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Biomedical subjects

J L Martin

Publications and source records attributed to J L Martin.

At least 325 records · Page 18Linked to original sources
PubMed1985

Transient responses of coronary flow in the blood-perfused isolated rat heart submitted to changes in oxygen content.

This study examines the transient response of coronary blood flow to acute changes in O2 content at normal and high arterial PO2 (Pa, O2) in the blood-perfused, working isolated rat heart. The perfusion system used in this study presents the following advantages: it eliminates the gas/blood interface, includes a peripheral circulation for control of pre-load and after-load, and allows for rapid change of perfusates and continuous recording of aortic and coronary blood flow. With this system the isolated rat heart is capable of stable haemodynamic performance for periods in excess of 4 h. A sudden decrease in O2 content from 0.147 to 0.067 11(-11) at constant Pa,O2 (133 mmHg; n = 15) was associated with a marked increase in coronary blood flow (QCOR). This increase showed two phases: a rapid phase which reached 200% of the control value in 20 s, followed by a slow phase (235% in 90 s). When the same decrease in O2 content (0.135 to 0.057 11(-1] was associated with an increase in Pa, O2 (n = 22; 143 to 412 mmHg), the response of QCOR was limited both in amplitude (175% rather than 235%) and in rate of onset (response time of 15.6 instead of 9.2 s). These results are consistent with the majority of currently popular hypotheses regarding control of QCOR including the adenosine hypothesis and that of vessel wall PO2 being a direct mediator. The time course of changes in coronary vascular resistance, with a Pa, O2-dependent rapid phase, suggests the simultaneous function of the two mechanisms.

Animals↗
PubMed1985

Plaque autoradiography assay for the detection and quantitation of thymidine kinase-deficient and thymidine kinase-altered mutants of herpes simplex virus in clinical isolates.

A plaque autoradiography assay to detect and quantitate thymidine kinase (TK) mutants of herpes simplex virus type 1 (HSV-1) and HSV-2 in clinical samples is described. This method utilizes the selective incorporation of [125I]iododeoxycytidine, a pyrimidine analog selectively phosphorylated by the HSV TK. Only cells infected with TK-competent virus will efficiently incorporate iododeoxycytidine and are the only cells detected by autoradiography. Furthermore, this assay discriminates between TK+ virus (TK competent) and TKA virus (TK altered or reduced). This ability to differentiate TK+ from TKA virus is enhanced when infected cells are labeled with [14C]thymidine in tandem with iododeoxycytidine labeling. Reconstruction experiments with mixtures of TK+ (HSV-1 Patton) virus and TK-deficient (TK-) (B2006) or TKA (IUDRr) mutants were performed to determine the limits of detection of this technique. Ten percent TK- or TKA virus was the lower limit for the detection of TK mutants in a mixed population, whereas 1 in 1,000 TK+ virus revertants could be detected in a TK- virus population. In reconstructed populations and 45 clinical samples, a good correlation existed between the increase in 50% inhibitory dose for acyclovir and the percent TK mutant virus present. Similarly, the results of this technique correlated well with the acyclovir phosphorylating activity of extracts from cells infected with isolates or reconstructed mixtures. Plaque autoradiography with [125I]iododeoxycytidine was able to distinguish mixed populations of TK+ and TK- virus and homogeneous populations of TKA virus. The tandem use of [125I]iododeoxycytidine and [14C]thymidine readily identified TKA virus, which appeared as TK+ virus when labeled with [14C]thymidine alone. This technique provides a sensitive screen for antiviral resistance due to alterations in the viral TK and can be used to analyze clinical samples.

Acyclovir↗
PubMed1985

Characteristics of vascular hydraulic load in patients with heart failure.

