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Biomedical subjects

David FitzPatrick

Publications and source records attributed to David FitzPatrick.

9 recordsLinked to original sources
PubMed2007

Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation.

We report on three unrelated mentally disabled patients, each carrying a de novo balanced translocation that truncates the autism susceptibility candidate 2 (AUTS2) gene at 7q11.2. One of our patients shows relatively mild mental retardation; the other two display more profound disorders. One patient is also physically disabled, exhibiting urogenital and limb malformations in addition to severe mental retardation. The function of AUTS2 is presently unknown, but it has been shown to be disrupted in monozygotic twins with autism and mental retardation, both carrying a translocation t(7;20)(q11.2;p11.2) (de la Barra et al. in Rev Chil Pediatr 57:549-554, 1986; Sultana et al. in Genomics 80:129-134, 2002). Given the overlap of this autism/mental retardation (MR) phenotype and the MR-associated disorders in our patients, together with the fact that mapping of the additional autosomal breakpoints involved did not disclose obvious candidate disease genes, we ascertain with this study that AUTS2 mutations are clearly linked to autosomal dominant mental retardation.

Abnormalities, Multiple↗
PubMed2006

Statistical design of unicompartmental tibial implants and comparison with current devices.

This study defines, in the context of unicompartmental tibial replacement, the medial and lateral resection surfaces of 34 tibiae at a depth of 5 mm below the articular surface. Using statistical techniques, three optimal theoretical size and shape unicompartmental tibial designs, (i) implants of consistent shape in varying size (ii) implants symmetric about their ML axis; (iii) implants of varying size and shape, were constructed to best fit the population. Two currently available commercial implants, the Preservation Uni System (DePuy Orthopaedics Inc., Warsaw, IN) and the LCS Uni System (DePuy Orthopaedics Inc., Warsaw, IN), which were similar to types (i) and (ii) respectively, of the theoretical designs, were also included in the analysis. All implants, commercial and theoretical, were compared with one another to determine which implant designs gave the best cortical bone coverage on both the medial and lateral compartments. Of the commercial implants, the type (i) design fitted best, with an average of 67% of the implant edge lying on cortical bone, compared with 57% for the type (ii) implants. Of the theoretical implants, 72%, 67% and 76% of the implant edge lay on cortical bone for types (i), (ii) and (iii) designs, respectively, indicating that there is room for improvement in current implant designs to achieve better coverage in both the medial and lateral compartments combined.

Adult↗
PubMed2006

A tibial-based coordinate system for three-dimensional data.

An accurate and repeatable tibial measurement system will aid in the definition of tibial geometry and improving tibial prosthesis design. Unlike in the femur, there is no standardized method for constructing a tibial coordinate frame. Most tibial measurements are given relative to femoral axes or the coordinate frame of the CT/MRI scanner or radiograph machine. The objective of this study was to establish an independent tibial coordinate frame. Data consisted of CT scans from 34 subjects. The tibial anatomical axis was chosen as the axial axis. The anteroposterior (AP) axis was selected to be parallel to the lateral surface of the tibial shaft and orthogonal to the anatomical axis and from this the mediolateral axis could be derived. The selected AP axis was compared with the surgical tibial AP axis by measuring their variability relative to a common axis, the posterior tibial condylar line (PTCL). The mean angle between the selected AP axis and the perpendicular to the PTCL was measured as -4.07 degrees, standard deviation of 4.28 degrees. The mean angle between the surgical AP axis and the perpendicular to the PTCL was measured as -18.56 degrees, standard deviation of 4.66 degrees. There was no significant difference in the variance of the two sets of measurements (p=0.63). Variability of the selected AP axis was even smaller (standard deviation of 2.74 degrees) when measured independently from the PTCL reference axis, by aligning virtual resection profiles. Anatomically, the selected AP axis was almost perpendicular to the posterior tibial condylar axis. This coordinate system can aid in gathering consistent and repeatable anthropometric data that can be used to improve tibial implant design and could also, in combination with CT/MR imaged-based computer assisted surgery, be used as a guideline for tibial component positioning in TKR.

Adult↗
PubMed2006

Purity and the dangers of regenerative medicine: regulatory innovation of human tissue-engineered technology.

This paper examines the development of innovation in human tissue technologies as a form of regenerative medicine, firstly by applying 'pollution ideas' to contemporary trends in its risk regulation and to the processes of regulatory policy formation, and secondly by analysing the classificatory processes deployed in regulatory policy. The analysis draws upon data from fieldwork and documentary materials with a focus on the UK and EU (2002-05) and explores four arenas: governance and regulatory policy; commercialisation and the market; 'evidentiality' manifest in evidence-based policy; and publics' and technology users' values and ethics. The analysis suggests that there is a trend toward 'purification' across these arenas, both material and socio-political. A common process of partitioning is found in stakeholders' attempts to define a clear terrain, which the field of tissue-engineered technology might occupy. We conclude that pollution ideas and partitioning processes are useful in understanding regulatory ordering and innovation in the emerging technological zone of human tissue engineering.

