Flat patch mesh versus three-dimensional mesh (plug) for open umbilical or epigastric hernia repair. A retrospective study.

INTRODUCTION: Hernia repair using prosthetic mesh materials has become the preferred method of repair, as the recurrence rates are much lower than with conventional repair techniques. The aim of this retrospective study was to compare open small- and medium-sized abdominal wall hernia repair with flat patch mesh versus three-dimensional mesh (plug) in terms of recurrence and complication rates. METHODS: The medical records of 300 patients who underwent abdominal wall hernia repair using flat patch mesh versus three-dimensional mesh between January 2010 to December 2015 were reviewed. All patients were followed up after 1 month, 3 month and 1 year. The rate of recurrence, and short-term postoperative complications such as incidence of Surgical Site Infections (SSIs), hematoma and seroma were evaluated. RESULTS: Short-term follow-up data were available for all patients. The first group was composed of 150 patients that were treated with a flat polypropylene mesh (68% presened umbilical hernia and 32% presented epigastric hernia). The second group was composed of 150 patients that were treated with a three-dimensional polypropylene mesh (60% presented umbilical hernia and 40% presented epigastric hernia). The majority of postoperative (1-month) complications were wound related, representing superficial SSI or seroma. Our results showed a statistically significant reduction of SSIs [3 (2%) vs 13 (8.6%); p = 0.038] and seroma [2 (1.3%) vs 12 (8%); p = 0.030] in the group of patients treated with plugs compared to flat-mesh group. There was no statistically significant difference in hernia recurrences. DISCUSSION: Usage three-dimensional mesh for open small- and medium-sized umbilical or epigastric hernia repair represents a feasible and safe technique that significantly lowers the incidence of complications such as SSIs and seroma. Furthermore, compared to flat patch mesh, plugs displayed non-inferiority in terms recurrence. Further, well-designed clinical trials could be realized to investigate possible applications of plugs in treatment of small- and medium-sized umbilical and epigastric hernias. KEY WORDS: Mesh, Umbilical Hernia.

Acute Colonic Diverticulitis: CT Findings, Classifications, and a Proposal of a Structured Reporting Template.

Acute colonic diverticulitis (ACD) is the most common complication of diverticular disease and represents an abdominal emergency. It includes a variety of conditions, extending from localized diverticular inflammation to fecal peritonitis, hence the importance of an accurate diagnosis. Contrast-enhanced computed tomography (CE-CT) plays a pivotal role in the diagnosis due to its high sensitivity, specificity, accuracy, and interobserver agreement. In fact, CE-CT allows alternative diagnoses to be excluded, the inflamed diverticulum to be localized, and complications to be identified. Imaging findings have been reviewed, dividing them into bowel and extra-intestinal wall findings. Moreover, CE-CT allows staging of the disease; the most used classifications of ACD severity are Hinchey's modified and WSES classifications. Differential diagnoses include colon carcinoma, epiploic appendagitis, ischemic colitis, appendicitis, infectious enterocolitis, and inflammatory bowel disease. We propose a structured reporting template to standardize the terminology and improve communication between specialists involved in patient care.

Postcholecystectomy syndrome: biliary-related complications.

In Italy, about 100,000 cholecystectomies are carried out annually, the majority of them laparoscopically. Complications following cholecystectomy are common and increase morbidity and cost burden. Biliary damage (0.08-0.5%), bile leak (0.42-1.1%), retained common bile duct stones (0.8-5.7%), postcholecystectomy syndrome (10-15%), and postcholecystectomy diarrhea (5-12%) are a few of the most often occurring laparoscopic cholecystectomy consequences. In many instances, endoscopy can offer conclusive management and is crucial for the identification and treatment of biliary problems. Regarding the ideal treatment strategy for biliary problems, there is no universal agreement. A skilled interdisciplinary team should therefore approach biliary problems. The surgeon must be knowledgeable on how to handle these issues.

Spontaneous Abdominal Wall Hematoma Treated with Percutaneous Transarterial Embolization: Diagnostic Findings, Procedural Outcome, and Efficacy-A Multicenter Study.

