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Biomedical subjects

M J Myers

Publications and source records attributed to M J Myers.

At least 19 recordsLinked to original sources
PubMed1992

Dimethylnitrosamine (DMN)-induced IL-1 beta, TNF-alpha, and IL-6 inflammatory cytokine expression.

Altered immune functions have been demonstrated in mice following exposure to dimethylnitrosamine (DMN). In particular, changes in cell-mediated immune responses resulted from chronic DMN exposure in vivo. Since cytokines are potent immunoregulatory peptides, experiments were performed to determine whether DMN exposure results in the induction of serum-borne inflammatory cytokines. Animals were exposed to either vehicle (PBS) or DMN (5.0 mg/kg) every 24 hr for 14 days. Serum and liver samples were obtained from individual mice at 0, 1, 2, 3, 6, 12, and 24 hr following the first exposure, with additional samples collected every 24 hr preceding the daily DMN exposure. Sera were then analyzed for IL-1 beta, IL-3, IL-6, CSF-1, GM-CSF, and TNF-alpha activities using either biological or immunological assays. In addition, liver total cellular RNA was probed for the induction of IL-1 beta transcripts using the solution hybridization/RNase protection assay. IL-1 beta, IL-6, and TNF-alpha serum activities were observed within 2 hr of DMN exposure and returned to vehicle control levels by 3 days even though DMN exposure was maintained. Chronic expression of cytokine activity (after 72 hr) was only observed for GM-CSF. A rapid induction of IL-1 beta transcripts (within 1 hr) in both vehicle and DMN-treated animals was observed by solution hybridization. However, by 3 hr postexposure, transcript levels decreased in the vehicle-treated animals while remaining elevated in the DMN-treated animals for 6 hr. These results demonstrated that DMN exposure in vivo induced: (1) the expression of serum-borne cytokine activities, and (2) IL-1 beta transcription in liver tissue.

Animals↗
PubMed1992

Intrasplenic blood cell kinetics in man before and after brief maximal exercise.

1. After a 4 min period of maximal exercise in 10 normal subjects (14 studies), there was a consistent decrease in total blood volume and a consistent increase in erythrocyte indices, which were maximal immediately after exercise. Peripheral platelet and leucocyte counts increased, but did not reach maximal values until 5-10 min after the end of exercise. 2. The distributions of 99mTc-labelled erythrocytes (five studies), 111In-labelled platelets (five studies) and 111In-labelled granulocytes (four studies) were monitored with a gamma-camera immediately after injection and before and after maximal exercise performed 60 min after injection. 3. Labelled erythrocytes equilibrated rapidly between the spleen and circulating blood after injection, whereas labelled platelets and granulocytes equilibrated more slowly. After exercise, each cell type was released from the spleen with a time course that was the reciprocal of the time course of the corresponding cell count in peripheral blood. Thus, whereas the radioactivity of 99mTc-labelled erythrocytes in the spleen, which fell to 0.46 (SD 0.09) of the pre-exercise value, increased towards its baseline value as soon as exercise was completed, the radioactivities of 111In-labelled platelets and 111In-labelled granulocytes decreased, to respective minimum values of 0.61 (0.09) and 0.63 (0.09) of the pre-exercise levels, 5-10 min after the end of exercise. The exercise-induced changes in lung radioactivity for each cell type, and their time courses, broadly reflected those in the corresponding cell counts in peripheral blood. Liver radioactivity tended to decrease for each cell type.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Non-invasive techniques for the measurement of extraction fraction and permeability surface area product of 99Tcm DTPA in the human forearm.

Only a very limited number of clinical studies have been reported on the measurement of endothelial permeability to hydrophilic solutes (molecular weight less than 6000 Daltons) that normally gain free access to the extravascular space. Because of high extraction efficiencies into the extravascular space, the transfer rates of small solutes of molecular weight about 500 Daltons, like 99Tcm DTPA, are perfusion-dependent as well as diffusion-dependent. We describe non-invasive techniques for measurement of clearance and extraction fraction of 99Tcm DTPA into the extravascular space of the resting forearm using a scintillation probe, from which we then calculated permeability surface area (PS) product. Our values for extraction fraction of about 0.5 and for PS product of about 3 ml per minute per 100 ml tissue are comparable to the values reported in the literature for resting skeletal muscle using more invasive techniques.

