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Biomedical subjects

G R Sutherland

Publications and source records attributed to G R Sutherland.

At least 217 records · Page 12Linked to original sources
PubMed1995

The brn-2 gene regulates the melanocytic phenotype and tumorigenic potential of human melanoma cells.

The Oct transcription factors N-Oct-3 and N-Oct-5 are differentially expressed in normal melanocytes, melanoma tumors and cell lines. We have cloned the human brn-2 gene and have shown that it encodes both the N-Oct-3 and N-Oct-5 octamer binding activities detected in melanoma cells. The brn-2 genomic locus has been mapped to chromosome 6q16 and although chromosomal aberrations are common in this region in melanoma, no deletion or rearrangement of the brn-2 gene in melanoma cell lines was observed. Sequencing of the entire gene showed that there are no intervening sequences within the open reading frame. Antisense RNA-mediated inhibition of brn-2 gene expression in melanoma cells was associated with a change in morphology and loss of melanocytic and neural crest markers, including the melanocyte transcription factor microphthalmia and the TYRP pigmentation genes. In addition, loss of brn-2 in these cells resulted in the complete loss of ability to form tumors in SCID and nu/nu mice. These results suggest roles for brn-2 in the determination of the melanocytic lineage and in the tumorigenic phenotype of melanoma.

Animals↗
PubMed1995

Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2.

The fragile site FRA11B has been localized to the p(CCG)n repeat of the CBL2 proto-oncogene. A proportion of Jacobsen (11q-) syndrome patients inherited a chromosome carrying a CBL2 p(CCG)n expansion, which was truncated close to FRA11B. These results have broad implications for the role of p(CCG)n repeat expansion in the aetiology of genetic disease involving chromosome rearrangements.

Base Sequence↗
PubMed1995

Simple tandem DNA repeats and human genetic disease.

The human genome contains many repeated DNA sequences that vary in complexity of repeating unit from a single nucleotide to a whole gene. The repeat sequences can be widely dispersed or in simple tandem arrays. Arrays of up to 5 or 6 nt are known as simple tandem repeats, and these are widely dispersed and highly polymorphic. Members of one group of the simple tandem repeats, the trinucleotide repeats, can undergo an increase in copy number by a process of dynamic mutation. Dynamic mutations of the CCG trinucleotide give rise to one group of fragile sites on human chromosomes, the rare folate-sensitive group. One member of this group, the fragile X (FRAXA) is responsible for the most common familial form of mental retardation. Another member of the group FRAXE is responsible for a rarer mild form of mental retardation. Similar mutations of AGC repeats give rise to a number of neurological disorders. The expanded repeats are unstable between generations and somatically. The intergenerational instability gives rise to unusual patterns of inheritance--particularly anticipation, the increasing severity and/or earlier age of onset of the disorder in successive generations. Dynamic mutations have been found only in the human species, and possible reasons for this are considered. The mechanism of dynamic mutation is discussed, and a number of observations of simple tandem repeat mutation that could assist in understanding this phenomenon are commented on.

Chromosome Mapping↗
PubMed1995

Open access echocardiography in management of heart failure in the community.

OBJECTIVE: To assess the value of an open access echocardiography service. DESIGN: Study of new open access service for general practitioners, who were invited to refer patients taking diuretics for suspected heart failure, untreated patients with symptoms of possible heart failure, and asymptomatic patients with risk factors for left ventricular systolic dysfunction. SETTING: Regional cardiology centre. SUBJECTS: 259 consecutive patients. MAIN OUTCOME MEASURES: Presence or absence of left ventricular systolic dysfunction and consequent changes in clinical management. RESULTS: 119 treated patients, 99 untreated patients, and nine asymptomatic patients were referred over five months. 32 were considered to be inappropriately referred. Among the treated patients, 31 had impaired left ventricular systolic function and five had valvular disease; angiotensin converting enzyme inhibitors were recommended for 34 of these patients. In addition, 53 were thought not to need diuretics. Eight untreated patients had impaired systolic function and six valvular disease. CONCLUSIONS: The service was well used by general practitioners and led to advice to change management in more than two thirds of patients.

