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Biomedical subjects

W Lew

Publications and source records attributed to W Lew.

At least 37 records · Page 2Linked to original sources
PubMed1998

Myelosuppressive changes from single or repeated doses of radioantibody therapy: effect of bone marrow transplantation, cytokines, and hematopoietic suppression.

Myelosuppression is the dose-limiting side effect of most forms of radioimmunotherapy (RAIT). Long-term leukopenia (4-8 weeks) has been documented from a single maximum tolerated dose (MTD) in experimental mice. Several methods for alleviating RAIT-induced marrow toxicity have been evaluated preclinically, including cytokine intervention, bone marrow transplantation (BMT), and hemoregulatory peptide administration. To improve the therapeutic potential of RAIT, multiple doses of radioantibody must be delivered. Maximizing the frequency of radioantibody administration is desirable. However, little is known about the myelotoxic effects of multiple cycles of RAIT. In the studies presented here we compared the magnitude of myelosuppression, the time of nadir, and the duration of toxicity associated with one or two MTDs of 1-131-MN-14 anti-carcinoembryonic antigen immunoglobulin G (250 microCi) administered to BALB/c mice 49 days apart, the shortest interval possible without producing lethality. Studies were conducted with radioantibody alone or with cytokines (interleukin-1/granulocyte-macrophage colony-stimulating factor), BMT, or Hp5b to determine whether bone marrow became more "brittle" after the first dose. Profiles of myelosuppression and recovery were monitored weekly for 7 weeks after each dose in both granulocyte and lymphocyte populations. The results demonstrated that granulocyte suppression was greater and of longer duration after the second dose of RAIT administered alone, with cytokines, or with BMT, but less severe with Hp5b. For example, in the RAIT + BMT treatment, the second dose resulted in an 87% loss of granulocytes, whereas a 30% loss occurred after the first dose. The nadir of toxicity lasted until days 21 to 28 after the second dose and until day 14 after the first dose. Lymphocyte suppression was of greater duration after the second cycle of RAIT alone or RAIT with BMT, plateauing at <50% of untreated levels between days 28 and 49, but was of shorter duration when RAIT was given with cytokines or Hp5b. The results are discussed in terms of 1) the radiosensitivity of each subpopulation, 2) the effects on progenitors and on stromal cells, 3) the benefits of increasing dose frequency vs. increasing dose intensity, and 4) the possibility of using preclinical data to optimize the frequency of dosing in patient trials.

Agranulocytosis↗
PubMed1997

Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity.

The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described. The double bond position in the carbocyclic analogues plays an important role in NA inhibition as demonstrated by the antiviral activity of 8 (IC50 = 6.3 microM) vs 9 (IC50 > 200 microM). Structure-activity studies of a series of carbocyclic analogues 6a-i identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position with an IC50 value of 1 nM for NA inhibition. The X-ray crystallographic structure of 6h bound to NA revealed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. The high antiviral potency observed for 6h appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 6 starting from (-)-quinic acid is also described.

Acetamides↗
PubMed1995

Opposing effects of ultraviolet B irradiation on interleukin-1 receptor antagonist and interleukin-1 alpha messenger RNA expression in a human epidermoid carcinoma cell line.

Interleukin-1 receptor antagonist (IL-1RA) is a cytokine that acts to antagonize IL-1 activity without agonist function. The expression of IL-1RA has been reported in many cell types, including the keratinocyte that covers the outer most part of the skin. However the modulation of IL-1RA by ultraviolet B (UVB), which is the most biologically active UV, has not been reported yet. We therefore selected a keratinocyte cell line with a cytokine-producing profile similar to that of keratinocytes and tested the effect of UVB on its ability to produce IL-1RA mRNA. IL-1RA mRNA was constitutively expressed in the cell line and began to be suppressed by 3 h after the UVB irradiation with 100 mJ/cm2. The level of IL-1RA expression became lowest by 16 h after the irradiation with 100 mJ/cm2. Simultaneously, IL-1 alpha mRNA started to increase by 1 h and peaked by 3-16 h after the irradiation with 10-100 mJ/cm2. The differential expression of IL-1 alpha and IL-1RA mRNA following exposure to a high dose (100 mJ/cm2) of UVB may markedly potentiate the role of IL-1 in UV-induced inflammation.

