Loperamide-induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity.

This study evaluated the impact of the ABCB1-1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty-two healthy intact Collies consisting of dogs with either a wild-type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole-genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide-induced changes in gene expression which were specifically associated with ivermectin-sensitive phenotypes in Collies possessing the ABCB1-1Δ mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL-8, were identified. Collie dogs harboring ABCB1-1Δ mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL-8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1-1∆ mutation associated with ivermectin sensitivity.

Depletion of florfenicol in lactating dairy cows after intramammary and subcutaneous administration.

Eighteen Holstein dairy cows ranging in body weight from 500-700 kg and with an average milk yield of 37 ± 6 kg/day were used to investigate the depletion of florfenicol (FFL) in milk and plasma of dairy cows. Three groups of six were administered FFL: Group A, intramammary (IMM) infusion of ~2.5 mg FFL/kg BW at three consecutive milking intervals (total amount of ~7.5 mg/kg BW); Group B, one IMM infusion (20 mg/kg BW) into one quarter and Group C, one subcutaneous (SC) treatment (40 mg/kg BW). IMM infusions were into the right front quarter. Cows were milked daily at 06:00 and 18:00 h. The highest concentrations (Cmax ) and time to Cmax (Tmax ) were: 1.6 ± 2.2 µg·FFL/mL milk at 22 h (Group A), 5.5 ± 3.6 µg·FFL/mL milk at 12 h (Group B), and 1.7 ± 0.4 µg·FFL/mL milk at 12 h (Group C). The half-lives (t1/2 ) were ~19, 5.5, and 60 h, for Groups A, B, and C, respectively. FFL was below the limit of detection (LOD) by 60 h in three Group B cows, but above the LOD at 72, 84, and 120 h in three cows. FFL was above the LOD in milk from Group C's cows for 432-588 h. Plasma values followed the same trends as milk. The results demonstrate that IMM-infused FFL is bioavailable and below the LOD within 72-120 h. The concentration of FFL was detectable in both plasma and milk over the course of 2-3 weeks after SC administration. The absence of residue depletion data presents problems in determining safe levels of FFL residues in milk and edible tissues. The data presented here must not be construed as approval for extra-label use in food animals.

[Factors related to suicide attempts in a Tunisian sample of patients with schizophrenia]. / Les facteurs liés aux tentatives de suicide dans une population tunisienne de patients atteints de schizophrénie.

INTRODUCTION: The mortality rate in schizophrenia is 4.5 times higher than in the general population. Suicide is one of the main causes of premature death in this affection. Life time prevalence of this behavior ranges from 10 to 15%, which represents a risk 20 to 50 times higher than in the general population. In addition, 40 to 93% of patients who committed suicide had attempted suicide previously. Thus, assessment of correlated variables with suicide attempts is a fundamental issue for developing preventive and therapeutic strategies in suicidal behavior. To the best of our knowledge, no systematic study has yet investigated suicide attempts in an Arabic Muslim population with schizophrenia, although many authors have demonstrated cultural differences in socio-demographic and clinical variables related to suicide attempts within many geographic areas around the world. OBJECTIVES: The objectives of this study were to assess the frequency and characteristics of lifetime suicide attempts in Tunisian schizophrenic outpatients and to determine the correlated socio-demographic, clinical and therapeutic variables. METHODS: A total of 134 patients with a DSM-IV diagnosis of schizophrenia who attended the outpatient department of the university psychiatric hospital of Tunis were included. The main demographic and lifetime clinical variables considered were: gender, marital status, family history of psychiatric disorders and suicide attempts, age at time of recruitment, age at onset of illness, duration of untreated psychosis defined as the interval between the onset of the illness and the first antipsychotic treatment, the type and dose of current treatment, dose of antipsychotic drugs converted to chlorpromazine equivalents, extrapyramidal side effects assessed with the Simpson Angus rating scale, number of hospitalizations, comorbid substance abuse, cigarette smoking, severity of psychopathology measured with the Positive And Negative Syndrome Scale (PANSS), and history of at least one suicide attempt. A suicide attempt was defined as a self-destructive act carried out with at least some intent to end one's life. We also assessed the number, the used methods and the causes of suicide attempts. We subdivided the sample into two sub samples according to the presence or absence of suicidal attempts. We analyzed and compared the demographic, clinical and therapeutic variables. RESULTS: Out of the 134 patients, 45 (32%) had attempted suicide at least once. Half of them (49%) had attempted suicide more than once. The number of suicide attempts varied from one to five with an average of 1.8. The most used methods were medication overdose (n=18, 23.4%), followed by organophosphate poisoning (n=11, 14.3%), defenestration (n=9, 11.7%) and hanging or using sharp objects (n=7, 9.1% for each of them). The main reported reasons of suicide attempts were depressive symptoms (n=46, 60%) including depressed mood and hopelessness, stressful life events (bereavement, divorce, separation) (n=35, 46%) and presence of delusions and/or auditory hallucinations (n=25, 32.5%). No differences were found between the two groups regarding the different socio-demographic variables. Significant differences were found with respect to a duration of untreated psychosis equal to or more than one year (P<0.001), smoking in men (P=0.03), positive symptoms score on the PANSS (P<0.001), scores of Simpson-Angus scale (P=0.029) and poor medication compliance (P=0.02). CONCLUSION: Demographic variables as suggested by other studies are less valuable predictors of suicide attempts in patients with schizophrenia. Interventions for reducing such behavior should focus on clinical variables and integrate an early diagnosis of the disease, reduce positive psychotic symptoms and tobacco consumption, correct extrapyramidal signs and improve medication compliance.

