Cannabidiol Promotes Neuronal Differentiation Using Akt and Erk Pathways Triggered by Cb1 Signaling.

Recently, the scientific community has started to focus on the neurogenic potential of cannabinoids. The phytocompound cannabidiol (CBD) shows different mechanism of signaling on cannabinoid receptor 1 (CB1), depending on its concentration. In this study, we investigated if CBD may induce in vitro neuronal differentiation after treatment at 5 µM and 10 µM. For this purpose, we decided to use the spinal cord × neuroblastoma hybrid cell line (NSC-34) because of its proliferative and undifferentiated state. The messenger RNAs (mRNAs) expression profiles were tested using high-throughput sequencing technology and Western blot assay was used to determine the number of main proteins in different pathways. Interestingly, the treatment shows different genes associated with neurodifferentiation statistically significant, such as Rbfox3, Tubb3, Pax6 and Eno2. The CB1 signaling pathway is responsible for neuronal differentiation at 10 µM, as suggested by the presence of p-ERK and p-AKT, but not at 5 µM. A new correlation between CBD, neurodifferentiation and retinoic acid receptor-related orphan receptors (RORs) has been observed.

The Role of Hypoxia in Improving the Therapeutic Potential of Mesenchymal Stromal Cells. A Comparative Study From Healthy Lung and Congenital Pulmonary Airway Malformations in Infants.

Mesenchymal stromal cells (MSCs) play an important role in the field of regenerative medicine thanks to their immunomodulatory properties and their ability to secrete paracrine factors. The use of MSCs has also been tested in children with congenital lung diseases inducing fibrosis and a decrease in lung function. Congenital malformations of the pulmonary airways (CPAM) are the most frequently encountered lung lesion that results from defects in early development of airways. Despite the beneficial properties of MSCs, interventions aimed at improving the outcome of cell therapy are needed. Hypoxia may be an approach aimed to ameliorate the therapeutic potential of MSCs. In this regard, we evaluated the transcriptomic profile of MSCs collected from pediatric patients with CPAM, analyzing similarities and differences between healthy tissue (MSCs-lung) and cystic tissue (MSCs-CPAM) both in normoxia and in cells preconditioned with hypoxia (0.2%) for 24 h. Study results showed that hypoxia induces cell cycle activation, increasing in such a way the cell proliferation ability, and enhancing cell anaerobic metabolism in both MSCs-lung and MSCs-CPAM-lung. Additionally, hypoxia downregulated several pro-apoptotic genes preserving MSCs from apoptosis and, at the same time, improving their viability in both comparisons. Finally, data obtained indicates that hypoxia leads to a greater expression of genes involved in the regulation of the cytoskeleton in MSCs-lung than MSCs-CPAM.

Laparoscopic giant hiatal hernia repair with absorbable mesh.

Background: The best operative approach to large hiatal hernias still remains controversial between suture cruroplasty and prosthetic hiatal herniorrhaphy. This study aims at analysing results from a single institution in Italy in terms of subjective and objective outcomes. Methods: Retrospectively collected data of all patients that underwent laparoscopic hiatal hernia repair since 2011 were considered. Sixty-five patients were included overall; 17 of them fit the criteria of large hiatal hernia. Follow-up (FU) was assessed by visit, questionnaires and X-ray imaging. Results: No major complications occurred in the post-operative course. No patient was lost during the FU period. Out of all the patients included, 13 agreed to have an X-ray with water-soluble contrast. The questionnaires showed a 76.5% rate of satisfaction (13 patients), and the recurrence rate demonstrated by radiology was 29.4% (five patients). There were no major mesh-related complications. Conclusion: The best operative approach for large hiatal hernias remains far from standardised: There is a lack of evidence on the use of a mesh for this kind of surgery as well as substantial controversy over the definition of what a giant hiatal hernia is. Nevertheless, the results from this study and the main studies in the literature seem to be encouraging in improving giant hiatal hernia repair outcomes.

SARS-CoV-2 Exposed Mesenchymal Stromal Cell from Congenital Pulmonary Airway Malformations: Transcriptomic Analysis and the Expression of Immunomodulatory Genes.

