Modeling childhood cancer in Drosophila melanogaster.

Childhood cancer is a major cause of death in developed countries, and while treatments and survival rates have improved, long-term side effects remain a challenge. The genetic component of pediatric tumors and their aggressive progression, makes the study of childhood cancer a complex area of research. Here, we introduce the fruit fly Drosophila melanogaster as study model. We emphasize its numerous advantages, including binary gene expression systems that enable precise control over the timing and location of gene expression manipulation, the capacity to combine multiple genes associated with cancer or the testing of human cancer variants within a live, intact animal. As an illustrative example, we focus on the Drosophila cancer paradigm which involves medically relevant genes, the Notch and PI3K/Akt signaling pathways. We describe how this cancer paradigm allows assessing two critical aspects of tumorigenesis during juvenile stages: (1) viability (do animals with particular cancer mutations survive into adulthood?), and (2) tumor burden (what percentage of animals bearing the cancer mutations actually develop cancer and what is the extent of the tumor?). We highlight the potential of Drosophila as a molecular therapeutic tool for drug screening and drug repurposing of medicines already approved to treat other diseases in children, thereby accelerating the potential translation of results into humans. This preclinical animal model sustains huge potential and is cost-effective. It allows screening of thousands of compounds and genes at a relatively low cost and human efforts, opening innovative venues to explore more effective and safer treatments of childhood cancer.

The first report of the buckled thyroid cartilage in a human cadaver.

We present the first case of buckled thyroid cartilage identified in a human cadaver. This rare anatomical variant, in patients, often produces dysphonia and is a potential source for diagnostic confusion. In the cadaveric case described, the laryngeal prominence is deviated to the left without deviation of the internal structures of the larynx, such as vocal folds and vocalis muscles. The medical history of the patient is not known. Finally, a review of current literature on the buckled thyroid cartilage is presented. Such a case represents a rare opportunity to visualize this deformity via anatomical dissection.

Embryology of the Abdominal Wall and Associated Malformations-A Review.

In humans, the incidence of congenital defects of the intraembryonic celom and its associated structures has increased over recent decades. Surgical treatment of abdominal and diaphragmatic malformations resulting in congenital hernia requires deep knowledge of ventral body closure and the separation of the primary body cavities during embryogenesis. The correct development of both structures requires the coordinated and fine-tuned synergy of different anlagen, including a set of molecules governing those processes. They have mainly been investigated in a range of vertebrate species (e.g., mouse, birds, and fish), but studies of embryogenesis in humans are rather rare because samples are seldom available. Therefore, we have to deal with a large body of conflicting data concerning the formation of the abdominal wall and the etiology of diaphragmatic defects. This review summarizes the current state of knowledge and focuses on the histological and molecular events leading to the establishment of the abdominal and thoracic cavities in several vertebrate species. In chronological order, we start with the onset of gastrulation, continue with the establishment of the three-dimensional body shape, and end with the partition of body cavities. We also discuss well-known human etiologies.

Fat: Quality, or Quantity? What Matters Most for the Progression of Metabolic Associated Fatty Liver Disease (MAFLD).

OBJECTIVES: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). METHODS: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD-low concentration of PA (main fat source-corn and soybean oils); 2. HP-WD-high concentration of PA (main fat source-palm oil); 3. HP-Trans-WD-high concentration of PA (mainly transfat). RESULTS: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. CONCLUSIONS: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.

Anatomic mapping of the collateral branches of the external carotid artery with regard to daily clinical practice.

