Initial Rapid Decline Research Articles

Surface marker and histopathologic correlation with long-term survival in advanced large-cell non-Hodgkin's lymphoma.

Since 1974, a group of consecutive adult patients with non-Hodgkin's lymphoma have been prospectively analyzed for tumor-surface membrane-marker phenotype and histopathologic correlation with response to treatment and survival. The results are reported in a subset of 35 patients with advanced (Stages III-IV) large-cell variants, most of whom would be classified by Rappaport criteria as histiocytic. An attempt has been made to define those marker characteristics that will identify long-term survivors in this diverse group who remain in continuous disease-free remission. There were ten patients with complete remissions with intensive treatment. The most common subgroup within the complete responders were patients with cells that were nonexpressive (null) and were classified by Lukes-Collins criteria as the large, noncleaved follicular center cell variant. Currently there are seven patients remaining in complete remission, five of whom have been in continuous disease-free remission for more than two years (total survival 34+-42+ months) following cessation of all treatment. Of those five, four were in the null group and four were classified as large non-cleaved. The actuarial survival curve for all null patients is characterized by a rapid initial decline and a subsequent plateau, which contains four of the long survivors. In contrast, the B-derived group has a more graded decline in survival with time; this curve currently contains the remaining long survivor. Although the overall prognosis of B-derived tumors appears to be superior to that of the null subset, the subgroup with the potential for cure at this point in our study includes patients with both null and B-derived tumors, particularly those classified by Lukes-Collins criteria as the large noncleaved follicular center cell variant.

Pharmacokinetics and Organ Distribution of Methotrexate in the Rat

After intravenous injection of 31 mg/kg methotrexate (MTX), its concentrations were determined in plasma, liver, kidney, bone marrow, stomach, duodenum, jejunum, colon and muscle up to 23 days, using an enzymatic assay. Plasma pharmacokinetics were described by a triexponential function, with a terminal half-life of 4.2 h. Up to 1.5 h after injection, the initial rapid decline of MTX concentrations in bone marrow, kidney, and liver roughly paralleled that in plasma. The terminal half-life of MTX in bone marrow was greatly prolonged (37 h), while MTX remained nearly constant in liver (0.57 microgram/ml) and kidney (0.53 microgram/ml) from 6 h to 23 days. In the intestines, luminal as well as tissue MTX concentrations were determined. The stomach showed a triexponential decay of tissue MTX and low luminal concentrations throughout. In the duodenum, the middle of jejunum, and the colon tissue MTX seemed to follow a bi- or triexponential function. However, high luminal concentrations due to MTX biliary excretion, when reaching a given intestinal portion, increased the MTX tissue concentration in this segment.

Investigations on connective tissue metabolism: Ageing of the human heart

In any given phase of the age process, the rates of synthesis and degradation of collagen and other macromolecules are diversely influenced by changes in the respective enzyme activities. This naturally affects and reflects the contents of the intracellular as well as extracellular macromolecules. In our studies, the total contents of desoxyribonucleic acid (DNA), hydroxyproline, hexosamines and uronic acids of the four compartments of the human heart were estimated and plotted against age. The results obtained for DNA showed an initial rapid decline in its content to about the middle of the third decade of life, i.e. around the end of the maturation period. Thereafter, the DNA curves showed a relatively slower decrease until the fifth decade, after which a slight increase was observed during senescence. This holds for both the left and the right sides of the heart. Hydroxyproline levels, on the other hand, remained unchanged in all the different compartments except in the left atrium, where the initial phase of the curve showed a significant drop until the middle of the fourth decade. Hydroxyproline values in the atria were twice as high as in the ventricles, which in turn showed higher levels of hexosamines than uronic acids. Both hexosamines and uronic acids in the atrial walls showed an initial decline followed by a gradual rise during ageing. Contents of uronic acids in the ventricles showed a gradual but steady rise throughout life.