The inflammatory response plays a central role in the complications of congenital pulmonary airway malformations (CPAM) and severe coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the transcriptional changes induced by SARS-CoV-2 exposure in pediatric MSCs derived from pediatric lung (MSCs-lung) and CPAM tissues (MSCs-CPAM) in order to elucidate potential pathways involved in SARS-CoV-2 infection in a condition of exacerbated inflammatory response. MSCs-lung and MSCs-CPAM do not express angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TRMPSS2). SARS-CoV-2 appears to be unable to replicate in MSCs-CPAM and MSCs-lung. MSCs-lung and MSCs-CPAM maintained the expression of stemness markers MSCs-lung show an inflammatory response (IL6, IL1B, CXCL8, and CXCL10), and the activation of Notch3 non-canonical pathway; this route appears silent in MSCs-CPAM, and cytokine genes expression is reduced. Decreased value of p21 in MSCs-lung suggested no cell cycle block, and cells did not undergo apoptosis. MSCs-lung appears to increase genes associated with immunomodulatory function but could contribute to inflammation, while MSCs-CPAM keeps stable or reduce the immunomodulatory receptors expression, but they also reduce their cytokines expression. These data indicated that, independently from their perilesional or cystic origin, the MSCs populations already present in a patient affected with CPAM are not permissive for SARS-CoV-2 entry, and they will not spread the disease in case of infection. Moreover, these MSCs will not undergo apoptosis when they come in contact with SARS-CoV-2; on the contrary, they maintain their staminality profile.

Laparoscopic adrenalectomy for giant adrenal tumours: Technical considerations and surgical outcome.

BACKGROUND: Giant adrenal tumours are tumours with size ≥6 cm. These are rare cancer associated with malignancy in 25% of cases. PATIENTS AND METHODS: A retrospective review was conducted on the medical records of patients admitted to our high-volume centre of Careggi University Hospital with a giant adrenal tumour and submitted to adrenalectomy between January 2008 and December 2018. The group of patients who underwent to laparoscopic adrenalectomy was compared with a group of patients that was submitted to open adrenalectomy. RESULTS: In the past 10 years, we performed about 245 adrenalectomies for benign and malignant adrenal tumours. Fifty (20.4%) of these were giant tumours. The medium size was 9.9 cm (7-22 cm). The mean age was 57 years (21-81 years). Thirty-four (68%) of these cancers were laparoscopically removed and 16 (32%) with an open approach. The surgical outcomes in these patients were optimal if compared to the group of patients submitted to open approach in terms of good pain control, hospital stay, mean operative time and bloodless. No difference was observed about post-operative complications in the two groups. The follow-up after 30 months for malignant tumours did not show local recurrences. CONCLUSION: Our results pinpoint the advantages of performing a laparoscopic adrenalectomy for giant adrenal tumours. The tumour size is only a predictive parameter of possible malignancy, and the laparoscopic approach is a safe and feasible method in terms of surgical and oncological, only if performed by expert surgeons and in high-volume centres.

Perioperative outcomes of robotic and laparoscopic adrenalectomy: a large international multicenter experience.

BACKGROUND: The aim of the study was to describe the surgical outcomes of a retrospective series of consecutive patients treated with laparoscopic and robotic approach for adrenal masses in two tertiary referral centers. METHODS: We retrospectively gathered data of 477 patients submitted to adrenalectomy performed at two Institutions from March 2008 to February 2018 by six highly experienced surgeons. We excluded from the analysis 43 patients that had an open approach for tumors or for anesthetic contraindications to minimally invasive surgery (MIS). Patients were selected for surgery after a radiologic and an endocrinology work up. Preoperative, perioperative and postoperative data were recorded. RESULTS: Overall, 477 patients were included in the study. The robotic and the laparoscopic group included 110 and 367 patients, respectively. The preoperative characteristics were similar in both groups except for ASA score with a median (IQR) of 3 and 2 in the robotic and in the laparoscopic group, respectively (p = 0.03). Tumor size of adrenal tumors treated robotically (4, IQR 2.6-6 cm) was significantly larger than those treated laparoscopically (3, IQR 2.3-4.1 cm) (p = 0.01). The intraoperative complication rates were similar between robotic and laparoscopic groups (6.3% and 6%, respectively). The postoperative complication rate was 5.4% for robotic group and similarly 3.5% for laparoscopic adrenalectomy strategy. We analyzed the tumor ≥ 6 cm, with 29 patients in the robotic group and 43 in the laparoscopic one, with an overall complication rate of 19.5%. At multivariable analyses tumor size (OR 1.287; CI 1.128-1.468; p < 0.001) was the only independent predictor of overall complication. CONCLUSION: Adrenal tumors can be safely treated either by robotic or laparoscopic strategy. MIS seems to be feasible also in larger adrenal masses (≥ 6 cm). Tumor size represents the only predictive factors for overall complication.

