Regulation of parasitaemia in mice infected with Trypanosoma brucei.
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Aging↗
Biomedical subjects
M Murray
Publications and source records attributed to M Murray.
Susceptibility of different breeds of goats in Kenya to experimental infection with Trypanosoma congolense.
To assess whether there was any evidence of genetic resistance to African trypanosomiasis, five breeds of goat (East African, Galla, and crossbreds between East African and Galla, Nubian or Toggenburg) were experimentally infected with Trypanosoma congolense either by needle inoculation or by tsetse-transmission. The goats had not been previously exposed to trypanosomiasis. With both methods of infection all breeds were found to be highly susceptible and suffered severe disease. Following tsetse-transmitted infection no significant differences were observed between breeds in the development, duration and size of the chancre reaction or in the degree and duration of parasitaemia. While Nubian goats developed anaemia more rapidly than the other breeds, all animals experienced a pronounced reduction in packed red cell volume. Similarly following needle inoculation no differences were found between breeds in the severity of anaemia or in the kinetics of parasitaemia. Immune responses against both metacyclic and bloodstream trypanosomes of the infecting serodeme were similar in all breeds as were the erythropoietic responses to the infection. No alterations in leucocyte parameters occurred.
Animals↗
African trypanosomiasis in cattle: working with nature's solution.
Both acquired and innate resistance to African trypanosomiasis can occur in cattle. The former raises the possibility of a vaccine against tsetsetransmitted metacyclic trypanosomes which have been shown to have a smaller repertoire of variable antigens than bloodstream parasites. The latter provides two further avenues of approach: firstly, trypanotolerant breeds are being increasingly exploited and improved by conventional management and breeding methods including embryo transfer; secondly, research is being carried out into the factors associated with their innate resistance, i.e., the control of trypanosome growth, the development of effective immune responses and resistance to anaemia. If the mechanisms underlying these factors are identified it might be possible by immunisation, by specific drug treatment or by transfection of appropriate genes to produce highly productive cattle resistant to trypanosomiasis.
Anemia↗
Cytochrome P-450 and monooxygenase activity in hepatic microsomes from N-phenylimidazole-treated rats.
Repeated administration of N-phenylimidazole (PI) to rats (3 daily doses of 200 mumol/kg/day) enhanced hepatic microsomal cytochrome P-450 levels (approx. 130%) and aminopyrine N-demethylase (APDM) and aniline p-hydroxylase (APH) activities (approx. 140%); aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase (ECOD) activities were not enhanced over control values under similar conditions. Spectral studies with PI-induced microsomes indicated that although type II PI-binding characteristics were similar to those observed in controls, the 427 nm/455 nm absorbance ratio of the type III dihydrosafrole metabolite-cytochrome P-450 complex was lower than that in control microsomes. The results suggest that the inducing characteristics of PI bear some resemblance to those of phenobarbital (PB).
7-Alkoxycoumarin O-Dealkylase↗
Computed tomographic analysis of the effects of hyperosmolar mannitol and methylprednisolone on myocardial infarct size.
Using contrast-enhanced computed tomography, the effects of hyperosmolar mannitol and methylprednisolone on experimentally produced myocardial infarcts were evaluated serially over the course of approximately 1 month. Infarct size, initial perfusion defect (jeopardized segment) and noninfarcted muscle mass were determined in three groups of conditioned mongrel dogs. Group 1 (n = 11) served as the control group, groups 2 and 3 were pretreated with mannitol (375 mg/kg, n = 10) or methylprednisolone (7.5 mg/kg, n = 11). Each animal in the treatment groups was treated with identical doses of the originally administered agent twice daily for 7 days after coronary occlusion. Each group developed increases in the noninfarcted muscle mass of the left ventricle (compensatory hypertrophy). The mean increase averaged more than 20% over 30 days when all groups were included together. Infarct size was smaller in both of the treatment groups. However, at 4 days after infarction, mannitol-treated dogs had a mean infarct size that was 68 +/- 8% (+/- standard error of the mean) of the size of control infarcts (p less than 0.01) and methylprednisolone-treated dogs had a mean infarct size that was 77 +/- 6% of the size of control infarcts (p less than 0.01) (referenced to the initial perfusion defect). At 30 days, these differences were less substantial (though still significant), 88 +/- 4% and 85 +/- 5%, respectively. Pharmacologic interventions can be shown to alter the size of an acute myocardial infarction, particularly when examined over the time course of infarct healing.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Suppression of Trypanosoma congolense, T. vivax and T. brucei infection rates in tsetse flies maintained on goats immunized with uncoated forms of trypanosomes grown in vitro.
