Behavioral evaluation of 65 aggressive dogs following a reported bite event.

Peer-reviewed scientific publications on the topic of dog bites are numerous. Montreal was one of the first municipalities in the province of Quebec to require mandatory assessment of aggressive dogs by veterinarians. In 2019, dogs reported as aggressive and considered a potential risk to public safety by city officials were scheduled for a mandatory behavioral assessment by a veterinarian. For the purpose of this study, only aggressive dogs that had bitten (N = 65) were included. The goals were to better describe the aggressive behavior of these dogs (behavioral sequence, type of aggression, and overall reactivity) and perhaps identify new possible risk factors related to severity of injury and dangerousness. The number of signs of increased arousal/reactivity was positively and significantly associated with the injury severity score. Dangerousness increased with size of dogs. Entire males were most dangerous despite absence of recognizable differences in body weight between neutered and unneutered males.

Évaluation comportementale de 65 chiens agressifs à la suite d'un épisode de morsure. Les publications scientifiques révisées par des pairs sur le sujet des morsures canines sont nombreuses. La Ville de Montréal fut parmi les premières municipalités du Québec à exiger l'évaluation comportementale de chiens agressifs par des médecins vétérinaires. En 2019, les chiens rapportés comme agressifs et jugés plus problématiques par des représentants de la ville furent soumis à une évaluation comportementale obligatoire par un médecin vétérinaire. Dans le cadre de cette étude, seuls les chiens ayant mordu (N = 65) ont été inclus. Les objectifs de l'étude étaient de mieux décrire le comportement agressif et d'identifier possiblement des facteurs de risques quant à la sévérité des blessures et la dangerosité des chiens. Le nombre de signes de réactivité augmentée était positivement et significativement associé avec le score de sévérité des blessures. La dangerosité augmentait avec le poids de l'animal. Les mâles entiers étaient plus dangereux que les mâles castrés et ce, sans différence de poids significative entre les chiens stérilisés ou entiers.(Traduit par les auteurs).

Pain behaviors before and after treatment of oral disease in cats using video assessment: a prospective, blinded, randomized clinical trial.

BACKGROUND: Specific behaviors associated with pain in cats with oral disease have not been consistently studied. The aim of this exploratory study was to identify pain-induced behaviors in cats before and after treatment of oral disease using video assessment. Twenty-four cats (6 ± 3.3 years old; 4.9 ± 1.7 kg) were included in a prospective, blinded, randomized clinical trial. Cats were equally divided into minimal (G1: minimal dental treatment) or severe (G2: multiple dental extractions) oral disease groups. After acclimation at day 0, they underwent oral examination, radiographs, scaling, and dental extractions under general anesthesia (anesthetic protocol: acepromazine, hydromorphone, propofol, isoflurane, meloxicam, and local anesthetic blocks; day 1), and were discharged at day 6. Cats were filmed remotely for 10 min using a wide-angle glass lens camera before surgery (baseline) and throughout the study at different time points (36 h of video recording). The videos consisted of four parts namely general, playing, feeding and post-feeding behaviors. A board-certified behaviorist evaluated the duration/frequency of different behaviors based on an ethogram, which were analyzed using linear mixed models and a generalized linear model, respectively (p < 0.05). RESULTS: In comparison with baseline, duration of "not pawing the face" was significantly shorter at day 3 in G2. These cats spent significantly longer time "standing" and "laying" at days 3 and 6, respectively; G1 spent significantly less time "walking" and "standing" at days 3 and 4, respectively and significantly longer time "immobile" at day 3. Duration of "no/slow tail movement" was significantly longer in G2 than G1 at day 5. Duration of "pawing the ribbon" (playing) was significantly shorter in G2 than G1 at day 1. Feeding and post-feeding behaviors with soft food were not significantly different between groups or over time. Frequency of "difficulty grasping dry food" was significantly higher in G2 than G1 up to day 6. Frequency of post-feeding "head shaking" was significantly higher in both groups at day 6 when compared with baseline. CONCLUSIONS: This study identified pain-induced behaviors in cats undergoing treatment of oral disease. These behaviors may be used to differentiate painful versus pain-free cats in clinical practice.

Medical and behavioral evaluation of 8 cats presenting with fabric ingestion: An exploratory pilot study.