Metabolic effects of starvation in the snakehead, Ophiocephalus maculatus

1.1. Snakeheads (Ophiocephalus maculatus) were kept in fresh water at 21 ± 1 °C without food for 142 days.2.2. After an initial rapid decline in body weight, the rate of decrease in body weight was constant (0.14%/day).3.3. Inanition resulted in marked decline in ammonia excretion rate and plasma cortisol level.4.4. Plasma glucose concentration and hematocrit were reduced, plasma protein level was elevated but plasma free fatty acids level was increased after an initial decline.5.5. Both the hepatosomatic index and liver protein concentration fell rapidly during the initial 33 days but were maintained constant thereafter. Oxygen consumption rate also declined sharply during the first 60 days but increased subsequently.6.6. Liver glycogen was depleted but muscle glycogen was unaffected.7.7. It is suggested that in the snakehead, protein catabolism is reduced with the onset of starvation.

Diazepam kinetics in acute alcohol withdrawal

We performed a within-subject comparison of the kinetics of diazepam given to 7 alcoholic subjects during acute alcohol withdrawal and again after detoxification. The initial rapid exponential decline of plasma diazepam concentrations (t1/2 alpha) was more rapid during (0.21 +/- 0.03 hr) than after withdrawal (0.44 +/- 0.14 hr, p less than 0.05). Terminal t1/2, clearance, and volumes of distribution changed in individual patients, but mean values did not change. Protein binding was less in patients (93.4 +/- 2.4%) than in healthy controls (97.0 +/- 1.0, p less than 0.05). The effects of alcohol withdrawal on diazepam disposition do not explain the high doses of diazepam commonly required to treat the withdrawal.

Regional cerebral blood flow measured by 133Xe inhalation in tracheostomized and laryngectomized men and women

The question of contamination of cerebral clearance curves utilized for measureing regional cerebral blood flow by radioactivity derived from the nasopharyngeal air passages following inhalation of 133Xe was tested in patients with chronic tracheostomy. The peak counts for head curves were 5–9% higher when 133Xe was inhaled via a face mask than when inhaled via the tracheal stoma. Calculated flow values using standard recommended start-fit-times were not significantly different between these two different methods. Present results indicate that neither overestimation of fast flow values due to contamination from rapid 133Xe washout recorded from the air passages nor the underestimation of slow flow due to contamination from 133Xe trapped in the air sinuses produces significant measurement errors. However, if earlier start-fit-times were used, flow values were artificially high, particularly for brain stem/cerebellar probes because of an initial rapid decline in the head desaturation curves due to an arterial peak believed to be derived from the basilar artery.

Time courses of carbachol-induced responses in guinea pig atria under the influence of ouabain, calcium, and rate of stimulation.

The response of isolated left atria of guinea pigs to carbachol was measured in the presence and during washout of the drug. The time courses of the negative inotropic effect and of the rate of shortening in action potential duration were compared. The initial rapid decline in force of contraction was followed by a slowly developing partial recovery (fading). After removal of the drug, a transient phase of hypercontractility was observed before the control level was reached again. In contrast to the mechanical effect, the drug-induced shortening of the action potential duration proceeded monophasically. The fading and hypercontractility phenomena shown by the mechanical response to the drug were influenced by the stimulation rate and by the presence of ouabain. From the dissociation of electrical and mechanical effects it is concluded that fading and hypercontractility are not due to changes of receptor sensitivity but reflect a change in cellular calcium distribution.

Glucose-Lowering Effect of Insulin by Different Routes in Obese and Lean Nonketotic Diabetic Patients*