Significant suppression in the incidence of cyclical development of Trypanosoma congolense, T. vivax and T. brucei occurred in Glossina morsitans centralis maintained on goats immunized with in vitro-propagated uncoated forms of T. congolense, T. vivax and T. brucei, respectively. This was observed when tsetse given a T. congolense-infected feed were subsequently maintained on uninfected immunized goats and also when uninfected tsetse were fed on immunized goats infected with T. congolense, T. vivax and T. brucei. Suppression of infection rates in tsetse was trypanosome species specific, but was independent of the trypanosome stock used for immunization of goats. These findings were reflected in antibody responses to uncoated trypanosomes, as measured by immunofluorescence and the solid-phase immunoradiometric binding assay. Thus, antibody from goats immunized with uncoated trypanosomes of one species exhibited minimal reactivity with uncoated forms of other species of trypanosomes, but showed high levels of activity with uncoated forms of the same or unrelated stocks of the same species. However, in view of the range of hosts upon which tsetse feed, it is open to question whether the use of a vaccine which suppresses trypanosome infection rates in tsetse would have any significant effect in the field.
Animals↗
Induction of protective immunity in cattle by tsetse-transmitted cloned isolates of Trypanosoma congolense.
Cattle infected with cyclically (tsetse)-transmitted clones of Trypanosoma congolense were treated with the trypanocidal drug diminazene aceturate ('Berenil') at various intervals during development of local skin reactions (chancres), in order to investigate the role played by trypanosomes in the skin in the induction of protective immunity. Cattle, treated on or before Day 12 after infection and prior to detection of trypanosomes in the blood, showed a range of susceptibility to cyclically-transmitted homologous challenge three weeks later. An animal treated on Day 5, when the skin reaction was first detected, was completely susceptible, whereas of the animals treated on Days 10 to 12 at the peak of the skin reaction, some were immune, others exhibited partial immunity, while the rest were susceptible. The susceptible animals, however, showed evidence of sensitization to trypanosomes, as demonstrated by development of Arthus-type reactions following homologous challenge with tsetse-transmitted parasites or intradermal inoculation with lysed or irradiated homologous trypanosomes. Cattle treated 15 or more days after cyclically-transmitted infection, when chancre reaction was subsiding and trypanosomes were present in the blood, were completely immune to challenge. Immunity was achieved by treating cattle on Day 5 and Day 10 after infection with cyclically-transmitted trypanosomes but only if this procedure was repeated on several occasions, indicating that bloodstream forms of trypanosomes were not essential for the induction of protective immunity. Protective immunity appeared to be effective against the metacyclic trypanosomes at the level of the skin, as animals which were immune to homologous challenge with cyclically-transmitted parasites did not develop detectable skin reactions at the site of the tsetse bite. Furthermore, the time of the appearance in the serum of antibody which completely neutralized the metacyclic population (Day 15) coincided with the time at which cattle had developed immunity against homologous challenge. The immunity produced lasted for five months.
Animals↗
The role of humoral immune responses in determining susceptibility of A/J and C57BL/6 mice to infection with Trypanosoma congolense.
