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Biomedical subjects

R Coleman

Publications and source records attributed to R Coleman.

At least 271 records · Page 15Linked to original sources
PubMed1987

Pharmacodynamics of warfarin at steady state.

We studied the pharmacodynamics of warfarin in chronically treated patients. Two methods were used to estimate the pharmacodynamic parameters M/Kd and Cmax (mg/L). In Method 1 the prothrombin time response was modeled directly without use of warfarin concentrations and Method 2 used warfarin concentrations and prothrombin time response to estimate M/Kd and Cmax. The mean Cmax and M/Kd for Method 1 (n = 88) were 5.5 +/- 2.3 mg/L and 51 +/- 46 and for Method 2 (n = 27) 6.3 +/- 2.8 mg/L and 35.4 +/- 13. When Method 1 was applied to the same 27 patients in Method 2, the mean Cmax and M/Kd were 5.7 +/- 3.3 mg/L and 36.1 +/- 14.9. These differences were not significant. Multiple regression analysis revealed that the value of Cmax and M/Kd varied between medical centers. No other patient characteristics were found to be significant. We conclude that modeling steady-state prothrombin time response directly adequately describes pharmacodynamic response to warfarin.

Humans↗
PubMed1987

Effects of long-term running stress on the ultrastructure of the aging mouse heart.

Apical regions of the left ventricular myocardium of female C57BL/6J mice, aged between 6 and 27 months, that had been subjected to endurance running for 2, 10 or 15 months, were examined by light and electron microscopy. Focal degenerative changes were found in myocytes of these experimental mice, including loss of myofibrils, erosion of myocytes and changes in nuclei, lipofuscin content and mitochondria. The interstitial connective tissue showed an increase in collagen in aged myocardia. Endurance-trained runners frequently showed signs of platelet aggregation or microthrombi in small capillaries associated with myocytes. These were most common in endurance-trained middle-aged and very elderly mice, but were not found in sedentary age-matched controls. Our experiments indicate that running stress may be damaging to cardiac tissue in aged animals. Our findings may be of significance in helping the understanding of the development and the etiology of stress-induced cardiovascular damage in the elderly.

Aging↗
PubMed1987

Giant mitochondria in the myocardium of aging and endurance-trained mice.

During the course of an ultrastructural study on the apex region of the left ventricular myocardium of experimental female C57BL/6J mice, aged between 6 and 27 months, and that had been subjected to long-term daily enforced endurance running schedules, we encountered some instances of unusual giant mitochondria. These mitochondria showed degenerative changes including the disruption, disorganization and loss of cristae and the development of a very electron-lucent matrix. In many instances, these giant mitochondria showed dense inclusions within the matrix. The giant mitochondria appear to have developed as a result of fusion between adjacent hypertrophic mitochondria followed by a sequence of progressive degenerative changes. These giant mitochondria were most common in the myocardium of mice that had followed endurance training schedules for 10 or 15 months and were not encountered in age-matched nonrunning control mice.

Aging↗
PubMed1987

Endocytosis of proteins by salivary gland duct cells.

The ability of the intralobular duct cells of the rat parotid gland to take up protein from the lumen was examined by retrograde infusion of exogenous proteins and by immunogold localization of endogenous secretory proteins. Small amounts of native horseradish peroxidase (HRP) were taken up by intercalated and striated duct cells, and were present in small vesicles, multivesicular bodies, and lysosomes. In contrast, HRP modified by periodate oxidation was avidly internalized by the duct cells and was present in large apical vacuoles that acquired lysosomal hydrolase activity. Native and cationized ferritin were taken up in a similar manner when infused at a high concentration (up to 10 mg/mL). At lower concentrations (0.3-1.0 mg/mL), endocytosis of cationized ferritin occurred mainly in small apical tubules and vesicles in striated duct cells. Little native ferritin was taken up at these concentrations. After stimulation of acinar cell secretion by isoproterenol, similar vacuoles were occasionally observed in both intercalated and striated duct cells. Labeling of thin sections with antibodies to amylase and to a 26,000-dalton secretory protein (protein B1), followed by protein A-gold, revealed the presence of these proteins in the vacuoles, indicating endocytosis of acinar secretory proteins by the duct cells. Although uptake of acinar proteins by duct cells occurs at a low rate in normal animals, previous work suggests that extensive endocytosis may occur in certain pathological conditions. This may be a mechanism for removing abnormal or modified proteins from saliva before it reaches the oral cavity.

