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J Maynard

Publications and source records attributed to J Maynard.

At least 37 records · Page 2Linked to original sources
PubMed1995

Towards the finer mapping of facioscapulohumeral muscular dystrophy at 4q35: construction of a laser microdissection library.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder which has been mapped to the 4q35 region. In order to saturate this distal 4q region with DNA markers, a laser-based chromosomal microdissection and microcloning procedure was used to construct a genomic library from the distal 20% of chromosome 4, derived from a single human metaphase spread. Of the 100 microclones analyzed from this library, 94 clones contained inserts sized from 80-800 bp, with an average size of 340 bp. Less than 20% of these clones hybridized to human repeat sequences. Seventy-two single-copy clones were further characterized by Southern blot hybridization against a DNA panel of somatic cell hybrids, containing various regions of chromosome 4. Forty-two clones mapped to chromosome 4, of which 8 clones mapped into the relevant 4q35 region. Twenty of these chromosome 4-specific clones were screened against "zoo-blots"; 11 clones, of which 3 mapped to 4q35, identified conserved sequences. This is the first report to describe the isolation of potential expressed sequences derived from the FSHD region. These chromosome region-specific microclones will be useful in the construction of the physical map of the region, the positional cloning of potential disease-associated genes, and the identification of additional polymorphic markers from within the distal 4q region.

Biomarkers↗
PubMed1995

Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD)

In facioscapulohumeral muscular dystrophy (FSHD), the wide range of clinical severity observed both within and between families has obscured past attempts to identify any phenotypic differences between families from which phenotype-genotype correlation could proposed, although it is noted that age at onset is youngest and severity greatest in isolated cases. From 14/16 large 4q35-linked FSHD families, and 25/34 isolated cases exhibiting a de novo D4F104S1 DNA fragment, we find a significant correlation between proband age at onset and FSHD-associated D4F104S1 fragment size (r = 0.56; p < 0.001), with the smallest fragments occurring in isolated cases. A similar correlation (r = 0.70; p < 0.01) with fragment size is observed for age to loss of ambulation in 16 subjects using a wheelchair. We find also that age at onset appears younger with successive generations in the 4q35 families. We propose that fragment size at D4F104S1, together with a possible generational effect, accounts for a significant part of the wide phenotypic variation in FSHD. Our results predict a more limited range for severity within families, and in one family with a 4q35-linked 38kb fragment support scapulohumeral presentation without facial involvement as a late onset variant of FSHD. We propose that in FSHD, quantitative variation in a uniform mutation mechanism influences age at onset, but by deletion rather than expansion of DNA.

Adolescent↗
PubMed1995

Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene.

Neurofibromatosis type 1 is one of the most common inherited disorders with an incidence of 1 in 3000. The search for NF1 mutations has been hampered by the overall size of the gene, the large number of exons, and the high mutation rate. To date, fewer than 90 mutations have been reported to the NF1 mutation analysis consortium and the details on 76 mutations have been published. We have identified five new mutations using single strand conformation polymorphism (SSCP) and heteroduplex analysis (HA) and three intragenic deletions with the microsatellite markers. Of the five new mutations, two were in exon 27a, two in exon 45, and one in exon 49 and these include 4630delA, 4572delC, R7846X, T7828A, and one in the 3' untranslated region (3' UTR). The two nucleotide alterations in exon 27a and the one in exon 45 are predicted to produce a truncated protein.

Adolescent↗
PubMed1995

Phenotypic-genotypic correlation will assist genetic counseling in 4q35-facioscapulohumeral muscular dystrophy.

The wide range of severity in facioscapulohumeral muscular dystrophy (FSHD) complicates genetic advice, although onset age is youngest and severity is greatest in isolated cases. From 14 of 16 large FSHD families which are 4q35 linked, and from 25 of 34 isolated cases exhibiting a de novo D4F104S1 DNA fragment, we find a correlation between proband age at onset and FSHD-associated D4F104S1 fragment size (r = 0.56; P < 0.001), with the smallest fragments occurring in isolated cases. A 4q35-linked 38-kb fragment in one family supports scapulohumeral presentation without facial involvement as a milder late-onset variant of FSHD, and with apparent "unaffected" recombinants in small families, suggests that nonpenetrance is more likely with large fragment sizes. Our results, predicting a more limited range for severity within families, and suggesting > 85% of FSHD maps to 4q35, will facilitate genetic counseling. We propose that quantitative variation in a uniform mutation mechanism influences age at onset, but by deletion rather than expansion of DNA.

