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Biomedical subjects

J Clarke

Publications and source records attributed to J Clarke.

At least 199 records · Page 11Linked to original sources
PubMed1993

Use of recombinant granulocyte-colony stimulating factor to treat neutropenia occurring during craniospinal irradiation.

PURPOSE: To investigate the effectiveness of recombinant human Granulocyte-Colony Stimulating Factor, a hematopoietic growth factor which stimulates neutrophil production, in the treatment of neutropenia caused by Craniospinal Irradiation. METHODS AND MATERIALS: Four consecutive patients who developed neutropenia (neutrophils less than 1.5 X 10(9)/l in peripheral blood) during craniospinal irradiation for primary intracranial tumors received intermittent subcutaneous injections of Granulocyte-Colony Stimulating Factor. Two of the patients had medulloblastoma, one had a primitive neuroectodermal tumor and the other a pinealocytoma. No patient received prior or concurrent chemotherapy. RESULTS: In all cases peripheral blood neutrophil counts returned rapidly to normal levels following Granulocyte-Colony Stimulating Factor injections and treatment delays were therefore avoided. Platelet counts were unaffected by Granulocyte Colony Stimulating Factor treatment. In one case, slight elevation of peripheral blood monocyte and lymphocyte counts occurred after each Granulocyte-Colony Stimulating Factor injection. No toxicity was encountered. CONCLUSION: Our results suggest that Granulocyte-Colony Stimulating Factor is a safe and effective treatment for neutropenia caused by extended field radiotherapy.

Adult↗
PubMed1993

Engineered disulfide bonds as probes of the folding pathway of barnase: increasing the stability of proteins against the rate of denaturation.

Disulfide bridges have been introduced into barnase to act as probes of folding. One disulfide (between residues 85 and 102) links two loops known to pack together early in the folding pathway. A second disulfide bond (between residues 43 and 80) links two elements of secondary structure known to pack together only after the rate-determining step of folding. The disulfide-bridged proteins are more stable than wild-type by 4.1 and 1.2 kcal mol-1, respectively. The kinetics of unfolding and refolding of the mutant proteins has been measured, and a comparison of the disulfide proteins and their corresponding dithiol forms has been made by use of thermodynamic cycles. These data have been used to construct folding profiles of the disulfide proteins. The disulfide bond engineered into the part of the protein that folds early confers stability upon the intermediate and transition states of folding. The protein with a disulfide bond connecting parts of the protein that fold late is not stabilized until the protein reaches its final folded form. Conversely, in the unfolding pathway, the rate of unfolding of this mutant is lowered considerably. This points to a method of decreasing the rate of denaturation of proteins that are used in medical and biotechnological applications: elements of structure that unfold in or before the rate-determining step of overall unfolding may be stabilized and so slow down the overall unfolding process. The barnase mutant linked between Cys 43 and Cys 80, for example, unfolds 20 times slower than wild-type and 170 times slower than the reduced protein.

Bacillus↗
PubMed1993

Coronary vasomotor effects of serotonin in patients with angina. Relation to coronary stenosis morphology.

BACKGROUND: Previous experimental studies have shown that the effect of serotonin on a coronary stenosis depends on whether that stenosis is compliant or fixed. However, the relation between coronary stenosis morphology and the response to serotonin in patients with angina is not known. METHODS AND RESULTS: Using computerized quantitative coronary angiography, we studied the effects of intracoronary infusion of serotonin on 38 coronary stenoses of different morphologies (concentric, eccentric, complicated) in 11 patients with stable angina and 4 with variant angina. In response to the maximum infused concentration of serotonin, 100% of complicated stenoses and 50% of concentric stenoses constricted by > or = 20% (P < .05). The magnitude of constriction was greater at eccentric stenoses (32.08 +/- 4.1%) than concentric stenoses (15.68 +/- 2.8%, P < .05) and greater in complicated stenoses (57.69 +/- 7.6%, P < .05) than eccentric stenoses. At complicated stenoses, the constriction was greater (0.85 +/- 0.16 mm, P < .05) than at the adjacent reference segments (0.42 +/- 0.12 mm). It was similar to the reference segment for both concentric and eccentric stenoses. The constriction at the stenosis was greater for irregular (complicated) lesions than for smooth (concentric and eccentric) lesions in both patients with stable (51.8 +/- 7.3% versus 22.5 +/- 4.1%, P < .001) and those with variant (77 +/- 17% versus 28.2 +/- 8.1%, P < .05) angina. There was a weak correlation (r = .39) of magnitude of constriction with stenosis length but not with baseline stenosis severity (minimum diameter). CONCLUSIONS: In these patients, the magnitude of the vasoconstrictor response to serotonin at the site of an atheromatous coronary plaque depends on the morphological characteristics of the plaque and is more closely related to irregular contour than stenosis severity or length. This relation suggests that variations in receptor type or density or in the smooth muscle cell response to stimulation may determine the response to locally released serotonin in patients with coronary disease.