The aims of this pilot study were to: i) conduct a thorough behavioral and medical evaluation of cats presenting for chronic fabric ingestion; and ii) implement specific treatments for conditions identified and evaluate the outcome of treatment on fabric ingestion. Eight cats which ingested fabric at least weekly were recruited. Cat owners recorded daily baseline frequency of pica and gastrointestinal signs for 1 month prior to the behavioral and medical investigation and again during a follow-up period. Diagnoses were made and response to treatment was monitored and modified as needed. Abnormalities included mild hypercholesterolemia (n = 7), gastric or intestinal eosinophilic infiltrates (n = 6), suspected delayed gastric emptying (n = 4), suspected gastric reflux (n = 1), and Giardia spp. (n = 1). Four of the eight cats responded partially to treatments. Treatment of fabric ingestion in cats remains a challenge and further investigation is needed.

Évaluation médicale et comportementale de huit chats ingérant des tissus: une étude pilote. Les objectifs de cette étude pilote étaient: i) d'entreprendre une évaluation médicale et comportementale chez des chats présentant un comportement chronique d'ingestion de tissus; et ii) de mettre en place des traitements spécifiques pour les conditions identifiées et d'évaluer les résultats sur le comportement d'ingestion de tissus. Huit chats qui ingéraient hebdomadairement du tissu furent recrutés. Les propriétaires compilèrent la fréquence quotidienne de pica et les autres signes digestifs pendant un mois avant le début de l'étude puis de nouveau lors du suivi. À la suite du diagnostic posé, la réponse aux traitements de chaque chat fut suivie et les traitements étaient modifiés au besoin. Les changements observés incluaient une légère hypercholestérolémie (n = 7), une infiltration gastrique ou intestinale éosinophilique (n = 6), une suspicion de retard de vidange gastrique (n = 4), une suspicion de reflux gastrique (n = 1) et la présence de Giardia spp. (n = 1). La moitié des chats ont répondu partiellement aux traitements instaurés. Le traitement d'ingestion de tissus demeure un défi et de la recherche future s'avère nécessaire.(Traduit par les auteurs).

Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are neuromuscular disorders that primarily affect boys due to an X-linked mutation in the DMD gene, resulting in reduced to near absence of dystrophin or expression of truncated forms of dystrophin. Some newer therapeutic interventions aim to increase sarcolemmal dystrophin expression, and accurate dystrophin quantification is critical for demonstrating pharmacodynamic relationships in preclinical studies and clinical trials. Current challenges with measuring dystrophin include the variation in protein expression within individual muscle fibers and across whole muscle samples, the presence of preexisting dystrophin-positive revertant fibers, and trace amounts of residual dystrophin. Immunofluorescence quantification of dystrophin can overcome many of these challenges, but manual quantification of protein expression may be complicated by variations in the collection of images, reproducible scoring of fluorescent intensity, and bias introduced by manual scoring of typically only a few high-power fields. This review highlights the pathology of DMD and BMD, discusses animal models of DMD and BMD, and describes dystrophin biomarker quantitation in DMD and BMD, with several image analysis approaches, including a new automated method that evaluates protein expression of individual muscle fibers.

Expected consequences of convenience euthanasia perceived by veterinarians in Quebec.

In companion animal practice, convenience euthanasia (euthanasia of a physically and psychologically healthy animal) is recognized as one of the most difficult situations. There is little published on veterinary perceptions of the consequences of convenience euthanasia. A qualitative study on the subject based on interviews with 14 veterinarians was undertaken. The animal's interests in the dilemma of convenience euthanasia was taken into consideration, strictly from the point of view of the physical suffering and stress related to the procedure. The veterinarian's goal was to respect the animal's interests by controlling physical pain. Most often, veterinarians made their own interests and those of the owners a priority when considering the consequences of their decision to perform or refuse convenience euthanasia.

Conséquences attendues de l'euthanasie de commodité selon les perceptions des médecins vétérinaires au Québec. En pratique des animaux de compagnie, l'euthanasie de commodité (l'euthanasie d'un animal en bonne santé physique et psychologique) est reconnue comme l'une des situations les plus difficiles. Il y a eu peu de travaux publiés sur les perceptions vétérinaires des conséquences de l'euthanasie de commodité. Une étude qualitative sur le sujet basée sur des entrevues auprès de 14 médecins vétérinaires a été entreprise. Les intérêts de l'animal dans le dilemme de l'euthanasie de commodité ont été pris en considération, strictement du point de vue des souffrances physiques et du stress lié à l'intervention. Le but du médecin vétérinaire consistait à respecter les intérêts de l'animal en contrôlant la douleur physique. Le plus souvent, les médecins vétérinaires jugeaient leurs propres intérêts et ceux des propriétaires comme étant prioritaires lors de la considération des conséquences de leur décision de réaliser ou de refuser l'euthanasie de commodité.(Traduit par Isabelle Vallières).

