Interstitial cells of Cajal: histological and pathophysiological studies.The story of a still mysterious cell in the 21st century...

Cajal découvrit à la fin du XIXe siècle des cellules allongées munies de longs prolongements cytoplasmiques, intercalées entre les couches musculaires du tube digestif. Ces cellules interstitielles gardèrent longtemps leurs secrets, la coloration utilisée par Cajal étant délicate à reproduire… Grâce aux progrès technologiques du XXe siècle, le microscope électronique à transmission permet la caractérisation ultrastructurale de ces cellules, et les techniques de biologie moléculaire en assurent la détection en routine. En effet, une technique immunohistochimique révèle la présence, sur la membrane cellulaire, de KIT, récepteur à activité tyrosine kinase. Cette protéine a aidé à comprendre quelques fonctions des cellules interstitielles de Cajal dans la motilité digestive et a favorisé le développement d’une nouvelle classe thérapeutique spécifique, les inhibiteurs d’activité tyrosine kinase.At the end of the 19th century, Cajal discovered elongated cells with numerous thin ramified cytoplasmic processes located between the muscle layers of the gastrointestinal tract. These interstitial cells kept their secrets for a long time, as Cajal’s coloration was difficult to reproduce. The arrival of the transmission electron microscope in the 20th century resulted in the ultrastructural characterization of interstitial cells of Cajal, and molecular biology is now used for their routine detection. An immunohistochemical technique is able to detect the KIT receptors with tyrosine kinase activity on the cell membrane. The discovery of this protein helped understand several functions of the interstitial cells of Cajal in digestive motility, and initiated the development of a new therapeutic class known as tyrosine kinase inhibitors

A new subunit vaccine based on nucleoprotein nanoparticles confers partial clinical and virological protection in calves against bovine respiratory syncytial virus

Human and bovine respiratory syncytial viruses (HRSV and BRSV) are two closely related, worldwide prevalent viruses that are the leading cause of severe airway disease in children and calves, respectively. Efficacy of commercial bovine vaccines needs improvement and no human vaccine is licensed yet. We reported that nasal vaccination with the HRSV nucleoprotein produced as recombinant ringshaped nanoparticles (NSRS) protects mice against a viral challenge with HRSV. The aim of this work was to evaluate this new vaccine that uses a conserved viral antigen, in calves, natural hosts for BRSV. Calves, free of colostral or natural anti-BRSV antibodies, were vaccinated with NSRS either intramuscularly, or both intramuscularly and intranasally using MontanideTM ISA71 and IMS4132 as adjuvants and challenged with BRSV. All vaccinated calves developed anti-N antibodies in blood and nasal secretions and N-specific cellular immunity in local lymph nodes. Clinical monitoring post-challenge demonstrated moderate respiratory pathology with local lung tissue consolidations for the non vaccinated calves that were significantly reduced in the vaccinated calves. Vaccinated calves had lower viral loads than the nonvaccinated control calves. Thus NSRS vaccination in calves provided cross-protective immunity against BRSV infection without adverse inflammatory reaction

Sterilni neutrofilni dermatitis u mačke

A 6.7 kg 7 year-old castrated male domestic short hair cat was presented with several dermatological lesions on the ventral abdomen. The skin of the abdomen and inner thighs was affected. Both inner thighs were equally involved. They were covered with thick and folded, “card-board” devitalised skin. Some ulcerative haemorrhagic lesions were coated by greyish pseudomembranes of necrotic epithelium and fibrin. There was a distinctive margin between normal and affected skin. On the abdomen there was patchy erythema and papules. No other skin lesions were found on the rest of the body. Differential diagnoses for the lesions included: drug reaction, erythema multiforme, toxic epidermal necrolysis, vasculitis, and impetigo. Histopathology revealed different lesions: superficial pustules, ulceration and fibrin exudation, pustule disease with hair follicle destruction. There was no evidence of bacteria on cytology and histopathology. All previously prescribed drugs were stopped. On the day after initial proceeding lesions become less haemorrhagic and less thick. On the fourth day skin lesions were dry. Local therapy (povidone iodine) was maintained and the cat was sent home on day 5. Conclusion of case is sterile neutrophilic dermatitis.Kastrirani mačak, kratkodlake domaće pasmine, u dobi od 7 godina, mase 6,7 kilograma dobio je nekoliko lezija na trbušnoj koži. Koža je bila debela i naborana poput kartona. Nekoliko ulcerativnih hemoragičnih lezija bilo je pokriveno sivim pseudomembranoznim nekrotizirajućim epitelom i fibrinom. Granica između normalne i promijenjene kože bila je jasna. Na trbuhu je uočen eritem i papule. Druge lezije na koži nisu uočene. Diferencijalno-dijagnostički u obzir je uzeta reakcija na lijekove, erythema multiforme, toksična epidermalna nekroza, vaskulitis i impetigo. Patohistološkom pretragom uočene su površinske pustule, ulceracija i eksudacija fibrina, destrukcija dlačnih folikula. Citološkom i patohistološkom pretragom nisu uočene bakterije. Sva do tada propisana terapija je prekinuta, dan nakon prvog pregleda lezije su postale manje hemoragične i koža nešto manje zadebljala. Četvrtoga dana kožne lezije bile su suhe, lokalna terapija je nastavljena 1 %-tnim povidone jodom i mačak je pušten na kućnu njegu petoga dana. Postavljena dijagnoza bila je sterilni neutrofilni dermatitis

