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- Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness.Wang JL, Shamah SM, Sun AX, Waldman ID, Haggarty SJ, Perlis RHTransl Psychiatry
- Long Noncoding RNA HOTAIR as an Independent Prognostic Marker in Cancer: A Meta-Analysis.Zhang S, Chen S, Yang G, Gu F, Li M, Zhong B, Hu J, Hoffman A, Chen MPLoS One
- The Effect of India's Total Sanitation Campaign on Defecation Behaviors and Child Health in Rural Madhya Pradesh: A Cluster Randomized Controlled Trial.Patil SR, Arnold BF, Salvatore AL, Briceno B, Ganguly S, Colford JM, Gertler PJPLoS Med
- Circulating Tumor Microemboli Diagnostics for Patients with Non-Small-Cell Lung Cancer.Carlsson A, Nair VS, Luttgen MS, Keu KV, Horng G, Vasanawala M, Kolatkar A, Jamali M, Iagaru AH, Kuschner W, Loo BW, Shrager JB, Bethel K, Hoh CK, Bazhenova L, Nieva J, Kuhn P, Gambhir SSJ Thorac Oncol
- Extraordinary.Puri SJAMA
- Dynamic Changes in Phase-Amplitude Coupling Facilitate Spatial Attention Control in Fronto-Parietal Cortex.Szczepanski SM, Crone NE, Kuperman RA, Auguste KI, Parvizi J, Knight RTPLoS Biol
- Simulation-based mastery learning with deliberate practice improves clinical performance in spinal anesthesia.Udani AD, Macario A, Nandagopal K, Tanaka MA, Tanaka PPAnesthesiol Res Pract
- Dynamic hydration shell restores Kauzmann's 1959 explanation of how the hydrophobic factor drives protein folding.Baldwin RLProc Natl Acad Sci U S A
- Nonlytic viral spread enhanced by autophagy components.Bird SW, Maynard ND, Covert MW, Kirkegaard KProc Natl Acad Sci U S A
- Diversity and clonal selection in the human T-cell repertoire.Qi Q, Liu Y, Cheng Y, Glanville J, Zhang D, Lee JY, Olshen RA, Weyand CM, Boyd SD, Goronzy JJProc Natl Acad Sci U S A
- RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection.Wang J, Quake SRProc Natl Acad Sci U S A
- Overview of the gene ontology task at BioCreative IV.Mao Y, Van Auken K, Li D, Arighi CN, McQuilton P, Hayman GT, Tweedie S, Schaeffer ML, Laulederkind SJ, Wang SJ, Gobeill J, Ruch P, Luu AT, Kim JJ, Chiang JH, Chen YD, Yang CJ, Liu H, Zhu D, Li Y, Yu H, Emadzadeh E, Gonzalez G, Chen JM, Dai HJ, Lu ZDatabase (Oxford)
- Defining disability: development and validation of a mobility-Disability Severity Index (mDSI) in Charcot-Marie-tooth disease.Ramchandren S, Shy M, Feldman E, Carlos R, Siskind CJ Neurol Neurosurg Psychiatry
- Statin-induced Diabetes: How Important is Insulin Resistance?Abbasi F, Reaven GMJ Intern Med
- Clinical Pertinence Metric Enables Hypothesis-Independent Genome-Phenome Analysis for Neurologic Diagnosis.Segal MM, Abdellateef M, El-Hattab AW, Hilbush BS, De La Vega FM, Tromp G, Williams MS, Betensky RA, Gleeson JJ Child Neurol
- Starving our Microbial Self: The Deleterious Consequences of a Diet Deficient in Microbiota-Accessible Carbohydrates.Sonnenburg ED, Sonnenburg JLCell Metab
- Are confusional arousals pathological?Ohayon MM, Mahowald MW, Leger DNeurology
- Factors Associated with Repetitive Strain, and Strategies to Reduce Injury Among Breast-Imaging Radiologists.Thompson AC, Kremer Prill MJ, Biswal S, Rebner M, Rebner RE, Thomas WR, Edwards SD, Thompson MO, Ikeda DMJ Am Coll Radiol
- Validation of a Novel Radiographic Scoring System for Calcinosis Affecting the Hands of Patients with Systemic Sclerosis.Chung L, Valenzuela A, Fiorentino D, Stevens K, Li S, Harris J, Hutchinson C, Assassi S, Beretta L, Lakshminarayanan S, Rodriguez-Reyna TS, Denton CP, Taillefer RG, Herrick AL, Baron M, on behalf of the Scleroderma Clinical Trials Consortium Calcinosis Working GroupArthritis Care Res (Hoboken)
- Actin Is Required for IFT Regulation in Chlamydomonas reinhardtii.Avasthi P, Onishi M, Karpiak J, Yamamoto R, Mackinder L, Jonikas MC, Sale WS, Shoichet B, Pringle JR, Marshall WFCurr Biol
- Internalization and TLR-dependent type I interferon production by monocytes in response to Toxoplasma gondii.Han SJ, Melichar HJ, Coombes JL, Chan SW, Koshy AA, Boothroyd JC, Barton GM, Robey EAImmunol Cell Biol
- MRI of the Hip for the evaluation of femoroacetabular impingement; past, present, and future.Riley GM, McWalter EJ, Stevens KJ, Safran MR, Lattanzi R, Gold GEJ Magn Reson Imaging
- Comparison of three ECG criteria for athlete pre-participation screening.Pickham D, Zarafshar S, Sani D, Kumar N, Froelicher VJ Electrocardiol
- Hepatic encephalopathy is associated with significantly increased mortality among patients awaiting liver transplantation.Wong RJ, Gish RG, Ahmed ALiver Transpl
- Burns ITU admissions: Length of stay in specific levels of care for adult and paediatric patients.Maan ZN, Frew Q, Din AH, Unluer Z, Smailes S, Philp B, El-Muttardi N, Dziewulski PBurns
- A randomized comparison of proximal and distal ultrasound-guided adductor canal catheter insertion sites for knee arthroplasty.Mariano ER, Kim TE, Wagner MJ, Funck N, Harrison TK, Walters T, Giori N, Woolson S, Ganaway T, Howard SKJ Ultrasound Med
- Value of short-interval computed tomography when sonography fails to visualize the appendix and shows otherwise normal findings.Shah BR, Stewart J, Jeffery RB, Olcott EWJ Ultrasound Med
- Rates and Patterns of Recurrence after Curative Intent Resection for Gastric Cancer: A United States Multi-Institutional Analysis.Spolverato G, Ejaz A, Kim Y, Squires MH, Poultsides GA, Fields RC, Schmidt C, Weber SM, Votanopoulos K, Maithel SK, Pawlik TMJ Am Coll Surg
- In reply:.Carvalho B, Ahsan ZS, Yao JJ Hand Surg Am
- Selective attention. Long-range and local circuits for top-down modulation of visual cortex processing.Zhang S, Xu M, Kamigaki T, Hoang Do JP, Chang WC, Jenvay S, Miyamichi K, Luo L, Dan YScience
- Raising the bar for the care of seriously ill patients: results of a national survey to define essential palliative care competencies for medical students and residents.Schaefer KG, Chittenden EH, Sullivan AM, Periyakoil VS, Morrison LJ, Carey EC, Sanchez-Reilly S, Block SDAcad Med
- New ways to dismantle a ticking time bomb: microRNA 712/205 and abdominal aortic aneurysm development.Maegdefessel L, Spin JM, Tsao PSArterioscler Thromb Vasc Biol
