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The newly synthesized 3-(2-Hydroxyphenyl)-1-phenyl propenone was analyzed. In this work, optimization of the 3-(2-hydroxyphenyl)-1-phenyl propanone was carried out with DFT using B3LYP method utilizing 6-311++G(d,p) basis set. The structure parameters of the compounds as molecular geometry, bond lengths, bond angles, atomic charge, and HOMO-LUMO energy gap have been investigated and compound with the reported experimental results. The donor and acceptor interactions in 3-(2-Hydroxyphenyl)-1-phenyl propenone were investigated using natural bond orbital (NBO) analysis. By matching the obtained UV-Vis spectra to the time-dependent (TD)-DFT analysis, the energies of band gap, absorption wavelength, and oscillatory strength of 3-(2-Hydroxyphenyl)-1-phenyl propenone were found. Density of states for total (TDOS), partial (PDOS), and also overlap population (OPDOS) analysis were obtained. Molecular electrostatic potential (MEP) provides the information on the electrophilic, nucleophilic, and free radical prone reactive sites of the molecule. Non-linear optical features were demonstrated from the first-order hyperpolarizability. Based on the above results the 3-(2-Hydroxyphenyl)-1-phenyl propenone compound was investigated for further biological investigation. TD-DFT analysis was also performed to calculate energies, oscillator strength of electronic singlet-singlet transitions, and the absorption wavelengths. The Molecular docking (ligand-protein) simulations have been performed using the Auto Dock version 4.2.6.

Background: Myopathies are a group of neuro muscular diseases that cause muscle weakness, cramps, and spasms due to a primary defect of the muscle fiber. We undertook this study of hereditary muscle disorders to identify the clinical patterns and laboratory findings in these conditions and study the correlation between them, which will help in recognizing them early for adequate management with rehabilitation measures and for prognostication. Aim: To assess the correlation between the clinical and investigational profile in Hereditary muscle disorders. Methods: A cross sectional study was conducted among 44 patients with clinical features suggestive of hereditary muscle disorders who sort health care at Institute of neurology, Madras Medical college, Chennai using various investigation techniques like Serum CK measurement, Nerve conduction Study, Electromyography, Muscle biopsy. Results: CK elevation was found in all patients in our study, but the degree of elevation differs among various hereditary muscle disorders. It was maximal (>25 times normal) in patients with DMD (50%), BMD (40%) and in LGMD (4%). High degree of correlation between clinical diagnosis of hereditary muscle disorders and myopathic EMG was found. Myopathic pattern was observed in all patients of Muscular dystrophy, congenital myopathy and distal myopathy.

Background: Myopathies are disorders in which a primary functional or structural impairment of skeletal muscle. In general, Muscle disorders are classified into hereditary and acquired disorders. The approach to a patient with a suspected muscle disease is to determine the correct site of the lesion from history and physical examination. This will help to decide on management and prognostication issues. We undertook this study of hereditary muscle disorders to identify the demographic profile and clinical spectrum of hereditary muscle disorders. Aims and Objectives: To study the demographic profile of patients with hereditary muscle disorders and to study the clinical spectrum of hereditary muscle disorders. Methods and Materials: A cross sectional study was conducted on Institute of Neurology, Madras Medical College, Chennai during the period of July 2018 to February 2019 (8 months), among 44 patients (Males-32, Females-12), with clinical features suggestive of hereditary muscle disorders, with certain exclusion criteria’s. Clinical evaluation was done by detailed history taking followed by general and CNS examination, along with motor system examination. All the data were tabulated in Microsoft XL sheet, followed by analysis using SPSS software (version 20.0).

Preserving islet health and function is critical during pretransplant culture to improve islet transplantation outcome and for ex vivo modeling of diabetes for pharmaceutical drug discovery. The limited islet engraftment potential is primarily attributable to loss of extracellular matrix (ECM) support and interaction. Multipotent cells with ECM depositing competency improve islet survival during short coculture period. However, role of pancreatic stellate cells (PSCs) and their ECM support in preserving ex vivo islet physiology remains largely unknown. Here, we report novel cytoprotective effects of culture-adapted porcine PSCs and role of their ECM-mediated intercellular communication on pig, mouse and human islets ex vivo. Using direct-contact coculture system, we demonstrate that porcine PSCs preserve and significantly prolong islet viability and function from 7 ± 3 days to more than 28 ± 5 (P < .001) days in vitro. These beneficial effects of PSCs on islet health are not species-specific. Using NSC47924 to specifically inhibit 37/67 kDa laminin receptor (LR), we identified that LR-mediated intercellular communication is essential for PSCs to protect functional viability of islets in vitro. Finally, our results demonstrate that PSC co-transplantation improved function and enhanced capacity of syngeneic islets to reverse hyperglycemia in mice with preexisiting diabetes. Cumulatively, our findings unveil novel effects of culture-adapted PSCs on islet health likely mirroring in vivo niche interaction. Furthermore, islet and PSC coculture may aid in development of ex vivo diabetes modeling and also suggests that a combined islet-PSC tissue engineered implant may significantly improve islet transplantation outcome.