Adolescent↗
PubMed1995

Germinal mosaicism in facioscapulohumeral muscular dystrophy (FSHD).

Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant neuromuscular disorder with a prevalence of 1 in 20,000. The DNA marker p13E-11 (D4F104S1) detects a de novo DNA rearrangement in the majority of sporadic and FSHD cases. These rearrangements consist of deletions of multiple copies of tandem repeat (D4Z4). We have studied 34 new mutation FSHD families of which 26 showed a de novo fragment with p13E-11. In three of the remaining eight families without a de novo fragment, germinal mosaicism was noted. In each case, the proband had inherited a small EcoR1 fragment from the clinically unaffected mother; however, the hybridization signal intensity of this fragment in the mother's DNA was significantly reduced in all three families. This is the first study to describe such mosaicism in FSHD families using DNA analysis and therefore has a considerable significance for genetic counseling and prenatal diagnosis.

Adolescent↗
PubMed1994

De novo facioscapulohumeral muscular dystrophy defined by DNA probe p13E-11 (D4F104S1).

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition with variable age of onset and severity. Identification of a de novo DNA fragment by probe p13E-11 (D4F104S1) established the diagnosis of new mutation FSHD in 27 of 31 sporadic cases. The clinical data for these certain new mutation cases were as follows: 13 boys, 14 girls; mean age of onset 6.8 years; significant leg weakness in 19/27 (70%) (8/27 (30%) used wheelchairs at a mean age of 17.7 years); high tone sensorineural deafness in 10/27; visual acuity and direct ophthalmoscopy were normal. Congenital facial diplegia and sensorineural deafness in three children suggest that infantile FSHD is not a genetically separate disorder from FSHD. Ascertainment bias may explain the difference in severity between this group and typical familial cases. Molecular analysis for FSHD should be considered in children with either congenital or early onset facial weakness or diplegia.

Adolescent↗
PubMed1993

Molecular analysis of British facioscapulohumeral dystrophy families for 4q DNA rearrangements.

Facioscapulohumeral muscular dystrophy is an important autosomal dominant neuromuscular disorder that has been localised to 4q35. We have analysed our extensive panel of 45 families with a new DNA marker p13E-11. The findings, based on multiply informative individual meioses and multipoint mapping, suggest that probe p13E-11 is the closest marker for the disorder and it is likely to be located proximal to the disease locus as are all the other present markers. In nine of the ten new mutations studied, a new smaller EcoRI fragment which was not present in either of the parents was detected, indicating that a de novo DNA rearrangement is indeed associated with the development of the disease state. However, in view of the difficulty in defining the size of over 30kb alleles and the recombinant events observed with p13E-11, we suggest that it should be used in combination with another VNTR marker until a close distal flanking marker for this condition is identified or the gene itself is isolated.

Adult↗
PubMed1992

Analysis of mutations at the neurofibromatosis 1 (NF1) locus.

A panel of 200 unrelated NF1 individuals has been screened for mutations using a panel of specific clones for the entire gene. DNA analysis on conventional Southern blots indicated that (20) 10% of NF1 patients showed aberrant bands. Small lesions involving nucleotide alterations were detected in a further 10 patients; 5 of these alterations have been fully characterised and are the novel mutations in the NF1 gene. A number of mutations were identified in exon 2. Identical mutations in this exon in two unrelated individuals involved an insertion of cytosine into codon 5662 and resulted in an inappropriate stop codon. This mutation also created a new MnlI site. Another novel mutation in exon 2 resulted from the insertion of thymidine at nucleotide 5678, which also created an inappropriate stop codon. We have so far completed the screen of exons 1-9 of the NF1 gene for the identification of mutations and have found no evidence of clustering of such mutations in the gene.

Amino Acid Sequence↗
PubMed1990

Prioritising waiting lists.

