Long-Term Intranasal Nerve Growth Factor Treatment Favors Neuron Formation in de novo Brain Tissue.

Objective: To date, no safe and effective pharmacological treatment has been clinically validated for improving post-stroke neurogenesis. Growth factors are good candidates but low safety has limited their application in the clinic. An additional restraint is the delivery route. Intranasal delivery presents many advantages. Materials and Methods: A brain lesion was induced in twenty-four rats. Nerve growth factor (NGF) 5 µg/kg/day or vehicle was given intranasally from day 10 post-lesion for two periods of five weeks, separated by a two-week wash out period with no treatment. Lesion volume and atrophy were identified by magnetic resonance imaging (MRI). Anxiety and sensorimotor recovery were measured by behavior tests. Neurogenesis, angiogenesis and inflammation were evaluated by histology at 12 weeks. Results: Remarkable neurogenesis occurred and was visible at the second and third months after the insult. Tissue reconstruction was clearly detected by T2 weighted MRI at 8 and 12 weeks post-lesion and confirmed by histology. In the new tissue (8.1% of the lesion in the NGF group vs. 2.4%, in the control group at 12 weeks), NGF significantly increased the percentage of mature neurons (19% vs. 7%). Angiogenesis and inflammation were not different in the two groups. Sensorimotor recovery was neither improved nor hampered by NGF during the first period of treatment, but NGF treatment limited motor recovery in the second period. Interpretation: The first five-week period of treatment was very well tolerated. This study is the first presenting the effects of a long treatment with NGF and has shown an important tissue regeneration rate at 8 and 12 weeks post-injury. NGF may have increased neuronal differentiation and survival and favored neurogenesis and neuron survival through subventricular zone (SVZ) neurogenesis or reprogramming of reactive astrocytes. For the first time, we evidenced a MRI biomarker of neurogenesis and tissue reconstruction with T2 and diffusion weighted imaging.

Cervical tracheal rupture with persistence of a pseudotrachea in a dog.

A dog was examined because of acute onset of respiratory distress following a cervical dog bite. Physical examination revealed a deep ventral cervical bite wound associated with localized mild subcutaneous emphysema. Thoracic radiographs showed moderate pneumomediastinum. Medical management consisting of oxygen therapy, antibiotics, and anti-inflammatories was initiated. After 2 days, respiratory distress suddenly worsened. Tracheoscopy showed a discontinuity between the tracheal rings of the cervical trachea; however, the inner tracheal wall appeared intact. Computed tomography scan revealed a ~3-cm complete rupture of all layers of the trachea. Surgical resection and anastomosis of the trachea were performed successfully. Follow-up 15 days after surgery showed complete resolution of respiratory signs, as well as subcutaneous emphysema. A mild ventral angulation of the trachea at the surgical site was noticed on thoracic radiographs. This is the first case report of a pseudotrachea in a dog. Persistence of a pseudotrachea may initially result in only minor clinical signs responsive to medical therapy despite tracheal rupture. In the presence of a pseudotrachea, tracheal rupture may be difficult to identify with tracheoscopy alone. Therefore, CT scan should be proposed in every patient with suspected tracheal trauma. Key clinical message: This case report highlights the importance of including a tracheal rupture in the differential diagnosis of cervical subcutaneous emphysema, even if the amount is small and not associated with significant respiratory signs. The presence of a pseudotrachea may result in less severe clinical signs than expected based on the actual degree of tracheal injury; however, the clinical status may rapidly deteriorate and become life-threatening. This case report also underlines the importance of a CT scan as a complement to tracheoscopy, which may not be sufficient to identify a tracheal rupture in the presence of a pseudotrachea.