Animals↗
PubMed1986

1-Naphthylisothiocyanate-induced permeability of hepatic tight junctions to proteins.

We have studied the early action of 1-naphthylisothiocyanate (ANIT) in relation to its effect on the permeability barrier formed by hepatic tight junctions. Materials having different Mr values [inulin (5000), horseradish peroxidase (HRP) (40,000), ovalbumin (also 40,000) and pig gamma-globulin (IgG) (160,000)] were individually pulsed, within 1 min, into perfused rat livers operating under single-pass conditions. In untreated rats, a small peak of HRP and ovalbumin and a comparatively larger peak of inulin were observed in the bile at 7 min. In rats treated with ANIT, with increasing duration of ANIT treatment the inulin peak increased proportionally, whereas the HRP and ovalbumin peaks remained unchanged until after 10 h of ANIT exposure; gamma-globulin was not detected in the 7 min bile sample until after 14 h of ANIT treatment. Bile flow in all rats remained approximately the same until after 14 h of ANIT pretreatment, when substantial bile-flow reduction was observed. Phenobarbitone pretreatment increased the effect of ANIT and massively elevated the first HRP peak; it also shortened the time (to 4 h) at which the increase in permeability to this protein was observed. In contrast, the first HRP peak was virtually abolished in rats that had received the mixed-function-oxidase inhibitor SKF 525A. These experiments suggest that (i) ANIT progressively increased the permeability of the junctional barrier before the reduction in bile flow, (ii) the ANIT-increased permeability change seems to be inversely dependent upon the Mr of the infused proteins, and (iii) metabolites of ANIT were involved in the development of the junctional permeability change.

1-Naphthylisothiocyanate↗
PubMed1986

Selective biliary lipid secretion at low bile-salt-output rates in the isolated perfused rat liver. Effects of phalloidin.

At high bile-salt-secretion rates the biliary secretion of phospholipids and cholesterol is dependent on that of the bile salts. However, at low bile-salt outputs some secretion remains. Isolated perfused rat livers were used in these experiments in order to study the bile-salt-independent secretion of biliary lipids. The livers were isolated and saline (0.9% NaCl), or phalloidin dissolved in saline, was added to the perfusion fluid after 1 h of liver isolation. The concentration and output of cholesterol was significantly decreased in phalloidin-treated livers compared with the controls, whereas there was no significant decrease in phospholipids; the secretion of cholesterol and phospholipids can thus be uncoupled from each other by the action of phalloidin. These experiments suggest that a proportion of cholesterol gets into bile independently of bile salts and phospholipids. These findings are discussed in relation to the supersaturation of some biles with cholesterol and its relationship to the bile-salt-independent fraction of cholesterol.

Animals↗
PubMed1986

Control of biliary phospholipid secretion. Effect of continuous and discontinuous infusion of taurocholate on biliary phospholipid secretion.