Endovascular management of abdominal wall hematomas (AWHs) is now the primary treatment option in hemodynamically stable patients, and it is often preferred to surgical interventions. The purpose of this multicentric study was to assess the safety, technical, and clinical success of percutaneous transarterial embolization (PTAE) of spontaneous AWHs to evaluate the efficacy of blind or empiric embolization compared to targeted embolization and to compare the outcome of the endovascular treatment approach in patients affected by COVID-19 and non-COVID-19 patients. We retrospectively enrolled 112 patients with spontaneous AWHs who underwent PTAE, focusing on signs of bleeding at pre-procedural CTA and DSA. Patients were separated into two groups depending on whether a blind or targeted embolization approach was used. We also divided patients into COVID-19 and non-COVID-19 groups. The mean age of the study population was 68.6 ± 15.8 years. CTA and DSA revealed signs of active bleeding in 99 and 88 patients, respectively. In 21 patients, blind embolization was performed. The overall technical success rate was 99%. Clinical success was obtained in 96 patients (86%), while 16 (14%) re-bled within 96 h. One patient reported a major peri-procedural complication. The comparison between blind and targeted embolization approaches showed no statistically significant differences in the characteristics of groups and technical and clinical success rates. No significant differences were found in the procedural outcome between COVID-19 and non-COVID-19 groups. Our study confirmed that PTAE is effective for treating spontaneous AWHs, even in COVID-19 patients. It suggests that the efficacy and safety of blind embolization are comparable to targeted embolization.

Laparoscopic prosthetic repair of laparocele. A comparison of techniques and a review of the literature.

Incisional hernia, or post-laparotomy hernia, is a defect in the abdominal wall, which can produce mechanical and systemic changes in both respiratory and splanchnic circulation. This pathology has an important impact on Health and Society, with an incidence ranging from 2% to 20%, stimulating the improvement or development of surgical techniques, to reduce discomfort and complications, e.g. imprisonment, strangulation and recurrences. The growing availability of prostheses, with greater resistance and lower risk of visceral adhesions, has improved the result and reduced relapses. Over the past 15 years, further improvements have been achieved, thanks to the greater use of laparoscopy, decreasing relapses and complications and improving patient comfort. In this regard, the Ventralight Echo PS prosthesis, introduced for the first time in 2013 and routinely used by our team, have shown encouraging results. In this work, a retrospective study aims to compare in different aspects two groups of patients, suffering from defects on the abdominal wall and undergoing reconstructive surgery with laparoscopic technique. It has been used simple prostheses for the first, whereas the Echo PS~ Positioning System with Ventralight - ST Mesh or Composix - L/P Mesh for the second group. In our experience, we conclude that the use of prostheses, such as the Ventralight Echo PS, in the treatment of incisional hernias, regardless of the location of the defect, is a valid and safe alternative to the use of non-self-expandable prostheses. KEY WORDS: Incisional Hernia, Hernia Repair, Laparoscopic Technique.

Fixation free laparoscopic obliteration of inguinal hernia defects with the 3D dynamic responsive scaffold ProFlor.

Laparoscopic TAPP/TEP approaches are well-established options for the cure of inguinal hernias. As in the open approach, mesh fixation and poor-quality biologic response represent controversial questions and are a source of concerns. Furthermore, hernia defect patency represents another problem which seems not well acknowledged among surgeons. These problems are considered the cause of frequent intra and postoperative complications. To overcome these concerns, recently a different concept of cure has emerged. Based on a newly developed dynamic responsive 3D scaffold named ProFlor, a permanent hernia defect obliteration has been finalized. Following its inherent centrifugal expansion due to its dynamic responsivity, this hernia device is positioned fixation free within the defect and induces a probiotic biological response allowing for the re-establishment of the degenerated inguinal barrier. A laparoscopic approach with the 3D scaffold has been tested on 71 patients to demonstrate its effectiveness in reducing intra and postoperative complications. The operated patients presented with bilateral and/or recurrent inguinal hernia. Overall, 122 hernia defects were obliterated with 119 dynamic responsive scaffolds. The procedures were carried out from January 2018 to January 2022 with a defined protocol and detailed procedural steps. The laparoscopic technique with the 3D hernia scaffold allowed for fixation free placement, permanent defect obliteration and dynamically induced regenerative effects. The technique proved effective in reducing intra and postoperative complications. In particular, early postoperative pain and discomfort significantly decreased. No chronic pain and no recurrences were reported during follow up. The results achieved with the described laparoscopic technique seem to embody an innovative concept for inguinal hernia repair. Fixation free, dynamic responsive, permanent defect obliteration, histologically proven regenerative effects are the distinctive features of this 3D scaffold. It seems to embody a more physiological and pathogenetically coherent concept of cure, thus improving treatment results of this widespread disease.

