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Biomedical subjects

S Cooper

Publications and source records attributed to S Cooper.

At least 181 records · Page 10Linked to original sources
PubMed1994

Myelosuppressive effects in vivo with very low dosages of monomeric recombinant murine macrophage inflammatory protein-1 alpha.

Macrophage inflammatory protein (MIP)-1 alpha has myelosuppressive/myeloprotective effects in vivo in mice. We recently reported that > 99.7% of recombinant murine (rm) MIP-1 alpha polymerizes rapidly at relatively high concentrations in physiological salt solution, and it is the monomeric form of MIP-1 alpha that is active in vitro as a myelosuppressive factor. Polymerized MIP-1 alpha is inactive in this effect and does not block the myelosuppressive action of monomeric MIP-1 alpha. MIP-1 alpha could be maintained in monomeric form in physiological saline if diluted to low concentrations. This led us to reevaluate the actual amounts of MIP-1 alpha necessary for myelosuppression in vivo. C3H/HeJ mice were injected intravenously (i.v.) with monomeric rmMIP-1 alpha or control diluent and effects were evaluated on progenitor cells--multipotent colony-forming units (CFU-GEMM), burst-forming units-erythroid (BFU-E), and colony-forming units-granulocyte/macrophage (CFU-GM)--as described in previous studies in which MIP-1 alpha concentrations were used that we now know to have been mainly in polymerized form. Monomeric MIP-1 alpha rapidly decreased cycling rates and absolute numbers of myeloid progenitor cells in marrow and spleen. These effects, which occurred with about 1000-fold less MIP-1 alpha than we previously reported, were dose-dependent, time-related, and reversible. Suppressive effects were noted within 3 hours for cell cycling and within 24 hours for absolute numbers of progenitor cells in marrow and spleen and were lost by 48 hours. Decreased circulating neutrophils were noted at 48 hours. Column-separated polymerized rmMIP-1 alpha was inactive in vivo. These results demonstrate the potency of low doses of monomeric MIP-1 alpha in vivo. Since clinical administration of large amounts of an agent that is mainly in an inactive form may result in severe pharmacological side effects, the information presented here is of relevance for potential clinical trials using MIP-1 alpha as a myelosuppressive/myeloprotective agent.

Animals↗
PubMed1993

Identification and determination of the enantiomers of moprolol and their metabolites in human urine by high-performance liquid chromatography and gas chromatography-mass spectrometry.

A simple and sensitive high-performance liquid chromatographic (HPLC) method using chiral derivatization was developed to screen and determine the enantiomers of moprolol and their metabolites in human urine. The recovery of (+)- and (-)-moprolol from urine was 70.8-81.1% at different concentrations. The coefficients of variation (C.V.) were less than 3.2 and 6.5% for intra- and inter-assays, respectively. Moprolol could be detected in urine up to 24 h after oral administration of a 50-mg dose of moprolol. Unconjugated and conjugated enantiomers of moprolol and their metabolites were analyzed by gas chromatography (GC). A gas chromatographic-mass spectrometric (GC-MS) confirmatory method was established to identify the metabolites of moprolol. The double derivation procedure for moprolol and their metabolites with S-(-)-methyl chloroformate [(-)-MCF] and N-methyl(trimethylsilyl)trifluoroacetamide (MSTFA) gave very good GC-MS properties of the derivatized compounds and provided reliable structural information for their confirmation analysis. This is the first published report on the use of a GC-MS method for the detection of the enantiomers of moprolol and their metabolites in human urine.

Acetamides↗
PubMed1993

Human interferon-inducible protein 10: expression and purification of recombinant protein demonstrate inhibition of early human hematopoietic progenitors.