Adolescent↗
PubMed1995

Gene duplication of the human peptide YY gene (PYY) generated the pancreatic polypeptide gene (PPY) on chromosome 17q21.1.

Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) are structurally related but functionally diverse peptides, encoded by separate genes and expressed in different tissues. Although the human NPY gene has been mapped to chromosome 7, we demonstrate here that the genes for human PYY and PP (PPY) are localized only 10 kb apart from each other on chromosome 17q21.1. The high degree of homology between the members of this gene family, both in primary sequence and exon/intron structure, suggests that the NPY and the PYY genes arose from an initial gene duplication event, with a subsequent tandem duplication of the PYY gene being responsible for duplication of the PYY gene being responsible for the creation of the PPY gene. A second weaker hybridization signal also found on chromosome 17q11 and results obtained by Southern blot analysis suggest that the entire PYY-PPY region has undergone a further duplication event.

Amino Acid Sequence↗
PubMed1995

Correlation between Gd-enhanced MR imaging and histopathology in treated and untreated 9L rat brain tumors.

Gadolinium-based MR imaging contrast agents cause signal enhancement of intracerebral tumors on T1-weighted MR images because they cross the compromised blood-brain barrier, increasing the T1 relaxation rate of extracellular water. Tumor extent measured by Gd-enhanced MR imaging often does not agree with T2-weighted MRI or biopsy measurements, due to possible peritumoral barrier defects or infiltration of tumor cells beyond the region of enhancement. In this study, the 9L rat brain tumor model was used to measure the correlation between tumor size measured by Gd-enhanced and unenhanced MRI and histological measurements. There was excellent agreement between Gd-enhanced MRI measurements and histology. Morphological features of untreated 9L intracranial tumors and those treated with radiation and/or cisplatin were compared with histological features. No significant change in intracranial tumor size was detected in the treated animals up to 7 days following treatment, despite substantial tumor necrosis evident on histological analysis.

Animals↗
PubMed1995

The molecular basis of fragile sites in human chromosomes.

Fragile sites on chromosomes have been classified into a number of groups according to their frequency and the conditions required to induce them. A number of the rare folate-sensitive fragile sites have been characterized and shown to be amplified methylated CCG trinucleotide repeats. One common fragile site has been partly characterized and appears to be a region of fragility, rather than a single site.

Aphidicolin↗
PubMed1995

Identification and characterization of a new member of the TNF family that induces apoptosis.

A novel tumor necrosis factor (TNF) family member has been cloned and characterized. This protein, designated TNF-related apoptosis-inducing ligand (TRAIL), consists of 281 and 291 aa in the human and murine forms, respectively, which share 65% aa identity. TRAIL is a type II membrane protein, whose C-terminal extracellular domain shows clear homology to other TNF family members. TRAIL transcripts are detected in a variety of human tissues, most predominantly in spleen, lung, and prostate. The TRAIL gene is located on chromosome 3 at position 3q26, which is not close to any other known TNF ligand family members. Both full-length cell surface expressed TRAIL and picomolar concentrations of soluble TRAIL rapidly induce apoptosis in a wide variety of transformed cell lines of diverse origin.

Amino Acid Sequence↗
PubMed1995

Optimizing muscle synchronization after dynamic cardiomyoplasty. Two educational cases.

Muscle stimulator programming is fundamental in ensuring optimal latissimus dorsi graft function after cardiomyoplasty. The ventricle-muscle synchronization delay has a significant effect on graft function, but can be difficult to optimize. The established method for ensuring appropriate synchronization involves the use of M-mode echocardiography. We present two educational cases in which M-mode and Doppler echocardiography have been instrumental in illustrating electrophysiologic and haemodynamic factors which need to be considered in evaluating an appropriate synchronization delay.

Atrial Fibrillation↗
PubMed1995

Ruptured and unruptured intracranial aneurysms--surgical outcome.

