The effect of diazoxide on uterine blood flow in pregnant sheep

Diazoxide, a labor inhibiting agent, was administered intravenously at various rates to seven pregnant, near-term sheep to evaluate its effect on cardiovascular and uterine hemodynamics. Uterine blood flow was measured with electromagnetic flow transducers. Rapid administration of diazoxide resulted in a profound maternal tachycardia with hypotension, an increase in uterine vascular resistance, and a significant decrease in uterine blood flow. With slow infusion of the drug, the changes in heart rate and blood pressure were minimized, uterine vascular resistance was decreased, and uterine blood flow was maintained. Therefore, slow infusion appears to be the preferred method for inhibiting labor with diazoxide.     

The antibody response in sheep vaccinated with experimental Nairobi sheep disease vaccines

The antibody responses to experimental Nairobi sheep disease vaccines have been assayed. The responses to an inactivated methanol precipitated vaccine were comperable with those following infection with virulent virus. The responses to attenuated vaccines were inadequate to protect against challenge with virulent virus.     

Effects of continuous infusion of endothelin-1 in pregnant sheep

Plasma concentration of endothelin-1, a potent vasoconstrictor produced by the vascular endothelium, has been observed to be significantly increased in a number of pathophysiological states, including preeclampsia. In the present study we have evaluated the effects of elevated plasma endothelin-1 in pregnant sheep by continuous exogenous endothelin-1 administration. Nine pregnant ewes (110+/-5 days' gestation) were instrumented for measurements of maternal mean arterial pressure, renal blood flow, and uterine blood flow. After recovery, endothelin-1 was infused intravenously for 4 hours at a dose that was adjusted to raise mean arterial pressure by approximately 20 mm Hg by the end of the first hour (range 5 to 20 ng/kg per minute). Mean arterial pressure, renal blood flow, uterine blood flow, urinary protein excretion, hematocrit, and plasma endothelin-1 concentration were measured hourly, and renal and uterine vascular resistances were calculated. Endothelin-1 produced significant increases (% change from baseline at t=4 hours) in mean arterial pressure (45+/-8%), renal vascular resistance (353+/-66 %), and uterine vascular resistance (59+/-21%). Endothelin-1 also increased microvascular permeability both systemically and within the kidney, as suggested by marked increases in hematocrit (0.27+/-0.01 to 0.32+/-0.01) and urinary protein concentration (0.95+/-0.1 to 7.9+/-3.2 mg/mL per mg creatinine). There was a highly significant correlation (P<.0001) between plasma endothelin-1 and mean arterial pressure, renal vascular resistance, uterine vascular resistance, hematocrit, and urinary protein content in all sheep studied. In addition, plasma endothelin-1 corresponded well with the time course of the changes in cardiovascular parameters and urinary protein excretion observed. These results provide evidence to suggest that elevation of circulating endothelin-1 in pregnant sheep can produce cardiovascular and hemodynamic changes that in many ways resemble the human disease preeclampsia. This supports the hypothesis that endothelial cell damage and/or dysfunction that is associated with increased production of endothelin-1 could directly contribute to the progression of preeclampsia.     

Fasciolinip-1: experimental fasciolicidal activity in sheep

The aim of the present study was to evaluate the flukicide efficacy of the 2-amino-5(6)-chloro-1-methoxycarbonylbenzimidazole (II), named Fasciolinip-1, against eight and twelve-week old flukes in sheep. In a first experiment 35 young sheep were infected each with 300 metacercariae of Fasciola hepatica. Eight weeks postinfection five groups of seven animals each were treated as follows: Groups 1, 2 and 3 were given 2.5, 5 and 10 mg/kg of Fasciolinip-1. Groups 4 and 5 remained as non-treated and vehicle controls, respectively. In a second study, 32 sheep were infected each with 150 metacercariae. Twelve weeks postinfection, the animals were divided into 4 groups of 8 sheep each. Groups 1, 2 and 3 were treated orally with 5, 10 and 15 mg/kg of Fasciolinip-1, respectively. Group 4 remained as non-treated control. Fifteen days after treatment, all sheep from both experiments were killed to collect the flukes present in liver. Results indicated efficacies of 19.1%, 49.6% and 65.2% for groups 1, 2 and 3 of the first study and 48.3%, 64.8 and 90.6% for sheep of the second experiment, respectively. It was concluded that Fasciolinip-1 removed 8-week old flukes in limited numbers and 12-week old flukes in 90.6% when used at 15 mg/kg body weight.     

