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Biomedical subjects

D A Clark

Publications and source records attributed to D A Clark.

At least 217 records · Page 12Linked to original sources
PubMed1992

Granulocyte-macrophage colony-stimulating factor with dose-intensified treatment of cancer.

GM-CSF decreases the hematopoietic toxicity of both nonablative and marrow ablative intensive chemotherapy regimens. Data are limited at this time, particularly in regard to optimal schedules and GM-CSF dosing regimens with particular chemotherapy programs. The importance of GM-CSF scheduling in relationship to chemotherapy is becoming more clear. The dose-intensive regimens supported by GM-CSF produce a high complete remission rate in several types of malignancy. Evidence that these remissions will be durable is still lacking. Future directions will include filling some of these voids in our knowledge, as well as exploring various cytokine combinations for improved hematopoietic recovery and other chemotherapeutic regimens for improved antitumor effect. The near complete cytoreduction produced by these dose-intensive regimens may also create a better setting for attempts at therapeutic immunomodulation. Yet another, but more difficult, task will be to identify those situations where progenitor cell replacement is beneficial and appropriate.

Adult↗
PubMed1991

Cardiac catheterization 1990: a report of the Registry of the Society for Cardiac Angiography and Interventions (SCA&I).

This report presents the first year's experience of a totally computerized cardiac catheterization laboratory reporting system, including the results and complications of invasive and interventional procedures. Sixty-three laboratories reported a total of 71,916 patients studied between January 1 through December 31, 1990. Two previous registry reports have been published. Compared with data acquired by previous methods, in spite of an older and sicker population, the mortality for diagnostic procedures has remained remarkably constant (0.11%). The computerized format facilitates data collection and analysis, helps resolve new issues as they arise and serves as a method of monitoring quality of laboratories and individuals.

Adult↗
PubMed1991

Generation of lymphokine-activated killer cells in human ovarian carcinoma ascitic fluid: identification of transforming growth factor-beta as a suppressive factor.

The effect of cell-free ascitic fluid from patients with epithelial ovarian carcinoma on the generation of lymphokine-activated killer cells (LAK) was compared to the activity generated in control medium containing 10% fetal bovine serum, using Daudi target cells. Samples of ascitic fluid from nine different patients tested inhibited LAK generation. Suppressive activity was evident as early as 24 h of incubation in the presence of ascitic fluid and increasing suppression developed with prolonged exposure. Suppression was concentration-dependent, present at 10%-20% and increasing with concentrations up to 80%. The suppressive effect of ascitic fluid was only partially reversed on increasing the concentration of interleukin-2 (IL-2) from 10 units to 1000 units/ml. Activated LAK appeared to maintain the majority of their activity on further culture in ascitic fluid in the presence of IL-2 but further enhancement of lytic activity was prevented. Fractionation of a suppressive sample by HPLC, using 0.1 M KCl/acetic acid buffer pH 2.6, revealed that the dominant peak of suppressive activity eluted at 25 kDa; with pH 7.0 TRIS-buffered saline, most of the activity was lost on the column. Antibody neutralization studies of the 25-kDa suppressive peak as well as on whole ascitic fluid have revealed that transforming growth factor beta (TGF beta) is the major suppressive factor present in ascitic fluid. Factors that suppress LAK generation in vitro were present in all samples tested. The effect on the lytic activity of activated LAK cells was minimal. This suggests that, in the clinical setting, the greatest impact would be achieved by activating LAK cells ex vivo and subsequently transferring them to the peritoneal cavity in the presence of IL-2 rather than by attempting to generate them in situ by injecting IL-2 into the peritoneal cavity. However, reversal of TGF beta-mediated suppression in situ may be necessary to allow local proliferation of LAK cells to achieve an effective killer-to-target ratio.

Ascitic Fluid↗
PubMed1991

Histamine is a transient marker of small intestinal injury induced by luminal acetic acid and casein.

