Over-the-scope clip as first-line treatment of peptic ulcer bleeding: a multicenter randomized controlled trial (TOP Study).

BACKGROUND: First-line over-the-scope (OTS) clip treatment has shown higher efficacy than standard endoscopic therapy in acute nonvariceal upper gastrointestinal bleeding (NVUGIB) from different causes. We compared OTS clips with through-the-scope (TTS) clips as first-line mechanical treatment in the specific setting of peptic ulcer bleeding. METHODS: We conducted an international, multicenter randomized controlled trial on consecutive patients with suspected NVUGIB. Patients with Forrest Ia-IIb gastroduodenal peptic ulcer were randomized 1:1 to OTS clip or TTS clip treatment. The primary outcome was the rate of 30-day rebleeding after successful initial hemostasis. Secondary outcomes included the rates of successful initial hemostasis and overall clinical success, defined as the composite of successful initial hemostasis and no evidence of 30-day rebleeding. RESULTS: 251 patients were screened and 112 patients were randomized to OTS (n = 61) or TTS (n = 51) clip treatment. The 30-day rebleeding rates were 1.6% (1/61) and 3.9% (2/51) in patients treated with OTS clips and TTS clips, respectively (Kaplan-Meier log-rank, P = 0.46). Successful initial hemostasis rates were 98.4% (60/61) in the OTS clip group and 78.4% (40/51) in the TTS clip group (P = 0.001). Overall clinical success rates were 96.7% (59/61) with OTS clips and 74.5% (38/51) with TTS clips (P = 0.001). CONCLUSIONS: Low rates of 30-day rebleeding were observed after first-line endoscopic treatment of acute peptic ulcer bleeding with either OTS or TTS clips. However, OTS clips showed higher efficacy than TTS clips in achieving successful initial hemostasis and overall clinical success.

Endoscopic lithotripsy of a gallstone impacted in lumen-apposing metal stent positioned for cholecysto-gastrostomy.

Video 1Endoscopic lithotripsy of a gallstone impacted in the lumen-apposing metal stent positioned for cholecysto-gastrostomy.

Safety of a novel 1L-polyethylene glycol-ascorbate solution for colonoscopy cleansing (REAL Study).

BACKGROUND AND AIM: Very low-volume bowel preparation (BP) for colonoscopy with 1-liter polyethylene glycol plus ascorbate (1L-PEG-Asc) has displayed high tolerability and quality of bowel cleansing. Concerns have been raised regarding its safety. We aimed to evaluate the incidence of adverse events (AEs) following BP with 1L-PEG-Asc or 2L-PEG-Asc. PATIENTS AND METHODS: From January 2019 to September 2020, data from all consecutive adult outpatients who underwent colonoscopy in Our Unit were collected. AEs were assessed by reviewing the clinical and laboratory data of patients who attended the Emergency Department (ED) of Modena District Hospitals in the 7 days following the colonoscopy, and were classified as "BP-related" or "BP-unrelated". RESULTS: During the study, 4069 (68.03%) and 1912 (31.97%) patients underwent colonoscopy after taking 2L-PEG-Asc or 1L-PEG-Asc, respectively. Regarding AEs, 77 (1.29%) patients attended ED, 53 (53/4069, 1.30%) and 24 (24/1912, 1.25%) after taking 2L-PEG-Asc and 1L-PEG-Asc. BP-related AEs were observed in 5 (5/4069, 0.12%) and 4 (4/1912, 0.21%) patients, respectively. The most frequent BP-related AEs were tachyarrhythmias (6/5981, 0.10%). CONCLUSION: The incidence rate of clinically relevant BP-related AEs is extremely low. This strongly suggests that 1L-PEG-Asc colonoscopy BP is as safe as 2L-PEG-Asc BP in a real-life clinical setting of unselected patients.

Sorafenib Repurposing for Ophthalmic Delivery by Lipid Nanoparticles: A Preliminary Study.

