Phase Of Rapid Decline Research Articles

Proliferation, apoptosis and thymic involution

The thymus reaches its maximal size at the age of 1 month in ICR mice and thereafter, the thymic cortex undergoes an exponential decline. This study was designed to compare the proliferation and apoptosis of thymocytes in different parts of the thymus of ICR female mice at the beginning and after the rapid phase of decline of the thymic cortical cellularity.The pattern of proliferation and apoptosis of the thymus was studied in situ in 1-month-old ICR female mice (10 mice) compared to mice at 7 months of age (10 mice). Staining for argyrophylic nucleolar organizer region by histochemistry was used to determine the proportion of type 2 thymocytes, which are considered as cells at S phase of the cell cycle. The mean number of type 2 cells in four random samples of 50 cells in each part of the thymus was defined as the proliferation index of this part of the thymus. In situ detection of apoptosis of thymocytes was carried out using the Apoptag kit, which can detect a single cell apoptosis. The mean number of apoptotic cells in five randomly selected fields of each part of the thymus was defined as the apoptotic index of this part of the thymus. The proliferation index of the peripheral cortex of the 1-month-old mice was 3.6 times higher than the proliferation index of the deep cortex and 5.8 times higher than the proliferation index of the medulla (P< 0.0001). The proliferation index of the peripheral cortex of the 7-month-old mice was reduced by 45% compared to the 1-month-old mice (P< 0.005). The apoptotic index of the corticomedullary junction of the 1-month-old mice was six times higher than the apoptotic index of the cortex and 18 times higher than the apoptotic index of the medulla. The apoptotic index of the thymic cortex was elevated by 66% in the 7-month-old mice compared to the 1-month-old mice (P< 0.0001).We conclude that there is a reduction of the proliferation index and an elevation of the apoptotic index of the thymic cortex in adult mice compared to young mice. These changes might account for the reduction of thymic cortical cellularity during thymic involution.

A functional assessment of the relative cardiotoxicity of adriamycin and epirubicin in the rat

The cardiotoxicity of the two anthracyclines, adriamycin and epirubicin, were studied in 14-week-old Sprague-Dawley rats after the intravenous administration of single doses of 1–4 mg/kg of adriamycin and 2–6 mg/kg of epirubicin. These doses of the two drugs were well tolerated with little acute toxicity. Acute toxicity was characterised by a transient reduction in body weight with recovery within 14 days. The cardiac output of the rats was measured at 4-weekly intervals, for up to 20 weeks, using an external counting technique with the radioactive tracer, 99mTc. The time-related changes in cardiac function in the rat after adriamycin and epirubicin were similar. The time course of the changes in cardiac output were biphasic. There was an initial phase of rapid decline in cardiac output in the first 12 weeks (phase I) and a second phase of persistent depression in cardiac function (phase II) after 12 weeks. The late progression of anthracycline-induced cardiotoxicity could be predicted from the measurements of cardiac output at 12 weeks. The relative cardiotoxicity of adriamycin and epirubicin was evaluated from the reductions in cardiac output and from the incidence of deaths related to cardiotoxicity. Both methods of evaluation showed that adriamycin was approximately twice as cardiotoxic as epirubicin. This relationship was independent both of the dose level of drugs used and of the damage level used for the evaluation. Dose-response curves were steeper for adriamycin than for epirubicin. The present findings agree with the somewhat limited clinical data suggesting that the present rat model is highly predictive and clinically relevant.

Factors affecting the survival and growth of bacteria introduced into lake water.

