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1.  Endoscopic Anterior Skull Base Surgery: Intraoperative Considerations of the Crista Galli 
Skull Base  2011;21(2):83-86.
We sought to measure the anatomic dimensions of the crista galli in a consecutive series of patients undergoing the endoscopic transcribriform approach for anterior skull base tumors at a tertiary academic university hospital. We performed a retrospective chart review of patients undergoing purely endoscopic transcribriform surgery for sinonasal and skull base lesions. Main outcome measures included radiological dimensions of the crista galli. A total of 12 patients were identified and treated by the senior authors at the University of Pennsylvania. The average crista galli dimensions were 12.7 ± 2.4 mm (anterior-posterior) and 12.9 ± 2.5 mm (cranial-caudal dimension). Knowledge of the dimensions of the crista galli is important in preoperative planning for both instrumentation and access.
doi:10.1055/s-0030-1263283
PMCID: PMC3312591  PMID: 22451806
Endoscopic skull base surgery; transcribriform; crista galli; radiology; anatomy
2.  Endoscopic Transcranial and Intracranial Resection: Case Series and Design of a Perioperative Management Protocol 
Skull Base  2011;21(1):13-22.
Purely endoscopic resections of transcranial/intracranial pathology represent an exciting minimally invasive option for some patients. There is an abundance of literature on surgical techniques, though very little deals with perioperative management, which is critical for good outcomes. We present a detailed case review and a perioperative management protocol with specific reference to skull base and neuroanatomy. We performed a retrospective chart review and analysis of outcomes and complications by approach and design and prospective employment of a perioperative management protocol in a major tertiary care referral hospital. We included patients undergoing endoscopic skull base approaches by the two senior surgeons from September 2005 to April 2009, selecting of transcranial/intracranial cases for detailed review. Our main outcome measures included perioperative morbidity, mortality, and complications; degree of resection; recurrence rate; and survival. Fifteen patients met study criteria. No perioperative mortality occurred. There were two major and four minor complications. Mean follow-up was 15 months; 11/13 patients with malignancies had no evidence of disease. A perioperative management protocol was designed from these data and has resulted in decreased lumbar drainage and increased fluid/electrolyte monitoring. Endoscopic transcranial/intracranial anterior skull base surgery is both safe and effective when a complete understanding of the surgery and perioperative management is achieved.
doi:10.1055/s-0030-1261265
PMCID: PMC3312415  PMID: 22451795
Extended endonasal approach; endoscopic; anterior skull base; skull base neoplasm
5.  Spongosine Production by a Vibrio harveyi Strain Associated with the Sponge Tectitethya crypta 
Journal of natural products  2015;78(3):493-499.
Spongosine (1), deoxyspongosine (2), spongothymidine (Ara T) (3), and spongouridine (Ara U) were isolated from the Caribbean sponge Tectitethya crypta and given the general name “spongonucleosides”. Spongosine, a methoxyadenosine derivative, has demonstrated a diverse bioactivity profile including anti-inflammatory activity and analgesic and vasodilation properties. Investigations into unusual nucleoside production by T. crypta-associated microorganisms using mass spectrometric techniques have identified a spongosine-producing strain of Vibrio harveyi and several structurally related compounds from multiple strains.
Graphical abstract
doi:10.1021/np5009762
PMCID: PMC5065018  PMID: 25668560
6.  Virulence Associated Genes-Deleted Salmonella Montevideo Is Attenuated, Highly Immunogenic and Confers Protection against Virulent Challenge in Chickens 
To construct a novel live vaccine against Salmonella enterica serovar Montevideo (SM) infection in chickens, two important bacterial regulatory genes, lon and cpxR, which are associated with invasion and virulence, were deleted from the wild type SM genome. Attenuated strains, JOL1625 (Δlon), JOL1597 (ΔcpxR), and JOL1599 (ΔlonΔcpxR) were thereby generated. Observations with scanning electron microscopy suggested that JOL1625 and JOL1599 cells showed increased ruffled surface which may be related to abundant extracellular polysaccharide (EPS) production. JOL1597 depicted milder ruffled surface but showed increased surface corrugation. ConA affinity-based fluorometric quantification and fluorescence microscopy revealed significant increases in EPS production in JOL1625 and JOL1599. Four weeks old chickens were used for safety and immunological studies. The mutants were not observed in feces beyond day 3 nor in spleen and cecum beyond day 7, whereas wild type SM was detected for at least 2 weeks in spleen and cecum. JOL1599 was further evaluated as a vaccine candidate. Chickens immunized with JOL1599 showed strong humoral responses, as indicated by systemic IgG and secretory IgA levels, as well as strong cell-mediated immune response, as indicated by increased lymphocyte proliferation. JOL1599-immunized groups also showed significant degree of protection against wild type challenge. Our results indicate that Δlon- and/or ΔcpxR-deleted SM exhibited EPS-enhanced immunogenicity and attenuation via reduced bacterial cell intracellular replication, conferred increased protection, and possess safety qualities favorable for effective vaccine development against virulent SM infections.
doi:10.3389/fmicb.2016.01634
PMCID: PMC5060950  PMID: 27785128
Salmonella Montevideo; live attenuated vaccine; chicken model; protection efficacy; deletion mutants
7.  Reduced Mortality by Physician-Staffed HEMS Dispatch for Adult Blunt Trauma Patients in Korea 
Journal of Korean Medical Science  2016;31(10):1656-1661.
The aim of this study was to investigate the efficiency of domestic physician-staffed helicopter emergency medical service (HEMS) for the transport of patients with severe trauma to a hospital. The study included patients with blunt trauma who were transported to our hospital by physician-staffed HEMS (Group P; n = 100) or nonphysician-staffed HEMS (Group NP; n = 80). Basic patient characteristics, transport time, treatment procedures, and medical treatment outcomes assessed using the Trauma and Injury Severity Score (TRISS) were compared between groups. We also assessed patients who were transported to the hospital within 3 h of injury in Groups P (Group P3; n = 50) and NP (Group NP3; n = 74). The severity of injury was higher, transport time was longer, and time from hospital arrival to operation room transfer was shorter for Group P than for Group NP (P < 0.001). Although Group P patients exhibited better medical treatment outcomes compared with Group NP, the difference was not statistically significant (P = 0.134 vs. 0.730). However, the difference in outcomes was statistically significant between Groups P3 and NP3 (P = 0.035 vs. 0.546). Under the current domestic trauma patient transport system in South Korea, physician-staffed HEMS are expected to increase the survival of patients with severe trauma. In particular, better treatment outcomes are expected if dedicated trauma resuscitation teams actively intervene in the medical treatment process from the transport stage and if patients are transported to a hospital to receive definitive care within 3 hours of injury.