OBJECTIVE Total pancreatectomy with islet autotransplantation (TPIAT) is indicated to alleviate debilitating pancreas-related pain and mitigate diabetes in patients with acute recurrent and chronic pancreatitis when medical/endoscopic therapies fail. Our aim was to evaluate predictors of insulin requirement at 1 year following TPIAT in a cohort of children. RESEARCH DESIGN AND METHODS This was a review of 43 pediatric patients followed after TPIAT for 1 year or longer. Primary outcome was insulin use at 1 year, categorized as follows: insulin independent, low insulin requirement ( RESULTS At 1 year after TPIAT, 12 of 41 (29%) patients were insulin independent and 21 of 41 (51%) had low and 8 of 41 (20%) had high insulin requirement. Insulin-independent patients were younger than those with low and high insulin requirement (median age 8.2 vs. 14.6 vs. 13.1 years, respectively; P = 0.03). Patients with insulin independence had a higher number of transplanted islet equivalents (IEQ) per kilogram body weight (P = 0.03) and smaller body surface area (P = 0.02), compared with those with insulin dependence. Preoperative exocrine insufficiency was associated with high insulin requirement (P = 0.03). Higher peak C-peptide measured by stimulated mixed-meal tolerance testing (MMTT) at 3 and 6 months post-TPIAT was predictive of lower insulin requirement at 1 year (P = 0.006 and 0.03, respectively). CONCLUSIONS We conclude that insulin independence following pediatric TPIAT is multifactorial and associated with younger age, higher IEQ per kilogram body weight transplanted, and smaller body surface area at time of operation. Higher peak C-peptide measured by MMTT following TPIAT confers a higher likelihood of low insulin requirement.

Theoretical and experimental investigations on the molecular structure of 2-amino-5-chloro-3-nitropyridine (2A5Cl3NP) are presented. The molecular equilibrium geometry of the title molecule is fully optimized. Quantum chemical calculations of the HOMO-LUMO energies, energy gap (ΔE), electron negativity (χ), and chemical potential (μ), global hardness (ƞ), and global softness (S) are calculated for the title molecule. The title compound has a low softness value (0.2770) and the calculated value of electrophilicity index (7.7250) describes the biological activity. The stability and charge delocalization of the title molecule are studied by Natural Bond Orbital Analysis (NBO), Non-Linear Optical (NLO) behaviour in terms of first order hyperpolarizability, dipole moment, anisotropy of polarizability are accounted. The computed values of dipole moment (μ) for 2A5Cl3NP molecule is 3.0173 Debye, polarizability (α) is 1.6017 × 10–23esu, hyperpolarizability (β) is 5.08173 × 10–30esu. The high β value and non-zero value of μ indicate that the title compound might be a good candidate for NLO material. The strength of the interaction between electron donors and electron acceptors is measured by the magnitude of energy of hyper conjugative interactions E (2). The second-order Fock matrix is calculated to study the donor–acceptor interactions in NBO analysis.

The research exploration will comprise of investigating the hyperpolarizability, frontier molecular orbital analysis and NBO, the data analyzed through theoretical methods using Density Functional Theories (DFT) involves the basic principle of solving the Schrodinger equation for many body systems. The results of the organic amine 2–4-difluoroaniline is analyzed and discussed using higher basis set 6-311++G(d, 2p). The energy gap between the HOMO and the LUMO of 2, 4-difluoroaniline is found to be 5.2186 eV. The chemical hardness of the 2, 4-difluoroaniline molecule is found to be 2.6093, indicating that the chemical hardness is very high and hence, the compound is chemically stable. The electrophilicity index of the title molecule using the B3LYP method is 2.3371 for 2, 4-difluoroaniline molecule. Thus the chosen molecule is a potential candidate for NLO applications.