Blotting, Southern↗
PubMed1992

Production and characterization of monoclonal antibodies to Treponema pallidum.

This study was attempted to produce the monoclonal antibodies specific for Treponema pallidum and to investigate their characteristics, thereby contributing to identify the antigenic structure and to apply the diagnosis of syphilis. The seven clones (YS 3, YS 75, YS 307, YS 481, YS 343, YS 1 and YS 406) secreting monoclonal antibodies reactive with T. pallidum were produced. The isotypes of the seven monoclonal antibodies produced were defined. Optical densities of the 7 monoclonal antibodies were ranged from 0.59 to 1.48 as measured by ELISA. Monoclonal antibodies from 5 of the 7 clones which could agglutinate sheep RBC sensitized with T. pallidum, showed strong fluorescences. The monoclonal antibody from YS 343 was cross-reactive with non-pathogenic treponemes, but the other 6 monoclonal antibodies reacted with T. pallidum specifically. On immunoblotting, monoclonal antibodies from 5 of the 7 clones reacted with a polypeptide of a molecular weight of 47 kDa, and monoclonal antibodies from YS 343 reacted with a polypeptide of 64 kDa common to both T. pallidum and T. phagedenis. The above results revealed that 7 clones secreting monoclonal antibodies reactive to T. pallidum were produced successfully, and specific antibodies reacting with major antigenic polypeptides of a molecular weight of 47 kDa would be useful in the diagnosis of syphilis in the future.

Animals↗
PubMed1988

Gynaecological cytology screening in South Australia: a 23-year experience.

The Cytology Laboratory at The Queen Elizabeth Hospital, Adelaide, processed 630,131 gynaecological smears from 347,389 patients between September 1, 1959 and July 31, 1982. The data suggested a lack of compliance with the recommendations of screening frequency, with an average of only 1.8 smear-tests per woman being performed during the 23-year study period. There was a two-fold increase in the incidence of histologically-confirmed cervical dysplasia and carcinoma-in-situ from 1977, but no increase in the incidence of invasive carcinoma. The age distributions of the incidence of dysplasia and carcinoma-in-situ moved towards younger age-groups during the study period. By the end of the study period (1977-1981), the incidence peaks of dysplasia and carcinoma-in-situ were both at ages 25 to 34 years compared with 30 to 39 years of age and 35 to 44 years of age, respectively, in 1962-1966. Invasive carcinoma had a much broader age distribution, with two incidence peaks, and the distribution shifted towards older age groups. The first peak had moved from 40 to 49 years of age (1962-1966) to 50 to 59 years of age (1977-1981) and the second peak moved from 60 to 69 years of age to 75 to 84 years of age. Error rates in cytological assessment were determined by comparing the histological diagnosis with the result of the most recent smear-test. By means of this method the sensitivity was 84.6%. The sensitivity was increased to 91.4% if the estimate were based on the most abnormal result of a smear-test before the histological diagnosis. A poor correlation was found between a mildly-atypical (inflammatory) cytological result (class 2) and a benign histological diagnosis: 48% of class-2 smears were diagnosed histologically as dysplasia or worse. In very few of these cases had an elapsed time of more than five years occurred between the class-2 result of a smear-test and the subsequent diagnosis of neoplasia. Thus, the majority of these cases were either underdiagnosed by cytology or had developed within five years, which indicates the importance of the careful follow-up of women with class-2 smears. Finally, the data illustrate the ability of gynaecological cytology screening to assist in the detection of extracervical gynaecological neoplasms of the uterus, ovary, vagina and vulva, as 132 such cases were diagnosed during the study period after positive results of a smear-test led to further investigations.

Adult↗
PubMed1988

Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor.

The cDNA coding for human monocyte-derived neutrophil-specific chemotactic factor (MDNCF) was cloned from LPS-stimulated human monocyte mRNA. The cDNA sequence codes for a polypeptide consisting of 99 amino acids, including a putative signal sequence. Comparison of the deduced amino acid sequence with the NH2-terminal amino acid sequence of natural MDNCF shows that the mature functional protein comprises 72 amino acids, beginning with serine at residue 28. The deduced amino acid sequence shows striking similarity to several platelet-derived factors, a v-src-induced protein, a growth-regulated gene product (gro), and an IFN-gamma inducible protein. The availability of the MDNCF cDNA enabled us to use it as a probe to identify inducers of MDNCF mRNA expression in human PBMC. MDNCF mRNA was increased greater than 10-fold within 1 h after stimulation with LPS, IL-1, or TNF, but not by IFN-gamma, IFN-alpha, or IL-2. Furthermore, we also determined that LPS, IL-1, and TNF stimulated the mononuclear cells to produce biologically active MDNCF. This observation may account for the in vivo capacity of IL-1 and TNF to induce netrophil infiltrates.