Heme Oxygenase-1 Overexpression Promotes Uveal Melanoma Progression and Is Associated with Poor Clinical Outcomes.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. To date, the main strategies to counteract its progression consist of focal radiation on the tumor site and ocular enucleation. Furthermore, many UM patients develop liver metastasis within 10 years following diagnosis, eventually resulting in a poorer prognosis for those patients. Dissecting the molecular mechanism involved in UM progression may lead to identify novel prognostic markers with significative clinical applications. The aim of the present study was to evaluate the role of Heme Oxygenase 1 (HO-1) in regulating UM progression. UM cell lines (92.1) were treated with Hemin (CONC e time), a strong inducer of HO-1, and VP13/47, a selective inhibitor of its enzymatic activity. Interestingly, our results showed an enhanced 92.1 cellular proliferation and wound healing ability following an HO-1 increase, overall unveiling the role played by this protein in tumor progression. Similar results were obtained following treatment with two different CO releasing molecules (CORM-3 and CORM-A1). These results were further confirmed in a clinical setting using our UM cohort. Our results demonstrated an increased median HO-1 expression in metastasizing UM when compared to nonmetastasizing patients. Overall, our results showed that HO-1 derived CO plays a major role in UM progression and HO-1 protein expression may serve as a potential prognostic and therapeutical factor in UM patients.

Neuropathic inguinal pain: neurectomy associated with open prosthetic hernioplasty for the prevention of post-operative pain.

INTRODUCTION: Inguinal hernia is one of the most common surgical diseases in the world. Today, this disease is treated by surgical technique only. Among the late complications after surgery, the most frequent is the appearance of chronic post-operative pain after surgical treatment. The incidence of this complication is about 28% of patients undergoing hernioplasty suffering a varying degree of chronic pain, severe enough to interfere with normal daily activities. OBJECTIVES: In this study we evaluated the onset of the neuropathic pain as a complication of inguinal prosthetic hernioplasty surgery. METHODS: This is a prospective observational study run between September 2019 and August 2020. All patients, during the first visit conducted in an outpatient clinic, were recruited in a specific database. Subsequently, surgery was planned in election on one day surgery, patients were administered a specific questionnaire aiming at the identification of any pain and its exact location. The Inguinal Pain Questionnarie (IPQ) was used. During the surgical procedure the selective neurectomy of the 3 nerves has been documented, the entire population of patients has undergone a standardized surgical treatment. At the end of surgery, a follow-up was carried out administering two questionnaires (IPQ Short Form Modified and the IPQ Short Form Paresthesia Modified) concerning the possible chronic post-operative pain and the eventual paresthesia. The questionnaires were administered at first, third and sixth month from the date of surgery. RESULTS: A total of 266 patients were screened from September 2019 to October 2020. Fiftyseven male patients were included in the study with a confirmed diagnosis of primary inguinal hernia. Clinical data, baseline characteristics and outcomes are described. Preoperatively, at the time of IPQ administration, 1.8% of patients had a pain score of 6, 10% of 5, 21% of 4, 31% of 3, 28% with a score of 2 and 7% of patients with a score of 1. In all cases the ileoinguinals and ileohypogastric nerves found were subjected to neurectomy, in 19% of cases also the genitofemoral nerve was subjected to surgical resection. At the end of the follow-up, the first questionnaire (IPQ Short Form Modified) results did show that, among the total of patients who had an open prosthetic hernioplasty with extensive nerves resection in the inguinal canal, 84% of them indicated a pain score equal to 0 (no pain) after 6 months of treatment and only 1.7% indicated a score equal to 4. Analyzing the second questionnaire on paresthesia (IPQ Short Form Paresthesia Modified), 79% of patients indicated a score equal to 0 by describing no paresthesia and no changes in sensitivity; 15.7% score 1; 3.5% score 2; 1.7% score 3. CONCLUSIONS: Based on our experience and according to the modern literature, we would advise prophylactic total neurectomy of the inguinal canal nerves during prosthetic inguinal hernioplasty. KEY WORDS: Abdominal Surgery, Chronic pain, Inguinal hernioplasty, Neurectomy, Paresthesia.