The relative resistance of C57BL/6 mice to infection with Trypanosoma congolense as compared to A/J mice was found to be independent of the infective dose of trypanosomes and required an intact immune system, as sublethal levels of gamma irradiation abolished the differences in susceptibility between the two strains. C57BL/6 mice produced earlier and quantitatively superior antibody responses both to the variable surface glycoprotein and to common membrane antigens on the trypanosome than A/J mice. No difference was observed in the class of antibody produced. In parallel with the specific response, C57BL/6 mice also generated higher levels of antibody to an unrelated antigen (TNP) and developed higher levels of total serum IgM. However, despite the low levels of both specific antibody and antibody to TNP in A/J mice, these animals developed massive increases in total serum IgG2a. The role of this selective activation of IgG2a producing cells in the susceptibility of the A/J mice was unclear. Although susceptibility was closely correlated with specific antibody responses during infection, the two strains of mice showed a similar capacity to respond to fixed doses of irradiated trypanosomes. This indicates that an inherent difference in immune responsiveness to the trypanosomal antigens is not the major factor determining susceptibility. Moreover, the finding that a proportion of A/J mice which received infective and irradiated trypanosomes simultaneously showed depressed antibody responses to the trypanosome, suggests that active infection of A/J mice with T. congolense impairs their ability to initiate an appropriate immune response to the trypanosome.
Animals↗
Hepatic-lipidosis in a post parturient mare.
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Animals↗
Relation between parents' and children's smoking behaviour and attitudes.
In the MRC/Derbyshire Smoking Study, a cohort of about 6000 adolescents was surveyed annually about their smoking behaviour, attitudes, and other issues from when they entered secondary school at 11-12 until 15-16 years and then again at 18-19 years. Their parents answered a similar questionnaire when their children were aged 11-12 and 15-16 years. In this paper we report the findings of an investigation focussed on the relation between parents' and childrens' smoking behaviour and attitudes at different stages of adolescence. It reveals substantial agreement between children's and parents' reports of parents' smoking behaviour and attitudes, that children from one-parent families are more likely than their peers to smoke, and that boys are more likely to smoke if their fathers smoke and girls if their mothers smoke. In addition, maternal attitudes were independently related to the boys' smoking behaviour. The implications of these findings for health education are discussed.
Adolescent↗
Induction of rat-hepatic microsomal cytochrome P-450 and aryl hydrocarbon hydroxylase by 1,3-benzodioxole derivatives.
Several 1,3-benzodioxoles (BD) and related compounds were studied in relation to their ability to generate metabolite complexes with hepatic cytochrome P-450 following administration in vivo to rats. BD derivatives that formed stable metabolite complexes with cytochrome P-450 were considerably more effective inducers of cytochrome P-450 and aryl hydrocarbon (benzo[alpha]pyrene) hydroxylase (AHH) activity than derivatives that did not form stable complexes. Linear regression analysis showed that AHH activity was well correlated (r = 0.980) with total (i.e. complexed plus uncomplexed) cytochrome P-450 content and was not correlated with levels of uncomplexed cytochrome P-450. Aminopyrine N-demethylase (APDM) activity in hepatic microsomes from rats treated with 1,3-benzodioxoles was moderately correlated in a linear relationship with uncomplexed levels of cytochrome P-450 and not with total cytochrome P-450.
Aminopyrine N-Demethylase↗
Selective inhibitory interactions of alkoxymethylenedioxybenzenes towards mono-oxygenase activity in rat-hepatic microsomes.