Graphical Abstract
doi:10.3346/jkms.2016.31.10.1656
PMCID: PMC4999411  PMID: 27550497
Injuries; Emergencies; Aircraft; Resuscitation; Treatment Outcome; Prehospital Emergency Care; Trauma Centers
8.  Exome Sequencing and Prediction of Long-Term Kidney Allograft Function 
PLoS Computational Biology  2016;12(9):e1005088.
Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients.
Author Summary
The article describes a new concept to help match donor organs to recipients for kidney transplantation. The concept relies on the ability to measure the individual DNA of potential donors and recipients. When the data about genomes (i.e., DNA) of possible donors and recipients are available, the article describes how data can be computationally compared to identify differences in these genomes and quantify the possible future impact of these differences on the functioning of the graft. The concept presented in the article determines a score for each pair of possible donor and recipient. This score is called the allogenomics mismatch score. The study tested the ability of this score to predict graft function (the ability of the graft to filter blood) in the recipient several years after transplantation surgery. The study found that, in three small sets of patients tested, the score is a strong predictor of graft function. Prior studies often assumed that only a small number of locations in the genome were most likely to have an impact on graft function, while this study found initial evidence that differences across DNA that code for a large number of proteins can have a combined impact on graft function.
doi:10.1371/journal.pcbi.1005088
PMCID: PMC5042552  PMID: 27684477
9.  Non-invasive detection of 2-hydroxyglutarate in IDH-mutated gliomas using two-dimensional localized correlation spectroscopy (2D L-COSY) at 7 Tesla 
Background
Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the “oncometabolite” 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism. This study aims to assess tumor metabolism using 2D L-COSY at 7T for the detection of 2HG in IDH-mutant gliomas.
Methods
Nine treatment-naïve patients with suspected intracranial neoplasms were scanned at 7T MRI/MRS scanner using the 2D L-COSY technique. 2D-spectral processing and analyses were performed using a MATLAB-based reconstruction algorithm. Cross and diagonal peak volumes were quantified in the 2D L-COSY spectra and normalized with respect to the creatine peak at 3.0 ppm and quantified data were compared with previously-published data from six normal subjects. Detection of 2HG was validated using findings from immunohistochemical (IHC) staining in patients who subsequently underwent surgical resection.
Results
2HG was detected in both of the IDH-mutated gliomas (grade III Anaplastic Astrocytoma and grade II Diffuse Astrocytoma) and was absent in IDH wild-type gliomas and in a patient with breast cancer metastases. 2D L-COSY was also able to resolve complex and overlapping resonances including phosphocholine (PC) from glycerophosphocholine (GPC), lactate (Lac) from lipids and glutamate (Glu) from glutamine (Gln).
Conclusions
This study demonstrates the ability of 2D L-COSY to unambiguously detect 2HG in addition to other neuro metabolites. These findings may aid in establishing 2HG as a biomarker of malignant progression as well as for disease monitoring in IDH-mutated gliomas.
doi:10.1186/s12967-016-1035-1
PMCID: PMC5034563  PMID: 27659543
2-Hydroxyglutarate; Isocitrate dehydrogenase; Phosphocholine; Correlation spectroscopy; Brain tumor
10.  Development and validation of a prognostic index for allograft outcome in kidney recipients with transplant glomerulopathy 
Kidney international  2016;89(2):450-458.
We studied 92 patients with transplant glomerulopathy to develop a prognostic index based on the risk factors for allograft failure within five years of diagnosis (Development cohort). During 60 months (median) follow up, 64 patients developed allograft failure. A chronic-inflammation score generated by combining Banff ci, ct and ti scores, serum creatinine and proteinuria at biopsy, were independent risk factors for allograft failure. Based on the Cox model, we developed a prognostic index and classified patients into risk groups. Compared to the low risk group (median allograft survival over 60 months from diagnosis), patients in the medium risk group had a hazard ratio of 2.83 (median survival 25 months), while those in the high risk group had a hazard ratio of 5.96 (median survival 3.7 months). We next evaluated the performance of the prognostic index in an independent external cohort of 47 patients with transplant glomerulopathy (Validation cohort). The hazard ratios were 2.18 (median survival 19 months) and 16.27 (median survival 1.6 months), respectively, for patients in the medium and high risk groups, compared to the low risk group (median survival 47 months). Our prognostic index model did well in measures of discrimination and calibration. Thus, risk stratification of transplant glomerulopathy based on our prognostic index may provide informative insight for both the patient and physician regarding prognosis and treatment.
doi:10.1038/ki.2015.288
PMCID: PMC4814368  PMID: 26422505
chronic allograft nephropathy; kidney biopsy
11.  Technology-Enabled Remote Monitoring and Self-Management — Vision for Patient Empowerment Following Cardiac and Vascular Surgery: User Testing and Randomized Controlled Trial Protocol 
JMIR Research Protocols  2016;5(3):e149.
Background
Tens of thousands of cardiac and vascular surgeries (CaVS) are performed on seniors in Canada and the United Kingdom each year to improve survival, relieve disease symptoms, and improve health-related quality of life (HRQL). However, chronic postsurgical pain (CPSP), undetected or delayed detection of hemodynamic compromise, complications, and related poor functional status are major problems for substantial numbers of patients during the recovery process. To tackle this problem, we aim to refine and test the effectiveness of an eHealth-enabled service delivery intervention, TecHnology-Enabled remote monitoring and Self-MAnagemenT—VIsion for patient EmpoWerment following Cardiac and VasculaR surgery (THE SMArTVIEW, CoVeRed), which combines remote monitoring, education, and self-management training to optimize recovery outcomes and experience of seniors undergoing CaVS in Canada and the United Kingdom.
Objective
Our objectives are to (1) refine SMArTVIEW via high-fidelity user testing and (2) examine the effectiveness of SMArTVIEW via a randomized controlled trial (RCT).