The 'top 22' patient conditions on the general surgical waiting list at Guy's Hospital were rated independently by five general surgeons. Each surgeon estimated the peri-operative mortality rates associated with each treatment; the proportion of patients who failed to benefit; the effect of successful treatment on life expectancy and on the patients' quality of life. the mean values were used to estimate the expected net benefits (in terms of quality-adjusted life-years) from treatment one year earlier than might otherwise have been the case. These benefits were then related to the operating times and length of stay associated with each treatment; this identified which treatments offered the greatest benefit per unit of each constrained resource. Of all conditions examined anal fissures where shown to be the least resource intensive in relation to the benefits generated, whilst varicose veins and epigastric hernias proved otherwise. For the full potential of this approach to be realised it needs to be repeated in other places and in other specialties. It nevertheless offers a more rational basis for interpreting waiting list data than presently exists and by using the short-cut methods is a relatively cheap way of generating much useful data.

Data Collection↗
PubMed1988

Hereditary xanthinuria in 2 Pakistani sisters: asymptomatic in one with beta-thalassemia but causing xanthine stone, obstructive uropathy and hypertension in the other.

We describe a 3-year-old Pakistani girl who presented with recurrent urinary infections. She had a nonfunctioning hydronephrotic right kidney and hypertension. At operation a calculus was impacted in the right ureter with dilatation of the pelviocaliceal system. Nephrectomy was performed. Histology revealed end stage pyelonephritis. The calculus consisted of pure xanthine. Further investigations demonstrated low serum uric acid and absent urinary uric acid with increased excretion of xanthine. Eight months after nephrectomy blood pressure had decreased to normal. Her 5-year-old sister, who has beta-thalassemia, also has a low serum uric acid concentration and xanthinuria. The treatment of choice is to increase fluid intake so that the urine xanthine concentration remains below the level at which xanthine crystallizes. This may require adjustment of the urine pH.

Child, Preschool↗
PubMed1987

Long-term renal risk factors in children with meningomyelocele.

We studied renal function and structure in 42 patients with meningomyelocele, 28 treated with intermittent catheterization and 14 with ileal loop diversion. Patients were observed for a minimum of 60 months. Nine of the 28 patients who underwent intermittent catheterization had evidence of unilateral or bilateral reflux, and all patients with ileal loop diversion had free ureteral reflux. Bacteriuria was present in 38% +/- 5% of cultures obtained from patients with catheterization and in 70% +/- 7% of cultures from those with diversion (P less than 0.001). Four (14%) of 28 patients with catheterization had worsening renal function or anatomic appearance by intravenous pyelogram, and required a diversion. Three (28%) of 14 patients with diversion had changes in renal structure or function. Eight of 31 patients from both groups studied with voiding cystourethrography before the onset of therapy had small, noncompliant, trabeculated bladders; all seven patients who had worsening in function or anatomic appearance were from this subset (P less than 0.01). None of the patients with flaccid or distensible bladders demonstrated these changes. Renal disease was unrelated to the level of neurologic function. A small, noncompliant, trabeculated bladder is a risk factor associated with loss of renal function in patients with meningomyelocele.

Adult↗
PubMed1982

Ultrastructural evaluation of biochemical events of bone resorption in human chronic otitis media.

Bone resorption is a significant component of chronic inflammatory ear disease. Bone is a unique tissue requiring both demineralization and collagen degradation for breakdown. Mineral removal probably occurs prior to collagen destruction. A localized change in pH may be one of the mechanisms that induces demineralization. Localized accumulations of lysosomal acid hydrolases could provide the acidic environment necessary for mineral removal. The present study utilizes the electron microscope to localize the lysosomal enzyme acid phosphatase in specimens removed from patients with chronic otitis media. Areas of localized bone resorption exhibited mononuclear inflammatory cells attached to the resorption margin. These cells contained abundant acid phosphatase, as did isolated fibroblasts within the zone of inflammation at the resorption margin. Extra cellular acid phosphatase was seen in these areas. Within the bone, osteocytes adjacent to resorption displayed increased cytoplasmic organelle patterns and contained the acid phosphatase reaction. The localization of destructive enzymes in mononuclear inflammatory cells and osteocytes explains the bony destructive changes observed in human chronic otitis media in the absence of multinucleated osteoclasts.

Acid Phosphatase↗
PubMed1981

Lymphangitis carcinomatosa.

A case of lymphangitis carcinomatosa secondary to a primary gastric adenocarcinoma is reported. Diagnosis was suspected clinically and radiologically, but was established only at autopsy. The condition is reviewed. When suspected, transbronchial lung biopsy would allow histological confirmation of the diagnosis.

Adenocarcinoma↗