Laparoscopic Deployment of Biliary Self-Expandable Metal Stent (SEMS) for One-Step Palliation in 23 Patients with Advanced Pancreatico-Biliary Tumors—a Pilot Trial

Background Exploratory laparoscopy is commonly undertaken in patients with highly suspicious biliary and pancreatic lesions to facilitate diagnosis and staging cancer is present. If an unresectable tumor is identified, a second endoscopic procedure may be required do deploy a self-expandable metal stent (SEMS) for palliation. As endoscopic retrograde cholangio pancreatography (ERCP) may be unsuccessful in up to 20% of patients, we evaluated the feasibility and safety of deployment of self-expandable metal stents at the same time as the initial laparoscopy. Patients and Methods A total of 23 eligible patients (8 male and 15 female) with malignant obstruction of the common bile duct underwent deployment of SEMS at laparoscopy. Primary outcome measure was the successful laparoscopic deployment of stent and secondary outcome measure was complications rates. Results Indications for stent deployment were unresectable pancreatic cancer in 18, cholangiocarcinoma in two, neuroendocrine tumor in one and ampullary adenocarcinoma in two patients. The median age was 73 years (range 49–93). Twenty-two of 23 stents were deployed successfully: 17 stents were deployed transcystically and five via a choledochotomy. Median times for laparoscopic exploration and SEMS deployment were 165 min (range 105–230) and 20 min (range 10–50), respectively. Pre- and post-procedures median total bilirubin were 9.4 mg/dl (range 5.4–17.5) and 4.0 (range 2.6–7.1). The median size of the pancreatic mass was 3 cm (range 2–5 cm) and that of the common bile duct (CBD) from 9.2 mm (range 7.2–17.4). The mean duration of laparoscopy was 170 min (range 120–230 min) and that for stent deployment 23 min (range 10–50 min). Complications included bleeding, obstruction, and wound infection. Bleeding occurred on day 7 in two patients and on day 30 in one patient; bleeding occurred at the gastrojejunal anastomosis site and was successfully treated with endoscopic hemostasis. A total of three stent obstructions were identified: one each at 60, 90, and 120 days follow-up. All complications were successfully managed endoscopically. There were a total of seven deaths, six as a result of progressive cancer and one of surgical wound infection and ensuing complications. Conclusion This study demonstrates that laparoscopic deployment of self-expandable metal bile duct stents is feasible and safe. This option appears to be a reasonable option in patients with inoperable malignant obstruction of the distal common bile duct.     

High Recovery of Functional Islets Stored at Low and Ultralow Temperatures

BACKGROUND: Poor recovery of islets upon cryopreservation is the main hurdle in islet banking. Pancreatic islets have a poor antioxidative defense mechanism, and exposure of islets to low temperature leads to oxidative stress. AIM: We aimed to investigate whether known compounds such as metformin, γ aminobutyric acid (GABA), docosahexanoic acid (DHA), or eicosapentaenoic acid (EPA) alone or in combination are capable of reducing oxidative stress for better islet recovery upon storage at suboptimal temperatures. METHODS: Islets isolated from mouse pancreas were stored at low temperature (4°C) for 15 days and at ultralow temperature (-196°C) for 30 days with or without additives. After revival from cold storage, islets were assessed by using three methods: (1) specificity by dithizone (DTZ), (2) viability by fluorescein diacetate/propidium iodide (FDA/PI) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT) assay, and (3) functionality by glucose-stimulated insulin secretion (GSIS). The oxidative status of the islets stored at suboptimal temperatures was determined by both intracellular free radical release (fluorometric analysis) and lipid peroxidation (enzymatic determination). RESULTS: Supplementation with additives led to an improvement in islet survival upon storage at suboptimal temperatures, without depletion of insulin secretory activity, which was comparable to that of controls. The additives acted as cryoprotectants and antioxidants as revealed by high recovery of viable islets and reduction in total reactive oxygen species (ROS) and malonidealdehyde (MDA), respectively. CONCLUSIONS: Our results demonstrate for the first time that supplementation with EPA, DHA, and metformin may lead to higher islet recovery from -196°C storage, enabling proper islet banking.     

Recent progress in development of 2,3-diaminomaleonitrile (DAMN) based chemosensors for sensing of ionic and reactive oxygen species

2,3-Diaminomaleonitrile (DAMN) has proved to be a valuable organic π-conjugated molecule having many applications in the area of chemosensors for sensing of ionic and neutral species because of its ability to act as a building block for well-defined molecular architectures and scaffolds for preorganised arrays of functionality. In this article, we discussed the utilization of 2,3-diaminomaleonitrile (DAMN) for the design and development of chemosensor molecules and their application in the area of metal ion, anion and reactive oxygen species sensing. Along with these, we present different examples of DAMN based chemosensors for multiple ion sensing. We also discuss the ion sensing mechanism and potential uses in other related areas of research.