The pathogenesis of experimental membranous glomerulonephritis induced with homologous nephritogenic tubular antigen

The renal tubular epithelial antigen (Tub-Ag) of rats was solublized by Pronase and purified by gel filtration and acrylamide gel electrophoresis. Purified Tub-Ag was a glycoprotein with S20,W value of 8.4. Utilizing radiolabeled Tug-Ag, a sensitive radioimmunoassay for Tub-Ag and homologous antibody (anti-Tub-Ag) was developed. Tub-Ag activity associated with a protein of the same molecular size was demonstrated in the serum, as well as in Pronase extracts of all the organs tested, including kidney, liver, lung, spleen, intestine, stomach, and heart. The physiochemical properties of the Tub-Ag of rats and its distribution were essentially the same as the Tub-Ag of humans, which had been found in immune deposits in the kidney of some patients with idiopathic membranous glomerulonephritis. Rats were immunized with the purified Tub-Ag emulsified in Freund's complete adjuvant and followed for Tub-Ag and anti-Tub-Ag in the serum, as well as for proteinuria and immunohistological changes in the kidney. Serum Tub-Ag dropped sharply after 20 days, when anti-Tub-Ag appeared in the circulation. Persistent, massive proteinuria appeared still later, more than 30 days after injection, when anti-Tub-Ag disappeared and Tub-Ag reappeared in the serum of some of those rats. In others, anti-Tub-Ag in the serum persisted throughout the observation period of 90 days. The pathology of the kidney of the rats with proteinuria was that of a typical membranous glomerulonephritis; thickening of glomerular capillary walls with granular deposits of gamma-globulin and Tub-Ag was observed. On the basis of these results, Tub-Ag in the serum, probably released from cellular membranes of various organs as a physiological metabolite, is considered to maintain the pathological process in the kidney by providing the antigen continuously to form immune complexes.     

The interrelationship of alpha4 integrin and matrix metalloproteinase-2 in the pathogenesis of experimental autoimmune encephalomyelitis

Previous studies have suggested that surface expression of alpha4 integrin by autoreactive T-cell clones is necessary for the clones to induce experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. To provide direct evidence for this phenomenon, we have transfected alpha4 integrin into C19alpha4-LO, a myelin basic protein-reactive T-cell clone that does not express alpha4 integrin and does not induce EAE when adoptively transferred into a susceptible mouse strain. Transfection of alpha4 integrin converted this clone to an alpha4 integrin-expressing clone that induced EAE. We then examined potential mechanisms by which alpha4 integrin may facilitate the disease process. C19 T-cell clones adhered equally to a monolayer of microvascular endothelial cells, regardless of level of alpha4 integrin expression. However, in contrast to T-cell clones that do not express alpha4 integrin, T-cell clones that express alpha4 integrin (endogenously or by transfection) transmigrated through an endothelial cell layer and subendothelial matrix at an enhanced rate and adhered to recombinant vascular cell adhesion molecule-1 (rVCAM-1) and the CS1 fragment of fibronectin, and after adhesion to these ligands, a matrix-degrading metalloproteinase (MMP-2) was induced and activated. The clones were also shown to constitutively express the membrane-type matrix metalloproteinase (MT1-MMP), an enzyme that activates MMP-2. GM6001 and UK-221,316, inhibitors of metalloproteinases, reduced alpha4 integrin-mediated transmigration and EAE induction by C19 T-cell clones. In addition, we studied a second EAE-inducing T-cell clone, MM4, which constitutively expresses alpha4 integrin and MMP-2. Engagement of alpha4 integrin on the MM4 clone up-regulated the expression and activation of MMP-2, without changing the expression of MT1-MMP. MMP inhibitors also reduced transmigration of and EAE induction by the MM4 T-cell clone. These studies demonstrate directly that expression of alpha4 integrin by autoreactive T-cell clones is required for adoptive transfer of EAE in this model. We also define a role for alpha4 integrin in the disease process in mediating the induction and coordinate activation of a matrix metalloproteinase (MMP-2), which facilitates T-cell transmigration.     