Replacement of β cells is only a curative approach for type 1 diabetes (T1D) patients to avoid the threat of iatrogenic hypoglycemia. In this pursuit, islet allotransplantation under Edmonton’s protocol emerged as a medical miracle to attain hypoglycemia-free insulin independence in T1D. Shortage of allo-islet donors and post-transplantation (post-tx) islet loss are still unmet hurdles for the widespread application of this therapeutic regimen. The long-term survival and effective insulin independence in preclinical studies have strongly suggested pig islets to cure overt hyperglycemia. Importantly, CRISPR-Cas9 technology is pursuing to develop “humanized” pig islets that could overcome the lifelong immunosuppression drug regimen. Lately, induced pluripotent stem cell (iPSC)-derived β cell approaches are also gaining momentum and may hold promise to yield a significant supply of insulin-producing cells. Theoretically, personalized β cells derived from a patient’s iPSCs is one exciting approach, but β cell-specific immunity in T1D recipients would still be a challenge. In this context, encapsulation studies on both pig islet as well as iPSC–β cells were found promising and rendered long-term survival in mice. Oxygen tension and blood vessel growth within the capsules are a few of the hurdles that need to be addressed. In conclusion, challenges associated with both procedures, xenotransplantation (of pig-derived islets) and stem cell transplantation, are required to be cautiously resolved before their clinical application.

Background Osmotic demyelination syndrome commonly occurs after rapid correction of hyponatremia. But it has also been reported after graded correction of hyponatremia in the presence of other risk factors like chronic alcoholism, malnutrition, liver disease, and hypokalemia. Case Report We report a case of a 67-year-old man who presented with dysphagia and nasal regurgitation and had features suggestive of bulbar palsy on neurological examination. He had spontaneous rapid correction of hyponatremia from a serum sodium level of 122 mEq/L to 132 mEq/L after discharge from our hospital. Neuroimaging was suggestive of extrapontine myelinolysis involving the basal ganglia. Why Should an Emergency Physician Be Aware of This? An emergency physician should be aware of this because osmotic demyelination syndrome should also be considered in the differential diagnosis of patients presenting with bulbar palsy to the emergency department.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Total pancreatectomy with islet autotransplantation is performed to treat chronic pancreatitis in children. Successful islet isolation must address the challenges of severe pancreatic fibrosis and young donor age. We have progressively introduced modifications to optimize enzymatic and mechanical dissociation of the pancreas during islet isolation. We evaluated 2 islet isolation metrics in 138 children-digest islet equivalents per gram pancreas tissue (IEQ/g) and digest IEQ per kilogram body weight (IEQ/kg), using multiple regression to adjust for key disease and patient features. Islet yield at digest had an average 4569 (standard deviation 2949) islet equivalent (IEQ)/g and 4946 (4009) IEQ/kg, with 59.1% embedded in exocrine tissue. Cases with very low yield (

BACKGROUND AND AIMS: Many patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for severe, refractory chronic pancreatitis or recurrent acute pancreatitis have a history of endoscopic retrograde cholangiopancreatography (ERCP). Using data from the multicenter POST (Prospective Observational Study of TPIAT) cohort, we aimed to determine clinical characteristics associated with ERCP and the effect of ERCP on islet yield. METHODS: Using data from 230 participants (11 centers), demographics, pancreatitis history, and imaging features were tested for association with ERCP procedures. Logistic and linear regression were used to assess association of islet yield measures with having any pre-operative ERCPs and with the number of ERCPs, adjusting for confounders. RESULTS: 175 (76%) underwent ERCPs [median number of ERCPs (IQR) 2 (1–4)]. ERCP was more common in those with obstructed pancreatic duct (p=0.0009), pancreas divisum (p=0.0009), prior pancreatic surgery (p=0.005), and longer disease duration (p=0.004). A greater number of ERCPs was associated with disease duration (p