- Curation accuracy of model organism databases.Keseler IM, Skrzypek M, Weerasinghe D, Chen AY, Fulcher C, Li GW, Lemmer KC, Mladinich KM, Chow ED, Sherlock G, Karp PDDatabase (Oxford)
- Risk of subsequent cancers in renal cell carcinoma survivors with a family history.Chen T, Fallah M, Sundquist K, Liu H, Hemminki KEur J Cancer
- Hepatitis C virus infection and coronary artery disease risk: a systematic review of the literature.Wong RJ, Kanwal F, Younossi ZM, Ahmed ADig Dis Sci
- Narcolepsy is a common phenotype in HSAN IE and ADCA-DN.Moghadam KK, Pizza F, La Morgia C, Franceschini C, Tonon C, Lodi R, Barboni P, Seri M, Ferrari S, Liguori R, Donadio V, Parchi P, Cornelio F, Inzitari D, Mignarri A, Capocchi G, Dotti MT, Winkelmann J, Lin L, Mignot E, Carelli V, Plazzi GBrain
- GigaDB: promoting data dissemination and reproducibility.Sneddon TP, Zhe XS, Edmunds SC, Li P, Goodman L, Hunter CIDatabase (Oxford)
- Safe application of topical negative pressure dressings to exposed brain before definitive reconstruction.Davis CR, Mitsala G, Malcolm G, Orlando AJ Plast Reconstr Aesthet Surg
- Isoniazid hepatotoxicity requiring liver transplantation.Sheen E, Huang RJ, Uribe LA, Nguyen MHDig Dis Sci
- On-chip separation and analysis of RNA and DNA from single cells.Shintaku H, Nishikii H, Marshall LA, Kotera H, Santiago JGAnal Chem
- An anti-inflammatory NOD-like receptor is required for microglia development.Shiau CE, Monk KR, Joo W, Talbot WSCell Rep
- Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia.Loktev AV, Jackson PKCell Rep
- Synthesis of modified Trichinella spiralis disaccharide epitopes and a comparison of their recognition by chemical mapping and saturation transfer difference NMR.Cui L, Ling CC, Sadowska J, Bundle DRCarbohydr Res
- Evidence that duplications of 22q11.2 protect against schizophrenia.Rees E, Kirov G, Sanders A, Walters JT, Chambert KD, Shi J, Szatkiewicz J, O'Dushlaine C, Richards AL, Green EK, Jones I, Davies G, Legge SE, Moran JL, Pato C, Pato M, Genovese G, Levinson D, Duan J, Moy W, Göring HH, Morris D, Cormican P, Kendler KS, O'Neill FA, Riley B, Gill M, Corvin A, Wellcome Trust Case Control Consortium, Craddock N, Sklar P, Hultman C, Sullivan PF, Gejman PV, McCarroll SA, O'Donovan MC, Owen MJMol Psychiatry
- In vivo readout of CFTR function: ratiometric measurement of CFTR-dependent secretion by individual, identifiable human sweat glands.Wine JJ, Char JE, Chen J, Cho HJ, Dunn C, Frisbee E, Joo NS, Milla C, Modlin SE, Park IH, Thomas EA, Tran KV, Verma R, Wolfe MHPLoS One
- Augmenting endogenous Wnt signaling improves skin wound healing.Whyte JL, Smith AA, Liu B, Manzano WR, Evans ND, Dhamdhere GR, Fang MY, Chang HY, Oro AE, Helms JAPLoS One
- Protective effects of inhaled carbon monoxide in endotoxin-induced cholestasis is dependent on its kinetics.Vanova K, Suk J, Petr T, Cerny D, Slanar O, Vreman HJ, Wong RJ, Zima T, Vitek L, Muchova LBiochimie
- Resting ST amplitude: prognosis and normal values in an ambulatory clinical population.Zarafshar S, Wong M, Singh N, Aggarwal S, Adhikarla C, Froelicher VFAnn Noninvasive Electrocardiol
- A novel engineered anti-CD20 tracer enables early time PET imaging in a humanized transgenic mouse model of B-cell non-Hodgkins lymphoma.Natarajan A, Hackel BJ, Gambhir SSClin Cancer Res
- Talking to children matters: early language experience strengthens processing and builds vocabulary.Weisleder A, Fernald APsychol Sci
- Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development.Yang J, Zeini M, Lin CY, Lin CJ, Xiong Y, Shang C, Han P, Li W, Quertermous T, Zhou B, Chang CPCardiovasc Res
- The immune system and inflammation in breast cancer.Jiang X, Shapiro DJMol Cell Endocrinol
- In vitro immunomodulation of a whole blood IFN-γ release assay enhances T cell responses in subjects with latent tuberculosis infection.Gaur RL, Suhosk MM, Banaei NPLoS One
Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness.
Transl Psychiatry. 2014;4:e428
Authors: Wang JL, Shamah SM, Sun AX, Waldman ID, Haggarty SJ, Perlis RH
Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics.
PMID: 25158003 [PubMed - as supplied by publisher]
Long Noncoding RNA HOTAIR as an Independent Prognostic Marker in Cancer: A Meta-Analysis.
PLoS One. 2014;9(8):e105538
Authors: Zhang S, Chen S, Yang G, Gu F, Li M, Zhong B, Hu J, Hoffman A, Chen M
BACKGROUND: HOTAIR, a newly discovered long intergenic noncoding RNA (lincRNA), has been reported to be aberrantly expressed in many types of cancers. This meta-analysis summarizes its potential role as a biomarker in malignancy.
METHODS: A quantitative meta-analysis was performed through a systematic search in Pubmed, Medline and Web of Science for eligible papers on the prognostic impact of HOTAIR in cancer from inception to Feb. 28, 2014. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to summarize the effect.
RESULTS: Nineteen studies were included in the study, with a total of 2033 patients. A significant association was observed between high HOTAIR expression and poor overall survival (OS) in patients with cancer (pooled HR 2.22, 95% CI: 1.68-2.93). Place of residence (Asian or Western countries), type of cancer (digestive or non-digestive disease), sample size (more or less than 100), and paper quality (score more or less than 85%) did not alter the significant predictive value of HOTAIR in OS from various kinds of cancer but preoperative status did. By combining HRs from Cox multivariate analyses, we found that HOTAIR expression was an independent prognostic factor for cancer patients (pooled HR 2.26, 95% CI: 1.62-3.15). Subgroup analysis showed that HOTAIR abundance was an independent prognostic factor for cancer metastasis (HR 3.90, 95% CI: 2.25-6.74). For esophageal carcinoma, high HOTAIR expression was significantly associated with TNM stage (III/IV vs. I/II: OR 6.90, 95% CI: 2.81-16.9) without heterogeneity. In gastric cancer, HOTAIR expression was found to be significantly associated with lymph node metastases (present vs. absent: OR 4.47, 95% CI: 1.88-10.63) and vessel invasion (positive vs. negative: OR 2.88, 95% CI: 1.38-6.04) without obvious heterogeneity.
