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Biomedical subjects

K Cain

Publications and source records attributed to K Cain.

At least 55 records · Page 3Linked to original sources
PubMed1991

Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.

Twenty-seven newly diagnosed patients with idiopathic pulmonary fibrosis (IPF) who were previously untreated for IPF were enrolled in a prospective, double-blind, randomized, placebo-controlled study to compare the therapeutic effect of combined prednisone/azathioprine (n = 14) with prednisone plus placebo (n = 13). Prednisone was started at 1.5 mg/kg/day (not to exceed 100 mg/day) for the first 2 wk followed by a biweekly taper to a maintenance dose of 20 mg/day. Azathioprine was administered at a daily dose of 3 mg/kg (not to exceed 200 mg/day). The patients tolerated the use of azathioprine well with few associated side effects. Changes in lung function at 1 yr, as measured by resting alveolar-arterial oxygen difference P[A-a]O2, FVC, and single breath diffusing capacity for carbon monoxide (DLCOSB), were all somewhat better in the azathioprine/prednisone group compared with the prednisone alone group, although none of these comparisons were statistically significant. Six of 14 (43%) patients randomized to prednisone plus azathioprine died during the 9-yr follow-up period, compared with 10 of 13 (77%) patients randomized to prednisone plus placebo. A Cox model survival analysis shows a nonsignificant but potentially large survival advantage for azathioprine/prednisone (hazard ratio 0.48, with 95% confidence interval increasing from 0.17 to 1.38). When adjusted for age, the survival advantage of azathioprine/prednisone becomes marginally significant (hazard ratio 0.26, with 95% confidence interval increasing from 0.08 to 0.88; p = 0.02 by large sample approximation, p = 0.05 by randomization test). We conclude that combined prednisone and azathioprine is a safe and possibly effective regimen for the treatment of IPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Azathioprine↗
PubMed1990

The preparation of highly enriched fractions of binucleated rat hepatocytes by centrifugal elutriation and flow cytometry.

A procedure is described for the isolation of highly enriched fractions of binucleated hepatocytes from rat liver. Liver cells isolated by EGTA and collagenase perfusion were initially subjected to centrifugal elutriation and second to flow cytometry coupled with Hoechst 33342 staining. The elutriation step yielded hepatocyte fractions which contained almost entirely mononuclear diploid cells and fractions enriched in binucleate hepatocytes. The fractions with the highest proportion of binucleated hepatocytes contained between 50 and 56% of these cells. Subsequent flow cytometric cell sorting yielded fractions which contained greater than 80% binucleated cells. These cells were viable in culture as demonstrated by the immunohistochemical detection of bromodeoxyuridine incorporation.

Aneuploidy↗
PubMed1990

What is too much variation? The null hypothesis in small-area analysis.

A small-area analysis (SAA) in health services research often calculates surgery rates for several small areas, compares the largest rate to the smallest, notes that the difference is large, and attempts to explain this discrepancy as a function of service availability, physician practice styles, or other factors. SAAs are often difficult to interpret because there is little theoretical basis for determining how much variation would be expected under the null hypothesis that all of the small areas have similar underlying surgery rates and that the observed variation is due to chance. We developed a computer program to simulate the distribution of several commonly used descriptive statistics under the null hypothesis, and used it to examine the variability in rates among the counties of the state of Washington. The expected variability when the null hypothesis is true is surprisingly large, and becomes worse for procedures with low incidence, for smaller populations, when there is variability among the populations of the counties, and when readmissions are possible. The characteristics of four descriptive statistics were studied and compared. None was uniformly good, but the chi-square statistic had better performance than the others. When we reanalyzed five journal articles that presented sufficient data, the results were usually statistically significant. Since SAA research today is tending to deal with low-incidence events, smaller populations, and measures where readmissions are possible, more research is needed on the distribution of small-area statistics under the null hypothesis. New standards are proposed for the presentation of SAA results.

Age Factors↗
PubMed1989

Morphology of left anterior descending coronary territory lesions as a predictor of anterior myocardial infarction: a CASS Registry Study.

Despite a growing awareness of the correlation of coronary artery stenoses morphology with clinical syndromes, no comprehensive, prospective analysis of the implications of stenosis morphology on risk of myocardial infarction has been reported. Angiograms from 118 patients, representative of the 4.9% of medically treated Coronary Artery Surgery Study (CASS) patients who during subsequent 3 year follow-up study had an anterior myocardial infarction, were matched on the basis of arteriographic anatomy and disease with 141 patients who did not have an anterior infarction. Angiograms from these 259 patients with 557 left anterior descending artery stenoses were reviewed without knowledge of clinical outcome. Conditional regression analyses were performed to determine the importance of stenosis morphology, relative to computer-determined stenosis severity and other clinical variables, in the prediction of risk of infarction. Univariate analysis revealed luminal roughness (odds ratio 4.5; p = 0.001) and lesion length (odds ratio 1.7 per unit length; p = 0.007) to be highly correlated with future risk of infarction. Multivariate analysis revealed left anterior descending artery percent stenosis greater than or equal to 50%, lesion roughness, left circumflex artery stenosis and smoking, in that order, to be predictive of anterior myocardial infarction, whereas 22 other morphologic variables were not independently predictive of outcome. The importance of stenosis roughness may relate to its propensity for thrombogenesis and should be considered in clinical decision making.

