Endocranial volume is heritable and is associated with longevity and fitness in a wild mammal.

Research on relative brain size in mammals suggests that increases in brain size may generate benefits to survival and costs to fecundity: comparative studies of mammals have shown that interspecific differences in relative brain size are positively correlated with longevity and negatively with fecundity. However, as yet, no studies of mammals have investigated whether similar relationships exist within species, nor whether individual differences in brain size within a wild population are heritable. Here we show that, in a wild population of red deer (Cervus elaphus), relative endocranial volume was heritable (h2 = 63%; 95% credible intervals (CI) = 50-76%). In females, it was positively correlated with longevity and lifetime reproductive success, though there was no evidence that it was associated with fecundity. In males, endocranial volume was not related to longevity, lifetime breeding success or fecundity.

Adult male coatis play with a band of juveniles.

This study examined the play behaviour in one group of coatis (Nasua narica) at La Selva Biological Station in Costa Rica. We incidentally found adult males playing with juvenile coatis, and conducted post-hoc analyses to investigate this interaction. Coati groups consist of adult females and juveniles of both sexes until male juveniles reach two years of age and leave the band to become solitary. Adult males only tolerate juveniles for a brief period during breeding season when the males court females to mate. Outside of the breeding season, adult males are known to prey on juveniles. In this study, when adult males were present with the band, play occurred more than was expected by chance, and adult males engaged in many of these play bouts. Because the mechanisms driving infanticidal behaviour are not well understood, and adult male coatis show a range of behaviours from infanticide to highly affiliative interactions with juveniles, using coatis as a model system may elucidate mechanisms underlying infanticide.

Excretion and metabolism of tipredane, a novel glucocorticoid, in the rat, mouse, monkey, and human.

The excretion and metabolism of [3H]tipredane, a novel glucocorticoid, has been studied in mice, rats, marmosets, rhesus and cynomolgus monkeys, and humans. After oral administration, [3H]tipredane was rapidly absorbed, metabolized, and excreted into urine and feces. In mice and male rats, radioactivity was excreted primarily into feces or bile, whereas in female rats, monkeys, and humans, excretion was mainly via the renal route. Some sex differences in the proportions excreted into urine and feces were noted in rodents, with females eliminating relatively more radioactivity in urine. Tipredane was shown to be extensively metabolized, but the routes were highly species-dependent and, in the rat, they were sex-dependent. Unchanged tipredane was not detected in any urine, bile, or blood extracts. Urinary and blood extract profiles indicated that there were between 10 and 30 metabolites in rats and mice, the majority of which constituted < 2% of the dose. In these species, the major pathways involved loss of the thioethyl moiety, S-oxidation of the thiomethyl group, and saturation of the adjacent saturated C16-17 bond. Hydroxylation of the steroid B-ring was seen in the 7 alpha-position in mice and female rats, and in the 6 beta-position in male rats. Metabolism of tipredane in rhesus and cynomolgus monkeys and humans was similar, but less extensive and different to that seen in rodents. The major products, the 6 beta-hydroxylated sulfoxide and sulfone metabolites of tipredane, accounted for 21-36% of the dose in human and monkey urine, and were also major components in blood. In contrast to mice and rats, S-oxidation and an unsaturated C16-17 bond were evident in primates. Metabolism of tipredane was rapid and complex, with significant species differences, although the disposition in rhesus and cynomolgus monkeys seemed to be similar to humans.

Induction of rodent hepatic drug-metabolizing enzyme activities by the novel anticonvulsant remacemide hydrochloride.

Remacemide hydrochloride [FPL 12924AA; 2-amino-N-(1-methyl-1,2-diphenylethyl) acetamide hydrochloride] is being evaluated as a novel neuroprotective treatment for epilepsy and stroke. Preliminary safety evaluation studies in the rat have shown that repeated doses of the compound produce histological and biochemical changes consistent with hepatic enzyme induction. To examine this further, the levels and activities of the major drug metabolizing cytochrome P450 (CYP) subfamilies (CPY1, CYP2, and CYP3) were monitored in microsomal samples from male Sprague-Dawley rats dosed by gavage with FPL 12924AA (250 mg base.kg-1.day-1 for 28 days) or an equivalent volume of vehicle (controls). The interpretation of the findings was aided by comparison with the effects of phenobarbitone (75 mg.kg-1.day-1 ip for 4 days) and beta-naphthoflavone (a single intraperitoneal dose at 80 mg.kg-1.day-1). No significant changes in total hepatic P450 levels (1.44 +/- 0.40 nmol.mg-1 vs. 1.31 +/- 0.19 nmol.mg-1 in controls) or ethoxyresorufin O-deethylase activity (a CYP1A induction probe) were observed after remacemide treatment. The pattern of induction produced by remacemide was very similar to that observed with phenobarbitone. The nonspecific CYP-dependent reaction ethoxycoumarin O-deethylation was induced approximately 2-fold. The specific CYP2B markers pentoxyresorufin O-depentylase and 16 beta-hydroxytestosterone production were both increased markedly by FPL 12924AA (approximately 100- and 20-fold, respectively). 2 beta- and 6 beta-Hydroxytestosterone production were also elevated, indicating the induction of CYP3A1/2. Similar effects on isoform-selective P450-dependent activities were observed in male and female mice treated with remacemide as part of a dose-ranging study.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure-activity studies of sulfate transfer: the hydrolysis and aminolysis of 3'-phosphoadenosine 5'-phosphosulfate (PAPS).

