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Biomedical subjects

W G Cole

Publications and source records attributed to W G Cole.

At least 19 recordsLinked to original sources
PubMed1992

Characterization of three osteogenesis imperfecta collagen alpha 1(I) glycine to serine mutations demonstrating a position-dependent gradient of phenotypic severity.

Type I collagen alpha 1(I) glycine to serine substitutions, resulting from G-to-A mutations, were defined in three cases of osteogenesis imperfecta (OI). The Gly substitutions displayed a gradient of phenotypic severity according to the location of the mutation in the collagen triple helix. The most C-terminal of these, Gly565 to Ser, led to the lethal perinatal (type II) form of OI, whereas the more N-terminal mutations, Gly415 and Gly352 to Ser, led to severe OI (type III/IV) and moderate OI (type IVB) respectively. These data support the notion that glycine substitutions towards the C-terminus of the alpha 1(I) or alpha 2(I) chains will be more clinically severe than those towards the N-terminus. This results from the more disruptive effect of the mutations at the C-terminus on helix initiation and C- and N-terminal helix directional propagation. This generalization must be modified by considering the nature of the glycine substitution and the surrounding amino acid sequence, since the helix is composed of subdomains of differing stability which will affect the ability of helix re-nucleation and propagation.

Amino Acid Sequence↗
PubMed1992

A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.

The dermal type I collagen of a patient with Ehlers-Danlos type VIIB (EDS-VIIB) contained normal alpha 2(I) chains and mutant pN-alpha 2(I)' chains in which the amino-terminal propeptide (N-propeptide) remained attached to the alpha 2(I) chain. Similar alpha 2(I) chains were produced by cultured dermal fibroblasts. Amino acid sequencing of tryptic peptides, prepared from the mutant amino-terminal pN-alpha 2(I) CB1' peptide, indicated that five amino acids, including the N-proteinase (the specific proteinase that cleaves the procollagen N-propeptide) cleavage site, had been deleted from the junction of the N-propeptide and the N-telopeptide (the nonhelical domain at the amino-terminus of the alpha chains of fully processed type I polypeptide chains) of the mutant pro-alpha 2(I)' chain. The corresponding 15 nucleotides, which were deleted from approximately half of the alpha 2(I) cDNA polymerase chain reaction products, of the alpha 2(I) cDNA polymerase chain reaction products, were encoded by the +1 to +15 nucleotides of exon 6 of the normal alpha 2(I) gene (COL1A2). These 15 nucleotides were deleted in the splicing of alpha 2(I) pre-mRNA to mRNA as a result of inactivation of the 3' splice site of intron 5 by an AG to AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6. Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures. Collagen production by cultured dermal fibroblasts was doubled, possibly due to reduced feedback inhibition by the N-propeptides. In contrast to previously reported cases of EDS-VIIB, Lys5 of the N-telopeptide was not deleted and appeared to take part in the formation of intramolecular cross-linkages. However, increased collagen solubility and abnormal extraction profiles of the mutant type I collagen molecules indicated that collagen cross-linking was abnormal in the dermis. The proband and her son were heterozygous for the mutation. It is likely that the heterozygous loss of the N-proteinase cleavage site, with persistence of a shortened N-propeptide, was the major factor responsible for the EDS-VIIB phenotype.

Adult↗
PubMed1992

Lethal perinatal osteogenesis imperfecta due to a type I collagen alpha 2(I) Gly to Arg substitution detected by chemical cleavage of an mRNA:cDNA sequence mismatch.

A single base mismatch was detected by a chemical cleavage method in heteroduplexes formed between patient mRNA and a control collagen alpha 2(I) cDNA probe in a case of osteogenesis imperfecta type II. The region of the mRNA mismatch was amplified using the polymerase chain reaction, cloned and sequenced. A heterozygous point mutation of G to C at base pair 1,774 of the collagen alpha 2(I) mRNA resulted in the substitution of glycine with arginine at amino acid position 457 of the helix. Type I collagen of alpha 1(I)- and alpha 2(I)-chains from the patient migrated slowly on electrophoresis due to increased levels of posttranslational modification of lysine. The parents' fibroblast collagen did not contain the mRNA mismatch and the collagens showed normal electrophoretic behaviour. Two-dimensional electrophoresis of the CNBr peptides from the patient's collagen confirmed the excessive posttranslational modification of the alpha 1(I)- and alpha 2(I)-chains in the CNBr peptides N-terminal to the mutation due to disruption of the obligatory Gly-X-Y triplet repeat of the helix. The mutation led to reduced procollagen secretion and helix destabilization as evidenced by a decreased thermal stability. These data lend further support to the accumulating evidence that type I collagen alpha 2(I) glycine substitution mutations result in the same spectrum of clinical severity as those in the alpha 1(I)-chain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Treatment of ipsilateral supracondylar and forearm fractures in children.