Conceptualization of convenience euthanasia as an ethical dilemma for veterinarians in Quebec.

Companion animal welfare in our society has become increasingly important, yet many healthy animals are euthanized in veterinary facilities. How is it possible to explain the simultaneous presence of these opposing views of obligation toward animals? The goal of this study was to describe convenience euthanasia of companion animals as experienced by veterinarians in order to understand their thought processes. A qualitative study was undertaken to analyze the results of interviews of 14 veterinarians. The study showed that veterinarians interviewed assessed convenience euthanasia based mainly on their subjective evaluation of the owner-animal bond. As most owner-animal bonds stem from an anthropocentric point of view, decisions on convenience euthanasia were taken mostly by considering the veterinarian's and the client/owner's interests.

Conceptualisation de l'euthanasie pour des raisons de commodité comme dilemme éthique pour les vétérinaires du Québec. Le respect du bien-être des animaux de compagnie dans notre société est devenu de plus en plus important. Fait paradoxal, beaucoup d'animaux en santé sont euthanasiés dans les établissements vétérinaires. Comment peut-on expliquer la présence concomitante de ces vues opposées à l'égard des obligations envers les animaux? Le but de cette étude consistait à décrire l'euthanasie des animaux de compagnie pour des raisons de commodité selon les expériences des vétérinaires afin de comprendre leurs processus de réflexion. Une étude qualitative a été entreprise afin d'analyser les résultats d'entrevues avec 14 médecins vétérinaires. L'étude a signalé que les vétérinaires interviewés évaluaient l'euthanasie pour des raisons de commodité surtout en se basant sur leur évaluation subjective du lien entre le propriétaire et l'animal. Comme la majorité des liens entre propriétaires et animaux découlent d'un point de vue anthropocentrique, les décisions pour l'euthanasie pour des raisons de commodité étaient prises surtout en considérant l'intérêt du médecin vétérinaire et du client/propriétaire.(Traduit par Isabelle Vallières).

L'euthanasie de convenance des animaux de compagnie : portrait du dilemme au sein de la profession vétérinaire québécoise.

Convenience euthanasia in companion animals: Dilemma among veterinarians in Quebec. Many veterinarians working in the field of companion animal medicine have to deal with requests for convenience euthanasia in their practices. As it is the case in other medical fields, veterinarians are trained to treat their patients. It is thus easy to understand that veterinarians consider convenience euthanasia as one of the most difficult ethical dilemmas they have to deal with in their practice. Regulatory boundaries concerning the practice of euthanasia are limited to the method use to induce the death of the animal but do not give any indication as to what should be the proper circumstances surrounding the request. To date, there are few articles on this matter and the perspective of veterinarians on the subject was rarely addressed. This article reports results obtained following a study conducted upon Québec's veterinarians on the topic of convenience euthanasia. The data was obtained via an online survey created by the research team to evaluate the perspective of veterinarians on the topic, how they perceived consequences of convenience euthanasia and what were the solutions they would take into consideration in order to help the profession on resolving their dilemma. The data collected sheds light on the existing duality between double allegiance regarding the duties emerging from the relation with the patient (animal) and the client (pet owner) veterinarian are facing in their daily practice. On one hand veterinarians recognized that 'convenience euthanasia' is contrary to animal welfare. On the other hand they also recognized the pet owner's right to ask for 'convenience euthanasia' when he can no longer care for its pet.(Translated by Dr. Rathwell-Deault).

Validation de la version francophone d'une échelle composite multidimensionnelle pour l'évaluation de la douleur postopératoire chez les chats.

Validation of the French version of the UNESP-Botucatu multidimensional composite pain scale for assessing postoperative pain in cats. The aim of this study was to validate the French version of the UNESP-Botucatu multidimensional composite pain scale (MCPS-Fr) to assess postoperative pain in cats. Two veterinarians and one DVM student identified three domains of behavior based on video analyses: "psychomotor change", "protection of the painful area" and "physiological variables". Internal consistency was excellent (Cronbach's alpha coefficient of 0.94, 0.90 and 0.61, respectively). Criterion validity was good to very good when evaluations from the three observers were compared with a "gold standard". Inter- and intra-rater reliability for each scale item were good to very good. The optimal cut-off point identified with a ROC curve was > 7 (scale range 0-30 points), with a sensitivity of 97.8% and specificity of 99.1%. The MCPS-Fr is a valid, reliable and responsive instrument for assessing acute pain in cats undergoing ovariohysterectomy.(Translated by Dr. Beatriz Monteiro).

