Sero-prevalence and risk factors of Toxoplasma gondii infection in wild cervids in Denmark.

Toxoplasma gondii is a zoonotic protozoan parasite capable of infecting possibly all warm-blooded animals including humans, and is one of the most widespread zoonotic pathogens known. Free-ranging wildlife can be valuable sentinels for oocyst contaminated environments, as well as a potential source for human foodborne infection with T. gondii. Here we aimed to determine the sero-prevalence of T. gondii in Danish wild deer populations and examine risk factors associated with increased exposure to the parasite. Blood samples were collected from 428 cervids (87 fallow deer (Dama dama), 272 red deer (Cervus elaphus), 55 roe deer (Capreolus capreolus) and 14 sika deer (Cervus Nippon) from 23 hunting sites in Denmark. The animals were shot during the hunting season 2017/2018, and screened for antibodies against T. gondii using a commercial ELISA kit. One hundred and five (24.5%) cervids were sero-positive. Sero-prevalence was significantly different between species (p < 0.05), with odds of sero-positivity being 4.5 times higher in roe deer than fallow deer, and 3.0 times higher in red deer than in fallow deer. A significant increase in sero-prevalence with age was observed, driven by a significant increase in risk in adult red deer compared to calves (OR: 13.22; 95% CI: 5.96-33.7). The only other significant risk factor associated with wild cervid T. gondii sero-positivity was fencing, with the highest exposure associated with deer from non-fenced hunting areas (OR: 2.21; 95% CI: 1.05-4.99). This study documented a widespread exposure to T. gondii in Danish cervids. Therefore the meat of the wild deer, in particular from roe deer and red deer, should be considered a significant risk of T. gondii infections to humans, if not properly cooked. Further, molecular studies to confirm the presence of infective parasitic stages in the muscles of deer used for consumption is recommended.

Internal fixation of femoral shaft fractures in children and adolescents: a ten- to twenty-one-year follow-up of 52 fractures.

In a long-term follow-up (mean 16 years) of 52 femoral shaft fractures treated by internal fixation in 50 children and adolescents, we noted a mean overgrowth of 1 mm after plating and a mean undergrowth or relative shortening of 2 and 9 mm after nailing with broad (IMN) and slender (flexible rods: IMR) intramedullary nails, respectively. The mean overgrowth was 8 mm in children, but adolescents had a mean undergrowth of 5 mm (p < 0.01). Excessive overgrowth tended to occur less frequently after intramedullary nailing than after plating (p = 0.1). Undergrowth tended to occur with increasing frequency with increasing age and attained troublesome levels in three patients with severe trauma. Three cases of moderate valgus deformity of the hip and one case of late arthrosis of the hip occurred after intramedullary nailing with IMN introduced through the greater trochanter. We conclude that this method should not be used in patients with open physes.

New antihistamines: substituted piperazine and piperidine derivatives as novel H1-antagonists.

Structural manipulation of polycyclic piperazinyl imide serotonergic agents led to the synthesis of compound 8, 2-[4-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-4, 4a,5,5a,6,6a-hexahydro-4,6-ethenocycloprop[f]isoindole-1,3(2H,3 aH)-dione, which demonstrated good H1-antagonist activity. Substitution of a xanthinyl moiety for the polycyclic imide group led to the identification of novel xanthinyl-substituted piperazinyl and piperidinyl derivatives with potent antihistamine H1-activity without the undesirable antidopaminergic activity of 8. One compound, 24, 7-[3-[4-(diphenylmethoxy)-1-piperidinyl]propyl]- 3,7-dihydro-1,3-dimethyl-1H-pyrine-2,6-dione (WY-49051), is a potent, orally active H1-antagonist with a long duration of action and a favorable central nervous system profile.

Sulphasalazine fails to prevent development of mucosal ulceration and 5-lipoxygenase activity in guinea-pigs with chronic inflammatory bowel disease induced by combined bacterial immunization and oral carrageenin.

A model of inflammatory bowel disease in guinea-pigs involving a 14 day initial treatment with formalin-killed Bacteroides vulgatus subcutaneously and oral carrageenin plus live B. vulgatus for 10 days was used to determine the effects of sulphasalazine 100 mg kg-1 day-1 b.i.d., p.o. given for 4, 7 and 10 days after cessation of the bacterial/carrageenin treatment on the morphological and histological states of the established disease and on the production of the principal 5-lipoxygenase products, 5-hydroxyeicosatetraenoic acid and leukotriene B4. The drug treatment did not cause any significant changes in this established disease as measured by these parameters.