Human interferon-inducible protein 10 (IP-10), a member of the family of the small secreted proteins called intercrine cytokines or chemokines, is secreted by interferon gamma-stimulated T cells, monocytes, endothelial cells, and keratinocytes. We have begun to explore the biological properties of IP-10 by cloning and overexpression in baculovirus and in bacterial protein expression systems. A 9.9-kD protein was secreted by infected insect cells, which on sodium dodecyl sulfate-polyacrilamide gel electrophoresis comigrated with keratinocyte IP-10 and with f(22-98), a bacterial recombinant fragment lacking the signal sequence but containing all other residues of IP-10. All three reacted with antibodies recognizing residues 10-98 (alpha IP-10) and 77-98 of IP-10 (alpha 22), demonstrating that it is secreted by keratinocytes and insect cells after removal of the signal sequence but without proteolysis of the COOH-terminal end. Purified rIP-10 suppresses in vitro colony formation by early human bone marrow progenitor cells which need r-steel factor (rSLF) and rGM-CSF or rSLF and r-erythropoeitin (rEPO). The inhibition is dose dependent, is complete at concentrations > or = 50 ng/ml, is prevented by preincubation of rIP-10 with alpha IP-10, but not by alpha 22, and is seen with highly purified CD34+ cells, suggesting direct effect of rIP-10 on the progenitors. Combination of rIP-10 and other chemokines at inactive concentrations inhibited colony formation in a synergistic manner. rIP-10 did not affect colony formation in the absence of any growth factors or in the presence of rEPO or rGM-CSF but in absence of rSLF. The effects of IP-10 may be relevant to normal marrow function and might be harnessed to protect human hematopoietic progenitors from the cytotoxic effects of chemotherapy.

Amino Acid Sequence↗
PubMed1993

Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression.

Macrophage inflammatory protein (MIP)-1 alpha, part of a family termed chemokines, has been implicated in suppression of hemopoietic stem and progenitor cell proliferation. The chemokine family has been organized into two subgroups with MIP-1 alpha, MIP-1 beta, macrophage chemotactic and activating factor (MCAF) and RANTES belonging to one subgroup, and GRO-alpha, MIP-2 alpha (GRO-beta), MIP-2 beta (GRO-gamma), platelet factor 4 (PF4), IL-8, and neutrophil activating peptide (NAP)-2 belonging to the other. These molecules were evaluated for effects on colony formation by human bone marrow multipotential (CFU-GEMM), erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells. None of the chemokines stimulated colony formation in the absence of CSF, or influenced colony formation stimulated by a single growth factor such as granulocyte-macrophage-CSF or erythropoietin. However, MIP-1 alpha, MIP-2 alpha, PF4, IL-8, and MCAF suppressed in dose-response fashion colony formation of immature subsets of myeloid progenitor cells stimulated by GM-CSF plus steel factor. Effects were apparent on low density and CD34 HLA-DR(+)-sorted marrow cells in which up to 88.4% of the cells were composed of progenitor cells, suggesting direct effects on the progenitors themselves. Up to 2500-fold less of each chemokine could be used to demonstrate synergistic suppression when any two of these five chemokines were used together at low concentrations, effects also apparently directly on the progenitors. In contrast, MIP-1 beta, MIP-2 beta, GRO-alpha, NAP-2, and RANTES were not suppressive nor did they synergize with MIP-1 alpha, MIP-2 alpha, PF4, IL-8, or MCAF to suppress. However, a fivefold excess of MIP-1 beta blocked the suppressive effects of MIP-1 alpha. Similarly, a fivefold excess of either MIP-2 beta or GRO-alpha blocked the suppressive effects of IL-8 and PF4. These suppressing, synergizing and blocking effects may be of relevance to blood cell regulation.

Animals↗
PubMed1993

Polymerization of murine macrophage inflammatory protein 1 alpha inactivates its myelosuppressive effects in vitro: the active form is a monomer.

Macrophage inflammatory protein (MIP) 1 alpha has myelosuppressive and myeloprotective activity. That MIP-1 alpha polymerizes is known; this phenomenon was evaluated in terms of myelosuppression by assessing the effects of recombinant murine MIP-1 alpha on colony formation of murine and human myeloid progenitor cells in vitro. The following results are reported: (i) Polymerization is diluent- and concentration-dependent. (ii) Monomeric MIP-1 alpha is the active suppressive form for myeloid progenitor cells in vitro. (iii) Polymerized MIP-1 alpha is inactive and does not interfere with suppression by monomeric MIP-1 alpha. (iv) MIP-1 alpha has approximately 1000-fold higher specific activity than has been reported, but its effects are still specific for immature subsets of myeloid progenitors. (v) Suppression is initiated during the DNA-synthesis phase of the cell cycle. We conclude that polymerization of MIP-1 alpha might be a control mechanism that limits the myelosuppressive effects of monomeric MIP-1 alpha.