Relapse of immune-mediated thrombotic thrombocytopenic purpura following mRNA COVID-19 vaccination: a prospective cohort study.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease. Vaccination has been reported to be a trigger of onset and relapse of autoimmune diseases. We evaluated after mRNA COVID-19 vaccination 32 adult patients previously diagnosed with iTTP by means of weekly monitoring of complete blood count and ADAMTS13 testing. Thirty of 32 patients received at least one dose of Pfizer-BioNTech, the remaining two received Moderna. A total of five patients, all vaccinated with Pfizer-BioNTech, had a biochemical relapse at a median post-vaccination time of 15 days following the second or third vaccine dose, presenting without measurable ADAMTS13 activity and a median anti- ADAMTS13 autoantibody value of 34 U/mL. Four of five cases had concomitant clinical relapse and were treated with corticosteroids alone or daily sessions of plasma exchange and caplacizumab, while one patient was closely monitored with ADAMTS13 with no onset of anemia and thrombocytopenia. Although the benefits of vaccination exceed its potential risks, clinicians should be aware that iTTP relapse might follow COVID-19 vaccination. Therefore, laboratory and clinical monitoring of iTTP patients should be done in the first post-vaccination month, in order to promptly diagnose and treat any relapse.

Intracorporeal versus extracorporeal anastomosis in laparoscopic right hemicolectomy A retrospective study and review of literature.

INTRODUCTION: Several studies have suggested that intracorporeal anastomosis (IC) has advantages over extracorporeal anastomosis (EC) in laparoscopic right colectomy. Scientific evidence is lacking. The aim is to define the possible benefits of intracorporeal anastomosis compared with extracorporeal anastomosis in elective surgery. METHODS: A single-centre retrospective study was performed. The primary endpoint was duration of hospital stay. Secondary outcomes included operative time, bowel recovery, conversion to open surgery and postoperative complications. RESULTS: In the IC group mean hospital stay was 7,100 days, mean age was 70,5 years, mean operating time was 233 minutes and mean time to restoration of digestive function was 3,950 days. In the EC group mean hospital stay was 9,455 days, mean age was 72,55 years, mean operating time was 183 minutes, mean time to restoration of digestive function was 5,364 days. CONCLUSION: This study shows many clinical outcomes advantages for the intracorporeal anastomosis technique in laparoscopic right colectomy. IA was associated with earlier bowel recovery, decreased hospital stay and fewer complications; operative time was shorter in EA KEY WORDS: Anastomosis, Colon cancer, Laparoscopy, Hemicolectomy, Retrospective.

Symptomatic Parapelvic Cysts in Children: Anatomical and Histological Features, Diagnostic Pitfalls and Urological Management.