We compared the time course of histamine release with other markers of intestinal injury in a rabbit model of necrotizing enterocolitis. Injury was induced by luminal acetic acid (200 mM) and casein (10 mg/ml) and experiments terminated after 45 min or 3 hr. Compared to saline controls there was a significant elevation of epithelial permeability (51Cr-EDTA clearance) and luminal protein levels at both time points. Luminal fluid histamine levels were approximately 120-fold greater than saline controls at 45 min but were indistinguishable from control values at 3 hr. We conclude that although mast cell activation is a characteristic of this model, elevations in histamine levels are transient.

Acetates↗
PubMed1991

Misoprostol attenuates acetic acid-induced damage in rabbit distal small intestine.

The influence of misoprostol pretreatment (100 micrograms/loop intraluminally) on small intestinal damage induced by acetic acid was evaluated in anesthetized rabbits. In this model injury was induced by intraluminal administration into loops of distal small intestine, of a solution of calcium gluconate (50 mg/ml) and acetic (200 mM). After 3 hr damage was associated with increase in loop fluid volume, loop fluid protein levels and epithelial permeability to 51Cr-EDTA, all of which were attenuated by misoprostol pretreatment. Similar protective effects were noted 45 min after the insult, suggesting that misoprostol may be therapeutically useful in conditions where the epithelial barrier is compromised.

Acetates↗
PubMed1991

Factors determining the ability of cytokine-activated killer cells to lyse human ovarian carcinoma targets.

Lysis of human ovarian carcinoma cells by natural killer (NK) cells, interferon-alpha activated NK cells (alpha-NK) and lymphokine-activated killers cells (LAK) was studied using both fresh tumor cells and a cell line (HEY) as targets. A clonogenic assay to measure cell kill was more sensitive than a 4-h 51Cr release assay. Both assays showed that single cells were more effectively lysed than were tumor clumps (spheroids). Freshly isolated tumor cells studied in the 51Cr release assay appeared equally susceptible to lysis by LAK cells whether in the form of clumps or single cells, but NK and alpha-NK effectors appeared much less effective in lysing susceptible target cells when they were in clumps. Tumor cells from some patients showed marked resistance to lysis by NK and alpha-NK cells in fractions enriched for clonogenic cells, even when tested in a single cell-suspension, whereas LAK cells were always cytolytic. These data suggest that intrinsic resistance of ovarian carcinoma to lysis by LAKs is unlikely to explain failure of LAK + IL-2 therapy to eradicate tumor in vivo.

Carcinoma↗
PubMed1991

Acute intestinal injury induced by acetic acid and casein: prevention by intraluminal misoprostol.

Acute injury was established in anesthetized rabbits by intraluminal administration of acetic acid with and without bovine casein, into loops of distal small intestine. Damage was quantified after 45 minutes by the blood-to-lumen movement of 51Cr-labeled ethylenediaminetetraacetic acid (EDTA) and fluorescein isothiocyanate-tagged bovine serum albumin as well as luminal fluid histamine levels. The amount of titratable acetic acid used to lower the pH of the treatment solutions to pH 4.0 was increased by the addition of calcium gluconate. Luminal acetic acid caused a 19-fold increase in 51Cr-EDTA accumulation over saline controls; casein did not modify this effect. In saline controls, loop fluid histamine levels bordered on the limits of detection (1 ng/g) but were elevated 19-fold by acetic acid exposure and markedly increased (118-fold) by the combination of acid and casein. Intraluminal misoprostol (3 or 30 micrograms/mL), administered 30 minutes before acetic acid, significantly attenuated the increase in epithelial permeability (luminal 51Cr-EDTA, fluorescein isothiocyanate-bovine serum albumin accumulation) and histamine release (P less than 0.05). Diphenhydramine, alone or in combination with cimetidine, and indomethacin (5 mg/kg IV) were not protective. It is concluded that exposure of the epithelium to acetic acid promotes the transepithelial movement of casein leading to enhanced mast cell activation and mucosal injury. Damage to the epithelial barrier can be prevented by misoprostol.

Acetates↗
PubMed1991

The detection of spermine and spermidine in human in vitro fertilization supernatants and their relation to early embryo-associated suppressor activity.

