Real-world accuracy of computed tomography in patients admitted with small bowel obstruction: a multicentre prospective cohort study.

PURPOSE: Small bowel obstruction (SBO) is a common surgical emergency. Previous studies have shown the value computed tomography (CT) scanning in both confirming this diagnosis and identifying indications for urgent surgical intervention, such as strangulated bowel or closed loop obstructions. However, most of the literature is based on retrospective expert review of previous imaging and little data regarding the real-time accuracy of CT reporting is available. Here, we investigated the real-world accuracy of CT reporting in patients admitted with SBO. METHODS: This was a multicentre prospective study including consecutive patients admitted with SBO. The primary outcomes were the sensitivity and specificity of CT scanning for bowel obstruction with ischaemia and closed loop obstruction. Data were retrieved from the original CT reports written by on-call radiologists and compared with operative findings. RESULTS: One hundred seventy-six patients were included, all of whom underwent CT scanning with intravenous contrast followed by operative management of SBO. Bowel obstruction with ischaemia was noted in 20 patients, with a sensitivity and specificity of CT scanning of 40.0% and 85.5%, respectively. Closed loop obstructions were noted in 26 patients, with a sensitivity and specificity of CT scanning of 23.1% and 98.0%, respectively. CONCLUSIONS: The real-world accuracy of CT scanning appears to be lower than previously reported in the literature. Strategies to address this could include the development of standardised reporting schemas and to increase the surgeon's own familiarity with relevant CT features in patients admitted with SBO.

Management and short-term outcomes of patients with small bowel obstruction in Denmark: a multicentre prospective cohort study.

AIMS: The optimal management of small bowel obstruction (SBO) remains a matter of debate and treatment varies internationally. In Denmark, a more surgically aggressive strategy has traditionally been used, but to what extent patient outcomes differ from international reports is unknown. This study aimed to describe the current management and outcomes of patients admitted with SBO in Denmark. METHODS: This was a prospective cohort study conducted at six acute hospitals in Denmark over a 4-month period. Patients aged ≥ 18 years with a clinical or radiological diagnosis of SBO were eligible. Primary outcomes were 30 day morbidity and mortality rates. RESULTS: 316 patients were included during the study period. The median age was 72 years and 56% were female. Diagnosis was made by computed tomography (CT) in 313 patients (99.1%), with the remaining three diagnosed clinically. Non-operative management was the initial strategy in 152 patients (48.1%) and successful in 119 (78.3%). Urgent surgery was performed in the remaining 164 (51.9%), with a laparoscopic approach used in 84 patients (51.2%). The entire cohort had a 30 day mortality rate of 7.3% and a 30 day morbidity rate of 17.1%. CONCLUSIONS: The management of SBO in Denmark differs markedly to previous international reports, with an almost ubiquitous use of CT for diagnosis and a high proportion of patients undergoing urgent surgery. Despite higher rates of surgery, patient outcomes are broadly similar to reports of more conservative strategies, perhaps due to a reduction in delayed operations. TRIAL REGISTRATION: Trial registration number: NCT04750811. Trial registration date: 11/02/2021.

A Comparison of Pig Farmers' and Veterinarians' Perceptions and Intentions to Reduce Antimicrobial Usage in Six European Countries.

Antimicrobial (AM) resistance is an increasing problem in human and veterinary medicine. To manage this problem, the usage of AM should be reduced in pig farming, as well as in other areas. It is important to investigate the factors that influence both pig farmers' and veterinarians' intentions to reduce AM usage, which is a prerequisite for developing intervention measures. We conducted a mail survey among pig farmers (N = 1,294) and an online survey among veterinarians (N = 334) in Belgium, Denmark, France, Germany, Sweden and Switzerland. The farmers' survey assessed the perceived risks and benefits of and need for AM usage; the intention to reduce AM usage; farmers' efficacy (i.e. perception of their ability to reduce AM usage); support from their veterinarian; and the future reduction potential of AM usage. Additionally, self-reported reduction behaviours, the perceived farmers' barriers to reduce AM usage and relationships with farmers were assessed in the veterinarians' survey. The results showed that farmers and veterinarians had similar perceptions of the risks and benefits of AM usage. Veterinarians appeared to be more optimistic than pig farmers about reducing AM usage in pig farming. Farmers believed that their efficacy over AM reduction was relatively high. Farmers' intention to reduce AM usage and veterinarians' self-reported reduction behaviours were mainly associated with factors concerning the feasibility of reducing AM usage. To promote prudent AM usage, pig farmers should learn and experience how to reduce usage by applying alternative measures, whereas veterinarians should strengthen their advisory role and competencies to support and educate farmers.

Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels.

Ataxia is the predominant clinical manifestation of cerebellar dysfunction. Mutations in the human CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 (P/Q-type) calcium channels, underlie several neurological disorders, including Episodic Ataxia type 2 and Familial Hemiplegic Migraine type 1 (FHM1). Several mouse mutants exist that harbor mutations in the orthologous Cacna1a gene. The spontaneous Cacna1a mutants Rolling Nagoya (tg(rol)), Tottering (tg) and Leaner (tg(ln)) mice exhibit behavioral motor phenotypes, including ataxia. Transgenic knock-in (KI) mouse strains with the human FHM1 R192Q and S218L missense mutations have been generated. R192Q KI mice are non-ataxic, whereas S218L KI mice display a complex behavioral phenotype that includes cerebellar ataxia. Given the dependence of γ-aminobutyric acid type A (GABAA) receptor subunit functioning on localized calcium currents, and the functional link between GABAergic inhibition and ataxia, we hypothesized that cerebellar GABAA receptor expression is differentially affected in Cacna1a mutants and contributes to the ataxic phenotype. Herein we quantified functional GABAA receptors and pharmacologically dissociated cerebellar GABAA receptors in several Cacna1a mutants. We did not identify differences in the expression of GABAA receptor subunits or in the number of functional GABAA receptors in the non-ataxic R192Q KI strain. In contrast, tg(rol) mice had a ∼15% decrease in the number of functional GABAA receptors, whereas S218L KI mice showed a ∼29% increase. Our data suggest that differential changes in cerebellar GABAA receptor expression profile may contribute to the neurological phenotype of cerebellar ataxia and that targeting GABAA receptors might represent a feasible complementary strategy to treat cerebellar ataxia.

Positive allosteric modulation of α4ß2 nAChR agonist induced behaviour.

Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4ß2 receptors being the most abundant heteromer. The stoichiometry of α4ß2 receptors can be either (α4)(3)(ß2)(2) or (α4)(2)(ß2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4ß2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4ß2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4ß2 nAChR in rotational and analgesic responses and confirm striatal α4ß2 receptors to be of the HS form.

Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.

BACKGROUND AND PURPOSE: Positive allosteric modulation of α4ß2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively. EXPERIMENTAL APPROACH: Effects of NS9283 were evaluated in vitro using fluorescence-based Ca(2+) imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats. KEY RESULTS: NS9283 was shown to increase agonist-evoked response amplitude of (α4)(3) (ß2)(2) nACh receptors in electrophysiology paradigms. (α2)(3) (ß2)(2) , (α2)(3) (ß4)(2) and (α4)(3) (ß4)(2) were modulated to comparable extents, but no effects were detected at α3-containing or any 2α : 3ß stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHßE-sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five-choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors. CONCLUSIONS AND IMPLICATIONS: These results provide compelling evidence that positive allosteric modulators acting at the (α4)(3) (ß2)(2) nACh receptors can augment activity across a broad range of cognitive domains, and that α4ß2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.

Effect of tulathromycin on the carrier status of Actinobacillus pleuropneumoniae serotype 2 in the tonsils of pigs.

The effect of a single or double dose of tulathromycin was evaluated in pigs carrying Actinobacillus pleuropneumoniae serotype 2 in their tonsils. Twenty-nine pigs from a reinfected specific pathogen-free-herd were selected from animals testing positive in an A pleuropneumoniae serotype 2-specific pcr test on tonsil scrapings and they were divided into three groups. The pigs in group 1 were treated subcutaneously with 2.5 mg/kg tulathromycin on day 0, the pigs in group 2 were treated with 2.5 mg/kg tulathromycin on days 0 and 4, and the pigs in group 3 were left untreated as controls. The pigs were tested by pcr on tonsil scrapings on days 0, 4, 11 and 33, and on day 33 all the animals were euthanased. There were no significant differences between the numbers of PCR-positive animals in the three groups on any of the sampling dates.

