Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy

IntroductionPost translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy.MethodsA citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model.ResultsWe show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide.ConclusionWe propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

TIVA for ECMO and VAD

In recent decades, the use of temporary and permanent use of mechanical assist devices is on the rise for patients with end-stage cardiac failure. These support strategies hold inherently different risks in the face of noncardiac critical illness and require multidisciplinary treatment strategies. The main issues with all mechanical devices whether extracorporeal membrane oxygenation (ECMO) or ventricular assist device (VAD), are related to thrombosis, anticoagulation, infection, avoiding hypertension and thus use of intravenous drugs, which requires intense monitoring, to circumvent further renal, ischemic or neurological injury and prevent complication

Ayurvedic Management of Hydrosalpinx: A Case Report

Infertility is caused by different factors like ovulatory, endometrial, tubal factors etc., and tubal factors are more responsible for infertility in patients of chronic pelvic inflammatory disease. Among the Garbha Sambhava Samagri, tubal factors come under Kshetra Vikriti. The present article a case report of female with primary infertility with the involvement of bilateral hydrosalpinx is presented. A female patient aged about 27 years approached the OPD of Prasutitanntra and Striroga department, Arogyashala of National Institute of Ayurveda, Jaipur. Her initial complaints were severe pain before the onset of menstruation, intermittent on and off pain in left inguinal region, scanty menstruation and primary infertility. She was found to have huge hydrosalpinx in her USG findings. So treatment was planned accordingly and she was treated with Ayurvedic regimen consisting of Shodhana and Shamana therapy. Yonivarti was planned as Sthanika chikitsa along with Triphala Guggulu and Godanti bhasma as oral medications. Her USG was repeated after treatment which revealed hydrosalpinx was resolved possessing normal fallopian tube diameter

Comparison the Effect of Etomidate vs. Thiopentone on Left Ventricular Strain and Strain Rate at the Time of Anesthesia Induction in Patients Undergoing Elective Coronary Artery Bypass Surgery: A Randomized Double Blind Controlled Trial

Myocardial strain imaging with speckle tracking echocardiography (STE) is getting popularity because it does not depends on insonation angle and has shown good correlation with intraoperative and postoperative ventricular function in patients with coronary artery disease. The impact of thiopentone and etomidate induction on myocardial function was studied and compared on sixty patients undergoing elective coronary artery bypass grafting. Three loops for each views (apical 4 chamber, apical 2 chamber, and apical long axis ) were acquired at base line (T0) and 1 minute (T1) after induction for offline analysis. In Group T, significant increase in HR from the base line values (67.8 ± 13.8 vs 79.2 ± 15.6, p = 0.001) occurred post induction, where as in Group E it remain near to the base line (71.7 ± 8.3 vs 70.1± 8.9, p = 0.345). A reduction in mean arterial pressure (MAP) was noted in both the groups after the injection of the allocated drug. There was no significant difference in the index of contractility (ICON) (T0 vs T1: 48.7 ± 10.6 vs 47.0 ± 11.7, p = 0.120) in Group E where as in Group T there was a reduction in the ICON value (T0 vs T1: 45.0 ± 10.7 vs 41.0 ± 8.4, p = 0.005). A similar picture was also noted in systemic vascular resistance index. A significant decrease in cardiac index (CI) was seen in Group E (T0 vs T1: 2.7 ± 0.4 vs 2.5 ± 0.4, p = 0.027), however it remain near to the base line in Group T. There occurred no changes in stroke index (SI) in Group E (T0 vs T1: 38.7 ± 6 vs 37.0± 5.3, p = 0.134), where as a significant decrease was noted after injection of thiopental (T0 vs T1: 38.0 ± 6.2 vs 36.1± 4.9, p = 0.049). A significant decline in cardiac performance index (CPI) was also recorded in Group E (T0 vs T1: 0.57 ± 0.15 vs 0.52 ± 0.12, p = 0.032), and not in Group T. There was decrease in left ventricular ejection fraction (LVEF) after the injection of both the drugs (Group E, T0 vs T1: 57 ± 3.7 vs 54± 3.7, p= 0.001; and Group T, T0 vs T1: 57 ± 3.7 vs 54± 3.7, p = 0.001). In Group E, global longitudinal peak systolic strain (GLPSS) showed no change after the injection of the drug (T0 vs T1: −13.2 ± 2.2 vs −13.1± 2.3, p = 0.631). However, a significant decrease in GLPSS (T0 vs T1: −13.5 ± 1.5 vs – 10 ± 1.8, p = 0.001) after injection of thiopental. Longitudinal peak systolic strain rate (LPSSR) was significantly decreased in all echocardiographic views after the injection of respective drugs. However, the decrease in LPSSR was significantly less in Group E in comparison to Group T. To conclude, STE provides accurate and reliable real time quantitative regional and global LV assessment. Use of thiopentone for anesthesia induction is associated with more profound impairment of LV function in comparison to etomidate as assessed by a decreased longitudinal peak systolic strain rate and global longitudinal peak systolic strain. Further studies are warranted to understand the exact clinical impact, which may influence the choice of intravenous induction agent based upon preoperative patient characteristics