The populations of Pseudomonas sp. B4, Escherichia coli, Klebsiella pneumoniae, Micrococcus flavus, and Rhizobium leguminosarum biovar phaseoli declined rapidly in lake water. The initially rapid decline of the two pseudomonads and R. phaseoli was followed by a period of slow loss of viability, but viable cells of the other species were not found after 10 days. The rapid initial phase of decline was not a result of Bdellovibrio spp., bacteriophages, or toxins in the water since Bdellovibrio spp. were not present and passage of the lake water through filters that should not have removed bacteriophages or soluble toxins led to the elimination of the rapid phase of decline. The addition of 250 micrograms of cycloheximide and 30 micrograms of nystatin per ml eliminated viable protozoa form the lake water, and the population of Pseudomonas sp. B4 did not fall and the decline of E. coli and K. pneumoniae was delayed or slowed under these conditions. Pseudomonas sp. L2 proliferated rapidly in lake water amended with glucose, phosphate, and NH4NO3, but its numbers subsequently fell abruptly; however, in water amended with cycloheximide and nystatin, which killed indigenous protozoa, the population density was higher and the fall in numbers was delayed. Of the nutrients, the chief response was to carbon, but when glucose was added, phosphorus and nitrogen stimulated growth further. Removing other bacteria by filtering the lake water before inoculation with Pseudomonas sp. L2 suggested that competition reduced the extent of response of the pseudomonad to added nutrients.(ABSTRACT TRUNCATED AT 250 WORDS)

Residues of dalapon and TCA in sediments and irrigation water

AbstractWhen dalapon and TCA are used for the management of aquatic weeds in irrigation distribution systems, they are often applied to established stands of Typha spp. and Phragmites australis in autumn or early winter, after draining water from the system. It has been assumed that the herbicides would dissipate from the sediments within 6 weeks, so that water supplies could be safely restored. In field experiments the decay of dalapon and TCA in sediments followed the classical pattern for a microbially mediated process, with a slow lag‐phase, followed by a rapid phase of decline, but not to completion. Particularly for TCA, there was a final slow phase in which residues were sufficient to contaminate eluting water at concentrations much greater than the legally prescribed tolerance, even when the interval between herbicide treatment and water re‐supply was more than 6 weeks. Although the overall pattern of dissipation in the sediment was similar for the two herbicides, concentrations of TCA were higher than those of dalapon in the elution water, probably reflecting differences in herbicide mobility and elution efficiency. Dye tracers were used in three field experiments to investigate the efficiency of herbicide elution and carryover of contaminated water when canals were filled to capacity, drained and refilled. Together with the rate of dissipation from sediments, canal topography and draining efficiency determined the safety of the elution process in removing surplus residues before re‐supply of water for irrigation. In large‐scale management operations, where the dissipation interval was only 17‐19 days, the TCA was eluted from the sediment into flowing water in proportion to the square root of time, giving average concentrations over 3 days of discharge of more than 0.4gm−3. Ideally, the interval between spraying and water re‐supply should be extended beyond 6 weeks. Alternatively, herbicide use should be restricted, or provision made for elution of surplus residues and disposal of contaminated water to waste, or onto tolerant crops or fallow land.

Development of BSER in kittens: Evidence for different central and peripheral maturation rates

Brainstem evoked responses (BSER) were recorded in 30 kittens from 7 litters. Animals were unanesthetized but restrained. Signals were condensation clicks presented in free field. Latencies and amplitudes of BSER waves I and V were measured at various times during the first 90 postnatal days. Plots of BSER component latencies as a function of postnatal age were computer‐fitted by decaying exponentials of the form Y = a + b* exp(−cX). In all kittens, wave I latency attained adult status earlier than wave V. At 90‐dB peak SPL, for example, 95% of the adult latency value was achieved at a mean age of 34.4 days for wave I and 38.1 days for wave V. The age‐versus‐latency plots are not simple offsets of each other, however. Wave I latency shows only a rapid decline to its asymptotic value, but wave V latency shows a rapid decline phase followed by an extended period of slow decline. The data support the notion that maturation of central auditory responses is not explained entirely by maturation of the cochlea and auditory nerve.