The absorption of insulin and its glucose-lowering effect were compared after the administration of crystalline insulin by sc, im, and iv routes in 29 obese and 10 lean nonketotic diabetic patients, none of whom had consciously received insulin previously. Each of the patients received insulin in a dose of 0.1 U/kg BW by the im, sc, and iv routes in a randomized fashion on 3 different days. Plasma glucose, immunoreactive insulin (IRI), and immunoreactive glucagon (IRG) were measured at intervals over the first 4 h. The t1/2 (mean +/- SEM) after iv administration of insulin in obese and lean diabetics was, respectively, 5.3 +/- 0.2 and 4.8 +/- 0.4 min; these were not significantly different. Intravenous injection produced its highest level of IRI in 2 min in both groups. Thereafter, a rapid drop was observed with return to the basal level by 90 min. Equivalent amounts of im and sc insulin produced a maximal increase in plasma IRI at 60 min in both groups. Plasma IRI after iv insulin injection was significantly higher than after sc and im insulin injections at 10 and 20 min (P less than 0.001) and significantly lower than the im and sc groups at 60, 90, 120, 150, 180, 210, and 240 min (P less than 0.001). After iv insulin, plasma glucose at 30, 40, 50, and 60 min was significantly lower than after im and sc insulin (P less than 0.001), but over the 4-h study period, the glucose-lowering effect and the area under the curves for glucose response to IRI by the three routes were the same in both lean and obese diabetic subjects. The mean basal IRI in lean patients was 18 +/- 4 microU/ml, which was significantly lower (P less than 0.05) than in obese patients (26 +/- 2 microU/ml). No significant difference was observed in fasting IRG in lean (96 +/- 12 pg/ml) vs. obese (108 +/- 10 pg/ml) patients. No significant increase in IRG was noted with equivalent amounts of sc, im, and iv injection in the lean and obese patients. These studies demonstrated that although iv injection of insulin produces a more rapid initial decline in plasma glucose, the overall glucose-lowering effect by insulin given iv, im or sc is similar in nonketotic lean or obese diabetic subjects.

Clinical Pharmacokinetics of Lignocaine

Lignocaine is widely used as a local anaesthetic and antiarrhythmic drug. It is commonly administered to patients with acute myocardial infarction as prophylaxis for ventricular fibrillation, although its efficacy in preventing primary ventricular fibrillation is still debated. Toxicity, sometimes with serious clinical consequence, is not uncommom and is usually related to overdosage. Blood lignocaine concentrations correlate roughly with antiarrhythmic and toxic effects and might be useful as an end point for monitoring prophylactic therapy. Administration of lignocaine as a local anaesthetic may result in blood lignocaine concentration in the antiarrhythmic or even toxic ranges. Expected peak levels for various routes of local anaesthesia are tabulated so that 'safe' total doses can be calculated. Intramuscular injection of high doses results in sustained therapeutic levels but is often associated with early minor toxicity. Lignocaine is eliminated primarily by hepatic metabolism, which appears to be limited by liver perfusion. Active metabolites may contribute to therapeutic and/or toxic effects. Disease states such as cardiac failure or drugs that alter hepatic blood flow may significantly affect lignocaine clearance. Pharmacokinetic studies in man show wide variability in drug disposition between patients, even when cardiac and hepatic status is considered, making specific dosing recommendations a problem. With intravenous injection, multicompartment kinetics is observed, with an initial rapid decline phase and initial decline in antiarrhythmic activity due to redistribution. With constant infusion, steady state concentrations of lignocaine are seen after 3 to 4 hours in normal subjects and after 8 to 10 hours in patients with myocardial infarction without circulatory insufficiency. In patients with cardiac failure, blood lignocaine concentration may continue to rise for 24 to 48 hours. In the presence of cardiac failure, decreased volumes of distribution and clearance require reduction in loading and maintenance doses. Lignocaine clearance is reduced in patients with liver disease and appears to be a sensitive index of liver dysfunction. A dosing algorithm for treatment of patients with myocardial infarction is presented.

Environmental factors affecting Escherichia coli and Salmonella typhimurium numbers on land used for effluent disposal

Escherichia coli cells applied to soil and pasture in piggery effluent, or as a bacteria in water suspension, were found to be susceptible to desiccation in grey clay loam soil when the soil dry matter exceeded 90%, the approximate wilting point of this soil. Inoculation of the cells onto dry soil resulted in c. 99% reduction in cell numbers in 24 hr, even when the soil was shaded. Surviving cells were observed to persist for 8 weeks after inoculation. Salmonella typhimurium cell suspensions added to experimental plots displayed similar persistence characteristics to E. coli. E. coli cells in effluent or suspensions added to moist soil did not exhibit a rapid initial decline in number. The number of E. coli on the pasture diminished quickly even when the soil below was moist. Only a small percentage of inoculum cells were collected in run-off water from the plots after heavy rainfall, although the absolute number of cells was sufficient to pollute a large volume of water if discharged directly into a watercourse.