The cloud offers more services across multiple infrastructures and rapidly growing areas of development in medical care. In the cloud, Network virtualization allows multiple isolated virtual networks (VNs) for flexible sharing of network resources. The virtual network mapping in Network virtualization provides the dynamic virtual node and link resources to satisfy the user needs. The major challenges of cloud computing are optimally and resourcefully responds to each user service requests with minimum time. To address these problems in distributed and hybrid cloud environments, Multicriteria Dragonfly based Graph Theory Resource Optimized Virtual Network Mapping (MD-GTROVNM) technique is introduced. The main objective of the MD-GTROVNM technique is to improve the efficiency of virtual network request mapping with less resource utilization. In the MD-GTROVNM technique, Multicriteria Dragonfly based Graph Theory performs both virtual node mapping and link mapping with reasonable resource utilization such as CPU, memory, and bandwidth. In node mapping, the Multicriteria Dragonfly optimization technique is applied to find the optimal physical node among the population that satisfies the resource constraints. The proposed Multicriteria Dragonfly optimization algorithm achieved a more optimal solution for virtual network mapping. The experimental scenario is carried out with various parameters such as mapping efficiency, computation time, Request acceptance ratio and memory consumption with a number of VN requests. The observed results confirm that the MD-GTROVNM technique effectively increases the mapping efficiency, Request acceptance ratio and minimizes the computation time as well as memory consumption when compared to the existing techniques.

PURPOSE: Human islet isolation requires a defined collagenase-protease enzyme combination for obtaining a successful islet yield. While different islet laboratories use different enzyme combinations, a systematic methodology to identify optimal enzyme combinations and their concentrations within a single donor pancreas has not been tested. In this study, we designed a trisected pancreas model to test efficacy of three clinical grade enzyme blends (VitaCyte, Roche, SERVA) within a single pancreas. METHODS: Islet isolations were performed using brain-dead donor pancreases (n = 15) applying the enzyme-related design of experiments (DOEs) and the trisected model approach. After trimming, split each pancreas into three individual lobes (head, body, tail). As per the DOEs, the lobes were altered between different experiments, to minimize anatomical bias. Islets isolated from each lobe (27 lobes totally) were subjected to functional assessments. Insulin staining and islet area fraction were determined for tissue sections obtained from each lobe. RESULTS: Utilizing the trisected model, we identified that the collagenase dose from three different vendors did not affect the pancreas digestion and islet yield, but islet morphology after isolation with the neutral protease and BP-protease was better than thermolysin. In addition, the head lobe yielded a lower islet mass and higher tissue volume compared to other two lobes, irrespective of enzyme combination used. CONCLUSIONS: This study demonstrates that the trisected model is a promising methodology in assessing donor and isolation associated parameters. Based on this study, we conclude that the donor characteristics and an optimal enzyme dose play a critical role in achieving higher islet yields.

Background and aims Successful clinical human allo or auto-islet transplantation requires the recovery of a sufficient number of functional islets from either brain-dead or chronic pancreatitis pancreases respectively. Methods In the last two decades (2000–2019), significant progress has been made in improving the human islet isolation procedures and in standardizing the use of different tissue dissociation enzyme (TDE; a mixture of collagenase and protease enzymes) blends to recover higher islet yields. Results and Conclusions This review presents information focusing on properties and role of TDE blends during the islet isolation process, particularly emphasizing on the current developments, associated challenges and future perspectives within the field.

Brugada phenocopy is a brugada-like pattern in ECG seen in some diseases without an inherited channelopathy. The causes of brugada phenocopy are usually reversible. Once the reversible condition resolves, the ECG pattern disappears. There are many conditions that cause brugada phenocopy like myocardial infarction, hyperkalemia etc. Here we report a case of brugada phenocopy induced by consumption of yellow oleander seeds (T. Peruviana).

One of the rare causes of diffuse T-wave inversion (TWI) in electrocardiogram (ECG) is memory T-waves. This should be considered among the differentials of diffuse TWI in ECG of patients presenting to the emergency department (ED), especially when they have previous episodes of ventricular tachycardia (VT) or pacemaker implantation or Wolff-Parkinson-White syndrome. These TWIs are benign and do not require any treatment. However, it is of paramount importance for the emergency physician to differentiate it from ischemia-related T-wave changes. In the following case series, we report three cases of memory T-waves. Two of the cases had TWI in leads II, III, aVF, and V3 to V6 following reversion of VT. The other patient, with a? VVI (Left ventricle paced, Left ventricle sensed, Inhibition to sensing) pacemaker, had memory T-waves in the ECG taken during normal sinus rhythm. In all the three patients, we considered memory T-waves to be the possible cause of TWI. The electrocardiographic diagnostic criteria for memory T-waves are positive T in lead aVL and positive/isoelectric T in the lead I; and precordial TWI >inferior TWI. These criteria are 92% sensitive and 100% specific. In the following case series, we also provide an algorithmic approach for patients with suspected memory T-waves in their 12-lead ECG when they present to the ED.