Observations on the development of mural thrombi in chronic experimental aneurysms in sheep

Observations were made on mural thrombi in experimental venous pouch aneurysms in sheep. Thrombi associated with mural tears and dissection consisted predominantly of laminated fibrin masking the earlier platelet deposition and infiltrating the wall to some extent. Thrombus growth was associated with platelet masses of Zahn and secondary fibrin deposition. Intervening spaces contained a variable quantity of coagulated plasma, fibrin mesh, leucocytes, disintegrating red cells and platelets rather than red thrombus as often suggested. Periodic deposition of platelet masses with surface rippling, the whorling patterns of laminated fibrin and mechanical disruption of red cells indicated the importance of haemodynamics. Coarse macroscopic lamination of mural thrombi was attributed in part to recurrent dissections between the wall and the mural thrombus and of the thrombus itself. These accounted for growth of thrombus with expansion of the wall and interference with organization of the thrombus. The model has proved suitable for the study of thrombogenesis and thrombus behaviour in aneurysms.     

The pregnant woman in industry

The intent of this paper is to relate current thought in proper perspective to the mounting concern for the pregnant woman in industry. Embryo toxicology may demonstrate a need for lowered standards of exposure for the woman worker during a pregnancy. Lastly, a plan is offered to obtain data for comparison of female work populations which may or may not be exposed to certain, primarily airborn, contaminants.     

Liver segmentectomy as anatomically precise resections. An experimental study in sheep

OBJECTIVE: To assess a new technique of anatomically precise hepatic segmental resection and to compare the degree of precision and biochemical profiles with results after traditional segmental resection and a sham operation. DESIGN: Experimental study. SETTING: University hospital, Germany. MATERIAL: 50 sheep (10 each had segments II, III, and IV removed by the new technique, and 10 each were studied in the traditional resection and sham operated groups). INTERVENTIONS: Operative ultrasonography and injection of methylene blue to identify segmental boundaries. In traditional operations boundaries were identified only from knowledge of the surface structure of the liver. MAIN OUTCOME MEASURES: Degree of precision, duration of operation, blood loss, mortality, transaminase activities and liver function tests. RESULTS: Anatomically precise segmentectomies were achieved in 6/9 (67%) for segment II, 6/9 (67%) for segment III, and 4/8 (50%) for segment IV. Using the traditional technique (segment III only) there was only 1/10 anatomically precise resections, together with 5 perisegmentectomies and 4 incomplete resections (p < 0.02). The operations for anatomically precise resection lasted significantly longer, but resection time was similar. Blood loss, survival, and transaminase activities were similar for the two groups, but the margin of necrosis at the cut edge was significantly less in anatomically precise resections. CONCLUSION: Anatomically precise hepatic resections are technically feasible with the use of intraoperative ultrasonography and selective staining of the segment(s) to be removed with methylene blue. Although it takes longer, there are no detrimental consequences compared with the considerably less accurate traditional technique.     

The pathogenesis of infertility in men

With the purpose of gaining insights into the general regularities and particular features of pathogenesis of sterility of urogenital genesis, we undertook the present studies on biopsy specimens of testes, epididymis, deferent ducts, prostate, spermogramme, blood plasma content of gonadotrophic and sex hormones in 162 patients with infertility of urogenital genesis, and in 412 rats. Infertility pathogenesis was found out to have two stages: compensatory-adaptive alterations and irreversible disorders. Infertility is believed to be a polyetiologic, monopathogenetic medical condition.     