Phospholipid Turnover in Soybean Tissue Cultures

The degradation rates of phospholipids in soybean (Glycine max L. Merrill) suspension cultures were studied by pulse-chase experiments. The only chloroform-soluble product of incorporation of radioactive choline was phosphatidylcholine, the bulk of which had a half-life of 36 hours. Ethanolamine was incorporated primarily into phosphatidylethanolamine, phosphatidylcholine at an intermediate level, and phosphatidylmonomethylethanolamine to a small extent. The phosphatidylethanolamine decayed in a triphasic fashion with half-lives of 12, 34, and 136 hours. Phosphatidylcholine in this case increased in radioactivity up to day 4 and thereafter declined with a 92-hour half-life. The radioactivity rose slightly to day 4 in phosphatidylmonomethylethanolamine after an initial rapid decline. When serine was used as a substrate, half-lives similar to those obtained with ethanolamine were obtained. Phosphatidylcholine contained the greatest amount of label, however, with phosphatidylethanolamine containing slightly less, and phosphatidylserine contained the least. Data also are presented for glycerol and acetate phospholipid product degradation.

Luteolysis induced by prostaglandin F2 alpha before and after hysterectomy in heifers.

In a Latin Square design, each of 6 heifers was given (im) 5, 10 and 15 mg PGF20 during diestrus during three consecutive estrous cycles. Then the uterus and cervix were removed. Thirty to 45 days after surgery, each hysterectomized heifer was given 30 mg PGF3 � to induce estrus before the same experimental doses of PGF20 were resumed at 15-day intervals beginning 10 to 12 days after this induced estrus. Ten and 15 mg PGF20 were luteolytic in 10 of 12 heifers before and after hysterectomy. While 5 mg PGF3 � was not luteolyticin intactheifers,it caused luteolysis in three of four heifers after hysterectomy. Thus, the uterus is not required for luteolysis induced by exogenous PGF20 in heifers. To the contrary, the uterus may interfere with luteolysis induced by PGF20. Serum (jugular) progesterone changes were similarforthe first 6 h after 5, 10 or 15 mg PGF20 in heifers before and after hysterectomy, whether or not PGF2 � was luteolytic. After the first 6 h, progesterone remained elevated at about 60 percent of pretreatment values in heifers which did not exhibit estrous behavior, while progesterone declined to less than 1 ng/ml within 36 h in heifers which exhibited estrus. Following the initial rapid decline in progesterone, serum LH doubled within 3 h after administration of PGF20 and LH remained elevated until 6 h in all heifers; it returned to pretreatment values within 12 to 24 h when heifers exhibited no estrus, but it remained elevated when PGF20 was luteolytic. Serum estradiol increased within 18 h when PGF20 was luteolytic, and estrus began at 78 ± 5 h in these heifers. There was no rise in serum estradiol when heifers failed to exhibit estrus after PGF2 �. Thus, beginning within 18 h, elevated estrogen secretion may participate in the Iuteolysis begun by exogenous PGF2 �. Serum testosterone was unaffected by PGF20 injections before or after hysterectomy.

The stability of tyrosine aminotransferase and other proteins in enucleated rat hepatoma tissue culture cells.

The role of the nucleus in bringing about the induction of tyrosine aminotransferase (TAT) by glucocorticosteroid hormone and its deinduction upon steroid removal has been studied in enucleated rat hepatoma tissue culture cells (FU5-5). Both processes require the presence of the nucleus. However, cytoplasts from preinduced cells show an initial rapid decline in enzyme activity immediately after enucleation followed by maintenance of a constant level of activity. This initial decline in enzyme activity can be partially prevented by trypan blue, an inhibitor of lysosomal activity. This suggests that the early fall in enzyme activity could be due to an increase in the level of lysosomal activity immediately after enucleation. The subsequent constant level of activity seems due to maintenance rather than synthesis and degradation since it is not affected by cycloheximide. The absence of degradation applies to other kinds of proteins in enucleated FU5-5 cells and enucleated mouse fibroblast L cells. These experiments suggest that some kind of labile RNA or protein dependent on the presence of the nucleus is required for the degradation of all classes of proteins in different kinds of cells.

Pharmacokinetics of Bay g 2821 in the dog and in man.

