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G R Sutherland

Publications and source records attributed to G R Sutherland.

At least 163 records · Page 9Linked to original sources
PubMed1997

The gene for the human interleukin-11 receptor alpha chain locus is highly homologous to the murine gene and contains alternatively spliced first exons.

The gene for the murine interleukin-11 receptor alpha chain (mIL-11R alpha) contains two loci (1 and 2), of which locus 2 is restricted to only some mouse strains. Two alternatively spliced exons (1a and 1b) encode the 5' untranslated region (5'UTR) of the murine locus 1. We have characterized the gene for the human interleukin-11 receptor alpha chain locus (hIL-11R alpha), examined its expression by Northern analysis and determined its chromosomal location by fluorescence in situ hybridization. The presence of exon(s) encoding the 5'UTR and mapping of transcription initiation sites was determined by reverse-transcriptase polymerase chain reaction and 5' rapid amplification of cDNA ends (5'RACE) techniques. The human locus spanned 10 kilobasepairs (kb) and consisted of 14 exons. Two alternatively spliced first exons (1a and 1b) encoding the 5'UTR were identified and shared 76 and 73% nucleotide identity with murine exons 1a and 1b. Multiple transcription start sites were demonstrated for human exon 1a. The promoter regions of both human exons 1a and 1b did not display a canonical TATA box. A predominant 1.8 kb transcript for the hIL-11R alpha was present in heart, brain, skeletal muscle, lymph nodes, thymus, appendix, pancreas and foetal liver. The hIL-11R alpha gene was localized to chromosome 9p13. In summary, the hIL-11R alpha gene was highly related to locus 1 of the murine gene and there was no evidence of a second hIL-11R alpha locus.

Alternative Splicing↗
PubMed1997

FMR2 expression in families with FRAXE mental retardation.

Normal individuals express the two alternative transcripts, FMR2 and Ox19, from the FRAXE-associated CpG island. Molecular analysis of the Ox19 transcript suggests that it is a truncated isoform of the FMR2 gene with an alternative 3' end. Both isoforms showed a similar pattern of expression, with the Ox19 isoform expressed at a much lower level. Fibroblasts, chorionic villi and hair roots showed the highest level of FMR2 expression, whole blood cells and amniocytes showed very low expression, and the transcript was not detected in lymphoblasts. Fibroblasts of 11 individuals from seven families segregating FRAXE were assayed for FMR2 expression and FRAXE CpG island methylation. A man with an unmethylated expansion of 0.6 kb expressed FMR2 and represents a pre-mutation carrier. All chromosomes with FRAXE CCG expansions of 0.8 kb or greater were fully methylated and did not express the FMR2 gene, analogous to the mechanism of silencing the FMR1 gene in carriers of the FRAXA full mutation. The boundary between FRAXE pre-mutation and FRAXE full mutation is between 0.7 and 0.8 kb. Two men with absence of FMR2 expression in fibroblasts were not mentally impaired, suggesting that IQ in some men with FRAXE full mutation may remain within the normal range. Although molecular tools to study FRAXE non-specific mental retardation are now available, further psychometric and molecular studies are needed to characterize the effect of the FRAXE full mutation for the purpose of genetic counselling.

Base Sequence↗
PubMed1997

The prevalence of left ventricular diastolic filling abnormalities in patients with suspected heart failure.

AIMS: It is reported that one third of patients with heart failure have normal left ventricular systolic function, and may or may not have left ventricular diastolic dysfunction. We sought to define the prevalence of left ventricular diastolic filling abnormalities in a large unselected group of patients, unlike the diagnosis by exclusion in the small highly selected groups of patients studied previously. METHODS AND RESULTS: Patients were referred by general practitioners to an open-access echocardiography service for assessment of possible heart failure. Echocardiography included a Doppler study of transmitral flow at the tips of the mitral leaflets and calculation of an E/A ratio. Of 534 patients referred and assessed, 371 patients had normal systolic function and a measurable E/A ratio. These were compared with age-adjusted reference ranges to give 9 above the reference range and 19 below. This is only 10 more than would be expected if our patients were normal. In the same group of patients we found 96 cases of left ventricular systolic dysfunction, or 52 amongst the 423 with a measurable E/A ratio. CONCLUSION: Either left ventricular diastolic filling abnormalities are very much less common than previously supposed or the E/A ratio is almost useless for their detection.

Adult↗
PubMed1997

Assessing diagnosis in heart failure: which features are any use?

We assessed the value of symptoms, past history, medications and signs in the evaluation of patients who might have heart failure secondary to left ventricular systolic dysfunction. An open-access echocardiography service was set up to help identify patients with left ventricular systolic dysfunction who might benefit from treatment with an angiotensin-converting-enzyme inhibitor. History and examination were recorded for each of these patients. The patients were divided into groups according to whether left ventricular systolic function was preserved or not and whether various clinical features were present or not. Of 259 consecutive patients studied, 41 had impairment of left ventricular systolic function as assessed by echocardiography. Past history of myocardial infarction and displaced apex beat were the best single predictors of left ventricular systolic dysfunction as assessed by echocardiography. The combination of past history of myocardial infarction and displaced apex had the best positive predictive value of all. Patients with such clinical features or combinations of clinical features may not need echocardiography, and where access to this resource is limited, it could be reserved for patients without such diagnostic features.