BACKGROUND: The treatment of unruptured, intracranial aneurysms has been the topic of debate. Although recent studies have advocated surgical intervention for unruptured aneurysms, the risk of such treatment in comparison to outcome from ruptured aneurysms has not been established. METHOD: This retrospective study examines the outcome of 134 patients with 179 ruptured and unruptured intracranial, saccular aneurysms treated by a single surgeon. RESULTS: Of the 98 ruptured aneurysms where early surgical intervention was undertaken (less than 48 hours post hemorrhage), 70 had an excellent outcome, 13 were good, four were moderate, two poor and nine patients died postoperatively. Outcome assessment in these cases was correlated to preoperative neurological status. Patients who presented with unruptured aneurysms fell into two categories: symptomatic and asymptomatic. Seven incidental, asymptomatic aneurysms were clipped concurrently to the surgical isolation of the culprit lesion following subarachnoid hemorrhage without influencing outcome, whilst, for varying reasons, eight unruptured aneurysms were not operated upon. Of the remaining 66 surgically treated, unruptured aneurysms, 64 had an excellent postoperative result, one was good (persisting right incomplete third nerve palsy) and one was moderate (left hemiparesis). Thirteen of these aneurysms were symptomatic, whilst 21 were asymptomatic, multiple aneurysms requiring secondary elective repair and 32 were true incidental aneurysms. CONCLUSION: Unruptured aneurysms less than 25 mm in size may be safely, surgically treated relative to the expected natural history and, certainly, with less risk than operative intervention upon ruptured cerebral aneurysms.

Adult↗
PubMed1995

Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2.

The epilepsies comprise a group of syndromes that are divided into generalized and partial (focal) types. Familial occurrence has long been recognized but progress in mapping epilepsy genes has been slow except for rare cases where the inheritance is easily determined from classical genetic studies. Linkage is established for three generalized syndromes: the EBN1 and EBN2 genes for benign familial neonatal convulsions (BFNC) map to chromosomes 20q and 8q (refs 2-5), the EPM1 gene for Unverricht-Lundborg disease maps to 21q (ref. 6) and the gene for the northern epilepsy syndrome maps to 8p (ref. 7). A claim for linkage of the EJM1 gene for the common generalized syndrome of juvenile myoclonic epilepsy to 6p is currently in dispute. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was recently described in five families. We now report the chromosomal assignment, to 20q13.2, for the gene for ADNFLE in one large Australian kindred with 27 affected individuals spanning six generations.

Chromosomes, Human, Pair 20↗
PubMed1995

A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.

Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.

Amino Acid Sequence↗
PubMed1995

Cloning of the sulphamidase gene and identification of mutations in Sanfilippo A syndrome.

Sanfilippo A syndrome is one of four recognised Sanfilippo sub-types (A, B, C and D) that result from deficiencies of different enzymes involved in the lysosomal degradation of heparan sulphate; patients suffer from severe neurological disorders. The Sanfilippo syndrome sub-types are also known as mucopolysaccharidosis (MPS) type III (MPS-IIIA, B, C and D), and are part of the large group of lysosomal storage disorders. Each of the MPS-III types is inherited as an autosomal recessive disorder with considerable variation in severity of clinical phenotype. The incidence of Sanfilippo syndrome has been estimated at 1:24,000 in The Netherlands with MPS IIIA (MIM #252900) the most common. MPS-IIIA is the predominant MPS-III in the United Kingdom, and has a similar high incidence to that found in The Netherlands (E. Wraith, personal communication). There is a particularly high incidence of a clinically severe form of MPS-IIIA in the Cayman Islands with a carrier frequency of 0.1 (ref. 4). Due to the mild somatic disease compared to other MPS disorders there is difficulty in diagnosing mild cases of MPS-III, hence Sanfilippo syndrome may be underdiagnosed, especially in patients with mild mental retardation. Here, we report the isolation, sequence and expression of cDNA clones encoding the enzyme sulphamidase (EC 3.10.1.1). In addition, we report the chromosomal localisation of the sulphamidase gene as being 17q25.3. An 11-bp deletion, present in sulphamidase cDNA from two unrelated Sanfilippo A patients, is described.

Amino Acid Sequence↗