Comparison of the novel subtype-selective GABAA receptor-positive allosteric modulator NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with diazepam, zolpidem, bretazenil, and gaboxadol in rat models of inflammatory and neuropathic pain.

Spinal administration of GABA(A) receptor modulators, such as the benzodiazepine drug diazepam, partially alleviates neuropathic hypersensitivity that manifests as spontaneous pain, allodynia, and hyperalgesia. However, benzodiazepines are hindered by sedative impairments and other side effect issues occurring mainly as a consequence of binding to GABA(A) receptors containing the alpha(1) subunit. Here, we report on the novel subtype-selective GABA(A) receptor-positive modulator NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], which possesses a functional efficacy selectivity profile of alpha(5) > alpha(3) > alpha(2) > alpha(1) at GABA(A) alpha subunit-containing receptors. Oral administration of NS11394 (1-30 mg/kg) to rats attenuated spontaneous nociceptive behaviors in response to hindpaw injection of formalin and capsaicin, effects that were blocked by the benzodiazepine site antagonist flumazenil. Ongoing inflammatory nociception, observed as hindpaw weight-bearing deficits after Freund's adjuvant injection, was also completely reversed by NS11394. Likewise, hindpaw mechanical allodynia was fully reversed by NS11394 in two rat models of peripheral neuropathic pain. Importantly, NS11394-mediated antinociception occurred at doses 20 to 40-fold lower than those inducing minor sedative or ataxic impairments. In contrast, putative antinociception associated with administration of either diazepam, zolpidem, or gaboxadol only occurred at doses producing intolerable side effects, whereas bretazenil was completely inactive despite minor influences on motoric function. In electrophysiological studies, NS11394 selectively attenuated spinal nociceptive reflexes and C-fiber-mediated wind-up in vitro pointing to involvement of a spinal site of action. The robust therapeutic window seen with NS11394 in animals suggests that compounds with this in vitro selectivity profile could have potential benefit in clinical treatment of pain in humans.

NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy.

The novel positive allosteric modulator NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] possesses a functional selectivity profile at GABA(A) receptors of alpha(5) > alpha(3) > alpha(2) > alpha(1) based on oocyte electrophysiology with human GABA(A) receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABA(A)-alpha(3) receptors while maintaining low efficacy at GABA(A)-alpha(1) receptors. NS11394 has an excellent pharmacokinetic profile, which correlates with pharmacodynamic endpoints (CNS receptor occupancy), yielding a high level of confidence in deriving in vivo conclusions anchored to an in vitro selectivity profile and allowing for translation to higher species. Specifically, we show that NS11394 is potent and highly effective in rodent anxiety models. The anxiolytic efficacy of NS11394 is most probably mediated through its high efficacy at GABA(A)-alpha(3) receptors, although a contributory role of GABA(A)-alpha(2) receptors cannot be excluded. Compared with benzodiazepines, NS11394 has a significantly reduced side effect profile in rat (sedation, ataxia, and ethanol interaction) and mouse (sedation), even at full CNS receptor occupancy. We attribute this benign side effect profile to very low efficacy of NS11394 at GABA(A)-alpha(1) receptors and an overall partial agonist profile across receptor subtypes. However, NS11394 impairs memory in both rats and mice, which is possibly attributable to its efficacy at GABA(A)-alpha(5) receptors, albeit activity at this receptor might be relevant to its antinociceptive effects (J Pharmacol Exp Ther 327:doi;10.1124/jpet.108.144, 2008). In conclusion, NS11394 has a unique subtype-selective GABA(A) receptor profile and represents an excellent pharmacological tool to further our understanding on the relative contributions of GABA(A) receptor subtypes in various therapeutic areas.

Postweaning multisystemic wasting syndrome in Danish pig herds: productivity, clinical signs and pathology.