Methods
CaVS patients and clinicians will engage in two cycles of focus groups and usability testing at each site; feedback will be elicited about expectations and experience of SMArTVIEW, in context. The data will be used to refine the SMArTVIEW eHealth delivery program. Upon transfer to the surgical ward (ie, post-intensive care unit [ICU]), 256 CaVS patients will be reassessed postoperatively and randomly allocated via an interactive Web randomization system to the intervention group or usual care. The SMArTVIEW intervention will run from surgical ward day 2 until 8 weeks following surgery. Outcome assessments will occur on postoperative day 30; at week 8; and at 3, 6, 9, and 12 months. The primary outcome is worst postop pain intensity upon movement in the previous 24 hours (Brief Pain Inventory-Short Form), averaged across the previous 14 days. Secondary outcomes include a composite of postoperative complications related to hemodynamic compromise—death, myocardial infarction, and nonfatal stroke— all-cause mortality and surgical site infections, functional status (Medical Outcomes Study Short Form-12), depressive symptoms (Geriatric Depression Scale), health service utilization-related costs (health service utilization data from the Institute for Clinical Evaluative Sciences data repository), and patient-level cost of recovery (Ambulatory Home Care Record). A linear mixed model will be used to assess the effects of the intervention on the primary outcome, with an a priori contrast of weekly average worst pain intensity upon movement to evaluate the primary endpoint of pain at 8 weeks postoperation. We will also examine the incremental cost of the intervention compared to usual care using a regression model to estimate the difference in expected health care costs between groups.
Results
Study start-up is underway and usability testing is scheduled to begin in the fall of 2016.
Conclusions
Given our experience, dedicated industry partners, and related RCT infrastructure, we are confident we can make a lasting contribution to improving the care of seniors who undergo CaVS.
doi:10.2196/resprot.5763
PMCID: PMC4999307  PMID: 27480247
technology-enabled self-management; remote automated external monitoring; usability testing; randomized controlled trial
12.  CCR5 ameliorates Japanese encephalitis via dictating the equilibrium of regulatory CD4+Foxp3+ T and IL-17+CD4+ Th17 cells 
Background
CCR5 is a CC chemokine receptor involved in the migration of effector leukocytes including macrophages, NK, and T cells into inflamed tissues. Also, the role of CCR5 in CD4+Foxp3+ regulatory T cell (Treg) homing has recently begun to grab attention. Japanese encephalitis (JE) is defined as severe neuroinflammation of the central nervous system (CNS) following infection with mosquito-borne flavivirus JE virus. However, the potential contribution of CCR5 to JE progression via mediating CD4+Foxp3+ Treg homing has not been investigated.
Methods
Infected wild-type (Ccr5+/+) and CCR5-deficient (Ccr5−/−) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, NK- and JEV-specific T cell responses were analyzed. Adoptive transfer of CCR5+CD4+Foxp3+ Tregs was used to evaluate the role of Tregs in JE progression.
Results
CCR5 ablation exacerbated JE without altering viral burden in the extraneural and CNS tissues, as manifested by increased CNS infiltration of Ly-6Chi monocytes and Ly-6Ghi granulocytes. Compared to Ccr5+/+ mice, Ccr5−/− mice unexpectedly showed increased responses of IFN-γ+NK and CD8+ T cells in the spleen, but not CD4+ T cells. More interestingly, CCR5-ablation resulted in a skewed response to IL-17+CD4+ Th17 cells and correspondingly reduced CD4+Foxp3+ Tregs in the spleen and brain, which was closely associated with exacerbated JE. Our results also revealed that adoptive transfer of sorted CCR5+CD4+Foxp3+ Tregs into Ccr5−/− mice could ameliorate JE progression without apparently altering the viral burden and CNS infiltration of IL-17+CD4+ Th17 cells, myeloid-derived Ly-6Chi monocytes and Ly-6Ghi granulocytes. Instead, adoptive transfer of CCR5+CD4+Foxp3+ Tregs into Ccr5−/− mice resulted in increased expression of anti-inflammatory cytokines (IL-10 and TGF-β) in the spleen and brain, and transferred CCR5+ Tregs were found to produce IL-10.
Conclusions
CCR5 regulates JE progression via governing timely and appropriate CNS infiltration of CD4+Foxp3+ Tregs, thereby facilitating host survival. Therefore, this critical and extended role of CCR5 in JE raises possible safety concerns regarding the use of CCR5 antagonists in human immunodeficiency virus (HIV)-infected individuals who inhabit regions in which both HIV and flaviviruses, such as JEV and West Nile virus, are endemic.
doi:10.1186/s12974-016-0656-x
PMCID: PMC5050958  PMID: 27439902
CCR5; Japanese encephalitis; CD4+Foxp3+ Tregs; IL-17+CD4+ Th17; Neuroinflammation
13.  Impact of the National Health Service Health Check on cardiovascular disease risk: a difference-in-differences matching analysis 
Background:
The National Health Service Health Check program in England is the largest cardiovascular risk assessment and management program in the world. We assessed the effect of this program on modelled risk of cardiovascular disease, individual risk factors for cardiovascular disease, prescribing of relevant medications and diagnosis of vascular disease.
Methods:
We obtained retrospective electronic medical records for a randomly selected sample of 138 788 patients aged 40–74 years registered with 462 English general practices participating in the Clinical Practice Research Datalink between 2009 and 2013. We used a quasi-experimental design of difference-indifferences matching analysis to compare changes in outcomes between Health Check attendees and nonattendees, with a median follow-up time of 2 years.
Results:
Overall, 21.4% of the eligible population attended a Health Check. After matching (n = 29 672 in each group), attendees had a significant absolute reduction in modelled risk for cardiovascular disease (−0.21%, 95% confidence interval [CI] −0.24% to −0.19%) and individual risk factors: systolic blood pressure (−2.51 mm Hg, 95% CI −2.77 to −2.25 mm Hg), diastolic blood pressure (−1.46 mm Hg, 95% CI −1.62 to −1.29 mm Hg), body mass index (−0.27, 95% CI −0.34 to −0.20) and total cholesterol (−0.15 mmol/L, 95% CI −0.18 to −0.13 mmol/L). Statins were prescribed for 39.9% of attendees who were at high risk for cardiovascular disease. The program resulted in significantly more diagnoses of selected vascular diseases among attendees, with the largest increases for hypertension (2.99%) and type 2 diabetes mellitus (1.31%).