BACKGROUND: To identify the anatomical variations of the main branches of the external carotid artery (lingual, facial, occipital, ascending pharyngeal and sternocleidomastoid), giving information about the calibers and origins with the aim of creating a new classification useful in clinical practice. MATERIAL AND METHODS: 193 human embalmed body-donors were dissected. The data collected were analyzed using the Chi² test. The results of previous studies were reviewed. RESULTS: The majority of the anterior arterial branches (superior thyroid, facial and lingual artery) were observed with an independent origin, respectively, classified as pattern I (80.83%, 156/193). In 17.62% (34/193) a linguofacial trunk, pattern II, has been observed, only in 1,04% (2/193) a thyrolingual trunk, pattern III, has been found and in one case (1/193, 0.52%) one thyrolinguofacial trunk, pattern IV, was found. Depending on the posterior branches (occipital and ascending pharyngeal), four different types could be determined: type a, the posterior arteries originated independently, type b, the posterior arteries originated in a common trunk, type c, the ascending pharyngeal artery was absent, type d, the occipital artery was absent. CONCLUSION: Anatomical variations in these arteries are relevant in daily clinical practice due to growing applications, e.g., in Interventional Radiology techniques. Knowledge of these anatomical references could help clinicians in the interpretation of the carotid system.

Comparative anatomo-radiological study of intrahepatic venous vascularization in the Spain.

BACKGROUND: Anatomic variations in the hepatic venous system are the least understood aspect of hepatic anatomy. The variations are diverse, and data are lacking with respect to the population of Spain and methods of detection. The objective was to examine morphological patterns of variations in hepatic venous vascularization using cadaveric dissections vs. radiological imaging, and to analyze the findings with respect to Spain and to published studies. METHODS: Thirty-one livers were anatomically dissected and analyzed for their hepatic venous anatomy and then compared to the venous anatomy of livers examined in 216 CT scans from 119 men and 97 women, ranging between 27 and 89 years of age. Statistical analysis was done using the Chi squared and Fisher homogeneity tests. RESULTS: The hepatic portal vein showed morphological variations in cadavers vs. CT of 67.3% vs. 67.6% (p-I), 29% vs. 12.2% (p-II), 0% vs. 14.6% (p-III), 0% vs. 14.6% (p-IV), 3.2% vs. 0.5% (p-V) and 6.5% vs. 1.9% (p-VI), respectively in cadavers vs. CT. Hepatic vein pattern variation were found in 64.5% vs. 50.7% (h-I), 32.2% vs. 31.5% (h-II), 0% vs. 2.3% (h-III), 0% vs. 4.7% (h-IV), respectively in dissections vs. CT). In Accessory Hepatic Veins the frequency in pattern variation was 64.5% vs. 18.8% (a-2.1), 29.0% vs. 8.0% (a-2.2), 58.1% vs. 11.3% (a-2.3), 9.7% vs. 0.9% (a-2.4), 67.7% vs. 16.9% (a-2.5), 9.7% vs. 4.2% (a-2.6) and 0% vs. 0.5% (a-2.7), respectively, in cadavers vs. CT. CT showed in 27.2% no accessory hepatic veins. Sex was not a factor influencing patterns of variation. CONCLUSION: Anatomical variants of the hepatic portal vein, the hepatic vein and accessory hepatic veins are very diverse and show greater variability in the specimens compared to those detected with radiological images, finding a wider spectrum of variations as it allows the clinician to have a more precise definition of the vasculature. A higher precision in the definition of anatomical variations is warranted for surgical planning in liver resection and transplantation.

The bronchial segmentation and its anatomical variations. A clinical-anatomic and bronchoscopy study.

The development in interventional respiratory medicine entails the need of bronchial anatomical knowledge, whose variations assume their greatest importance nowadays. The aim of this study was to describe the frequency of these variations and to analyze the bronchial lengths, barely registered before in literature. This observational descriptive study (from June 2018 until April 2019) was conducted in a sample of 17 pairs of lungs, which were dissected and measured at the Cadaver Donation Centre (Universidad Complutense, Madrid), and a second sample of 50 bronchoscopies, performed at the San Carlos Clinic Hospital, which were analyzed during the procedure. Our results show that there are no significant differences in the incidence of variations by sex in any of both samples, and neither in the average length of any bronchus by sex nor lobar pattern. Left main bronchus presents the longest length and left upper lobe bronchus the shortest. The highest percentage of variations is contained in the right lower lobe (25.4%), and the most frequent variation in the subsuperior bronchus (B*) (19.4%). The middle lobe and the left lower lobe present the lowest percentage of variations (11.9%). Only 37.3% of the pairs of lungs/patients did not have any anatomical variation in the general sample. Despite of the small size of the sample, results show a high percentage of variations and a minority of completely normal pairs of lungs, which invites us to reflect about the probable high prevalence of variations in the general population. Further studies with greater samples are needed to confirm our hypothesis.