Observer variation in the radiographic classification of ankle fractures.

We recorded inter- and intra-observer variations in the classification of ankle fractures by the Lauge Hansen and Weber systems. Radiographs of 94 patients were classified independently by four observers. The observer variation was calculated by kappa statistics, which corrects the obtained values for the agreement expected by chance. There was an acceptable level of agreement for the overall classification into both systems. For the staging of supination-adduction and supination-eversion fractures in the Lauge Hansen system the agreement was poor. The results indicate that future classification systems should be subject to reliability analysis before they are accepted.

Inflammatory bowel disease induced by combined bacterial immunization and oral carrageenan in guinea pigs. Model development, histopathology, and effects of sulfasalazine.

A model of experimentally induced inflammatory bowel disease (IBD) featuring colitis, originally devised by Onderdonk and co-workers in guinea pigs, was modified to establish the optimal conditions for ulcer development. Upon varying the time of subcutaneous immunization with Bacteroides vulgatus and concomitant oral administration of acid-degraded iota-carrageenan and viable B. vulgatus, it was found that the optimal times of administering these agents were one to two weeks and five to six days, respectively. Light microscopy of the colon and cecum of the guinea pigs given the optimized treatment for ulcer induction revealed pronounced edema, inflammation, and lesions of the mucosa. Transmission electron microscopy of the mucosa from these animals showed the presence of large numbers of leukocytes in the subepithelial region, the majority being polymorphonuclear neutrophils which possessed large electron-dense granules or rods. Oral administration of 300 mg/kg/day sulfasalazine (salicylazosulfapyridine) for 14 days to guinea pigs given the optimized treatment for ulcer induction failed to reduce the numbers of ulcers or the histopathology gradings and fine structural changes of the mucosal inflammatory changes, but did reduce the symptoms of diarrhea.

Systemic administration of N-acetylcysteine has no effect on postoperative lung function following elective upper laparotomy in lung healthy patients.

In a randomized, double-blind study, 131 consecutive patients, subjected to elective upper laparotomy, were prophylactically given the recommended dose of N-acetylcysteine (NAC) (Mucomyst, ASTRA) (200 mg x 3) or placebo against postoperative pulmonary complications. The effect was evaluated by lung function tests (VC and FEV1), arterial blood gas analyses and chest x-ray. No benefit could be demonstrated, either to postoperative pulmonary function or in the frequency of atelectasis in the recommended dose. However, no patients with preoperative bronchopulmonary disease demanding treatment with bronchodilatators were included in the study. A positive effect of NAC in this category of patients could not be excluded.

Peroral N-acetylcysteine as prophylaxis against bronchopulmonary complications of pulmonary surgery.

In a randomized, double-blind study, 38 patients undergoing elective pulmonary surgery were given N-acetylcysteine (Fabrol, Ciba-Geigy) in recommended dosage (200 mg X 3) or placebo. The prophylactic effect on postoperative bronchopulmonary complications was evaluated from arterial blood-gas analyses and chest radiography. The alveolo-arterial oxygen difference increased substantially and similarly in both patient groups, and no intergroup difference was found in incidence of atelectasis or pneumonic infiltration. Thus there was no demonstrable benefit of N-acetylcysteine in the recommended dosage. For future similar studies, employment of considerably higher doses is proposed.

Syntheses and gastric acid antisecretory properties of the H2-receptor antagonist. N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d]isot hiazol-3-amine 1,1-dioxide and related derivatives.

The synthesis and gastric acid antisecretory properties of several N-substituted thieno[3,4-d]isothiazol-3-amine 1,1-dioxides and analogues are described. Two of the more potent compounds, N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide (6a) and N-[4-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide, showed greater potencies as H2-receptor antagonists (in vitro) than ranitidine. They also had potent gastric acid antisecretory activities in vivo, inhibiting basal acid secretion in the rat, histamine-stimulated acid secretion in the dog, and food-stimulated acid secretion in the dog. These were selected for further pharmacological evaluation.

Sulfasalazine and 5-aminosalicylic acid inhibit contractile leukotriene formation.