Suppressor activity in human IVF supernatants is dependent on the activity of monoamine oxidase present in nonheat-treated FBS and is therefore likely a polyamine. Pooled suppressive growth phase IVF supernatants were concentrated and subjected to HPLC fractionation. The inhibitory peak in the 1,000 to 2,000 d range was neutralized by antibody reactive with spermine and spermidine, and the presence of both polyamines was confirmed by TLC and by ELISA. These data suggest that IVF supernatant polyamines (spermine and spermidine) are responsible for the early embryo-associated suppressor activity correlating with pregnancy success.

Chromatography, High Pressure Liquid↗
PubMed1991

Macrophages and migratory cells in endometrium relevant to implantation.

The implantation of an appropriately developed embryo into a suitably conditioned uterine lining depends on the synchronous maturation of the preimplantation embryo and uterine lining. The pre- and postimplantation embryo also requires protection from immunocompetent maternal immune effectors. Preimplantation embryo development is affected by genotype, intercellular communication and autocrine growth factors (polyamines, TGF-alpha, TGF-beta 1, PAF). Factors of maternal origin may also enhance embryo development (EGF, TGF-alpha, TGF-beta 1, IGF, polyamines). The preimplantation embryo signals its presence to the mother by release of factor(s) such as IFN-alpha-II and a PAF-like factor. PAF may induce EPF in the mother and enhances vascular permeability at the implantation site. Uterine or peritoneal leukocytosis may inhibit development via toxic effects of lymphokines/monokines (IL-2, IL-1?, IFN-gamma, TNF-alpha). Immunoprotection of the preimplantation embryo is conferred by embryo derived maternal factors (EPF, T-cell suppressor factors). The uterus is receptive during a limited period of time (implantation window) and the substrate adhesion molecules produced by uterine and embryonic trophectoderm cells are crucial for the initial stages of implantation. At implantation, trophoblast expression of MHC and non-MHC antigens is shut off and both immunocompetent maternal cells (macrophages, dendritic cells, granulocytes, IELs, immunocytes) and lymphatics become sparse at implantation sites. Peri-implantation cytokines of maternal origin, such as CSF-1, GM-CSF and IGF-1 binding protein, are probably important for trophoblast growth and development. Immuno-protection of the embryo at this stage may be mediated by embryo derived factors that inactivate macrophages and by a population of large, hormone dependent Lyt 2+ (CD8+) suppressor cells. It is possible that these CD8+ cells respond to progesterone and secrete molecules that inactivate natural effector (NK-type) cells against trophoblast. Prostaglandins (PGE2) may play a brief role in immunosuppression at the time of implantation but its role is probably more important with respect to the decidual response. Defects in the pre- and peri-implantation stages of pregnancy may lead to delayed failure in the form of clinical miscarriage.

Animals↗
PubMed1991

Substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones as hypoglycemic agents.

A series of dihydrobenzofuran and dihydrobenzopyran thiazolidine-2,4-diones (compounds 3-26) was synthesized from the corresponding aryl aldehydes 1 in two steps. These compounds represent conformationally restricted analogues of the novel hypoglycemic ciglitazone. The series was evaluated by hypoglycemic effects in vitro by measuring stimulation of 2-deoxyglucose uptake in L6 myocytes and stimulation of expression of the glucose transporter protein in 3T3-L1 adipocytes. In vivo hypoglycemic effects were evaluated in the genetically obese ob/ob mouse, and structure-activity relationships are discussed. On the basis of this in vivo potency, we have selected the 2(R)-benzylbenzopyran derivative to be further studied in a clinical setting.

Adipose Tissue↗
PubMed1991

Benzyloxazolidine-2,4-diones as potent hypoglycemic agents.

A series of benzyloxazolidine-2,4-diones, containing oxazole-based side chains, were found to lower blood glucose levels in the genetically obese ob/ob mouse. Incorporation of a benzofuran structural element in these compounds provides greatly enhanced in vivo potency. The syntheses and structure-activity relationships for this series are detailed.

Animals↗
PubMed1991

Protein topology prediction through constraint-based search and the evaluation of topological folding rules.

