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Biomedical subjects

D A Clark

Publications and source records attributed to D A Clark.

At least 271 records · Page 15Linked to original sources
PubMed1988

Active suppression of host-vs graft reaction in pregnant mice. IX. Soluble suppressor activity obtained from allopregnant mouse decidua that blocks the cytolytic effector response to IL-2 is related to transforming growth factor-beta.

Non-Ts cells in murine allopregnancy decidua release potent immunosuppressor factors in vitro that block the action of IL-2. Previous studies have shown that both primary and secondary CTL responses are inhibited as well as the generation of Il-2 activated killer cells. In this paper we show that the suppressor factor(s) can arrest ongoing IL-2 dependent CTL responses but does not block binding of anti-IL-2R antibody or radiolabeled IL-2 to the IL-2R. The suppressive activity is associated with molecules that adhere to hydroxylapatite and con A-agarose but do not bind to activated charcoal or partition as lipids. HPLC TSK 3000 separation showed a major peak of suppressive activity at 60 to 100 kDa, with additional activity at 300 kDa, and at less than 1000. Under acid conditions, suppressive activity resolved as a major peak at 13 kDa with some residual activity at 65 kDa and at less than or equal to 1000. A specific rabbit IgG antibody to transforming growth factor-beta neutralized suppressor activity in unseparated supernatant and in the 13-kDa fraction whereas neutralizing antibodies to progesterone or PGE-2 did not affect suppression but could neutralize their respective ligands. Inasmuch as transforming growth factor-beta has a 25 kDa Mr, the 13-kDa decidua-associated suppressor factor would appear to represent a related but distinct regulatory molecule that associates with a variety of carrier molecules.

Animals↗
PubMed1988

The balloon on a wire device: a new ultra-low-profile coronary angioplasty system/concept.

A new ultra-low-profile coronary angioplasty device, a "balloon probe," is presented. This device consists of a balloon on a coronary guidewire and is the lowest profile dilatation system presently available. The balloon material is polyethylene terephthalate, a new polymer with high inflation pressure limits and very low compliance. This report discusses this device and its usage in coronary artery disease.

Aged↗
PubMed1988

Transluminal coronary angioplasty in the treatment of silent ischemia.

Fifty-four asymptomatic patients with positive thallium exercise tests underwent coronary angiography followed by coronary angioplasty (PTCA), as the primary therapy for silent ischemia. The procedure was technically successful in 89% of these patients. Emergency bypass graft surgery was necessary in 2 (3.6%) and q-wave myocardial infarction occurred in 1 (1.8%) of these. All fifty-four patients have been followed for a mean of 35 months since angioplasty. Of the 48 patients with initially successful PTCA, 12 had either clinical restenosis (9/14 or 19%) or a new lesion (3/48 or 6%) during follow-up, which required a repeat PTCA. At the longest follow-up, 46 (85%) had been successfully treated with on or more PTCA procedures. Two patients (3.6%) had sustained late q-wave myocardial infarction and two additional patients reported angina pectoris. There were no deaths. Angioplasty as a primary therapy for silent ischemia appears efficacious, with success and restenosis rates comparable to those in the symptomatic population. Event-free survival is improved, compared with natural history data for patients with silent ischemia from other studies. Prudent risk/benefit analysis may help to define subgroups most likely to benefit from this intervention.

Adult↗
PubMed1988

A bacterial pathogenicity determinant associated with necrotizing enterocolitis.

Predominant enterobacteria from infants with necrotizing enterocolitis (NEC) were examined for an unusual ability to ferment lactose. One such isolate, a Klebsiella pneumoniae strain, was partially induced for lactose operon expression in tryptone containing media, and was also pathogenic in a rabbit ileal loop model for NEC. A spontaneous segregant of this strain was no longer partially induced for lactose operon expression, and was no longer pathogenic in the rabbit model. The gene responsible for this phenotype was cloned. The resulting plasmid was shown to cause both partially induced lactose operon expression and pathogenicity when introduced into a laboratory K. pneumoniae strain. A K. pneumoniae mutant deficient in lactose repressor synthesis was also pathogenic in the rabbit model. These results and previous studies on the intraluminal biochemistry of infants with NEC support the hypothesis that an increased ability for lactose fermentation may be a bacterial pathogenic trait with respect to NEC.

Animals↗
PubMed1988

Identification of two species of suppressive factor of differing molecular weight released by in vitro fertilized human oocytes.

Preimplantation human embryos have been shown to release factors that have immunosuppressive activity and that are highly correlated with successful implantation. The present study was undertaken to determine the molecular weight of these factors using HPLC. Two peaks of suppressive activity were found associated with molecular weights of 3.7 +/- 0.3 and 1.2 +/- 0.1 kd, respectively. The potential significance of low molecular weight immunosuppressor factors in avoiding maternal inflammatory and immunologic responses is discussed.