Interpretation:
The National Health Service Health Check program had statistically significant but clinically modest impacts on modelled risk for cardiovascular disease and individual risk factors, although diagnosis of vascular disease increased. Overall program performance was substantially below national and international targets, which highlights the need for careful planning, monitoring and evaluation of similar initiatives internationally.
doi:10.1503/cmaj.151201
PMCID: PMC4938708  PMID: 27141033
14.  Divergent clonal selection dominates medulloblastoma at recurrence 
Morrissy, A. Sorana | Garzia, Livia | Shih, David J. H. | Zuyderduyn, Scott | Huang, Xi | Skowron, Patryk | Remke, Marc | Cavalli, Florence M. G. | Ramaswamy, Vijay | Lindsay, Patricia E. | Jelveh, Salomeh | Donovan, Laura K. | Wang, Xin | Luu, Betty | Zayne, Kory | Li, Yisu | Mayoh, Chelsea | Thiessen, Nina | Mercier, Eloi | Mungall, Karen L. | Ma, Yusanne | Tse, Kane | Zeng, Thomas | Shumansky, Karey | Roth, Andrew J. L. | Shah, Sohrab | Farooq, Hamza | Kijima, Noriyuki | Holgado, Borja L. | Lee, John J. Y. | Matan-Lithwick, Stuart | Liu, Jessica | Mack, Stephen C. | Manno, Alex | Michealraj, K. A. | Nor, Carolina | Peacock, John | Qin, Lei | Reimand, Juri | Rolider, Adi | Thompson, Yuan Y. | Wu, Xiaochong | Pugh, Trevor | Ally, Adrian | Bilenky, Mikhail | Butterfield, Yaron S. N. | Carlsen, Rebecca | Cheng, Young | Chuah, Eric | Corbett, Richard D. | Dhalla, Noreen | He, An | Lee, Darlene | Li, Haiyan I. | Long, William | Mayo, Michael | Plettner, Patrick | Qian, Jenny Q. | Schein, Jacqueline E. | Tam, Angela | Wong, Tina | Birol, Inanc | Zhao, Yongjun | Faria, Claudia C. | Pimentel, José | Nunes, Sofia | Shalaby, Tarek | Grotzer, Michael | Pollack, Ian F. | Hamilton, Ronald L. | Li, Xiao-Nan | Bendel, Anne E. | Fults, Daniel W. | Walter, Andrew W. | Kumabe, Toshihiro | Tominaga, Teiji | Collins, V. Peter | Cho, Yoon-Jae | Hoffman, Caitlin | Lyden, David | Wisoff, Jeffrey H. | Garvin, James H. | Stearns, Duncan S. | Massimi, Luca | Schüller, Ulrich | Sterba, Jaroslav | Zitterbart, Karel | Puget, Stephanie | Ayrault, Olivier | Dunn, Sandra E. | Tirapelli, Daniela P. C. | Carlotti, Carlos G. | Wheeler, Helen | Hallahan, Andrew R. | Ingram, Wendy | MacDonald, Tobey J. | Olson, Jeffrey J. | Van Meir, Erwin G. | Lee, Ji-Yeoun | Wang, Kyu-Chang | Kim, Seung-Ki | Cho, Byung-Kyu | Pietsch, Torsten | Fleischhack, Gudrun | Tippelt, Stephan | Ra, Young Shin | Bailey, Simon | Lindsey, Janet C. | Clifford, Steven C. | Eberhart, Charles G. | Cooper, Michael K. | Packer, Roger J. | Massimino, Maura | Garre, Maria Luisa | Bartels, Ute | Tabori, Uri | Hawkins, Cynthia E. | Dirks, Peter | Bouffet, Eric | Rutka, James T. | Wechsler-Reya, Robert J. | Weiss, William A. | Collier, Lara S. | Dupuy, Adam J. | Korshunov, Andrey | Jones, David T. W. | Kool, Marcel | Northcott, Paul A. | Pfister, Stefan M. | Largaespada, David A. | Mungall, Andrew J. | Moore, Richard A. | Jabado, Nada | Bader, Gary D. | Jones, Steven J. M. | Malkin, David | Marra, Marco A. | Taylor, Michael D.
Nature  2016;529(7586):351-357.
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
doi:10.1038/nature16478
PMCID: PMC4936195  PMID: 26760213
15.  Abstracts from the 5th International Conference for Healthcare and Medical Students (ICHAMS) 
Sweeney, Yvonne | O’Neill, Hugh | Duffy, Garry | Creegan, Daniel | Bustos, Viviana | Harvey, Brian J. | Dalphy, Alexander | O’Grady, Anthony | Kay, Elaine | Samelska, Katarzyna | Izdebska, Justyna | Kurowska, Anna | Al-Zubaidy, Rena | Mroz, Magdalena | Harvey, Brian | Fagan, Ryan | French, Helen | Cuddy, Vanessa | Ashton, Jennifer | Clarke, Michelle | Sayedalamin, Zaid | Baig, Mukhtiar | Almutairi, Osama | Allam, Hassan | Halawa, Taher F. | Atta, Hazem M. | Sirone, Linda | Erts, Renars | Pavare, Jana | Richter, Louis | Morris, Joseph | Oglesby, Irene | Dunne, Eimear | Kenny, Dermot | Khayyat, Ibrahim Mohammed Mahdi | Salgado, Viviana Bustos | Harvey, Brian J. | Tan, Jonavan | Moneley, Daragh | Leahy, Austin | Fitzgerald, Patricia | Fennelly, Evelyn | Harkin, Grace | Lee, John | O’Sullivan, Erica | Kirby, Brian | O’Neill, Sarah | Gonciar, Diana | Mocan, Teodora | Matea, Cristian | Mocan, Lucian | Iancu, Cornel | Doran, Chloe | Hoolahan, Sarah | Engel, Tobias | Alkhattab, Maha | Alekseeva, Tijna | Lackington, William | O’Brien, Fergal | Moollan, Nabeehah | Doran, Chloe | McElvaney, Noel Gerry | Gunaratnam, Cedric | Scanlon, Lorraine | Brady, Noeleen | Timmons, Suzanne | Bresler, Richard | Abreu, Zita | Trohonel, Stefan | Bargman, Joanne | Mirza, Ahmad A. | Badrek-Amoudi, Ahmed | Aun, Rakan H. | Senan, Hussam A. | Mirza, Abdulrahim A. | Binsaad, Mohammed S. | Farooq, Mian U. | Nandi, Saheli | D’Orsi, Beatrice | Prehn, Jochen | Zharova, Mariia | Umrukhin, Pavel | Evans-Uhegbu, Wendy | Doyle, Frank | Kudryashova, Hope | Dorris, Derek | Cummins, Anthony | Doheny-Shanley, Jemma | Woodward, Mark | Hayes, Wesley | Yostos, Marina | Cotter, David | Focking, Melanie | Stancu, Samantha | Iordache, Florin | Popescu, Bogdan A. | Akanmu, Muhammad-Mujtaba A. | Robert, Alero A. | Oridota, Ezekiel O. | Mirza, Ahmad A. | Alzahrani, Ali K. | Alfarhan, Omar | Eldin, Essam Nour | MacManus, Bronagh | Keane, Owen | Hillery, Patrick | Lee, James | O’Reilly, Hugh | Collins, Niamh | Abu saq, Ibrahim | Al Mufarrih, Abdullah | Jaafari, Muath | Al Mahayni, Abdullah | Bawazir, Amen | Alkhateeb, Sultan | Dhannoon, Amenah | Vareslija, Damir | Hill, Arnold | Young, Leonie | Donoghue, Declan | Walsh, Criona | McCabe, Aileen | Pope, John | Pasco, Saturnino | Fallon, Caroline | Solanki, Don | Kiernan, Fiona | Galvin, Sinead | Mucvimicc, Jquan | Mulvihill, Johanna | Mirza, Ahmad A. | Elmosry, Soha A. | De Souza, Lorenza Andres Ameida | de Oliveira, Yuri | Menezes, Diego | Santos, Alene Vanessa | Asraf, Ahmad Zaki | Stallings, Raymond | Piskareva, Olga | Conlon, Ross | Sweeney-Landers, Siún | Burke, Cathy | Behan, Paraic | Sreenan, Seamus | Organjee, Ahmed | Crosbie-Staunton, Tatsiana | Reeves, Emer | McElvaney, Noel | Mieres, Crystal | Young, Leonie | Charmsaz, Sara | Al-Jalamdeh, Aya | Corcoran, Mary | McElligott, Martha | Stevens, Niall | Humphreys, Hilary | Barnawi, Rashid | Ghurab, Abdulaziz | Alfaer, Sultan | Balubaid, Hassan | Hanbazazah, Kamal | Bukhari, Mohammed | Alsakkaf, Mohammed | Mirza, Ahmad | Mohammed, Amrallah | Pratanata, Anastasia | Nathania, Maria | Annisa, Tsabita | Dewi, Beti | Lee, Kuok Zhen | Carroll, Tomas P. | Fee, Laura | McElvaney, Noel G. | White, Rachel C. | Brady, Robert T | O’Brien, Fergal
BMC Proceedings  2016;10(Suppl 4):4.