[Prodromal symptoms in schizophrenic relapse: A descriptive and comparative study]. / Les prodromes des rechutes schizophréniques : étude descriptive et comparative.

INTRODUCTION: Schizophrenia is a severe, chronic psychiatric disorder. After recovery from a first psychotic episode, 70% of patients have exacerbations. These exacerbations are preceded in 66 to 100% of cases by early signs. Prevention of relapses is the main object of dealing with schizophrenia. In fact, after a psychotic relapse, 17% of patients develop residual symptoms which did not exist before the relapse. Moreover, symptoms resistant to antipsychotics appear in 35% of patients after a relapse. Each relapse increases the risk of future relapses. Finally, the cost of treating patients with relapses is four times higher than in patients without relapses. Prevention of relapses is possible if we detect early signs. In fact, when specific interventions are applied in time, relapses can be avoided. Surprisingly, there is a scarcity of data on prodromal symptoms of schizophrenic relapses in the literature. OBJECTIVE: In this study, we aimed to describe early signs of schizophrenic relapses, which are comparatively more frequent than those in stabilized outpatients. METHODS: We conducted a retrospective, descriptive and comparative trial. We included 30 patients with schizophrenia who had recently experienced a psychotic relapse and a member of their families. We also included a control group of 30 stabilized outpatients with schizophrenia. All of the patients were diagnosed schizophrenic according to the DSM IV and had no secondary diagnosis. Only patients aged from 18 to 55 years and having an illness with an episodic evolution were included. The relapse group must have had a period off illness of more than one year and duration of the last remission greater than 3 months. We built a structured interview based on the data of the literature on early symptoms of relapses and on our clinical experience. It contained 93 items describing symptoms and feelings relevant to the period of relapse. The interview lasted about 1h. We collected demographic information from both groups. The relapse group was composed of 21 men and nine women. Their average age was 34 years and their level of education was 9.3 years. The mean number of hospitalizations was 3.8 and 73.3% of patients had interrupted their medication. The stabilized outpatients group included 25 men and five women with an average age of 40.3 years. The mean level of education was 8.3 years, the number of hospitalizations was 2.7 and 16.7% of patients had interrupted their medication. RESULTS: The mean time interval between the beginning of symptoms and the need for hospitalization was 160.5 days. The more frequent symptoms in the relapse group than in stabilized patients were: overinvested ideas/delusions (93.3% of relapsing patients), trouble sleeping (80%), symptoms of disorganization (80%), and excitement/mood changes (73.3%). Globally, non-specific symptoms precede specific symptoms (149.4 days vs. 94.8 days). The earlier signs were influence syndrome (113.4 days before relapse), verbal aggressions against others (108.1 days) and suicidal thoughts (94.8 days). The latest signs were physical aggression against others (37.3 days), unmotivated smiles (35.4 days), aggression against self (35 days), strange thoughts (30.7 days) and breaking things (25.3 days). CONCLUSION: The time between perception of symptoms and hospitalization in schizophrenic patients in this study was very long (approximately 6 months). Non-psychotic prodromal symptoms precede psychotic symptoms. We recommend a major focus on teaching the patient and his/her family how to recognize early signs of decompensation and what steps to take to ensure effective treatment. We also recommend further research to determine the predictive positive value of early signs of relapse.