Dyspnea↗
PubMed1997

Evidence for a high free radical state in low-grade astrocytomas.

OBJECTIVE: It is postulated that reactive oxygen species may play an inductive role in neuro-oncogenesis. However, data pertaining to the redox state of astrocytomas are limited, which prompted us to undertake this study. METHODS: Intraoperative snap-frozen samples were obtained from the surface and core of 8 low-grade and 11 high-grade astrocytomas. Small portions of each specimen were fixed in 10% neutral formalin or cacodylate-buffered glutaraldehyde. Lipid peroxidation was estimated by measuring thiobarbituric acid-reactive substances, and total glutathione levels were determined. Light microscopy was performed to define the relevant histopathology, and electron microscopy was used to quantitate peroxisomal content. RESULTS: Thiobarbituric acid-reactive substance values for low-grade astrocytomas were significantly elevated compared to those for malignant lesions, as was the case for total glutathione. This discrepancy was especially marked at the tumor surface. Peroxisomes predominated in the low-grade category. CONCLUSION: We speculate regarding malignant transformation as a possible consequence of this decline in antioxidant capacity, as well as regarding the role of seizures and astrocytoma glutamate receptors in the initiation of free radical cascades. The therapeutic and teleological implications are considerable.

Adolescent↗
PubMed1997

Assessment of atrial septal defect morphology by transthoracic three dimensional echocardiography using standard grey scale and Doppler myocardial imaging techniques: comparison with magnetic resonance imaging and intraoperative findings.

OBJECTIVE: To determine whether transthoracic three dimensional echocardiography is an accurate non-invasive technique for defining the morphology of atrial septal defects (ASD). METHODS: In 34 patients with secundum ASD, mean (SD) age 20 (17) years (14 male, 20 female), the measurements obtained from three dimensional echocardiography were compared to those obtained from magnetic resonance imaging (MRI) or surgery. Three dimensional images were constructed to simulate the ASD view as seen by a surgeon. Measured variables were: maximum and minimum vertical and horizontal ASD dimension, and distances to inferior and superior vena cava, coronary sinus, and tricuspid valve. In each patient two ultrasound techniques were used to acquire three dimensional data: standard grey scale imaging (GSI) and Doppler myocardial imaging (DMI). RESULTS: Good correlation was found in maximum ASD dimension (both horizontal and vertical) between three dimensional echocardiography and both MRI (GSI r = 0.96, SEE = 0.05 cm; DMI r = 0.97, SEE = 0.04 cm) and surgery (GSI r = 0.92, SEE = 0.06 cm; DMI r = 0.95, SEE = 0.06 cm). The systematic error was similar for both three dimensional techniques when compared to both MRI (GSI = 0.40 cm (27%); DMI = 0.38 cm (25%)) and surgery (GSI = 0.50 cm (29%); DMI = 0.37 cm (22%)). A significant difference was found in both horizontal and vertical ASD dimension changes during the cardiac cycle. This change was inversely correlated with age. These findings were consistent for both DMI and GSI technique. In children (age < or = 17 years), the feasibility of detecting structures and undertaking measurements was similar for both echo techniques. However, in adult ASD patients (age > or = 18 years) this feasibility was higher for DMI than for GSI. CONCLUSIONS: Transthoracic three dimensional imaging using both GSI and DMI accurately displayed the varying morphology, dimensions, and spatial relations of ASD. However, DMI was a more effective technique than GSI in describing ASD morphology in adults.

Adult↗
PubMed1997

Localisation of a 10q breakpoint within the PAX2 gene in a patient with a de novo t(10;13) translocation and optic nerve coloboma-renal disease.

We describe a 5 year old boy with a de novo t(10;13) translocation and optic nerve coloboma-renal disease (ONCR). On the basis of GTG banding analysis of prometaphase chromosomes, the patient's karyotype was interpreted as either 46,XY,t(10;13)(q24.3;q12.3) or t(10;13) (q25.2;q14.1). Fluorescence in situ hybridisation (FISH) studies using a YAC clone containing the PAX2 gene and YAC clones adjoining FRA10B at 10q25.2 showed that the 10q breakpoint had occurred just within the PAX2 gene and was proximal to FRA10B. These FISH results suggest that the translocation causes a disruption of the PAX2 gene and leads to ONCR, in agreement with the recent reports of PAX2 mutations in two unrelated families with ONCR. Furthermore, we refined the regional mapping of the human PAX2 gene to the junction of bands 10q24.3 and 10q25.1.

Child, Preschool↗
PubMed1997

Measurement of cyclic variation in ultrasonic integrated backscatter in conscious, unsedated, clinically normal dogs.