A series of eight 4-n-alkoxymethylenedioxybenzene (AMDB) derivatives were evaluated for their inhibitory effects on several mono-oxygenase reactions and their capacity to form metabolite complexes with cytochrome P-450 in vitro in hepatic microsomes from phenobarbital (PB)-and Beta-naphthoflavone (Beta NF)-induced rats. Ethoxyresorufin O-deethylase in Beta NF-induced microsomes and aminopyrine N-demethylase in PB-induced microsomes were most susceptible to inhibition by the test compounds. In contrast, aldrin epoxidation and arylhydrocarbon hydroxylase in PB-and Beta NF-induced microsomes, respectively, were not inhibited by derivatives of AMDB. All AMDB derivatives elicited spectral complexes with cytochrome P-450, the characteristics of which were influenced by the microsomes employed and by the length of the AMDB alkoxy side-chain. Derivatives containing short-chain alkoxy substituents (C1 to C3) formed unstable metabolite complexes and generated substantial quantities of carbon monoxide (CO), those with intermediate length alkoxy groups (C4 to C6) generated little CO and rapidly formed intense spectral complexes (large delta A max), and those with the largest alkoxy groups (C7 and C8) formed no CO and elicited complexes of high stability. Quantitative structure-activity analyses showed that the biological data could be described by parabolic equations in II, the hydrophobic constant of the alkoxy substituent, and suggested the importance to AMDB interactions of a lipophilic-binding region at the active centre of the cytochrome P-450. The alkoxy chain length for optimal mono-oxygenase inhibition and complex formation with cytochrome P-450 appeared to be about five or six carbon atoms. The data suggest that the capacity of AMDB compounds to form stable inhibitory complexes with cytochrome P-450 may not always be associated with their ability to inhibit mono-oxygenase activity.
Aminopyrine N-Demethylase↗
Spectral and inhibitory interactions of methylenedioxyphenyl and related compounds with purified isozymes of cytochrome P-450.
Spectral and inhibitory interactions of two methylenedioxyphenyl (MDP) compounds (dihydrosafrole (DHS) and 4,5-dichloro-1,2-methylenedioxybenzene (DCMB] and 4-n-butyl dioxolane (BD) were studied in vitro in reconstituted systems incorporating cytochromes P-450b and P-450c, purified respectively from hepatic microsomes of phenobarbital (PB)- and beta-naphthoflavone (beta NF)-treated rats. In NADPH-fortified reconstituted systems containing P-450b, DHS yielded a stable type III spectral complex with peaks at 428 and 458 nm; a complex with a single 456 nm peak was formed in systems containing cytochrome P-450c. DCMB formed unstable 456-458 nm spectral complexes with both isozymes, and BD generated an unstable complex with a single Soret peak near 428 nm with cytochrome P-450b; no spectral interaction occurred between BD and cytochrome P-450c. Carbon monoxide was formed in incubations of DCMB with both isozymes but was not observed with either DHS or BD. Marked selectivity was observed in the ability of the test compounds to inhibit selected mono-oxygenase reactions in the reconstituted systems. Thus, while DHS was an effective inhibitor of cytochrome P-450b-mediated ethoxycoumarin O-deethylase (ECD), it failed to inhibit aldrin epoxidase (AE) in the same system; DCMB and BD inhibited both of these reactions. In reconstituted systems incorporating cytochrome P-450c, DHS and DCMB, but not BD, were effective inhibitors of ethoxyresorufin O-deethylase (ERD) activity but none of the compounds showed any inhibitory activity towards aryl hydrocarbon (benzo[alpha]pyrene)hydrolase (AHH) activity. The results indicate that metabolite complex formation with cytochrome P-450 is not the sole criterion for inhibition of mono-oxygenase activity by MDP and related compounds, and that in some cases type I competitive interactions at the substrate binding sites may be the primary contributing factor.
Animals↗
Clarifying ANA's resolution on titling and entry into practice.
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American Nurses' Association↗
Effect of prolonged renal dysfunction on intravascular and extravascular pulmonary fluid volumes during left atrial hypertension.