Amino Acid Sequence↗
PubMed1988

Analysis of the suppression of IL-1 alpha and IL-1 beta production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone.

The suppression of IL-1 production in human adherent PBMC by a glucocorticoid hormone was studied. From 10(-5) to 10(-8) M glucocorticoid hormone (prednisolone) inhibited both IL-1 alpha and IL-1 beta production by LPS-stimulated adherent human PBMC in a dose-dependent fashion, as assayed by Western blotting of cell-associated IL-1 and a thymocyte comitogenic bioassay. IL-1 alpha and -beta mRNA levels were concomitantly suppressed by glucocorticoid treatment, as determined by Northern blotting analysis. These data suggest that the suppression of IL-1 activity by glucocorticoids is consistently associated with decreased levels of IL-1 proteins and mRNA expression and therefore presumably regulated at the transcriptional level.

Depression, Chemical↗
PubMed1988

Aspects of cytokine induced modulation of immunity and inflammation with emphasis on interleukin 1.

Interleukin 1 (IL 1) contributes to both acute and chronic inflammatory processes. Purified IL 1 by itself is only one of the signals that induces local inflammation. The contribution of IL 1 to local inflammatory reactions is influenced by exogenous stimuli, antagonists such as steroid hormones and TGF beta (tissue growth factor beta) and agonists such as TNF (tissue necrosis factor). IL 1 production is depressed by glucocorticoids, but glucocorticoids induce expression of receptors for IL 1 on selected cell types including B lymphocytes and fibroblasts. Thus, complex interactions between hormones and cytokines modulate immunological and inflammatory responses.

Animals↗
PubMed1988

Decreased regional contractility in nonischemic myocardium during acute coronary artery occlusion in conscious pigs.

The purpose of this study was to use the relationship between end-systolic left ventricular pressure and segment length to assess the inotropic state of nonischemic myocardium during acute coronary artery occlusion in the conscious pig. Eight pigs were chronically instrumented with sonomicrometers to measure midwall segmental shortening and a micromanometer to measure left ventricular pressure. Occlusion of the inferior vena cava with a pneumatic occlusive cuff caused transient decreases in left ventricular pressure so that the relationship of left ventricular pressure and segment length at end systole could be determined over a range of pressures. In preliminary studies using open-chest pigs, this relation was shown to be highly linear and best quantified using a calculated segment length at a left ventricular pressure of 100 mm Hg (ESL100). During acute, 1-min occlusion of the left anterior descending coronary artery, the ESL100 of the nonischemic lateral and posterior walls was significantly increased from 8.75 +/- .18 mm to 9.64 +/- .21 mm (mean +/- SD, p less than .01), indicating a decreased inotropic state. Similarly, during occlusion of the left circumflex coronary artery, the ESL100 of the nonischemic anterior wall increased from 8.44 +/- 2.53 mm to 9.26 +/- 3.12 mm (p less than .05). This was not associated with a change in the amount of shortening during systole. Pharmacological autonomic blockade using atropine and propranolol failed to alter the response of nonischemic zones to acute coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

In vivo mechanical behavior of canine pericardium.