Uveal melanoma is the second most common melanoma and the most common intraocular malignant tumour of the eye. Among various treatments currently studied, Sorafenib was also proposed as a promising drug, often administered with other compounds in order to avoid resistance mechanisms. Despite its promising cellular activities, the use of Sorafenib by oral administration is limited by its severe side effects and the difficulty to reach the target. The encapsulation into drug delivery systems represents an interesting strategy to overcome these limits. In this study, different lipid nanoparticulate formulations were prepared and compared in order to select the most suitable for the encapsulation of Sorafenib. In particular, two solid lipids (Softisan or Suppocire) at different concentrations were used to produce solid lipid nanoparticles, demonstrating that higher amounts were able to achieve smaller particle sizes, higher homogeneity, and longer physical stability. The selected formulations, which demonstrated to be biocompatible on Statens Seruminstitut Rabbit Cornea cells, were modified to improve their mucoadhesion, evaluating the effect of two monovalent cationic lipids with two lipophilic chains. Sorafenib encapsulation allowed obtaining a sustained and prolonged drug release, thus confirming the potential use of the developed strategy to topically administer Sorafenib in the treatment of uveal melanoma.

Assessment of a New Nanostructured Microemulsion System for Ocular Delivery of Sorafenib to Posterior Segment of the Eye.

Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNFα, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NFκB), TNFα, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNFα, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases.

A large anastomotic leakage after esophageal surgery treated with endoluminal vacuum-assisted closure: a case report.

The treatment of anastomotic post-esophagectomy leaks and fistula is challenging. Endoluminal vacuum-assisted closure (EVAC) is an emerging technique that employs negative pressure wound therapy to treat anastomotic leaks endoscopically. Esosponge is specifically designed for esophageal EVAC therapy. We report on a 49-year-old woman who underwent a totally mini-invasive Ivor-Lewis esophagectomy and developed a giant postoperative leak with a complex pleural collection, but she was not fit for surgical re-intervention. The patient healed almost completely after 14 exchange sessions of Esosponge over 35 days.

Complement System and Age-Related Macular Degeneration: Implications of Gene-Environment Interaction for Preventive and Personalized Medicine.

Age-related macular degeneration (AMD) is the most common cause of visual loss in developed countries, with a significant economic and social burden on public health. Although genome-wide and gene-candidate studies have been enabled to identify genetic variants in the complement system associated with AMD pathogenesis, the effect of gene-environment interaction is still under debate. In this review we provide an overview of the role of complement system and its genetic variants in AMD, summarizing the consequences of the interaction between genetic and environmental risk factors on AMD onset, progression, and therapeutic response. Finally, we discuss the perspectives of current evidence in the field of genomics driven personalized medicine and public health.

Curcumin Modulates DNA Methyltransferase Functions in a Cellular Model of Diabetic Retinopathy.

Hyperglycaemia-induced oxidative stress appears to be involved in the aetiology of diabetic retinopathy (DR), a major public health issue, via altering DNA methylation process. We investigated the effect of hyperglycaemia on retinal DNA methyltransferase (DNMT) expression in diabetic mice, using Gene Expression Omnibus datasets. We also evaluated the effect of curcumin both on high glucose-induced reactive oxygen species (ROS) production and altered DNMT functions, in a cellular model of DR. We observed that three months of hyperglycaemia, in insulin-deficient Ins2 Akita mice, decrease DNMT1 and DNMT3a expression levels. In retinal pigment epithelium (RPE) cells, we also demonstrated that high glucose-induced ROS production precedes upregulation of DNMT expression and activity, suggesting that changes in DNMT function could be mediated by oxidative stress via a potential dual effect. The early effect results in decreased DNMT activity, accompanied by the highest ROS production, while long-term oxidative stress increases DNMT activity and DNMT1 expression. Interestingly, treatment with 25 µM curcumin for 6 hours restores ROS production, as well as DNMT functions, altered by the exposure of RPE to acute and chronic high glucose concentration. Our study suggests that curcumin may represent an effective antioxidant compound against DR, via restoring oxidative stress and DNMT functions, though further studies are recommended.

Resveratrol Modulates SIRT1 and DNMT Functions and Restores LINE-1 Methylation Levels in ARPE-19 Cells under Oxidative Stress and Inflammation.