CONCLUSIONS: HOTAIR abundance may serve as a novel predictive factor for poor prognosis in different types of cancers in both Asian and Western countries.
PMID: 25157956 [PubMed - as supplied by publisher]
The Effect of India's Total Sanitation Campaign on Defecation Behaviors and Child Health in Rural Madhya Pradesh: A Cluster Randomized Controlled Trial.
PLoS Med. 2014 Aug;11(8):e1001709
Authors: Patil SR, Arnold BF, Salvatore AL, Briceno B, Ganguly S, Colford JM, Gertler PJ
BACKGROUND: Poor sanitation is thought to be a major cause of enteric infections among young children. However, there are no previously published randomized trials to measure the health impacts of large-scale sanitation programs. India's Total Sanitation Campaign (TSC) is one such program that seeks to end the practice of open defecation by changing social norms and behaviors, and providing technical support and financial subsidies. The objective of this study was to measure the effect of the TSC implemented with capacity building support from the World Bank's Water and Sanitation Program in Madhya Pradesh on availability of individual household latrines (IHLs), defecation behaviors, and child health (diarrhea, highly credible gastrointestinal illness [HCGI], parasitic infections, anemia, growth).
METHODS AND FINDINGS: We conducted a cluster-randomized, controlled trial in 80 rural villages. Field staff collected baseline measures of sanitation conditions, behaviors, and child health (May-July 2009), and revisited households 21 months later (February-April 2011) after the program was delivered. The study enrolled a random sample of 5,209 children <5 years old from 3,039 households that had at least one child <24 months at the beginning of the study. A random subsample of 1,150 children <24 months at enrollment were tested for soil transmitted helminth and protozoan infections in stool. The randomization successfully balanced intervention and control groups, and we estimated differences between groups in an intention to treat analysis. The intervention increased percentage of households in a village with improved sanitation facilities as defined by the WHO/UNICEF Joint Monitoring Programme by an average of 19% (95% CI for difference: 12%-26%; group means: 22% control versus 41% intervention), decreased open defecation among adults by an average of 10% (95% CI for difference: 4%-15%; group means: 73% intervention versus 84% control). However, the intervention did not improve child health measured in terms of multiple health outcomes (diarrhea, HCGI, helminth infections, anemia, growth). Limitations of the study included a relatively short follow-up period following implementation, evidence for contamination in ten of the 40 control villages, and bias possible in self-reported outcomes for diarrhea, HCGI, and open defecation behaviors.
CONCLUSIONS: The intervention led to modest increases in availability of IHLs and even more modest reductions in open defecation. These improvements were insufficient to improve child health outcomes (diarrhea, HCGI, parasite infection, anemia, growth). The results underscore the difficulty of achieving adequately large improvements in sanitation levels to deliver expected health benefits within large-scale rural sanitation programs.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01465204 Please see later in the article for the Editors' Summary.
PMID: 25157929 [PubMed - as supplied by publisher]
Circulating Tumor Microemboli Diagnostics for Patients with Non-Small-Cell Lung Cancer.
J Thorac Oncol. 2014 Aug;9(8):1111-1119
Authors: Carlsson A, Nair VS, Luttgen MS, Keu KV, Horng G, Vasanawala M, Kolatkar A, Jamali M, Iagaru AH, Kuschner W, Loo BW, Shrager JB, Bethel K, Hoh CK, Bazhenova L, Nieva J, Kuhn P, Gambhir SS
INTRODUCTION:: Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non-small-cell lung cancer (NSCLC) patients undergoing imaging evaluation.
METHODS:: First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group.
RESULTS:: We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002).
CONCLUSION:: CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.
PMID: 25157764 [PubMed - as supplied by publisher]
JAMA. 2014 Aug 27;312(8):793-794
Authors: Puri S
PMID: 25157720 [PubMed - as supplied by publisher]
Dynamic Changes in Phase-Amplitude Coupling Facilitate Spatial Attention Control in Fronto-Parietal Cortex.
PLoS Biol. 2014 Aug;12(8):e1001936
Authors: Szczepanski SM, Crone NE, Kuperman RA, Auguste KI, Parvizi J, Knight RT
Attention is a core cognitive mechanism that allows the brain to allocate limited resources depending on current task demands. A number of frontal and posterior parietal cortical areas, referred to collectively as the fronto-parietal attentional control network, are engaged during attentional allocation in both humans and non-human primates. Numerous studies have examined this network in the human brain using various neuroimaging and scalp electrophysiological techniques. However, little is known about how these frontal and parietal areas interact dynamically to produce behavior on a fine temporal (sub-second) and spatial (sub-centimeter) scale. We addressed how human fronto-parietal regions control visuospatial attention on a fine spatiotemporal scale by recording electrocorticography (ECoG) signals measured directly from subdural electrode arrays that were implanted in patients undergoing intracranial monitoring for localization of epileptic foci. Subjects (n = 8) performed a spatial-cuing task, in which they allocated visuospatial attention to either the right or left visual field and detected the appearance of a target. We found increases in high gamma (HG) power (70-250 Hz) time-locked to trial onset that remained elevated throughout the attentional allocation period over frontal, parietal, and visual areas. These HG power increases were modulated by the phase of the ongoing delta/theta (2-5 Hz) oscillation during attentional allocation. Critically, we found that the strength of this delta/theta phase-HG amplitude coupling predicted reaction times to detected targets on a trial-by-trial basis. These results highlight the role of delta/theta phase-HG amplitude coupling as a mechanism for sub-second facilitation and coordination within human fronto-parietal cortex that is guided by momentary attentional demands.
PMID: 25157678 [PubMed - as supplied by publisher]
Simulation-based mastery learning with deliberate practice improves clinical performance in spinal anesthesia.
Anesthesiol Res Pract. 2014;2014:659160
Authors: Udani AD, Macario A, Nandagopal K, Tanaka MA, Tanaka PP
Introduction. Properly performing a subarachnoid block (SAB) is a competency expected of anesthesiology residents. We aimed to determine if adding simulation-based deliberate practice to a base curriculum improved performance of a SAB. Methods. 21 anesthesia residents were enrolled. After baseline assessment of SAB on a task-trainer, all residents participated in a base curriculum. Residents were then randomized so that half received additional deliberate practice including repetition and expert-guided, real-time feedback. All residents were then retested for technique. SABs on all residents' next three patients were evaluated in the operating room (OR). Results. Before completing the base curriculum, the control group completed 81% of a 16-item performance checklist on the task-trainer and this increased to 91% after finishing the base curriculum (P < 0.02). The intervention group also increased the percentage of checklist tasks properly completed from 73% to 98%, which was a greater increase than observed in the control group (P < 0.03). The OR time required to perform SAB was not different between groups. Conclusions. The base curriculum significantly improved resident SAB performance. Deliberate practice training added a significant, independent, incremental benefit. The clinical impact of the deliberate practice intervention in the OR on patient care is unclear.
PMID: 25157263 [PubMed]
Dynamic hydration shell restores Kauzmann's 1959 explanation of how the hydrophobic factor drives protein folding.