The chicken embryo, a model for digestive tract development

The chick embryo was the first animal model used to study the extraordinarily complex process of embryonic development. The chick model led to the discovery of cell lineages involved in the constitution of the digestive muscle wall and of the molecular mechanisms underlying the development of structures and patterning of the digestive wall. First we describe the breakthrough achieved in the 1970s with the construction of quail-chick chimeras, which led to the identification of the embryonic origin of enteric neurons and interstitial cells of Cajal. Functional studies are now possible based on gene transfer technics and transcriptomic analysis. Gain and loss of function approaches are used to target the visceral mesoderm, involved in the constitution of the muscle layer of the digestive tract. This model still holds many promises for the future!Le poulet a été le premier modèle animal utilisé pour comprendre le processus extraordinairement complexe du développement embryonnaire. Ce modèle a permis, en particulier, la découverte des lignages cellulaires impliqués dans la constitution de la paroi musculaire digestive et des mécanismes moléculaires à l'origine de la structuration et de la régionalisation de la paroi digestive. On rappelle d'abord l'avancée réalisée, dès les années 1970, par la construction de chimères caille-poulet, qui ont permis l'identification de l'origine embryologique des neurones entériques et des cellules interstitielles de Cajal. Des études fonctionnelles sont désormais possibles chez le poulet grâce aux techniques de transfert de gènes et à l'analyse transcriptomique. Par des approches de perte ou de gain de fonction, on peut cibler le mésoderme viscéral qui participe à la constitution de la couche musculaire du tube digestif. Ainsi, ce modèle est encore promis à un bel avenir

Cutaneous melanoma: what if Laënnec was right? Search for a common malignancy marker in mammals

Cutaneousmelanomas are characterized by considerable inter and intraspecific heterogeneity. In 1806, René Laënnec used a single term to describe these malignant tumours believed to originate from melanocytes. Due to their highmetastatic potential, the prognosis ofmelanomas remains unfavourable. To improve it, early diagnosis is essential since metastasis-free stages can be treated. This is why we sought malignancy markers for melanomas. We identified the RACK1 protein as a marker of malignancy in humanmelanomas. A commonmalignancymarker for differentmammalianmelanomas would support the use of the single term “melanoma”. In the present article, we review current knowledge on the molecular basis of melanocyte tumorigenesis to explain our interest in the RACK1 protein.Les mélanomes cutanés se caractérisent par une considérable hétérogénéité intra et interspécifique. Ces tumeurs malignes censées dériver des mélanocytes ont été décrites sous un terme unique par René Laënnec en 1806. Par leur forte capacité métastatique, elles sont toujours de sombre pronostic. Pour améliorer celui-ci, leur diagnostic précoce est indispensable car les stades sans métastase peuvent être traités efficacement. Aussi, des marqueurs de malignité du mélanome sont recherchés. Nous avons identifié la protéine RACK1 comme marqueur de malignité des mélanomes chez l'homme. Un marqueur de malignité commun des mélanomes de mammifères conforterait l'utilisation du terme unique « mélanome ». Nous commentons les connaissances actuelles des bases moléculaires de la tumorigenèse des mélanocytes pour expliquer notre intérêt pour la protéine RACK1

Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neural cells

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by deficient β-glucuronidase (β-gluc) activity. Significantly reduced β-gluc activity leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. Numerous combinations of mutations in GUSB (the gene that codes for β-gluc) cause a range of neurological features that make disease prognosis and treatment challenging. Currently, there is little understanding of the molecular basis for MPS VII brain anomalies. To identify a neuronal phenotype that could be used to complement genetic analyses, we generated two iPSC clones derived from skin fibroblasts of an MPS VII patient. We found that MPS VII neurons exhibited reduced β-gluc activity and showed previously established disease-associated phenotypes, including GAGs accumulation, expanded endocytic compartments, accumulation of lipofuscin granules, more autophagosomes, and altered lysosome function. Addition of recombinant β-gluc to MPS VII neurons, which mimics enzyme replacement therapy, restored disease-associated phenotypes to levels similar to the healthy control. MPS VII neural cells cultured as 3D neurospheroids showed upregulated GFAP gene expression, which was associated with astrocyte reactivity, and downregulation of GABAergic neuron markers. Spontaneous calcium imaging analysis of MPS VII neurospheroids showed reduced neuronal activity and altered network connectivity in patient-derived neurospheroids compared to a healthy control. These results demonstrate the interplay between reduced β-gluc activity, GAG accumulation and alterations in neuronal activity, and provide a human experimental model for elucidating the bases of MPS VII-associated cognitive defects

Sílabo de Finanzas I

El curso de Finanzas I es de naturaleza aplicativa y se propone desarrollar en los estudiantes la competencia para explicar y aplicar los principios y los modelos de la Teoría Financiera en la gestión financiera de una empresa con el objetivo de maximizar el valor de la empresa. El curso sirve de base para los cursos de Finanzas II ,Presupuestos, Contabilidad Gerencial y Formulación y Evaluación de Proyectos