Laser reflectometry of submegahertz liquid meniscus ringing.

Optical techniques that permit nondestructive probing of interfacial dynamics of various media are of key importance in numerous applications such as ellipsometry, mirage effect, and all-optical switching. Characterization of the various phases of microjet droplet formation yields important information for volume control, uniformity, velocity, and rate. The ringing of the meniscus and the associated relaxation time that occurs after droplet breakoff affect subsequent drop formation and is an indicator of the physical properties of the fluid. Using laser reflectometry, we present an analysis of the meniscus oscillations in an orifice of a piezoelectric microjet.

Carriage of group B streptococcus in pregnant women from Oxford, UK.

OBJECTIVE: To investigate asymptomatic vagino-rectal carriage of group B streptococcus (GBS) in pregnant women. METHODS: Women in the final trimester of pregnancy were recruited. A single vagino-rectal swab was taken, with consent, for culture of GBS. Two microbiological methods for isolation of GBS from vagino-rectal swabs were compared. The distribution of capsular serotypes of the GBS identified was determined. Epidemiological data for a subset (n = 167) of the pregnant women participating were examined. RESULTS: 21.3% were colonised vagino-rectally with GBS. Risk factors for neonatal GBS disease (maternal fever, prolonged rupture of membranes, and preterm delivery) were present in 34 of 167 women (20.4%), and the presence of these factors correlated poorly with GBS carriage. Capsular serotypes III (26.4%), IA (25.8%), V (18.9%), and IB (15.7%) were prevalent in the GBS isolates. Selective broth culture of vagino-rectal swabs was superior to selective plate culture, but the combination of both methods was associated with increased detection of GBS (7.5%). An algorithm for the identification of GBS from vagino-rectal swabs was developed. CONCLUSIONS: GBS carriage is prevalent in pregnant women in Oxfordshire, UK. The poor correlation between risk factors and GBS carriage requires further investigation in larger groups, given that the identification of these surrogate markers is recommended to guide administration of intrapartum antibiotic prophylaxis by the Royal College of Obstetricians of the UK. A selective broth culture detected more GBS carriers than a selective plate culture.

Peliod hepatocellular carcinoma in a domesticated ferret (Mustela putorius furo).

Peliod hepatocellular carcinoma was diagnosed in a domesticated ferret (Mustela putorius furo). The diagnosis was made using immunohistochemical analysis, histologic examination, and the accepted classification schemes based on histomorphologic features. Bilateral, adrenocortical hyperplasia also was evident. Speculation about a possible association between the variant of hepatocellular neoplasia diagnosed in this animal and its adrenal pathologic changes was done.

The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design.

BACKGROUND: HIV reverse transcriptase (RT) is a key target of anti-AIDS therapies. Structural studies of HIV-1 RT, unliganded and complexed with different non-nucleoside inhibitors (NNIs), have pointed to a common mode of binding and inactivation through distortion of the polymerase catalytic site by NNIs containing two hinged rings. The mode of binding of the TIBO family of inhibitors is of interest because these compounds do not fit the two-hinged-ring model. RESULTS: The structure of HIV-1 RT complexed with 9-chloro-TIBO (R82913) has been determined at 2.6 A resolution. As reported for the lower resolution analysis of another TIBO compound, this inhibitor binds at the same site as other NNIs, but our higher resolution study reveals the Cl-TIBO is distorted from the conformation seen in crystals of the inhibitor alone. This allows Cl-TIBO to mimic the binding of NNIs containing two hinged rings. Inhibitor-protein interactions are again predominantly hydrophobic and the protein conformation corresponds to that seen in complexes with other tight-binding NNIs. CONCLUSIONS: Although Cl-TIBO is chemically very different from other NNIs, it achieves remarkable spatial equivalence and shape complementarity with other NNIs on binding to RT. Comparison of the different RT-NNI complexes suggests modifications to the TIBO group of inhibitors which might enhance their binding and hence, potentially, their therapeutic efficacy.