A case-control study of 74 herds with postweaning multisystemic wasting syndrome (pmws) and 74 matched control herds was carried out. In the case herds the mortality rates of weaner and finisher pigs were 11.2 and 5.2 per cent respectively, compared with 3.1 and 3.2 per cent in the control herds. In most case herds, pmws developed within the first four weeks after weaning. Wasting, diarrhoea and respiratory signs were observed in 10 per cent of the weaner pigs (7 to 30 kg) in the case herds compared with 7 per cent in the control herds. The average daily gains of the weaner pigs and finisher pigs were 36 g and 52 g less in the case herds than in the control herds. By examining three weaner pigs from each herd the pmws diagnosis was confirmed by histopathology and immunohistochemistry in 78 per cent of the case herds, but at least one pmws-positive weaner pig was found in 19 of the control herds. The prevalence of pmws-positive pigs among illthriven weaner pigs was 45 per cent (101/222) in the case herds, and 12 per cent (27/222) in the control herds. Specific gross pathological findings were associated with a positive pmws diagnosis; pigs with heavy, rubber-like lungs, atonic intestines, and enlarged bronchial and inguinal lymph nodes, had a 0.7 probability of a positive pmws diagnosis by laboratory examinations. However, for illthriven pigs, this probability of having pmws was equal in the case herds and the control herds.

Prevalence of clinical signs of disease in Danish finisher pigs.

Between December 1999 and February 2001, two visits, eight weeks apart, were made to 90 herds of Danish finisher pigs. The prevalence of clinical signs was recorded by three veterinary technicians from the Danish Bacon and Meat Council according to a standardised procedure; they had been trained and their observations were monitored and validated before and during the study. A total of 154,347 finisher pigs were examined and 22,136 clinical signs were recorded. Vices accounted for 43 per cent of the signs. The highest mean prevalence was observed for ear necrosis (4.44 per cent), followed by respiratory signs (2.17 per cent), lameness (1.92 per cent), other skin diseases (1.73 per cent), tail bites (1.26 per cent), umbilical hernia (0.78 per cent), flank bites (0.52 per cent), diarrhoea (0.27 per cent), respiratory distress (0.12 per cent), atrophic rhinitis (0.10 per cent), recumbency (0.09 per cent) and central nervous disease (0.05 per cent). The prevalence of atrophic rhinitis was higher in conventional herds than in specific pathogen-free herds. The prevalence of clinical signs of atrophic rhinitis was higher among finishers weighing 51 to 75 kg than among finishers weighing up to 50 kg, and the prevalence of respiratory signs was higher among finishers weighing 51 to 75 kg then among finishers weighing 76 to 100 kg.

Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach.

BACKGROUND AND PURPOSE: Tesofensine is a centrally acting drug under clinical development for Alzheimer's disease, Parkinson's disease and obesity. In vitro, the major metabolite of tesofensine (M1) displayed a slightly higher activity, which however has not been determined in vivo. The aims of this investigation were (i) to simultaneously accomplish a thorough characterization of the pharmacokinetic (PK) properties of tesofensine and M1 in mice and (ii) to evaluate the potency (pharmacodynamics, PD) and concentration-time course of the active metabolite M1 relative to tesofensine and their impact in vivo using the PK/PD modelling approach. EXPERIMENTAL APPROACH: Parent compound, metabolite and vehicle were separately administered intravenously and orally over a wide dose range (0.3-20 mg kg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [(3)H]WIN35,428 as the pharmacodynamic measure. KEY RESULTS: Pharmacokinetics of tesofensine and M1 were best described by one-compartment models for both compounds. Nonlinear elimination and metabolism kinetics were observed with increasing dose. The PK/PD relationship was described by an extended E(max) model. Effect compartments were used to resolve observed hysteresis. EC(50) values of M1, as an inhibitor of the dopamine transporter, were 4-5-fold higher than those for tesofensine in mice. CONCLUSIONS AND IMPLICATIONS: The lower potency of M1 together with approximately 8-fold higher through steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.

Genomic analysis of PCV2 isolates from Danish archives and a current PMWS case-control study supports a shift in genotypes with time.