Table of contents
O1: Assessing the protective effect of dexrazoxane against doxorubicin-induced toxicity in HL-1 cardiomyocytes
Yvonne Sweeney, Hugh O’Neill, Garry Duffy
O2: Role of KCNQ1 in epithelial barrier repair
Daniel Creegan, Viviana Bustos, Brian J. Harvey
O3: The suitability of non-small cell lung cancer cytology preparations for the analysis of anaplastic lymphoma kinase gene rearrangements
Alexander Dalphy, Anthony O’Grady, Elaine Kay
O4: Penetrating keratoplasty and descemet’s stripping automated endothelial keratoplasty may lead to deterioration in glaucoma management
Katarzyna Samelska, Justyna Izdebska, Anna Kurowska
O5: The effect of Resolvin D1 on normal and cystic fibrosis human bronchial epithelium
Rena Al-Zubaidy, Magdalena Mroz, Brian Harvey
O6: Validity of clinical assessment compared with plantar fascia thickness on ultrasound for plantar fasciitis: a cross-sectional study
Ryan Fagan, Helen French, Vanessa Cuddy, Jennifer Ashton, Michelle Clarke
P1: Undergraduate medical research in Gulf Cooperation Council (GCC) countries: A descriptive study of students’ views
Zaid Sayedalamin, Mukhtiar Baig, Osama Almutairi, Hassan Allam, Taher F. Halawa, Hazem M. Atta
P2: Positive fluid balance as a prognostic factor in children with sepsis during first 3 hours of resuscitation in intensive care unit
Linda Sirone, Renars Erts, Jana Pavare
P3: Patients on aspirin: Too little or too much?
Louis Richter, Joseph Morris, Irene Oglesby, Eimear Dunne, Dermot Kenny
P4: Beta catenin/TCF4 activation reduces KCNQ1 current in colonic monolayers
Ibrahim Mohammed Mahdi Khayyat, Viviana Bustos Salgado, Brian J. Harvey
P5: Size Matters. Abdominal aortic aneurysm: adherence to surveillance imaging guidelines
Jonavan Tan, Daragh Moneley, Austin Leahy, Patricia Fitzgerald
P6: Endoscopic retrograde cholangiopancreatography in the west of Ireland: Procedural outcomes and peri-procedural complications
Evelyn Fennelly, Grace Harkin, John Lee
P7: The effect of the extracellular redox environment on polyamine-platelet interactions
Erica O’Sullivan, Brian Kirby, Sarah O’Neill
P8: Functionalized gold nanoparticles: preliminary data on in vitro toxicity and comparative photothermal effect
Diana Gonciar, Teodora Mocan, Cristian Matea, Lucian Mocan, Cornel Iancu
P9: Imaging proteasomal inhibition after seizures in the brain: A study into cellular activity in the hippocampus of epileptic transgenic mice
Chloe Doran, Sarah Hoolahan, Tobias Engel
P10: Investigating the ability of the Olfactory epithelial stem cells to differentiate into glial cells by assessing cell morphology and marker expression
Maha Alkhattab, Tijna Alekseeva, William Lackington, Fergal O’Brien
P11: Beaumont Hospital cystic fibrosis service audit and annual report
Nabeehah Moollan, Chloe Doran, Noel Gerry McElvaney, Cedric Gunaratnam
P12: Quick cognitive screening: the 6-item cognitive impairment test and the temporal orientation score
Lorraine Scanlon, Noeleen Brady, Suzanne Timmons
P13: Granular analysis of causes of peritoneal dialysis technique failure in the first six months of therapy
Richard Bresler, Zita Abreu, Stefan Trohonel, Joanne Bargman
P14: Job satisfaction of surgeons working in hajj pilgrimage: a multicenter study
Ahmad A. Mirza, Ahmed Badrek-Amoudi, Rakan H. Aun, Hussam A. Senan, Abdulrahim A. Mirza, Mohammed S. Binsaad, Mian U. Farooq
P15: Investigation of the role of Bok using wild-type, bax-, bok-, and bax/bok-double-deficient mice
Saheli Nandi, Beatrice D’Orsi, Jochen Prehn
P16: Is it possible to predict resistance of an organism to stress based on the level of corticosterone?
Mariia Zharova, Pavel Umrukhin
P17: Investigating the strength model of self-regulation (ego depletion) and medical decision making and error in medical students
Wendy Evans-Uhegbu, Frank Doyle, Hope Kudryashova, Derek Dorris, Anthony Cummins
P18: Does bladder drainage with intermittent catheterisation preserve kidney function in boys with posterior urethral valves?