Stimulation of the switch in myometrial activity from contractures to contractions in the pregnant sheep and nonhuman primate

The process of parturition is regulated by a set of interrelated endocrine, paracrine, and autocrine systems. Many of these systems demonstrate positive feed-forward characteristics. The sequential recruitment of signals that promote the labour process demonstrates that it is not possible to attribute the designation of the factor responsible for the 'initiation of parturition' uniquely to any one signalling mechanism. For this reason we prefer to avoid the term initiation of parturition since, mechanistically, each cellular and molecular mechanism that contributes to the process is itself initiated by an earlier process. In a very real sense, the initiation of parturition can be considered to be fertilisation. Therefore we prefer to describe the key mechanisms involved as promoting, rather than initiating, the process of labour and delivery. Despite many interspecies differences, an increase in maternal plasma oestrogen in late gestation appears to play a central role in promotion of parturition. In both sheep and monkeys signals from the fetal hypothalamo-pituitary-adrenal axis increase oestrogen production by the placenta. We propose that the key fetal adrenal product is cortisol in the sheep and androgen in the monkey. Oestrogen then recruits a range of stimulators, uterotonins, that act on the prepared myometrium to initiate the switch in myometrial activity from contractures to contractions. The various mechanisms central to the process can be considered to be either, or both, activators and/or stimulators of one or more of the key terminal steps involved.     

Oxidant-antioxidant imbalance in the experimental interstitial lung disease induced in sheep by visna-maedi virus

X-linked Alport syndrome (AS) is a heritable disorder which is associated with mutations in the type IV collagen alpha 5 (IV) chain gene (COL4A5) located on chromosome X. Following renal transplantation, an average of 6% of male AS patients develop anti-GBM nephritis. We studied the specificity of the antibodies against type IV collagen in the serum of a patient with COL4A5 partial deletion. The specificity of these alloantibodies was determined against collagenase-digested GBM, as well as against recombinant non-collagenous (NC1) domains of the type IV collagen alpha 1(IV)-alpha 6(IV) chains expressed in escherichia coli. Immunoblotting and ELISA demonstrated that these antibodies bound specifically to the NC1 domain of alpha 5(IV) collagen. There was no binding to the NC1 domain of the other chains, including the Goodpasture antigen. Competitive ELISA confirmed the results obtained by ELISA and immunoblotting. This patient developed alloantibodies directed against antigens present in the grafted kidney, but absent from his Alport kidney. The pathogenesis of post-transplantation glomerulonephritis in the Alport patient studied is thus similar to that of Goodpasture syndrome, with the exception that the pathogenic antibodies are targeted to another alpha chain of type IV collagen.     

Plasma insulin and growth hormone concentrations in pregnant sheep II: post-absorptive levels in mid- and late pregnancy

1. The incorporation of L-[U-14C]leucine, L[U-14C]histidine and L-[U-14C]phenylalanine into casein secreted during perfusion of isolated guinea-pig mammary glands was demonstrated. 2. The extent of incorporation of label into casein residues was consistent with their being derived from free amino acids of the perfusate plasma. 3. The mean transit time of the amino acids from perfusate into secreted casein was approx. 100 min. 4. Whereas radioactive histidine and phenylalanine were incorporated solely into milk protein, radioactivity from [U-14C]valine was also transferred to CO2 and to an unidentified plasma component, and from [U-14C]leucine to plasma glutamic acid. 5. Evidence from experiments with [U-14C]phenylalanine suggests that, as in rats, but in contrast with ruminant species, guinea-pig mammary tissue does not possess phenyl alanine hydroxylase activity. 6. The results are discussed in relation to the possible role of essential amino acid catabolism in the control of milk-protein synthesis.     

The common diarrhoeas of sheep in Britain

As every sheep farmer knows, diarrhoea is of common occurrence in animals of all ages in his flock. In lambs it can result in sigificant mortality while in older animals growth rates are reduced and weight loss can occur. Although diarrhoea can be an incidental finding in many sheep diseases, particularly in their terminal stages, only on those conditions are commented on in which diarrhoea is the predominant feature of the clinical syndrome. The subject is discussed below on both an age and seasonal basis and, if an initial assumption is made that lambing takes place at the traditional March/April period, animals will be increasing in age as the seasons progress. Thus the sequence commences in the spring with the young lamb and concludes the following winter with the adult.