Angiography↗
PubMed1988

Prediction of risk of anterior myocardial infarction by lesion severity and measurement method of stenoses in the left anterior descending coronary distribution: a CASS Registry Study.

To assess the 3 year risk of anterior myocardial infarction in patients with left anterior descending coronary artery territory disease (30 to 100% stenosis), National Heart, Lung, and Blood Institute (NHLBI) Coronary Artery Surgery Study (CASS) registry patients were identified who were 1) medically treated, and 2) had evidence of viable anterior myocardium at the time of baseline angiography. Prospectively, 118 patients having an anterior infarction within 3 years of baseline angiography were identified from annual follow-up of 4,535 medically treated patients who had left anterior descending coronary artery disease and viable anterior myocardium. From the large residual pool of patients without infarction, 141 were randomly selected from a stratified matrix to represent the entire group. The maximal percent stenosis was estimated by the CASS multiple angiographers, by a current single observer rereading and by contemporary computer measurement techniques. Absolute lumen dimension was assessed by computer measurement. The 3 year risk of anterior infarction was 2% for patients with their most severe left anterior descending stenosis less than 50%, 6% for patients with one such stenosis greater than or equal to 50% and 11% for patients with two or more such stenoses greater than or equal to 50% (p less than 0.02). Stenoses of 90 to 98% had the highest (15%) 3 year risk of anterior myocardial infarction. The three methods used to measure maximal percent stenosis differed little with regard to their predictiveness. Absolute lumen dimension was less predictive of risk. These results may provide a more rational basis on which to base coronary revascularization decisions.

Clinical Trials as Topic↗
PubMed1986

Possible mechanism for differences in sensitivity to cis-platinum in human prostate tumor cell lines.

Two human prostate tumor cell lines which exhibit a 2.4-fold difference in sensitivity to cis-platinum (cis-Pt) were found to possess slightly different sulphydryl contents, and the presence of a metallothionein-like zinc-binding protein was demonstrated in the line exhibiting relative resistance to cis-Pt. Although these factors have been postulated to play a role in the mechanism(s) of resistance to cis-Pt in other cell types, preliminary data in this report suggest that differences found in drug uptake and subsequent binding to DNA are most likely responsible for variations in cis-Pt sensitivity displayed by these prostate tumor cell lines.

Cell Line↗
PubMed1984

A comparison of isometallothionein synthesis in rat liver after partial hepatectomy and parenteral zinc injection.

The time course of hepatic zinc-isometallothionein synthesis was studied in the regenerating liver and compared with that produced after the parenteral injection of zinc (6 mg of Zn2+/kg). In the regenerating liver, zinc levels rose rapidly after partial hepatectomy and reached a maximum at approx. 14h before declining to approximately normal levels at 48h post-operation. During this 48h period most of the zinc was incorporated into metallothionein. Purification of the latter into the charge-separable isometallothioneins (i.e. MT1 and MT2) showed that, in the regenerating liver, there was an unequal distribution of zinc between the two isoproteins. Thus at operation the endogenous thionein had an MT2/MT1 ratio of 1; after regeneration this ratio increased, and all times during the time course there was more MT2 than MT1. In contrast, the intraperitoneal injection of zinc produced a biphasic uptake of zinc into the liver with maxima at 10h and 32h. During the first phase of zinc uptake, metallothionein synthesis increased rapidly and, unlike the regenerating liver, the MT2/MT1 ratio of 1 remained constant. Thereafter, this ratio increased in a manner analogous to that exhibited by the regenerating liver. Half-life determinations for thionein disappearance/degradation shows that MT2 and MT1 were degraded with half-lives (t1/2) of 26.18h and 16.44h respectively in the regenerating liver and 14.75h and 9.3h after zinc injection. Thus thionein disappearance/degradation in the regenerating liver was slower than that seen after zinc injection. However, in both situations MT2 was always removed at a slower rate than MT1. Calculation of the rates of thionein synthesis (assuming the above disappearance rates were constant throughout the time course) showed that, in the regenerating liver, the rate of MT2 synthesis was approximately twice that of MT1. This was not the case after zinc injection, where both isometallothioneins were synthesized in equal amounts. These results demonstrate that the rates of synthesis of MT2 and MT1 can be altered according to the metabolic status of the cell and suggest a specific role for MT2 during liver regeneration.