Porcine circovirus type 2 (PCV2) is the primary cause of Postweaning Multisystemic Wasting Syndrome (PMWS) in pigs. PCV2, however, is found in both PMWS-affected herds and non-affected herds. The objective of this study was to clarify if PCV2 genome nucleotide sequences isolated from pigs from PMWS-affected herds and non-affected herds cluster phylogenetically in two separate groups. All isolates (45) belonged to PCV2 group 1 and shared a nucleotide sequence identity of 99.4-100% indicating a very homogeneous PCV2 population in Denmark. Phylogenetic analysis of the PCV2 isolates revealed no distinctive clustering of case- and control-herds suggesting that there is no link between PCV2 sequences and herd disease status. The appearance of only PCV2 group 1 isolates in this study (isolates from 2003/2004) led us to determine if PCV2 nucleotide sequences had changed in Denmark over time. Interestingly, all PCV2 isolates from before the first outbreak of PMWS (2001) belonged either to a new PCV2 group identified for the first time in this study and named group 3 (isolates from 1980, 1987 and 1990) or PCV2 group 2 (isolates from 1993 and 1996). The shift from PCV2 group 2 to 1 was confirmed on a more global scale by placing all full genome PCV2 sequences submitted to GenBank from 1997 to 2006 in either of the groups by phylogenetic analysis. The analysis showed that the shift happened in 2003 or even earlier. This may indicate that PCV2 group 1 is a more adapted form of PCV2 and possibly could be more pathogenic.

Serotonin transporter density and anxiolytic-like effects of antidepressants in mice.

BACKGROUND: Chronic treatment with the dual serotonin/noradrenaline reuptake inhibitor (SNRI) duloxetine reduces the density of serotonin transporter sites in cortex and engenders an anxiolytic-like response. To determine the reproducibility of these effects and their generality to other antidepressants we compared the effects of chronic duloxetine treatment with another SNRI, venlafaxine, and two selective serotonin reuptake inhibitors, paroxetine and fluoxetine. METHODS: Separate groups of mice were administered vehicle, fluoxetine (15 mg/kg), paroxetine, duloxetine or venlafaxine (10 mg/kg) perorally twice daily for 28 days and tested in the mouse zero-maze and in motility cages on days 21 and 22, respectively, to determine effects on anxiety and motor activity. On day 28 brains were analysed for serotonin transporter (SERT) density in cortex and noradrenaline transporter (NET) density in cortex and hippocampus. RESULTS: Duloxetine and fluoxetine both reduced SERT density in cortex and induced anxiolytic-like effects. Paroxetine had an identical profile, but it is unclear if this drug down-regulated the SERT since extensive washing of cortical tissue did not remove all drug. Venlafaxine had no effect on behavioural or biochemical parameters. Only duloxetine reduced NET density in cortex, although not hippocampus. CONCLUSIONS: The reduction in SERT density and anxiolytic-like effects with duloxetine, fluoxetine and, potentially, paroxetine suggest that down-regulation of the SERT may be a relevant mechanism in therapeutic response to these antidepressants.

Nicotine and clozapine selectively reverse a PCP-induced deficit of PPI in BALB/cByJ but not NMRI mice: comparison with risperidone.

Schizophrenic patients have deficits in prepulse inhibition (PPI) that may be alleviated by smoking/nicotine. The effect of nicotinic agents on PPI in rodents is equivocal and few studies in mice have been reported. Thus, we assessed nicotine's (0.03-1mg/kg) effect on PPI in five mouse strains with no effects. We next determined if nicotine would reverse a phencyclidine (PCP)-induced deficit of PPI in BALB/cByJ and NMRI mice. BALB/cByJ mice have a low density of [(125)I]alpha-bungaratoxin binding in the hippocampus and poor inhibitory gating of auditory evoked potentials (AEPs), a model related to PPI. At 1mg/kg, nicotine selectively reversed the PCP-induced deficit of PPI in BALB/cByJ mice. The pharmacokinetic profile of nicotine (T(1/2), C(max), T(max) and AUC) was identical in both strains, obviating this as a factor for the strain-dependent effect observed. Moreover, 1mg/kg nicotine inhibited in vivo [(3)H]epibatidine binding with the same time-course in both strains, indicating no difference in brain "kinetics". Since high doses of nicotine were effective in BALB/cByJ mice a role for low-affinity nicotinic receptors, e.g. alpha(7) receptors, is plausible. Clozapine, but not risperidone, also only reversed the PCP deficit of PPI in BALB/cByJ. Clozapine and nicotine also enhance inhibitory gating of AEPs in DBA/2 mice, and clozapine's effect is antagonized by an alpha(7) antagonist. Our data and previous evidence possibly suggest a role for low-affinity nicotinic receptors in the effects of clozapine and nicotine. Furthermore, BALB/cByJ mice may represent a model to test the effects of nicotinic agents acting at low-affinity nicotinic receptors.