Protein aggregation after transient cerebral ischemia.

Protein aggregates containing ubiquitinated proteins are commonly present in neurodegenerative disorders and have been considered to cause neuronal degeneration. Here, we report that transient cerebral ischemia caused severe protein aggregation in hippocampal CA1 neurons. By using ethanolic phosphotungstic acid electron microscopy (EM) and ubiquitin immunogold EM, we found that protein aggregates were accumulated in CA1 neurons destined to die 72 hr after 15 min of cerebral ischemia. Protein aggregates appeared as clumps of electron-dense materials that stained heavily for ubiquitin and were associated with various intracellular membranous structures. The protein aggregates appeared at 4 hr and progressively accumulated at 24 and 48 hr of reperfusion in CA1 dying neurons. However, they were rarely observed in dentate gyrus neurons that were resistant to ischemia. At 4 hr of reperfusion, protein aggregates were mainly associated with intracellular vesicles in the soma and dendrites, and the nuclear membrane. By 24 hr of reperfusion, the aggregates were also associated with mitochondria, the Golgi apparatus, and the dendritic plasmalemma. High-resolution confocal microscopy further demonstrated that protein aggregates containing ubiquitin were persistently and progressively accumulated in all CA1 dying neurons but not in neuronal populations that survive in this model. We conclude that proteins are severely aggregated in hippocampal neurons vulnerable to transient brain ischemia. We hypothesize that the accumulation of protein aggregates cause ischemic neuronal death.

Subcellular localization and PKC-dependent regulation of the human lysophospholipase A/acyl-protein thioesterase in WISH cells.

Lysophospholipases play essential roles in keeping their multi-functional substrates, the lysophospholipids, at safe levels. Recently, a 25 kDa human lysophospholipase A (hLysoPLA I) that is highly conserved among rat, mouse, human and rabbit has been cloned, expressed and characterized and appears to hydrolyze only lysophospholipids among the various lipid substrates. Interestingly, this enzyme also displays acyl-protein thioesterase activity towards a G protein alpha subunit. To target the subcellular location of this hLysoPLA I, we have carried out immunocytochemical studies and report here that hLysoPLA I appears to be associated with the endoplasmic reticulum (ER) and nuclear envelope in human amnionic WISH cells and not the plasma membrane. In addition, we found that the hLysoPLA I can be up-regulated by phorbol 12-myristate 13-acetate (PMA) stimulation, a process in which phospholipase A(2) is activated and lysophospholipids are generated in WISH cells. Furthermore, the PMA-induced hLysoPLA I expression can be blocked by the protein kinase C (PKC) inhibitor Gö6976. The regulated expression of the LysoPLA/acyl-protein thioesterase by PKC may have important implications for signal transduction processes.

Crystallization and X-ray diffraction study of recombinant platelet-derived endothelial cell growth factor.

Crystals of recombinant platelet-derived endothelial cell growth factor (PD-ECGF) were obtained by the hanging drop vapour diffusion technique. The crystals belong to the space group P2(1)2(1)2(1) with unit cell dimensions a = 63.7 A, b = 70.4 A, c = 219.6, alpha = beta = gamma = 90 degrees, and probably contain a single dimer in the asymmetric unit. Diffraction to a minimum Bragg spacing of 3.5 A has been obtained using a synchrotron X-ray source.

Hormones regulating lipid and carbohydrate metabolism in premenopausal women: modulation by dietary lipids.