Aortic input impedance and hydraulic power were derived from simultaneous catheter recordings of ascending aortic pressure and velocity in eight normal subjects and 11 age-matched subjects with clinical heart failure secondary to idiopathic congestive cardiomyopathy. Resting data revealed the characteristic depression of cardiac output and elevation of systemic vascular resistance in patients with heart failure. The pulsatile component of vascular hydraulic load, characteristic impedance (Zc), was similar in both groups (Zc normal: 85 +/- 30 dyne-sec-cm-5; Zc cardiomyopathy: 93 +/- 33 dyne-sec-cm-5). The oscillatory fraction of aortic input power in patients with heart failure (14 +/- 4%) was also similar to that of normal subjects (11 +/- 2%). The transition from rest to exercise in patients with heart failure was marked by a decrease in the steady component of arterial hydraulic load, although characteristic impedance did not change. A similar qualitative response occurred in normal subjects, although the systemic vascular resistance during exercise remained above normal in patients with heart failure. The modulus of the first harmonic of impedance significantly decreased during exercise in normal subjects but did not change significantly in patients with heart failure. Furthermore, the modulus of the first harmonic of the reflection coefficient decreased significantly during exercise in normal subjects but did not change in patients with heart failure in spite of systemic vasodilation. Exercise appears to impose no additional increase in vascular hydraulic load on the ejecting left ventricle. The similar aortic characteristic impedances in patients with heart failure and in normal subjects, at rest and during exercise, are consistent with a constant oscillatory fraction of input power.

Adult↗
PubMed1985

Real-time kinetics of sarcomere relaxation by laser diffraction.

Kinetics of sarcomere movement were studied in real-time by laser diffraction. Instantaneous sarcomere shortening was measured during afterloaded twitches simultaneously with instantaneous shortening and tension of the whole trabecula excised from rat right ventricle. Resting sarcomere length at optimal length was 2.20 +/- 0.02 micron (mean +/- SEM). Maximum amplitude of sarcomere shortening was 0.30 +/- 0.01 and 0.16 +/- 0.01 micron, respectively, in twitches loaded with preload only, and in "isometric" twitches. When the isotonic load (expressed as a percentage of maximum isometric force TF) increased, the maximum velocity of sarcomere relaxation max Vr (micron/sec) decreased: max Vr = -4 exp (-2.5 X 10(-2) % TF); r = 0.95. The time course of sarcomere relaxation appeared to be progressively delayed when the total load increased from preload only up to "isometric" load. Sarcomere relaxation occurred in two successive exponential phases, a rapid phase [time constant (msec): tau 1] followed by a slower one (time constant: tau 2). When the total load increased, tau 1 increased and tau 2 decreased according to the linear relations: % TF = 0.2 tau 1 + 4.8 (r = 0.83) and % TF = -0.1 tau 2 + 157 (r = 0.95). The relative predominance of both the time course and the amplitude of these two phases depended upon the level of total load. The rapid process predominated at low load, the slow one at high load. The role of load and/or shortening in the time course of these two phases is discussed.

Animals↗
PubMed1985

Production of insulin-like growth factor I and its binding protein by adult rat hepatocytes in primary culture.

This study examines the production and characteristics of insulin-like growth factor I (IGF I) and its binding protein (BP) from adult rat hepatocytes in primary culture. IGF I and BP in samples of conditioned medium were separated by automated high pressure gel permeation chromatography at pH 2.8, with total recovery of both species. Measured by a specific RIA, with about 2% IGF II cross-reactivity, the rate of production of IGF I [compared with a human IGF I (hIGF I) standard] was 4.39 +/- 0.57 pmol/mg cell protein X 24 h; measured by a radioligand assay using radioiodinated hIGF I as tracer, BP was produced at a rate of 2.97 +/- 0.54 pmol binding sites/mg cell protein X 24 h. High pressure permeation chromatography studies indicated approximate mol wts of 7,500 for hepatocyte IGF I and 50,000 for BP. The pI of hepatocyte IGF I was 8.8, and of the predominant BP species, 6.8. Rat serum treated in the same way as hepatocyte medium showed IGF I and BP activities at identical pI values to those from hepatocytes but, in addition, contained BP activity at more acidic pI values, apparently not produced directly by the liver. Competitive binding studies using acid-chromatographed hepatocyte or serum BP, and hIGF I and IGF II as labeled and unlabeled ligands, also suggested that BP activity in serum was heterogeneous, while BP from hepatocytes appeared to be a single species with similar affinities for IGF I and IGF II. It is concluded that adult rat hepatocytes produce immunoreactive IGF I, pI 8.8, and BP, pI 6.8, which are released into the circulation, but that additional, more acidic, BP species which are also found in serum could result from extrahepatic production or processing.