Do subtype-selective gamma-aminobutyric acid A receptor modulators have a reduced propensity to induce physical dependence in mice?

Recent evidence suggests that GABA(A) receptors containing an alpha1 subunit mediate the sedative effect of diazepam, whereas receptors with an alpha2 subunit mediate this benzodiazepine's anxiolytic effect. Thus, compounds selective for GABA(A)-alpha2 receptors may offer advantages, i.e., lack of sedation, over current benzodiazepines. Whether such compounds would offer additional advantages over benzodiazepines is unclear. Here, we address the issue of physical dependence by comparing the GABA(A)-alpha1 affinity-selective drug zolpidem, the novel compounds 7-(1,1-dimethylethyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,5-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (L-838,417) and 6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one (SL651498) with functional selectivity for certain non-alpha(1) GABA(A) receptors, nonselective partial agonists [bretazenil, 1-[1-[3-(3-pyridyl)phenyl]benzimidazol-5-yl]ethanone O-ethyloxime (NS2710), and 5-furan-3-yl-1-(3-imidazol-1-phenyl)-1H-benzoimidazole (NS2664)], and nonselective full efficacy benzodiazepines, in a rapid precipitated withdrawal assay using the inverse agonist N-methyl-beta-carboline-3-carboxamide (FG-7142). For all compounds, we determined in vitro IC50 values to displace [3H]flunitrazepam from rat cortex and in vivo ED50 values for displacement of [3H]flunitrazepam from mouse forebrain (including length of in vivo occupancy). In the precipitated withdrawal model, compounds were administered at a dose giving approximately 80% receptor occupancy, obviating major differences in central nervous system bioavailability. Mice were administered compounds twice daily for 4 days and on day 5, 20 h after the final dose, given a dose of FG-7142 (40 mg/kg i.p.) that did not induce seizures in control animals. In mice treated with the three subtype-selective compounds, FG-7142 did not induce seizures. Moreover, there was a low propensity for FG-7142 to induce seizures in animals treated with the partial agonists, whereas seizures were clearly seen in animals treated with most benzodiazepines. Nonetheless, differences among the benzodiazepines themselves, similarities between the partial agonists and subtype-selective compounds, the in vitro/in vivo potency, and in vivo receptor exposure time data suggest a complex interaction among selectivity, efficacy, potency, and receptor exposure in determining physical dependence liability of benzodiazepine site modulators in mice.

Chronic treatment with duloxetine is necessary for an anxiolytic-like response in the mouse zero maze: the role of the serotonin transporter.