We examined the in vivo mechanical behavior of the pericardium by measuring simultaneous atrial and intrapericardial pressures and mutually orthogonal, circumferential, and longitudinally oriented pericardial segment lengths (ultrasonic gauges) in 10 open-chest dogs. Venous return was varied by a combination of caval occlusion followed by volume loading. Up to a mean left atrial pressure of 25 mmHg, the pericardium lengthened virtually exclusively in the circumferential direction (n = 9). Thus, at an intrapericardial pressure of 6.0 +/- 1.0 (+/- SD) mmHg, circumferential strain (normalized to length at pericardial pressure 0 mmHg) was 0.30 +/- 0.28, whereas longitudinal strain was 0.02 +/- 0.06 (P less than 0.05). In five of these dogs, alteration of external pericardial loading by severing the pericardial diaphragmatic attachments did not change the difference between circumferential and longitudinal strain, and in two the same directional strain difference was observed during production of cardia tamponade. In three additional dogs the square of the circumferential segment length was closely correlated with the directly measured intrapericardial volume when saline was infused into the pericardial space in an in situ, arrested heart preparation. Our results indicate that there is marked directional variability in lengthening of the pericardium when the volume of its contents is altered in vivo. This phenomenon is probably the result of complex interactions between the properties of the pericardial tissue and the influence of its internal and external loads.

Animals↗
PubMed1983

Hemodynamic and electrocardiographic effects in man of a new nonionic contrast agent (iohexol): advantages over standard ionic agents.

Iohexol is a new, nonionic contrast material that has been shown in animal studies to hold great promise as an agent for coronary arteriography and ventriculography with fewer adverse hemodynamic effects than standard ionic media. At present, it has not been studied systematically in man. Fifty patients referred for elective cardiac catheterization were randomized to receive either iohexol or meglumine sodium diatrizoate (Renografin-76). Both operator and patient were blinded as to which agent was being used. Hemodynamic variables measured were pulmonary artery wedge pressure and systemic blood pressure. In addition, the following electrocardiographic indexes were evaluated: S-T segment shifts, changes in Q-T interval, changes in T-wave amplitude, and changes in heart rate. These variables were measured after left ventriculography and after both left and right coronary arteriography. Both iohexol and sodium meglumine diatrizoate produced small transient elevations in pulmonary artery wedge pressure. Systemic hypotension occurred with both agents but was more profound and longer-lasting with sodium meglumine diatrizoate. Iohexol injection resulted in no electrocardiographic changes, whereas sodium meglumine diatrizoate produced marked Q-T prolongation, as well as changes in T-wave amplitude and heart rate. Iohexol was well tolerated by the patients, and radiographic opacification was good to excellent in all cases. Thus, iohexol produces fewer deleterious hemodynamic and electrocardiographic changes than sodium meglumine diatrizoate when studied in a typical adult population requiring diagnostic cardiac catheterization. This favorable preliminary experience in man has potential widespread importance because of the large number of patients undergoing angiographic procedures.

Aged↗
PubMed1979

Assessment of pulmonary valve echogram in normal subjects and in patients with pulmonary arterial hypertension.

To assess the validity of ultrasound criteria for pulmonary arterial hypertension, we studied pulmonary valve motion in 28 patients and 20 normal subjects. In the latter group, we categorised normal movement of the posterior leaflet of the pulmonary valve in a fashion not previously described. Of the 28 patients, 19 had pulmonary arterial hypertension (pulmonary artery mean pressure more than 20 mmHg, range 22 to 72). Negative, flat, and positive e to f slopes occurred equally in normal subjects and patients. Maximal a wave excursion was less than 2 mm in 9 of 13 patients with pulmonary hypertension who had sinus rhythm, but was more than 2 mm in all normals and in the 9 patients with normal pulmonary artery pressure (69% sensitivity and 100% specificity). The b to c slope was more than 450 mm/s in 6 of 18 patients with pulmonary arterial hypertension and was less than 450 mm/s in all others (33% sensitivity and 100% specificity). The normalised right ventricular pre-ejection period was more than 0.095 (range 0.10 to 0.16) in 13 of the 19 patients with pulmonary arterial hypertension and less than 0.095 in all others (68% sensitivity and 100% specificity). A midsystolic notch occurred in patients with pulmonary arterial hypertension and in no normal subjects or patients with normal pulmonary arterial pressure. Of the 19 patients with pulmonary arterial hypertension, 18 were identified by one or more ultrasound criteria. Of the 5 patients who met only 1 criterion (increased normalised right ventricular pre-ejection period), 4 had atrial fibrillation. We conclude that measurement of the pulmonary valve e to f slope is useless for identifying pulmonary arterial hypertension. However, changes in normalised right ventricular pre-ejection, maximal a wave excursion, b to c slope, and the presence of a midsystolic notch, while insensitive, are highly specific for pulmonary atrial hypertension.

Adolescent↗