A major determinant of biliary lipid secretion is bile-salt secretion. Taurocholate (TC), a micelle-forming bile salt, was infused continuously at different rates in both isolated perfused livers and biliary-fistula rats. In both of these systems, infusion of TC brought about an elevated secretion of phosphatidylcholine for the duration of the TC infusion period. Initial phospholipid/bile-salt ratios in the bile were higher in the whole-animal model than in isolated livers, but at the higher infusion rates both secreted approx. 6 mol of phospholipid for every 100 mol of bile salt. The secretion of phospholipid, which was maintained even at high rates of bile-salt infusion, suggest a continuous and regulated phospholipid supply and secretion mechanism. In contrast, however, multiple short pulses of TC to the perfused liver, which brought about relatively equal biliary bile-salt output pulses, did not bring about equal phospholipid outputs, since the phospholipid peak size declined with each bile-salt pulse. These experiments taken together suggest either that a threshold (intracellular) bile-salt concentration may be required to 'switch-on' the phospholipid supply and that it may need to be maintained for continuous biliary phospholipid supply to the canalicular membrane.

Animals↗
PubMed1986

Does stem cell self renewal and progenitor cell commitment operate through an effector-memory cell mechanism?

We propose a model for stem cell self renewal and transition into commitment towards a variety of cell lineages. In this model the production of both "effector cells" (as represented by the mature cells in the different cell lineages) and of progenitor "memory" lymphocytes, takes place concomitantly. The experimental evidence supporting this model is as follows: Pure lymphocytic suspensions (PLS) are established and persist in culture when nude mouse-spleen and lymph-node cells are maintained on X-irradiated fibroblast monolayers in the presence of the S-phase cytotoxic agent cytosine arabinoside (Ara-C). From these PLS the following colony types can be initiated by the corresponding inducing (stimulating) factors (CSF): histiocytes (tissue macrophages) - CSF-1; granulocytes-macrophages (GM) - CSF-GM; mast cells - MMSF; granular-NK mucus secreting cells - IL-2; and multilineage colonies - IL-3. Mitotically active blast cells (formed by transformation of lymphocytes), condense into motile small cells when the stimulatory factor is removed. These "memory" lymphocytes are committed as they carry the receptors for the specific CSF; they respond by retransformation into blast cells. A dramatic increase in mast-cell colony forming cells is found in bone marrow, spleen and lymph-nodes of mice infected with Schistosoma mansoni. By maintaining PLS with both Ara-C and each of the CSFs and then titrating the incidence of CFC in the residual PLS, we find that each one of the CSFs acts on an independent set of cells in the PLS to produce the corresponding colony type. Finally, the concept suggests that the various blast cells carrying the receptors, undergo condensation into memory lymphocytes when dissociated from the environment prevailed by the corresponding CSF. In this way pluripotential blast-cells condense into motile lymphocytes which are committed to pluripotentiality.

Animals↗
PubMed1986

Phospholipid degradation in, and protein content of, rat fistula bile. Contamination of bile with pancreatic juice.

The extent to which pancreatic juice can contaminate bile collected from a rat with a biliary fistula has been investigated by cannulating the bile duct proximal to either the duodenum or the liver, and by stimulating pancreatic flow with secretin. Bile collected via a fistula proximal to the duodenum showed marked pancreatic contamination. Thus, bile collected via a fistula proximal to the duodenum has a higher flow rate, a greater total protein and amylase content and a different polypeptide profile than bile collected via a fistula proximal to the liver. The phospholipid content also differed in that phosphatidylcholine was converted enzymically to lysophosphatidylcholine. Secretin increased bile flow and the biliary output of total protein and amylase when the fistula was proximal to the duodenum, but had no effect upon these parameters when the fistula was proximal to the liver, or in the isolated perfused rat liver.

Amylases↗
PubMed1985

Transcytosis and paracellular movements of horseradish peroxidase across liver parenchymal tissue from blood to bile. Effects of alpha-naphthylisothiocyanate and colchicine.