Proc Natl Acad Sci U S A. 2014 Aug 25;
Authors: Baldwin RL
Kauzmann's explanation of how the hydrophobic factor drives protein folding is reexamined. His explanation said that hydrocarbon hydration shells are formed, possibly of clathrate water, and they explain why hydrocarbons have uniquely low solubilities in water. His explanation was not universally accepted because of skepticism about the clathrate hydration shell. A revised version is given here in which a dynamic hydration shell is formed by van der Waals (vdw) attraction, as proposed in 1985 by Jorgensen et al. [Jorgensen WL, Gao J, Ravimohan C (1985) J Phys Chem 89:3470-3473]. The vdw hydration shell is implicit in theories of hydrophobicity that contain the vdw interaction between hydrocarbon C and water O atoms. To test the vdw shell model against the known hydration energetics of alkanes, the energetics should be based on the Ben-Naim standard state (solute transfer between fixed positions in the gas and liquid phases). Then the energetics are proportional to n, the number of water molecules correlated with an alkane by vdw attraction, given by the simulations of Jorgensen et al. The energetics show that the decrease in entropy upon hydration is the root cause of hydrophobicity; it probably results from extensive ordering of water molecules in the vdw shell. The puzzle of how hydrophobic free energy can be proportional to nonpolar surface area when the free energy is unfavorable and the only known interaction (the vdw attraction) is favorable, is resolved by finding that the unfavorable free energy is produced by the vdw shell.
PMID: 25157156 [PubMed - as supplied by publisher]
Nonlytic viral spread enhanced by autophagy components.
Proc Natl Acad Sci U S A. 2014 Aug 25;
Authors: Bird SW, Maynard ND, Covert MW, Kirkegaard K
The cell-to-cell spread of cytoplasmic constituents such as nonenveloped viruses and aggregated proteins is usually thought to require cell lysis. However, mechanisms of unconventional secretion have been described that bypass the secretory pathway for the extracellular delivery of cytoplasmic molecules. Components of the autophagy pathway, an intracellular recycling process, have been shown to play a role in the unconventional secretion of cytoplasmic signaling proteins. Poliovirus is a lytic virus, although a few examples of apparently nonlytic spread have been documented. Real demonstration of nonlytic spread for poliovirus or any other cytoplasmic constituent thought to exit cells via unconventional secretion requires demonstration that a small amount of cell lysis in the cellular population is not responsible for the release of cytosolic material. Here, we use quantitative time-lapse microscopy to show the spread of infectious cytoplasmic material between cells in the absence of lysis. siRNA-mediated depletion of autophagy protein LC3 reduced nonlytic intercellular viral transfer. Conversely, pharmacological stimulation of the autophagy pathway caused more rapid viral spread in tissue culture and greater pathogenicity in mice. Thus, the unconventional secretion of infectious material in the absence of cell lysis is enabled by components of the autophagy pathway. It is likely that other nonenveloped viruses also use this pathway for nonlytic intercellular spread to affect pathogenesis in infected hosts.
PMID: 25157142 [PubMed - as supplied by publisher]
Diversity and clonal selection in the human T-cell repertoire.
Proc Natl Acad Sci U S A. 2014 Aug 25;
Authors: Qi Q, Liu Y, Cheng Y, Glanville J, Zhang D, Lee JY, Olshen RA, Weyand CM, Boyd SD, Goronzy JJ
T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.
PMID: 25157137 [PubMed - as supplied by publisher]
RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection.
Proc Natl Acad Sci U S A. 2014 Aug 25;
Authors: Wang J, Quake SR
Latent viral infection is a persistent cause of human disease. Although standard antiviral therapies can suppress active viral replication, no existing treatment can effectively eradicate latent infection and therefore a cure is lacking for many prevalent viral diseases. The prokaryotic immune system clustered regularly interspaced short palindromic repeat (CRISPR)/Cas evolved as a natural response to phage infections, and we demonstrate here that the CRISPR/Cas9 system can be adapted for antiviral treatment in human cells by specifically targeting the genomes of latent viral infections. Patient-derived cells from a Burkitt's lymphoma with latent Epstein-Barr virus infection showed dramatic proliferation arrest and a concomitant decrease in viral load after exposure to a CRISPR/Cas9 vector targeted to the viral genome.
PMID: 25157128 [PubMed - as supplied by publisher]
Overview of the gene ontology task at BioCreative IV.
Database (Oxford). 2014;2014
Authors: Mao Y, Van Auken K, Li D, Arighi CN, McQuilton P, Hayman GT, Tweedie S, Schaeffer ML, Laulederkind SJ, Wang SJ, Gobeill J, Ruch P, Luu AT, Kim JJ, Chiang JH, Chen YD, Yang CJ, Liu H, Zhu D, Li Y, Yu H, Emadzadeh E, Gonzalez G, Chen JM, Dai HJ, Lu Z
Gene Ontology (GO) annotation is a common task among model organism databases (MODs) for capturing gene function data from journal articles. It is a time-consuming and labor-intensive task, and is thus often considered as one of the bottlenecks in literature curation. There is a growing need for semiautomated or fully automated GO curation techniques that will help database curators to rapidly and accurately identify gene function information in full-length articles. Despite multiple attempts in the past, few studies have proven to be useful with regard to assisting real-world GO curation. The shortage of sentence-level training data and opportunities for interaction between text-mining developers and GO curators has limited the advances in algorithm development and corresponding use in practical circumstances. To this end, we organized a text-mining challenge task for literature-based GO annotation in BioCreative IV. More specifically, we developed two subtasks: (i) to automatically locate text passages that contain GO-relevant information (a text retrieval task) and (ii) to automatically identify relevant GO terms for the genes in a given article (a concept-recognition task). With the support from five MODs, we provided teams with >4000 unique text passages that served as the basis for each GO annotation in our task data. Such evidence text information has long been recognized as critical for text-mining algorithm development but was never made available because of the high cost of curation. In total, seven teams participated in the challenge task. From the team results, we conclude that the state of the art in automatically mining GO terms from literature has improved over the past decade while much progress is still needed for computer-assisted GO curation. Future work should focus on addressing remaining technical challenges for improved performance of automatic GO concept recognition and incorporating practical benefits of text-mining tools into real-world GO annotation. Database URL: http://www.biocreative.org/tasks/biocreative-iv/track-4-GO/.
PMID: 25157073 [PubMed - in process]
Defining disability: development and validation of a mobility-Disability Severity Index (mDSI) in Charcot-Marie-tooth disease.
J Neurol Neurosurg Psychiatry. 2014 Aug 25;
Authors: Ramchandren S, Shy M, Feldman E, Carlos R, Siskind C
OBJECTIVE: To develop and validate a reliable patient-reported scale that grades the severity of disability in Charcot-Marie-tooth disease (CMT), from an in-depth analysis of patient and healthcare provider perspectives on what mobility changes constitutes mild, moderate and severe disability.
DESIGN: In this prospective, cross-sectional study, a 19-item Disability Questionnaire was developed following literature and expert review. Between 2011 and 2012, the Disability Questionnaire was provided to healthcare providers experienced in CMT attending national scientific meetings, and to patients self-registered with the Inherited Neuropathy Consortium-Rare Diseases Clinical Research Consortium on-line contact registry. Provider and patient responses were compared utilising a two-sided unpaired t test with Bonferroni correction. The questionnaire was then assessed for validity, reliability and unidimensionality.
