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Biomedical subjects

J Fleming

Publications and source records attributed to J Fleming.

At least 127 records · Page 7Linked to original sources
PubMed1988

The clinical and endocrine assessment of three different antiandrogen regimens combined with a very long-acting gonadotrophin-releasing hormone analogue.

Tumor flare is reported in up to 40% of patients treated with gonadotrophin-releasing hormone analogues for prostate cancer. In order to investigate the optimal way to eliminate tumor flare, we have treated patients with one of three different antiandrogen regimens used in combination with gonadotrophin-releasing hormone (GnRH) agonist. The early results of this study are presented here. Thirty patients with advanced symptomatic disease were randomized to receive either cyproterone acetate 50 or 100 mg three times daily or flutamide 250 mg three times daily given for 1 week before and during the first month of GnRH agonist treatment. The endocrine profiles of these patients were compared with those of historic controls treated with depot agonist alone. Three patients treated with low-dose cyproterone acetate and one with flutamide developed a transient exacerbation of their disease. No patients treated with the higher-dose cyproterone acetate regimen developed tumor flare. No patients treated with cyproterone acetate had an increase in serum testosterone above baseline following depot GnRH agonist implantation. All patients treated with flutamide had increases in serum testosterone, but this did not significantly increase further with implantation. This study suggests that all patients receiving GnRH agonist treatment should be pretreated with cyproterone acetate 100 mg three times daily for 1 week before implantation and for the first treatment month.

Aged↗
PubMed1988

The effect of supplementary oral nutrition in poorly nourished patients with chronic obstructive pulmonary disease.

We carried out a prospective, randomized, controlled trial to investigate the effect of a 3-month period of supplementary oral nutrition in 14 poorly nourished outpatients with COPD. Seven patients were randomized into Group 1 who received their normal diet during Months 1 to 3, a supplemented diet during Months 4 to 6, and their original normal diet during Months 7 to 9. The other 7 patients received their normal diet for the entire 9-month study period (Group 2). Seven well-nourished patients (Group 3) matched for age and severity of air-flow obstruction served as control subjects; they received their normal diet for the 9-month study period. Measurements of nutritional status, respiratory muscle and handgrip strength, sternomastoid muscle function (including frequency/force curves, maximal relaxation rate, and a fatigability test), lung function, arterial blood gas tensions, general well-being and breathlessness scores, and 6-min walking distances were carried out monthly in all patients. At the start of the study, the poorly nourished patients had lower mean daily calorie and protein intakes than did the well-nourished patients. The poorly nourished patients had lower respiratory muscle and handgrip strength, and abnormal contractility and increased fatigability of the sternomastoid muscle compared with those in the well-nourished patients. After 3 months of supplementary oral nutrition, there was a significant improvement in the nutritional status of Group 1 patients, as evidenced by an increase in body weight, triceps skinfold thickness, and midarm muscle circumference. Respiratory muscle and handgrip strength increased in parallel with nutritional status, although there were no significant changes in lung function or arterial blood gas tensions.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

cis and trans control of erythroid cell-specific gene expression during erythropoiesis.

The overall aim of our group's work is to investigate the molecular mechanisms regulating erythroid cell-specific gene expression during erythroid cell differentiation. We have been successful in cloning two non-globin genes of interest: the first encodes the rabbit red cell-specific lipoxygenase (LOX), which has a role in degrading mitochondrial lipids during maturation of the reticulocyte to the erythrocyte; and the second, mouse glutathione peroxidase (GSHPX), an important seleno-enzyme responsible for protection against peroxide-damage. Characterization of the GSHPX gene revealed that the seleno-cysteine residue in the active site of the enzyme is encoded by UGA, which usually functions as a translation-termination codon. This novel finding has important implications regarding the role of mRNA sequence context effects in codon recognition. In contrast with the beta-globin locus, very little is known about the mechanisms responsible for the erythroid-specific expression of the alpha-globin genes. By a combination of functional transfection assays and studies of the interactions of nuclear sequence-specific DNA-binding proteins with promoter sequences in vitro, we have recently defined two regions upstream of the mouse alpha-globin gene involved in its erythroid-specific expression: one contains a sequence motif (GATAAG) that binds to a species-conserved and erythroid-specific factor both in vitro and in vivo. Interestingly, GATAAG motifs binding the same factor are found also in the mouse and chicken adult beta-globin gene promoters, the erythroid-specific promoter of the haem pathway enzyme, porphobilinogen (PBG) deaminase and the chicken beta-globin 3' enhancer. We are now commencing purification of this erythroid-specific GATAAG-binding factor, investigating in more detail how it functions in relation to other globin gene control regions and determining whether GATAAG-like regions have a functional role in the erythroid-specific expression of other genes. We have begun to investigate the regulation of the GSHPX and red cell LOX genes. The presence of tissue-specific 3' DNAse I-hypersensitive sites (DHSS) suggests that different 3' flanking regions of the GSHPX gene may be important in its regulation in the various cell types in which it is highly expressed, i.e. erythroid cells, liver and kidney.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Regulation of erythroid cell-specific gene expression during erythropoiesis.

