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Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum-mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich's ataxia, and Charcot-Marie-Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

Endoscopic removal of large (>= 20 mm) non-pedunculated colorectal lesions (LNPCLs) may result in major adverse events, such as delayed bleeding (DB) and delayed perforation (DP), despite closure of the mucosal defects with clips. Topical application of a coverage agent refers to the creation of a shield with a biocompatible medical device (tissue or hydrogel) with proven bioactive properties. Coverage of the eschar after endoscopic resection provides shielding protection to prevent delayed complications. The aim of the present review was to systematically collect and review the currently available literature regarding the prevention of DB and DP with coverage agents after endoscopic mucosal resection or endoscopic submucosal dissection of LNPCLs.

Cofilin is an actin-binding protein that plays a major role in the regulation of actin dynamics, an essential cellular process. This protein has emerged as a crucial molecule for functions of the nervous system including motility and guidance of the neuronal growth cone, dendritic spine organization, axonal branching, and synaptic signalling. Recently, other important functions in cell biology such as apoptosis or the control of mitochondrial function have been attributed to cofilin. Moreover, novel mechanisms of cofilin function regulation have also been described. The activity of cofilin is controlled by complex regulatory mechanisms, with phosphorylation being the most important, since the addition of a phosphate group to cofilin renders it inactive. Due to its participation in a wide variety of key processes in the cell, cofilin has been related to a great variety of pathologies, among which neurodegenerative diseases have attracted great interest. In this review, we summarized the functions of cofilin and its regulation, emphasizing how defects in these processes have been related to different neurodegenerative diseases.

BACKGROUND: Small Bowel Capsule Endoscopy is the first-choice technique for investigating the majority of small bowel diseases. Its most common complications are related to incomplete examinations and capsule retention. There is no consensus on how patients with previous gastrointestinal surgery should receive the capsule. OBJECTIVE: The primary endpoint was to compare therateof complete small-bowel examinations (completion rate) between oral ingestion and endoscopic delivery of the capsule. The secondary endpoint was to compare diagnostic yield and adverse events in the two groups. METHODS: A retrospective observational study was conducted in nine hospitals in Spain. Demographic data, previous surgery, indication for capsule endoscopy, intestinal transit time, diagnosis, completion rate (percentage of capsules reaching the caecum), diagnostic yield (percentage of results compatible with indication for the exam) and adverse events were collected. RESULTS: From January 2009 to May 2019 fifty-seven patients were included (39 male, mean age 66±15 years). The most common indications for the exam were "overt" (50.9%) and "occult" (35.1%) small bowel bleeding. Previous Billroth II gastrectomy and Roux-en-Y gastric bypass were present in 52.6% and 17.5% of patients respectively. The capsule was swallowed in 34 patients and placed endoscopically in 23 patients. No significant differences were observed between the oral ingestion and endoscopic delivery groups in terms of completion rate (82.4% vs 78.3%; p = 0.742), diagnostic yield (41.2% vs 52.2%; p = 0.432) or small bowel transit time (301 vs 377 min, p = 0.118). No capsule retention occurred. Only one severe adverse event (anastomotic perforation) was observed in the endoscopic delivery group. CONCLUSIONS: In our case series, there were no significant differences between oral ingestion and endoscopic delivery in terms of completion rate, diagnostic yield or safety. Being less invasive, oral ingestion of the capsule should be the first-choice method in patients with previous gastrointestinal surgery.

The approval of istradefylline, an adenosine 2A receptor (A2AR) antagonist, as an add-on treatment in adult patients with Parkinson's disease by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), is the latest proof of the importance of the adenosinergic system in the nervous system. Adenosine is an endogenous purine nucleoside with a role as a modulator of both neurotransmission and the inflammatory response. As such, the expression pattern of the 4 adenosine receptors (A1R, A2AR, A2BR and A3R) and the extracellular adenosine levels have attracted great interest in the pathogenesis and possible treatment of rare neurodegenerative diseases with motor symptoms. These include Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), restless legs syndrome (RLS) and Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3, SCA3). In this review, we shall focus on the role of the different adenosine receptor subtypes in the development and possible treatment of the aforementioned rare neurodegenerative diseases with motor symptoms using the currently available data. The last section discusses the possibility of a role for the adenosine receptors in the treatment of other rare diseases based on the available molecular pathology knowledge.