Sulfasalazine, used therapeutically in the treatment of ulcerative colitis, is cleaved in vivo to form 5-aminosalicylic acid (5-ASA) and sulfapyridine. In an isolated preparation of rat peritoneal cells both sulfasalazine (IC50 = 0.15 mM) and 5-ASA (IC50 = 2.3 mM), but not sulfapyridine, inhibited calcium ionophore-stimulated formation of contractile leukotriene activity. This activity, although not identified directly, is attributable to a mixture of leukotriene C4 and leukotriene D4 (commonly referred to as SRS-A, or slow-reacting substance of anaphylaxis). Reference compounds evinced expected activities (IC50 = 0.024 mM for phenidone, IC50 = 0.3 microM for nordihydroguaiaretic acid, IC50 = 0.033 mM for BW 755C), whereas para-aminosalicylic acid and thiosalicylic acid were inactive. These properties of sulfasalazine may contribute to its therapeutic efficacy in vivo.

The effect of secretagogue selection on potency determinations for gastric acid antisecretory agents.

The most common treatment for gastric and duodenal ulcers is by suppressing the secretion of gastric acid by the parietal cells of the stomach. Two major categories of drugs can accomplish this specifically: histamine H2-receptor antagonist and (H+ + K+)ATPase inhibitors. Using a canine model of gastric acid secretion and either histamine or food as secretagogues, the effects of two drugs from each of these classes were investigated. The two H2-antagonists (ranitidine, Wy-45,727) demonstrated a significantly greater antisecretory potency when acid secretion was stimulated by histamine as compared to a food stimulus. Conversely, the (H+ + K+)ATPase inhibitors (omeprazole, timoprazole) were equipotent regardless of stimulus.

Protection by the calcium antagonist Wy-47,037 against stress ulceration in the rat.

Wy-47,037, a novel compound with both intracellular and extracellular calcium-blocking properties, was evaluated for its effects on cold/restraint stress induced ulceration in the rat. Wy-47,037 dose-dependently inhibited ulcerogenesis; with an ED50 of 8 mg/kg, PO, it was approximately twice as potent as nitrendipine (ED50 = 15 mg/kg). Wy-47,037 also reduced basal gastric acid secretion (ED50 = 7 mg/kg) and gastrointestinal motility (ED50 = 16 mg/kg). It is thus possible that Wy-47,037's alteration of basal gastric acid secretion and/or of gastrointestinal motility may contribute to its therapeutic efficacy against stress induced ulcer formation.

Phenylephrine derivatives as leukotriene D4 antagonists.

Two series of phenylephrine derivatives were prepared and tested as inhibitors of leukotriene D4 (LTD4) induced and ovalbumin-induced bronchospasm in the guinea pig. The most potent compound of the urea series, (R)-N,N-diethyl-N-[2-hydroxy-2-[3-(2-quinolinylmethoxy)phenyl]ethyl]-N- methylurea (3, Wy-47,120), was orally active with ED50's of 56 mg/kg vs. LTD4 and 55 mg/kg vs. ovalbumin. When tested as an antagonist of LTD4-induced contraction of isolated guinea pig tracheal strips, 3 was a competitive inhibitor with a p kappa B value of 5.22. In the second series, (R)-3-methyl-5-[3-(2-quinolinylmethoxy)phenyl]-2-oxazolidinone (26, Wy-47,674) had oral ED50's of 36 mg/kg against LTD4 and 95 mg/kg against ovalbumin. Compound 26 selectively antagonized contractile responses of guinea pig trachea evoked by LTD4 (p kappa B = 6.09). In the cat coronary artery, 3 dilated the preparation and blocked the coronary constrictor effect of LTD4. Compound 3 (0.13 mg/kg, iv) also preserved myocardial integrity in rats 48 h after coronary artery ligation. When tested in the rat alcohol-induced gastric lesion model, 3 and 26 manifested a dose-dependent mucosal protection against ethanol.

Excretion of iohexol and metrizoate in human breast milk.

Six lactating women undergoing contrast media examination had milk and blood taken to determine the rate and extent of excretion of iohexol (Omnipaque) (four mothers) and metrizoate (Isopaque) (two mothers). Blood samples were taken up to 45 minutes and milk samples up to 48 hours after the contrast medium injection. The excretion was low, reaching a maximum at 3 to 6 hours and showing a slow decay curve (t1/2 = 15 to 108 hours). One mother, who was weaning her baby, showed a different excretion pattern. The amount excreted during 24 hours was about 0.5 per cent of the weight adjusted maternal dose for both iohexol and metrizoate. It is not likely, that such a low dose of poorly absorbed drug would cause any adverse effects in the infant, unless it is hypersensitive to the drug already. The authors consider breast feeding to be acceptable for mothers receiving iohexol or metrizoate.

Characterization of the H2 receptor antagonist and gastric acid antisecretory properties of Wy-45,727.