Soft Magnetic Composite (SMC) materials possess isotropic magnetic and thermal properties, very low eddy current loss and relatively low total core loss at medium and higher frequencies. This paper presents the application potential of iron powder SMC in switched reluctance machine (SRM) and its performance enhancement. The results of extensive finite element simulation and experimental validation of the proposed fabricated prototype are delineated. The study concludes that the use of SMC as magnetic core of a switched reluctance motor enhances its thermal and vibration characteristics in comparison with the conventional lamination counterpart.

Virtual network mapping (VNM) is a significant problem to be resolved in network virtualization to increase the quality of services in home healthcare system. A lots of research work have been designed for VNM. But, mapping performance of conventional works was not effective. Furthermore, processing time (PT) taken for VNM was higher. In order to overcome these limitations, Annealed Glowworm Optimization Graph Theory based Virtual Network Mapping (AGOGT-VNM) technique is proposed. AGOGT-VNM technique enhances the utilization of network resources in cloud. The resources taken in AGOGT-VNM technique are processing resources i.e. Central Processing Unit (CPU), memory and bandwidth respectively. The AGOGT-VNM technique comprises two key process namely node mapping, link mapping. In AGOGT-VNM technique, Annealed Glowworm Optimization Graph Theory (AGOGT) maps a virtual network requests (VNR) to an optimal physical nodes that satisfies the resource constraints. Besides, any physical node (PN) chosen for mapping is close as possible to earlier mapped PN. Link mapping algorithm in AGOGT-VNM technique maps a virtual link to shortest substrate path of virtual link. AGOGT-VNM technique conducts the experimental process using metrics such as mapping efficiency (ME), PT and acceptance ratio (AR) with dissimilar number of VNRs. The experimental result shows that the AGOGT-VNM technique is able to increases mapping efficiency by 12% with minimum PT by 28% and acceptance ratio by 19% when compared to state-of-the-art works.

Background: This article deals with the analysis on improved performance and efficiency of induction motor by using nano composites for stator winding. Methods: The nanocomposites are added with different enamel. Enamel is mostly preferred for induction motors’ winding, due to three main reasons: adhesion, infusion and plaster. To predetermine the plaster and nanocomposite conductor’s behavior when they are used for transmitting AC currents and developing AC magnetic field, a numerical analysis is performed. The total heat losses are determined by the heat run test. Open circuit and short circuit tests are used to analyze the performance and efficiency of the proposed induction motor. Results: The AC losses of composite and plaster conductors having good accord are compared with previous solid and hollow conductors. Analysis of the coil by a composite and plaster conductor shows that the AC losses in low current are lower than the coil, which is wrapped by a solid, and hallow conductors. Due to this reason, composite and plaster conductors are considered advantageous for low and medium power motors. Conclusion: Adding nano composites with the plaster material will help to improve electrical, thermal and mechanical characteristics. The property of enamel can change the lifetime of induction motor. The induction motor winding makes use of nano composites SiO2 and TiO2 with enamel coated.

Background Patients with coronavirus disease 2019 (COVID-19) commonly present with fever, constitutional symptoms, and respiratory symptoms. However, atypical presentations are also well known. Though isolated mesenteric arterial occlusion associated with COVID-19 has been reported in literature, combined superior mesenteric arterial and venous thrombosis is rare. We report a case of combined superior mesenteric arterial and venous occlusion associated with COVID-19 infection. Case Report We report a case of a 45-year-old man who was a health care worker who presented to the emergency department with severe abdominal pain. The clinical examination was unremarkable, but imaging revealed acute mesenteric ischemia caused by superior mesenteric artery and superior mesenteric vein occlusion. Imaging of the chest was suggestive of COVID-19 infection, which was later confirmed with reverse transcription polymerase chain reaction of his nasopharyngeal swab. To date, only 1 case of combined superior mesenteric artery and superior mesenteric vein thrombosis caused by COVID-19 has been reported. Why Should an Emergency Physician Be Aware of This? During the COVID-19 pandemic it is important to keep mesenteric ischemia in the differential diagnosis of unexplained abdominal pain. Routinely adding high-resolution computed tomography of the chest to abdominal imaging should be considered in patients with acute abdomen because it can help to identify COVID-19 immediately. © 2020 Elsevier Inc.