BACKGROUND: Symptomatic parapelvic cysts (PPC) are rare entities. Our objective is to highlight specific features of PPC to avoid a misdiagnosis of UPJ obstruction. METHODS: We retrospectively reviewed the records of children managed between 2012-2017. RESULTS: All four patients (18 months-8 years) presented with acute renal colic with a large intra-sinusal liquid mass (42-85 mm) on ultrasound, evoking a diagnosis of UPJ obstruction. On preoperative renal scintigraphy (n = 3) there was no dilatation of the renal pelvis and ipsilateral differential function was impaired in 2. Diagnosis of PPC was suspected preoperatively in three children (CT scan (n = 1); MRI (n = 2)) and made peri-operatively (n = 1). Preoperative retrograde pyelography (n = 3) and a further intraoperative retrograde pyelography with methylene blue (n = 1) did not identify communication with the cyst. No renal pelvis was identified in two patients. De-roofing of the cyst was curative in all cases at 5 years mean follow-up (no leakage, cyst recurrence or loss of function) and all 4 patients became asymptomatic after surgery. Histology demonstrated a single flat epithelial cell layer. Renal function normalized in one patient but remained impaired in the other. CONCLUSION: In case of symptoms of UPJ obstruction with a medial renal liquid mass on ultrasound, PPC should be considered when no dilatated pelvis on renal scan is identified. In such cases, a complementary imaging work-up is mandatory prior to surgery.

Identification of the most common BRCA alterations through analysis of germline mutation databases: Is droplet digital PCR an additional strategy for the assessment of such alterations in breast and ovarian cancer families?

Breast and ovarian cancer represent two of the most common tumor types in females worldwide. Over the years, several non­modifiable and modifiable risk factors have been associated with the onset and progression of these tumors, including age, reproductive factors, ethnicity, socioeconomic status and lifestyle factors, as well as family history and genetic factors. Of note, BRCA1 and BRCA2 are two tumor suppressor genes with a key role in DNA repair processes, whose mutations may induce genomic instability and increase the risk of cancer development. Specifically, females with a family history of breast or ovarian cancer harboring BRCA1/2 germline mutations have a 60­70% increased risk of developing breast cancer and a 15­40% increased risk for ovarian cancer. Different databases have collected the most frequent germline mutations affecting BRCA1/2. Through the analysis of such databases, it is possible to identify frequent hotspot mutations that may be analyzed with next­generation sequencing (NGS) and novel innovative strategies. In this context, NGS remains the gold standard method for the assessment of BRCA1/2 mutations, while novel techniques, including droplet digital PCR (ddPCR), may improve the sensitivity to identify such mutations in the hereditary forms of breast and ovarian cancer. On these bases, the present study aimed to provide an update of the current knowledge on the frequency of BRCA1/2 mutations and cancer susceptibility, focusing on the diagnostic potential of the most recent methods, such as ddPCR.

Grynfeltt-Lesshaft hernia Personal experience of nine cases and a review of the literature.

Grynfeltt's lumbar hernia, from the author who first described it in 1866, is the rarest among all hernias of the abdominal wall and it represents, according to the most recent literature, only 2% of all hernias. Of these, about 20% are congenital, secondary mainly to defects of embryonic development, while 80% are acquired defects. Surgeries, penetrating wounds, and infections are risk factors for the development of secondary and therefore iatrogenic lumbar hernias. In the literature, there is a predominance of the left Grynfeltt hernia while a bilateral presentation is exceptional. Our recent observation of a massive Grynfeltt hernia brought us to perform a revision of the literature and of our case studies. Based on our personal experience, with the most recent literature, we believe that in the case of Grynfeltt's lumbar hernias, the laparotomy approach with the use of prosthetic materials is the most appropriate, thus making the procedure fast, easy, and safe, compared to the treatment of all other wall defects that often require a laparoscopic approach. To confirm this, it is perceived that the open technique is currently more widespread; in fact, a small lumbotomy is easy to perform, fast, and can also be performed under loco-regional or epidural anaesthesia. KEY WORDS: Lumbar hernioplasty, Grynfeltt hernia, Hernia repair.

Status of Alternative Approaches for Thyroidectomy: Is There Any Evidence to Substitute in Place of Conventional Surgery?