Rupture trachéale cervicale avec persistance d'une pseudotrachée chez un chien. Un chien a été présenté pour une dyspnée aiguë modérée consécutive à des morsures cervicales par un autre chien. L'examen clinique révéla une plaie cervicale ventrale profonde associée à un emphysème sous-cutané localisé léger. Les radiographies thoraciques ont montré un pneumomédiastin modéré. Un traitement médical consistant en une oxygénothérapie, des antibiotiques et des anti-inflammatoires a été initié. Après deux jours, la dyspnée s'aggrava brutalement. Une trachéoscopie révéla une discontinuité entre les anneaux trachéaux malgré la persistance d'une paroi trachéale interne intègre. L'examen par tomodensitométrie montra une rupture trachéale cervicale complète dans toute son épaisseur, sur 3 cm de long. Une chirurgie de résection-anastomose de la trachée a été réalisée avec succès.Il s'agit de la première description de pseudotrachée chez un chien. La persistance d'une pseudotrachée peut initialement ne provoquer que des signes cliniques mineurs, notamment un emphysème sous-cutané léger et une dyspnée répondant au traitement médical, malgré une lésion trachéale en réalité importante. Par conséquent, un examen par tomodensitométrie de la trachée doit être envisagé chez tous les patients pour lesquels un traumatisme trachéal est suspecté.Message clinique clé :Ce cas souligne l'importance d'inclure une rupture trachéale dans le diagnostic différentiel de l'emphysème souscutané cervical, et cela même s'il n'est présent qu'en petite quantité et associé à faibles signes cliniques respiratoires. La persistance d'une pseudotrachée peut entraîner des signes cliniques moins importants qu'une rupture trachéale complète, cependant l'état respiratoire de l'animal peut rapidement s'aggraver et devenir une urgence vitale.Ce cas souligne de plus l'importance de l'examen par tomodensitométrie en complément de la trachéoscopie, qui peut parfois s'avérer insuffisante pour le diagnostic des ruptures trachéales, en particulier en présence d'une pseudotrachée.(Traduit par les auteurs).

Genetic heterogeneity of polydactyly in Maine Coon cats.

OBJECTIVES: Polydactyly has been described in two breeds of domestic cats (Maine Coon and Pixie Bob) and in some outbred domestic cats (eg, Hemingway cats). In most cases, feline polydactyly is a non-syndromic preaxial polydactyly. Three variants located in a regulatory sequence involved in limb development, named ZRS (zone of polarising activity regulatory sequence), have been identified to be responsible for feline polydactyly. These variants have been found in outbred domestic cats in the UK (UK1 and UK2 variants) and in Hemingway cats in the USA (Hw variant). The aim of this study was to characterise the genetic features of polydactyly in Maine Coon cats. METHODS: Genotyping assay was used to identify the variant(s) segregating in a cohort of 75 polydactyl and non-polydactyl Maine Coon cats from different breeding lines from Europe, Canada and the USA. The authors performed a segregation analysis to identify the inheritance pattern of polydactyly in this cohort and analysed the population structure. RESULTS: The Hw allele was identified in a subset of polydactyl cats. Sequencing of two regulatory sequences involved in limb development did not reveal any other variant in polydactyl cats lacking the Hw allele. Additionally, genotype-phenotype and segregation analyses revealed the peculiar inheritance pattern of polydactyly in Maine Coon cats. The population structure analysis demonstrated a genetic distinction between Hw and Hw-free polydactyl cats. CONCLUSIONS AND RELEVANCE: Polydactyly in Maine Coon cats is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity, and this trait is characterised by genetic heterogeneity in the Maine Coon breed. Maine Coon breeders should be aware of this situation and adapt their breeding practices accordingly.

Congenital lacrimal fistula in two prim'Holstein calves.

Two 4- and 8-month-old prim'Holstein calves were presented for chronic epiphora. Examination of the affected eyes revealed an abnormal duct opening inferonasal to the medial canthus. A diagnosis of congenital lacrimal fistula was made based on conventional and computed tomographic-dacryocystography findings. These revealed an ectopic channel connecting the nasolacrimal duct to the skin opening near the medial canthus. Both of the calves were surgically treated with resection and closure of the ectopic duct and placement of a nasolacrimal stent.

Clinical characterisation of polydactyly in Maine Coon cats.