Animals↗
PubMed1985

Rat hepatocyte insulin-like growth factor I and binding protein: effect of growth hormone in vitro and in vivo.

This study examines the regulation of insulin-like growth factor I (IGF I) and binding protein (BP) release by adult rat hepatocytes in primary culture. Increasing the density of plating of cells had a marked positive effect on the IGF I production rate per mg cell protein, with the highest rate, approximately 4 pmol/mg cell protein X 24 h, seen at densities of 1 X 10(5) cells/cm2 or higher. Cycloheximide (15 micrograms/ml) inhibited both IGF I and BP production by more than 90%, while actinomycin D (0.1 microgram/ml) caused less marked, but still significant, inhibition. Over the insulin range 30 pM-300 nM there was a 45% increase in IGF I production, but no effect on BP production. Bovine GH stimulated production of both peptides, significant effects (up to 50% stimulation) being seen at concentrations from 20-500 ng/ml. Cells from hypophysectomized rats, with serum IGF I and GH levels reduced more than 90% from normal, had IGF I and BP production rates only 7% of normal, measured after 48 h in culture. In vivo replacement with rat GH, 150 micrograms/day for 5 days by osmotic minipump, significantly restored the production of both peptides by hepatocytes. Cells isolated from rats bearing the GH-secreting tumor, MtT/W15, had IGF I and BP production rates approximately twice as high as normal. A significant stimulatory effect of bovine GH (200 ng/ml) in vitro was seen on cells from normal and hypophysectomized, GH-replaced rats, but not from unreplaced hypophysectomized, or tumor-bearing rats. The results in hypophysectomized, animals are consistent with known changes in hepatic GH receptors, while the lack of GH responsiveness in tumor-bearing rats indicates a persistence of maximal stimulation in culture. The reflection of in vivo GH status by hepatocytes cultured for 48 h suggests that messenger RNA turnover for IGF I and BP must be slow. The close parallel in the regulation of the two peptides under most conditions might be indicative of coordinated synthesis.

Animals↗
PubMed1985

Antibody against acid-stable insulin-like growth factor binding protein detects 150,000 mol wt growth hormone-dependent complex in human plasma.

In order to measure the 150,000 mol wt binding complex for insulin-like growth factors in human plasma without the need for acidification to dissociate endogenous ligands, we have purified an acid-stable plasma binding protein (BP) and raised a specific rabbit antiserum against it. When used in RIA, with a covalent complex of binding protein and radioiodinated insulin-like growth factor-I as tracer, pure BP and human plasma samples gave parallel displacement curves. Incubation of plasma with pure insulin-like growth factor-I or -II (5 micrograms/ml) had no effect on the immunoreactivity of the samples. Compared to purified BP standard, the immunoreactive BP content of plasma from normal adults was 9.20 +/- 1.59 micrograms/ml (mean +/- SD, n = 10), from acromegalic subjects, 22.5 +/- 3.63 micrograms/ml (n = 10), and from GH-deficient subjects, 4.10 +/- 1.59 micrograms/ml (n = 7). Although this antibody reacted with a protein of approximately 60,000 mol wt in acidified plasma, gel chromatography of plasma at pH 7 indicated that a GH-dependent protein of mol wt 150,000 was measured almost exclusively in unacidified samples. Direct binding of insulin-like growth factor-II, however, showed the major peak of binding activity in normal plasma in the 40-45,000 mol wt region, whereas in acromegalic plasma most ligand binding was in the 150,000 mol wt region. It is concluded that there is essentially no free immunoreactive acid-stable BP in native plasma, that the unoccupied binding sites of 40-45,000 mol wt, detectable by ligand binding, are present on an immunologically distinct protein, and that the immunoreactive 150,000 mol wt binding complex in native plasma is strongly GH-dependent.