Biomedical Technology↗
PubMed2006

Clinical and molecular genetic features of ARC syndrome.

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.

Abnormalities, Multiple↗
PubMed2004

Modelling of annulus fibrosus imbalance as an aetiological factor in adolescent idiopathic scoliosis.

OBJECTIVE: To assess and model the influence of collagen fibre imbalance within the annulus fibrosus on the initiation and progression of adolescent idiopathic scoliosis deformity. BACKGROUND: A number of aetiological factors have been proposed for idiopathic scoliosis, including a contribution from the intervertebral disc. The specific influence of the annulus fibrosus has yet to be effectively modelled. METHODS: A mathematical model was used to determine the contribution of collagen fibre orientation and directional imbalance within the annulus fibrosus to vertebral rotation and overall deformity of thoracic spine. Rotations, due to collagen fibre imbalance, and translations, due to rapid growth, were applied to a simplified model of the thoracic spine, using a three-dimensional transformation matrix approach. RESULTS: The ratio of clockwise to anti-clockwise fibres in the intervertebral disc (from unity to 0.80) influenced the induced rotation. The three-dimensional model illustrates the initiation and progression of the scoliotic deformity during adolescent growth, being most obvious at larger growth rates. CONCLUSIONS: Imbalance in the ratio of clockwise and anti-clockwise collagen fibres within the annulus fibrosus has been demonstrated to have the potential to contribute to the progression of scoliosis. For a given fibre ratio, the rate of growth does not influence the induced rotation, but directly influences the severity of the resulting deformity. RELEVANCE: The model defines the potential contribution of collagen fibre imbalance to adolescent idiopathic scoliosis, supporting the clinical observation that greatest progression of deformity occurs during phases of rapid adolescent growth. However, the underlying mechanism is within the annulus fibrosus, assisting in the search for the responsible genes.

Adolescent↗
PubMed2003

Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy.

Charcot-Marie-Tooth type 2B (CMT2B) is clinically characterized by marked distal muscle weakness and wasting and a high frequency of foot ulcers, infections, and amputations of the toes because of recurrent infections. CMT2B maps to chromosome 3q13-q22. We refined the CMT2B locus to a 2.5-cM region and report two missense mutations (Leu129Phe and Val162Met) in the small GTP-ase late endosomal protein RAB7 which causes the CMT2B phenotype in three extended families and in three patients with a positive family history. The alignment of RAB7 orthologs shows that both missense mutations target highly conserved amino acid residues. RAB7 is ubiquitously expressed, and we found expression in sensory and motor neurons.

Amino Acid Sequence↗
PubMed2002

Delineation of an estimated 6.7 MB candidate interval for an anophthalmia gene at 3q26.33-q28 and description of the syndrome associated with visible chromosome deletions of this region.

Anophthalmia or microphthalmia occur in approximately one in 10 children who have severe visual impairment. These eye malformations are often of unknown aetiology, but can be inherited in autosomal dominant, recessive or X-linked forms, and can also occur in association with specific chromosome abnormalities. Four children are described in the medical literature with microphthalmia or anophthalmia in association with chromosome rearrangements involving distal 3q, suggesting the presence of a micro/anophthalmia gene in this region. We have identified two further patients with micro/anophthalmia and chromosome rearrangements involving 3q26-->3q27 and identified a 6.7 MB common deleted region. Patient 1 had multiple abnormalities including bilateral anophthalmia, abnormalities of the first and second cranial nerves and partial absence of the corpus callosum. His karyotype was 46,XY,del(3)(q26.33q28). Patient 2 had right anophthalmia and left extreme microphthalmia. Her karyotype was 46,XX,del(3)(q26.33q28)t(3;7)(q28;q21.1). Both patients had intrauterine growth retardation (IUGR) and strikingly similar dysmorphic facies consisting of bossed forehead, downward-slanting palpebral fissures, grooved bridge of the nose, prominent low-set ears, small down-turned mouth and small mandible. We identified BAC clones mapping to distal 3q from the ENSEMBL and NCBI Entrez databases. These BAC clones were used as fluorescence in situ hybridisation (FISH) probes to identify the minimum deleted region common to both patients. This interval, between clones RPC11-134F2 and RPC11-132N15, was estimated to be 6.7 MB. We conclude that there is an anophthalmia locus within this interval. Candidate genes mapping to this region include Chordin and DVL3, a homologue of the Drosophila Dishevelled gene.

Anophthalmos↗