The aim of our group's work over the past few years has been to investigate the molecular mechanisms regulating erythroid cell-specific gene expression during erythroid cell differentiation. In addition to the alpha-globin gene, we have focussed on two non-globin genes of interest encoding the rabbit red cell-specific lipoxygenase (LOX) and the mouse glutathione peroxidase (GSHPX), an important seleno-enzyme responsible for protection against peroxide-damage. Characterisation of the GSHPX gene showed that the seleno-cysteine residue in the active site of the enzyme is encoded by UGA, which usually functions as a translation-termination codon. This novel finding has important implications regarding mRNA sequence context effects affecting codon recognition. The regulation of the GSHPX and red cell LOX genes has been investigated by functional transfection experiments. The 700 bp upstream of the GSHPX promoter seems to function equally well when linked to the bacterial chloramphenicol acetyl transferase (CAT) gene and transfected into mouse erythroid or fibroblast cell lines. However, the presence of tissue-specific DNase I hypersensitive sites (DHSS) in the 3' flanking region of the GSHPX gene suggests that such sites may be important in its regulation in the various cell types in which it is highly expressed, i.e., erythroid cells, liver and kidney. The transcription unit of the RBC LOX gene has also been defined and 5' and 3' flanking regions are being investigated for erythroid-specific regulatory elements: a region upstream of the LOX gene gives increased expression of a linked CAT gene when transfected into mouse erythroid cell lines compared to non-erythroid cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1987

A 60-kDa polypeptide in mammalian cells with epitopes related to actin.

We have identified a novel actin-related 60-kDa polypeptide in mammalian cells. The relatedness of this polypeptide to actin is indicated by its affinity for DNase I, two monoclonal anti-actin antibodies, and two independent peptide-specific anti-actin antibodies which bind to actin at around amino acid 244. It is not incorporated into cytoskeletal stress fibers, although it is a stable protein. Its expression (60-kDa polypeptide, pI of 5.4 to 5.5) is inhibited by the K+ ionophore, nonactin, which is known to collapse the energy-dependent translocation of cytoplasmically synthesized proteins into mitochondria.

Actins↗
PubMed1987

Cloning of a rabbit erythroid-cell-specific lipoxygenase mRNA.

We report the isolation of cDNA recombinants representing part of the rabbit reticulocyte (immature red blood cell, RBC) lipoxygenase (LOX) mRNA. One cDNA predicts an amino acid (aa) sequence matching exactly the unique N-terminal 30-aa sequence of the purified enzyme. Further, the reticulocyte mRNA, hybrid-selected by this recombinant, can be translated in vitro to give a polypeptide that comigrates with the purified reticulocyte LOX and is recognized by affinity-purified anti-RBC LOX polyclonal antibodies. Southern blotting experiments hybridising the RBC LOX cDNAs available to total rabbit genomic DNA digested with various restriction enzymes gives a fairly simple hybridisation pattern under moderate stringency conditions: moreover, the same pattern is obtained with a cloned fragment of genomic DNA containing the RBC LOX gene. This indicates that the RBC LOX gene is unique in the genome and seems not to be very closely related to the genes encoding the other tissue LOXs. We also show by Northern transfer/hybridisation experiments that the RBC LOX mRNA is expressed only in the red cell lineage but not in white blood cells (bone marrow or spleen) or in other non-erythroid cells tested (e.g., brain and lung).

Amino Acid Sequence↗
PubMed1987

Ferritin: isolation of aluminum-ferritin complex from brain.

Ferritin was isolated from the livers and brains of two groups of rats, one of which was fed aluminum chloride (100 microM) for 1 year in the drinking water. Brain tissue contained about one-third of the amount of ferritin found in the liver. While brain ferritin from normal rats contained 42.1 +/- 14.3 mol of aluminum, that from the aluminum-fed group contained 115.4 +/- 48.3 mol of aluminum per mol of ferritin. Liver ferritin from both groups contained similar amounts of both aluminum and iron, and the amounts were less than that found associated with brain ferritin. Ferritin isolated from the brains of patients who died of Alzheimer disease contained more aluminum and more iron than that from age-matched controls. Human brain ferritin is composed of two types of subunits--about 70% heavy chain (Mr, 22,000) and 30% light chain (Mr, 19,500). The isoelectric focusing pattern of human brain ferritin was considerably different from that of human liver. Only 5 of the 20 brain ferritin bands migrated similarly to the acidic isoferritins from the liver, and the major component of brain ferritin, representing 30% of the total ferritin, had a pI of 8.0.

