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Biomedical subjects

M Murray

Publications and source records attributed to M Murray.

At least 343 records · Page 19Linked to original sources

Haemorrhagic lesions resulting from Trypanosoma vivax infection in Ayrshire cattle.

Infection of Ayrshire cattle with a stock of Trypanosoma vivax from the Galana Ranch, Kenya, resulted in an acute disease characterised by profound anaemia and haemorrhage, which reached maximum severity between 3 and 5 weeks after infection. Bleeding from the ears, nose and rectum occurred. At necropsy, petechial and ecchymotic haemorrhages were widespread, but were particularly severe in the gastrointestinal tract. In confirmation of the gross findings, congestion, haemorrhage and degenerative changes in most tissues and organs were found histologically. Thrombi were seen in the lymphatic vessels and clots of fibrin were present in the ventricles of the brain. The anaemia was a consequence of frank blood loss through haemorrhaging, exacerbated by erythrophagocytosis of deformed red blood cells, whose occurrence was indicative of microangiopathic changes. Animals were euthanised between 23 and 36 days after infection when they became recumbent with PCV values as low as 9%. There is no doubt that animals affected by this syndrome in the field would die within a few weeks of infection, if left untreated.

Acute Disease↗

Assessing university nephrology training as preparation for community consultative practice.

The authors gathered information about the consultative practice of nephrology in a community environment and used this information to speculate about improvements that could be made in the training of nephrologists in academic medical centers, based on their knowledge of such training. Data were gathered on the specialty affiliations of the physicians who requested 211 consecutive consultations, on the clinical problems encountered, and on the most likely diagnosis for each problem. In some instances the referral patterns, patient mixes, and clinical diagnoses observed in the community-based practice differed significantly from those often emphasized in training programs in academic medical centers. Such differences may be unintentionally reinforced, because the clinical literature in which new findings are reported and validated largely arises from university-type clinical practices. Specific examples of the differences observed and some suggestions for change are given. Although additional research is needed to confirm the findings of this study, and although these findings may not be applicable to other settings or other internal medicine subspecialties, these findings raise questions about the appropriateness of completely university-based training in preparing physicians for practice in a community setting. The authors suggest that cooperation between community hospitals and established university programs could bring about the best opportunities for clinical training.

Community Medicine↗

UVB-induced melanogenesis may be mediated through the MSH-receptor system.

Ultraviolet B radiation (UVB) elicits an increase in melanin production in mammalian skin. The mechanisms regulating this process are not understood, although it is well documented that there is an increase in the number of melanin-producing melanocytes. The melanotropins (MSH) are a family of peptides that increase the melanin content of melanocytes through an interaction with high affinity receptors. We have obtained evidence that the effects of UVB on melanogenesis may be mediated through an increase in MSH receptor activity on melanocytes. First, exposure of Cloudman S91 mouse melanoma cells to UVB resulted in increased binding of 125I-MSH to cells within 24 h. In five separate experiments, UVB-irradiated cultures displayed 2-10-fold increases in MSH binding capacity over that of unirradiated control cultures (optimum doses 10-20 mJ/cm2). Second, UVB and MSH potentiated one another in promoting cutaneous melanogenesis in both mice and guinea pigs. In the areas of guinea pig skin that received both UVB and MSH, there was a fivefold increase in active melanocytes/mm2 over the sum of active melanocytes/mm2 in areas receiving either MSH or UVB separately. Our results suggest that UVB light causes an increase in MSH receptor activity on cutaneous melanocytes, thus increasing cellular responsiveness to MSH. Implicit in this mechanism is a transduction of radiant energy into chemical energy during the process of UVB-induced melanogenesis.

Animals↗

Analysis of Propionibacterium acnes-induced non-specific immunity to Trypanosoma brucei in mice.