Capillary Permeability↗
PubMed1991

Role of cytochrome P450 IA2 in acetanilide 4-hydroxylation as determined with cDNA expression and monoclonal antibodies.

The role of P450 IA2 in the hydroxylation of acetanilide was examined using an inhibitory monoclonal antibody (MAb) 1-7-1 and vaccinia cDNA expression producing murine P450 IA1 (mIA1), murine P450 IA2 (mIA2), or human P450 IA2 (hIA2). Acetanilide hydroxylase (AcOH) activity was measured using an HPLC method with more than 500-fold greater sensitivity than previously described procedures. This method, which does not require the use of radioactive acetanilide, was achieved by optimizing both the gradient system and the amount of enzyme needed to achieve detection by uv light. MAb 1-7-1 inhibits up to 80% of the AcOH activity in both rat liver microsomes and cDNA expressed mouse and human P450 IA2. MAb 1-7-1, which recognizes both P450 IA1 and P450 IA2, completely inhibits the aryl hydrocarbon hydroxylase (AHH) activity of cDNA expressed in IA1. The inhibition of only 80% of the AHH activity present in MC liver microsomes by MAb 1-7-1 suggests that additional P450 forms are contributing to the overall AHH activity present in methylcholanthrene (MC)-liver microsomes as MAb 1-7-1 almost completely inhibits the AHH activity of expressed mIA1. Maximal inhibition of IA2 by 1-7-1 results in an 80% decrease in acetanilide hydroxylase activity in both liver microsomes and expressed mouse and human IA2. The capacity of MAb 1-7-1 to produce identical levels of inhibition of acetanilide hydroxylase activity in rat MC microsomes (80%) and in expressed mouse (81%) and human P450 IA2 (80%) strongly suggests that P450 IA2 is the major and perhaps the only enzyme responsible for the metabolism of acetanilide. These results demonstrate the complementary utility of monoclonal antibodies and cDNA expression for defining the contribution of specific P450 enzymes to the metabolism of a given substrate. This complementary approach allows for a more precise determination of the inhibitory capacity of MAb with respect to the metabolic capacity of the target P450.

Acetaminophen↗
PubMed1991

Enhanced macrophage anti-microbial activity following dimethylnitrosamine exposure in vivo is related to augmented production of reactive oxygen metabolites.

Previous results demonstrated that mice exposed in vivo to DMN were more resistant to both bacterial and tumor challenges. Furthermore, macrophages (M phi) isolated from these animals demonstrated increased functional properties. As reactive oxygen intermediates (ROI) represent a key mechanism of anti-microbial action, it was important to determine whether ROI levels in M phi were related to augmented anti-microbial action in animals exposed to DMN in vivo. Peritoneal exudate M phi elicited with either thioglycollate (TG), Con A or C. parvum (CP) were examined for the production of ROIs. TG-M phi, Con A-M phi and CP-M phi obtained from animals exposed to DMN showed increased superoxide anion (O2-) production in vitro following stimulation with either phorbol myristate acetate (PMA) or opsonized zymosan (Op-zym) when compared to vehicle M phi. ROI production by bone marrow-derived macrophages (BMDM) produced by either GM-CSF or CSF-1 was also determined. BMDM from DMN-exposed animals obtained using either growth factor, had increased ROI production at 3, 5, 7 and 9 d of culture compared to vehicle BMDM. There was no shift in the kinetics of ROI production during differentiation of these BMDM. Analysis of extracellular anti-listericidal activity of TG- and CA-elicited M phi demonstrated that only TG-M phi obtained from DMN-exposed animals had enhanced killing capacity. There were no differences in intracellular anti-microbial activity in TG- and CA-elicited M phi obtained from either vehicle or DMN-exposed animals. TG-elicited M phi from either vehicle or DMN-exposed animals were examined for anti-microbial activity and H2O2 production following in vitro exposure to PMA. M phi from both vehicle and DMN treatment groups had enhanced killing and H2O2 production following PMA treatment, while PMA-stimulated TG-M phi from DMN-exposed animals demonstrated significantly higher levels of H2O2 production and cell killing as compared to all other treatment groups. These results suggest that previously observed increases in anti-microbial action by M phi from DMN-exposed animals are due in-part to enhanced ROI production.

