Biomedical subjects
J Fletcher
Publications and source records attributed to J Fletcher.
Low plasma C4 concentrations: association with microangiopathy in insulin dependent diabetes.
Plasma C4 concentrations were measured in insulin dependent diabetics with and without microangiopathy and in controls. The diabetics had significantly lower C4 values than controls (p less than 0.001), and patients with insulin dependent diabetes and microangiopathy had lower values than those without this complication (p less than 0.001). There was a 7.1-fold increase in the prevalence of complications in the diabetics with low C4 values. Of 41 diabetics whose rate of albumin excretion was measured, 13 had increased rates and 11 of these had low C4 concentrations. Low plasma C4 concentration in insulin dependent diabetes is strongly associated with microvascular disease and may identify diabetics with a particular propensity to develop this complication.
Inhibition of human neutrophil secondary granule discharge by antiinflammatory agents.
Human neutrophil cobalamin binding protein (NCBP) is located exclusively in the neutrophil secondary granules. The soluble stimuli formlymethionyl-leucyl-phenylalanine and the low-molecular-weight complement fragment C5a both promote the dose-dependent release of NCBP from cytochalasin B-treated neutrophils in vitro. The extracellular discharge of NCBP induced by higher secretagogue is inhibited by prior exposure of neutrophils to the corticosteroids hydrocortisone and methylprednisolone and the nonsteroidal antiinflammatory agents indomethacin and ibuprofen. The four antiinflammatory agents function as competitive antagonists of neutrophil secondary granule discharge with a site of action at or near the cell surface. These findings support the hypothesis that antiinflammatory agents prevent neutrophil activation in vitro by inhibition of stimulus-receptor coupling. The significance of these observations with regard to the in vivo actions of these agents remains uncertain, however.
Defective phagocytosis in insulin controlled diabetics: evidence for a reaction between glucose and opsonising proteins.
Neutrophils from diabetic patients controlled with insulin showed impaired phagocytosis of a yeast, Candida guilliermondii. The defect was detected by measuring the initial rate of phagocytosis at optimal concentrations of phagocytes and organisms in autologous plasma. By mixing normal neutrophils in diabetic plasma and vice versa both cellular and plasma abnormalities were shown. The defect was reproduced by incubating normal plasma at a D-glucose concentration of 15 mmol/l for 3 h or for shorter periods at higher concentrations of glucose. The data suggest that defective phagocytosis is partly due to a reaction between glucose and the plasma proteins concerned with opsonisation. Defective phagocytosis may be important not only in coping with infections but also in other diabetic complications as plasma proteins are concerned with the removal of damaged or effete cells as well as foreign antigens.
Materials management...the future.
Explore the source record for details and available documents.
The care of the terminally ill: morality and economics.
Are current expenditures on dying patients disproportionate, unreasonable, or unjust? Although a review of empirical data reveals that care for the terminally ill is very costly, it is not appropriate to conclude that such expenditures represent a morally troubling misallocation of societal resources. Moreover, though efforts to reduce the costs of caring for the dying are not unreasonable, they must be undertaken with great caution. At present, such efforts should concentrate on three basic goals: development of better criteria for admission to intensive- and critical-care units; promotion of patient and family autonomy with regard to decisions to stop or refuse certain kinds of treatment; and promotion of alternative forms of institutional care, such as hospice care. The most difficult moral problems will arise when patients and their physicians seek access to therapies judged only marginally useful. There may be conflict between administrators with broad institutional responsibilities and clinicians committed to particular patients.
The effects of surgery on the activity of neutrophil granule proteins.
Activities of the neutrophil granule-associated proteins beta-glucuronidase, lysozyme and vitamin B12 binding protein were measured, serially, in the cells and serum of 10 patients undergoing total abdominal hysterectomy. The neutrophil leucocytosis which followed total abdominal hysterectomy was accompanied by a fall in the intraneutrophilic activities of all three granule-associated proteins. Intraneutrophilic lysozyme activity and intraneutrophilic vitamin B12 binding capacity were maximally reduced within 4 h of surgery and fell to 62 +/- 13% (mean +/- SEM) and 63 +/- 9% of their preoperative levels, respectively. This contrasted with the activity of intraneutrophilic beta-glucuronidase which was not maximally reduced until 24 h post-surgery when a fall to 80 +/- 6% of the preoperative level was observed. By the fifth postoperative day activities of the three intraneutrophilic granule proteins were increasing and approaching those observed preoperatively. Serum lysozyme and plasma unsaturated vitamin B12 binding capacity (UBBC) rose steadily following surgery and were significantly elevated by the fifth postoperative day. It is suggested that activation and in vivo degranulation of circulating neutrophils may be responsible for these changes in activity of neutrophil granule proteins following surgery.
Tropolone: a lipid solubilizing agent for cationic metals.
Lipid soluble agents which chelate radioactive cations have several potential uses in nuclear medicine including: brain imaging, labeling of blood elements, and identifying fatty infiltration of organs. A tropolone-gallium complex has been characterized by the determination of in vitro partition ratios correlated with in vivo organ distribution in the rat. Partition ratios were determined for gallium-67 citrate, indium-114m chloride, and iron-59 chloride cations complexed with tropolone in chloroform + water, octanol + water, olive oil + water, and olive oil + plasma two-phased systems. Tropolone proved to be highly effective in the lipid solubilization of these metal cations. Distribution studies in animals of these cations complexed with tropolone demonstrated an increased concentration of these cation complexes in tissues of high lipid content when compared with appropriate controls.