RESULTS: We analysed 259 Disability Questionnaires (167 patients, 92 providers); these showed perfect agreement between patient and provider responses on qualitative descriptions of disability, but significant differences in quantitative responses on items corresponding to minimal or severe disability (p<0.001). Validity and test-retest reliability of the questionnaire was excellent (Cronbach's α=0.96; intraclass correlation coefficients (ICC)=0.977 (0.951 to 0.993). Exploratory factor analysis and the Mokken Scaling Procedure supported the unidimensionality of the mobility-Disability Severity Index.
CONCLUSIONS: The mobility-Disability Severity Index is a unique instrument, categorising disability from the patient's perspective, and will undergo further cross-validation studies in CMT.
PMID: 25157034 [PubMed - as supplied by publisher]
Statin-induced Diabetes: How Important is Insulin Resistance?
J Intern Med. 2014 Aug 22;
Authors: Abbasi F, Reaven GM
Waters and associates have shown that elevations of blood pressure, fasting glucose, and triglyceride (TG) concentrations are predictors of type 2 diabetes (T2DM) in statin-treated individuals (1). These changes, along with some degree of glucose intolerance, comprise the cluster of abnormalities initially designated as Syndrome X (2), secondary to a defect in insulin-stimulated glucose disposal (insulin resistance). Since insulin resistance is a predictor of type 2 diabetes (2; 3), we evaluated the possibility that significant differences in baseline prevalence of insulin resistance and glucose tolerance might exist in a population of nondiabetic persons with hypercholesterolemia. This article is protected by copyright. All rights reserved.
PMID: 25156816 [PubMed - as supplied by publisher]
Clinical Pertinence Metric Enables Hypothesis-Independent Genome-Phenome Analysis for Neurologic Diagnosis.
J Child Neurol. 2014 Aug 24;
Authors: Segal MM, Abdellateef M, El-Hattab AW, Hilbush BS, De La Vega FM, Tromp G, Williams MS, Betensky RA, Gleeson J
We describe an "integrated genome-phenome analysis" that combines both genomic sequence data and clinical information for genomic diagnosis. It is novel in that it uses robust diagnostic decision support and combines the clinical differential diagnosis and the genomic variants using a "pertinence" metric. This allows the analysis to be hypothesis-independent, not requiring assumptions about mode of inheritance, number of genes involved, or which clinical findings are most relevant. Using 20 genomic trios with neurologic disease, we find that pertinence scores averaging 99.9% identify the causative variant under conditions in which a genomic trio is analyzed and family-aware variant calling is done. The analysis takes seconds, and pertinence scores can be improved by clinicians adding more findings. The core conclusion is that automated genome-phenome analysis can be accurate, rapid, and efficient. We also conclude that an automated process offers a methodology for quality improvement of many components of genomic analysis.
PMID: 25156663 [PubMed - as supplied by publisher]
Starving our Microbial Self: The Deleterious Consequences of a Diet Deficient in Microbiota-Accessible Carbohydrates.
Cell Metab. 2014 Aug 20;
Authors: Sonnenburg ED, Sonnenburg JL
The gut microbiota of a healthy person may not be equivalent to a healthy microbiota. It is possible that the Western microbiota is actually dysbiotic and predisposes individuals to a variety of diseases. The asymmetric plasticity between the relatively stable human genome and the more malleable gut microbiome suggests that incompatibilities between the two could rapidly arise. The Western lifestyle, which includes a diet low in microbiota-accessible carbohydrates (MACs), has selected for a microbiota with altered membership and functionality compared to those of groups living traditional lifestyles. Interactions between resident microbes and host leading to immune dysregulation may explain several diseases that share inflammation as a common basis. The low-MAC Western diet results in poor production of gut microbiota-generated short-chain fatty acids (SCFAs), which attenuate inflammation through a variety of mechanisms in mouse models. Studies focused on modern and traditional societies, combined with animal models, are needed to characterize the connection between diet, microbiota composition, and function. Differentiating between an optimal microbiota, one that increases disease risk, and one that is causative or potentiates disease will be required to further understand both the etiology and possible treatments for health problems related to microbiota dysbiosis.
PMID: 25156449 [PubMed - as supplied by publisher]
Are confusional arousals pathological?
Neurology. 2014 Aug 26;83(9):834-41
Authors: Ohayon MM, Mahowald MW, Leger D
OBJECTIVE: The objective of this study was to determine the extent that confusional arousals (CAs) are associated with mental disorders and psychotropic medications.
METHODS: Cross-sectional study conducted with a representative sample of 19,136 noninstitutionalized individuals of the US general population aged 18 years or older. The study was performed using the Sleep-EVAL expert system and investigated sleeping habits; health; and sleep, mental, and medical conditions (DSM-IV-TR, ICSD-II, ICD-10).
RESULTS: A total of 15.2% (95% confidence interval 14.6%-15.8%) (n = 2,421) of the sample reported episodes of CAs in the previous year; 8.6% had complete or partial amnesia of the episodes and 14.8% had CAs and nocturnal wandering episodes. Eighty-four percent of CAs were associated with sleep/mental disorders or psychotropic drugs. Sleep disorders were present for 70.8% of CAs. Individuals with a circadian rhythm sleep disorder or a long sleep duration (≥9 hours) were at higher risk of CAs. Mental disorders were observed in 37.4% of CAs. The highest odds were observed in individuals with bipolar disorders or panic disorder. Use of psychotropic medication was reported by 31.3% of CAs: mainly antidepressant medications. After eliminating possible causes and associated conditions, only 0.9% of the sample had CA disorder.
CONCLUSIONS: CAs are highly prevalent in the general population. They are often reported allegedly as a consequence of the treatment of sleep disorders. For the majority of subjects experiencing CAs, no medications were used, but among those who were using medications, antidepressants were most common. Sleep and/or mental disorders were important factors for CAs independent of the use of any medication.
PMID: 25156346 [PubMed - in process]
Factors Associated with Repetitive Strain, and Strategies to Reduce Injury Among Breast-Imaging Radiologists.
J Am Coll Radiol. 2014 Aug 21;
Authors: Thompson AC, Kremer Prill MJ, Biswal S, Rebner M, Rebner RE, Thomas WR, Edwards SD, Thompson MO, Ikeda DM
PURPOSE: To investigate the prevalence of repetitive strain injury (RSI) among breast-imaging radiologists, the factors associated with such symptoms, and strategies to reduce injury.
METHODS: In 2012, an anonymous survey regarding RSI and work habits was administered to 2,618 physician members of the Society of Breast Imaging via e-mail. Analysis of 727 (27.8%) de-identified responses was completed using STATA 12.1. Pain levels before and after implementation of digital imaging were compared with the Wilcoxon signed-rank test. The associations between RSI symptoms and work habits were assessed with logistic regression and test for trend.
RESULTS: In the survey 438 of 727 (60.2%) respondents reported RSI symptoms, and 242 of 727 (33.3%) reported prior diagnosis/treatment. Results showed a statistically significant trend for the odds of RSI symptoms to increase with decreasing age (P = .0004) or increasing number of daily hours spent working (P = .0006), especially in an awkward position (P < .0001). Respondents recalled a significant increase in pain level after implementation of PACS, and a decrease in pain after ergonomic training or initiating use of an ergonomic mouse, adjustable chair, or adjustable table (P < .001, all comparisons). Only 17.7% (129 of 727) used an ergonomic mouse and 13.3% (97 of 727) had attended ergonomic training. Those with RSI symptoms or prior diagnosis of a Repetitive Strain Syndrome (RSS) were more likely to desire future ergonomic training compared with those without symptoms or injury (odds ratio 5.36, P < .001; odds ratio 2.63, P = .001, respectively).