Microdissection of the Human Renal Nervous System: Implications for Performing Renal Denervation Procedures.

Despite the use of renal denervation to treat hypertension, the anatomy of the renal nervous system remains poorly understood. We performed a detailed quantitative analysis of the human renal nervous system anatomy with the goal of optimizing renal denervation procedural safety and efficacy. Sixty kidneys from 30 human cadavers were systematically microdissected to quantify anatomic variations in renal nerve patterns. Contrary to current clinical perception, not all renal innervation followed the main renal artery. A significant portion of the renal nerves (late arriving nerves) frequently reached the kidney (73% of the right kidney and 53% of the left kidney) bypassing the main renal artery. The ratio of the main renal artery length/aorta-renal hilar distance proved to be a useful variable to identify the presence/absence of these late arriving nerves (odds ratio, 0.001 (95% CI, 0.00002-0.0692; P: 0.001) with a cutoff of 0.75 (sensitivity: 0.68, specificity: 0.83, area under ROC curve at threshold: 0.76). When present, polar arteries were also highly associated with the presence of late arriving nerve. Finally, the perivascular space around the proximal main renal artery was frequently occupied by fused ganglia from the solar plexus (right kidney: 53%, left kidney: 83%) and/or by the lumbar sympathetic chain (right kidney: 63%, left kidney: 60%). Both carried innervation to the kidneys but importantly also to other abdominal and pelvic organs, which can be accidentally denervated if the proximal renal artery is targeted for ablation. These novel anatomic insights may help guide future procedural treatment recommendations to increase the likelihood of safely reaching and destroying targeted nerves during renal denervation procedures.

Vascular clinical anatomy of the submandibular gland.

OBJECTIVE: The aim of this study is to describe in depth the precise anatomy of the vascular supply of the submandibular gland, trying to determine the existence of patterns of glandular vascularization. Knowledge of these patterns could facilitate surgical management of the gland and the submandibular gland flap. MATERIAL AND METHODS: Neck dissections of formaldehyde preserved human cadavers were performed. Submandibular and transmandibular approaches were used during the dissections. All the vascular branches found were registered and classified into 2groups: main or accessory branches. The anatomical data analyzed was: The diameter and length of the main and accessory branches, as well as the most important measurements of the submandibular gland flap pedicle. RESULTS: 33 glands were dissected to study the arterial supply of the submandibular gland (17 right, 16 left; 17 males, 16 females) and 29 were dissected to study the venous supply (15 left, 14 right; 15 males,14 females). A total of 123 arterial branches were found reaching the 33 submandibular glands (47 main and 76 accessories) and 116 venous branches were found draining the 29 submandibular glands (47 main branches and 69 accessory branches). A constant main venous branch that ran parallel to the Wharton duct and drained in the sublingual vein was found in all of cases (Concomitant Wharton Duct Vein or CWDV). CONCLUSION: The CWDV is a constant venous branch for the drainage of the gland and should be considered as venous pedicle during the dissection of submandibular gland flaps.

Anatomical study of the masseteric and obturator nerves: Application to face transplant and reanimation procedures.

The masseteric nerve (MN) and the anterior branch of the obturator nerve (ON) that innervate the transferred gracilis muscle have proved highly efficient for reanimating paralyzed facial muscles when muscle transfer is required. Previous researchers have published the total axonal load for myelinated fibers in both nerves. However, the real motor axonal load has not been established. We performed the study on 20 MN and 13 ON. The segments of the MN and the ON were embedded in paraffin, sectioned at 10 µm, and stained following a standard immunohistochemical procedure using anti-choline acetyltransferase to visualize the motor fibers. The MN has a higher axonal load than the ON. There were statistically significant differences between the axonal load of the proximal segment of the MN and the ON. These findings confirm that end-to-end anastomoses between the MN and the ON should preferably use the proximal segment. However, MN neurotomy should ideally be performed between the proximal and distal segments, preserving innervation to the deep fascicles. Our results show that the MN is ideal as a donor motor nerve for reinnervating transplanted muscle for dynamic reanimation of the paralyzed face. The neurotomy should ideally be performed between the first and second collateral branches of the MN. Clin. Anat. 32:612-617, 2019. © 2019 Wiley Periodicals, Inc.