The pH-rate profile for the hydrolysis of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) in aqueous solution has been measured. Comparison with other data suggests that hydrolysis occurs by almost complete unimolecular elimination of sulfur trioxide, with weak involvement of a molecule of water in the transition state. The catalytic power (kcat/kuncat) of the sulfotransferases is estimated to be in the order of 10(10)-10(12). Amines--exemplified by morpholine--react spontaneously with PAPS in water at 39 degrees C by attack at both sulfuryl and (5')phosphoryl groups in a ratio of 2:3. The mechanism of activation of the coenzyme, PAPS, by the sulfotransferases that catalyse N-sulfation must involve suppression of its native N-phosphorylating reactivity and specific enhancement of its N-sulfating reactivity. Studies of the aminolysis of the coenzyme in aprotic solvent-water mixtures suggest how this might be accomplished.

Does vasectomy cause testicular cancer?

Between 1975 and 1990, 330 men developed testicular tumours in Northern Ireland. Their names were cross matched with a sample of 2904 men who had undergone vasectomy between 1970 and 1985. The expected numbers of tumours in vasectomised patients was 2, while the actual number was 1. Our experience does not indicate that vasectomy causes testicular cancer.

PIP: The overall incidence of testicular cancer, like vasectomy, is increasing. A recent report from Scotland suggests a link between the two. This study was conducted to investigate any association between vasectomy and the subsequent development of testicular cancer. Over the period 1975-1990, 330 men developed testicular tumors in northern Ireland. Their names were cross-matched with a sample of 2904 men who had undergone vasectomy between 1970 and 1985. Researchers expected 2 tumors in vasectomized patients, but found only 1. The authors' experience does not suggest that vasectomy causes testicular cancer.

The incorporation of 3-phenoxybenzoic acid and other xenobiotic acids into xenobiotic lipids by enzymes of the monoacylglycerol pathway in microsomes from adult and neonatal tissues.

The incorporation of 3-phenoxybenzoic acid (3PBA) into xenobiotic lipids by enzymes of the monoacylglycerol (MG) pathway was measured using microsomes prepared from rat liver as an enzyme source. The mean activities of the three enzymes involved were: acyl-CoA synthetase, 1.1 nmol/min/mg protein; MG acyltransferase, 75 pmol/min/mg protein; and diacylglycerol acyltransferase, 11.4 pmol/min/mg protein. MG and DG acyltransferase also showed activity with benzoyl-CoA or 1-naphthylacetyl-CoA as acyl donor but none with clofibryl-CoA or 2,4-dichlorophenoxyacetyl-CoA. MG acyltransferase activity, using 3PBA-CoA, was higher in microsomes from rat intestinal mucosa and pig liver, and lower in rat adipose tissue, rat liver and mouse liver. This ranking of activities corresponds to published activities using natural substrates. There was a large increase in MG acyltransferase, using either 3PBA-CoA or palmitoyl-CoA as substrate, in microsomes from the livers of rats 16-18 days old. Lysophosphatidic acid (lyso-PA) and lysophosphatidylethanolamine (lyso-PE), but not other phospholipids or detergents, stimulated MG acyltransferase activity more than two-fold. Lyso-PA (5 microM) increased the Vmax but had little effect on the Km for 2-hexadecylglycerol, whereas 100 microM lyso-PE decreased the Km and had a smaller effect on the Vmax. These results illustrate that the incorporation of xenobiotic acids into diacyl- and triacylglycerol by enzymes of the MG pathway may be a more general phenomenon than was previously suspected and that it may be subject to a variety of developmental and physiological controls.

Gastrointestinal bleeding due to multiple ileal duplications diagnosed by scintigraphy and barium studies.

A case of multiple ileal duplications presenting with gastrointestinal bleeding is described. Technetium-99m Pertechnetate scintigraphy in conjunction with barium studies provided the initial clue and accurately localised the abnormality pre-operatively.

Vasectomy reversal.

A small personal series of vasovasostomies and a review of the literature on this subject are presented. The importance is stressed of good counselling before vasectomy is undertaken in the first place.