The effect of high- and low-fat diets with different levels of fatty acid unsaturation on plasma hormones involved in lipid metabolism was studied during different phases of the menstrual cycle in 31 premenopausal women. Subjects were divided into two groups and were fed controlled diets containing 39% fat with a ratio of polyunsaturated to saturated fatty acids (P:S) of either 0.3 or 1.0 for four menstrual cycles and then switched to a 19% fat diet with the same P:S for another four cycles. Blood samples were analyzed during both the follicular and luteal phases. A significant direct effect of level of dietary fat was observed on plasma cortisol and dehydroepiandrosterone-sulphate whereas an inverse relationship was seen for plasma insulin. Both plasma insulin and growth hormone levels were higher during the luteal compared with the follicular phase of the menstrual cycle. None of the hormones was affected by the level of unsaturation of dietary fats.

The epidemiology of Salmonella typhimurium in cattle: plasmid profile analysis of definitive phage type (DT) 204c.

During the period 1979-1991, Salmonella Typhimurium DT 204c was the cause of a major epidemic of salmonellosis in calves in the UK. Plasmid profile analysis of DT 204c isolates from England and Wales commenced in 1986 and isolates from all subsequent incidents were examined by this technique. Forty-three different plasmid profile types (PPTs) were detected, of which the commonest, designated type E, constituted 44.6-80.2% of the annual incidents during the study period. Some PPTs, e.g., F and P, were detected throughout most years of the study, whereas PPTs O and 6 persisted for short periods. Until 1984, most isolates were resistant to neomycin, but the subsequent predominant PP type E was sensitive to this antibacterial agent. It was concluded that during the epidemic there was an evolution of new genotypes, of which only some persisted; again, antibacterial resistance genes may be acquired or lost. The study demonstrated the value of PP typing for epidemiological studies.

Photovoice ethics: perspectives from Flint Photovoice.

Photovoice is a participatory health promotion strategy in which people use cameras to document their health and work realities. As participants engage in a group process of critical reflection, they may advocate for change in their communities by using the power of their images and stories to communicate with policy makers. In public health initiatives from China to California, community people have used photovoice to carry out participatory needs assessment, conduct participatory evaluation, and reach policy makers to improve community health. This article begins to address ethical issues raised by the use of photovoice: the potential for invasion of privacy and how that may be prevented; issues in recruitment, representation, participation, and advocacy; and specific methodological techniques that should be used to minimize participants' risks and to maximize benefits. The authors describe lessons learned from the large-scale Flint Photovoice involving youth, adults, and policy makers.

Antimicrobial resistance in Salmonella isolated from animals and their environment in England and Wales from 1988 to 1999.

Resistance to 16 antimicrobial agents was monitored in 109,125 Salmonella cultures isolated from animals, their environment and feedstuffs between 1988 and 1999. The sensitivity of the 6512 isolates of Salmonella enterica enterica serotype Dublin to all the antimicrobial agents tested varied from 98.2 per cent in 1997 to 99.7 per cent in 1990 and 1996. In contrast, among 28,053 isolates of Salmonella enterica enterica serotype Typhimurium, there was a marked decrease in their sensitivity to all the antimicrobial agents tested, from 57.4 per cent in 1992 to 7.6 per cent in 1995, owing to the widespread occurrence in farm animals of S Typhimurium isolates of the definitive type DT104, resistant to ampicillin, sulphonamides, streptomycin, chloramphenicol and tetracyclines, although the percentage of sensitive isolates increased to 18.4 per cent in 1999, when the incidence of DT104 had decreased. Some isolates of DT104 also showed an increase in resistance to potentiated sulphonamides (2.4 per cent in 1989 to 19.2 per cent in 1999) and nalidixic acid (0 per cent in 1992, 3.8 per cent in 1995 to a peak of 16.9 per cent in 1998). In 1996, 5.1 per cent of 1086 isolates of S Typhimurium from cattle and 35.9 per cent of 192 isolates of S Typhimurium from poultry showed resistance to nalidixic acid. Of the other 74,528 Salmonella isolates, the percentage of strains sensitive to all the antimicrobials tested decreased slightly from 88.2 per cent in 1988 to 70.6 per cent in 1996 and then increased slightly to 73.7 per cent in 1999. The commonest of these other Salmonella serotypes was Salmonella Enteritidis (20,982), which remained predominantly susceptible (ranging from 81.4 to 97.4 per cent) during the study period. Few isolates were resistant to commonly used veterinary antimicrobials, for example, furazolidone, the use of which was banned in 1990, and the aminoglycoside, apramycin.