Angina Pectoris↗
PubMed1993

[The possible role of the inner mitochondrial membrane in regulating oxidative phosphorylation in cells in vivo].

It has been shown for the first time that the outer mitochondrial membrane has a low permeability for ADP and can control its diffusion into cells in vivo. Respiration of saponin-skinned cardiac and skeletal muscle fibers is maximally stimulated by millimolar concentrations of external ADP. The apparent Km values for ADP are equal to 297 +/- 35 and 334 +/- 54 microM, respectively. After complete extraction of myosin with 0.8 M KCl, which fully preserves the intact structure of the mitochondria, the apparent Km values for exogenously added ADP does not change. However, disruption of the outer mitochondrial membrane by osmotic shock (treatment with 40 mOsM KCl) causes a reduction of the apparent Km value down to 32.3 +/- 5.0 microM of ADP. The apparent Km for ADP in isolated heart mitochondria is 17.6 +/- 1.0 microM. It is concluded that there exists an intracellular factor in the cells in vivo which controls the outer mitochondrial membrane and notably decreases its permeability for ADP. After isolation of mitochondria this factor is lost. When mitochondrial creatine kinase is activated, weak intracellular fluxes of ADP passing through the outer mitochondrial membrane in the skinned fibers are amplified manifold due to the tight functional coupling between mitochondrial creatine kinase and the oxidative phosphorylation system. This coupling is considered to be the central mechanism in the control of cell respiration.

Adenosine Diphosphate↗
PubMed1992

Initiation of transcription by T7 RNA polymerase as its natural promoters.

A kinetic assay has been developed to measure the strength of natural T7 promoters. By determining the rate of appearance of initiation products in the presence of constant concentrations of T7 RNA polymerase, an incomplete mixture of ribonucleoside triphosphates, and increasing promoter concentrations, a maximum rate of product formation (Vmax) and a promoter concentration giving half of the maximal activity ([P]Vmax/2) can be determined for any cloned T7 promoter. On supercoiled plasmids, it was found that the [P]Vmax/2 measured for the six promoters phi 1.1B, phi 1.3, phi 3.8, phi 6.5, phi 10, and phi 13 ranged from 3.4 +/- 1.1 to 12.0 +/- 2.4 nM while the Vmax values showed no significant trends. On plasmids that had been linearized by cleavage at a single site with a restriction endonuclease, the cloned T7 promoters assayed fell into two broad classes that appear to be characterized by the T7 class II and III promoters. Generally, the class II promoters required higher promoter concentrations to produce half of the maximum rates of initiation ([P]Vmax/2 values) than the class III promoters. The [P]Vmax/2 values for the class II promoters ranged from 20 +/- 2.7 to 23 +/- 3.6 nM, while the [P]Vmax/2 values for the class III promoters phi 10 and phi 13 were 13 +/- 1.6 nM and 7.8 +/- 1.4 nM. The one exception is the class III promoter phi 6.5 whose [P] Vmax/2 (17 +/- 5 nM) falls between the [P]Vmax/2 values of the class II promoters and the strong class III promoters. The Vmax values measured on linear templates are variable, but it appears that phi 10 is more active than the other five promoters.

Adenosine Triphosphate↗
PubMed1992

Allelic loss on chromosome 11p is a less frequent event in bilateral than in unilateral Wilms' tumours.

Analyses to detect loss of heterozygosity (LOH) were performed at 11 polymorphic loci on chromosome 11 and, using a polymorphic CA repeat sequence in the WT1 gene, on a series of 39 tumours from 28 unilateral and 10 tumours from 6 bilateral Wilms' tumour (WT) patients. LOH was seen in 13 out of 35 patients including 12 out of 29 unilateral tumours, but only one of 10 bilateral tumours. This suggests that bilateral WT represents a subgroup of WT in which tumour initiating events less frequently involve LOH on chromosome 11 and that either epigenetic events, point mutations or another non-chromosome 11p locus are important in bilateral tumours. The observation of LOH in one WT but not another WT in a bilateral WT patient provides evidence that these tumours arising in the same patient are not monoclonal proliferations and most likely arise via different molecular pathways.

Alleles↗
PubMed1992

Inhaled steroids in patients with bronchiectasis.

The effect of inhaled beclomethasone diproprionate (1500 micrograms day-1) on symptoms, pulmonary function and sputum production was examined in a double-blind, placebo-controlled, cross-over study in 20 patients with bronchiectasis. An 18% reduction in daily sputum production (P less than 0.003) was observed on treatment with inhaled steroid compared to placebo. A small, significant, improvement in morning peak expiratory flow rate (P less than 0.03) and forced expiratory volume in 1 s (P less than 0.03) was seen but the absolute changes are unlikely to be of clinical importance. Symptom scores for cough improved significantly (P less than 0.02). Inhaled steroids may have a role in the management of bronchiectasis by reducing cough and sputum production.

Administration, Inhalation↗