Mice treated with dead Propionibacterium acnes (previously called Corynebacterium parvum), up to 30 days before infection with any of three strains of Trypanosoma brucei, were more able to limit the level of first-wave parasitaemia than untreated controls. Reduced parasitaemia was not due to enhanced phagocytosis of input parasites and was associated with a dramatic reduction in the proportion of multiplying T. brucei in the blood of treated as compared to control mice. For 4 days after P. acnes treatment, T. brucei growth-inhibitory molecules, assayed by their effect on T. brucei multiplication under axenic culture conditions, were detected in the serum of recipient mice. The molecules were released by macrophages collected from the peritoneal cavity of P. acnes-treated mice, and similar molecules were produced in vitro by macrophages from normal mice after incubation with P. acnes. Accessory studies suggested that the molecules were breakdown products of P. acnes and were unlikely to be responsible for the long-term in-vivo effects of the P. acnes treatment. It was also shown that monokines and lymphokines which are likely to be induced by in-vivo P. acnes treatment, i.e. IL-1, IL-2, TNF alpha, INF alpha, INF beta, INF gamma, PGE1, PGE2, PGF2 alpha and biological mediators present in Con-A and LPS-induced spleen cell supernatants (collected 20, 40, 60 or 80 h after mitogen stimulation) had no influence on T. brucei growth under axenic culture conditions over a wide range of concentrations. The studies suggest that the P. acnes effect was not due to a direct interaction of these biological mediators with the T. brucei. We suggest that the reduction in T. brucei parasitaemia in P. acnes-treated mice reflects secondary physiological effects of one or more unidentified biological mediators.

Animals↗

Comparison of intramuscular recombinant alpha interferon (rIFN-2A) with topical acyclovir for the treatment of first-episode herpes genitalis and prevention of recurrences.

Intramuscular recombinant alpha interferon (rIFN-2A; 9 million IU given for 5 days during a 9-day treatment period) was compared with topical acyclovir in a double-blind, placebo-controlled trial for the treatment of first-episode genital herpes simplex virus (HSV) infection and for subsequent alteration of the frequency of recurrences. rIFN-2A (within 96 h of onset of the first episode) was not superior to topical acyclovir in a well-matched group of 105 patients. The early use of rIFN-2A also did not alter the frequency or severity of genital HSV recurrences within either the first or second 6 months following therapy. Separate analyses by HSV type and by type of infection (primary versus nonprimary) did not change this conclusion. Furthermore, there was significant toxicity associated with rIFN-2A therapy. rIFN-2A is not indicated for the treatment of genital HSV infections.

Acyclovir↗

Downregulation of the male-specific hepatic microsomal steroid 16 alpha-hydroxylase, cytochrome P-450UT-A, in rats with portal bypass. Relevance to estradiol accumulation and impaired drug metabolism in hepatic cirrhosis.

Elevated serum estradiol concentrations and specific changes in the biliary excretion of some androstenedione metabolites have been reported in male rats with portal bypass produced by portal vein ligation (PVL). In this study, the hypothesis that male-specific forms of cytochrome P-450 are altered after PVL was tested by measuring microsomal steroid hydroxylase activities. Consistent with earlier findings in the intact animal, androstenedione 16 alpha-hydroxylase activity was reduced after PVL to 44% of control (P less than 0.05). Other pathways of androstenedione hydroxylation, and total estrogen formation (after androstenedione aromatization) were unchanged. Although total estrogen formation was not different, a sevenfold greater proportion of estradiol was produced in PVL rat microsomes. Additional experiments revealed that PVL selectively reduced the rate of microsomal estradiol 16 alpha-hydroxylation (to 56% of control, P less than 0.02). Levels of cytochrome P-450UT-A, the microsomal steroid 16 alpha-hydroxylase, were lower after PVL (56% of control, P less than 0.05), so that the present observations are consistent with the earlier suggestion that portal bypass is associated with the selective downregulation of this enzyme. Since downregulation of cytochrome P-450UT-A also occurs in experimental hepatic cirrhosis, portal hypertension may well contribute significantly to altered drug metabolism in liver disease. Impaired hepatic elimination of androstenedione by hydroxylation may indirectly enhance extrahepatic aromatization of the androgen. The decreased activity of hepatic estradiol 16 alpha-hydroxylation after PVL would enhance the accumulation of estradiol, the biologically more potent estrogen.

Androstenedione↗

Beta 1- and beta 2-adrenergic 125I-pindolol binding sites in the interpeduncular nucleus of the rat: normal distribution and the effects of deafferentation.