2,3-Diamniomaleonitrile (DAMN) is valuable π-conjugated organic scaffold molecule for designing of efficient chemosensors for sensing of ionic and Reactive Oxygen Species (ROS).     

Depletion and dysfunction of Vγ2Vδ2 T cells in HIV disease: mechanisms,impacts and therapeutic implications

Infection with human immunodeficiency virus (HIV) disrupts the balance among γδ T cell subsets, with increasing Vδ1+ cells and substantial depletion of circulating Vδ2+ cells. Depletion is an indirect effect of HIV in CD4-negative Vδ2 cells, but is specific for phosphoantigen-responsive subpopulations identified by the Vγ2-Jγ1.2 (also called Vγ9-JγP) T cell receptor rearrangement. The extent of cell loss and recovery is related closely to clinical status, with highest levels of functional Vδ2 cells present in virus controllers (undetectable viremia in the absence of antiretroviral therapy). We review the mechanisms and clinical consequences for Vδ2 cell depletion in HIV disease. We address the question of whether HIV-mediated Vδ2 cell depletion, despite being an indirect effect of infection, is an important part of the immune evasion strategy for this virus. The important roles for Vδ2 cells, as effectors and immune regulators, identify key mechanisms affected by HIV and show the strong relationships between Vδ2 cell loss and immunodeficiency disease. This field is moving toward immune therapies based on targeting Vδ2 cells and we now have clear goals and expectations to guide interventional clinical trials.     

Echocardiographic Assessment of Right Atrial Pressure in a Pediatric and Young Adult Population

Right atrial pressure (RAP) reflects right-sided cardiac hemodynamics and is useful in management of patients with cardiac and systemic disease. Studies in older adults demonstrated that inferior vena cava (IVC) diameter, IVC collapsibility index, hepatic vein systolic filling fraction (SFF), and right atrial volume (RAV) correlated with mean RAP at catheterization. This study aimed to assess the utility of echocardiographic parameters for assessment of RAP in children and young adults. Patients with pulmonary hypertension or heart transplantation undergoing right heart catheterization were recruited for this prospective observational pilot study. Transthoracic echocardiographic assessment of RAP was performed simultaneously with catheterization. For each parameter, three consecutive cardiac cycles were recorded. Long- and short-axis images of the IVC were obtained. RAV was assessed by area–length and biplane methods. IVC diameters and RAV were indexed to body surface area (BSA)^0.5 and (BSA)^1.4, respectively. Relationships between echocardiographic parameters and mean RAP were correlated using “Pearson’s r.” Fifty subjects aged 0.3–23 years (median 13, mean 12.3 ± 7 years) were enrolled. Mean RAP correlated modestly with RAV (r = 0.51, p < 0.001). Long-axis IVC_max (r = 0.30, p < 0.05) and tricuspid E wave velocity (r = 0.36, p < 0.01) also correlated with mean RAP. RV free wall tissue Doppler velocities, IVC collapsibility index, and hepatic vein SFF had no relation to mean RAP. In a pediatric and young adult population with pulmonary hypertension or heart transplantation, echocardiographic assessment of RAV and long-axis IVC_max provided a reasonable estimate of mean RAP. IVC collapsibility index and hepatic vein SFF demonstrated no association with mean RAP.     

NCoR1 fine-tunes type-I IFN response in cDC1 dendritic cells by directly regulating Myd88-IRF7 axis under TLR9

Plasmacytoid dendritic cells (DCs) are reported to induce robust type-I interferon (IFN) response, whereas cDC1 DCs develop moderate type-I IFN response upon TLR9 stimulation. It is very interesting to understand how this signaling under TLR9 is tightly regulated for the induction of type-I IFNs. Here, we report co-repressor protein NCoR1 as the major factor fine-tuning the signaling pathways regulating IFN-β expression under TLR9 in cDC1 DCs. We found that NCoR1 knockdown induced a robust IFN-β-mediated antiviral response upon TLR9 activation in cDC1 DCs. At the molecular level, we showed that NCoR1 directly repressed MyD88-IRF7 signaling axis in cDC1 cells. Therefore, NCoR1 depletion enhanced pIRF7 levels, IFN-β secretion, and downstream pSTAT1-pSTAT2 signaling, leading to sustained induction of IFN stimulatory genes. Integrative genomic analysis depicted strong enrichment of an antiviral gene-module in CpG-activated NCoR1 knockdown DCs upon TLR9 activation. Moreover, we confirmed our findings in primary DCs derived from splenocytes of WT and NCoR1 DC^−/− animals, which showed protection from Sendai and Vesicular Stomatitis viruses upon CpG activation. Ultimately, we identified that NCoR1–HDAC3 complex is involved in repressing the type-I IFN response in cDC1 DCs.