Star gazing in a dog: atypical manifestation of upper gastrointestinal disease.

A Yorkshire terrier dog was presented for episodes of "star gazing" behavior expressed as upward raising of the head and neck extension with subsequent staring at the ceiling or sky. Erosive gastritis with reflux esophagitis was diagnosed. Treatment of these conditions was associated with resolution of the behavior, suggesting a causal link.

Présentation atypique d'une douleur gastro-intestinale haute chez un chien. Un Yorkshire terrier a été présenté pour des épisodes fréquents de 'star gazing,' notés comme une extension du cou et une élévation de la tête vers le plafond ou le ciel. Une gastrite érosive ainsi qu'une oesophagite de reflux ont été diagnostiquées. Suite au traitement de ces deux conditions, une résolution clinique du comportement de 'star gazing' a été notée, suggérant que ce comportement représente une manifestation clinique des pathologies gastrointestinales identifiées.(Traduit par les auteurs).

Owner-perceived signs and veterinary diagnosis in 50 cases of feline osteoarthritis.

Veterinarians contacted to identify cats diagnosed with osteoarthritis (OA) provided information on signalment, method of diagnosis, treatment and concurrent disease. Owners of 50 cats were interviewed to collect information on specific OA signs observed in the home, relating to mobility, self-maintenance, social and exploratory behavior, and activity and habits at diagnosis and after treatment. Mean age at diagnosis was 12 y; concurrent diseases were common (44%). Owner-reported abnormalities led to OA diagnosis in most cases; either as the primary finding (30%), or combined with abnormal physical examination or radiographic findings (64%). Owners frequently reported changes in mobility, particularly gait, jumping, and use of stairs. Oral or injectable disease-modifying osteoarthritis drugs were the most common treatments (71%). Feline OA diagnosis and therapeutic monitoring appear to rely heavily on owner-perceived signs; physical examination abnormalities may not be detected. Questioning of owners revealed various observable signs potentially useful in OA detection and monitoring.

Signes d'arthrose que perçoivent les propriétaires de chats. Des vétérinaires furent contactés pour identifier des cas d'arthrose féline, et ils ont fourni les informations concernant le signalement, la méthode de diagnostic et les traitements administrés à ces chats. Les propriétaires de 50 chats arthrosiques furent sondés pour caractériser les signes d'arthrose liés à la mobilité et l'activité, les soins du corps, le comportement exploratoire, et les habitudes particulières du chat au moment du diagnostic et suite au traitement. L'âge moyen était de 12,0 ans, et plusieurs chats avaient des maladies concomitantes (44 %). Le diagnostic est fondé sur les observations des propriétaires rapportées au vétérinaire compatibles avec de l'arthrose (30 %), ou sur leur recoupement avec les découvertes de l'examen physique ou radiographique (64 %). Les changements au niveau de la mobilité (surtout la démarche, le saut, et la façon de prendre les escaliers) étaient fréquents. Les traitements les plus fréquents étaient les agents structuro-modulateurs (71 %). Actuellement, les observations de changements subtils à la maison de la part du propriétaire sont utilisées pour le diagnostic et le suivi de l'arthrose féline, car des anomalies ne sont pas toujours évidentes lors de l'examen physique. Le questionnement précis des propriétaires a révélé d'autres signes potentiels d'arthrose féline.(Traduit par les auteurs).

Prospective medical evaluation of 7 dogs presented with fly biting.

Fly biting describes a syndrome in which dogs appear to be watching something and then snapping at it. Medical work-up of fly biting in dogs has never been reported. The aims of this case series were to characterize fly biting and perform a complete medical evaluation of dogs displaying fly biting.

Évaluation médicale prospective de 7 chiens présentés pour un comportement de gobeur de mouches. Le comportement de gobeur de mouches décrit un syndrome où les chiens semblent regarder quelque chose, puis tentent ensuite de le mordre. Le bilan médical de l'attrapage de mouches chez les chiens n'a jamais été signalé. Les objectifs de cette série de cas étaient de caractériser l'attrapage de mouches et de réaliser une évaluation médicale complète des chiens manifestant un comportement d'attrapage de mouches.(Traduit par Isabelle Vallières).