The plasticity of the beta 1- and beta 2-adrenergic receptor subtypes was examined in the interpeduncular nucleus (IPN) of the adult rat. The beta-adrenergic receptor antagonist 125I-pindolol (125I-PIN) was used in conjunction with the selective subtype antagonists ICI 118,551 and ICI 89,406 to determine the subnuclear distribution of beta 1- and beta 2-adrenergic receptors in this nucleus and to correlate the receptor distribution with the distribution of both noradrenergic afferents from the locus coeruleus (LC) and non-noradrenergic afferents from the fasiculus retroflexus (FR). The density of these binding sites was examined following lesions that decreased (LC lesions) or increased (FR lesions) the density of the noradrenergic projection in the IPN. Quantitative radioautography indicated that beta 1-labeled binding sites account for the larger percentage of binding sites in the IPN. The beta 1-binding sites are densest in the those subnuclei that receive a noradrenergic projection from the LC: the central, rostral, and intermediate subnuclei. beta 1-binding sites are algo homogeneously distributed throughout the lateral subnuclei, where there is no detectable noradrenergic innervation. beta 2-binding sites have a more restricted distribution. They are concentrated in the ventral half of the lateral subnuclei, where they account for 70% of total 125I-PIN binding sites. beta 2-binding sites are also present along the ventral border of the IPN. Some of this labeling extends into the central and intermediate subnuclei. Bilateral lesions of the LC, which selectively remove noradrenergic innervation to the IPN, result in an increase in the beta 1-binding sites. Bilateral lesions of the FR, which remove the major cholinergic and peptidergic input from the IPN, elicit an increase in noradrenergic projections and a decrease in beta 1-binding sites. beta 1-binding sites thus exhibit both up-regulation and down-regulation which is correlated with the density of the noradrenergic projection. Our results suggest, therefore, that the density of beta 1-binding sites is regulated by noradrenergic input. beta 2-binding sites increase in density in response to both the LC and FR lesions, suggesting that they are postsynaptic to both of these afferents. The distribution suggests that some of these binding sites may reflect binding to glial cells. The beta 2-binding sites may therefore be regulated by both noradrenergic and non-noradrenergic mechanisms.

Adrenergic beta-Antagonists↗

Relay bioavailability and toxicity of isometamidium residues: a model for human risk assessment.

The bioavailability and potential toxicity of the residues of the antitrypanosomal drug isometamidium (ISMM) in bovine tissues were investigated in male Sprague-Dawley rats. They were allowed to feed for 7 and 21 days on a standard diet, to which were added lyophilized tissues from a calf treated im with a combination of 45 mg 14C-ISMM and 73 mg unlabelled ISMM (1 mg/kg bodyweight). Cumulative excretion of radioactivity of the residues in feces of the rats was on average 90% of the dose. No radioactivity was detectable in the tissues examined, including the kidney, liver, spleen, muscle, stomach and small intestine. No clinical effects were seen in any of the rats, and both gross and histopathological examinations did not reveal any lesions. In rats given 14C-ISMM (2.245 mg/kg bodyweight) by oral gavage, cumulative excretion of radioactivity in feces after 48 hr amounted to about 93% of the dose, and no radioactivity was detectable in tissues. Similarly, none of the rats showed any clinical effects and no gross lesions were seen at necropsy. This study shows that ISMM residues are not significantly bioavailable and exhibit no subchronic toxicity.

Animals↗

Inhibition of oxidative drug metabolism by orphenadrine: in vitro and in vivo evidence for isozyme-specific complexation of cytochrome P-450 and inhibition kinetics.