Phagocytosing neutrophils rapidly release a factor which inhibits granulopoiesis in vitro.
Phagocytosis of the heat-killed opsonised yeast, Candida guilliermondii, by human neutrophils resulted in the rapid release of a potent factor which suppressed granulopoiesis in vitro. The factor has been shown to act on monocytes and macrophages by inhibiting the production and release of colony-stimulating factor (CSF) which is the specific stimulator of granulocytic colony-forming cell (CFUc) proliferation in vitro. When added directly to target cells containing CFUc, the inhibitory factor had no effect on colony growth. The absence of detectable inhibitor in media conditioned for short periods with resting neutrophils or neutrophils challenged with unopsonised Candida which are not phagocytosed confirmed that active phagocytosis was the stimulus for inhibitor release. In further experiments, addition of endotoxin to the cultures was shown to suppress the inhibitory effect. We suggest that feedback inhibition of CSF production in vivo may be mediated by products derived from phagocytosing neutrophils.
Cardiovascular, respiratory, and hematologic effects of leukotriene D4 in primates.
Explore the source record for details and available documents.
Assisting the elderly with drug therapy in the home.
Explore the source record for details and available documents.
The discharge of primary and secondary granules during immune phagocytosis by normal and chronic granulocytic leukaemia polymorphonuclear neutrophils.
The two types of granule in polymorphonuclear neutrophils may have distinct functions. The primary granule enzymes are responsible for killing and digesting ingested micro-organisms while the secondary granule constituents may have regulatory functions outside the cell. This hypothesis is supported by finding that during immune phagocytosis of a yeast, nearly all of the neutrophil's secondary granule vitamin B12-binding protein is lost from the cell and 80% can be accounted for in the medium. Much less of the primary granule enzymes, beta-glucuronidase and acid phosphatase, are lost from the cells and very little can be detected in the medium. Lysozyme is a constituent of both types of granule and its behaviour is intermediate. There is no difference in the release of these granule constituents from chronic granulocytic leukaemia neutrophils compared with normal neutrophils.
Phagocytosing neutrophils and granulopoiesis.
Explore the source record for details and available documents.
Exploring byroads in medical ethics.
Explore the source record for details and available documents.
Failure of chronic-granulocytic-leukaemia leucocytes to release an inhibition of granulopoiesis.
Phagocytosing, but not resting, neutrophils normally release an inhibitor of in-vitro granulopoiesis which suppresses the production or release of colony-stimulating factor by monocytes and macrophages. Neutrophils from 12 patients with chronic granulocytic leukaemia (CGL) were found to contain the inhibitor, but in 11 of the 12 patients there was failure to release significant amounts during phagocytosis. It is suggested that such a defect in the feedback control of granulopoiesis could lead to the progressive inappropriate accumulation of morphologically normal granulocytes, as seen in CGL.
Sperm abnormalities and cigarette smoking.
Sperm samples from a carefully matched group of 43 cigarette smokers and 43 non-smokers attending an infertility clinic were examined for morphological abnormality. The smokers were found to have a significantly greater percentage of abnormal forms. In the light of other work showing increased chromosome damage in blood lymphocytes of cigarette smokers and the known propensity for mutagens to induce sperm abnormalities in animals, it is suggested that the sperm abnormalities in cigarette smokers may reflect genetic damage to these cells as a consequence of exposure to smoke products.
Non-Hodgkin's lymphoma, chronic lymphatic leukaemia and the lung.
In a retrospective study of 81 patients with non-Hodgkins's lymphoma and 35 patients with chronic lymphatic leukaemia, pulmonary involvement was found in 25% of cases and pleural effusion in 19%. Twenty-four patients (20%) had intrathoracic lymphadenopathy and 12 of these had associated pleural or lung involvement. Infiltration occurred almost exclusively in diffuse lymphocytic lymphoma and chronic lymphatic leukaemia, whereas round lesions were seen only in undifferentiated lymphomas. Pleural effusion complicated most histological types of non-Hodgkin's lymphoma but was uncommon in chronic lymphatic leukaemia. Pleural biopsy was successful in diagnosing lymphoma in nine of ten patients with an effusion in whom it was performed. Both pulmonary and pleural involvement responded poorly to treatment and had an adverse effect on prognosis. In contrast, intrathoracic lymphadenopathy responded well to radiotherapy and/or chemotherapy and did not affect prognosis adversely when it occurred in the absence of other intrathoracic manifestations of lymphoma.
Effects of surgery on neutrophil granulocyte function.
The high incidence of postoperative infections raises the possibility of a reduced defense to infection during this period. For this reason, neutrophil function and enzyme activity were investigated after surgical trauma. The microbicidal ability of neutrophils was markedly impaired within 2 h of elective abdominal hysterectomy, but phagocytosis was unaffected. Loss of microbicidal activity was associated with loss of the lysosomal enzyme myeloperoxidase. It is suggested that these changes are due to activation and partial degranulation of circulating neutrophils. Defective microbial killing by individual cells should be compensated by an accompanying rise in the number of circulating neutrophils.