The treatment of ipsilateral supracondylar fractures of the humerus and fractures of the forearm bones was evaluated in 11 children. After an average of 6 years, 10 children had excellent or good results and one had a poor result from Volkmann's ischaemic contracture. Displaced supracondylar fractures of the humerus associated with distal fractures of the forearm bones are best treated by closed reduction and percutaneous pin fixation of the humeral fracture and a below-elbow plaster backslab.

Bone Nails↗
PubMed1992

The clinicopathological features of three babies with osteogenesis imperfecta resulting from the substitution of glycine by valine in the pro alpha 1 (I) chain of type I procollagen.

The features of three babies with perinatal lethal osteogenesis imperfecta (OI II) resulting from substitutions of glycine by valine in the triple helical domain of the alpha 1(I) chain of type I collagen were studied. The babies were heterozygous for this substitution at residue 1006 in case 1 (OI35), 973 in case 2 (OI59), and 256 in case 3 (OI7B). OI35 had the most severe clinical form, OI IIC, with premature rupture of membranes, severe antepartum haemorrhage, stillbirth, severe short limbed dwarfism, and extreme osteoporosis. OI59 was a better formed baby but was also born prematurely as a result of premature rupture of membranes and severe antepartum haemorrhage. She had the radiographic features of OI IIA. OI7B was born at term and also had the radiographic features of OI IIA. Pathological examination of the skeletons of OI35 and OI59 showed grossly deficient intramembranous and endochondral ossification. Trabecular bone was sparse in the long bones and vertebrae. The trabeculae contained a cartilage core and an overlying layer of woven bone or osteoid. The diaphyses lacked cortical bone. The periosteal fibroblasts of OI35 contained grossly distended rough endoplasmic reticulum consistent with the 53% reduction in collagen secretion by cultured dermal fibroblasts. The aorta, skin, and lungs were hypoplastic in OI35 and OI59. The findings in this study show that glycine substitutions by valine in Gly-X-Y triplets, from glycine 256 to glycine 1006, of the triple helical domain of alpha 1(I) chains produce the OI II phenotype. The phenotype was most severe in the baby with the most carboxy-terminal substitution.

Adult↗
PubMed1992

Open fractures of the tibia in children.

We describe the results of treatment of open tibial fractures in 92 children; 22 fractures were Gustilo type I, 51 type II and 19 type III. All children received tetanus prophylaxis, systemic antibiotics for 48 hours and thorough debridement and irrigation of the wound. Fifty-one wounds with minimal soft-tissue injury were closed primarily. The other 41 were initially left open; of these, 18 small wounds were allowed to heal secondarily and 23 larger wounds required split skin grafts or soft-tissue local or microvascular free flaps. Stable fractures were reduced and immobilised in an above-knee plaster cast (71%) and external fixation (28%) was used for unstable fractures, extensive soft-tissue injury and multiple injuries. Short-term complications included compartment syndrome (4%), superficial infection (8%), deep infection (3%), delayed union (16%), nonunion (7.5%) and malunion (6.5%): these incidences are similar to those reported in adults. Selective primary closure of wounds did not increase the incidence of infection. External fixation was associated with a greater occurrence of delayed and nonunion than plaster immobilisation, but this technique was used most often for the more severe injuries. Late review, at 1.5 to 9.8 years, showed a high incidence of continuing morbidity including pain at the healed fracture site (50%), restriction of sporting activity (23%), joint stiffness (23%), cosmetic defects (23%) and minor leg-length discrepancies (64%). Open tibial fractures in children are associated with a high incidence of early and late complications, which are more frequent in children with Gustilo type III injuries. The Gustilo classification was a useful guide for predicting the outcome and planning treatment.

Adolescent↗
PubMed1991

Low basal transcription of genes for tissue-specific collagens by fibroblasts and lymphoblastoid cells. Application to the characterization of a glycine 997 to serine substitution in alpha 1(II) collagen chains of a patient with spondyloepiphyseal dysplasia.