Background and objectives: endoscopic septotomy of the cricopharyngeal muscle (ESCM) is a technique used for the treatment of Zenker's diverticulum (ZD). The experience with computerized vascular sealing systems (LigaSure (R) type) is limited. The objective of this study was to evaluate the efficacy and safety of ESCM using LigaSure (R). Methods: this was a long-term prospective study of 18 patients with ZD, who were referred to our hospital due to ESCM between 2010 and 2016. The severity of the symptoms was determined using the Dakkak-Bennett validated scale for dysphagia and the rest with numerical scales. The rates of relapse and retreatment were evaluated. Results: ESCM with LigaSure (R) was performed in 17 cases, one case was excluded due to technical difficulties. The median age was 72 years and regurgitation, dysphagia and respiratory symptoms were found in 100%, 89% and 56% of cases, respectively. The median size of the diverticulum was 28 mm (20-60 mm). The median time of the procedure was 35 minutes (25-45 minutes). There were four complications, two hemorrhages and two perforations. The median follow-up was 13 months (range: 12-82 months). Clinical improvements were observed for all symptoms and were maintained 12 months after treatment (p < 0.05). There was no relapse during follow-up in 13 patients. A complete section was not achieved and clinical relapse occurred after a median time of seven months that required retreatment in the remaining patients. Conclusions: ESCM with LigaSure (R) may be a safe and effective technique in long-term follow-up situations, with low rates of relapse.

Background and aims: to assess the usefulness, efficacy and safety of single-operator cholangiopancreatoscopy (SOCP) with the SpyGlass (TM) system for the management of biliopancreatic diseases. Methods: a retrospective analysis of patients undergoing SOCP with the SpyGlass (TM) between September 2008 and April 2016 was performed. Data was obtained from a prospectively-maintained database at a tertiary referral center. The primary study outcomes were technical and complete endoscopic success of the procedure. Two different SpyGlass (TM) systems were employed; the former is called legacy and the latter, digital system (DS). Results: a total of 107 SOCP procedures in 93 patients performed by a single operator were analyzed.Technical success of the SpyGlass (TM) examination was achieved in 90/93 (97%) of patients and complete success by resolving the biliopancreatic condition in 82/93 (88%) cases. In indeterminate biliary strictures, a complete success was achieved in 45/52 (85%) of cases. With regard to stone treatment, technical success was achieved in 34/34 (100%) patients and complete success, in 31/34 (91%) cases. Electrohydraulic lithotripsy was applied in 16/34 (47%) of cases.There were a total of 7/93 adverse effects (7.5%). Conclusions: SOCP is a useful and safe technique for the treatment of biliopancreatic diseases with a low rate of adverse effects. The procedure seems technically demanding and dedication is required.

Objective: Total hip arthroplasty (THA) preoperative planning requires the calibration of X-ray. We evaluate the magnification in standard pelvis hip X-ray and determine its relation with biometric factors. Methods: The magnification of 140 THA X-ray were calculated with the known femoral head (MFFH ) and acetabular component (MFAC). Gender, age, height, weight, and BMI were correlated to the magnification. Results: The MFFH and MF(AC )were 113.2 +/- 4,4 and 113,4 +/- 3,6 respectively. No significant differences by gender and no correlation with height, weight or BMI. Conclusion: The X-ray magnification should be calibrated in every institution to improve the accuracy of preoperative planning.