Jemma Doheny-Shanley, Mark Woodward, Wesley Hayes
P19: Investigating the role of Stonin 2, a Clathrin Mediated Endocytosis adaptor protein, in altered hippocampal synaptic transmission characterized in schizophrenia
Marina Yostos, David Cotter, Melanie Focking
P20: Predicting complications after colon resection
Samantha Stancu, Florin Iordache, Bogdan A. Popescu
P21: Knowledge, attitude and practice of the methods of primary and secondary prevention of cervical cancer among NYSC members in Lagos state, Nigeria
Muhammad-Mujtaba A. Akanmu, Alero A. Robert, Ezekiel O. Oridota
P22: Incidental glucose and lipid metabolisms disorders among office workers: a cross sectional study
Ahmad A. Mirza, Ali K. Alzahrani, Omar Alfarhan, Essam Nour Eldin
P23: Differentiating clinically significant spinal injuries; a review of emergency department presentations
Bronagh MacManus, Owen Keane, Patrick Hillery, James Lee, Hugh O’Reilly, Niamh Collins
P24: Pattern of renal colic occurrence due to urinary stones during Ramadan and other months of the year at King Abdulaziz Medical City, Riyadh, KSA
Ibrahim Abu saq, Abdullah Al Mufarrih, Muath Jaafari, Abdullah Al Mahayni, Amen Bawazir, Sultan Alkhateeb
P25: Proteomic analysis reveals novel AIB1 co-factors that may contribute to acquired endocrine resistance in breast cancer
Amenah Dhannoon, Damir Vareslija, Arnold Hill, Leonie Young
P26: Improving sedation practice in general ICU in Beaumont Hospital
Declan Donoghue, Criona Walsh, Aileen McCabe, John Pope, Saturnino Pasco, Caroline Fallon, Don Solanki, Fiona Kiernan, Sinead Galvin, Jquan Mucvimicc, Johanna Mulvihill
P27: Diagnosis and control of hypertension as indicators of the level of awareness among relatives of medical students
Ahmad A. Mirza, Soha A. Elmosry
P28: Evaluation of the antitumor potential from extracts of endemic plants of Brazilian caatinga against melanoma and hepatocarcinoma
Lorenza Andres Ameida De Souza, Yuri de Oliveira, Diego Menezes, Alene Vanessa Santos
P29: The role of Chromogranin A as a biomarker in drug resistant neuroblastoma
Ahmad Zaki Asraf, Raymond Stallings, Olga Piskareva, Ross Conlon
P30: Membrane sweep at term gestation in CUMH; a case-control study
Siún Sweeney-Landers, Cathy Burke
P31: Study of the variability of glucose levels in patients with diabetes undergoing continuous glucose monitoring
Paraic Behan, Seamus Sreenan
P32: Inflammatory cytokine response to decreased plasma alpha-1 antitrypsin levels in individuals with the MZ genotype
Ahmed Organjee, Tatsiana Crosbie-Staunton, Emer Reeves, Noel McElvaney
P33: Analysing the role of SRC-1 in breast cancer stem cell formation and activity
Crystal Mieres, Leonie Young, Sara Charmsaz
P34: Screening Streptococcus pneumoniae isolates for virulence genes
Aya Al-Jalamdeh, Mary Corcoran, Martha McElligott, Niall Stevens, Hilary Humphreys
P35: Assessment of the relevance of admission clerking criteria taught to medical students at King Abdulaziz University to real hospital practice
Rashid Barnawi, Abdulaziz Ghurab, Sultan Alfaer, Hassan Balubaid, Kamal Hanbazazah, Mohammed Bukhari
P36: Pattern of emergency department visits during Hajj period
Mohammed Alsakkaf, Ahmad Mirza, Amrallah Mohammed
P37: Anti-Dengue activity of Aspergillus terreus (sulochrin); An in vitro study
Anastasia Pratanata, Maria Nathania, Tsabita Annisa, Beti Dewi
P38: The comorbidome in alpha-1 antitrypsin deficiency
Kuok Zhen Lee, Tomas P. Carroll, Laura Fee, Noel G. McElvaney
P39: MLO-Y4 cells behave more like osteocytes in response to mechanical stimulation when cultured in 3D
Rachel C. White, Robert T Brady, Fergal O’Brien
doi:10.1186/s12919-016-0004-2
PMCID: PMC4943480
16.  Generation of Salmonella ghost cells expressing fimbrial antigens of enterotoxigenic Escherichia coli and evaluation of their antigenicity in a murine model 
Salmonella Typhimurium ghost cells expressing K88ab, K88ac, K99, and FasA fimbriae of enterotoxigenic Escherichia coli (ETEC) in their envelopes were constructed. The genes encoding the fimbriae were individually cloned into an expression plasmid, pMMP81, carrying the asd gene, which was subsequently electroporated into the Δasd S. Typhimurium mutant. Plasmid pJHLP99, carrying the phiX174 lysis gene E, was also subsequently electroporated into the Salmonella mutant. The presence of the individual fimbriae on the ghost cells was examined by Western blot analysis. Forty BALB/c mice were equally divided into 2 groups of 20 mice each. Group A mice were intramuscularly vaccinated with a mixture of the 4 ghost cells expressing the individual fimbriae. The group B mice were inoculated with sterile phosphate-buffered saline as a control. The antigen-specific serum IgG concentrations were significantly higher in group A than in group B from week 2 until week 6 after inoculation. In addition, the antigen-specific IgA concentrations in fecal samples were significantly higher in group A than in group B at week 2 after inoculation. A large difference between the groups in the number of antigen-specific IgA-secreting cells in the small intestine was observed by immunohistochemical study. Also, the splenic lymphocyte proliferative responses were significantly greater in group A than in the control mice. These results suggest that vaccination with our Salmonella ghost cells can induce both humoral and cell-mediated immune responses and that the increased number of antigen-specific IgA-secreting cells in the small intestine may be correlated with the elevated fecal IgA immune response.
PMCID: PMC4686033  PMID: 26733731
17.  Modulation of LMNA splicing as a strategy to treat prelamin A diseases 
The Journal of Clinical Investigation  null;126(4):1592-1602.