Wy-45,727, structurally similar to ranitidine, was characterized in various models to define its gastric acid antisecretory potency and mechanism of action. In vitro it antagonized the histamine-induced 1) positive chronotropism in isolated guinea pig right atria (pA2 = 8.23, Schild coefficient +/- S.E.M. = 1.09 +/- 0.01), and 2) [14C]aminopyrine uptake in rat isolated gastric mucosal cells. It inhibited acid secretion in dogs (p.o.) prepared with innervated gastric pouches (ED50 = 0.2 mg/kg) and in the pylorus-ligated rat (ED50 = 0.43 mg/kg). ED50 values for ranitidine were 0.9 mg/kg (dog) and 9.97 mg/kg (rat). After an 18-hr pretreatment period with doses up to 300 mg/kg p.o., inhibition of acid secretion in the rat barely exceeded 50%, indicating that the duration of action of Wy-45,727 was not excessive. Wy-45,727 appears to be a selective histamine H2 receptor antagonist.

REV 5901 and Ly 171,883 protect rat gastric mucosa against ethanol-induced damage.

The effect of the leukotriene antagonist, Ly 171,883, or the 5-lipoxygenase inhibitor, REV 5901, on ethanol-induced gastric lesion formation in the rat was investigated. Pretreatment with REV 5901 resulted in a dose dependent decrease in lesion length. Doses of 32 and 64 mg/kg induced nearly complete protection against ethanol, while doses of 1 and 8 mg/kg were much less effective. With Ly 171,883, 32 and 64 mg/kg doses less dramatically reduced lesion length. These findings implicate products of the 5-lipoxygenase pathway in the production of ethanol-induced gastric lesions.

Tiotidine and ICIA 5165 inhibit central and peripheral H2 receptors with equal potency.

Histamine, acting through H2 receptors, increases cAMP formation in homogenates of guinea pig hippocampus. The activities of two H2 antagonists, tiotidine and ICIA 5165, as inhibitors of the histamine-induced increase were investigated. ICIA 5165 and tiotidine were potent antagonists of histamine with a pKi of 8.0 and 7.6, respectively. Similarly, the positive chronotropic response of isolated guinea pig atria to histamine was antagonized by tiotidine and ICIA 5165 with a pKB of 7.8 and 7.9, respectively. These studies suggest that histamine H2 receptors in the CNS and atria are similar.

Structural modification of H2-receptor antagonists provide post-H2-receptor gastric antisecretory activity.

Structural analogues (e.g., Wy-46,499) of a known H2-antagonist (Wy-45,662) were found to inhibit acid secretion in the pylorus ligated rat and to block forskolin and DBcAMP-stimulated [14C]amino-pyrine (AP) uptake by rat isolated gastric mucosal cell preparations. Wy-45,662 (N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno [3,4- d]isothiazol-3-amine 1, 1-dioxide), a very potent histamine H2-antagonist and antisecretory agent in the rat (ED50 approximately equal to 0.3 mg/kg), had no effect in vitro at 1 microM on forskolin-induced [14C]AP uptake while 10 nM Wy-45,662 completely suppressed histamine-stimulated [14C]AP uptake. In contrast, the N-benzylated form of Wy-45,662, Wy-46,499, dose-dependently (1 X 10(-7) -3 X 10(-6)M) suppressed forskolin-stimulated [14C]AP uptake while retaining modest antisecretory activity (ED50 approximately equal to 8 mg/kg) in vivo. Wy-46,499's modest antisecretory activity was thus attributable to inhibition via a post-histamine H2-receptor mechanism.

Inhibition of [14C]aminopyrine uptake in rat isolated gastric mucosal cells by two classes of psychotropic agents.

Certain CNS-active compounds decrease gastric acid secretion in vivo. In this study a number of tricyclic antipsychotic or antidepressant compounds together with haloperidol, a nontricyclic antipsychotic agent, were shown to inhibit dibutyryl-cAMP-stimulated [14C]aminopyrine uptake, an index of acid secretory activity in a rat isolated gastric mucosal cell preparation. The observed order of potency was: thioridazine greater than chlorpromazine greater than haloperidol approximately equal to desipramine approximately equal to imipramine greater than clozapine. Comparison of these potencies with those of the known (H+ + K+)ATPase inhibitors timoprazole and omeprazole revealed that the potency of timoprazole was similar to the one of clozapine while omeprazole was intermediate between thioridazine and chlorpromazine. Pirenzepine was ineffective.