Animals↗
PubMed1993

In vivo effects of recombinant interleukin-11 on myelopoiesis in mice.

Purified recombinant human interleukin-11 (rhuIL-11) was assessed for its in vivo effects on the proliferation and differentiation of hematopoietic progenitors as well as its capacity to accelerate the recovery of a drug-suppressed hematopoietic system. Dosage and time sequence studies demonstrated that administration of IL-11 to normal mice resulted in increases in absolute numbers of femoral marrow and splenic myeloid (granulocyte-macrophage colony-forming unit [CFU-GM], burst-forming unit-erythroid [BFU-E], CFU-granulocyte, erythroid, macrophage, megakaryocyte) progenitor cells and in stimulation of these progenitors to a higher cell cycling rate. This was associated with increased numbers of circulating neutrophils. Administration of IL-11 to mice pretreated with cyclophosphamide decreased the time required to regain normal levels of neutrophil and platelet counts in peripheral blood. In addition, IL-11 accelerated reconstitution to normal range of myeloid progenitors from bone marrow and spleen of myelosuppressed mice. These data suggest that IL-11 may play an important role in the regulation of hematopoiesis, and the application of this novel cytokine may have clinical therapeutic benefits.

Animals↗
PubMed1993

Lack of effect of ipriflavone on osteoclast motility and bone resorption in in vitro and ex vivo studies.

Using in vitro and ex vivo experimental procedures specifically designed to visualize pharmacological effects on parameters of bone resorption, studies were performed to elucidate whether ipriflavone's reported effect in osteoporosis is due to an effect on the motility and resorptive activity of osteoclasts, as has been shown to be the case with salmon calcitonin. Concentrations of ipriflavone used were higher by a factor of > 100 than peak blood levels measured in patients given standard therapeutic doses. Despite this, neither quantitative nor qualitative changes were observed in the motility of isolated rat osteoclasts or in their resorptive activity when incubated with bone slices. The conclusion is that ipriflavone does not possess antiosteoclastic and antiresorptive activity of the type documented for salmon calcitonin in the models employed and that further investigation of its mode of action is therefore necessary.

Animals↗
PubMed1993

Interstitial pH during myocardial preservation: assessment of five methods of myocardial preservation.

We investigated changes in myocardial pH during cardioplegic arrest with five methods of preservation at 15 degrees +/- 1 degree C. Twenty-five dogs were subjected to cardiopulmonary bypass for 150 minutes. Group I (control) had hypothermia only. Group II received THAM-buffered blood cardioplegia, group III a bicarbonate-buffered blood cardioplegic solution, group IV infusions of hyperkalemic blood, and group V oxygenated St. Thomas 2 solution. After 120 minutes of ischemia, interstitial pH in group I was markedly depressed (6.4 +/- 0.07; p < 0.01). The pH in groups II and IV was well maintained (7.23 +/- 0.05 and 7.27 +/- 0.07) and differed significantly (p < 0.05) from that of the remaining groups. The pH in groups III and V was less well maintained (7.14 +/- 0.02 and 7.01 +/- 0.05), with no significant difference (p > 0.05) between these two groups. Postreperfusion functional recovery after 45 minutes was 24% +/- 6% in group I, 92% +/- 3% in group II, 82% +/- 5% in group III, 84% +/- 4% in group IV, and 66% +/- 6% in group V. Creatine kinase levels were significantly (p < 0.01) increased and ultrastructural damage was more prominent in group I compared with the remaining groups. Myocardial water content significantly increased in all groups. We conclude that a strongly buffered blood-based cardioplegic solution is more effective in preventing interstitial acidosis during moderate hypothermia and that maintenance of an optimal tissue pH plays an important role in postischemic functional recovery.

Animals↗
PubMed1993

Single dose and multidose analgesic study of ibuprofen and meclofenamate sodium after third molar surgery.