Animals↗
PubMed1990

Synthetic peptide antigens elicit monoclonal and polyclonal antibodies to cytochrome P450 IA2.

Two peptide sequences from cytochrome P450 IA2 were synthesized, coupled to ovalbumin and used as antigens to generate anti-peptide monoclonal and polyclonal antibodies. Antisera to both peptides reacted with rat IA2 but not the structurally similar IA1 form as determined by enzyme-linked immunosorbent assay. However, antisera to both peptides detected both rat IA2 and IA1 on immunoblots. In addition immunoblots of human liver microsomes revealed that both antisera recognized human IA2, but not IA1. Monoclonal antibodies generated against one of the peptides recognized rat IA2 and IA1 but did not detect human IA2. These results demonstrate the utility of anti-peptide antisera as a practical approach for the generation of P450 specific antibodies.

Amino Acid Sequence↗
PubMed1990

Prognostic significance of radionuclide-assessed diastolic function in hypertrophic cardiomyopathy.

To evaluate the prognostic significance of diastolic function in hypertrophic cardiomyopathy (HC), technetium-99m gated equilibrium radionuclide angiography, acquired in list mode, was performed in 161 patients. Five diastolic indexes were calculated. During 3.0 +/- 1.9 years, 13 patients had disease-related deaths. With univariate analysis, these patients were younger (29 +/- 20 vs 42 +/- 16 years; p less than 0.05), had a higher incidence of syncope (p less than 0.025), dyspnea (p less than 0.001), reduced peak filling rate (2.9 +/- 0.9 vs 3.4 +/- 1.0 end-diastolic volume/s; p = 0.09) with increased relative filling volume during the rapid filling period (80 +/- 7 vs 75 +/- 12%; p = 0.06) and decreased atrial contribution (17 +/- 7 vs 22 +/- 11%; p = 0.07). Stepwise discriminant analysis revealed that young age at diagnosis, syncope at diagnosis, reduced peak ejection rate, positive family history, reduced peak filling rate, increased relative filling volume by peak filling rate and concentric left ventricular hypertrophy were the most statistically significant (p = 0.0001) predictors of disease-related death (sensitivity 92%, specificity 76%, accuracy 77%, positive predictive value 25%). Discriminant analysis excluding the diastolic indexes, however, showed similar predictability (sensitivity 92%, specificity 76%, accuracy 78%, positive predictive value 26%). To obtain more homogeneous groups for analysis, patients were classified as survivors (116) or electrically unstable (40), including sudden death, out-of-hospital ventricular fibrillation and nonsustained ventricular tachycardia during 48-hour ambulatory electrocardiography, and heart failure death or cardiac transplant (5).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Comparison of DuP 996, with physostigmine, THA and 3,4-DAP on hypoxia-induced amnesia in rats.

DuP 996, 3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one, physostigmine (PH), tetrahydroaminoacridine (THA) and 3,4-diaminopyridine (3,4-DAP) were compared for their ability to protect against hypoxia-induced performance deficits in a passive avoidance (PA) task. The ability to retain PA response was found to decrease as the oxygen concentration decreased with the largest retention deficit occurring at 6.5% oxygen. DuP 996 (0.01-0.1 mg/kg SC), 3,4-DAP (0.1-10.0 mg/kg SC), THA (0.3-5.0 mg/kg SC) and PH (0.001-0.1 mg/kg SC) administered one minute after PA training produced dose-dependent increases in retention latencies following exposure to 6.5% oxygen. In comparing each compound for side effects, DuP 996 induced tremor and mortality at 10 and 40 mg/kg SC, respectively, and PH at 0.3 and 0.8 mg/kg SC, respectively. With PH the 0.3 mg/kg SC dose also produced hypersalivation and a decrease in lift strength. THA produced tremor and mortality at 6.0 and 40 mg/kg SC, respectively, and 3,4-DAP at 50 and 200 mg/kg SC, respectively. 3,4-DAP also produced chromodacryorrhea and hypersalivation at 50 mg/kg SC. Dividing the dose necessary to produce mortality by the highest effective dose active in the hypoxia test yielded a safety ratio for DuP 996 of 400, for 3,4-DAP 20, for PH 8, and for THA 8, showing a greater safety margin for DuP 996 than the other cholinergic agents. These results suggest that DuP 996 may be of use in the treatment of diseases associated with cognitive impairment and may have a greater safety margin than other cholinergic agents.