An algorithm for predicting protein alpha/beta-sheet topologies from secondary structure and topological folding rules (constraints) has been developed and implemented in Prolog. This algorithm (CBS1) is based on constraint satisfaction and employs forward pruned breadth-first search and rotational invariance. CBS1 showed a 37-fold increase in efficiency over an exhaustive generate and test algorithm giving the same solution for a typical sheet of five strands whose topology was predicted from secondary structure with four topological folding constraints. Prolog specifications of a range of putative protein folding rules were then used to (i) replicate published protein topology predictions and (ii) validate these rules against known protein structures of nucleotide-binding domains. This demonstrated that (i) manual techniques for topology prediction can lead to non-exhaustive search and (ii) most of these protein folding principles were violated by specific proteins. Various extensions to the algorithm are discussed.

Algorithms↗
PubMed1991

Exaggerated intestinal histamine release by casein and casein hydrolysate but not whey hydrolysate.

Loops of rabbit distal small intestine received luminal acetic acid (pH 4.0) alone or in combination with bovine casein, casein hydrolysate, or whey hydrolysate. Blood-to-lumen movement of 51Cr-labeled ethylenediaminetetraacetic acid (EDTA) (an index of epithelial permeability) and loop fluid histamine levels were quantified after 45 min. Luminal acetic acid caused a marked increase in 51Cr-EDTA accumulation which was not modified by the addition of bovine casein or hydrolysates by of casein or whey. However, acetic acid-induced histamine release was potentiated by casein and casein hydrolysate (six- and four-fold respectively) but was not altered by whey hydrolysate. Casein hydrolysate-dependent histamine release was evident in naloxone-pretreated rabbits, suggesting that beta-casomorphins were not solely responsible. We conclude that luminal casein or casein hydrolysate, but not whey hydrolysate. can activate intestinal mast cells under conditions of enhanced epithelial permeability. This effect appears to involve components other than beta-casomorphins.

Caseins↗
PubMed1991

Potential role of histamine monochloramine in a rabbit model of ileitis.

Histamine chloramines, derived from the chlorination of histamine by granulocyte-derived oxidants, are potential mediators of intestinal injury and dysfunction in states of atopy or inflammation. We assessed the ability of histamine monochloramine to increase epithelial permeability in rabbit distal small intestine and determined whether the conditions for histamine chloramine formation are favorable in a rabbit model of ileitis. Epithelial permeability, quantified by the blood-to-lumen clearance of 51Cr-labeled ethylenediaminetetraacetic acid, was enhanced by luminal perfusion with either histamine or histamine monochloramine (10 microM), although the latter was twice as effective (p less than 0.05). In a rabbit model of ileitis induced by a luminal solution of acetic acid (200 mM) and casein (10 mg/ml) there was a marked increase in epithelial permeability and in the release into the lumen of histamine, myeloperoxidase, 6-keto-prostaglandin F1 alpha and protein. These results suggest that the conditions are favorable for histamine chloramine formation and that histamine and histamine chloramine may impair the integrity of the epithelial barrier.

Acute Disease↗
PubMed1991

Metabolism of a new thiazolidinedione hypoglycemic agent CP-68,722 in rat: metabolite identification by gas chromatography mass spectrometry.

1. After i.v. administration to rat of CP-68,722, a new thiazolidinedione antidiabetic drug, four metabolites were excreted in bile, as glucuronide conjugates. 2. Incubation of the drug with a rat liver microsomal preparation yielded the four in vivo metabolite aglycones and several additional in vitro metabolites. 3. Seven in vivo-generated metabolites were isolated by h.p.l.c. Each metabolite was converted to stable isotope labelled or non-labelled derivatives. Capillary g.l.c.-mass spectrometric analysis of the derivatives indicated that five metabolites result from hydroxylation and one from oxidation to the chromanone. The sites of metabolism were deduced from the electron ionization spectra. 4. Authentic standards for five metabolites were synthesized. Agreements of mass spectra and chromatographic retention times confirmed the five proposed structures. Two metabolites, detected only in vivo, await structure confirmation.

Animals↗