The anti-parkinsonian agent orphenadrine has been shown to form an in vitro metabolic intermediate (MI) complex in hepatic microsomes isolated from phenobarbital (PB)-treated rats. The present study was undertaken to assess the cytochrome P-450 isozyme specificity of inhibition and MI complexation. Spectral studies with untreated and PB-induced rat hepatic microsomes confirmed earlier reports on the selectivity of P-450 complexation by orphenadrine; MI complex formation was only observed with PB-induced microsomes. Inhibition studies with the P-450 substrates androst-4-ene-3,17-dione (androstenedione) and 7-pentoxyresorufin revealed selective inhibition of P-450 PB-B/D-associated monooxygenase activity. Thus, in microsomes from untreated male rats, orphenadrine failed to significantly inhibit (less than 50% inhibition up to a concentration of 300 microM) any of the major pathways of P-450-associated androstenedione metabolism. Preincubation of these microsomal fractions with orphenadrine and NADPH was not associated with increased inhibition of androstenedione metabolism. However, in PB-induced microsomes, P-450 PB-B/D-specific androstenedione 16 beta-hydroxylase activity was significantly and selectively inhibited (IC50 = 90 microM). Preincubation of orphenadrine with NADPH-supplemented PB-induced microsomes for 2, 4, or 8 min before androstenedione addition resulted in increased inhibition toward 16 beta-hydroxylase activity, lowering the observed IC50 to 6.6, 0.47, and 0.06 microM), respectively. Preincubation did not affect the selectivity of inhibition. In the absence of preincubation, orphenadrine appeared to be a potent mixed (competitive/noncompetitive)-type inhibitor of P-450 PB-B/D-associated pentoxyresorufin O-depentylation (Ki = 3.8 microM). Preincubation of orphenadrine with NADPH-supplemented microsomal fractions for 4 min resulted in a 30-fold lowering of the apparent inhibitor constant (Ki = 0.13 microM) and a change in the apparent inhibition kinetics to noncompetitive. Treatment of rats with orphenadrine (75 mg/kg/day intraperitoneally for 3 days) was associated with a 2-fold induction of total hepatic P-450, a 5- and 2.4-fold induction of androstenedione 16 beta- and 6 beta-hydroxylase activity, respectively, and formation of an orphenadrine-P-450 MI complex. Western blots of orphenadrine-induced microsomes revealed a 20-fold increase in P-450 PB-B/D-immunoreactive protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstenedione↗

Factors affecting duration and intensity of trypanosome infection of domestic animals.

Domestic animals can become infected with several species of trypanosomes that are transmitted by tsetse, including Trypanosoma congolense, T. vivax, T. brucei, T. simiae, T. rhodesiense and T. gambiense. The intensity and duration of the resulting parasitaemia are affected by the parasite, the host and detection methods. Techniques currently used to detect parasites range in sensitivity from one to 10(5) organisms per ml. At the same time, parasite kinetics vary greatly both within and between species of trypanosomes, although as a rule, at least for cattle, it is usual for T. vivax to give rise to higher parasitaemias (greater than 10(6) per ml) than T. congolense (less than 10(6) per ml) which is generally more persistent, while T. brucei results in only scanty transient parasitaemia (less than 10(5) per ml). It should also be appreciated that both T. vivax, and T. brucei, unlike T. congolense, invade tissues. Species of the host infected has a significant effect on parasitaemia patterns, e.g., in contrast to cattle, dogs develop high parasitaemias (greater than 10(7) per ml) when infected with T. brucei. Certain animals possess a remarkable inherent capacity to control, reduce and even self-cure infections, irrespective of the species of infecting trypanosome. This is best demonstrated by trypanotolerant breeds of cattle such as the NDama and West African Shorthorn, as well as by most species of wild Bovidae and Suidae. Physiological and environmental factors can probably influence the kinetics of infection but these are poorly defined and await quantification.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Nutritional Physiological Phenomena↗

Effect of liver regeneration on hepatic cytochrome P450 isozymes and serum sex steroids in the male rat.