Cultured dermal fibroblasts were shown, using amplification of cDNA by the polymerase chain reaction, to produce very low levels of spliced transcripts from the COL2A1 gene that encodes the cartilage-specific alpha 1(II) chains of type II collagen. Cultured lymphoblastoid cells were also shown to produce very low levels of spliced transcripts from the COL1A1 and COL1A2 genes that encode the alpha 1(I) and alpha 2(I) chains of type I collagen, the COL2A1 gene that encodes type II collagen, and the COL3A1 gene that encodes the alpha 1(III) chains of type III collagen. Amplified cDNAs prepared from lymphoblastoid cells were used to identify previously characterized heterozygous mutations in the COL1A1 and COL1A2 genes from two patients with osteogenesis imperfecta and in the COL3A1 gene from a patient with the Ehlers-Danlos syndrome type IV. Amplified alpha 1(II) cDNA from fibroblasts and lymphoblastoid cells of a child with spondyloepiphyseal dysplasia congenita was also used to localize sequence mismatches using chemical modification of cDNA:cDNA heteroduplexes by hydroxylamine and cleavage with piperidine. The amplification products containing the mismatched region were sequenced and the mutation was shown to change the codon GGC for glycine 997 to AGC for serine in the triple helical domain of the alpha 1(II) chains. The corresponding region of the genomic DNA was sequenced and the heterozygous point mutation was shown to be in exon 48 of the COL2A1 gene. Allelic restriction mapping showed that neither parent carried the mutation in their leucocytes. This mutation emphasizes the importance of COL2A1 mutations in producing the spondyloepiphyseal dysplasia phenotype. The low basal rate of transcription ("illegitimate transcription"), splicing, and polyadenylation of tissue-specific mRNAs by cultured dermal fibroblasts and lymphoblastoid cells provides the opportunity to localize and sequence mutations in amplified cDNA in patients from whom affected tissue is unavailable.

Base Sequence↗
PubMed1991

Characterization of a type I collagen alpha 2(I) glycine-586 to valine substitution in osteogenesis imperfecta type IV. Detection of the mutation and prenatal diagnosis by a chemical cleavage method.

A chemical cleavage method for detecting mismatched bases in heteroduplexes formed between patient mRNA and control cDNA probes was employed to identify a single base mutation in a heterozygous case of osteogenesis imperfecta type IV. The parents' fibroblast mRNA did not contain the mutation. The region of the mRNA mismatch was amplified by using the polymerase chain reaction, cloned and sequenced. A point mutation of G to U at base-pair 2162 of the collagen alpha 2(I) mRNA resulted in the substitution of glycine by valine at amino acid position 586 of the helix. This substitution disrupted the critical Gly-Xaa-Yaa repeating unit of the collagen triple helix and resulted in helix destabilization, as evidenced by a decreased thermal stability. This local disturbance to helix propagation from the C-terminus to the N-terminus led to the overmodification of the collagen helix downstream towards the N-terminus. However, collagen secretion in vitro was normal, and the clinical phenotype probably resulted from the secretion into the extracellular matrix of the mutant collagen combined with a decrease in collagen production to 65% of control values. The rapid detection of the osteogenesis imperfecta mutation by using the chemical cleavage method afforded the opportunity to apply the technique to prenatal diagnosis in the next pregnancy of the mother of the osteogenesis imperfecta patient. The absence of a mismatched base in chorionic villus mRNA and control cDNA heteroduplexes indicated that the foetus did not carry the mutation, which was confirmed by the subsequent delivery of a normal baby.

Amino Acid Sequence↗
PubMed1991

Flexion supracondylar fractures of the humerus in children: treatment by manipulation and extension cast.

We have reviewed, at an average of 7 years, 14 children with flexion supracondylar fractures of the humerus. These fractures accounted for 6 per cent of the 288 displaced supracondylar fractures treated from 1981 to 1985. A total of 12 patients had typical fractures that were treated by manipulation and immobilization in an extension cast. Two patients had atypical fractures with anterior displacement and posterior angulation of the distal fragment; they were treated by manipulation, but were more stable when immobilized with the elbow flexed with strapping and collar and cuff support. Overall, excellent or good results were achieved in 10 cases and poor results in four cases. Of the poor results, two were due to cubitus varus. These children were the only ones under 2 years of age, and in each the deformity was due to the persistence of an abnormally large Baumann angle. Plaster immobilization was inadequate at this stage. The other two poor results were due to mild stiffness of the elbow. For typical fractures, we conclude that excellent results can be expected in most children over the age of 2 years when treated with manipulation and immobilization in extension for 3 weeks. For the rarer atypical fractures, we conclude that excellent results can be expected after manipulation and immobilization in flexion for 3 weeks.