Chevrel technique for ventral incisional hernia. Is it still an effective procedure?

BACKGROUND: Incisional hernia still represents the most frequent late complication of abdominal surgery. After a direct repair, in literature is reported a recurrence rate ranging from 31 to 49%, meanwhile after a prosthetic repair such values were much lower, with a recurrence rate up to 10%. The sites of prosthetic placement in the abdominal wall are premusculo-aponeurotic (onlay, or Chevrel technique), retromuscular-prefascial and preperitoneal (Rives technique, Stoppa technique), whereas intraperitoneal insertion can be done with open or laparoscopic surgery. The aim of this study was to evaluate the immediate and late postoperative results in patients treated with a Chevrel technique for ventral incisional hernia. METHODS: A retrospective review was conducted on the medical records of patients undergoing ventral hernia repair between January 2008 and December 2018 at the Emergency Surgery Unit of the Careggi University Hospital in Florence. RESULTS: Between January 2008 and December 2018 at the Emergency Surgery Unit of the Careggi University Hospital in Florence, 461 patients (245 male, 216 female) with a mean age of 61,52 years were submitted to ventral incisional hernia repair with a Chevrel technique. The mean operatory time was 95.29 min (±50.48) and in 72 patients (15.61%) human fibrin glue was vaporized under the mesh using a spray device. Mean postoperative hospital stay was 5 days and all drain tubes were removed after 7.1 days as mean (±4.3). No intraoperative mortality nor postoperative mortality was reported. In our experience the Chevrel technique for ventral incisional hernia show a recurrence rate (3.2%). Parietal complications observed were seroma in 7.1% of patients, hematoma in 4.7%, localized skin necrosis in 5.2%, surgical site infection in 6.7%, data comparable with the results reported in the other studies. CONCLUSIONS: Most of the objections to the Chevrel procedure focus on the parietal complications and risk of infection. Chevrel procedure cannot be considered an obsolete intervention, in our series, results were very satisfactory in both immediate and late follow-up; moreover this technique is safe and easy to perform.

Germline Mutation in KIF1Bß Gene Associated with Loss of Heterozygosity: Usefulness of Next-Generation Sequencing in the Genetic Screening of Patients with Pheochromocytoma.

The genetic approach of pheochromocytomas and paragangliomas has changed in the last two decades. Nowadays, we know that more than 40% of patients have a germline mutation in one of the susceptibility genes identified to date. Our aim is to underline how genetic diagnosis by next-generation sequencing (NGS) can improve the management of patients affected by pheochromocytomas and paragangliomas in our routine diagnostic screening. We reported a case presentation and next-generation sequencing analysis supported by in silico studies and evaluation of mitochondrial status in KIF1Bß tissue. A 46-year-old male affected by a left secreting pheochromocytoma underwent surgery in 2017. After surgery, the normetanephrine levels decreased very slowly and a suspected abdominal lymph node was detected. We found a novel germline KIF1Bß gene mutation, c.4052C > T, p. Pro1351Leu associated with tumor loss of heterozygosity, and resulted likely-pathogenetic by in silico studies. This mutation was also associated with an increased number of mitochondria through the electron microscopy compared with wild-type tissues as suggestive for mitochondria neoformation compensatory to the mitochondrial autophagic figures observed. Our results underline the usefulness of next-generation sequencing in the presence of multiple tumor predisposition genes and how, at the same time, its use may result challenging for the clinicians. To date, performing the genetic analysis according to the latest Consensus Statement is mandatory in patients affected by PHEO/PGL.

Comparison among different techniques for en-bloc resection of rectal lesions: transanal endoscopic surgery vs. endoscopic submucosal dissection vs. full-thickness resection device with Over-The-Scope Clip® System.

BACKGROUND: The aim of our retrospective study is to compare the efficacy and indications of transanal endoscopic microsurgery (TEM), endoscopic submucosal dissection (ESD), and endoscopic full-thickness resection device (FTRD) with Over-The-Scope Clip (OTSC®) System for en-bloc resection of rectal lesions. METHODS: This study collected 76 cases of rectal neoplasms from a single hospital institution. Primary endpoints were complete en-bloc resection, intraprocedural adverse events, R0 en-bloc resection and an early discharge of the patient. Secondary endpoints included procedure-related adverse events. RESULTS: Mean tumor sizes were statistically significant smaller among patients treated with FTRD rather than TEM and ESD. TEO and FTRD treated patients experienced a higher en-bloc resection rate, with a shorter procedure time and hospital stay. No significant difference concerning the R0 resection was found. TEO and FTRD recorded lower perforation rates as compared to ESD, whereas no difference emerged concerning the bleeding rate and the post-polypectomy syndrome rate. CONCLUSIONS: Our study showed that each technique has specific features, so that each one offers advantages and disadvantages. Nevertheless, all of them ensure high en-bloc resection rates, whereas no difference exists for R0 resection rate. TEO provides the possibility to remove low rectal large lesions as compared to ESD and FTRD.

