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Biomedical subjects

J Fleming

Publications and source records attributed to J Fleming.

At least 109 records · Page 6Linked to original sources
PubMed1991

Localization of the gene encoding the GABAA receptor beta 3 subunit to the Angelman/Prader-Willi region of human chromosome 15.

Deletions of the proximal long arm of chromosome 15 (bands 15q11q13) are found in the majority of patients with two distinct genetic disorders, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). The deleted regions in the two syndromes, defined cytogenetically and by using cloned DNA probes, are similar. However, deletions in AS occur on the maternally inherited chromosome 15, and deletions in PWS occur on the paternally derived chromosome 15. This observation has led to the suggestion that one or more genes in this region show differential expression dependent on parental origin (genetic imprinting). No genes of known function have previously been mapped to this region. We show here that the gene encoding the GABAA (gamma-aminobutyric acid) receptor beta 3 subunit maps to the AS/PWS region. Deletion of this gene (GABRB3) was found in AS and PWS patients with interstitial cytogenetic deletions. Evidence of beta 3 gene deletion was also found in an AS patient with an unbalanced 13;15 translocation but not in a PWS patient with an unbalanced 9;15 translocation. The localization of this receptor gene to the AS/PWS region suggests a possible role of the inhibitory neurotransmitter GABA in the pathogenesis of one or both of these syndromes.

Amino Acid Sequence↗
PubMed1991

Child health and education in Kenyan schools programmes.

Jane Fleming describes the health education in schools programme launched by the Aga Khan Health Services in Kisumu, Kenya. The project has brought major improvements in child health and mortality rates as well as better health awareness to the community as a whole.

Child↗
PubMed1990

Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia.

A strong immunoreactivity for ferritin was observed in the neuritic (senile) plaques in Alzheimer's disease hippocampus. The ferritin accumulation was almost exclusively associated with the microglia, which appeared to have proliferated greatly. These cells were also positive for HLA-DR, a putative marker for reactive microglia. In contrast, in the diffuse plaques, which were without neuritic pathology, the ferritin-stained microglia appeared to be normal. Microglia were seen frequently in contact with neurons undergoing neurofibrillary changes but only the tangles in the extracellular space were ferritin positive. No ferritin was detected, by Western blots, in paired helical filaments isolated from Alzheimer's disease brain, suggesting that ferritin was most likely weakly associated with and was not a constituent of these fibrils. No correlation between increased ferritin/microglia activity and blood-brain barrier leakage was detected. Ferritin, an iron-storage protein, might have a role in the formation of amyloid through the action of free radicals generated during the release of iron from the ferritin molecule. Alternatively, the ferritin/microglia system might be secondarily involved in the removal and processing of the amyloid.

Aged↗
PubMed1990

Hypoxic viscosity and diabetic retinopathy.

Diabetic and sickle retinopathy have features in common--for example, venous dilatation, microaneurysms, and capillary closure preceding neovascularisation. Bearing in mind that haemoglobin in poorly controlled diabetes is abnormal and that extremely low oxygen tensions (known to cause sickling) exist in the healthy cat retina, we wished to explore the possibility that diabetic blood, like that of sickle cell disease, may become more viscous when deoxygenated. To do this we measured whole blood viscosity, under oxygenated and deoxygenated conditions, of 23 normal persons, 23 diabetic patients without retinopathy, and 34 diabetic patients with retinopathy. The shear rate used was 230 s-1, which is similar to that thought to prevail in the major retinal veins. The viscosity of blood from normal persons, corrected for packed cell volume, did not change significantly on deoxygenation: mean 4.54 (SD 0.38) cps, versus, 4.57 (0.39) paired t test, p = 0.66. Similarly the blood from diabetics without retinopathy showed no change: 4.42 (0.45) versus 4.42 (0.30), p = 0.98; whereas the blood from patients with retinopathy changed from 4.82 (0.48) to 4.95 (0.63), p = 0.027. The hypoxic viscosity ratio (deoxygenated divided by oxygenated viscosity) correlated with total serum cholesterol (r = 0.44, p = 0.018) but not with HbA1, serum glucose, triglycerides, or age. A disproportionate increase in venous viscosity relative to arterial viscosity would lead to increased intraluminal and transmural pressure and therefore exacerbate leakage across capillary walls.

Adult↗
PubMed1990

Transesophageal Doppler ultrasonography: evidence for improved cardiac output monitoring.

Cardiac output monitoring by transesophageal Doppler ultrasound has not gained wide clinical acceptance. A recently developed transesophageal Doppler device, Accucom 2, features technological advances aimed to reduce the error of this approach to the monitoring of cardiac output. To determine if Accucom 2 enables more accurate cardiac output monitoring, a prospective investigation was undertaken. Analyses of 923 simultaneous measurements of transesophageal Doppler and thermodilution cardiac output in 47 anesthetized patients were compared. Results using Accucom 2 were highly correlated with the results obtained with thermodilution (R = 0.91) and provided significantly greater accuracy in comparison with a previously developed Doppler cardiac output monitor, Accucom 1. Technological advances in transesophageal Doppler ultrasound hold promise for clinically useful noninvasive monitoring of cardiac output.