4-Aminopyridine↗
PubMed1990

A simplified approach to alpha dosimetry for small spheres labelled on the surface.

The radiation doses to spheres of radii 5-200 microns, labelled on the surface with alpha emitters were studied in order to simulate conditions of radioimmunotherapy for small tumours. The absorbed fraction of emitted energy and the mean absorbed dose per alpha particle in smaller concentric spherical targets were calculated for different source sizes. Calculations were first performed for monoenergetic emissions. We then considered the dosimetry of two common alpha emitters described in the literature (211At and 212Bi). The results agree well with different analytical approaches reported in the literature, but differ from those obtained using a Monte Carlo code. The computing features have been deliberately kept to a low level to allow for simple introduction into hospital work. Comparison of the mean absorbed dose per particle between alpha and beta emitters seems to favour the use of alpha emitters. However, their high toxicity introduces a practical radiation protection problem and our mathematical dosimetric approach is valid only for homogeneous distributions of radionuclides when, in the case of alpha emitters, the total dose delivered would be much too high to be of practical use.

Alpha Particles↗
PubMed1990

Left lower lobe ventilation is reduced in patients with cardiomegaly in the supine but not the prone position.

To determine the effect of the heart on regional ventilation, Krypton-81m (81mKr) tomographic (SPECT) ventilation scans were recorded in seven patients with cardiomegaly and four normal subjects in the supine and prone positions. All patients had a cardiothoracic ratio of greater than 0.50 and clear lung fields radiographically. Using standard gamma camera tomographic reconstruction techniques, images of transaxial slices were obtained during a 360 degree rotation around the thorax of the subject breathing the radioactive gas 81mKr. The transaxial images, acquired over 10 min were aligned in each posture at the level of the cardiac apex, mid-heart, and aortic arch and were matched in relation to a radioactive marker on the chest wall and to anatomic landmarks. A horizontal line (gravity independent and parallel to the couch) was drawn on the transaxial section through the dorsal regions of the right and left lung. Counts per resolution element (12 to 15 mm) were plotted along this line and the ratios of the peak values in right and left lung compared. These ratios represent differences in regional ventilation per unit lung volume. In controls the mean left-to-right (L/R) peak count ratio varied from 0.91 to 1.00 at the three levels (range: 0.76 to 1.04); there were no significant differences between supine and prone. In patients with cardiomegaly the mean (+/- SEM) L/R peak count ratio at cardiac apex, mid-heart, and aortic arch was 0.46 (+/- 0.08), 0.55 (+/- 0.07), and 0.89 (+/- 0.08) when supine and 1.04 (+/- 0.07), 1.05 (+/- 0.05), and 1.08 (+/- 0.07) when prone, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Regulation of IL-1 and TNF-alpha expression during the differentiation of bone marrow derived macrophage.