Administration, Oral↗
PubMed1987

Routine culturing for Legionella in the hospital environment may be a good idea: a three-hospital prospective study.

The source for nosocomial Legionnaires' disease is the water distribution system. However, the implications for legionella contamination in a hospital without known Legionnaires' disease is unclear. Therefore, culturing for Legionella pneumophila in the environment has not been routinely recommended. The authors conducted a prospective pneumonia study in three hospitals, none of which was known to have a major problem with endemic legionellosis. The water system of Hospital 1 was colonized with L. pneumophila, serogroup 1; Hospital 2 was colonized by L. pneumophila, serogroup 5 (which is rarely associated with disease); Hospital 3 was essentially free of L. pneumophila. Sputum culture on selective legionella media, direct fluorescent antibody testing, and serology were performed for all nosocomial pneumonias regardless of clinical impression. At the end of the study the incidence of nosocomial legionnaires' disease was found to be 9%, 0%, and 0% in Hospitals 1, 2, and found to be 9%, 0%, and 0% in Hospitals 1, 2, and 3, respectively. In Hospital 1, monoclonal antibody subtyping confirmed that the patient isolates were identical to the environmental isolates. The authors conclude that environmental culturing, despite the absence of known Legionnaires' disease, is useful. Positive cultures from the hospital water supply would mandate the introduction of legionella testing into the laboratory and stimulate physicians to consider Legionnaires' disease when encountering nosocomial pneumonias.

Cross Infection↗
PubMed1987

Changes in blood flow, portal pressure and shunting during the development of cirrhosis in response to beta-blockade.

An experimental model of cirrhosis was developed in the rat to assess the effect of disease and pharmacological manipulation on blood flow, shunting and portal pressure. With progression in the severity of histological cirrhosis there was a steady fall in effective liver blood flow as measured with radioisotope labelled colloid. This corresponded to a rise in portal pressure and shunting with a close correlation between the two (r = 0.7, p less than 0.01). In control animals and when portal hypertension was caused by extrahepatic obstruction, beta-blockade with propranolol, but not selective beta 2 blockade, significantly decreased liver blood flow. With cirrhosis there was a variable response to propranolol depending on the histological severity of disease, the height of portal pressure and degree of shunting. There is a possibility therefore that a potential may exist for lowering portal pressure by manipulating intrahepatic shunting.

Adrenergic beta-Antagonists↗
PubMed1987

Sternomastoid muscle function and fatigue in breathless patients with severe respiratory disease.

In patients with severe respiratory disease, the work of breathing is increased and the respiratory muscles, particularly those of inspiration, may become fatigued. Hitherto, there has been little information on the incidence of respiratory muscle fatigue in acutely breathless patients. We studied 34 patients with severe respiratory disease on admission to hospital when they were most breathless, and then, if possible, 7 to 14 days later after recovery for evidence of sternomastoid muscle fatigue or increased fatigability. Frequency/force curves, numerically expressed as the 20:50 ratio, were carried out in all patients on admission. Three of the 34 patients had evidence of low frequency fatigue (i.e., greater than 15% reduction in 20:50 ratio) in the sternomastoid muscle on admission when first studied (mean +/- SEM 20:50 ratio, 56.3 +/- 1.2%; n = 3). The mean 20:50 ratio in the remaining 31 patients on admission was 75.7 +/- 1.6% (n = 31) compared with 77.8 +/- 1.4% (n = 25) when symptomatically better (p less than 0.05). The mean 20:50 ratio on admission was also significantly lower than the mean 20:50 ratio in a group of age- and sex-matched normal control subjects (i.e., 78.5 +/- 1.4%, n = 25; p less than 0.05). Twenty-five patients were studied completely both on admission and recovery, including a fatigability test that involved the performance of 50 fatiguing head lifts with measurements of the 20:50 ratio 10 and 60 min later. Sternomastoid muscle fatigability was significantly increased on admission when the patients were most breathless, compared with recovery when they were less breathless (p less than 0.001 at both 10 and 60 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Cholinergic receptor mutants of the nematode Caenorhabditis elegans.