Blastocyst↗
PubMed1988

Human ovarian carcinoma: evidence for patient-related differences in susceptibility to cytotoxic effectors that attack different cellular subpopulations within a tumour.

Human ovarian carcinoma cells obtained from ascites were tested for susceptibility to lysis by peripheral blood NK cells, alpha-interferon-activated NK cells, and interleukin 2-activated killer cells. Cryopreserved tumour cell preparations were used to allow repeated testing of the same target, and the tumour cells were fractionated using albumin density gradients to determine if fractions containing clonogenic (stem) cells were killed. Four tumour cell donors were studied and each showed a different pattern of susceptibility of unfractionated tumour to lysis by different effector cells. Using fractionated tumour cells, we found that NK and interferon-activated NK cells did not always lyse cells in the clonogenic fractions and that interferon activation could in some cases shift killing away from the clonogenic fractions and towards the peak of proliferating (but not self-renewing) colony forming cells. Interleukin 2-activated killer cells (LAK) however, killed the fractions containing clonogenic cells in all 4 cases. The magnitude of killing seen when fractions of the original tumour were tested were often striking when compared to lysis of the unfractionated cells. Apparent heterogeneity between patients and stem cell susceptibility to effector cells may be important determinants of the efficacy of treatment of patients with biologic response modifiers such as interferon and interleukin 2.

Cell Separation↗
PubMed1988

Increased sensitivity to complement of megakaryocyte progenitors in paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is a haemolytic disorder characterized by an increased sensitivity of peripheral blood cells including platelets to the lytic action of complement (C'). Previous studies have demonstrated that in PNH bone marrow erythroid colony and burst forming units, as well as granulocytic-monocytic colony forming units, have an increased sensitivity to complement-induced injury as compared with normal erythroid and myeloid progenitors. The purpose of this study was to investigate the effect of complement on PNH and normal marrow megakaryocytic progenitors (CFU-M). Bone marrow non-adherent and T-cell depleted light density mononuclear cells from three patients with PNH and six normal volunteers were exposed to fresh or heat-inactivated AB human serum in the presence of medium or isotonic aqueous sucrose solution for 30 min at 37 degrees C. After being washed the cells were assayed for CFU-M by the plasma clot method in a complement free medium containing 6% medium conditioned by T-lymphocytes stimulated by phytohaemagglutinin. The number of megakaryocytic colonies grown from PNH marrow cells exposed to isotonic sucrose and C' was reduced to one third of those grown from PNH cells exposed to isotonic sucrose and heat-inactivated C', or to medium with and without C'. In contrast, the number of megakaryocytic colonies grown from normal marrow cells exposed to isotonic sucrose and C' was unchanged. These findings indicate that PNH marrow CFU-M express an increased sensitivity to C'-mediated injury similar to that detected on PNH-erythrocytes by the sucrose haemolysis test, and support the hypothesis that the PNH defect is expressed at the level of pluripotent haematopoietic stem cell.

Adult↗
PubMed1988

SOD prevents damage and attenuates eicosanoid release in a rabbit model of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) was produced in anesthetized rabbits by transmural injection of intestinal loops with an acidified solution of casein and calcium gluconate, mimicking the luminal milieu of afflicted neonates. Intravenous infusion of superoxide dismutase (SOD) 15 min after NEC induction prevented intestinal damage. In ex vivo perfused intestinal loops, we determined the sites of eicosanoid release and their contribution to the vascular effects of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) in damaged and SOD-salvaged intestine. The vascular effluent was the primary site of stimulated eicosanoid release. The vascular responses to fMLP (vasoconstriction) and PAF (vasodilation) were not altered by SOD, although vascular resistance was higher in the SOD group. SOD treatment attenuated 1) transmural fluid shifts in ex vivo perfused intestinal preparations, an index of vascular permeability, 2) fMLP-induced prostaglandin E2, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) release, and 3) PAF-induced release of 6-keto-PGF1 alpha and LTB4. Stimulated thromboxane B2 release was not altered by SOD. Thus NEC can be established by a luminal insult that causes local generation of free radicals and exaggerated release of prostaglandins and leukotrienes.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial.