Faecal carriage of verocytotoxin-producing Escherichia coli O157 in cattle and sheep at slaughter in Great Britain.

A 12-month abattoir survey was conducted between January 1999 and January 2000, to determine the prevalence of faecal carriage of verocytotoxin-producing Escherichia coli O157 (VTEC O157) in cattle and sheep slaughtered for human consumption in Great Britain. Samples of rectum containing faeces were collected from 3939 cattle and 4171 sheep at 118 abattoirs, in numbers proportional to the throughput of the premises. The annual prevalence of faecal carriage of VTEC O157 was 4.7 per cent (95 per cent confidence interval 4.1 to 5.4) for cattle and 1.7 per cent (1.3 to 2.1) for sheep, values which were statistically significantly different from each other (P < 0.001). The organisms were recovered from both cattle and sheep slaughtered throughout the year and at abattoirs in all regions of the country, but the highest prevalence was in the summer. The most frequency recovered VTEC O157 isolates were phage types 2, 8 and 21/28 in cattle and 4 and 32 in sheep, the five most frequently isolated phage types associated with illness in people in Great Britain during the same period.

Is electroconvulsive therapy unsuitable for children and adolescents?

Electroconvulsive therapy (ECT) as a treatment option for adults with affective disorders has a long history. ECT with children and adolescents, however, has not been widely used, and no empirical studies or controlled evaluations have been conducted. A review of the literature on ECT with minors reveals that it has an unknown mechanism of action, with a domain of applicability diminished yearly by legislation, litigation, and a wide range of intervention alternatives.

Epidemiology and characterization of animal Salmonella enterica subspecies Enterica serotype typhimurium DT104 in Hungary.

Reports on the internationally emerging significance of multiresistant zoonotic Salmonella in animals and man prompted studies to estimate the significance of multiresistant Salmonella enterica subspecies enterica serotype Typhimurium (S. Typhimurium) phage type DT104 of animal origin in Hungary. A collection of 231 strains (primarily of goose, turkey, poultry and porcine origin from the years 1997-1998) was tested for resistance against 7 selected antibiotics (ampicillin, chloramphenicol, enrofloxacin, nalidixic acid, streptomycin, tetracycline and sulphamethoxazole). Strains with resistance against 3 or more were defined as multiresistant. All strains were phage typed using Felix-Callow's S. Typhimurium phage typing system, and 91 of them (suspect DT104) were also typed according to Anderson's definitive typing (DT) system. In this study, 14% of animal strains from 1997-1998 was classified as DT104, for which turkey, pig and duck seemed to be the main carriers, and the multiresistant non-DT104 strains represented a further 6% of this collection. The prevalence of DT104 was highest among strains of turkey origin (50%), followed by strains of pig (29%), chicken (25%), duck (19%), and goose (3%) origin. The other DT104 related phage types (DT12 and U302) were only detected in the case of 4 strains (2 of porcine, and one each of turkey and of goose origin). The DT104 corresponded to the Felix-Callow types 2/3 or 2c/3 in each case, except in the case of 3 turkey strains where they corresponded to type 35/3. Nalidixic acid resistance was detected in all multiresistant turkey strains and in some of other animal origin but none of these strains were resistant to enrofloxacin. A retrospective analysis (based on the above relationship) indicated that S. Typhimurium strains corresponding to DT104 could be present and increase in the Hungarian farm animal population from about 2% to 20% between 1985 and 1990, in a manner similar to the emergence of human DT104, as reported elsewhere (Pászti et al., 2000). The 91 suspect DT104 strains were also tested for plasmid profile and for spvC gene indicating the presence of the large serotype specific plasmid (Ssp). No characteristic plasmid profile could be attributed to S. Typhimurium DT104. The serovar-specific large plasmid was detected by PCR for spvC in 100% of DT104 strains and in 77% of the non-DT104 strains. The virulence of two DT104 strains was tested in orally infected day-old chicks and compared with virulence of 4 non-DT104 strains. Higher colonizing virulence of DT104 strains could be established as compared to the other strains.

P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion.

Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.