Adolescent↗
PubMed1991

Ehlers-Danlos syndrome type IV: phenotypic consequences of a splicing mutation in one COL3A1 allele.

The features of a child with Ehlers-Danlos syndrome type IV (EDS IV) resulting from a mutation in one COL3A1 allele were studied. The child was heterozygous for a G- to A-transition at the splice donor site of intron 41. It resulted in the splicing out of the exon 41 encoded sequence from alpha 1(III) mRNA and the deletion of 36 amino acids from glycine775 to lysine810 of the triple helical domain of alpha 1(III) chains of type III collagen. The amount of type III collagen in the dermis was only about 11% of normal. The child had the acrogeric form of EDS IV. He had the characteristic facies with a pinched nose, thin lips, and prominent eyes. These facial features, his aesthenic build, thin skin, prominent subcutaneous veins, and aged hands produced a 'cachectic' appearance. These features were evident in early childhood and worsened up to 12 1/2 years when he was last reviewed. Spontaneous bruising, bleeding from the large bowel, constipation, and delayed gastric emptying were other features. In cross section, the dermal collagen fibrils were round and measured 93.3 +/- 11.5 nm in diameter which was not significantly different from control values of 102.5 +/- 13.4 nm. The serum type III procollagen amino-terminal propeptide level of 25.5 ng/ml was within the normal age matched values of 15.5 +/- 7.7 ng/ml despite the low production of type III collagen by cultured fibroblasts. The child probably had a spontaneous new mutation in one COL3A1 allele as only normal sequences were obtained from the corresponding amplified region of the parent's leucocyte DNA.

Adult↗
PubMed1991

Surgical treatment of double major scoliosis. Improvement of the lumbar curve after fusion of the thoracic curve.

We have evaluated two methods of surgical treatment of adolescent idiopathic double major scoliosis in 59 patients. In group 1, 31 patients were treated by fusion of the upper curve only. In group 2, 28 patients had lumbar fusions also including most of the lower curve. The magnitude of the lower curve and the correction obtained in traction were good indicators of the correction achieved postoperatively. Forty-four patients were reviewed at a minimum of 10 years after operation. Those in group 1 showed sustained improvement of the lower curve with minimal stiffness and pain. Group 2 patients had lumbar curves of similar severity at review, but had significantly more low back pain and stiffness. The number of lumbar segments which remained mobile appeared to be a critical factor in determining the outcome. Selective fusion of the upper curve in double major scoliosis produces satisfactory results if the lumbar curve is less than 50 degrees. It may also be appropriate for flexible lumbar curves of larger angle.

Adolescent↗
PubMed1991

Correction of coxa vara in childhood. The use of Pauwels' Y-shaped osteotomy.

The long-term results following the correction of coxa vara by Pauwels' Y-shaped intertrochanteric osteotomy have been evaluated in 14 children. Ten of the children had unilateral hip disease and were otherwise normal while four had bilateral hip disease due to generalised skeletal dysplasias. In each case, the growth plate was vertical, the femoral head was displaced inferiorly and there were abnormalities in the metaphysis of the femoral neck. The results indicate that this osteotomy provides lasting correction of the deformity, regardless of the cause, as long as the inclination of the growth plate is corrected to 40 degrees or less and adequate support is provided for the metaphyseal defect and the displaced femoral head.

Child↗
PubMed1991

Biodegradable pin fixation of elbow fractures in children. A randomised trial.

A prospective randomised clinical trial was undertaken to compare biodegradable polyglycolic acid pins with standard Kirschner wires used to fix displaced elbow fractures in children. Twenty-four children were enrolled in the trial; 14 had fractures of the lateral condyle of the humerus, eight of the medial epicondyle and two had olecranon fractures. Eleven fractures were fixed with Kirschner wires and 13 with polyglycolic acid pins. Fracture union with full function occurred in all cases within six months. Kirschner wires caused problems including infection in three cases, soft-tissue ossification in one and they required removal under general anaesthesia in nine cases. No such complications occurred with polyglycolic acid pins but one patient in this group developed avascular necrosis and premature fusion of the medial epicondyle.