The purpose of this study was to compare the analgesic efficacy and safety of meclofenamate sodium with ibuprofen after dental impaction surgery. This study was double-blind and used a unique methodology. Patients (N = 254) were first randomized into the single dose phase of the study that included placebo, meclofenamate 50 mg, meclofenamate 100 mg, ibuprofen 200 mg, and ibuprofen 400 mg, followed by a 7-day multidose phase in which patients in the placebo group were rerandomized into one of the active treatment cells. In the single dose phase, all active treatments were significantly more efficacious than placebo for every summary analgesic measure. A positive dose-response was seen for both active drugs with meclofenamate 100 mg and ibuprofen 400 mg exhibiting the greatest efficacy for pain relief, pain reduction, time to remedication, and overall evaluation. Side effects were reported by 26 patients. They were evenly distributed among treatment groups with headache and drowsiness being the most common. During the multidose phase, there were only small differences in efficacy measures among active treatment groups. However, meclofenamate produced a higher incidence of stomach cramps and diarrhea than did ibuprofen (8.8% and 7.2% versus 0.8% and 0.8%). This study indicates that higher doses of nonsteroidal anti-inflammatory drugs are most effective immediately after surgery and that lower doses of these drugs can be used after the first postoperative day. The side effect profile of nonsteroidal anti-inflammatory analgesics is best observed with the use of a multidose study design.

Abdominal Pain↗
PubMed1993

Peptidoglycan synthesis in Salmonella typhimurium 2616.

HPLC analysis of peptidoglycan synthesis in Salmonella typhimurium strain 2616 has revealed that: (i) there is observable variation in the composition, but no significant variation in the overall degree of cross-linking, of newly synthesized peptidoglycan during the division cycle; (ii) the types of muropeptide that constitute peptidoglycan do not vary over a wide range of growth rates; and (iii) the composition and maturation kinetics of S. typhimurium peptidoglycan are, as expected, similar to those of Escherichia coli. We propose a unitary model of peptidoglycan synthesis, with single-strand incorporation occurring at both side wall and polar sites.

Cell Division↗
PubMed1993

Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids.

Nedocromil sodium is a non-steroidal prophylactic agent developed for the management of asthma. We have assessed the steroid sparing potential of inhaled nedocromil sodium 4 mg four times daily in a randomized, double blind, placebo controlled study in 69 asthmatic subjects controlled on inhaled beclomethasone dipropionate in the dose range 1000-2000 micrograms daily. Following a 4 week run-in period subjects added nedocromil sodium or placebo by metered dose inhaler to their usual medication for a further 4 weeks. The dose of inhaled steroid was then reduced at fortnightly intervals according to a predetermined schedule, with monitoring of asthma severity, symptom scores, bronchodilator use and peak flow recordings. Sixty subjects entered the steroid reduction phase and achieved median (range) % decreases in steroid dose of 80 (17-100)% with nedocromil sodium compared to 65 (0-100)% with placebo (P = 0.34) with 14 patients in the nedocromil sodium group and 10 in the placebo group being withdrawn completely from inhaled steroids. Subjective global assessment scores were significantly better with nedocromil sodium (mean 2.14) than with placebo (2.93; P < 0.02) though there was no difference between individual daily symptom scores. In this study therefore in asthmatic patients controlled on high doses of inhaled steroids, nedocromil sodium was well tolerated but the small differences in steroid sparing effect between nedocromil and placebo were not statistically significant.

Administration, Inhalation↗
PubMed1993

An alternative to hysterectomy? GnRH analogue combined with hormone replacement therapy.

OBJECTIVE: To assess whether GnRH analogues are effective in relieving pelvic pain and congestion and whether menopausal symptoms caused by GnRH analogues can be minimised by supplementation with low dose continuous combined hormone replacement therapy (HRT). DESIGN: Open prospective study. SETTING: Tertiary referral clinic at a teaching hospital. PATIENTS: Twenty-one women with chronic pelvic pain. INTERVENTION: Four months' therapy with goserelin 3.6 mg/month combined with continuous oestradiol valerate 1 mg daily and medroxyprogesterone acetate 5 mg daily. MAIN OUTCOME MEASURES: Visual analogue scale for pain, menopausal symptoms, bleeding patterns, uterine area, endometrial status, oestradiol concentrations and venogram scores. RESULTS: Amenorrhoea was maintained in all but two women. Endometrial atrophy was maintained despite HRT supplementation. Two women had moderate menopausal symptoms but none had severe symptoms. Significant reduction of uterine cross sectional area was maintained throughout the study. There was no significant relief of pain. CONCLUSIONS: HRT supplementation of GnRH analogues abolishes menopausal symptoms and thus may improve patient acceptability. Potentially beneficial effects such as endometrial atrophy, reduction of uterine volume and amenorrhoea were not negated by HRT. This combination is not effective in the treatment of chronic pelvic pain and congestion.

