Investigación en fisuras faciales: quo vadis España? / Investigation in facial fissures: quo vadis Spain?

Las fisuras orofaciales representan un grupo heterogéneo de malformaciones congénitas que afectan a distintas estructuras de la cavidad oral y de la cara. Globalmente, los bebés con estos trastornos presentan una mayor morbilidad y mortalidad a lo largo de su vida en comparación con individuos no afectados. Por ello, los avances en la investigación biomédica resultan ineludibles. Así, el objetivo general de este trabajo fue llevar a cabo una revisión bibliográfica para analizar narrativamente los 10 principales estudios primarios sobre fisuras orofaciales llevados a cabo en España, publicados del 2018 hasta la actualidad. Según esto, a nivel institucional, destaca la Universidad Complutense de Madrid (UCM) con cuatro artículos publicados por el grupo de investigación UCM 920202. También sobresale la Universidad Rey Juan Carlos de Madrid, con tres artículos relacionados con diferentes aspectos de la personalidad y la calidad de vida de los pacientes fisurados, así como otras muchas variables cognitivo-emocionales. En relación con la Universidad de Valencia, encontramos dos artículos llevados a cabo en amplias muestras de pacientes con fisuras. Por último, en Barcelona resulta destacable un estudio observacional sobre problemas otorrinolaringológicos en pacientes operados de fisura palatina. En conclusión, si bien en los últimos años se han publicado varios artículos sobre distintos aspectos relacionados con las fisuras, aún queda mucho trabajo por hacer. España debería seguir potenciando proyectos con líneas de trabajo centradas en estas alteraciones del desarrollo craneofacial. Se necesitan estudios amplios, multicéntricos y colaborativos, para ahondar en los mecanismos etiológicos y, en última instancia, en las posibles herramientas para su prevención. Del mismo modo, se necesitan ayudas para dilucidar mejor las cuestiones relacionadas con los tratamientos en todas las dimensiones de la salud, preferentemente a partir de ensayos clínicos controlados aleatorizados, que faciliten la traslación de conocimientos y su accesibilidad universal dentro del sistema sanitario público español.

SUMMARY: Orofacial clefts represent a heterogeneous group of congenital malformations affecting different structures of the oral cavity and face. Overall, infants with these disorders have a higher lifetime morbidity and mortality compared to unaffected individuals. Therefore, advances in biomedical research are unavoidable. Thus, the overall objective of this work was to conduct a literature review to narratively analyse the 10 main primary studies on orofacial clefts carried out in Spain, published from 2018 to date. According to this review, at an institutional level, the Complutense University of Madrid (UCM) is notable with 4 articles published by the UCM 920202 research group. The Rey Juan Carlos University of Madrid also stands out, with three papers related to different aspects of the personality and quality of life of cleft patients, as well as many other cognitive-emotional variables. In relation to the University of Valencia, we found two studies carried out on large samples of cleft patients. Finally, in Barcelona, an observational study on otorhinolaryngological problems in cleft palate patients is noteworthy. In conclusion, although several studies have been published in recent years on different aspects related to clefts, there is still much work to be done. Spain should craniofacial development. Large, multicenter and collaborative studies are needed to delve deeper into the aetiological mechanisms and, ultimately, into the possible tools for their prevention. Similarly, support is needed to better elucidate questions related to treatments in all dimensions of health, preferably randomised controlled clinical trials, which facilitate the transfer of knowledge and its universal accessibility within the Spanish public health system.

An accessory abductor digiti minimi as possible risk factor of the median and ulnar nerves compression / Músculo abductor digiti minimi accesorio como posible factor de riesgo de la compresión de los nervios mediano y ulnar

SUMMARY: During routine dissection of a left upper limb of a 68-year-old male human cadaver, an unusual muscle was observed originating from the radius and flexor retinaculum, and continued in the hypothenar region with the muscle belly of the abductor digiti minimi. We checked that it was an accessory abductor digiti minimi (ADM). Its muscular belly was in close relation to the median and ulnar nerves. We review the literature regarding such muscle variations and discuss the potential for compression of the median and ulnar nerves. Although the accessory ADM is usually asymptomatic and only rarely results in nerve compression, it should be taken into account by surgeons when establishing a differential diagnosis in the compression neuropathies of the median and ulnar nerves. An ultrasound scanning can help establish the differential diagnosis.