The role of epigenetic alterations in the pathogenesis of retinal degenerative diseases, including age-related macular degeneration (AMD), has been pending so far. Our study investigated the effect of oxidative stress and inflammation on DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions, as well as on long interspersed nuclear element-1 (LINE-1) methylation, in human retinal pigment epithelial (ARPE-19) cells. Therefore, we evaluated whether treatment with resveratrol may modulate DNMT and SIRT1 functions and restore changes in LINE-1 methylation. Cells were treated with 25 mU/mL glucose oxidase (GOx) or 10 µg/mL lipopolysaccharide (LPS) to mimic oxidative or inflammatory conditions, respectively. Oxidative stress decreased DNMT1, DNMT3a, DNMT3b, and SIRT1 expression (p-values < 0.05), as well as total DNMTs (-28.5%; p < 0.0001) and SIRT1 (-29.0%; p < 0.0001) activities. Similarly, inflammatory condition decreased DNMT1 and SIRT1 expression (p-values < 0.05), as well as total DNMTs (-14.9%; p = 0.007) and SIRT1 (-20.1%; p < 0.002) activities. Interestingly, GOx- and LPS-treated cells exhibited lower LINE-1 methylation compared to controls (p-values < 0.001). We also demonstrated that treatment with 10 µM resveratrol for 24 h counteracted the detrimental effect on DNMT and SIRT1 functions, and LINE-1 methylation, in cells under oxidative and inflammatory conditions. However, further studies should explore the perspectives of resveratrol as a suitable strategy for the prevention and/or treatment of retinal degenerative diseases.

Active carbon sequestration in the Alpine mantle wedge and implications for long-term climate trends.

The long-term carbon budget has major implications for Earth's climate and biosphere, but the balance between carbon sequestration during subduction, and outgassing by volcanism is still poorly known. Although carbon-rich fluid inclusions and minerals are described in exhumed mantle rocks and xenoliths, compelling geophysical evidence of large-scale carbon storage in the upper mantle is still lacking. Here, we use a geophysical surface-wave seismic tomography model of the mantle wedge above the subducted European slab to document a prominent shear-wave low-velocity anomaly at depths greater than 180 km. We propose that this anomaly is generated by extraction of carbonate-rich melts from the asthenosphere, favoured by the breakdown of slab carbonates and hydrous minerals after cold subduction. The resulting transient network of carbon-rich melts is frozen in the mantle wedge without producing volcanism. Our results provide the first in-situ observational evidence of ongoing carbon sequestration in the upper mantle at a plate-tectonic scale. We infer that carbon sequestered during cold subduction may partly counterbalance carbon outgassed from ridges and oceanic islands. However, subducted carbon may be rapidly released during continental rifting, with global effects on long-term climate trends and the habitability of planet Earth.

Phase-Tunable Josephson Thermal Router.

A fundamental aspect of electronics is the ability to distribute a charge current among different terminals. On the other hand, despite the great interest in dissipation, storage, and conversion of heat in solid state structures, the control of thermal currents at the nanoscale is still in its infancy. Here, we show the experimental realization of a phase-tunable thermal router able to control the spatial distribution of an incoming heat current, thus providing the possibility of tuning the electronic temperatures of two output terminals. This ability is obtained thanks to a direct current superconducting quantum interference device (dc SQUID), which can tune the coherent component of the electronic heat currents flowing through its Josephson junctions. By varying the external magnetic flux and the bath temperature, the SQUID allows us to regulate the size and the direction of the thermal gradient between two drain electrodes. Our results offer new opportunities for all microcircuits requiring an accurate energy management, including electronic coolers, quantum information architectures, and thermal logic components.

Incidence and management of late postsurgical seizures in clinical practice.