Obstructive left side colon cancer: time for a tailored operative approach?

BACKGROUND: Colorectal cancer (CRC) obstruction is frequent but doubts remain on the best treatment. The aim of this study is to analyze the different operative approach used for CRC treatment and evaluate the outcomes for the different cases. METHODS: Patients were collected from January 2014 to December 2019 and divided in four groups: two "P" groups, namely the Hartmann's procedure (PH) group and the primary anastomosis (PA) group, and two "S" groups, namely the deviating stoma (SD) group and the self-expanding metallic stent (SS) group. The main endpoints were the quality of life and the oncologic safety. RESULTS: One hundred and eight patients were enrolled. The mean follow-up time was 39 months. The stomas were performed less frequently in SS but lasted more in that group. Only 45% underwent reversal surgery. Cumulative operating time was greater in S versus P groups. The rate of major complications was similar. PA had greater overall survival and disease-free survival rates than PH. CONCLUSIONS: The various options of treatment should have different indications: primary anastomosis in stable patients, Hartmann in critical cases, SEMS for palliative intent and stoma when neo-adjuvant therapy is needed.

The Italian National Registry for minimally invasive pancreatic surgery: an initiative of the Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS).

The value of minimally invasive pancreatic surgery (MIPS) is still uncertain, despite the growing number of publications, including reviews and meta-analyses, and the quick diffusion of these procedures worldwide. The Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS) was created under the auspices of three Scientific Societies: Associazione Italiana Studio Pancreas (AISP), Associazione Italiana Chirurgia Epato-Bilio-Pancreatica (AICEP, former IT-IHPBA), and Società Italiana di Chirurgia Endoscopica (SICE). The main aim of IGoMIPS is to develop and implement a national registry for MIPS. IGoMIPS was founded on February 22, 2019 in Pisa. The IGoMIPS registry became operational in September 2019, following approval by the Ethic Committees of founding Institutions, inscription into the Registry of Patient Registries (RoPR), and a wrap-up meeting held in Bologna during the Annual Congress of the Italian Surgical Society. During this meeting IGoMIPS members approved that the Italian Registry will provide data to the European Registry, while retaining the right to analyze and publish Italian data. An audience survey was also conducted to obtain information on perceived value and current implementation of MIPS in founding Institutions. MIPS is performed in 94.7% of IGoMIPS centers, including pancreaticoduodenectomy in 42.1%. Robotic assistance was employed in 52.6% of Institutions. The annual volume of MIPS was 6-10 cases in 38.9% of the centers, 11-20 cases in 16.7%, 21-30 cases in 22.2%, and > 30 cases in 22.2%. The registry was felt to be extremely important for both safety improvement and educational purposes by 94.5% of the centers.

Colonic splenic flexure carcinoma: is laparoscopic segmental resection a safe enough oncological approach?

BACKGROUND: The surgical approach to the colonic splenic flexure cancer (SFC) is yet to be technically standardized. The aim of this study has been to retrospectively evaluate the oncologic long-term results of our cases comparing our data with other authors' experiences. METHODS: Clinical data of patients with SFC operated on at our institute were retrospectively analyzed. The laparoscopic approach was used in the whole series, with limited resection distally and proximally to splenic flexure and the origin ligation of left colic artery and left branch of middle colic artery. Data on the oncological long-term safety were compared to our laparoscopic series of extended right colectomy for proximal two-third transverse colon cancer and high anterior resections for sigmoid-high rectal cancer and to the main evidences in the literature, found after a comprehensive review. RESULTS: From March 2008 to May 2018, we completed 53 laparoscopic splenic flexure resections (26 female and 27 male, age 71.5 ± 15.4 years). The conversion rate was 3.8%. Most of the cases were stage II (pT3 73.5%, the mean number of lymph nodes harvested was 19.1, with positivity for malignancy in 45.3%). During the FU (43.5 months), 2 patients dropped out. Out of the 51 residual cases, 37 were alive (72.5%) and 14 are deceased (27.5%). DISCUSSION: Compared to the literature, our survival rate does not show significant differences. The other oncological outcomes seem to be comparable with the data evaluated. CONCLUSIONS: More extended resections seem not to confer an increase of the overall survival rate.