Systematic review of the use of pheromones for treatment of undesirable behavior in cats and dogs.

OBJECTIVE: To systematically review the scientific literature to identify, assess the quality of, and determine outcomes of studies conducted to evaluate the use of pheromones for treatment of undesirable behavior in cats and dogs. DESIGN: Systematic review. STUDY POPULATION: Reports of prospective studies published from January 1998 through December 2008. PROCEDURES: The MEDLINE and CAB Abstracts databases were searched with the following key terms: dog OR dogs OR canine OR cat OR cats OR feline AND pheromone OR synthetic pheromone OR facial pheromone OR appeasing pheromone. A date limit was set from 1998 through 2008. Identified reports for dogs (n = 7) and cats (7) were systematically reviewed. RESULTS: Studies provided insufficient evidence of the effectiveness of feline facial pheromone for management of idiopathic cystitis or calming cats during catheterization and lack of support for reducing stress in hospitalized cats. Only 1 study yielded sufficient evidence that dog-appeasing pheromone reduces fear or anxiety in dogs during training. Six studies yielded insufficient evidence of the effectiveness of dog-appeasing pheromone for treatment of noise phobia (2 reports), travel-related problems, fear or anxiety in the veterinary clinic, and stress- and fear-related behavior in shelter dogs as well as vocalizing and house soiling in recently adopted puppies. CONCLUSIONS AND CLINICAL RELEVANCE: 11 of the 14 reports reviewed provided insufficient evidence and 1 provided lack of support for effectiveness of pheromones for the treatment of undesirable behavior in cats and dogs.

Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy.

OBJECTIVE: To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. METHODS: Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry. RESULTS: Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry. CONCLUSION: Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization. CLINICALTRIALSGOV IDENTIFIER: NCT02310906. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

Determination of the pharmacokinetics of a single oral dose of trazodone and its effect on the activity level of domestic pigeons (Columba livia).

OBJECTIVE: To determine the pharmacokinetics of a single oral dose of trazodone and its effect on the activity of domestic pigeons (Columba livia). ANIMALS: 6 healthy adult male domestic pigeons. PROCEDURES: During the first of 3 experiments, birds received orally administered trazodone at doses ranging from 3 to 30 mg/kg to determine the dose for subsequent experiments. During the second experiment, each bird received 1 dose of trazodone (30 mg/kg, PO). Blood was collected for determination of plasma trazodone concentration before and at predetermined times for 24 hours after drug administration. Pharmacokinetic parameters were calculated by noncompartmental analysis. During experiment 3, birds were instrumented with ultralightweight accelerometers and received orally administered trazodone (30 mg/kg) or an equal volume of water twice at a 48-hour interval. Activity of birds was monitored for 24 hours after administration of each treatment. RESULTS: No adverse effects were observed. Mean ± SD terminal half-life of trazodone was 5.65 ± 1.75 hours. Plasma trazodone concentrations remained > 0.130 µg/mL for approximately 20 hours. Trazodone did not affect the activity of birds during the first 2 and 15 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that oral administration of 1 dose (30 mg/kg) of trazodone to healthy pigeons was safe and resulted in plasma drug concentrations that were similar to those considered therapeutic in humans and dogs for up to 20 hours. Further research is necessary to characterize the pharmacokinetics for repeated doses as well as the clinical effects of trazodone in birds with behavior problems.

Validation of a Muscle-Specific Tissue Image Analysis Tool for Quantitative Assessment of Dystrophin Staining in Frozen Muscle Biopsies.