The alternatively spliced products of LMNA, lamin C and prelamin A (the precursor to lamin A), are produced in similar amounts in most tissues and have largely redundant functions. This redundancy suggests that diseases, such as Hutchinson-Gilford progeria syndrome (HGPS), that are caused by prelamin A–specific mutations could be treated by shifting the output of LMNA more toward lamin C. Here, we investigated mechanisms that regulate LMNA mRNA alternative splicing and assessed the feasibility of reducing prelamin A expression in vivo. We identified an exon 11 antisense oligonucleotide (ASO) that increased lamin C production at the expense of prelamin A when transfected into mouse and human fibroblasts. The same ASO also reduced the expression of progerin, the mutant prelamin A protein in HGPS, in fibroblasts derived from patients with HGPS. Mechanistic studies revealed that the exon 11 sequences contain binding sites for serine/arginine-rich splicing factor 2 (SRSF2), and SRSF2 knockdown lowered lamin A production in cells and in murine tissues. Moreover, administration of the exon 11 ASO reduced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model. Together, these studies identify ASO-mediated reduction of prelamin A as a potential strategy to treat prelamin A–specific diseases.
doi:10.1172/JCI85908
PMCID: PMC4811112  PMID: 26999604
18.  Protective efficacy and immune responses by homologous prime-booster immunizations of a novel inactivated Salmonella Gallinarum vaccine candidate 
Purpose
Salmonella enterica serovar Gallinarum (SG) ghost vaccine candidate was recently constructed. In this study, we evaluated various prime-boost vaccination strategies using the candidate strain to optimize immunity and protection efficacy against fowl typhoid.
Materials and Methods
The chickens were divided into five groups designated as group A (non-immunized control), group B (orally primed and boosted), group C (primed orally and boosted intramuscularly), group D (primed and boosted intramuscularly), and group E (primed intramuscularly and boosted orally). The chickens were primed with the SG ghost at 7 days of age and were subsequently boosted at the fifth week of age. Post-immunization, the plasma IgG and intestinal secretory IgA (sIgA) levels, and the SG antigen-specific lymphocyte stimulation were monitored at weekly interval and the birds were subsequently challenged with a virulent SG strain at the third week post-second immunization.
Results
Chickens in group D showed an optimized protection with significantly increased plasma IgG, sIgA, and lymphocyte stimulation response compared to all groups. The presence of CD4+ and CD8+ T cells and monocyte/macrophage (M/M) in the spleen, and splenic expression of cytokines such as interferon γ (IFN-γ) and interleukin 6 (IL-6) in the immunized chickens were investigated. The prime immunization induced significantly higher splenic M/M population and mRNA levels of IFN-γ whereas the booster showed increases of splenic CD4+ and CD8+ T-cell population and IL-6 cytokine in mRNA levels.
Conclusion
Our results indicate that the prime immunization with the SG ghost vaccine induced Th1 type immune response and the booster elicited both Th1- and Th2-related immune responses.
doi:10.7774/cevr.2016.5.2.148
PMCID: PMC4969279  PMID: 27489805
Salmonella; Ghost vaccine; Immunization scheme; Protection; Fowl typhoid
19.  Antimicrobial Doses in Continuous Renal Replacement Therapy: A Comparison of Dosing Strategies 
Purpose. Drug dose recommendations are not well defined in patients undergoing continuous renal replacement therapy (CRRT) due to limited published data. Several guidelines and pharmacokinetic equations have been proposed as tools for CRRT drug dosing. Dose recommendations derived from these methods have yet to be compared or prospectively evaluated. Methods. A literature search of PubMed, Micromedex, and Embase was conducted for 40 drugs commonly used in the ICU to gather pharmacokinetic data acquired from patients with acute and chronic kidney disease as well as healthy volunteers. These data and that obtained from drug package inserts were gathered for use in three published CRRT drug dosing equations. Doses calculated for a model patient using each method were compared to doses suggested in a commonly used dosing text. Results. Full pharmacokinetic data was available for 18, 31, and 40 agents using acute kidney injury, end stage renal disease, and normal patient data, respectively. On average, calculated doses differed by 30% or more from the doses recommended by the renal dosing text for >50% of the medications. Conclusion. Wide variability in dose recommendations for patients undergoing CRRT exists when these equations are used. Alternate, validated dosing methods need to be developed for this at-risk patient population.
doi:10.1155/2016/3235765
PMCID: PMC4940534  PMID: 27433357
20.  An Eustachian Tube Neuroendocrine Carcinoma: A Previously Undescribed Entity and Review of the Literature 
Case Reports in Surgery  2016;2016:4643615.
Primary sinonasal and middle ear neuroendocrine carcinomas are rare malignancies of the head and neck. Owing to the rarity of these tumors, the clinical behavior and optimal management of these tumors are not well defined. We present a case of an incidentally discovered sinonasal neuroendocrine carcinoma that was found to originate from the Eustachian tube, which has not previously been described in the literature. This patient was treated with primary surgical resection using a combination of transnasal and transaural approaches and achieved an incomplete resection. Follow-up imaging demonstrated continued tumor growth in the Eustachian tube as well as a new growth in the ipsilateral cerebellopontine angle and findings suspicious of perineural invasion. However, the tumor exhibited a benign growth pattern and despite continued growth the patient did not receive additional treatment and he remains asymptomatic 35 months following his original surgery.
doi:10.1155/2016/4643615
PMCID: PMC4939327  PMID: 27429827
21.  Somatotopic organization in the internal segment of the globus pallidus in Parkinson's disease 
Experimental neurology  2010;222(2):219-225.
Ablation or deep brain stimulation in the internal segment of the globus pallidus (GPi) is an effective therapy for the treatment of Parkinson's disease (PD). Yet many patients receive only partial benefit, including varying levels of improvement across different body regions, which may relate to a differential effect of GPi surgery on the different body regions. Unfortunately, our understanding of the somatotopic organization of human GPi is based on a small number of studies with limited sample sizes, including several based upon only a single recording track or plane. To fully address the three-dimensional somatotopic organization of GPi, we examined the receptive field properties of pallidal neurons in a large cohort of patients undergoing stereotactic surgery. The response of neurons to active and passive movements of the limbs and orofacial structures was determined, using a minimum of three tracks across at least two medial-lateral planes. Neurons (3183) were evaluated from 299 patients, of which 1972 (62%) were modulated by sensorimotor manipulation. Of these, 1767 responded to a single, contralateral body region, with the remaining 205 responding to multiple and/or ipsilateral body regions. Leg-related neurons were found dorsal, medial and anterior to arm-related neurons, while arm-related neurons were dorsal and lateral to orofacial-related neurons. This study provides a more detailed map of individual body regions as well as specific joints within each region and provides a potential explanation for the differential effect of lesions or DBS of the GPi on different body parts in patients undergoing surgical treatment of movement disorders.
doi:10.1016/j.expneurol.2009.12.030
PMCID: PMC4920550  PMID: 20059997
Basal ganglia; Parkinson's disease; Microelectrode; Pallidotomy; Deep brain stimulation; Somatotopic organization
22.  Exploring the psychological morbidity of waiting for sinus surgery using a mixed methods approach 
Background
Patients with chronic rhinosinusitis (CRS) often have to endure significant wait times for endoscopic sinus surgery (ESS). The pyschiatric impact of placement on a waitlist for ESS has not been explored.