Objectives Polydactyly has been reported in a number of vertebrate species, including the domestic cat. It is a common characteristic in some breeding lines of the Maine Coon. The aim of this study was to assess the limb phenotype of polydactyl cats using physical and radiographic examinations. Methods We used physical examination and radiography to characterise the polydactyly phenotype in a cohort of 70 Maine Coon cats, including 48 polydactyl cats from four different breeding lines from Europe, Canada and the USA. Results The phenotypic expression of polydactyly showed great variability, not only in digit number and conformation, but also in the structure of the carpus and tarsus. Comparison of the size of the radius in polydactyl and non-polydactyl 3-month-old kittens and adult females did not reveal any difference between polydactyl and non-polydactyl cats. Conclusions and relevance We conclude that polydactyly in Maine Coon cats is characterised by broad phenotypic diversity. Polydactyly not only affects digit number and conformation, but also carpus and tarsus conformation, with no apparent deleterious consequence on feline welfare.

Strength and fine dexterity recovery profiles after a primary motor cortex insult and effect of a neuronal cell graft.

The aim of this study was to set up (a) a large primary motor cortex (M1) lesion in rodent and (b) the conditions for evaluating a long-lasting motor deficit in order to propose a valid model to test neuronal replacement therapies aimed at improving motor deficit recovery. A mitochondrial toxin, malonate, was injected to induce extensive destruction of the forelimb M1 cortex. Three key motor functions that are usually evaluated following cerebral lesion in the clinic-strength, target reaching, and fine dexterity-were assessed in rats by 2 tests, a forelimb grip strength test and a skilled reaching task (staircase) for reaching and dexterity. The potential enhancement of postlesion recovery induced by a neuronal cell transplantation was then explored and confirmed by histological analyses. Both tests showed a severe functional impairment 2 days post lesion, however, reaching remained intact. Deficits in forelimb strength were long lasting (up to 3 months) but spontaneously recovered despite the extensive lesion size. This natural grip strength recovery could be enhanced by cell therapy. Histological analyses confirmed the presence of grafted cells 3 months postgraft and showed partial tissue reconstruction with some living neuronal cells in the graft. In contrast, fine dexterity never recovered in the staircase test even after grafting. These results suggest that cell replacement was only partially effective and that the forelimb M1 area may be a node of the sensorimotor network, where compensation from secondary pathways could account for strength recovery but recovery of forelimb fine dexterity requires extensive tissue reconstruction.

Transition from rest to movement: brain correlates revealed by functional connectivity.

It is suggested that resting state networks reflecting correlated neural regional activities participate significantly in brain functioning. A fundamental issue is to understand how these networks interact and how their activities change during behavioral transitions. Our aim was to understand better with functional MRI connectivity how the brain switched from a "resting" to a movement-related state by exploring the transitory readiness state for an intended movement of the right hand. Our study does not address movement preparation occurring in a time scale of milliseconds before movement which has been widely studied but movement-readiness which can last longer. At rest, in the absence of overt goal-directed behavior, a "default-mode" network, whose main areas are the posterior cingulate cortex and precuneus (PCC/Pcu), shows high activity interpreted as day dreaming, free association, stream of consciousness, and inner rehearsal. We found that, during rest, the "default-mode" network and the sensorimotor network were not functionally correlated. During movement-readiness, the two networks were functionally correlated through an interaction between the PCC/Pcu and the medial superior parietal cortex in the upper precuneus. The complex PCC/Pcu has been shown to be involved in retrieval and/or setting up spatial attributes for motor imagery, and thus, would be a key region in the movement-readiness phase. It might functionally connect to the medial superior parietal cortex to initiate the movement programming through retrieval of suited movement parameters. The anterior cingulum, functionally correlated to the primary sensorimotor cortex during movement-readiness would have a motivational role or could generate predictions about the movement.

Neural substrates of low-frequency repetitive transcranial magnetic stimulation during movement in healthy subjects and acute stroke patients. A PET study.