CONTEXT.­: Duchenne muscular dystrophy is a rare, progressive, and fatal neuromuscular disease caused by dystrophin protein loss. Common investigational treatment approaches aim at increasing dystrophin expression in diseased muscle. Some clinical trials include assessments of novel dystrophin production as a surrogate biomarker of efficacy, which may predict a clinical benefit from treatment. OBJECTIVES.­: To establish an immunofluorescent scanning and digital image analysis workflow that provides an objective approach for staining intensity assessment of the immunofluorescence dystrophin labeling and determination of the percentage of biomarker-positive fibers in muscle cryosections. DESIGN.­: Optimal and repeatable digital image capture was achieved by a rigorously qualified fluorescent scanning process. After scanning qualification, the MuscleMap (Flagship Biosciences, Westminster, Colorado) algorithm was validated by comparing high-power microscopic field total and dystrophin-positive fiber counts obtained by trained pathologists to data derived by MuscleMap. Next, the algorithm was tested on whole-slide images of immunofluorescent-labeled muscle sections from Duchenne muscular dystrophy, Becker muscular dystrophy, and control patients. RESULTS.­: When used under the guidance of a trained pathologist, the digital image analysis tool met predefined validation criteria and demonstrated functional and statistical equivalence with manual assessment. This work is the first, to our knowledge, to qualify and validate immunofluorescent scanning and digital tissue image-analysis workflow, respectively, with the rigor required to support the clinical trial environments. CONCLUSIONS.­: MuscleMap enables analysis of all fibers within an entire muscle biopsy section and provides data on a fiber-by-fiber basis. This will allow future clinical trials to objectively investigate myofibers' dystrophin expression at a greater level of consistency and detail.

Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy.

This analysis aims to describe the outcomes of two nonambulatory patients with Duchenne muscular dystrophy (DMD) who participated in two clinical studies. The two consecutive trials of eteplirsen (studies 201 and 202) were conducted in patients with DMD (N = 12) and confirmed genetic mutations amenable to exon 51 skipping.In study 201, 12 patients were randomized to receive once-weekly, double-blind intravenous infusions of eteplirsen 30 or 50 mg/kg or placebo for 24 weeks; patients then received open-label eteplirsen during weeks 25 through 28. All 12 patients continued onto open-label extension study 202 and received long-term treatment with eteplirsen. We compared cardiac, pulmonary, and upper limb function and dystrophin production in the nonambulatory twin patients versus the 10 ambulatory patients through 240 combined treatment weeks.Ten study patients remained ambulatory through both studies, while the identical twin patients both experienced early, rapid loss of ambulation. The twin patients had greater disease severity at baseline (6-minute walk test [6MWT], 330 and 256 m) versus the other patients (n = 10; 6MWT range, 341-418 m). They maintained cardiac and upper limb function through combined week 240, with outcomes similar to those of the patients who remained ambulatory. Dystrophin production was confirmed following eteplirsen treatment.Despite the loss of ambulation, other markers of disease progression remained relatively stable in the eteplirsen-treated twin patients and were similar to those of the ambulatory patients.

Laminin alpha5 is essential for the formation of the zebrafish fins.

The vertebrate fin fold, the presumptive evolutionary antecedent of the paired fins, consists of two layers of epidermal cells extending dorsally and ventrally over the trunk and tail of the embryo, facilitating swimming during the embryonic and larval stages. Development of the fin fold requires dramatic changes in cell shape and adhesion during early development, but the proteins involved in this process are completely unknown. In a screen of mutants defective in fin fold morphogenesis, we identified a mutant with a severe fin fold defect, which also displays malformed pectoral fins. We find that the cause of the defect is a non-sense mutation in the zebrafish lama5 gene that truncates laminin alpha5 before the C-terminal laminin LG domains, thereby preventing laminin alpha5 from interacting with its cell surface receptors. Laminin is mislocalized in this mutant, as are the membrane-associated proteins, actin and beta-catenin, that normally form foci within the fin fold. Ultrastructural analysis revealed severe morphological abnormalities and defects in cell-cell adhesion within the epidermis of the developing fin fold at 36 hpf, resulting in an epidermal sheet that can not extend away from the body. Examining the pectoral fins, we find that the lama5 mutant is the first zebrafish mutant identified in which the pectoral fins fail to make the transition from an apical epidermal ridge to an apical fold, a transformation that is essential for pectoral fin morphogenesis. We propose that laminin alpha5, which is concentrated at the distal ends of the fins, organizes the distal cells of the fin fold and pectoral fins in order to promote the morphogenesis of the epidermis. The lama5 mutant provides novel insight into the role of laminins in the zebrafish epidermis, and the molecular mechanisms driving fin formation in vertebrates.

Discovery of tight junction modulators: significance for drug development and delivery.

Tight junction biology has many important applications, from improving knowledge of diseases characterized by the loss of epithelial or endothelial tissue barrier function to providing a mechanistic basis for improving non-invasive drug delivery. A variety of chemical and molecular biological tools have been developed, including high throughput cell-based screening of molecular libraries that facilitate discovery of novel peptides and lipids to modulate tight junction function safely and reversibly. Further development of novel tight junction modulating excipients necessitates consideration of physicochemical, toxicological, pharmaceutical and regulatory issues.