Over the past 20 years, various alternative cervical minimally invasive (partly endoscopically assisted) and extracervical endoscopic (partly robot-assisted) approaches have been developed. All of these alternative access methods aim at optimizing the cosmetic results. In principle, the indication for the use of alternative access procedures does not differ from that for conventional surgery. Nonetheless, appropriate experience in traditional thyroid surgery and suitable patient selection, taking into account thyroid volumes and the underlying pathology, are important prerequisites. General contraindications for an alternative approach are large goiter with symptoms of compression, advanced thyroid carcinoma, recurrent interventions or previous radiotherapy in the operating area. The alternative surgical approaches to the thyroid can be divided into cervical minimally invasive, extracervical endoscopic (robot-assisted) and transoral procedures. This article gives an overview of the clinically used alternative approaches in thyroid surgery. The desire for an optimal cosmetic result should not be prioritized over patient safety. Only a few alternative procedures (minimally invasive video-assisted thyroidectomy, transaxillary robot-assisted thyroidectomy) can currently be viewed as a useful addition to conventional thyroid surgery, even when in responsible, experienced hands for a selected group of patients.

Lymph Node Dissection Morbidity in Thyroid Cancer: An Integrative Review.

Cervical lymphadenectomy is a common procedure for thyroid cancer. Some of the complications are congruent with the complications of thyroid surgery, in particular recurrent laryngeal nerve paresis and hypoparathyroidism as well as bleeding and wound infection. Specific complications of lateral cervical lymph node dissection are injuries to the accessory, phrenic and hypoglossal nerves, and the cervical plexus trunk and injuries, the salivary glands, and the lymphatic system, especially the ductus thoracicus. Most of these complications are very rare with an incidence of <1%. Profound anatomical knowledge and a careful dissection technique make a decisive contribution to minimizing complications.

Dermatome Mapping Test in the analysis of anatomo-clinical correlations after inguinal hernia repair.

BACKGROUND: Nerve identification is recommended in inguinal hernia repair to reduce or avoid postoperative pain. The aim of this prospective observational study was to identify nerve prevalence and find a correlation between neuroanatomy and chronic neuropathic postoperative inguinal pain (CPIP) after 6 months. MATERIAL: A total of 115 patients, who underwent inguinal hernia mesh repair (Lichtenstein tension-free mesh repair) between July 2018 and January 2019, were included in this prospective observational study. The mean age and BMI respectively resulted 64 years and 25.8 with minimal inverse distribution of BMI with respect to age. Most of the hernias were direct (59.1%) and of medium dimension (47.8%). Furthermore, these patients were undergoing Dermatome Mapping Test in preoperatively and postoperatively 6 months evaluation. RESULTS: Identification rates of the iliohypogastric (IH), ilioinguinal (II) and genitofemoral (GF) nerves were 72.2%, 82.6% and 48.7% respectively. In the analysis of nerve prevalence according to BMI, the IH was statistically significant higher in patients with BMI < 25 than BMI ≥ 25 P (< 0.05). After inguinal hernia mesh repair, 8 patients (6.9%) had chronic postoperative neuropathic inguinal pain after 6 months. The CPIP prevailed at II/GF dermatome. The relation between the identification/neurectomy of the II nerve and chronic postoperative inguinal pain after 6 months was not significant (P = 0.542). CONCLUSION: The anatomy of inguinal nerve is very heterogeneous and for this reason an accurate knowledge of these variations is needed during the open mesh repair of inguinal hernias. The new results of our analysis is the statistically significant higher IH nerve prevalence in patients with BMI < 25; probably the identification of inguinal nerve is more complex in obese patients. In the chronic postoperative inguinal pain, the II nerve may have a predominant role in determining postoperative long-term symptoms. Dermatome Mapping Test in an easy and safe method for preoperative and postoperative 6 months evaluation of groin pain. The most important evidence of our analysis is that the prevalence of chronic pain is higher when the nerves were not identified.

Uveal Melanoma Cells Elicit Retinal Pericyte Phenotypical and Biochemical Changes in an in Vitro Model of Coculture.