RATIONALE: Monoamine transporter inhibitor antidepressants have anxiolytic efficacy in man. However, preclinical data poorly reflect this, either because (1) few studies assess chronic antidepressant treatment in animal models, (2) antidepressants are anxiogenic after acute treatment; and (3) animal models of anxiety are insensitive to antidepressants. OBJECTIVE: We address issues (1) and (2) and ascertain potential mechanisms mediating anxiolytic effects demonstrated. METHODS: The effect of acute treatment with seven antidepressants covering the classes selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, noradrenaline reuptake inhibitors and tricyclic antidepressants were compared with the benzodiazepine, chlordiazepoxide, on the mouse zero maze, an unconditioned model of anxiety. Furthermore, citalopram, duloxetine, reboxetine and amitriptyline were assessed after chronic administration (10 mg/kg p.o., 21 days, twice daily) in this model. In mice treated chronically, (a) the hypothermic response to serotonin (5-HT)1A and 5-HT1B receptor ligands, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and m-chlorophenyl piperazine (mCPP), respectively, was assessed and (b) serotonin transporter (SERT) and noradrenaline transporter (NET) densities in the cortex and hippocampus, respectively, were determined. RESULTS: None of the antidepressants were anxiolytic after acute treatment, although reboxetine, duloxetine and amitriptyline were anxiogenic. Only chronic treatment with duloxetine induced an anxiolytic effect, which was dissociable from nonspecific motor effects. Duloxetine reduced SERT density in the cortex by approximately 75% compared to control, with no effect on NET density in the hippocampus. Citalopram and amitriptyline significantly reduced SERT density by approximately 20%, whereas reboxetine selectively reduced NET density. All drugs reduced the hypothermic response to 8-OHDPAT and mCPP. CONCLUSION: Duloxetine was anxiolytic after chronic but not acute treatment, reflecting clinical experience with antidepressants in general. Duloxetine's anxiolytic-like profile may be ascribed to the considerable reduction in the density of the SERT in the cortex.

Chronic pleuritis in Danish slaughter pig herds.

Respiratory disease is considered the most serious disease problem in modern pig production and the risk has increased with intensification of pig production. We quantified risk factors for chronic pleuritis (CP) in Danish pig herds in terms of herd and herd-owner characteristics, management and neighbourhood factors. The occurrence of CP was investigated in 540,104 slaughter pigs from 259 farrow-to-finish or finishing herds during the mandatory post-mortem meat inspection at 18 Danish abattoirs. The monthly herd- and abattoir-specific prevalences of CP were estimated for the months January through August 2000. Meat-inspection data, herd characteristics and neighbourhood factors were obtained from databases at the Danish Bacon and Meat Council. Data on herd-owner characteristics and management factors were obtained by telephone interviews. Data were analysed using a mixed model accounting for repeated measurements. Four factors were associated with increased herd prevalence of CP: low health status of the herd, pig density within a 5 km radius, mingling of pigs during the production period and the month of slaughter. Two factors protected against CP: feeding with only dry feed and practising all-in-all-out production.

Mycoplasma hyosynoviae arthritis in grower-finisher pigs.

The aetiology of acute lameness in pigs 3-5 months of age in nine Danish herds with high incidences of lameness was investigated. Eighty-seven acutely lame pigs, that exhibited lameness of varying degree in the hind legs, were selected. Non-lame pigs were matched on pen, sex and weight. The lame pigs had soft fluctuating joint swellings (odds ratio (OR), 7.21; 95% confidence interval (CI), 3.41-15.47). No indication of suppurative arthritis was observed. Joint infection with Mycoplasma hyosynoviae was found by culture in 20% (17 of 86) of the lame pigs and in 8% (seven of 83) of the non-lame pigs. Lameness and joint infection with M. hyosynoviae were significantly associated. Other ordinary bacteria were not found in any case. Macroscopic osteochondrotic lesions were observed at slaughter in 47% (37 of 78) of the previously lame pigs and in 35% (55 of 158) of an enlarged group without history of lameness. The cubital joints were most frequently affected and a history of hind leg lameness was not statistically associated with osteochondrotic lesions at slaughter (OR, 1.69; 95% CI, (1.94-3.05), or joint infection with M. hyosynoviae at slaughter (OR, 0.88; 95% CI, 0.31-2.40). Arthritis due to M. hyosynoviae infection was the primary cause of acute and severe lameness in grower-finisher pigs. Moreover, M. byosynoviae was isolated from joints of several pigs without signs of lameness. This suggests that M. hyosynoriae may be present in joints without provoking clinical illness. The mean daily incidence of treatments due to lameness in the herds was 5.4 per 1,000 pigs. Joint disease implied 30-90 min extra labour for surveillance and treatment every day per 1,000 pigs, and 5% of the affected individuals were euthanized due to lameness. The average daily weight gains in the selected pigs until slaughter seemed unaffected by the lameness.