Aged↗
PubMed1990

Regulation of erythroid-specific gene expression.

The aim of our group's work has been to elucidate how the alpha- and beta-globin genes come to be co-expressed together with a set of characteristic non-globin genes during erythroid cell differentiation. Our most significant progress concerns the identification and analysis of a species-conserved transcription factor, EF1, that appears to play a general role in the regulation of erythroid-specific gene transcription. We have shown that the 4 kb of 5' flanking region of the mouse alpha-globin gene contains two erythroid-specific cis-control elements, both of which involve EF1 binding sites. We have also identified functionally active EF1 binding sites in the mouse beta-globin promoter, as well as in the erythroid-specific promoter of the gene encoding the haem biosynthetic enzyme, porphobilinogen deaminase (PBG-D). The function of the PBG-D promoter depends in part on the cooperation between an EF1 binding site and an adjacent CACCC motif, this being abolished if their spacing is increased beyond 40 nt. We have also investigated the mechanisms involved in the up-regulation in erythroid cells of two non-globin genes we have cloned, encoding the RBC-specific lipoxygenase (LOX) and glutathione peroxidase (GSHPX). As judged by the presence of tissue-specific DNAse I hypersensitive sites, the tissue-specific regulation of the GSHPX gene seems to be due to regulatory regions 3' to the gene. The level of GSHPX is also regulated by selenium and this occurs at two levels: during mRNA formation, and during translation of the mRNA due to the regulation of selenocysteine incorporation specified by a unusual use of the UGA codon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Structure of the mRNA and of the gene coding for the rabbit erythroid 15-lipoxygenase.

The complete structure of the rabbit erythroid cell-specific 15-lipoxygenase mRNA and its gene was established by sequencing cDNA and genomic recombinants. The transcription initiation site was obtained by primer-extension sequencing. A presumptive promoter structure was characterized by sequencing 0.5 kb 5' to the transcription initiation site and by transfection experiments using constructs with the chloramphenicol transferase gene. The mRNA codes for a polypeptide of 662 amino acids. Its 3' untranslated region contains an intriguing repeated sequence of 10 copies with the consensus C4PuC3TCTTC4AAG which may be involved in its regulation during reticulocyte maturation. The transcription unit consists of 8.0 kb and is split like the gene for the leukocyte 5' lipoxygenase by 13 introns. Another interesting aspect in the structure of the 15-LOX gene is a highly conserved repeat in intron seven consisting of a unit of 54 nucleotides which is repeated eight times. Comparing the predicted amino acid sequence with those from other lipoxygenases published recently shows that lipoxygenases are a related group of enzymes which may have arisen from a common ancestral gene.

Amino Acid Sequence↗
PubMed1989

The promoter structure and complete sequence of the gene encoding the rabbit erythroid cell-specific 15-lipoxygenase.

We report the isolation and complete sequence of the gene encoding the rabbit erythroid-cell-specific 15-lipoxygenase (RBC 15-LOX), containing 14 exons spanning 8.0 kb. The transcription start point was mapped by S1 nuclease-protection experiments and comparison with the sequence of the RBC 15-LOX mRNA, as defined previously by primer extension experiments. The promoter contains a TATA-like motif, but no CCAAT motif in the canonical position, and lies within a 'CpG-rich island'. Functional analysis of the immediate 5'-flanking DNA by transfection experiments shows that a 150 nucleotide (nt) 5' fragment linked to the chloramphenicol acetyltransferase gene acts as a functional promoter in both erythroid and nonerythroid cell lines and responds in an erythroid-specific manner to the enhancer from the Friend murine leukaemia virus long terminal repeat, whereas a 40-nt fragment is inactive. Intron 7 contains eight copies of a 54-nt repeat containing a region with homology to the simian virus 40/immunoglobulin gene enhancers.

Animals↗
PubMed1989

The complete sequence of the rabbit erythroid cell-specific 15-lipoxygenase mRNA: comparison of the predicted amino acid sequence of the erythrocyte lipoxygenase with other lipoxygenases.

We report the complete sequence of the rabbit reticulocyte (RBC) 15-lipoxygenase (LOX) mRNA as deduced from (i) sequencing cDNA recombinants isolated by screening cDNA libraries or polymerase-chain-reactions, and (ii) the sequence originating from the transcription start point obtained by primer extension-sequencing reactions. Like the human leukocyte 5-LOX mRNA, the RBC 15-LOX mRNA contains a very short 5'-untranslated region with a long 3'-untranslated region. But, unlike the human leukocyte 5-LOX mRNA, the RBC 15-LOX mRNA contains an intriguing repeated sequence (ten copies with the consensus sequence C4PuC3TCTTC4AAG) just after the translational stop codon, which may be involved in its regulation during reticulocyte maturation. Comparison of the RBC 15-LOX mRNA sequence with those of the previously published human 5-LOX mRNA and the soybean 3-LOX gene shows only a few short regions of sequence similarity. However, the predicted amino acid sequences of the encoded LOX enzymes show certain conserved regions that are presumably involved in their catalytic activity, in particular a cluster of five conserved histidines that we predict chelate the iron moiety involved in the active site.