The pharmacokinetics of Bay g 2821, a new diuretic agent, were studied in dogs, healthy volunteers and in patients with renal insufficiency. The drug was rapidly absorbed after oral administration, peak plasma levels (approx. 0.4 microgram/ml) occurring within 1 hour. Elimination of the unchanged drug from plasma was biphasic - an initial rapid decline with a half-life of about 3 hours, followed by a longer second phase with a half-life of 13 to 17 hours. Results were similar in healthy volunteers and in patients with renal insufficiency. It is assumed that the drug is mainly eliminated in bile, probably after biotransformation, and elimination in the urine is a minor pathway.

The immune response of pigs to infection with the stomach worm Hyostrongylus rubidus (Hassall and Stiles, 1892) : II. Multiple infections and reinfections in growing pigs and sows

Pigs given multiple infections of third stage Hyostrongylus ribidus larvae over a 10-day period produced detectable circulating agglutinins 2–3 days after the initial infection. Titres were neither higher nor more prolonged than those of pigs which received a single infection of larvae, although fluctuations in titres over a 30-day period were more marked. Pigs reinfected with a single dose of third stage larvae, however, showed a rapid initial decline in titre followed by a gradual increase to a level higher than that detected at primary infection. Biological manifestations of immunity such as a decreased parasite egg output and increased prepatent period were also seen. The host reaction to reinfection is regarded as an anamnestic response.

Development of a synthetic pig sire line by selection with immigration 1. Results of selection and heritability estimates

SUMMARYStarting in 1959 from a crossbred foundation, a specialized synthetic sire line has been developed with the aim of making rapid genetic improvement in lean meat production. Within-line selection, firston ultrasonic backfat and then on a performance index, was supplemented over 11 generations by a process of competitive immigration, in which individuals of any breed from outside were incorporated into the line on merit. By Generation 11 the Sire Line contained genes from 9 pure breeds and 2 hybrid strains.After a rapid initial phenotypic decline in backfat, there was little apparent response to index selection. In Generation 11, a centrally tested sample of the Sire Line showed significant improvements over contemporary Large Whites in growth rate, feed efficiency, eye-muscle area, lean percentage and some fat depths, but was significantly worse in killing-out percentage. With the exception of teat number there was no evidence of a decline in reproductive performance, to which no attention was paid during selection. Estimated heritabilities of growth rate and backfat were not sufficiently different from those reported for purebred pig populations to indicate that additive genetic variance had been changed by mixing breeds. Some of the advantages and disadvantages of the ‘open synthetic’ method of genetic improvement are discussed.

Chlorine reactions with seawater constituents and the inhibition of photosynthesis of natural marine phytoplankton

The time course of ‘chlorine’ disappearance was followed in filtered (I), non-filtered (II) and u.v.-oxidized (III) seawater. In I and II there was an initial rapid decline in both free and residual ‘chlorine’ followed by a slower decline of these species. No decline was observed in III, suggesting that the removal of organic matter and/or the oxidation of metal ions by u.v. oxidation, removes those molecular species that react with ‘chlorine’. Reaction rate was more rapid in II than in I, suggesting that particulate organic matter may also react with ‘chlorine’. Reaction kinetics of ‘chlorine’ were complex but approximated second order in the ‘slow’ phase. The inhibition of phytoplankton photosynthesis by ‘chlorine’ was studied by adding hypochlorite to seawater samples in the laboratory and in field samples collected adjacent to an open coast marine outfall of an electric generating station. ‘Chlorine’ concentrations required for 50% inhibition varied with exposure time. For 24-hour incubations such inhibition took place with residual ‘chlorine’ concentrations about 10 parts/10 9. However, there was no recovery of photosynthetic activity when residual chlorine had fallen to undetectable levels. The inhibition appears to be irreversible. As noted earlier by others the principal deleterious impact on marine phytoplankton of the use of seawater for cooling power plants lies in the use of ‘chlorine’ to prevent slime build-up in the condenser systems. Hypochlorite reacts rapidly with the bromide ion in seawater to from hypobromous acid and hypobromite. Perhaps these and ‘residual bromine’ are the physiologically active substances formed on chlorinating seawater (Dove, 1970). If so, then biocidal concentrations of ‘chlorine’ for marine organisms would not necessarily be the same as those reported for freshwater organisms.