The aim of the study was to investigate, with an rTMS/PET protocol, the after-effects induced by 1-Hz repetitive transcranial magnetic stimulation (rTMS) in the regional cerebral blood flow (rCBF) of the primary motor cortex (M1) contralateral to that stimulated during a movement. Eighteen healthy subjects underwent a baseline PET scan followed, in randomized order, by a session of Real/Sham low-frequency (1 Hz) subthreshold rTMS over the right M1 for 23 min. The site of stimulation was fMRI-guided. After each rTMS session (real or sham), subjects underwent behavioral hand motor tests and four PET scans. During the first two scans, ten subjects (RH group) moved the right hand ipsilateral to the stimulated site and eight subjects (LH group) moved the left contralateral hand. All remained still during the last two scans (rest). Two stroke patients underwent the same protocol with rTMS applied on contralesional M1. Compared with Sham-rTMS, Real-rTMS over the right M1 was followed by a significant increase of rCBF during right hand movement in left S1M1, without any significant change in motor performance. The effect lasted less than 1 h. The same rTMS-induced S1M1 overactivation was observed in the two stroke patients. Commissural connectivity between right dorsal premotor cortex and left M1 after real-rTMS was observed with a psychophysiological interaction analysis in healthy subjects. No major changes were found for the left hand. These results give further arguments in favor of a plastic commissural connectivity between M1 both in healthy subjects and in stroke patients, and reinforce the potential for therapeutic benefit of low-frequency rTMS in stroke rehabilitation.

Methylphenidate modulates cerebral post-stroke reorganization.

OBJECTIVE: We hypothesized that a single dose of methylphenidate (MP) would modulate cerebral motor activation and behavior in patients having suffered a subcortical stroke. METHODS: Eight men with a single stroke on the corticospinal tract resulting in a pure motor hemiparesia were included in a randomized, cross-over, double-blind, placebo-controlled study. Patients were first evaluated 17 days after stroke onset by validated neurological scales, motor tests and fMRI (flexion/extension of the digits) after 20 mg MP or placebo. Seven days later, the patients underwent the same protocol and received the drug they had not taken at the first evaluation. Each patient was his own control. RESULTS: Placebo intake did not change performance. MP compared to placebo elicited a significant improvement in motor performance of the affected hand at the finger tapping test. MP induced: (1) a hyperactivation of the ipsilesional primary sensorimotor cortex including the motor hand and face areas and of the contralesional premotor cortex; (2) a hypoactivation of the ipsilesional anterior cingulum. Hyperactivation in the face motor area correlated positively with the improvement in performance. CONCLUSION: We demonstrated that the reorganized network may efficiently be targeted by the drug and that the effect of MP might partly rely on an improvement in attention/effort through cingulum modulation.

Plasma exogenous creatinine clearance test in dogs: comparison with other methods and proposed limited sampling strategy.

Plasma clearance of creatinine was evaluated for assessment of glomerular filtration rate (GFR) in dogs. In 6 healthy dogs (Experiment 1), we determined 24-hour urine clearance of endogenous creatinine, plasma, and urine clearances of exogenous creatinine administered at 40, 80, and 160 mg/kg in a crossover design (linearity study), plasma iothalamate clearance, and plasma and urine clearances of 14C-inulin. In Experiment 2, plasma creatinine and iothalamate clearances were compared, and a linearity study was performed as for Experiment 1 in 6 dogs with surgically induced renal impairment. Experiment 3 compared plasma creatinine clearance with plasma iothalamate clearance before and 3 weeks after induction of moderate renal impairment in 6 dogs. Plasma creatinine clearances were calculated by both noncompartmental and compartmental analyses. In Experiment 1, plasma inulin clearance was higher (P < .001) than other clearance values. Plasma creatinine clearances at the 3 dose rates did not differ from urine inulin clearance and each other. In Experiment 2, plasma creatinine clearances were about 14% lower than plasma iothalamate clearance (P < .05). In Experiment 3, decreases in GFR assessed by plasma clearances of iothalamate and creatinine were similar. Renal failure decreased the daily endogenous input rate of creatinine by 25%. Limiting sampling strategies for optimizing GFR calculation were proposed, allowing an error lower than 6.5% with 4 blood samples. These results suggest that determination of plasma creatinine clearance by a noncompartmental approach offers a reliable, inexpensive, rapid, and convenient means of estimating GFR in routine practice.