Correction to: SICE national survey: current state on the adoption of laparoscopic approach to the treatment of colorectal disease in Italy.

The surname and given name of author Riccardo Brachet Contul was incorrectly published.

Application of minimally invasive pancreatic surgery: an Italian survey.

The value of minimally invasive pancreatic surgery (MIPS) is still debated. To assess the diffusion of MIPS in Italy and identify the barriers preventing wider implementation, a questionnaire was developed under the auspices of three Scientific Societies (AISP, It-IHPBA, SICE) and was sent to the largest possible number of Italian surgeons also using the mailing list of the two main Italian Surgical Societies (SIC and ACOI). The questionnaire consisted of 25 questions assessing: centre characteristics, facilities and technologies, type of MIPS performed, surgical techniques employed and opinions on the present and future value of MIPS. Only one reply per unit was considered. Fifty-five units answered the questionnaire. While 54 units (98.2%) declared to perform MIPS, the majority of responders were not dedicated to pancreatic surgery. Twenty-five units (45.5%) performed < 20 pancreatic resections/year and 39 (70.9%) < 10 MIPS per year. Forty-nine units (89.1%) performed at least one minimally invasive (MI) distal pancreatectomy (DP), and 10 (18.2%) at least one MI pancreatoduodenectomy (PD). Robotic assistance was used in 18 units (31.7%) (14 DP, 7 PD). The major constraints limiting the diffusion of MIPS were the intrinsic difficulty of the technique and the lack of specific training. The overall value of MIPS was highly rated. Our survey illustrates the current diffusion of MIPS in Italy and underlines the great interest for this approach. Further diffusion of MIPS requires the implementation of standardized protocols of training. Creation of a prospective National Registry should also be considered.

SICE national survey: current state on the adoption of laparoscopic approach to the treatment of colorectal disease in Italy.

The real diffusion of laparoscopy for the treatment of colorectal diseases in Italy is largely unknown. The main purpose of the present study is to investigate among surgeons dedicated to minimally invasive surgery, the volume of laparoscopic colorectal procedures, the type of operation performed in comparison to traditional approach, the indication for surgery (benign and malignant) and to evaluate the different types of technologies used. A structured questionnaire was developed in collaboration with an international market research institute and the survey was published online; invitation to participate to the survey was issued among the members of the Italian Society of Endoscopic Surgery (SICE). 211 surgeons working in 57 surgical departments in Italy fulfilled and answered the online survey. A total of 6357 colorectal procedures were recorded during the year 2015 of which 4104 (64.1%) were performed using a minimally invasive approach. Colon and rectal cancer were the most common indications for laparoscopic approach (83.1%). Left colectomy was the operation most commonly performed (41.8%), while rectal resection accounted for 23.5% of the cases. Overall conversion rate was 5.9% (242/4104). Full HD standard technology was available and routinely used in all the responders' centers. The proportion of colorectal resections that are carried out laparoscopically in dedicated centers has now reached valuable levels with a low conversion rate.

Bedside diagnostic laparoscopy for critically ill patients in the Intensive Care Unit: Retrospective study and review of literature.

BACKGROUND: Bedside diagnostic laparoscopy could be helpful in extremely critically ill patients. The aim of this retrospective study is to evaluate the safety and diagnostic accuracy of bedside diagnostic laparoscopy in the identification of intra-abdominal pathology in critically ill patients and to compare its accuracy and outcomes with the ones of laparotomy. PATIENTS AND METHODS: A retrospective review was conducted on the medical records of patients admitted to the Intensive Care Unit (ICU) of Careggi University Hospital and submitted to bedside diagnostic laparoscopy between January 2006 and May 2017. This group of patients was compared with a group of patients that were admitted to the ICU and submitted directly to explorative laparotomy for suspected intra-abdominal pathologies. RESULTS: One hundred and twenty-nine patients (M/F = 81/48, mean age = 71.64 years) underwent bedside diagnostic laparoscopy in ICU. 154 patients instead were submitted directly to explorative laparotomy in operatory room (mean age 75.70 years, M/F = 94/60). Among the 129 patients submitted to bedside laparoscopy, 53.49% were positive for intra-abdominal pathologies whereas 46.51% were negative, while among the 154 patients submitted directly to laparotomy, 76.62% were positive for intra-abdominal pathologies whereas 23.38% were negative. In 55.03% of all patients submitted to bedside laparoscopy, a non-therapeutic laparotomy was avoided, while the 33.76% of patients submitted directly to laparotomy had a non-therapeutic laparotomy that could be avoidable. CONCLUSIONS: Our results pinpoint the advantages of performing bedside diagnostic laparoscopy in the ICU setting, which can be considered an option every time there is the suspicion of an intra-abdominal pathology.