Partial hepatectomy in male adult rats results in raised serum estrogen levels and demasculinization of certain aspects of hepatic metabolism. Some constitutive forms of hepatic cytochrome P450 are sex-dependent and we have previously demonstrated demasculinization of cytochrome P450 isozyme distribution in a rat model of cirrhosis. As liver regeneration is an integral component of cirrhosis, the present study was performed to ascertain the effects of regeneration on hepatic cytochrome P450 isozyme composition and serum sex steroid concentrations. Adult male rats were subjected to 65% partial hepatectomy or sham-operation. The position-specific hydroxylation of androstenedione was used as a probe for isozyme activity. Serum sex steroids, hepatic enzymes, and hepatic deoxyribonucleic acid synthesis were measured in groups of animals at 0, 6, 24, 48, and 72 h. By 72 h total microsomal cytochrome P450 in partially hepatectomized animals had fallen to 66% of that in nonoperated animals. In both partially hepatectomized and sham-operated animals, androstenedione 7 alpha- and 16 beta-hydroxylase activity returned to preoperative levels by 48 h. However, the male-specific androstenedione 16 alpha- and 6 beta-hydroxylase activities and aromatase activity remained suppressed in partially hepatectomized liver. Serum estradiol increased eightfold in partially hepatectomized rats and peaked at 6 h followed by a gradual fall to control values. No change in serum estradiol was observed in sham-operated animals. We conclude that demasculinization of hepatic oxidative metabolism occurs in regenerating rat liver. The early rise in serum estradiol is consistent with a role for this hormone in the changes in cytochrome P450 observed, and possibly the process of liver regeneration.

Androstenedione↗

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Health Resources↗

Tachykinin binding sites in the interpeduncular nucleus of the rat: normal distribution, postnatal development and the effects of lesions.

Tachykinin binding sites in the basal midbrain were labeled in adult and neonatal rats using 125I-Bolton Hunter (BH) substance P (SP) and 125I-BH eledoisin as ligands. In the adult, binding was very low in the tegmentum and raphe adjacent to the interpeduncular nucleus (IPN). Within the IPN, no binding with either ligand was seen in the target subnuclei of the habenular SP and substance K projections, the lateral subnuclei and the cap of the rostral subnucleus. Labeling with 125I-BH-SP was very light and was restricted primarily to the central subnucleus of the IPN while 125I-BH-eledoisin labeling was very dense over the dorsal, the ventral sector of the rostral, the intermediate and the central subnuclei. Lesions of major afferents to the IPN, the fasciculus retroflexus or the locus coeruleus, had no effect on the distribution or density of the binding of either ligand. In rats 0, 4 or 7 days or age, 125I-BH-SP binding was very dense in the ventral tegmental region, the raphe and in the dorsal, rostral and central subnuclei. 125I-BH-eledoisin binding was extremely dense in the raphe and in the dorsal, rostral, intermediate and central subnuclei but was less dense in the ventral tegmentum. Adult levels of binding in the midbrain were established by 11 days of age. Neonatal lesions restricted to the fasciculus retroflexus had no effect on the density of labeling with either ligand in animals allowed to reach adulthood.

Aging↗

Induction of xenobiotic biotransformation by the insecticide chlordimeform, a metabolite 4-chloro-o-toluidine and a structurally related chemical o-toluidine.

Chlordimeform, 4-chloro-o-toluidine and o-toluidine have all been found to have carcinogenic properties. Due to an empirical link between such properties and alteration of some biotransformation enzymes, the abilities of these three chemicals to affect cytochrome P-450 mediated biotransformation, epoxide hydrolase and glutathione S-transferase have been examined. Chlordimeform had no effect on the cytochrome P-450 content, aniline p-hydroxylase or glutathione S-transferase activities, but induced ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase and epoxide hydrolase activities and decreased aldrin epoxidase and aminopyrine N-demethylase activities. The metabolite 4-chloro-o-toluidine increased cytochrome P-450, ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase, glutathione S-transferase and epoxide hydrolase activities. o-Toluidine induced cytochrome P-450, ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase, and aldrin epoxidase activities. Ethoxy-resorufin-O-deethylase activity was induced approximately eight times by chlordimeform and 18 times by 4-chloro-o-toluidine and o-toluidine. Induction was seen at 50 mg/kg with chlordimeform and at 10 mg/kg with the other treatments. Chlordimeform increased the 7 alpha and 16 alpha androstenedione hydroxylase pathways. 4-Chloro-o-toluidine increased the 7 alpha, 16 beta and 16 alpha hydroxylase pathways, while o-toluidine increased the 7 alpha, 6 beta, 16 beta and 16 alpha hydroxylase pathways. All three chemicals marginally decreased the testosterone pathways. SDS-PAGE of rat microsomes revealed an increase in a protein band of MW c54,000 for the chlordimeform and 4-chloro-o-toluidine treated groups. Taken together with the increase in ethoxyresorufin-O-deethylase activity these observations are consistent with the induction of hepatic isozyme P-450d. Thus each chemical has been shown to induce various pathways of biotransformation with increases in the P-450c and P-450d specific substrate ethoxyresorufin-O-deethylase being a consistent finding.