Antibodies↗
PubMed1985

Hemodynamic and metabolic responses of the working heart in relation to the oxygen carrying capacity of the perfusion medium.

Hemodynamic and metabolic adaptations of isolated working heart perfused alternatively with normal or low oxygen carrying capacity medium were studied in an experimental model. A step change in arterial oxygen content (1.75 to 15.3 ml O2/100 ml) was followed by a decrease in coronary flow, an increase in aortic flow, external work, myocardial oxygen consumption and efficiency, respectively. Metabolic investigations (steady state values) showed the activities of both glycolysis and the Krebs cycle to increase with the oxygen carrying capacity of the perfusion medium. Within the limits of these aerobic conditions, most of the cardiac changes were reversible. The use of reconstituted blood provides physiological conditions of oxygenation, allows a dynamic equilibrium between oxygen supply and oxygen requirements and maintains a near physiological regulation between cardiac dynamic and metabolic functions. These conclusions stress the importance of optimal O2 carrying capacity of perfusion medium in metabolic studies on isolated working heart.

Aerobiosis↗
PubMed1984

Breast cancer and polyps of the colon. A case-control study.

A case-control study was conducted involving 145 patients with breast cancer and 144 controls. A pansigmoidoscopy was performed in each case and control. There was no statistically significant difference in the length of the colon explored (cases, 50.3 cm; controls, 48.9). The odds ratio for adenomatous polyps was 2.65 (confidence limits, 1.56 and 3.74). As adenomas of the colon can be considered as precursors of colon cancer, this study demonstrates new evidence of the close relationship between breast and colon cancer. These results show the usefulness of performing a pansigmoidoscopy in all breast cancer patients and, if positive, the removal of all of the polyps through the colonoscope.

Adenoma↗
PubMed1984

Acute coronary vasoconstrictive effects of cigarette smoking in coronary heart disease.

To investigate the effect of cigarette smoking on the coronary vasculature, coronary sinus flow and myocardial oxygen delivery were measured at rest and during incremental atrial pacing in 10 patients with coronary artery disease. Measurements were then repeated while the patients smoked 2 unfiltered, high-nicotine cigarettes. Although smoking significantly increased the heart rate at rest and double product, coronary sinus flow did not change significantly (141 +/- 32 vs 146 +/- 28 ml/min). At the lowest equivalent pacing rate before and during smoking, the double products were comparable. However, coronary sinus flow was reduced by smoking (146 +/- 28 vs 159 +/- 28 ml/min, p less than 0.01) and coronary vascular resistance was increased (0.96 +/- 0.15 vs 0.83 +/- 0.13 mm Hg ml-1 min, p less than 0.02). The double products were also comparable at the peak pacing rate before and during smoking. Nonetheless, the coronary sinus flow was again lower (167 +/- 23 vs 227 +/- 41 ml/min, p = 0.02) and the coronary vascular resistance was higher (0.77 +/- 0.10 vs 0.63 +/- 0.09 mm Hg ml-1 min, p less than 0.01) during smoking. The transmyocardial arteriovenous oxygen difference was unchanged by smoking; therefore, myocardial oxygen delivery was reduced in proportion to the reductions in coronary sinus flow. Thus, cigarette smoking appears to acutely alter the ability of the coronary vasculature to regulate flow in accordance with the oxygen requirements of the myocardium.

Aged↗
PubMed1984

Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: role of cardiac pump dysfunction as determined by the effect of dobutamine.