Macrophage differentiation is accompanied by the acquisition of both Ag presentation and tumoricidal activities. In this set of experiments, the expression of IL-1 by bone marrow-derived macrophage (BMDM) was found to be highly regulated, with both the expression of IL-1 mRNA and mIL-1 appearing only at discrete stages of activation. The accumulation of IL-1 alpha (membrane) mRNA was induced by endotoxin but not IFN-gamma or CSF-1. mIL-1 was detected by D10.G4.1 T cells on BMDM only after 7 days of in vitro differentiation. Secreted IL-1 beta was detected by day 3 of culture, with enhanced production observed after activation with endotoxin. IL-1 beta mRNA was found to be constitutively expressed in BMDM as early as day 3 of culture. The expression of IL-1 beta mRNA was up-regulated by endotoxin after 30 min of exposure with maximal expression occurring after 2 to 6 h of exposure. Constitutive expression of IL-1 alpha mRNA was not detected but 1 h of endotoxin exposure resulted in the appearance of IL-1 alpha transcripts. As with IL-1 beta, TNF-alpha mRNA was also constitutively expressed during a wide time period of differentiation; however, in contrast, to IL-1 beta, TNF-alpha mRNA expression was up-regulated by both endotoxin and IFN-gamma. The expression of TNF-alpha macrophage by BMDM coincided with the acquisition of tumoricidal activity. An examination of the mRNA sequences encoding the proto-oncogenes c-myc and c-fms demonstrated the expression of c-myc only on day 3, whereas c-fms was constitutively expressed throughout the culture period. Endotoxin stimulation of BMDM resulted in a transitory increase in c-myc expression only at day 3 of culture, whereas endotoxin had no effect on c-fms expression until 7 days of culture at which time expression declined. In contrast, the expression of transferrin receptor mRNA transcripts, which were also constitutively expressed throughout the entire culture period, were not affected by stimulation with either endotoxin or IFN-gamma. These results indicate BMDM expression of the affector molecules IL-1 alpha and beta and the effector molecule TNF-alpha are regulated separately during unique "differentiation-specific" phases of development.

Animals↗
PubMed1989

Regulation of MHC gene expression during the differentiation of bone marrow-derived macrophages.

The ability of the macrophage to express class II MHC gene products appears to arise from both T-dependent and T-independent mechanisms. One mechanism by which macrophages express Ia-antigens in the absence of T-lymphocytes is postulated to be controlled by differentiation. By using a liquid bone marrow culture system, we have studied both class I and class II surface expression and mRNA accumulation during macrophage differentiation in vitro. The results demonstrated that Ia expression increased until 7 days in culture and then slowly declined. In contrast, class I expression appeared to steadily increase throughout the differentiation period. Northern blot analysis of RNA isolated from bone marrow-derived macrophages (BMDM) at various periods during culture, using E alpha, A alpha, and class I cDNA probes, correlated well with the results of Ia and H-2K surface expression. Further analysis demonstrated that the expression of Ia-antigens on BMDM was not the result of T-helper lymphocytes. This was determined by demonstrating (1) that bone marrow cultures were devoid of mature T-lymphocytes, (2) the absence of interferon (IFN)-gamma transcripts in both adherent and nonadherent populations of bone marrow cells, and (3) that the addition of anti-IFN-gamma monoclonal antibody (mAb) to the bone cultures did not alter the percentage of Ia-positive BMDM. Moreover, the addition of anti-tumor necrosis factor-alpha mAb to the bone marrow cultures had no effect on Ia expression by BMDM. Taken together, these results allow us to conclude that Ia expression by BMDM is probably not mediated via exogenous signals but rather results from an intrinsically controlled process.

Animals↗
PubMed1989

Intraperitoneal radioimmunotherapy for ovarian cancer: pharmacokinetics, toxicity, and efficacy of I-131 labeled monoclonal antibodies.

Thirty-six patients with ovarian cancer were treated with intraperitoneal I-131 labeled monoclonal antibodies to tumor associated antigens. The activity of I-131 administered was increased from 20 mCi to 158 mCi and the pharmacokinetics and toxicity evaluated. Five patients who had developed HAMA (Human Antimouse Antibodies) were retreated, and the pharmacokinetics and toxicity of the first and second treatment compared. Patients receiving their first therapy (HAMA negative), had a maximum of 25% (range 19.8-39.8%) of the injected activity in their circulation. This was accompanied by severe marrow suppression at I-131 activities over 120 mCi. The 5 HAMA positive patients had only 5% injected activity in the systemic circulation (range 3.8-6%), with rapid urinary excretion and neglible marrow suppression. In 31 patients with assessable disease there were no responses in 8 patients with gross disease (nodules greater than 2 cms), partial responses in 2 out of 15 patients with nodules less than 2 cms, and complete responses in 3 out of 6 patients with microscopic disease. The non specific radiation dose to the peritoneal cavity was estimated to be less than 500 cGy by lithium fluoride TLD, and could not be expected to account for the responses seen.