The pathways for the entry of horseradish peroxidase (HRP) into bile have been investigated using the isolated perfused rat liver operating under one-pass conditions. Following a 1 min one-pass infusion of HRP, two peaks of HRP activity were noted in the bile. The first, at 5-7 min post-infusion, correlated with the biliary secretion of the [3H]methoxyinulin which was infused simultaneously with the HRP. The second peak of HRP activity occurred at 20-25 min, and correlated with the biliary secretion of 125I-IgA, which was also infused simultaneously with the HRP. If the isolated livers were perfused with a medium containing 2.5 microM-colchicine, the biliary secretion of IgA and the second secretion peak of HRP were inhibited by 60%. If rats were pretreated for 12h with alpha-naphthylisothiocyanate (25mg/100g body wt.) prior to liver isolation, the biliary secretion of [3H]methoxyinulin and the first secretion peak of HRP were increased. Taken together, these results suggest that HRP enters the bile via two routes. The faster route, which was increased by alpha-naphthylisothiocyanate and correlated with [3H]methoxyinulin entry into bile, was probably paracellular, involving diffusion across tight junctions. The slower route, which was inhibited by colchicine and correlated with the secretion of IgA, was probably due to transcytosis, possibly within IgA and other transport vesicles.

1-Naphthylisothiocyanate↗
PubMed1985

Infectious and bleeding complications in patients with glycogenosis Ib.

Clinical, hematologic, and immunologic findings were reviewed in 21 patients with glycogenosis Ib. Fifteen of the patients suffered from moderate to severe bacterial infections. Ten patients had excessive epistaxis or bleeding from surgical sites, and eight suffered oral and anal mucosal ulceration. Sixteen of 21 patients exhibited chronic neutropenia associated with abnormalities in myeloid maturation and decreases in the bone marrow storage and peripheral marginating pools. Diminished neutrophil motility was documented in 14 of 15 patients tested, and adherence was decreased in three patients studied. Neutrophil microbicidal activity, reduction of nitroblue tetrazolium, and ingestion were normal in all patients tested. Bleeding times were prolonged in five of eight patients, and results of platelet function studies were abnormal in five individuals. Excessive bleeding in patients with glycogenoses Ia and Ib are similar and may be secondary to the functional deficiency of glucose-6-phosphatase. However, neutropenia, neutrophil dysfunction, and the resulting infectious complications are specific for Ib disease and may be related to abnormal glucose-6-phosphate transport.

Adolescent↗
PubMed1985

Mitoxantrone as first-line chemotherapy in advanced breast cancer: results of a collaborative European study.

Mitoxantrone (Novantrone; dihydroxyanthracenedione) is a substituted anthraquinone with a spectrum of activity similar to doxorubicin in experimental tumors. One hundred and seventy three patients with advanced breast cancer and no prior cytotoxic therapy for advanced disease entered a phase II study of mitoxantrone, 14 mg/m2 i.v. repeated every 3 weeks. At the time of this analysis 116 patients were evaluable. Eight patients achieved a complete response and 27 a partial response, the overall response rate being 30% (95% confidence limits: 22-39%). The median time until response was recorded was 15 weeks. The median duration of response was 74+ weeks and the median time to progression or death for all 116 patients was 22+ weeks. Mitoxantrone was well tolerated with myelosuppression as the dose-limiting toxicity. The most frequent non-haematological toxicities were nausea and vomiting (65%) but they were rarely severe. Total alopecia occurred in only 6% of the patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174-256 mg/m2. Thus, mitoxantrone offers comparable efficacy and less acute toxicity than the most active single agents currently available in the treatment of advanced breast cancer.

Adult↗
PubMed1985

Granular natural-killer cells develop into mucus-secreting cells.

Colonies of granular natural-killer cells selectively develop in lymph-node cell cultures of nude mice after stimulation with rat T-cell growth factor. When these cells are grown on X-irradiated monolayers prepared from 16-18-day-old mouse embryos, they are triggered to synthesize and secrete a sulphated glycoprotein that can be identified as mucus. As a result of an erosive process of the granules, the mucoid material accumulates in pools in the cytoplasm matrix. The secretion is operated through a process of budding of double-membrane-bound vesicles. The successful triggering of mucous synthesis is interpreted by the successful growth of those mesenchymal cells in the embryonic monolayer that function in the induction of epithelial morphogenesis in the developing embryo.

Animals↗