CONCLUSIONS: RSI is highly prevalent among breast-imaging radiologists nationwide and may worsen after implementation of PACS or with longer work hours. Ergonomic training and ergonomic devices may diminish or prevent painful RSI among radiologists.
PMID: 25156201 [PubMed - as supplied by publisher]
Validation of a Novel Radiographic Scoring System for Calcinosis Affecting the Hands of Patients with Systemic Sclerosis.
Arthritis Care Res (Hoboken). 2014 Aug 22;
Authors: Chung L, Valenzuela A, Fiorentino D, Stevens K, Li S, Harris J, Hutchinson C, Assassi S, Beretta L, Lakshminarayanan S, Rodriguez-Reyna TS, Denton CP, Taillefer RG, Herrick AL, Baron M, on behalf of the Scleroderma Clinical Trials Consortium Calcinosis Working Group
Objective: There are currently no validated outcome measures to assess calcinosis severity in systemic sclerosis (SSc). We sought to develop and validate a novel radiographic scoring system for calcinosis affecting the hands of SSc patients for potential use in future clinical trials. Methods: Following a 1-hour teleconference training session, 12 investigators (8 rheumatologists, 1 dermatologist, 3 radiologists) scored 12 hand radiographs in random order using two scoring systems (termed "simple" and "complex"), and re-scored 2 randomly assigned radiographs after a minimum of 24 hours. Inter-rater and intra-rater reliability were assessed using a weighted kappa coefficient for the simple system, and intraclass correlation coefficient (ICC) for the complex system (ICC < 0.4 poor, 0.4-0.7 moderate, > 0.7 excellent). Results: Mean time to complete the complex scoring system was significantly longer than the simple scoring system (4.0 vs. 0.4 minutes, p<.0001). Overall inter-rater reliability for the simple scoring system was poor (kappa=0.39, 95% CI 0.1-0.52), but improved if dichotomized as mild/moderate vs. severe (kappa=0.51, 95% CI 0.26-0.7). Inter-rater reliability was excellent for the complex scoring system (ICC=0.89, 95% CI 0.86-0.92). Intra-rater reliability was moderate for the simple scoring system (kappa=0.67, 95% CI 0.37-0.96), but almost perfect for the complex scoring system (ICC=0.93, 95%CI 0.89-0.97). Conclusion: We developed a novel radiographic scoring system that accounts for the area coverage, density, and anatomic location of calcinosis affecting the hands in patients with SSc. This scoring system is feasible with excellent reliability and should undergo further validation testing for use in clinical trials. © 2014 American College of Rheumatology.
PMID: 25155948 [PubMed - as supplied by publisher]
Actin Is Required for IFT Regulation in Chlamydomonas reinhardtii.
Curr Biol. 2014 Aug 20;
Authors: Avasthi P, Onishi M, Karpiak J, Yamamoto R, Mackinder L, Jonikas MC, Sale WS, Shoichet B, Pringle JR, Marshall WF
Assembly of cilia and flagella requires intraflagellar transport (IFT), a highly regulated kinesin-based transport system that moves cargo from the basal body to the tip of flagella . The recruitment of IFT components to basal bodies is a function of flagellar length, with increased recruitment in rapidly growing short flagella . The molecular pathways regulating IFT are largely a mystery. Because actin network disruption leads to changes in ciliary length and number, actin has been proposed to have a role in ciliary assembly. However, the mechanisms involved are unknown. In Chlamydomonas reinhardtii, conventional actin is found in both the cell body and the inner dynein arm complexes within flagella [3, 4]. Previous work showed that treating Chlamydomonas cells with the actin-depolymerizing compound cytochalasin D resulted in reversible flagellar shortening , but how actin is related to flagellar length or assembly remains unknown. Here we utilize small-molecule inhibitors and genetic mutants to analyze the role of actin dynamics in flagellar assembly in Chlamydomonas reinhardtii. We demonstrate that actin plays a role in IFT recruitment to basal bodies during flagellar elongation and that when actin is perturbed, the normal dependence of IFT recruitment on flagellar length is lost. We also find that actin is required for sufficient entry of IFT material into flagella during assembly. These same effects are recapitulated with a myosin inhibitor, suggesting that actin may act via myosin in a pathway by which flagellar assembly is regulated by flagellar length.
PMID: 25155506 [PubMed - as supplied by publisher]
Internalization and TLR-dependent type I interferon production by monocytes in response to Toxoplasma gondii.
Immunol Cell Biol. 2014 Aug 26;
Authors: Han SJ, Melichar HJ, Coombes JL, Chan SW, Koshy AA, Boothroyd JC, Barton GM, Robey EA
The classic anti-viral cytokine interferon (IFN)-β can be induced during parasitic infection, but relatively little is know about the cell types and signaling pathways involved. Here we show that inflammatory monocytes (IMs), but not neutrophils, produce IFN-β in response to T. gondii infection. This difference correlated with the mode of parasite entry into host cells, with phagocytic uptake predominating in IMs and active invasion predominating in neutrophils. We also show that expression of IFN-β requires phagocytic uptake of the parasite by IMs, and signaling through Toll-like receptors (TLRs) and MyD88. Finally, we show that IMs are major producers of IFN-β in mesenteric lymph nodes following in vivo oral infection of mice, and mice lacking the receptor for type I IFN-1 show higher parasite loads and reduced survival. Our data reveal a TLR and internalization-dependent pathway in IMs for IFN-β induction to a non-viral pathogen.Immunology and Cell Biology advance online publication, 26 August 2014; doi:10.1038/icb.2014.70.
PMID: 25155465 [PubMed - as supplied by publisher]
MRI of the Hip for the evaluation of femoroacetabular impingement; past, present, and future.
J Magn Reson Imaging. 2014 Aug 23;
Authors: Riley GM, McWalter EJ, Stevens KJ, Safran MR, Lattanzi R, Gold GE
The concept of femoroacetabular impingement (FAI) has, in a relatively short time, come to the forefront of orthopedic imaging. In just a few short years MRI findings that were in the past ascribed to degenerative change, normal variation, or other pathologies must now be described and included in radiology reports, as they have been shown, or are suspected to be related to, FAI. Crucial questions have come up in this time, including: what is the relationship of bony morphology to subsequent cartilage and labral damage, and most importantly, how is this morphology related to the development of osteoarthritis? In this review, we attempt to place a historical perspective on the controversy, provide guidelines for interpretation of MRI examinations of patients with suspected FAI, and offer a glimpse into the future of MRI of this complex condition. J. Magn. Reson. Imaging 2014. © 2014 Wiley Periodicals, Inc.
PMID: 25155435 [PubMed - as supplied by publisher]
Comparison of three ECG criteria for athlete pre-participation screening.