A minimally invasive approach with a 3d imaging system for the treatment of esophageal perforation due to Boerhaave syndrome.

Boerhaave's syndrome is a rare life-threatening condition that requires urgent surgical management. There are various methods of managing it, with the main principles of limiting sepsis, draining the area and maintaining nutrition. Although the gold standard is open thoracotomy and/or laparotomy, mostly in patients with sepsis, we present a case of a 53-year-old man treated with a combination of laparoscopic suture (3D imaging system) of the oesophageal perforation site, decompressive percutaneous endoscopic gastrostomy and feeding jejunostomy. We conclude that this approach is a safe and a viable option in the management of Boerhaave syndrome in a septic patient presenting early. KEY WORDS: Boerhaave's syndrome, Laparoscopy, Minimally invasive surgery, Oesophageal Rupture, Surgery, 3D-laparoscopy.

Why laparoscopists may opt for three-dimensional view: a summary of the full HTA report on 3D versus 2D laparoscopy by S.I.C.E. (Società Italiana di Chirurgia Endoscopica e Nuove Tecnologie).

BACKGROUND: Three-dimensional view in laparoscopic general, gynaecologic and urologic surgery is an efficient, safe and sustainable innovation. The present paper is an extract taken from a full health technology assessment report on three-dimensional vision technology compared with standard two-dimensional laparoscopic systems. METHODS: A health technology assessment approach was implemented in order to investigate all the economic, social, ethical and organisational implications related to the adoption of the innovative three-dimensional view. With the support of a multi-disciplinary team, composed of eight experts working in Italian hospitals and Universities, qualitative and quantitative data were collected, by means of literature evidence, validated questionnaire and self-reported interviews, applying a final MCDA quantitative approach, and considering the dimensions resulting from the EUnetHTA Core Model. RESULTS: From systematic search of literature, we retrieved the following studies: 9 on general surgery, 35 on gynaecology and urology, both concerning clinical setting. Considering simulated setting we included: 8 studies regarding pitfalls and drawbacks, 44 on teaching, 12 on surgeons' confidence and comfort and 34 on surgeons' performances. Three-dimensional laparoscopy was shown to have advantages for both the patients and the surgeons, and is confirmed to be a safe, efficacious and sustainable vision technology. CONCLUSIONS: The objective of the present paper, under the patronage of Italian Society of Endoscopic Surgery, was achieved in that there has now been produced a scientific report, based on a HTA approach, that may be placed in the hands of surgeons and used to support the decision-making process of the health providers.

Essential role of hippocampal noradrenaline in the regulation of spatial working memory and TDP-43 tissue pathology.

Extensive loss of noradrenaline-containing neurons and fibers is a nearly invariant feature of Alzheimer's Disease (AD). However, the exact noradrenergic contribution to cognitive and histopathological changes in AD is still unclear. Here, this issue was addressed following selective lesioning and intrahippocampal implantation of embryonic noradrenergic progenitors in developing rats. Starting from about 3 months and up to 12 months post-surgery, animals underwent behavioral tests to evaluate sensory-motor, as well as spatial learning and memory, followed by post-mortem morphometric analyses. At 9 months, Control, Lesioned and Lesion + Transplant animals exhibited equally efficient sensory-motor and reference memory performance. Interestingly, working memory abilities were seen severely impaired in Lesion-only rats and fully recovered in Transplanted rats, and appeared partly lost again 2 months after ablation of the implanted neuroblasts. Morphological analyses confirmed the almost total lesion-induced noradrenergic neuronal and terminal fiber loss, the near-normal reinnervation of the hippocampus promoted by the transplants, and its complete removal by the second lesion. Notably, the noradrenergic-rich transplants normalized also the nuclear expression of the transactive response DNA-binding protein 43 (TDP-43) in various hippocampal subregions, whose cytoplasmic (i.e., pathological) occurrence appeared dramatically increased as a result of the lesions. Thus, integrity of ascending noradrenergic inputs to the hippocampus may be required for the regulation of specific aspects of learning and memory and to prevent TDP-43 tissue pathology.