Amino Acid Sequence↗
PubMed1989

A gamma camera method to monitor the use of degradable starch microspheres in hepatic arterial chemotherapy.

A gamma camera method to quantify the haemodynamic effects of degradable starch microspheres (DSM) in intra arterial hepatic therapy is described. Results are presented from ten patients with colorectal liver metastases. Intra hepatic arterio venous shunting was present in 1 patient prior to DSM and in 2 subjects after three 300 mg DSM fractions. DSM reduced the rate of flow of injectate to the lung in all cases. Conversely, an increased rate of flow of injectate to gut or spleen occurred with 300 mg fractions of DSM in 7/9 cases. Lower dose DSM fractions are indicated. At 2-3 min after DSM injection the mean fraction of the activity retained in the liver was 0.22. A DSM induced enhancement of tumour relative to normal tissue perfusion was obtained in four out of five tumour regions identified. All indices showed a wide variation between patients and between individual DSM doses, and the high incidence of extra hepatic shunting confirms the need for monitoring when using intra arterial microspheres.

Antineoplastic Agents↗
PubMed1989

Sleep architecture changes in depression: interesting finding or clinically useful.

1. Since the late 1970's, considerable progress in the description and quantification of EEG sleep changes in depression has been made. A consistent finding in the sleep of depressed patients is a shortening of the time from sleep onset to the appearance of the first REM period (short REM latency) suggesting that this finding might be used as a clinical test to differentiate depressed from nondepressed patients. 2. Sleep architecture changes in depression are described and factors influencing REM sleep are identified. The stability of REM sleep abnormalities and the specificity of these changes for depression are discussed. Methodological issues, which have been identified as possible contaminants affecting the reliability of research findings, are described before the author concludes with a summary of current obstacles to using polysomnography in the clinical assessment of depressed patients.

Depression↗
PubMed1989

Two-monthly depot gonadotropin releasing hormone agonist (buserelin) for treatment of prostatic cancer.

The agonist analogues of gonadotropin-releasing hormone provide an alternate medical therapy for prostatic cancer. Current methods of administration of these analogues by daily injection or nasal spray is sub-optimal in an elderly population. We have performed a pharmacological and endocrine evaluation of a new depot preparation of one such analogue, buserelin, active for 2 months. Thirty patients with advanced symptomatic prostatic cancer were treated. Serum testosterone was suppressed for the duration of treatment which ranged up to 14 months. The release characteristics of the depot were consistent and showed minimal variation between patients. This 2-month preparation of buserelin offers and advantage to the patient with prostatic cancer, over current treatment regimens.

Adult↗
PubMed1988

Mechanisms of organ selective tumour growth by bloodborne cancer cells.

The sites of tumour development for 6 rat tumours injected into syngeneic rats via different vascular routes was determined. Xenografts of human tumours were also injected intra-arterially (i.a.) into immunosuppressed rats. Following intravenous (i.v.) and intraportal (i.ptl.) injection of cells tumour colonies localized in lung and liver respectively due to tumour cell arrest. Arterially injected radiolabelled cells disseminated and arrested in a similar distribution to cardiac output and did not 'home' to any organs. Following arterial injection of unlabelled tumour cells colonies grew in many organs. While the pattern of growth for a particular tumour varied with the cell dose, the 'arterial patterns' for all of the tumours studied followed a similar pattern. Some organs (eg adrenals, ovaries and periodontal ligament) were consistently preferred, others (eg skin and skeletal muscle) only supported tumour growth following the delivery of large numbers of cells, while in some tissues (eg spleen and intestines) tumour never grew. Viable tumour cells could be demonstrated by bioassay in many organs for up to 24h after i.a. injection. However tumour growth only occurred in certain organs and the pattern of this growth was not related to the number of tumour cells arrested or their rate of autolysis. This site preference could be expressed quantitatively as the probability of an arrested cell developing into a tumour and was considered a 'soil effect'. Site preference was not directly related to organ vascularity. Organ colonisation was promoted by steroid treatment but the mechanism was unclear and was not secondary to T-cell immunosuppression or prostaglandin synthesis suppression. The adrenal glands were preferred sites of tumour growth but pharmacological manipulation of adrenal function did not alter tumour growth to this organ. Sites of injury and healing were preferred sites of tumour colonisation and this could not be accounted for by increased delivery of tumour cells to these regions. The possibility that the macrophage component of the inflammatory response promoted tumour growth was suggested from studies in which the interval between trauma and inoculation of tumour cells was varied as well as by promotion of intraperitoneal (i.p.) tumour growth by a macrophage infiltrate.

Animals↗