A randomized trial of anesthetic induction agents in patients with coronary artery disease and left ventricular dysfunction

The deleterious effects of anesthetic agents in patients suffering from coronary artery disease are well known. The risk increases when a patient has compromised ventricular function. There is a paucity of literature regarding the choice of the suitable agent to avoid deleterious effects in such patients. The use of etomidate and propofol has been considered superior to other intravenous anesthetic agents in these groups of patients. The aim of the present study is to compare the hemodynamic effects of anesthesia induction with etomidate, thiopentone, propofol, and midazolam in patients with coronary artery disease and left ventricular dysfunction. This randomized clinical trail was conducted at the All Indian Institute of Medical Sciences, New Delhi, India. Sixty patients with coronary artery disease and left ventricular dysfunction (ejection fraction &lt; 45&#x0025;) scheduled for elective coronary artery bypass surgery participated in this study. After stabilization baseline hemodynamic data stroke volume variation and systemic vascular resistance index were recorded for all patients (Flo Trac TM sensor with Vigileo cardiac output monitor used for hemodynamic monitoring). The patients were randomly alloted to one of the four groups and the intravenous induction agent was administered for over 60 - 90 seconds (Group E - Etomidate 0.2 mg/Kg; Group M - Midazolam 0.15 mg/Kg; Group T - Thiopentone 5 mg/Kg; Group P - Propofol 1.5 mg/Kg). Hemodynamic data were recorded at one minute intervals starting from induction till seven minutes after intubation, - the end point of the present study. There was a significant decrease in the heart rate in comparison to the baseline(-7 to -15&#x0025;, <i>P</i> = 0.001), mean arterial pressure (-27 to -32&#x0025;, <i>P</i> = 0.001), cardiac index (-36 to -38&#x0025;, <i>P</i> = 0.001), and stroke volume index (-27 to -34&#x0025;, <i>P</i> = 0.001) after induction in all four groups. The hemodynamic response was similar in all the four groups. There was no significant change in central venous pressure and stroke volume variation (SVV) during induction and intubation, while the effects on the systemic vascular resistance index (SVRI) were variable. The midazolam group was the most effective in preventing intubation stress (tachycardia,hypertension). The change from baseline values in heart rate (&#x002B; 4&#x0025;, <i>P</i> = 0.12) and mean arterial pressure (-1&#x0025;, <i>P</i> = 0.77) after intubation were not statistically significant in the midazolam group. The etomidate group was the least effective of all the four groups in minimizing stress response, with statistically significant increase from baseline in both heart rate (<i>P</i> = 0.001) and mean arterial pressure (<i>P</i> = 0.001) at 1 minute after intubation. All the four anesthetic agents were acceptable for induction in patients with coronary artery disease and left ventricular dysfunction despite a 30 - 40&#x0025; decrease in the cardiac index. Clinician experience along with knowledge of the potential interactions (e.g., premedication, concurrent opioid use) is needed to determine hemodynamic stability during anesthetic induction in these patients with ventricular dysfunction

Anaesthesia Challenges during Sternal Wound Debridement

A 50-year-old female weighing 80 kg is posted for a deep sternal wound debridement, post mitral valve replacement (MVR), and post-CABG (Coronary Artery Bypass Grafting) (left internal mammary artery (LIMA)→left anterior descending (LAD)). She had sternal osteomyelitis and had wound debridement thrice before. She had also history of cardiac injury repair during second wound debridement. Her initial three tissue cultures showed Acinetobacter positive. Her fourth tissue culture shows Staphylococcus haemolyticus positive. Histopathology shows necrotizing granuloma. Two-dimensional Echocardiography (ECHO) shows post-MVR, no Mitral regurgitation (MR), mild Tricuspid Regurgitation (TR) (right ventricular systolic pressure (RVSP)-24 + Retrograde autologous priming (RAP)), Inferior Vena Cava #x0028;IVC) 1.6 cm with respiratory collapse, no pericardial effusion, no Left atrium (LA) clot/veg, and normal biventricular function