Amidines↗

Complexation of cytochrome P-450 isozymes in hepatic microsomes from SKF 525-A-induced rats.

Potassium ferricyanide-elicited reactivation of steroid hydroxylase activities, in hepatic microsomes from SKF 525-A-induced male rats, was used as an indicator of complex formation between individual cytochrome P-450 isozymes and the SKF 525-A metabolite. Induction of male rats with SKF 525-A (50 mg/kg for three days) led to apparent increases in androst-4-ene-3,17-dione 16 beta- and 6 beta-hydroxylation to 6.7- and 3-fold of control activities. Steroid 7 alpha-hydroxylase activity was decreased to 0.8-fold of control and 16 alpha-hydroxylation was unchanged. Ferricyanide-elicited dissociation of the SKF 525-A metabolite-P-450 complex revealed an even greater induction of 16 beta- and 6 beta-hydroxylase activities (to 1.8- and 1.6-fold of activities in the absence of ferricyanide). Androst-4-ene-3,17-dione 16 alpha-hydroxylase activity increased 2-fold after ferricyanide but 7 alpha-hydroxylase activity was unaltered. An antibody directed against the male-specific cytochrome P-450 UT-A decreased androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to 13% of control in hepatic microsomes from untreated rats. In contrast, 16 alpha-hydroxylase activity in microsomes from SKF 525-A-induced rats, before and after dissociation with ferricyanide, was reduced by anti UT-A IgG to 32 and 19% of the respective uninhibited controls. Considered together, these observations strongly suggest that the phenobarbital-inducible cytochrome P-450 isozymes PB-B and PCN-E are present in an inactive complexed state in microsomes from SKF 525-A-induced rat liver. Further, the increased susceptibility of androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to inhibition by an antibody to cytochrome P-450 UT-A, following ferricyanide treatment of microsomes, suggests that this male sexually differentiated enzyme is also complexed after in vivo SKF 525-A dosage. In contrast, the constitutive isozyme cytochrome P-450 UT-F, which is active in steroid 7 alpha-hydroxylation, does not appear to be complexed to any extent in microsomes from SKF 525-A-induced rats.

Androstenedione↗

Effects of long-term choline deficiency on hepatic microsomal cytochrome P-450-mediated steroid and xenobiotic hydroxylases in the female rat.

Total cytochrome P-450 levels decreased to about 80% of control in hepatic microsomes from female rats maintained for 30 weeks on a choline-deficient diet. Livers from these rats were fibrotic and had extensive fatty infiltration but, unlike livers of male rats on the same regimen, were not cirrhotic. Steroid hydroxylase activities were assessed in microsomes of female rats that received the choline-deficient diet and it was noted that the activity of the cytochrome P-450 UT-F-mediated steroid 7 alpha-hydroxylase was decreased to about 50% of the activity present in choline-supplemented control rat microsomes. Similar decreases were observed for microsomal androstenedione 6 beta-hydroxylase and aniline 4-hydroxylase activities. In female rat hepatic microsomes these two activities are probably mediated by the isozyme cytochrome P-450 ISF-G. In contrast to these findings, the activities of four other xenobiotic metabolising enzymes, as well as rates of microsomal steroid 16 alpha- and 16 beta-hydroxylation, were unchanged from control. Thus, in hepatic microsomes from choline-deficient female rats, it appears likely that levels of the non-sexually differentiated cytochromes P-450 UT-F and ISF-G are decreased. Unlike the situation in male rats, long term choline deficiency does not appear to influence levels of sexually-differentiated P-450 enzymes in the female rat.

Androstenedione↗