Disposition and metabolism of 3-hydrazino-6-[N,N-bis(2-hydroxyethyl)amino] pyridazine dihydrochloride in man

Three healthy volunteers (two men and one woman) were given single oral doses of 14 mg ofl4C-labelled 3-hydrazino-6-[N,N-bis(2-hydroxyethyl)amino pyridazine dihydrochloride, a new anti-hypertensive agent. The drug was absorbed well, and peak levels ofl4C-activity in the plasma, reached after 1.5–2.0 hrs, ranged between 98 and 161 ng eq/ml. The plasma half-lives of total radiocarbon calculated from the decline in the concentration curves between 2 and 8 hrs varied between 1.4 and 2.1 hr. This phase of rapid decline was followed by a second one with a slower rate of disappearance of14C. Approximately 40% of the radioactivity in the whole blood was confined to the plasma. Within 6 days an average of 102% of the administered dose was recovered, 57% being excreted in the urine and 45% in the faeces. Of the total radioactivity excreted in the urine, more than 70% was eliminated within the first 8 hrs. In the 24-hr urine, the radioactivity due to the two identified metabolites, 3-[bis (2-hydroxyethyl)amino] pyridazine and 3-methyl-6-[bis (2-hydroxyethyl)amino] -s-triazole [4,3-b] pyridazine, did not account for more than 28% of the total radioactivity. Moreover, the second metabolite was shown to derive from another one present in the urine in substantial quantity (38%). It cannot be stated with certainty whether or not any unchanged drug was excreted in the urine.

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.

Methyl mercury: Acute toxicity, tissue distribution and decay profiles in the guinea pig

Acute toxicity studies with methyl mercuric chloride showed that the guinea pig was quite susceptible to methyl mercury intoxication. LD50 values were 5.5 mg Hg/kg ip and 16.5 mg Hg/kg po. One to 2 weeks after dosing, several animals began to display signs of neurotoxicity. Tissue distribution and pharmacodynamic studies with radiolabeled methyl mercuric chloride ([ 203Hg]CH 3HgCl) at 1 and 10 mg Hg/kg revealed that while most tissues decreased in mercury concentration from day 1 to day 7, cerebrum, cerebellum and muscle showed a delayed uptake of the alkyl mercurial. In CNS tissue the concentration of mercury decreased in the order cerebrum > cerebellum > spinal cord. Kidney and liver consistently contained the highest levels of mercury, and plasma the lowest, during the 49-day sampling period. One week after dosing the blood: brain ratios were less than 1. The tissue concentration of mercury was generally directly proportional to the dose administered; however, mercury levels in the gall bladder were significantly higher than anticipated on 5 of the 7 sacrifice days. Most of the tissues displayed a biphasic decay profile with a half-life of 2–3 days for the initial rapid phase of decline. This initial phase was followed by a slower tissue excretion rate for which the mean half-life for mercury was 15 ± 0.9 days and 15 ± 0.8 days for the low and high dose, respectively. The similarity of these values again indicates no dose-related effects.

FACTORS LIMITING MICROBIAL ACTIVITIES IN SOIL: III. SUPPLEMENTARY SUBSTRATE ADDITIONS

Studies were conducted to examine further the circumstances prevailing during the phase of rapid decline in the respiration rate of soil after the addition of a soluble carbon substrate, and to investigate the potential metabolic activity of the microbial population at different stages in its sequential development. When the supply of required inorganic nutrients was adequate, the rapid decline in the rate of respiration following attainment of the respiratory peak resulted primarily from depletion of available carbon substrates, even though by this time only 30 to 50% of the carbon in the substrate (glucose) added had been recovered as CO2. Supplementary additions of the same substrate, regardless of the concentration and time of addition, however, did not elicit secondary peaks comparable in height to the primary peaks, nor was the recovery as CO2 from the supplements as high as from the initial substrate addition. This attenuation of the metabolic activity was attributed to limiting factors introduced by the initial growth of a large and active microbial population which restricted the development of sequential populations. The nature of these limiting factors and their implication in maintaining the ecological balance of microorganisms in soil are discussed.