RESUMEN: Durante la disección de rutina de un miembro superior izquierdo de un cadáver humano masculino de 68 años, se observó un músculo inusual que se originaba en el radio y el retináculo flexor del carpo, y continuuaba en la región hipotenar con el vientre muscular del abductor digiti minimi manus. Verificamos que se trataba del músculo abductor digiti minimi accessorius (ADMA). Su vientre muscular se encontraba en estrecha relación con los nervios mediano y ulnar. Revisamos la literatura sobre variaciones musculares y discutimos la potencial compresión de los nervios mediano y ulnar. Aunque el ADMA suele ser asintomático y rara vez produce compresión nerviosa, los cirujanos deben tenerlo en cuenta al establecer un diagnóstico diferencial en las neuropatías de compresión de los nervios mediano y ulnar. Una ecografía puede ayudar a establecer el diagnóstico diferencial.

Does education about death and dying decrease stress generated in the dissection room? / ¿Disminuye el estrés generado en la sala de disección la formación sobre la muerte y el moribundo?

SUMMARY: Positive effects on reducing students' stress have been reported across numerous university settings when anatomy preparatory seminars have been provided. To date, this type of preparation for coping with cadaver dissection has not been studied in Spanish universities. The aim of this study is to evaluate how first-year Spanish medical students face the dissecting room and whether previous preparation about death and dying reduces the stress generated. We performed an interventional study with students who received preparatory classes before the dissection practices (Experimental Group, EG) and with students who did not (Control Group, CG). Sociodemographic data and a self-assessment on stress symptoms were collected through a questionnaire completed before and after the dissection practices. No differences were found in the self-report of symptoms of stress among students who consider themselves religious or not, or between students who had a family member in the healthcare environment or not. However, in the EG, the students who had ample experience with terminally ill patients or death reported fewer stress symptoms. Unexpectedly, the number of selfreported stress symptoms after the dissection practice was higher in EG students. In conclusion the stress levels of first-year Spanish medical students not only did not improve after receiving preparatory classes about death and dying and discussion groups, but it gets worse. We found a relationship between student stress measured and experience with terminally ill patients or death. Additional studies are needed to identify the most suitable preparation for Spanish medical students.

RESUMEN: Se han informado efectos positivos en la reducción del estrés en los estudiantes de numerosos entornos universitarios cuando se han impartido seminarios preparatorios de anatomía. Hasta la fecha, este tipo de preparación para hacer frente a la disección del cadáver no se ha estudiado en las universidades españolas. El objetivo de este estudio es evaluar cómo los estudiantes de medicina españoles de primer año se enfrentan a la sala de disección y si la preparación previa sobre la muerte y el moribundo reduce el estrés generado. Realizamos un estudio de intervención con estudiantes que recibieron clases preparatorias antes de las prácticas de disección (Grupo Experimental, GE) y con estudiantes que no las recibieron (Grupo de Control, GC). Se recogieron datos sociodemográficos y síntomas de estrés mediante un cuestionario de autoevaluación antes y después de las prácticas de disección. No se encontraron diferencias en los síntomas de estrés valorados, entre los estudiantes que se consideran religiosos y los que no, ni tampoco entre los estudiantes que tenían o no un familiar en el entorno sanitario. Sin embargo, en el GE, en los estudiantes que tenían una amplia experiencia con pacientes con enfermedades terminales o con la muerte se observaron menos síntomas de estrés. Inesperadamente, el número de síntomas de estrés recogidos después de la práctica de disección fue mayor en los estudiantes del GE. En conclusión, los niveles de estrés de los estudiantes españoles de medicina de primer año no solo no mejoraron después de recibir las clases preparatorias sobre la muerte y el moribundo y establecer grupos de discusión, sino que empeoraron. Encontramos una relación entre la medición del estrés en los estudiantes y la experiencia con pacientes con enfermedades terminales o con la muerte. Se necesitan estudios adicionales para identificar la preparación más adecuada para los estudiantes de medicina españoles.

An unusual case of primate arterial pattern in a human upper limb / Un caso inusual de patrón arterial de primates en un miembro superior humano

During routine undergraduate dissections of the upper limb, variations on the usual arterial and muscular patterns were observed in a 68 year-old male cadaver. The arterial and muscular pattern found in our specimen is similar to that of some primates in the following terms. 1) Brachial artery duplicity, on the right side, with a superficial brachio-ulnoradial artery. 2) In the right upper limb, the biceps brachii muscle continued with the superficial muscles of the forearm. 3) The brachial artery on the left side, cross over in front of the median nerve, as the only artery of the arm with a network axillary pattern. 4) On both sides, the ulnar artery was superficial and originated at the elbow from superficial brachial arteries. 5) The right anterior interosseous artery intervened in the vascularization of the hand. These results suggest that this may be a case of early detention of human embryonic development and/or the persistence of phylogenetic older patterns. In the literature, we have found no reference to the presence of all these variations in the same individual. The objective of our study was to analyze these variations from an embryological and phylogenetic perspective.