The maximal exercise capacity of patients with congestive heart failure (CHF) is frequently reduced, partly because of inadequate skeletal muscle nutritive flow. To investigate whether this altered muscle nutritive flow is a result of inability of the heart to increase cardiac output normally during exercise, the effect of dobutamine on systemic and leg blood flow and metabolism during maximal exercise was examined in 11 patients with CHF. At maximal exercise before dobutamine, all patients were limited by fatigue and had reduced maximal systemic oxygen uptake (11.9 +/- 1.1 ml/min/kg) (+/- standard error of the mean), markedly elevated leg oxygen extraction (85 +/- 2%) and elevated femoral venous lactate (53 +/- 5 mg/dl), consistent with impaired nutritive flow to working muscle. Dobutamine increased the peak cardiac output from (6.5 +/- 0.9 0.74 +/- 0.7 liters/min, p less than 0.01) and peak leg flow (from 1.7 +/- 0.3 to 2.1 +/- 0.3 liters/min, p less than 0.05) during exercise. In contrast, no change occurred in maximal exercise duration (5.5 +/- 0.8 vs 5.8 +/- 0.8 min), peak systemic VO2 (829 +/- 97 vs 869 +/- 77 ml/min), peak arterial lactate (34 +/- 2 vs 35 +/- 4 mg/dl) or peak leg lactate output (248 +/- 39 vs 275 +/- 53 mg/min), whereas peak leg oxygen extraction decreased (85 +/- 2 to 80 +/- 2%, p less than 0.01), suggesting no improvement in muscle nutritive flow. These data suggest that nutritive flow to working skeletal muscle is impaired in patients with CHF and that this impairment is not due simply to an inability of the heart to increase the cardiac output normally during exercise.

Blood Flow Velocity↗
PubMed1984

Histochemical identification of cultured cells from human endometrium.

Histochemical techniques have been applied to the identification of cell types cultured from human endometrium. Previous work from this laboratory characterized two principal cell types found in cultures of endometrium: a mature epithelial cell and another cell which was classified as the endometrial stromal cell based on light and electron microscopy. In this report we compare the histochemical staining of endometrial tissue in frozen sections to that of cultured cells. These results confirm the epithelial and stromal nature of the respective cell types. Several markers were found that could distinguish between cells of epithelial and stromal origin. The enzymes alkaline phosphatase, gamma-glutamyltranspeptidase, peroxidase, and beta-glucuronidase were localized in glandular and surface epithelia in frozen sections and in colonies of epithelial cells in culture. Stroma in frozen sections and cultured stromal cells contained leucine aminopeptidase and fibronectin. Epithelia in sections and in culture could also be distinguished from cells of stromal origin by preferential binding of lotus and peanut lectin. Several other markers were found in both endometrial epithelium and stroma.

Alkaline Phosphatase↗
PubMed1984

Sequential changes in regional coronary flow during pacing-induced angina pectoris: coronary flow limitation precedes angina.

To investigate the sequence of changes in regional myocardial perfusion which precedes stress-induced angina, we measured great cardiac vein flow (GCVF), draining the anterior left ventricle, during incremental atrial pacing in 10 patients with normal anterior perfusion (group I) and in 11 patients with greater than or equal to 50% diameter stenosis of the left main or proximal left anterior descending coronary artery (group II). Pacing produced angina in 11 of 11 and regional lactate production in 9 of 11 group II patients. Both groups had comparable resting GCVF (group I = 62 +/- 7 ml/min vs group II = 76 +/- 9 ml/min; p = NS) and both exhibited progressive increases in GCVF with pacing. However, the entire flow-demand relationship was displaced downward in group II, as evidenced by a reduction in the percent increase in GCVF both following the first 20-beat pacing increment (group I = 46 +/- 6% vs group II = 16 +/- 4%; p less than 0.001) and at angina (group I = 113 +/- 16% vs group II = 44 +/- 9%; p less than 0.001). The first 20-beat pacing increment increased the heart rate to only 77 +/- 2 bpm in group II whereas angina and ECG changes did not occur until a pacing rate of 117 +/- 6 bpm. These data indicate that regional flow abnormalities precede the onset of pacing-induced angina in patients with coronary disease (CAD) and that these flow abnormalities frequently are detectable at heart rates substantially below the anginal threshold.