Vascular pericytes are an important cellular component in the tumor microenvironment, however, their role in supporting cancer invasion is poorly understood. We hypothesized that PDGF-BB could be involved in the transition of human retinal pericytes (HRPC) in cancer-activated fibroblasts (CAF), induced by the 92.1 uveal melanoma (UM) cell line. In our model system, HRPC were conditioned by co-culturing with 92.1UM for 6 days (cHRPC), in the presence or absence of imatinib, to block PDGF receptor-ß (PDGFRß). The effects of the treatments were tested by wound healing assay, proliferation assay, RT-PCR, high-content screening, Western blot analysis, and invasion assay. Results showed profound changes in cHRPC shape, with increased proliferation and motility, reduction of NG2 and increase of TGF-ß1, α-SMA, vimentin, and FSP-1 protein levels, modulation of PDGF isoform mRNA levels, phospho-PDGFRß, and PDGFRß, as well as phospho-STAT3 increases. A reduction of IL-1ß and IFNγ and an increase in TNFα, IL10, and TGF-ß1, CXCL11, CCL18, and VEGF mRNA in cHRPC were found. Imatinib was effective in preventing all the 92.1UM-induced changes. Moreover, cHRPC elicited a significant increase of 92.1UM cell invasion and active MMP9 protein levels. Our data suggest that retinal microvascular pericytes could promote 92.1UM growth through the acquisition of the CAF phenotype.

Anti-angiogenic effect of quercetin and its 8-methyl pentamethyl ether derivative in human microvascular endothelial cells.

Angiogenesis is involved in many pathological states such as progression of tumours, retinopathy of prematurity and diabetic retinopathy. The latter is a more complex diabetic complication in which neurodegeneration plays a significant role and a leading cause of blindness. The vascular endothelial growth factor (VEGF) is a powerful pro-angiogenic factor that acts through three tyrosine kinase receptors (VEGFR-1, VEGFR-2 and VEGFR-3). In this work we studied the anti-angiogenic effect of quercetin (Q) and some of its derivates in human microvascular endothelial cells, as a blood retinal barrier model, after stimulation with VEGF-A. We found that a permethylated form of Q, namely 8MQPM, more than the simple Q, is a potent inhibitor of angiogenesis both in vitro and ex vivo. Our results showed that these compounds inhibited cell viability and migration and disrupted the formation of microvessels in rabbit aortic ring. The addition of Q and more significantly 8MQPM caused recoveries or completely re-establish the transendothelial electrical resistance (TEER) to the control values and suppressed the activation of VEGFR2 downstream signalling molecules such as AKT, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. Taken together, these data suggest that 8MQPM might have an important role in the contrast of angiogenesis-related diseases.

Tumor necrosis factor-related apoptosis-inducing ligand reduces the expression of the neuroprotective Na+ /Ca2+ exchanger isoform NCX3 in human neuroblastoma SH-SY5Y cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine belonging to the TNF superfamily, is regarded as a mediator of neurotoxicity. The constitutively expressed ion exchanger Na+ /Ca2+ exchanger isoform-3 (NCX3) has been shown to protect neurons from injury. Its expression is induced by nerve growth factor (NGF) through activation of its tyrosine kinase receptor trkA. The latter, in turn, activates downstream kinases, such as extracellular signal-regulated kinase (ERK) and the survival-related kinase protein kinase B (AKT). Here, we verified whether TRAIL could influence the expression of NCX3 via modulation of the NGF/trkA system. Differentiated human neuroblastoma SH-SY5Y cells were incubated with TRAIL and, subsequently, the expression of the NCX3 protein was studied at different times by means of western blot analysis. Then, the expression of the phosphorylated forms of either trkA, ERK or AKT was analyzed at identical intervals. Western blot analysis revealed that the expression of NCX3 protein decreased in a time-dependent fashion in SH-SY5Y cells treated with TRAIL, to reach its minimum at 48 h. On the other hand, p-trkA, p-ERK, and p-AKT expression was increased in cells treated with TRAIL after 6 and 16 h; then it declined to nearly undetectable levels after 48 h. Results indicate that the increase in TRAIL expression occurring during neuronal damage may be responsible of NCX3 down-regulation and weakens its neuroprotective effects. The TRAIL system could thus represent a potential target for treatment of neuronal damage characterized by NCX3 function impairment.