J Electrocardiol. 2014 Aug 2;
Authors: Pickham D, Zarafshar S, Sani D, Kumar N, Froelicher V
Controversy regarding adding the ECG to the evaluation of young athletes centers on the implications of false positives. Several guidelines have been published with recommendations for criteria to distinguish between ECG manifestations of training and markers of risk for cardiovascular (CV) sudden death. With an athlete dataset negative of any CV related abnormalities on follow-up, we applied three athlete screening criteria to identify the one with the lowest rate of abnormal variants.
METHODS: High school, college, and professional athletes underwent 12L ECGs as part of routine physicals. All ECGs were recorded and processed using CardeaScreen (Seattle, WA). The European (2010), Stanford (2011), and Seattle criteria (2013) were applied.
RESULTS: From March 2011 to February 2013 1417 ECGs were collected. Mean age was 20±4years (14-35years), 36% female, 38.5% non-white (307 high school, 836 college and 284 professional). Rate of abnormal variants differed by criteria, predominately due to variation in interval thresholds for QT interval and QRS duration. There was a four-fold difference in abnormal variants between European and Seattle criteria (26% v 6%).
CONCLUSION: The Seattle criterion was the most conservative resulting in 78% fewer abnormal variants than the European criteria. Variation was most evident with thresholds for QT prolongation, short QT interval, and intraventricular conduction delay. Continued research is needed to further understand normal training related adaptations and to improve modern ECG screening criteria for athletes.
PMID: 25155389 [PubMed - as supplied by publisher]
Hepatic encephalopathy is associated with significantly increased mortality among patients awaiting liver transplantation.
Liver Transpl. 2014 Aug 25;
Authors: Wong RJ, Gish RG, Ahmed A
The prioritization of liver transplantation (LT) for end-stage liver disease patients utilizes the model for end stage liver disease (MELD), which attempts to identify the sickest patients, and thereby those that are in greatest need for LT. Hepatic encephalopathy (HE) is not included in MELD, and severity of liver disease and risk of waitlist removal or waitlist death, may be underestimated by MELD in patients with HE. Utilizing United Network for Organ Sharing registry data, we evaluated the impact of HE on 90-day waitlist survival among adult LT waitlist registrants in the U.S. from 2003-2012. Survival was stratified by HE severity (none, grade 1-2, grade 3-4) and MELD. There were 84,947 new LT waitlist registrants during the study period; 36.8% had no HE, 57.4% had grade 1-2 HE, and 5.9% had grade 3-4 HE. 90-day waitlist mortality was significantly higher among patients with grade 3-4 HE compared to patients with grade 1-2 HE or no HE (24.4% vs. 6.8% vs. 3.5%, p < 0.001). When stratified by MELD, patients with grade 3-4 HE had 90-day waitlist mortality similar to non-encephalopathic patients with MELD scores 6-7 points higher. On multivariate Cox proportional hazards model, patients with grade 3-4 HE had 66% greater risk of 90-day mortality than patients without HE (HR, 1.66; 95% CI, 1.45-1.90; p < 0.001). The inclusion of HE severity to MELD improved the AUROC for predicting 90-day waitlist survival from 0.6508 to 0.6863. In conclusion, grade 3-4 HE at time of waitlist registration significantly increases 90-day waitlist mortality independent of MELD score. Incorporating HE in the assessment of LT priority may improve prognostication of liver disease severity and prioritization for LT. Liver Transpl , 2014. © 2014 AASLD.
PMID: 25155379 [PubMed - as supplied by publisher]
Burns ITU admissions: Length of stay in specific levels of care for adult and paediatric patients.
Burns. 2014 Aug 21;
Authors: Maan ZN, Frew Q, Din AH, Unluer Z, Smailes S, Philp B, El-Muttardi N, Dziewulski P
Prediction of total length of stay (LOS) for burns patients based on the total burn surface area (TBSA) is well accepted. Total LOS is a poor measure of resource consumption. Our aim was to determine the LOS in specific levels of care to better inform resource allocation. We performed a retrospective review of LOS in intensive treatment unit (ITU), burns high dependency unit (HDU) and burns low dependency unit (LDU) for all patients requiring ITU admission in a regional burns service from 2003 to 2011. During this period, our unit has admitted 1312 paediatric and 1445 adult patients to our Burns ITU. In both groups, ITU comprised 20% of the total LOS (mean 0.23±0.02 [adult] and 0.22±0.02 [paediatric] days per %burn). In adults, 33% of LOS was in HDU (0.52±0.06 days per %burn) and 48% (0.68±0.06 days per %burn) in LDU, while in children, 15% of LOS was in HDU (0.19±0.03 days per %burn) and 65% in LDU (0.70±0.06 days per %burn). When considering Burns ITU admissions, resource allocation ought to be planned according to expected LOS in specific levels of care rather than total LOS. The largest proportion of stay is in low dependency, likely due to social issues.
PMID: 25155115 [PubMed - as supplied by publisher]
A randomized comparison of proximal and distal ultrasound-guided adductor canal catheter insertion sites for knee arthroplasty.
J Ultrasound Med. 2014 Sep;33(9):1653-62
Authors: Mariano ER, Kim TE, Wagner MJ, Funck N, Harrison TK, Walters T, Giori N, Woolson S, Ganaway T, Howard SK
OBJECTIVES: Proximal and distal (mid-thigh) ultrasound-guided continuous adductor canal block techniques have been described but not yet compared, and infusion benefits or side effects may be determined by catheter location. We hypothesized that proximal placement will result in faster onset of saphenous nerve anesthesia, without additional motor block, compared to a distal technique.
METHODS: Preoperatively, patients receiving an ultrasound-guided nonstimulating adductor canal catheter for knee arthroplasty were randomly assigned to either proximal or distal insertion. A local anesthetic bolus was administered via the catheter after successful placement. The primary outcome was the time to achieve complete sensory anesthesia in the saphenous nerve distribution. Secondary outcomes included procedural time, procedure-related pain and complications, postoperative pain, opioid consumption, and motor weakness.
RESULTS: Proximal insertion (n = 23) took a median (10th-90th percentiles) of 12.0 (3.0-21.0) minutes versus 6.0 (3.0-21.0) minutes for distal insertion (n = 21; P= .106) to anesthetize the medial calf. Only 10 of 25 (40%) and 10 of 24 (42%) patients in the proximal and distal groups, respectively, developed anesthesia at both the medial calf and top of the patella (P= .978). Bolus-induced motor weakness occurred in 19 of 25 (76%) and 16 of 24 (67%) patients in the proximal and distal groups (P = .529). Ten of 24 patients (42%) in the distal group required intravenous morphine postoperatively, compared to 2 of 24 (8%) in the proximal group (P = .008), but there were no differences in other secondary outcomes.
CONCLUSIONS: Continuous adductor canal blocks can be performed reliably at both proximal and distal locations. The proximal approach may offer minor analgesic and logistic advantages without an increase in motor block.
PMID: 25154949 [PubMed - in process]
Value of short-interval computed tomography when sonography fails to visualize the appendix and shows otherwise normal findings.
J Ultrasound Med. 2014 Sep;33(9):1589-95
Authors: Shah BR, Stewart J, Jeffery RB, Olcott EW
OBJECTIVES: The purpose of this study was to evaluate the type and incidence of disorders revealed by short-interval computed tomography (CT) in patients with suspected appendicitis after graded compression sonography fails to reveal the appendix and shows otherwise normal findings.