Adolescent↗
PubMed1991

From meaning to term: semantic locality in the UMLS Metathesaurus.

The Unified Medical Language System Metathesaurus represents the results of a synthesis of existing biomedical naming systems (thesauri). The naming and other information about the meanings in the Metathesaurus can be used to find the preferred naming of that meaning in the source chosen by the user, by exploiting the property of semantic locality. The aspects of semantic locality in the Metathesaurus which can be thus exploited are the terms, the semantic types, the use of that term in a source context, and the co-occurrence of terms in MEDLINE. To find how a meaning is named in the source of choice, a user must exploit one of these aspects of semantic locality, entering a term somehow related to the term being sought, and navigating to the preferred term. While the first three of these aspects of semantic locality are normative, the last is empirical. Testing of the utility of the aspects of semantic locality in information retrieval would require a uniform interface with 1, no Metathesaurus, 2, the Metathesaurus without the aspects in question, and 3, the Metathesaurus including all the aspects. Other potential uses of empirically derived semantic locality include defining or suggesting potentially relevant concepts in a given situation.

Semantics↗
PubMed1991

The management of chronic osteomyelitis.

Chronic osteomyelitis of childhood is heterogeneous but it can be broadly classified into nonspecific or specific groups. Children with chronic osteomyelitis because of mycobacteria or mycoses are included within the specific group. The nonspecific group is the larger. It includes chronic osteomyelitis as a sequel to late acute osteomyelitis as well as chronic unifocal and chronic multifocal osteomyelitis. Whereas Staphylococcus aureus and other pyogenic organisms are commonly cultured from chronic lesions following late acute osteomyelitis, they are less frequently cultured from those with chronic unifocal osteomyelitis and rarely cultured from those with chronic multifocal osteomyelitis. The methods of treatment and the results also differ between these subgroups of nonspecific osteomyelitis. Lesions following late acute osteomyelitis are usually cured following surgery and antibiotics. Chronic unifocal osteomyelitis is usually cured with antibiotics only or with surgery and antibiotics. In contrast, surgery and antibiotics are largely ineffective in children with chronic multifocal osteomyelitis, but the disease appears to be self-limiting.

Child↗
PubMed1990

A base substitution at a splice site in the COL3A1 gene causes exon skipping and generates abnormal type III procollagen in a patient with Ehlers-Danlos syndrome type IV.

The dermis of a child with Ehlers-Danlos syndrome type IV (EDS-IV) contained about 11% of the normal amount of type III collagen and cultured dermal fibroblasts produced a reduced amount of type III procollagen which was secreted poorly. Type III collagen produced by these cells contained normal and abnormal alpha-chains and cyanogen bromide peptides. The site of the structural defect in the abnormal alpha 1 (III) chains was localized to the region of Met797, which is at the junction of the two carboxyl-terminal CB5 and CB9 cyanogen bromide peptides. Chemical cleavage of heteroduplexes formed between EDS-IV mRNA and a normal cDNA clone covering the CB5 and CB9 region showed that about 100 nucleotides were mismatched. Sequencing of amplified and cloned cDNA spanning the mutant region revealed a 108 nucleotide deletion corresponding to amino acid residues Gly775 to Lys810. The deleted nucleotide sequence corresponded to sequences that, by analogy to the organization of the type I collagen genes, should be precisely encoded by exon 41 of the COL3A1 gene. Sequencing of amplified genomic DNA, prepared using disimilar amounts of primers specific for exons 41 and 42, displayed a base substitution (G-to-A) in the highly conserved GT dinucleotide of the 5' splice site of intron 41. Normal sequences were also obtained from the normal allele. It is likely that the GT-to-AT transition at the splice donor site of intron 41 generated an abnormally spliced mRNA in which sequences of exon 40 and 42 were joined together with maintenance of the reading frame. The corresponding peptide deletion included the cyanogen bromide cleavage site Met797-Pro798 and the mammalian collagenase cleavage site at Gly781-Ile782. These losses account for the resistance of EDS-IV collagen to cyanogen bromide and mammalian collagenase digestion. Cultured fibroblasts produced normal homotrimer, mutant homotrimer, and mixed heterotrimer type III collagen molecules. The mutant homotrimer molecules were the major pepsin-resistant species and about 69% of the alpha 1(III) mRNA was in the mutant form.

Adenosine Triphosphatases↗