Which is the function of a martin-gruber connection?

Clinical and diagnostic variations may occur due to the variable presence of a connection between the median and ulnar nerves in the forearm (Martin-Gruber anastomosis). This incidence has a wide range at 7%-40%. Most commonly, the connection between the nerves is considered to be composed of motor fibers; although, a sensory role has also been described. It is important to note that the number of axons, or the nature of the fibers in this connection, have not yet been elucidated. Fifty upper limbs were examined evaluating morphometric characteristics of the Martin Gruber connection, dissected out, sectioned, and immunohistochemically stained for choline acetyltransferase (ChAT) and analyzed with ImageJ© . The connection was observed in 32% of all cases (16/50). The nerve connections were identified as those in Pattern 1 group (12%-type 1b, 19%-type 1a, and 69%-type 1c) and contained motor (ChAT positive) fibers (40.42 ± 10.5% per connection) with three to four fascicles in each. No statistically significant differences were found according to sex, side, or laterality. There were statistically significant differences in the percentages of ChAT positive fibers; however, this was dependent on the distribution being greater in those not distributed zonally. The presence of this connection is prevalent in almost a third of the cadavers dissected; the understanding of this complex composition in sensory and motor fibers allows for the optimization of diagnosis and treatment of certain median-ulnar nerve injuries. Clin. Anat. 32:501-508, 2019. © 2019 Wiley Periodicals, Inc.

Extracranial Course of the Facial Nerve Revisited.

INTRODUCTION: The extrapetrous course of the facial nerve has been a matter of study and debate since XIX century. Two different classifications have been classically proposed and widely accepted by most of the authors. Nevertheless, there are reported cases which do not fit in any of those. The aim of this study is to propose a new and useful classification. MATERIAL AND METHODS: We have used 23 embalmed Caucasian adult cadavers (11 male and 12 female) belonging to the Bodies Donation and Dissecting Rooms Centre of the University Complutense of Madrid. The extra-petrous facial nerve was dissected in the possible specimens resulting in 38 facial nerves. The studied parameters were length, diameter of divisions, terminal branches, and nerve connections. RESULTS: In every specimen two main divisions were found, temporofacial and cervicofacial. They divided into five terminal branches from cranial to caudal: temporal, zygomatic, buccal, marginal or mandibular, and cervical. Based on the comparison with previous proposed classifications, we have unified the patterns in 12 types being the most frequent types the type 3 (eight cases, 21.05%), with connections between temporal, zygomatic and buccal branches and the type 8 (eight cases, 21.05%), a complex network between temporal, zygomatic, buccal, and mandibular branches. The number of terminal branches was so variable. CONCLUSION: We propose a new 12-patterned classification which summarizes the previous ones. However, we consider that a good study of the number of terminal branches, connections between branches or with other cranial nerves are more useful for surgeons to avoid injuries to the facial nerve during surgery than complex classifications. Anat Rec, 302:599-608, 2019. © 2018 Wiley Periodicals, Inc.

The Human Laryngeal Innervation Revisited-The Role of the Neural Connections.

In spite that vascular inconvenients or immunological rejections have been solved in relation with larynx transplant, a successful functional reinnervation has not been achieved. Some studies have suggested that laryngeal nerve connection may contain motor fibers, which could explain unexpected evoked responses in electromyographic studies or the different positions adopted of the vocal folds after similar nerve lesions. Ten patients with unexpected evoked responses after laryngeal nerve stimulation were selected. All the patients underwent a total laryngectomy due to oncological causes. In every case, laryngeal nerve connections were observed. All of them were morphologic and histologic processed for choline-acetyltransferase immunohistochemistry. The presence of motor axons in the nerve connections has been demonstrated, which would explain that the motor innervation to the laryngeal muscles could be dual through these variable connections. This also would justify the difficulty of carrying out laryngeal nerve reinnervation procedures. Anat Rec, 302:646-651, 2019. © 2018 Wiley Periodicals, Inc.