Durante las disecciones de pregrado de rutina del miembro superior, se observaron variaciones en los patrones arteriales y musculares habituales en un cadáver macho de 68 años. El patrón arterial y muscular que se encuentra en nuestro espécimen es similar al de algunos primates en los siguientes términos. 1) Duplicidad de la arteria braquial, en el lado derecho, con una arteria braquioulnoradial superficial. 2) En el miembro superior derecho, el músculo bíceps braquial continuó con los músculos superficiales del antebrazo. 3) La arteria braquial en el lado izquierdo, se cruza frente al nervio mediano, como la única arteria del brazo con un patrón axilar en red. 4) En ambos lados, la arteria ulnar era superficial y se originó en el codo de las arterias braquiales superficiales. 5) La arteria interósea anterior derecha intervino en la vascularización de la mano. Estos resultados sugieren que este puede ser un caso de detención temprana del desarrollo embrionario humano y/o la persistencia de patrones filogenéticos más antiguos. En la literatura, no hemos encontrado ninguna referencia a la presencia de todas estas variaciones en el mismo individuo. El objetivo de nuestro estudio fue analizar estas variaciones desde una perspectiva embriológica y filogenética.

Maxillary growth in a congenital cleft palate canine model for surgical research.

We have recently presented the Old Spanish Pointer dog, with a 15-20% spontaneous congenital cleft palate rate, as a unique experimental model of this disease. This study aimed to describe the cleft palate of these dogs for surgical research purposes and to determine whether congenital cleft palate influences maxillofacial growth. Seven newborn Old Spanish Pointer dogs of both sexes, comprising a cleft palate group (n = 4) and a normal palate group (n = 3), were fed using the same technique. Macroscopic photographs and plaster casts from the palate, lateral radiographs and computer tomograms of the skull were taken sequentially over 41 weeks, starting at week 5. The cleft morphology, the size and the tissue characteristics in these dogs resembled the human cleft better than current available animal models. During growth, the cleft width varies. Most of the transverse and longitudinal measures of the palate were statistically lower in the cleft palate group. The cleft palate group showed hypoplasia of the naso-maxillary complex. This model of congenital cleft palate seems suitable for surgical research purposes. A reduced maxillofacial pre- and post-natal development is associated to the congenital cleft palate in the Old Spanish Pointer dog.

Injection and adhesion palatoplasty: a preliminary study in a canine model.

BACKGROUND: Raising mucoperiosteal flaps in traditional palatoplasty impairs mid-facial growth. Hyaluronic acid-based hydrogels have been successfully tested for minimally invasive craniofacial bone generation in vivo as carriers of bone morphogenetic protein-2 (BMP-2). We aimed to develop a novel flapless technique for cleft palate repair by injecting a BMP-2 containing hydrogel. MATERIAL AND METHODS: Dog pups with congenital cleft palate were either non-treated (n=4) or treated with two-flap palatoplasty (n=6) or with the proposed injection/adhesion technique (n=5). The experimental approach was to inject a hyaluronic acid-based hydrogel containing hydroxyapatite and BMP-2 subperiosteally at the cleft palate margins of pups aged six weeks. At week ten, a thin strip of the medial edge mucosa was removed and the margins were closed directly. Occlusal photographs and computed tomography (CT) scans were obtained up to week 20. RESULTS: Four weeks after the gel injection the cleft palate margins had reached the midline and engineered bone had enlarged the palatal bones. Removal of the medial edge mucosa and suturing allowed complete closure of the cleft. Compared to traditional palatoplasty, the injection/adhesion technique was easier, and the post-surgical recovery was faster. CT on week 20 revealed some overlapping or "bending" of palatal shelves in the two-flap repair group, which was not observed in the experimental nor control groups. CONCLUSION: A minimally invasive technique for cleft palate repair upon injectable scaffolds in a dog model of congenital cleft palate is feasible. Results suggest better growth of palatal bones. This represents an attractive clinical alternative to traditional palatoplasty for cleft palate patients.

Osteoinduction in the palatal submucosa by injecting BMP-2 on 2 different carriers.