Adult↗
PubMed1984

Myocardial energetics and clinical response to the cardiotonic agent MDL 17043 in advanced heart failure.

Cardiotonic agents may prove useful in the long-term treatment of chronic heart failure provided myocardial efficiency is enhanced and clinical status is improved. Accordingly, the short-term hemodynamic and clinical response to the phosphodiesterase inhibitor, MDL 17043, was evaluated. Intravenous increments of 0.05 mg/kg (maximal total 3 mg/kg) were given to a peak cardiac output response in 13 patients with New York Heart Association functional class IV heart failure secondary to ischemic or myopathic disease. Significant (p less than 0.05) responses at peak effect (1.7 mg/kg) included an increase in cardiac output (3.5 to 4.6 liters/min) and heart rate (86 to 90 beats/min) and a decrease in pulmonary capillary wedge (25 to 17 mm Hg), mean arterial (85 to 78 mm Hg) and right atrial (10 to 7 mm Hg) pressures. Coronary sinus flow (measured in nine patients) increased (122 to 144 ml/min, p less than 0.01) as did myocardial oxygen uptake (14.1 to 15.1 ml/min, p less than 0.01), whereas myocardial extraction of oxygen (78 to 72%, p less than 0.01) and lactate (24 to 9%, p less than 0.01) decreased with three patients producing lactate at the time of their peak cardiac output response. Nine of the 12 patients given long-term oral therapy improved at least one functional class at 2 weeks. This improvement was sustained at 20 weeks in five patients. Thus, MDL 17043 acutely improves the function of the failing heart. However, the decrease in oxygen extraction occurring with increased myocardial oxygen uptake suggests that intracoronary shunting may occur along with an increase in oxygen demand and contribute to myocardial anaerobiosis in some patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Functional group contributions to drug-receptor interactions.

The binding constants and structural components of 200 drugs and enzyme inhibitors have been used to calculate the average binding energies of 10 common functional groups. As expected, charged groups bind more strongly than polar groups, which in turn bind more tightly than nonpolar groups. The derived intrinsic binding energies (in kcal/mol) are (i) charged groups, CO-2, 8.2; PO2-4, 10.0; N+, 11.5; (ii) polar groups, N, 1.2; OH, 2.5; CO, 3.4; O or S ethers, 1.1; halogens, 1.3; (iii) nonpolar groups, C (sp2), 0.7; C (sp3), 0.8. These values may be used to determine the goodness of fit of a drug to its receptor. This is done by comparing the observed binding constant to the average binding energy calculated by summing the intrinsic binding energies of the component groups and then subtracting two entropy related terms (14 kcal/mol for the loss of overall rotational and translational entropy and 0.7 kcal/mol for each degree of conformational freedom). Drugs that match their receptors exceptionally well have a measured binding energy that substantially exceeds this calculated average value--examples include diazepam and biotin. Conversely, if the observed binding energy is very much less than the calculated average value, then the drug apparently matches its receptor less well than average. Examples of this type include methotrexate and buprenorphine.

Animals↗
PubMed1984

Promotional effect of diethylstilbestrol on human endometrial stromal cells pretreated with a direct-acting carcinogen.

Chronic treatment with 0.1 microM diethylstilbestrol (DES) increased the expression of phenotypic alterations in human endometrial stromal cells pretreated with the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Abnormal morphology, expression of gamma-glutamyltranspeptidase, and the ability to form colonies under restrictive conditions were more pronounced after combined treatment with carcinogen and DES compared to carcinogen or DES alone. This effect did not appear to be due simply to growth enhancement by DES, because acute treatment with DES did not alter colony formation, growth rate or thymidine incorporation into DNA in stromal cell cultures. Neither did the presence of DES after the toxicity of MNNG. DES did cause shifts in the isoenzyme distribution of lactate dehydrogenase which could be indicative of a hormonal response. The results suggest that DES may act as a tumor promoter or cocarcinogen in human cells through a mechanism other than simply stimulating cell proliferation, but that other estrogenic effects may contribute to the promotional process.

Carcinogens↗