PIP: 13 vasectomy reversals were performed between 1978-1988 at the Ulster Hospital, Belfast, Northern Ireland, on men aged 23-49, ranging from age 21.5-38 at the time of vasectomy. Reasons for requesting reversal were remarriage in 10, widowhood and remarriage in 1 and desiring more children in 2 men vasectomized at age 21-24. The surgical method employed a 3/0 gauge nylon double-ended straight needle stent suture advanced 1.5 cm through the lumen and brought outside the wall of the vas and the skin. The anastomosis was completed with 4 6/0 nylon seromuscular sutures. Each man had the Tray agglutination test for sperm and seminal antibodies, and seminal analysis at 1-2 and 3-5 months. The results were positive sperm counts indicating patency in 66%, 8 of 12. Complete data were available for 8 patients. 3 were azoospermic at first and another developed prostatitis and azoospermia. 2 of these 4 were poor candidates because of vasectomy in the convoluted part of the vas. In 4 of the remaining 5, sperm counts rose over time. Wives of 2 of the men have conceived. No sperm immobilizing or seminal antibodies were detected. In the discussion surgical methods, ways of managing stents, and counseling of vasectomy patients and those desiring vasovasostomy are reviewed.

Studies on the fate of flocoumafen in the Japanese quail (Coturnix coturnix japonica).

1. 14C-Flocoumafen, administered to Japanese quail as a single oral or i.p. dose, was rapidly and extensively eliminated in excreta; most was eliminated within 24 h. Extensive metabolism of the rodenticide was seen, with at least 8 metabolites detected; unchanged flocoumafen comprised 9% dose. The elimination kinetics and metabolic profiles were qualitatively similar after oral and i.p. dosing. 2. The major metabolites (60% dose) were labile to beta-glucuronidase, liberating aglycones with identical chromatographic mobilities to those of the unchanged flocoumafen isomers. 3. Radioactivity was retained mostly in the liver; largely as unchanged flocoumafen associated with the mitochondrial and microsomal fractions. Elimination of radioactivity from most tissues was biphasic with an initially rapid depletion (5 days) followed by a slow terminal elimination phase. The elimination half life from liver was greater than 100 days. 4. Livers of quail receiving extended dietary exposure to flocoumafen at 5, 15 and 50 ppm had concentrations of flocoumafen (1.0 nmol/g) that were independent of dose, indicating a capacity-limited binding site. These hepatic concentrations were similar to those after a single oral dose and were also similar to those in rats. The data indicate the presence in quail liver of a saturable high affinity flocoumafin binding site with similar characteristics and capacity to that in the rat. 5. The selective toxicity of flocoumafen to rats (highly toxic) and quail (moderately toxic) appears to arise from differences in metabolism rather than from anticoagulant binding in the liver. When hepatic binding sites of rats are saturated anticoagulant action becomes lethal, whereas quail are able to survive and extensively metabolize the compound.

The fate of 4-cyanoacetanilide in rats and mice; mechanism of formation of a novel electrophilic metabolite.

1. The metabolic fate of 4-cyanoacetanilide (CAA), labelled with 14C and 13C in the N-acetyl group, was studied in rats (oral dose, 22.5 mg/kg) and mice (oral dose 21.7 mg/kg). 2. The metabolic profile in the urine of rats was compared with that obtained previously with 4-cyano-N,N-dimethylaniline (CDA) and confirms the intermediacy of CAA in the metabolism of CDA. 3. The precursor of a major metabolite of CDA and CAA (the mercapturic acid N-acetyl-S-[2-keto-2-(4-cyanoanilino)ethyl]cysteine, metabolite C) was identified in the urine of CAA-dosed rats as the O-sulphate conjugate of N-(4-cyanophenyl)glycolamide. 4. Pretreatment of rats with the sulphotransferase inhibitor pentachlorophenol reduced the yield of the mercapturic acid metabolite C, further indicating the intermediacy of a sulphate conjugate. 5. Metabolite C was not formed from CAA by mice; thus, this species difference, also observed with CDA, occurs at the level side-chain (acetyl) hydroxylation as well as at N-acetylation of 4-cyanoaniline as previously proposed. 6. The significance of this pathway as a bioactivation reaction of CDA, CAA and other acetanilides is discussed.

The metabolism of o-fluoroaniline by rats, rabbits and marmosets.

o-Fluoroaniline is rapidly metabolized and excreted in rats, rabbits and marmosets. Following a single oral dose of 14C-fluoroaniline of about 20 mg/kg, more than 80% of the dose is excreted in 0-24 h, the urine being the major route of excretion for all three species. For all three species, 4-amino-3-fluorophenyl is a major metabolite, conjugated at oxygen with either sulphate or glucuronic acid. 4-Acetylamino-3-fluorophenyl sulphate or glucuronide are also significant metabolites. An h.p.l.c. method with electrochemical detection was developed for monitoring exposure of plant workers to o-fluoroaniline, based on 4-amino-3-fluorophenyl sulphate.

Detoxification of the organophosphorus insecticide chlorfenvinphos by rat, rabbit and human liver enzymes.

A good inverse correlation between the acute oral toxicity of chlorfenvinphos and its rate of oxidative detoxification in the liver exists for rats, mice, rabbits and dogs. Measurements of the rates of oxidative metabolism (O-de-ethylation) by in vitro liver preparations from rat, rabbit and human have been compared. When the results are expressed in terms of cytochrome P450, as opposed to microsomal protein, detoxification by the human liver enzyme(s) is almost as effective as that by rabbit enzyme(s). The rabbit is relatively resistant to the acute toxic action of the insecticide.