In this work, we investigated the ability of injected recombinant human bone morphogenetic protein 2 (rhBMP-2) on brushite cement (a ß-tricalcium phosphate-based biomaterial) and collagen gel as carriers to induce osteogenic differentiation in the palatal submucosa of 10-day-old rats. This was part of a broader study aiming to create bone in the palatal submucosa at cleft palate edges in the search for a minimally invasive treatment. Thirteen treated animals, 7 with rhBMP-2/brushite cement and 6 with rhBMP-2/collagen gel, were injected with 5 to 10 µL of each biomaterial in the right palatal submucosa at the level between the second and third rugae. The contralateral site was uninjected and served as the control. Six weeks after injection, both brushite cement and collagen gel were histologically unrecognizable in all treated animals. New bone structures such as ossicles of woven bone were not detected. However, an augmentation in the thickness of the palatal fibromucosa was observed at the injection site of all palates. In addition, immunolabeling for osteopontin, proliferating cell nuclear antigen, and TUNEL revealed intense osteogenic induction at the injection site with both constructs, which was negative in the control site from the same specimens; no differences regarding cell proliferation and death were observed. The present study confirms the feasibility of generating osteogenic cells in the palatal submucosa by injecting low doses of rhBMP-2 in these 2 biomaterials, together with their inability to form bone.

A new technique for feeding dogs with a congenital cleft palate for surgical research.

In humans, cleft palate (CP) is one of the most common malformations. Although surgeons use palatoplasty to close CP defects in children, its consequences for subsequent facial growth have prompted investigations into other novel surgical alternatives. The animal models of CP used to evaluate new surgical treatments are frequently obtained by creating surgically induced clefts in adult dogs. This procedure has been ethically criticized due to its severity and questionable value as an animal model for human CP. Dogs born with a congenital CP would be much better for this purpose, provided they developed CP at a sufficient rate and could be fed. Up until now, feeding these pups carried the risk of aspiration pneumonia, while impeding normal suckling and chewing, and thus compromising orofacial growth. We developed a technique for feeding dog pups with CP from birth to the time of surgery using two old Spanish pointer dog pups bearing a complete CP. This dog strain develops CP in 15-20% of the offspring spontaneously. Custom-made feeding teats and palatal prostheses adapted to the pups' palates were made from thermoplastic plates. This feeding technique allowed lactation, eating and drinking in the pups with CP, with only sporadic rhinitis. To determine whether the use of this palatal prosthesis interferes with palatal growth, the palates of three littermate German shorthaired pointer pups without CP, either wearing or not wearing (controls) the prosthesis, were measured. The results showed that the permanent use of this prosthesis does not impede palatal growth in the pups.

Immunohistochemical localization of fibrillin-1 protein in the cells of chick corneal and conjunctival epithelia during pre- and postnatal development.

Fibrillin-1 protein is a microfibrillar glycoprotein component of the extracellular matrix, widely distributed in ocular connective tissues. In this work, we show for the first time the expression pattern of fibrillin-1 protein in the corneal and conjunctival epithelia and in stromal keratocytes during embryo development. After hatching, protein expression was maintained in the corneal epithelium cells and nonsecreting epithelium cells of the conjunctiva and disappeared in the stromal keratocytes. In the limbus region, the basal cells were negative, while superficial cells were positive for the antibody. The expression in corneal epithelial cells suggests a role for fibrillin in development and disease. Therefore, some basal cells of the limbus region do not show fibrillin-1 immunolocalization, and this may be correlated with stem cell or stem-like properties.

Alteration of medial-edge epithelium cell adhesion in two Tgf-beta3 null mouse strains.

Although palatal shelf adhesion is a crucial event during palate development, little work has been carried out to determine which molecules are responsible for this process. Furthermore, whether altered palatal shelf adhesion causes the cleft palate presented by Tgf-beta3 null mutant mice has not yet been clarified. Here, we study the presence/distribution of some extracellular matrix and cell adhesion molecules at the time of the contact of palatal shelves in both wild-type and Tgf-beta3 null mutant palates of two strains of mice (C57/BL/6J (C57), and MF1) that develop cleft palates of different severity. We have performed immunohistochemistry with antibodies against collagens IV and IX, laminin, fibronectin, the alpha5- and beta1-integrins, and ICAM-1; in situ hybridization with a Nectin-1 riboprobe; and palatal shelf cultures treated or untreated with TGF-beta3 or neutralizing antibodies against fibronectin or the alpha5-integrin. Our results show the location of these molecules in the wild-type mouse medial edge epithelium (MEE) of both strains at the time of the contact of palatal shelves; the heavier (C57) and milder (MF1) alteration of their presence in the Tgf-beta3 null mutants; the importance of TGF-beta3 to restore their normal pattern of expression; and the crucial role of fibronectin and the alpha5-integrin in palatal shelf adhesion. We thus provide insight into the molecular bases of this important process and the cleft palate presented by Tgf-beta3 null mutant mice.