Background Alcoholic chronic pancreatitis (ACP) is a serious inflammatory disorder of the exocrine pancreatic gland. A previous study from this laboratory showed that ethanol (EtOH) causes cytotoxicity, dysregulates AMPKα and ER/oxidative stress signaling, and induces inflammatory responses in primary human pancreatic acinar cells (hPACs). Here we examined the differential cytotoxicity of EtOH and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters; FAEEs) metabolites in hPACs was examined to understand the metabolic basis and mechanism of ACP. Methods We evaluated concentration-dependent cytotoxicity, AMPKα inactivation, ER/oxidative stress, and inflammatory responses in hPACs by incubating them for 6 h with EtOH, acetaldehyde, or FAEEs at clinically relevant concentrations reported in alcoholic subjects using conventional methods. Cellular bioenergetics (mitochondrial stress and a real-time ATP production rate) were determined using Seahorse XFp Extracellular Flux Analyzer in AR42J cells treated with acetaldehyde or FAEEs. Results We observed concentration-dependent increases in LDH release, inactivation of AMPKα along with upregulation of ACC1 and FAS (key lipogenic proteins), downregulation of p-LKB1 (an oxidative stress-sensitive upstream kinase regulating AMPKα) and CPT1A (involved in β-oxidation of fatty acids) in hPACs treated with EtOH, acetaldehyde, or FAEEs. Concentration-dependent increases in oxidative stress and ER stress as measured by GRP78, unspliced XBP1, p-eIF2α, and CHOP along with activation of p-JNK1/2, p-ERK1/2, and p-P38MAPK were present in cells treated with EtOH, acetaldehyde, or FAEEs, respectively. Furthermore, a significant decrease was observed in the total ATP production rate with subsequent mitochondrial stress in AR42J cells treated with acetaldehyde and FAEEs. Conclusions EtOH and its metabolites, acetaldehyde and FAEEs, caused cytotoxicity, ER/oxidative and mitochondrial stress, and dysregulated AMPKα signaling, suggesting a key role of EtOH metabolism in the etiopathogenesis of ACP. Because oxidative EtOH metabolism is negligible in the exocrine pancreas, the pathogenesis of ACP could be attributable to the formation of FAEEs and related pancreatic acinar cell injury.

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples ( n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p ( P = 0.03), hsa-miR-148a-3p ( P = 0.04) and hsa-miR-221-3p ( P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p ( P = 0.04) and hsa-miR-7-5p ( P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p ( P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p ( P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg ( r = −0.20, P = 0.02). Also, hsa-miR-200c ( r = 0.18, P = 0.03) and hsa-miR-221-3p ( r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

Supplemental Material, sj-pdf-1-cll-10.1177_0963689721999330 for Circulating miRNA in Patients Undergoing Total Pancreatectomy and Islet Autotransplantation by Srividya Vasu, Jiemin M. Yang, James Hodges, Maisam A. Abu-El-Haija, David B. Adams, Appakalai N. Balamurugan, Greg J. Beilman, Srinath Chinnakotla, Darwin L. Conwell, Martin L. Freeman, Timothy B. Gardner, Betul Hatipoglu, Varvara Kirchner, Luis F. Lara, Katherine A. Morgan, Jaimie D. Nathan, Andrew Posselt, Timothy L. Pruett, Sarah J. Schwarzenberg, Vikesh K. Singh, Martin Wijkstrom, Piotr Witkowski, Bashoo Naziruddin and Melena D. Bellin in Cell Transplantation

Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved β-oxidation of fatty acids). These cells also showed significant ER stress as evidenced by the increased expression for GRP78, IRE1α, and PERK/CHOP arm of unfolded protein response promoting apoptosis and activating p-JNK1/2 and p-ERK1/2 with increased secretion of cytokines. AR42J cells treated with EtOH showed increased oxidative stress, impaired mitochondrial biogenesis, and decreased ATP production rate. However, AMPKα activation by AICAR attenuated EtOH-induced ER/oxidative stress, lipogenesis, and inflammatory responses as well as the formation of FAEEs and restored mitochondrial function in hPACs as well as AR42J cells. Therefore, it is likely that EtOH-induced inactivation of AMPKα plays a crucial role in acinar cell injury leading to pancreatitis. Findings from this study also suggest that EtOH-induced inactivation of AMPKα is closely related to ER/oxidative stress and synthesis of FAEEs, as activation of AMPKα by AICAR attenuates formation of FAEEs, ER/oxidative stress and lipogenesis, and improves inflammatory responses and mitochondrial bioenergetics.