Animals↗
PubMed1983

The identification and characterization of two separate carboxylesterases in guinea-pig serum.

The esterase activity of guinea-pig serum was investigated. A 3-fold purification was achieved by removing the serum albumin by Blue Sepharose CL-6B affinity chromatography. The partially purified enzyme preparation had carboxylesterase and cholinesterase activities of 1.0 and 0.22 mumol of substrate/min per mg of protein respectively. The esterases were labelled with [3H]di-isopropyl phosphorofluoridate (DiPF) and separated electrophoretically on sodium dodecyl sulphate/polyacrylamide gels. Two main labelled bands were detected: band I had Mr 80 000 and bound 18-19 pmol of [3H]DiPF/mg of protein, and band II had Mr 58 000 and bound 7 pmol of [3H]DiPF/mg of protein. Bis-p-nitrophenyl phosphate (a selective inhibitor of carboxylesterase) inhibited most of the labelling of bands I and II. The residual labelling (8%) of band I but not band II (4%) was removed by preincubation of partially purified enzyme preparation with neostigmine (a selective inhibitor of cholinesterase). Paraoxon totally prevented the [3H]DiPF labelling of the partially purified enzyme preparation. Isoelectrofocusing of [3H]DiPF-labelled and uninhibited partially purified enzyme preparation revealed that there were at least two separate carboxylesterases, which had pI3.9 and pI6.2, a cholinesterase enzyme (pI4.3) and an unidentified protein that reacts with [3H]DiPF and has a pI5.0. Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis of these enzymes showed that the carboxylesterase enzymes at pI3.9 and pI6.2 corresponded to the 80 000-Mr subunit (band I) and 58 000-Mr subunit (band II). The cholinesterase enzyme was also composed of 80 000-Mr subunits (i.e. the residual labelling in band I after bis-p-nitrophenyl phosphate treatment). The unidentified protein at pI5.0 corresponded to the residual labelling in band II (Mr 58 000), which was insensitive to neostigmine and bis-p-nitrophenyl phosphate. These studies show that the carboxylesterase activity of guinea-pig serum is the result of at least two separate and distinct enzymes.

Animals↗
PubMed1983

88MHz 113Cd-n.m.r. studies of native rat liver metallothioneins.

Well-resolved 113Cd-n.m.r. spectra of 113Cd-induced rat liver metallothioneins 1 and 2 are obtainable even at 88 MHz (9.4T). The line-widths of resonances are not dominated by chemical-shift-anisotropy relaxation. The increased spectral dispersion will significantly aid the study of the native (Cd- and Zn-containing) metallothioneins.

Animals↗
PubMed1983

Comparison of cadmium-metallothionein synthesis in parenchymal and non-parenchymal rat liver cells.

The time course of cadmium-metallothionein synthesis was studied in non-parenchymal and parenchymal cells, isolated by a cell-separation technique from the livers of rats after the simultaneous injection of CdCl2 (0.05 mg of Cd/kg) and a 10-fold molar excess of 2,3-dimercaptopropanol. Under these conditions of dosing, in contrast with the injection of CdCl2 alone, both cell types accumulate similar concentrations of Cd and synthesize equivalent concentrations of metallothionein. It is concluded that both cell types have a similar capacity to synthesize the metalloprotein, and that the limiting factor under normal cadmium exposure is the relatively inefficient metal uptake into the non-parenchymal cells.

Animals↗
PubMed1983

Cadmium-metallothionein-induced nephropathy: a morphological and autoradiographic study of cadmium distribution, the development of tubular damage and subsequent cell regeneration.

A single intravenous dose of 0.8 mg thionein-bound cadmium (Cd) per kg body weight, as the isolated (Cd, Zn)-metallothionein (MT) from rat liver, in rats of the same strain is nephrotoxic, but not lethal. Apical vesiculation in epithelial cells of the renal proximal convoluted tubules is apparent within 1 h of dosing and, by 4 h, is extensive in some of these cells that surround the larger arteries in the cortex. The membranes of these cells appear undamaged. The lesion at first progresses with time; by 24 h, the initially affected cells show extensive necrosis and most proximal convoluted tubular epithelia in other regions of the cortex are hydropically or vacuolarly degenerated. The inner stripe of the outer zone of the medulla and other portions of the nephron (glomerulus, distal tubule and collecting duct), however, appear essentially unaffected. The necrotic changes are maximal at 48 h but, after this time, regeneration begins. By seven days, much of the cell debris has been eliminated and cells of the regenerating or regenerated epithelia are similar in morphology to those of the normal kidney. Electron microscopic autoradiography of kidney sections from rats after administration of 109Cd-metallothionein of high specific activity shows that Cd is not concentrated in endocytotic vesicles, lysosomes, or any other cellular organelle, even at early times after dosing, but is distributed evenly throughout the epithelial cell. Thus, although Cd-MT appears to be taken up endocytotically in the kidney tubules, it appears that liberation of Cd from the metalloprotein must occur very early in the reabsorptive process.