To examine the development of pulmonary edema during experimental renal dysfunction, left atrial pressure was altered in 14 mongrel dogs divided into two groups. Group 1 was composed of seven control animals, and Group 2 was composed of seven animals with surgically induced renal failure (1 week of bilateral ureteral ligation). Data were obtained at two levels of matched transmural pulmonary vascular pressure (defined as mean left atrial pressure less serum protein osmotic pressure). In the animals with renal dysfunction, extravascular lung water (EVLW) (thermal-green dye technique) was higher at moderately (-1 to -2 mm Hg) and severely elevated (11 to 12 mm Hg) vascular driving pressures (11.5 +/- 1.2 cc/kg vs 10.6 +/- 0.8 cc/kg and 14.8 +/- 1.3 cc/kg vs 13.0 +/- 1.9 cc/kg, respectively, both P less than 0.05 vs control). Because protein osmotic pressure was lower in the renal failure group (15.0 +/- 1.8 mm Hg vs 18.4 +/- 1.4 mm Hg, P less than 0.05), greater accumulations of extravascular lung water occurred at lower levels of left atrial pressure (14.2 +/- 1.4 mm Hg vs 17.1 +/- 1.2 mm Hg, P less than 0.05; 26.8 +/- 2.6 mm Hg vs 29.5 +/- 2.3 mm Hg, P less than 0.01). In addition, when the ratio of EVLW/PBV (pulmonary blood volume) was examined in both groups at each stage of the experiment, the ratio was greater in the Group 2 animals at each elevated pressure, suggesting increased permeability with renal dysfunction. In conclusion, pulmonary edema formation occurs at lower left atrial pressures in the setting of sustained renal dysfunction, this phenomenon can be partially explained by lower protein osmotic pressure though altered pulmonary microvascular permeability may contribute to edema formation.
Animals↗
Effect of rifampin chemoprophylaxis on carriage eradication and new acquisition of Haemophilus influenzae type b in contacts.
We conducted a multicenter trial designed to assess the efficacy of three different drug regimens on eradication of Haemophilus influenzae type b (HIB) from the nasopharynx of household contacts of patients with invasive type b Haemophilus disease. The drug regimens studied were rifampin, 20 mg/kg, once daily for four days; rifampin, 10 mg/kg, twice a day for four days; and placebo, once daily for four days. Shortly after admission of the index patient to the hospital, 26% of 492 household contacts were found to be colonized with HIB. Both rifampin regimens eradicated carriage significantly better than placebo at 10 and 30 days (P = .001). However, among contacts whose cultures were initially negative, new acquisition of the organism occurred infrequently in this 30-day follow-up period regardless of the drug or placebo regimen prescribed. We also measured the concentration of anticapsular antibody in sera obtained from contacts younger than 6 years of age. Samples were obtained soon after admission of the index patient to the hospital and 30 days later. Several carriers younger than 2 years of age had low concentrations of antibody in both specimens. In contrast, nearly all carriers 2 to 5 years of age had high concentrations of antibody even in the first sample. Children who were not carriers usually had low antibody concentrations which did not increase during the period of observation. Our results suggest that most intrafamilial spread of HIB occurs prior to hospitalization of the index patient and stimulates immunity in contacts older than 2 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
In vitro effects of quinoline derivatives on cytochrome P-450 and aminopyrine N-demethylase activity in rat hepatic microsomes.
A series of quinoline drugs was evaluated for the ability to inhibit rat liver microsomal aminopyrine N-demethylase (APDM) activity in vitro. Quinine was found to be a quite potent inhibitor of APDM from control rat liver (I50 = 0.061 mM) but was only approximately half as potent against APDM from phenobarbitone-induced rat liver (I50 = 0.14 mM). Primaquine and amodiaquine were also relatively potent inhibitors of these activities, but quinidine and chloroquine were essentially non-inhibitory, especially against control-type APDM. Primaquine and quinine elicited characteristic type II optical difference spectra with oxidised cytochrome P-450 from both types of microsomes whereas chloroquine and quinidine were type IIb ligands for cytochrome P-450 in phenobarbitone-induced microsomal fractions. Good correlations were obtained for the logarithmic relationship between binding affinity (Ks) and inhibition potency (I50), as well as the logarithmic relationship between efficiency of binding (delta Amax/Ks) and inhibition. These findings suggest that the capacity of quinoline antimalarials, and similar drugs, to inhibit microsomal APDM activity is related to the affinity of the type II spectral binding interaction between the drug and oxidised cytochrome P-450.
Aminopyrine N-Demethylase↗