/- 10 gm/L after operation, and 191 +/- 14 gm/L at latest review. The only complication was mild swelling of the arm distal to the fistula in one patient. All patients reported improvement in exercise tolerance. Eight patients have continued evidence of fistula patency. Development of ipsilateral pulmonary arteriovenous fistulas has not been observed in any patient. Creation of an axillary arteriovenous fistula to augment pulmonary blood flow after a cavopulmonary shunt provides useful palliation for complex cyanotic heart disease when other options are limited. Such additional sources of pulmonary blood flow may influence the development of pulmonary arteriovenous fistulas.

Arteriovenous Shunt, Surgical↗
PubMed1995

Evidence of a locus for orofacial clefting on human chromosome 6p24 and STS content map of the region.

Orofacial clefting is genetically complex, no single gene being responsible for all forms. It can, however, result from a single gene defect either as part of a syndrome (e.g. van der Woude syndrome, Treacher-Collins syndrome, velo-cardio-facial syndrome) or as an isolated phenotypic effect (e.g. X-linked cleft palate; non-syndromic, autosomal dominant orofacial clefting). Several studies have suggested that chromosome 6p is a candidate region for a locus involved in orofacial clefting. We have used YAC clones from contigs in 6p25-p23 to investigate three unrelated cases of cleft lip and palate coincident with chromosome 6p abnormalities. Case 1 has bilateral cleft lip and palate and a balanced translocation reported as 46,XY,t(6,7)(p23;q36.1). Case 2 has multiple abnormalities including cleft lip and palate and was reported as 46,XX,del(6)(p23;pter). Case 3 has bilateral cleft lip and palate and carries a balanced translocation reported as 46,XX,t(6;9)(p23;q22.3). We have identified two YAC clones, both of which cross the breakpoint in cases 1 and 3 and are deleted in case 2. These clones map to 6p24.3 and therefore suggest the presence of a locus for orofacial clefting in this region. The HGP22 and AP2 genes, potentially involved in face formation, have been found to flank this region, while F13A maps further telomeric in 6p24.3/25.

Abnormalities, Multiple↗
PubMed1991

Characterization of N-myristoyl transferase inhibitors and their effect on HIV release.

Acylation of virus proteins is an important covalent modification which has been shown, in many cases, to be necessary for their normal function. Furthermore, it has been shown that cerulenin, an inhibitor of this process, inhibits formation of vesicular stomatitis virus and Rous sarcoma virus in infected cultures, as well as acylation of HIV proteins. However, in agreement with earlier reports, we found that the acylating enzyme, N-myristoyl transferase, was unaffected by cerulenin which did, however, inhibit protein synthesis, thereby making interpretation of its effects difficult. Analogues of myristic acid were found to inhibit acylation in intact cells without toxic effects on protein synthesis or mitochondrial function. Myristic acid analogues were also shown by an in vitro assay to act directly on the acylating activity (N-myristoyl transferase). Furthermore, myristic acid analogues were found to inhibit HIV release from HIV-infected cells and glucosamine, which has recently been shown to be a non-competitive inhibitor of N-myristoyl-transferase, also inhibited HIV release.

Acylation↗
PubMed1990

Internalization of growth hormone-releasing factor by rat anterior pituitary cells: inhibition by cerulenin, an inhibitor of fatty acid acylation.

The GH-releasing factor (GRF) analogue [His1,Nle27]-GRF(1-29) amide was used to study GRF receptor internalization in cultured rat anterior pituitary cells. The half-life of occupied receptors on the surface was approximately 10 min. Uptake of the analogue was followed by lysosomal breakdown, and receptors taken up were replaced to some extent by newly synthesized receptors, as indicated by reduced surface binding in the presence of cycloheximide. 2,3-Epoxy-4-oxo-7,10-dodecadienamide (cerulenin) inhibited internalization without affecting breakdown of the reduced amount of GRF analogue that entered the cells. The effect was half-maximal at 3 micrograms/ml for 1 h. Cerulenin inhibits fatty acid acylation of proteins. One explanation for its effect on GRF receptor internalization is that fatty acid acylation of a protein (possibly the receptor) is necessary for internalization, because cerulenin also inhibited internalization of the transferrin receptor which is known to be acylated. Cerulenin did not affect internalization of the somatostatin receptor present on the same cells, indicating the specificity of the inhibition.

Acylation↗
PubMed1988

GTP analogues cause release of the alpha subunit of the GTP binding protein, GO, from the plasma membrane of NG108-15 cells.

Incubation of membranes of neuroblastoma x glioma hybrid, NG108-15 cells with GDP beta S followed by immunoblotting of resolved membrane and supernatant fractions with specific anti-peptide antisera showed essentially all of the alpha subunit of Go to be associated with the membrane. Similar experiments with poorly hydrolyzed analogues of GTP caused release of a significant fraction (some 50% within 60 minutes) of Go alpha into the supernatant. This was not mimicked by analogues of ATP. Antisera directed against peptides corresponding to the extreme N and C-termini of GO alpha demonstrated that the released polypeptide was not proteolytically clipped. These experiments show that the alpha subunit of GO need not be invariably bound to the plasma membrane and that guanine nucleotide activation can release the alpha subunit of GO from its site of membrane attachment.

Animals↗