AIM: Seizures are a frequent complication in patients who undergo neurosurgery, and can complicate the post-operative course and deteriorate patients' quality of life. Evidence on the prophylactic anticonvulsant therapy after craniotomy is still lacking. MATERIAL AND METHODS: We undertook an observational longitudinal study following neurosurgical supratentorial interventions, to evaluate seizures onset or persistence, and differences in effectiveness between conventional and newer AEDs. RESULTS: A total of 100 consecutive subjects were enrolled. Each patient underwent a neurosurgical treatment by craniotomy. Pre-operative seizures occurred in 33% patients, early seizures in 13%. Late seizures occurred in 46 patients. At baseline (1 month after surgery) and during follow up the main therapeutic regimen was monotherapy. At last follow up adjustment of antiepileptic regimen or AED dosage had rendered 27 subjects seizure free. People taking newer AEDs at baseline maintain the same antiepileptic regimen more often than patients taking conventional AEDs; late seizures tended to have a higher incidence in the latter group. Adverse events from baseline AEDs were reported by 17% of patients. CONCLUSION: In this study population late postsurgical seizures had a remarkable occurrence. Newer AEDs were continued more often than conventional AEDs, with a better tolerability but no significant differences in late seizures incidence.

Delayed otogenic pneumocephalus complicating ventriculoperitoneal shunt.

Tension pneumocephalus complicating ventriculoperitoneal shunt is extremely rare. We report an elderly male who developed delayed tension pneumocephalus 12 months after ventriculoperitoneal shunt for hydrocephalus complicating aneurysmal subarachnoid hemorrhage. Fine-cut reformatted computer tomography scan revealed a large pneumatocele on the petrous apex associated with tegmen tympani defect. The shunt valve pressure was temporarily raised from 120 mm H 2 O to 200 mm H 2 O, and the patient underwent successful subtemporal extradural repair of the bony defect in the temporal bone. Although extremely rare, otogenic tension pneumocephalus is a potentially life-threatening condition, and urgent surgical repair of the bony defect in the temporal bone reduces the risk of both the morbidity and mortality.

Malignant transformation of intramedullary melanocytoma: case report.

OBJECTIVE: Meningeal melanocytomas are low-grade primary melanocytic tumors with benign histological features and a favorable clinical prognosis. Transition from meningeal melanocytoma to primary melanoma of the central nervous system is exceptionally rare, with only 5 cases having been previously reported. Here, we discuss a case of malignant transformation of an intramedullary melanocytoma to primary melanoma and review the pertinent literature. CLINICAL PRESENTATION: A 79-year-old woman presented with progressive paresis in the lower limbs followed by sphincter dysfunction. Magnetic resonance imaging scans disclosed an intramedullary lesion located at the T10-T11 level. INTERVENTION: The patient underwent subtotal resection of an intermediate-grade melanocytoma. Two years later, the tumor recurred locally, and the patient underwent additional surgery to remove the intramedullary mass. The histological findings of the tumor were consistent with an intramedullary malignant melanoma. CONCLUSION: The malignant transformation of melanocytic tumors of the central nervous system may occur years after surgical treatment, and its incidence remains unknown. Emphasis should be placed on the importance of careful and continued follow-up monitoring of the tumor.

Niels Stensen (1638-1686): scientist, neuroanatomist, and saint.

Niels Stensen (1638-1686) was a prominent Danish scientist who laid the foundations of paleontology, geology, and crystallography. He undertook a personal search for the truth, rejecting many assumptions of his time, and he struggled to acquire a firm foundation of knowledge based on close observation and rigorous experimentation. Niels Stensen is known eponymously for the discovery of the duct of the parotid gland (ductus stenonianus) but most clinicians are not familiar with his contributions to anatomy beyond his studies on the glands. In 1665, he delivered a lecture in Paris on the anatomy of the brain, the Discours sur l'anatomie du cerveau ("A Dissertation on the Anatomy of the Brain"), which is a seminal investigation on methods in neuroscience. His scientific letter on a hydrocephalic calf represents an early pathophysiological investigation on hydrocephalus. In 1667 Stensen converted to Catholicism and in 1677 he was consecrated titular bishop of Titiopolis. He spent the last years of his life in poverty and traveled continuously trying to bring back northern Europe to Catholicism. This essay highlights the life and the scientific contributions of Niels Stensen, with emphasis on his contributions to neuroscience.