Animals↗
PubMed1989

Solute transfer into the extravascular space: comparison of two non-invasive measurement techniques.

Little clinical attention has been paid to the quantification of microvascular permeability to small hydrophilic solutes, probably because of a paucity of non-invasive techniques. We describe a technique using the gamma camera which measures the clearance of 99mTc DTPA, a molecule similar in size to sucrose, from the intravascular to the extravascular space in the lumbar tissues below the kidneys. This regional clearance (PSr) is analogous to the permeability-surface area (PS) product, a well established concept for describing solute transfer across the capillary. We found a value in subjects with normal renal function of 1.0 (SD 0.2) ml.min-1.100 ml-1 tissue, which is broadly similar to the values anticipated from published values of the extraction fraction of 51Cr EDTA and plasma flow of resting human skeletal muscle. We also describe an index, the t95, of whole body microvascular permeability. This is the time at which the second exponential of the bi-exponential plasma 99mTc DTPA clearance curve becomes equal to 95% of the total curve. The index reflects the rate of equilibration of DTPA between intravascular and extravascular spaces, and should reflect whole body microvascular permeability. The t95 showed a significant inverse correlation with regional clearance (t95 = -12 PSr + 98 min; r = -0.61; n = 60; p less than 0.001) confirming their mutual dependence on capillary DTPA transfer. These non-invasive techniques, with their advantages of simplicity, could prove useful in a variety of clinical settings.

Capillary Permeability↗
PubMed1989

The perioperative changes in glomerular filtration and renal blood flow in patients with obstructive jaundice.

Experimental alterations in renal haemodynamics have been observed in obstructive jaundice and these may be the pathophysiological mechanism of increased renal susceptibility to injury in obstructive jaundice. Dynamic 99mTc-DTPA renal scintigraphy was done before and eight weeks after elective hepatobiliary surgery in six patients with obstructive jaundice (bilirubin greater than 100 mumol/l) and in six non-jaundiced control patients to assess changes in glomerular filtration and renal blood flow. Glomerular filtration was lower preoperatively in the jaundiced patients than in the control patients. Glomerular filtration increased postoperatively in jaundiced patients, but decreased in control patients. Renal blood flow was reduced postoperatively in control patients, but not in jaundiced patients. The changes in renal blood flow were different for each group of patients. These results provide clinical evidence of altered renal haemodynamics and a reversible impairment of glomerular filtration in obstructive jaundice. The changes seen in renal blood flow may be the underlying mechanism of increased renal susceptibility to injury.

Adult↗
PubMed1988

Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component.

The specific molecular affinity of the normal plasma protein, serum amyloid P component (SAP), for all known types of amyloid fibrils was used to develop a new general diagnostic method for in-vivo radionuclide imaging of amyloid deposits. After intravenous injection of 123I-labelled purified human SAP there was specific uptake into amyloid deposits in all affected patients, 7 with systemic AL amyloid, 5 with AA amyloid, and 2 with beta 2M amyloid, in contrast to the complete absence of any tissue localisation in 5 control subjects. Distinctive high-resolution scintigraphic images, even of minor deposits in the carpal regions, bone marrow, or adrenals, were obtained. This procedure should yield much information on the natural history and the management of amyloidosis, the presence of which has hitherto been confirmed only by biopsy. Clearance and metabolic studies indicated that, in the presence of extensive amyloidosis, the rate of synthesis of SAP was greatly increased despite maintenance of normal plasma levels. Furthermore, once localised to amyloid deposits the 123I-SAP persisted for long periods and was apparently protected from its normal rapid degradation. These findings shed new light on the pathophysiology of amyloid and may have implications for therapeutic strategies based upon specific molecular targeting with SAP.

Adult↗