Background and AimThe role of capsule endoscopy (CE) in established celiac disease (CD) remains unclear. Our objective was to analyze the usefulness of CE in the suspicion of complicated CD. MethodsThis was a retrospective multicenter study. One hundred and eighty-nine celiac patients (mean age: 46.616.6, 30.2% males) who underwent CE for alarm symptoms (n=86, 45.5%) or non-responsive CD (n=103, 54.5%) were included. Diagnostic yield (DY), therapeutic impact and safety were analyzed. ResultsCapsule endoscopy was completed in 95.2% of patients (small bowel transit time: 270.5100.2min). Global DY was 67.2%, detecting atrophic mucosa (n=92, 48.7%), ulcerative jejunoileitis (n=21, 11.1%), intestinal lymphoma (n=7, 3.7%) and other enteropathies (n=7, 3.7%, six Crohn's disease cases and one neuroendocrine tumor). The DY of CE was significantly higher in patients presenting with non-responsive disease compared to patients with alarm symptoms (73.8% vs 59.3%, P=0.035). The new findings of the CE modified management in 59.3% of the cases. There were no major complications. ConclusionCapsule endoscopy may be a moderately helpful and safe diagnostic tool in the suspicion of complicated CD, modifying the clinical course of these patients.

We present Fermat, an Intelligent Social Network for Mathematics Learning, which integrates an Intelligent Tutoring System as an extra feature to help students to improve the teaching and learning process. The intelligent tutor takes into account both cognitive and affective aspects. The social network and the affective tutoring systems are accessed from the web. Initial results in math show the benefits of using the tutoring system besides the all-known benefits of using a social network as the user interface.

Our Lord in the Attic is a historic house museum located in the historic center of Amsterdam, The Netherlands. It is a typical 17th century Dutch canal house, with a hidden Church in the attic. The Church was used regularly until 1887 when the house became a museum. The annual total number of visitors has grown from 36,000 in 1990 to 75,000 in 2005; this trend is exponentially increasing. The museum had between 100 – 650 visitors each day in 2005; they typically stayed in the building for about an hour. There were two visitation peaks: one in the mid-morning and another in mid-afternoon. On two separate days each year the museum records large numbers (well over 1,000) of visitors. Masses, weddings, and music concerts, attended by 50 – 150 persons, are regularly held in the Church. The museum has consequently expressed major concern over the impact of the growing number of visitors on the various collection environments. A historic indoor climate of 10% - 95% relative humidity was estimated, from when the central heating system, which may have caused the majority of damages to the collection, was installed in the 1950’s to the installation of humidifiers in the 1990’s. However, between January 2005 and January 2006, in spite of a few central heating system malfunctions and large visitor numbers that particular year, the recent climate in the museum building did not reach harmful levels for the collections. Direct impacts of visitors were documented as increases in temperature, relative humidity, and CO2 concentration when the museum opened each morning as well as during special events in the church. However, relative humidity peaks remained less than 75%, and the value decayed quickly after the visitors had left the rooms or near the end of the museum’s visiting hours. As confirmed through air exchange rate measurements in the church, a high infiltration rate of outside air was the reason for reduced peaks and fast decay of the relative humidity and CO2 concentration. Daily maxima of CO2 concentration exceeding 1500 ppm were recorded whenever the daily total of visitors exceeded 500. Daily averages over the 08:00 – 17:00 period exceeded 1000 ppm whenever more than 600 visitors were recorded. However, the high infiltration rate completely diluted the CO2 concentration to an ambient level by the following morning. From the consideration of the CO2 and moisture accumulations, 600 visitors per day, well-distributed over the museum’s operational hours, can be safely accommodated in winter. The number can be increased to twice this during the summer by opening the entrance door and a window in the attic for increased natural ventilation. However, other important issues, such as safe levels of floor loading and vibration, as well as overall visitor comfort and experience, will have to be taken into consideration and may well result in allowing fewer visitors than what is recommended based on these calculations.