Hormonal Regulation of Glycogen Metabolism in Human Fetal Liver: I. Normal Development and Effects of Dibutyryl Cyclic AMP, Glucagon, and Insulin in Liver Explants

Glycogen accumulates in human fetal liver beginning at the eighth week of gestation. A parallel increase in total glycogen synthase activity is found, although the I-form activity remains low and constant throughout the first two thirds of gestation. Total phosphorylase activity increases slightly during this period, with the proportion in the active form amounting to about one half of the total throughout. After an initial rapid decline, the glycogen concentration in explants of human fetal liver remained constant for twenty to forty hours at about 20 per cent of the in vivo level. Incubation with glucagon, cyclic AMP (adenosine 3',5'-monophosphate) or its dibutyryl derivative markedly reduced tissue glycogen concentrations while insulin brought about a small increase. The effect of maximal doses of dibutyryl cyclic AMP and glucagon were the same, and the combination of agents produced no further effect. The response to dibutyryl cyclic AMP was apparent by one hour and maximal by three to six hours, whereas the response to insulin required about six hours to be detected, and it continued for at least eighteen hours. Insulin antagonized the glycogenolytic effect of low doses of glucagon or theophylline but was without significant effect in the presence of high glucagon concentrations. Glucagon stimulated cyclic AMP output from explants, and this effect was further augmented by theophylline. Insultin had no consistent effect on cyclic AMP output in either the presence or the absence of glucagon or theophylline. Incubation with dibutyryl cyclic AMP resulted in a decrease of glycogen synthase I-form activity, while insulin tended to increase this enzyme activity. In neither circumstance was the proportion of active phosphorylase altered. These results suggest that the regulation of glycogen levels in human fetal liver by cyclic AMP, glucagon, and insulin may entail alterations in the activity of glycogen synthase activity without necessitating alterations in phosphorylase activity. Cyclic AMP or glucagon was capable of depleting tissue glycogen stores in tissue from fetuses of six weeks' gestation. Insulin increased tissue glycogen concentrations in tissue from fetuses of seven or more weeks.

Plasma Levels of Diazepam and Mood Ratings

Ten subjects received 10 and 20-mg. doses of diazepam intravenously. The plasma levels of the drug and its major metabolite, desmethyl-diazepam were measured and coordinated with answers to a subjective questionnaire. After initial rapid decline of the diazepam level, the level and shape of the remaining part of individual plasma curves showed considerable variance. Increases in diazepam levels were minute (0.04 plus or minus 0.03 mcg./ml.). Desmethyl-diazepam levels continued to build up until the end of sampling. Contrary to some previous reports, no recurrent drowsiness was evident after initial recovery. Correlation between plasma levels of diazepam and some of the subject's moods was significant. Nevertheless, further studies are needed to determine whether plasma levels can be meaningfully related to various cerebral effects of the drug.

Effects of tonicity on the resting tension in bullfrog ventricle.

A study of the effects of hyper -and hypotonic media on resting tension were examined in ventricular muscle of the bullfrog was undertaken because only few studies on resting tension from the viewpoint of E-C coupling in the heart muscle are available. Thin strips obtained from the bullfrog ventricle were perfused in the sucrose-gapped chamber, which allowed the effective stimulation and the simultaneous measurement of the contractile tension and the intracellular membrane potential. Hypertonic solutions up to 3.0 T, prepared by adding NaCl or sucrose, induced a triphasic response, namely an initial rapid decline, a secondary slow development of contracture and a final transient off-contraction. Both the second and the final responses were strongly sensitive to the calcium concentration of the bathing medium and were completely abolished by depleting external calcium ions. The initial decreasing phase was not sensitive to external calcium but was progressively augmented by increasing the initial muscle length, whereas the dehydration process, estimated by measuring the muscle weight, was unaffected by muscle stretch. The changes in the membrane potential were not essential for these responses. It was concluded that the initial tension decline results from the passive process due to volume change while the sustained contracture as well as the transient off-contraction are produced by some active process involved in E-C coupling. Hypotonic solutions induced a monophasic contracture which is insensitive both to the external calcium concentration and muscle stretch. The possible mechanism for the genesis of the response was discussed.