Adult↗
PubMed1993

Prenatal diagnosis of hypoplastic left heart syndrome.

Over a 21-month period 200 fetal echocardiographic studies were performed on pregnancies at high risk for congenital heart disease referred to the NSW Fetal Echocardiography Service. Four cases of hypoplastic left heart syndrome were diagnosed in-utero during this period. These cases demonstrated the heterogeneity of this lesion, its known association with other defects and chromosomal anomalies, and evidence of in-utero evolution. Hypoplastic left heart syndrome is reliably diagnosed by fetal echocardiography. This lesion is heterogenous and may evolve beyond the first trimester. Careful attention to ventricular function, endocardial echoes and Doppler flow may assist with diagnosis.

Female↗
PubMed1993

Synthesis of peptidoglycan and membrane during the division cycle of rod-shaped, gram-negative bacteria.

A modified procedure for determining the pattern of peptidoglycan synthesis during the division cycle has allowed the measurement of the rate of side wall synthesis during the division cycle without the contribution due to pole formation. As predicted by a model proposing that the surface growth of the cell is regulated by mass increase, we find a decrease in side wall synthesis in the latter half of the division cycle. This supports the proposal that, upon invagination, pole growth accommodates a significant proportion of the increasing cell mass and that residual side wall growth occurs in response to the residual mass increase not accommodated by pole volume. The observed side wall synthesis patterns support the proposal that mass increase is a major, and possibly sole, regulator of bacterial surface increase. Membrane synthesis during the division cycle of the gram-negative, rod-shaped bacteria Escherichia coli and Salmonella typhimurium has also been measured with similar methods. The rate of membrane synthesis--measured by incorporation of radioactive glycerol or palmitate relative to simultaneous labeling with radioactive leucine--exhibits the same pattern as peptidoglycan synthesis. The results are compatible with a model of cell surface growth containing the following elements. (i) During the period of the division cycle prior to invagination, growth of the cell occurs predominantly in the side wall and the cell grows only in length. (ii) When invagination begins, pole growth accommodates some cytoplasmic increase, leading to a concomitant decrease in side wall synthesis. (iii) Surface synthesis increases relative to mass synthesis during the last part of the division cycle because of pole formation. It is proposed here that membrane synthesis passively follows the pattern of peptidoglycan synthesis during the division cycle.

Cell Cycle↗
PubMed1993

Cultured cell lines from human teratomas: windows into tumour growth and differentiation and early human development.

Cultured cell lines from human teratomas provide models to study molecules which might regulate tumour growth or normal embryonic development. Here, we describe efforts to delineate the role of transcription factors, extracellular matrix, and growth factors in controlling growth and differentiation of human embryonal carcinoma and yolk sac tumour.

Antigens, Differentiation↗
PubMed1993

Data collection in the Adult Day Health Care Evaluation Study.

This report presents data collection measures and methods for the evaluation of Adult Day Health Care (ADHC) in the Department of Veterans Affairs (VA). Measures of patient health were survival, the Sickness Impact Profile, self-rated health, the Mini-Mental State Exam, Psychological Distress Scale, Social Support Scale, and Problem Behaviors Scale. Measures of health for the care giver were: Activities of Daily Living, Instrumental Activities of Daily Living, health perceptions, Psychological Distress Scale, life satisfaction, Social Support Scale, and Caregiver Burden Scale. We also assessed patient and care giver satisfaction with the care received by the patient. Measures of health status and outcomes were assessed primarily through patient and care giver interview at study enrollment, 6 months, and 12 months. Utilization and cost both within and outside VA were assessed for hospital, ambulatory care, nursing home, ADHC, home care, pharmacy, laboratory, and other forms of health care. Sources of utilization data included VA's computerized patient database, VA medical records, patient questionnaires, care giver questionnaires, and health care providers outside VA. Costs were obtained from VA's cost accounting system, VA Central Office, VA's contracts with outside providers, and directly from outside providers. Utilization and cost were assessed for each patient for a period of 1 year after entry into the study.

Activities of Daily Living↗