The survival benefit of combination chemotherapy to patients with advanced non-small-cell carcinoma of the lung (NSCLC) is controversial. To study this question, the National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a prospective randomized trial comparing best supportive care (BSC) to two chemotherapy regimens, vindesine and cisplatin (VP), and cyclophosphamide, doxorubicin, and cisplatin (CAP). Between February 1983 and January 1986, 23 centers across Canada entered 251 patients on study. Eighteen centers participated in the three-arm schema (150 patients); centers choosing not to participate in a study with a no-chemotherapy arm followed a two-arm schema comparing VP with CAP (101 additional patients). Altogether, 233 patients were eligible. Patients had measurable or evaluable disease, with either distant metastases (82.5%) or bulky limited disease considered inoperable or unsuitable for radical radiotherapy. The treatment groups were comparable in terms of age, sex, performance status, histology, disease extent, and weight loss. The overall response rates (complete response [CR] plus partial response [PR]) on the chemotherapy arms were CAP, 15.3%, and VP, 25.3% (P = .06). Patients on the three-arm portion of the trial had a median survival of 32.6 weeks when treated with VP, 24.7 weeks with CAP, and 17 weeks with BSC. The significance of the differences in survival, adjusted for prognostic factors, is as follows: chemotherapy v BSC, P = .02; VP v BSC, P = .01; and CAP v BSC, P = .05. Toxicity on the chemotherapy arms was significant, with leukopenia of severe or greater degree occurring in 37.8% (CAP) and 40.0% (VP), severe vomiting in 12.2% (CAP) and 23.3% (VP), and severe neurotoxicity in 15.6% (VP).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

The West Point Study: occurrence of coronary artery disease after 34 years.

This report reviews the current status of the West Point Study and addresses the prediction of risk of coronary artery disease (CAD) based on cholesterol levels measured at various times during the study. Subjects were grouped into quintiles by their risk index score calculated from the Framingham risk equation. The number of cases of CAD among the subjects in each of the quintiles was tabulated. The cases of CAD in these quintiles increased from the lowest to the highest quintiles and produced a significant correlation between the risk score and the percent of subjects in the quintiles having CAD, even when the data used for calculating the risk scores had been collected up to 26 years earlier. The numbers of CAD cases are small; they are only approximately 50% of the expected numbers computed for U.S. males of comparable ages, despite the increases in serum cholesterol and low density lipoprotein levels recorded during the first 6 years of the study. The authors speculate about possible explanations of these findings.

Adult↗
PubMed1988

The inaccuracy of Apgar scoring.

A short Apgar quiz was prepared with eight descriptive neonatal cases. The quiz was completed by 223 health professionals caring for newborns. Pediatricians and pediatric housestaff, the most accurate scorers, assigned the correct score only 68% of the time. Nurses from community hospitals were only 24% accurate. Improper scoring limits the usefulness of the Apgar score in comparing neonates within and between hospitals.

Apgar Score↗
PubMed1988

Contribution of oxygen-derived free radicals to experimental necrotizing enterocolitis.

Oxygen-derived free radicals, particularly superoxide anion, are considered important mediators of intestinal injury induced by ischemia/reperfusion based on the protective effects of superoxide dismutase and allopurinol. A role for free radicals was investigated in a model of necrotizing enterocolitis (NEC) which was initiated by a luminal, as opposed to a vascular, insult. Intestinal loops of weanling rabbits received either saline (control loops) or a solution of 10 mg/ml casein and 50 mg/ml calcium gluconate acidified to pH 4 with proprionic acid (treated loops). When the animals were sacrificed 3 hours later, severe damage was noted in the treated loops, which included blunting of villi and edema, with all animals surviving. At 16 hours only 5 of 8 rabbits survived, and 3 had hemorrhagic necrosis. Control loops were normal in each case. Intravenous infusion of superoxide dismutase (4 mg/kg/hr), commencing 15 minutes after NEC induction, totally prevented intestinal injury. On the other hand, pretreatment with allopurinol, an inhibitor of xanthine oxidase, for 2 days (30 and 60 mg/kg by mouth) was not protective against intestinal damage. A cellular infiltration in treated loops was not histologically evident in the majority of animals at 3 hours after treatment, a finding confirmed by the minimal accumulation of 111In-labeled leukocytes in damaged and intact intestinal tissue. These results suggest that superoxide generated locally from sources other than xanthine oxidase play a critical and early role in experimental NEC and that superoxide dismutase may prove to be an effective therapy in this devastating neonatal disease.

Allopurinol↗
PubMed1987

Immunosuppressor factor(s) produced by decidua-associated suppressor cells: a proposed mechanism for fetal allograft survival.

Mechanisms that explain failure of rejection of the antigenic fetus by the mother appear to lie at the fetomaternal interface. Successful pregnancies have been correlated with the presence of decidua-associated suppressor cells. Supernatants from these cells were tested for their ability to suppress the proliferation of interleukin 2-dependent cells and were also subjected to high-performance liquid chromatography. Decidual supernatant was found to have peak suppressive activity at two molecular weights (43,000 and 21,000 daltons). The activity of decidual supernatant was directed specifically at interleukin 2-dependent cells and interfered with interleukin 2 action. The importance of this mechanism in graft rejection is well known. Decidual supernatant may thus prevent fetal allograft rejection by preventing the maternal cytotoxic effectors from receiving the interleukin 2-dependent help that they need to proliferate and remain actively cytolytic.

Animals↗