Potential acetylcholine receptor (AChR) mutants of the nematode are selectable by resistance to the neurotoxic drug levamisole, a probable cholinergic agonist. To determine which mutants may have achieved resistance through loss of levamisole receptor function, we have assayed mutant extracts for specific 3H-meta-aminolevamisole binding activity in the presence and absence of mecamylamine. We find that mutants in 3 of the 7 genes associated with extreme levamisole resistance are obviously deficient in saturable specific 3H-meta-aminolevamisole binding activity. Mutants of the 4 other genes have abnormal binding activities that fail to undergo the apparent allosteric activation of saturable specific 3H-meta-aminolevamisole binding activity caused by mecamylamine. Thus, all 7 genes appear to be required to produce a fully functional levamisole receptor. Mutants of several other genes associated only with partial resistance to levamisole have at least grossly normal receptor binding activities.

Animals↗
PubMed1986

Pattern of spread of bloodborne tumour.

The pattern of bloodborne tumour spread has been studied experimentally in syngeneic rats. A variety of tumour types has been injected intravenously, intraportally and also intra-arterially via the left ventricle. Tumour cell arrest as a factor in the localization of metastases in the lung following intravenous injection of cells, and in the liver following intraportal injection, is emphasized. Once tumour cells have entered the arterial circulation they disseminate to almost all organs in similar proportions to the distribution of cardiac output. The dissemination and arrest of cells is not found to correlate with the later distribution of metastases. For example, certain organs (especially the adrenals) which receive only low fractions of injected cells, are always preferred sites for bloodborne metastasis. A strikingly similar pattern of 'arterial metastasis' is also seen for all the tumours used despite their very different histological and biological natures.

Animals↗
PubMed1986

Ferritin and in vivo beryllium toxicity.

Beryllium (Be+2), a divalent metal ion, is toxic to both man and animal. Although the molecular basis for its toxicity is unknown, it is well established that micromolar concentrations of beryllium specifically inhibit certain enzymes. Previous in vitro studies have shown that the presence of ferritin, an iron-storage protein, reactivated these enzymes by sequestering beryllium (Price and Joshi, 1984). In the present study we demonstrate in vivo that beryllium and zinc are bound by ferritin in greater amounts than Pb+2, Cu+2, and Cd+2. Beryllium did not induce the synthesis of metallothionein. In animals pretreated with an iron salt (ferric ammonium citrate, 40 mg/kg body wt), liver ferritin was elevated approximately five times and the toxicity of intravenously injected beryllium was significantly attenuated. Excretion and deposition studies suggested that iron salt treatment resulted in a reduction of liver beryllium. Thus the protection against beryllium toxicity by ferric ammonium citrate may be due to increased production of ferritin which binds beryllium and its subsequent elimination in the feces.

Animals↗
PubMed1986

Responses of in vivo renal microvessels to dopamine.

The split hydronephrotic kidney preparation was used to directly observe the effects of locally applied dopamine on the in vivo diameters of renal vessels. Dopamine (1 X 10(-6) to 3 X 10(-5) M) produced a concentration-dependent dilation of the arcuate and interlobular arteries and afferent arterioles. Efferent arterioles near the glomeruli also dilated to dopamine but the dilation was less than that of the preglomerular vessels. Higher dopamine concentrations (3 X 10(-4) and 1 X 10(-3) M) produced more variable effects, with a tendency for the arcuate and interlobular arteries and the afferent and efferent arterioles away from the glomeruli to decrease in diameter. After pretreatment with haloperidol, dopamine (1 X 10(-6) to 1 X 10(-4) M) did not dilate any pre- or postglomerular vascular segment, but the tendency for pre- and postglomerular constrictions with higher dopamine concentrations were not abolished. Pretreatment with phentolamine and propranolol enhanced the dilator response of the pre- and postglomerular vessels (except the afferent arterioles near glomeruli and efferent arterioles near welling points) to dopamine (3 X 10(-5) and 1 X 10(-4) M), and abolished the reductions in diameter produced by the high dopamine levels. These data indicate that the dilator effect of dopamine is mediated by interactions with specific dopaminergic receptors, while alpha and beta adrenergic receptors appear to mediate a constrictor influence observed with high dopamine concentrations. The overall effect of dopamine on the renal vessel diameters thus appears to depend on the balance of dilator and constrictor stimuli mediated by multiple receptors.

Animals↗
PubMed1986

Does radiolabelled diphosphonate retention reflect bone metabolism in the elderly?

The 24-h whole-body retention of diphosphonates (WBR), a useful measure of bone metabolism in young subjects, was measured in 27 elderly subjects (19 from home and eight in-patients). WBR rose with increasing age (r = 0.55, P less than 0.01) and was negatively correlated with renal function (r = -0.60, P less than 0.01). In five subjects given vitamin D, WBR did not fall. The measurement of WBR in the elderly has to be assessed in the light of an accurate assessment of renal function and so is rarely clinically useful.

Aged↗