The morphogenesis of the renal plexus: Renal artery and sympathetic fibers.

To examine the origin and development of the renal plexus and its relationship to the renal vessels in embryos and early human fetuses. Serial sections of 34 human embryos (stages 16 to 23 of Carnegie, 4 or 5-8 weeks) and 38 fetuses (9-19 weeks) were analyzed. Throughout the embryonic period, the kidney was not innervated by the renal plexus. Those nerves appeared at the beginning of the early fetal period (9 weeks) as branches given off by the immature autonomic abdominal plexus. The renal nerves started to approach to the kidney during the early fetal period at 9-10 weeks of development. They were distributed in close proximity to the renal arteries and their branches. They were observed first with the settlement of the renal veins. The renal artery is present as a branch of the abdominal aorta at stage 19 (between 6 and 7 weeks) prior to development of the renal plexus. The renal veins were not present during the embryonic period but appeared at the start of the fetal period, along with the renal nerves that emerged from segmented sympathetic para-aortic bodies (SPBs). Clin. Anat. 32:272-276, 2019. © 2018 Wiley Periodicals, Inc.

External laryngeal nerve landmarks revisited.

BACKGROUND: Because external laryngeal nerve (ELN) iatrogenic damage is frequent during neck surgery, its precise localization has been highly recommended. This study analyzes the different surgical landmarks previously proposed and the anatomy of the collateral and terminal branches of the ELN. METHODS: The necks of 157 (77 men and 80 women) human adult embalmed cadavers were examined. The ELN origin, length, and relationship to different landmarks were recorded and results statistically compared with those previously reported. RESULTS: The ELN is located deep to the ascending pharyngeal vein in 100% of patients. In most patients, it crosses the carotid axis at the thyroid artery origin level (47% of patients), passes medial to it (89% of patients), and shows an intramuscular trajectory through the inferior constrictor of the pharynx (80% of patients). CONCLUSION: The ELN position, in relation to classical landmarks, is highly variable. The most reliable relationships are those with the ascending pharyngeal vein or with the superior thyroid artery.

Understanding the anatomy of the larynx from the era of Gimbernat to the present day moving towards laryngeal transplantation

Knowledge of the gross anatomy of the larynx in Spain throughout the period when Gimbernat was working as a surgeon and anatomist was considerable; very much comparable to our present understanding. However, the lack of aseptic surgical technique, anaesthesia, and antibiotics limited the ability to undertake complex surgery. Nevertheless, it was during that period when for first time it became possible to diagnose some laryngeal pathologies, thanks to the invention, by a Spanishsinger, Manuel Garcia (1805-1906), of a primitive laryngoscope that made it possible to see the laryngeal interior. Only in 1873 was the first major surgery of the larynx was reported when Billroth undertook the first laryngectomy to treat surgically laryngeal carcinoma. It was more than a hundred years later, before the first laryngeal transplantation was attempted by Strome and his team (1998), and though initially meeting with some success, that transplanted larynx had to be removed 14 years later. Based on our current understanding of laryngeal anatomy and surgical technique, we argue that there are four factors that must be addressed if satisfactory transplantation of the larynx to be achieved: 1) psycho-social and ethicolegal aspects; 2) tissue viability vs. rejection; 3) restoration of a vascular, and 4) selective reinnervation of the larynx has to be achieved. The three first factors are being addressed, however, the selective reinnervation remains challenging because the nerve supply of the larynx is now known to be much more complex than many accounts imply. This is because: 1) each laryngeal muscle may receive a variable number of nerve branches; 2) there are multiple connections between the different laryngeal nerves; 3) many laryngeal nerves and connections are mixed conveying both motor and sensory fibres; and 4) the laryngeal muscles may receive a dual nerve supply, from both the recurrent laryngeal and superior laryngeal nerves (AU)