OBJECTIVE: To assess the feasibility and repeatability of measuring ultrasonic integrated backscatter in unsedated conscious dogs, using a protocol previously validated in pigs with open thorax. ANIMALS: 11 clinically normal conscious unsedated German Shorthair Pointers. PROCEDURE: A modified commercially available echocardiography system was used to record long-axis views of the heart. The radiofrequency data from 15 consecutive frames were digitized and analyzed. Regions of interest were chosen within the myocardium, and the ultrasonic integrated backscatter within each region was calculated in the time domain for each frame. RESULTS: Cyclic variation in integrated backscatter values was observed, with maximal values at end-diastole and minimal values at end-systole. Mean +/-SD amplitude of cyclic variation was 5.81 +/- 3.86 dB over all the regions chosen. CONCLUSIONS: Results agreed with those obtained by other investigators working with dogs with open thorax and those with closed thorax while under general anesthesia. The analysis of the components of variance indicates that this is a consistent, reliable technique in conscious unsedated dogs. CLINICAL RELEVANCE: Integrated ultrasonic backscatter measurement provides a noninvasive means of tissue characterization. Use of this protocol reliably yields cyclic variation in integrated backscatter and could be applied clinically to dogs with myocardial disease.

Anesthesia, General↗
PubMed1996

Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25.

The interferon regulatory factor (IRF) genes encode a family of transcription factors involved in the transcriptional regulation of interferon and the interferon stimulated genes through recognition of the interferon stimulated response element. We previously reported the cloning of a murine lymphocyte-specific IRF (mLSIRF), which was rapidly induced following B- or T-cell receptor crosslinking. To study the role of LSIRF in human lymphocyte development, we have cloned the complete 5.3-kb cDNA for the human homolog (hLSIRF). hLSIRF is a protein of 450 amino acids with a predicted molecular weight of 51.6 kDa and possesses 92% identity at the amino acid level to mLSIRF, including near identity in the DNA-binding domain. In Northern blot analysis, a single transcript of approximately 5 kb was highly expressed in spleen and peripheral blood lymphocyte. hLSIRF mRNA was rapidly induced in peripheral T cells after crosslinking the T-cell receptor. Analysis of tumor cell lines showed that hLSIRF mRNA was basally expressed in most B- but not T-cell lines. Surprisingly hLSIRF mRNA was also found in the melanoma line G361 and is expressed in normal melanocytes as well. Sequence from a genomic clone for hLSIRF was compared to that from mouse and revealed an identical exon-intron structure and a conserved PU-1-binding motif in the promoter. By FISH analysis, hLSIRF was mapped to 6p23-p25.

Amino Acid Sequence↗
PubMed1996

Molecular characterization of a nonneuronal human UNC18 homolog.

A cDNA clone encoding a human homolog of the Caenorhabditis elegans unc-18 gene was identified following random sequencing of clones from IL-2-activated human NK cells. This cDNA clone is related to the nonneuronal Munc-18b and so has been called Hunc-18b. The Hunc-18b transcripts were found in most human tissues, with the exception of brain and skeletal muscle, and in cells from all lymphoid lineages. The Hunc-18b gene was localized to human chromosome 19p13.2-p13.3, and the mouse homolog, Munc-18b, was mapped to the proximal region of mouse Chromosome 8.

Amino Acid Sequence↗
PubMed1996

Hippocampal neurons are damaged by caffeine-augmented electroshock seizures.

Caffeine-augmented electroconvulsive therapy has been introduced into medical practice without experimental confirmation that such seizure modification does not result in neuronal injury. In this report rats pretreated with caffeine prior to a series of nine electrically induced convulsions showed neuronal injury confined to hippocampal sectors and striatum. Electrically induced convulsions without caffeine pretreatment did not result in injury. The potential deleterious effects of caffeine augmentation of human electroconvulsive therapy require rigorous clinical assessment.

Animals↗
PubMed1996

bcl-w, a novel member of the bcl-2 family, promotes cell survival.

The prototypic mammalian regulator of cell death is bcl-2, the oncogene implicated in the development of human follicular lymphoma. Several homologues of bcl-2 are now known. Using a PCR-based strategy we cloned a novel member of this gene family, denoted bcl-w. The gene, which is highly conserved between mouse and human, resides near the T-cell antigen receptor alpha gene within the central portion of mouse chromosome 14 and on human chromosome 14 at band q11. Enforced expression of bcl-w rendered lymphoid and myeloid cells refractory to several (but not all) cytotoxic conditions. Thus, like Bcl-2 and Bcl-x, the Bcl-w protein promotes cell survival, in contrast to other close homologues, Bax and Bak, which facilitate cell death. Comparison of the expected amino acid sequence of Bcl-w with that of these relatives helps to delineate residues likely to convey survival or anti-survival function. While expression of bcl-w was uncommon in B or T lymphoid cell lines, the mRNA was observed in almost all murine myeloid cell lines analysed and in a wide range of tissues. These findings suggest that bcl-w participates in the control of apoptosis in multiple cell types. Its functional similarity to bcl-2 also makes it an attractive candidate proto-oncogene.

Amino Acid Sequence↗