Animals↗
PubMed1983

Studies of cadmium-thionein induced nephropathy: time course of cadmium-thionein uptake and degradation.

The renal uptake and degradation of cadmium-thionein (Cd-Mt) were examined in relation to nephrotoxic effects. Studies with Cd-Mt labelled with [3H]cystine showed that both Cd2+ and tritium uptake in the kidneys were complete 4 h after injection. During this period, renal copper content doubles due to the replacement of thionein-bound Cd2+ with Cu2+. This process probably occurs in the blood, prior to metallothionein uptake. Once reabsorbed, the protein is rapidly degraded in the lysosomes at a rate in step with uptake. Consequently, at 4 h virtually all of the Cd-Mt was degraded, resulting in a high concentration of non-thionein bound Cd2+. This Cd2+ (approx. 11-12 micrograms Cd2+/g, i.e. 70% of the total renal Cd2+ burden) produces the toxic effects. Between 2-4 h, new thionein synthesis is initiated and Cd2+ gradually becomes bound as the metallothionein. By 4 days, 80% of the renal Cd2+ is bound to endogenous thionein. These studies demonstrate that even small amounts of non-thionein bound Cd2+ are toxic to the kidney.

Animals↗
PubMed1981

Effects of thiol agents on the accumulation of cadmium by rat liver parenchymal and Kupffer cells.

The rate of Cd accumulation by adult rat liver parenchymal cells in serum free primary culture in the presence of 100 microM CdCl2 was 10 times greater than that by non-parenchymal Kupffer cells. Addition of the monothiol chelating agents, cysteine and penicillamine, decreased Cd uptake in both cell types, the effect becoming more pronounced as the monothiol concentration was increased from 0.1 to 1.0 mM. These monothiols thus appear to reduce the availability of Cd for transport across the cell membrane. In contrast 1-10 molar excesses of the dithiol agents 2,3-dimercaptopropanol (BAL) or dithiothreitol (DTT) stimulated to variable extents the rate of Cd accumulation 2-10-fold in parenchymal cells and by over 100-fold in Kupffer cells. Supplementation of the media with 3% serum had little effect on the Cd accumulation in the presence of dithiols. Intravenous injection of Cd (0.05 mg/kg DCdCl2) with up to a 10-fold molar excess of cysteine or penicillamine had little effect on the hepatocellular Cd distribution. However Cd uptake by non-parenchymal cells was increased markedly by the simultaneous administration of BAL or DTT in 2 or 10 molar excess. Evidence is provided that these results may be partially explained by the endocytosis, particularly in Kupffer cells, of colloidal complexes of Cd which are formed with the dithiols but not the monothiols. These observations demonstrate that the physicochemical form of Cd determines its hepatocellular distribution which may be an important factor in the manifestation of Cd toxicity after thiol treatment.

Animals↗
PubMed1980

Selective uptake of cadmium by the parenchyumal cells of liver.

The uptake of cadmium in vivo into parenchymal and non-parenchymal (sinusoidal) cells of the liver was studied by a cell-separation technique. Liver parenchymal cells accumulate cadmium more readily than do non-parenchymal cells and synthesize metallothionein. It is proposed that cadmium uptake and metabolism from injected CdCl2, is restricted almost exclusively to the liver parenchymal cells.

Animals↗
PubMed1979

Metallothionein degradation: metal composition as a controlling factor.

Degradation of the cadmium (Cd)-induced protein, metallothionein (MT) was studied in rat liver and kidney. The half-times (t1/2s) for degradation of the protein were found to vary according to the concentration of Cd in the tissues. In animals containing high Cd2+ concentrations, the t1/2 of degradation was significantly longer than in low Cd2+ animals. There were no significant differences in degradation times between liver and kidney. Purification of the MT by anion exchange chromatography revealed two species which had, in the liver at least, different degradation times. Since the metal content of the MTs did not vary throughout the time course of the experiment, it is proposed that the rate of degradation and hence the turnover of the protein is influenced by the ratio of Cd2+ to other bound cations (e.g. Zn2+ and Cu2+). Thus, the Cd/Zn ratio in the liver and the Cd/Cu ratio in the kidney determine the respective rates of degradation and hence turnover of the protein.

Animals↗