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Anatomoclinical features of trigeminal neuralgia caused by vertebrobasilar dolichoectasia

Vertebrobasilardolichoectasia (VBDE) is a rare cause of trigeminal neuralgia (TN). The size and tortuous course of the offending vessel poses a particular challenge when attempting a surgical treatment with microvascular decompression. There are few reports on the radiological and surgical anatomy encountered in this condition. The anatomical and radiological features of a surgical series of 7 patients with TN caused by VBDE and treated with microvascular decompression (MVD) are presented. Morphometric measurements and three-dimensional reconstructions obtained from preoperative magnetic resonance imaging were compared with microsurgical findings. Trigeminal nerve compression was found on the left side in six cases (86%). The neurovascular compression was caused by the basilar artery (BA) in 4 cases and the vertebral artery (VA) in three cases, with two cases showing a multiple compression involving other vessels. The BA showed a mean maximal diameter of 6,5 mm (5-9,1 mm), a mean lateral deviation of 19,3 mm (14,4- 22,1 mm) and a mean elevation of the basilar tip above the dorsum sellae of 10,5 mm (4,4-14,8 mm). MVD was successfully performed in all patients yielding a permanent pain relief in six of the patients. Preoperative assessment of the neurovascular relations within the cerebellopontine angle is paramount for the surgical planning in patients with TN caused by VBDE

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The gross anatomy of the renal sympathetic nerves revisited.

Catheter-based renal denervation techniques focus on reducing blood pressure in resistant hypertension. This procedure requires exact knowledge of the anatomical interrelation between the renal arteries and the targeted renal nervous plexus. The aim of this work was to build on classical anatomical studies and describe the gross anatomy and anatomical relationships of the renal arteries and nerve supply to the kidneys in a sample of human cadavers. Twelve human cadavers (six males and six females), age range 73 to 94 years, were dissected. The nervous fibers and renal arteries were dissected using a surgical microscope. The renal plexus along the hilar renal artery comprised a fiber-ganglionic ring surrounding the proximal third of the renal artery, a neural network along the middle and distal thirds, and smaller accessory ganglia along the course of the nerve fibers. The fibers of the neural network were mainly located on the superior (95.83%) and inferior (91.66%) surfaces of the renal artery and they were sparsely interconnected by diagonal fibers. Polar arteries were present in 33.33% of cases and the renal nerve pattern for these was similar to that of the hilar arteries. Effective renal denervation needs to target the superior and inferior surfaces of the hilar and polar arteries, where the fibers of the neural network are present. Clin. Anat. 29:660-664, 2016. © 2016 Wiley Periodicals, Inc.

Are the interarytenoid muscles supplied by branches of both the recurrent and superior laryngeal nerves?

OBJECTIVES/HYPOTHESIS: It has been generally accepted that the branches of the internal branch of the superior laryngeal nerve to the interarytenoid muscle are exclusively sensory. However, some experimental studies have suggested that these branches may contain motor axons, and therefore that the interarytenoid muscle is supplied by both the superior and recurrent laryngeal nerves. The aim of this work was to determine whether motor axons to the interarytenoid muscles are present in both laryngeal nerves. STUDY DESIGN: Basic research. METHODS: Twelve human internal branches of the superior laryngeal nerve were dissected, and its branches to the interarytenoid muscle were removed and processed for choline-acetyltransferase immunohistochemistry, a method not used previously in studying the nerve fiber composition of the laryngeal nerves. RESULTS: The internal branch of the superior laryngeal nerve divided into two to five branches to the interarytenoid muscle. All branches contained motor axons, with the proportion of motor axons varying from 6% to 31%. CONCLUSION: The present study confirms that the internal branch of the superior laryngeal nerve provides a motor innervation to the interarytenoid muscles. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1117-1122, 2016.

Guides and protocols for a good practice. I. Act of donation and donation card

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