Methods
Questionnaires measuring CRS symptom severity and health-related anxiety and stress (SNOT-22, HADS, WPAI-GH) were sent to patients diagnosed with CRS and currently on a waitlist for ESS. Fifteen representative waitlisted patients participated in one-on-one semi-structured interviews discussing their experience with their wait for ESS. A deductive thematic analysis was used to interpret the interview data using a quantitative driven mixed methods analysis.
Results
Participants waiting for ESS reported worsening clinical symptomatology during their waiting period. Participants reported waitlist and CRS impact on both work and social aspects of their lives. The HADS scale showed no overall significant level of depression or anxiety in the HADS screening questionnaire. The qualitative data describe the effects of the symptom burden of CRS.
Conclusions
Patients waitlisted for ESS did not demonstrate any significant level of psychiatric distress, however variability exists. The qualitative arm of this study elucidates how patients cope with their wait.
doi:10.1186/s40463-016-0149-z
PMCID: PMC4897809  PMID: 27266530
Rhinology; Chronic rhinosinusitis; Anxiety; Depression; Mixed methods; Qualitative; Survey; HADS; WPAI; Waitlist; Endoscopic sinus surgery
23.  A live attenuated Salmonella Enteritidis secreting detoxified heat labile toxin enhances mucosal immunity and confers protection against wild-type challenge in chickens 
Veterinary Research  2016;47:60.
A live attenuated Salmonella Enteritidis (SE) capable of constitutively secreting detoxified double mutant Escherichia coli heat labile toxin (dmLT) was developed. The biologically adjuvanted strain was generated via transformation of a highly immunogenic SE JOL1087 with a plasmid encoding dmLT gene cassette; the resultant strain was designated JOL1641. A balanced-lethal host-vector system stably maintained the plasmid via auxotrophic host complementation with a plasmid encoded aspartate semialdehyde dehydrogenase (asd) gene. Characterization by western blot assay revealed the dmLT subunit proteins in culture supernatants of JOL1641. For the investigation of adjuvanticity and protective efficacy, chickens were immunized via oral or intramuscular routes with PBS, JOL1087 and JOL1641. Birds immunized with JOL1641 showed significant (P ≤ 0.05) increases in intestinal SIgA production at the 1st and 2nd weeks post-immunization via oral and intramuscular routes, respectively. Interestingly, while both strains showed significant splenic protection via intramuscular immunization, JOL1641 outperformed JOL1087 upon oral immunization. Oral immunization of birds with JOL1641 significantly reduced splenic bacterial counts. The reduction in bacterial counts may be correlated with an adjuvant effect of dmLT that increases SIgA secretion in the intestines of immunized birds. The inclusion of detoxified dmLT in the strain did not cause adverse reactions to birds, nor did it extend the period of bacterial fecal shedding. In conclusion, we report here that dmLT could be biologically incorporated in the secretion system of a live attenuated Salmonella-based vaccine, and that this construction is safe and could enhance mucosal immunity, and protect immunized birds against wild-type challenge.
doi:10.1186/s13567-016-0348-7
PMCID: PMC4893257  PMID: 27262338
24.  Characteristics of Circulating Donor-Specific Anti-HLA Antibodies and Acute Rejection in the Kidney Allograft 
Transplantation  2015;99(6):1156-1164.
Background
Characteristics of pretransplant antibodies directed at donor HLA (DSA) associated with adverse outcomes in kidney transplant recipients are being elucidated but uncertainties exist.
Methods
Prospectively screening of pretransplant sera from 543 kidney recipients using single antigen bead assays identified 154 recipients with DSA and 389 without. We investigated the association of DSA features to acute rejection (AR) and graft failure.
Results
One-year AR incidence was higher in DSA positive group (P<0.001), primarily due to antibody mediated rejection (AMR, 13% vs. 1.8%, P<0.001) and not T-cell mediated rejection (ACR, 5% vs.6%, P=0.65). Risk of AMR increased progressively with a rise in DSA MFI-Sum (P<0.0001). Both DSA MFI-Sum ≥6000 (OR=18; 95%CI, 7.0 to 47; P<0.001) and DSA specificity, presence of DSA against both HLA class I and II (OR=39; 95%CI, 14 to 106; P<0.0001), predicted one-year AMR, independent of other covariates. In a combined model, DSA specificity predicted AMR, independent of DSA MFI-Sum. In multivariable Cox proportional hazards models, the covariate-adjusted hazard ratio for graft failure was 2.03 (95%CI, 1.05 to 3.92; P=0.04) for DSA MFI-Sum≥6000 and 2.23 (95% CI, 1.04 to 4.80; P=0.04) for class I and II DSA. Prediction of graft loss was not independent of AMR.
Conclusions
Our study supports the hypothesis that characterization of pretransplant DSA, specifically presence of DSA against both HLA class I and II and the strength, as quantified by DSA MFI-Sum, is useful to estimate AMR and graft failure risk in kidney graft recipients. Elevated risk of graft failure is attributable to increased risk of AMR.
doi:10.1097/TP.0000000000000511
PMCID: PMC4729299  PMID: 25629531
donor specific antibodies; acute rejection; graft loss; kidney transplant
25.  Human prion protein-induced autophagy flux governs neuron cell damage in primary neuron cells 
Oncotarget  2016;7(21):29989-30002.
An unusual molecular structure of the prion protein, PrPsc is found only in mammals with transmissible prion diseases. Prion protein stands for either the infectious pathogen itself or a main component of it. Recent studies suggest that autophagy is one of the major functions that keep cells alive and has a protective effect against the neurodegeneration. In this study, we investigated that the effect of human prion protein on autophagy-lysosomal system of primary neuronal cells. The treatment of human prion protein induced primary neuron cell death and decreased both LC3-II and p62 protein amount indicating autophagy flux activation. Electron microscope pictures confirmed the autophagic flux activation in neuron cells treated with prion protein. Inhibition of autophagy flux using pharmacological and genetic tools prevented neuron cell death induced by human prion protein. Autophagy flux induced by prion protein is more activated in prpc expressing cells than in prpc silencing cells. These data demonstrated that prion protein-induced autophagy flux is involved in neuron cell death in prion disease and suggest that autophagy flux might play a critical role in neurodegenerative diseases including prion disease.
doi:10.18632/oncotarget.8802
PMCID: PMC5058658  PMID: 27102156
prion protein; autophagy flux; neurodegeneration; PrPc; ATG5; Gerotarget

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