METHODS: Computed tomographic findings and clinical courses were assessed retrospectively for 318 patients identified consecutively in a searchable database who met inclusion criteria specifying that sonography was the initial imaging examination for suspected appendicitis; sonography revealed nonvisualization of the appendix and otherwise normal results; and abdominopelvic CT was performed within 48 hours after sonography.
RESULTS: Of the 318 patients, short-interval CT revealed normal findings in 250 (78.6%). Appendicitis was revealed in 52 (16.4%) others, of whom 7 had perforation and all of whom had pathologic results confirming these CT findings. Important alternative diagnoses other than appendicitis were revealed in 16 (5.0%) others, including 2 (0.6%) who required urgent surgery and 14 (4.4%) who did not. No significant differences were observed between adult patients (>18 years) and pediatric patients.
CONCLUSIONS: Most short-interval CT scans in this clinical setting reveal normal findings, and relatively few disclose appendicitis or disorders that require urgent surgery. In view of concerns regarding radiation exposure associated with CT, these observations argue for the development of clinical triage methods that differentiate patients who are likely to benefit from short-interval postsonography CT from those who are not.
PMID: 25154940 [PubMed - in process]
Rates and Patterns of Recurrence after Curative Intent Resection for Gastric Cancer: A United States Multi-Institutional Analysis.
J Am Coll Surg. 2014 Jun 26;
Authors: Spolverato G, Ejaz A, Kim Y, Squires MH, Poultsides GA, Fields RC, Schmidt C, Weber SM, Votanopoulos K, Maithel SK, Pawlik TM
BACKGROUND: Reports on recurrence and outcomes of US patients with gastric cancer are scarce. The aim of this study was to determine incidence and pattern of recurrence after curative intent surgery for gastric cancer.
STUDY DESIGN: Using the multi-institutional US Gastric Cancer Collaborative database, we identified 817 patients undergoing curative intent resection for gastric cancer between 2000 and 2012. Patterns and rates of recurrence along with associated risk factors were identified using adjusted regression analysis. Recurrences were classified as locoregional, peritoneal, or hematogenous.
RESULTS: Median patient age was 65.8 years (interquartile range [IQR] 56.4, 74.7); the majority of patients were male (n = 462, 56.6%) and white (n = 511, 62.5%). At the time of surgery, the majority of patients underwent a partial gastrectomy (n = 481, 59.2%) with a complete R0 resection achieved in 91.6% (n = 748) of patients. At the time of last follow-up, 244 (29.9%) of 817 patients developed a recurrence; 163 (66.8%) patients had recurrence at only a single site; the remaining 81 (33.2%) had multiple sites of initial recurrence. Among patients who recurred at a single site, recurrence was most common at a distant location and included hematogenous (n = 57, 23.4%) or peritoneal (n = 47, 19.3%) only metastasis. Tumors at the gastroesophageal junction (odds ratio [OR] 3.18, 95% CI 1.08 to 9.40; p = 0.04) were associated with higher risk of locoregional recurrence, while the presence of multiple lesions (OR 10.82, 95% CI 3.56 to 32.85; p < 0.001) remained associated with an increased risk of distant hematogenous recurrence after adjusted analysis. Recurrence was associated with worse survival, with a median recurrence-free survival of 10.8 months (IQR 8.9, 12.8) among those who experienced a recurrence.
CONCLUSIONS: Nearly one-third of patients experienced recurrence after gastric cancer surgery. The most common site of recurrence was distant.
PMID: 25154671 [PubMed - as supplied by publisher]
J Hand Surg Am. 2014 Sep;39(9):1888-9
Authors: Carvalho B, Ahsan ZS, Yao J
PMID: 25154582 [PubMed - in process]
Selective attention. Long-range and local circuits for top-down modulation of visual cortex processing.
Science. 2014 Aug 8;345(6197):660-5
Authors: Zhang S, Xu M, Kamigaki T, Hoang Do JP, Chang WC, Jenvay S, Miyamichi K, Luo L, Dan Y
Top-down modulation of sensory processing allows the animal to select inputs most relevant to current tasks. We found that the cingulate (Cg) region of the mouse frontal cortex powerfully influences sensory processing in the primary visual cortex (V1) through long-range projections that activate local γ-aminobutyric acid-ergic (GABAergic) circuits. Optogenetic activation of Cg neurons enhanced V1 neuron responses and improved visual discrimination. Focal activation of Cg axons in V1 caused a response increase at the activation site but a decrease at nearby locations (center-surround modulation). Whereas somatostatin-positive GABAergic interneurons contributed preferentially to surround suppression, vasoactive intestinal peptide-positive interneurons were crucial for center facilitation. Long-range corticocortical projections thus act through local microcircuits to exert spatially specific top-down modulation of sensory processing.
PMID: 25104383 [PubMed - indexed for MEDLINE]
Raising the bar for the care of seriously ill patients: results of a national survey to define essential palliative care competencies for medical students and residents.
Acad Med. 2014 Jul;89(7):1024-31
Authors: Schaefer KG, Chittenden EH, Sullivan AM, Periyakoil VS, Morrison LJ, Carey EC, Sanchez-Reilly S, Block SD
PURPOSE: Given the shortage of palliative care specialists in the United States, to ensure quality of care for patients with serious, life-threatening illness, generalist-level palliative care competencies need to be defined and taught. The purpose of this study was to define essential competencies for medical students and internal medicine and family medicine (IM/FM) residents through a national survey of palliative care experts.
METHOD: Proposed competencies were derived from existing hospice and palliative medicine fellowship competencies and revised to be developmentally appropriate for students and residents. In spring 2012, the authors administered a Web-based, national cross-sectional survey of palliative care educational experts to assess ratings and rankings of proposed competencies and competency domains.
RESULTS: The authors identified 18 comprehensive palliative care competencies for medical students and IM/FM residents, respectively. Over 95% of survey respondents judged the competencies as comprehensive and developmentally appropriate (survey response rate = 72%, 71/98). Using predefined cutoff criteria, experts identified 7 medical student and 13 IM/FM resident competencies as essential. Communication and pain/symptom management were rated as the most critical domains.
CONCLUSIONS: This national survey of palliative care experts defines comprehensive and essential palliative care competencies for medical students and IM/FM residents that are specific, measurable, and can be used to report educational outcomes; provide a sequence for palliative care curricula in undergraduate and graduate medical education; and highlight the importance of educating medical trainees in communication and pain management. Next steps include seeking input and endorsement from stakeholders in the broader medical education community.
PMID: 24979171 [PubMed - indexed for MEDLINE]
New ways to dismantle a ticking time bomb: microRNA 712/205 and abdominal aortic aneurysm development.
Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1339-40
Authors: Maegdefessel L, Spin JM, Tsao PS
PMID: 24951652 [PubMed - indexed for MEDLINE]
Curation accuracy of model organism databases.
Database (Oxford). 2014;2014
Authors: Keseler IM, Skrzypek M, Weerasinghe D, Chen AY, Fulcher C, Li GW, Lemmer KC, Mladinich KM, Chow ED, Sherlock G, Karp PD
Manual extraction of information from the biomedical literature-or biocuration-is the central methodology used to construct many biological databases. For example, the UniProt protein database, the EcoCyc Escherichia coli database and the Candida Genome Database (CGD) are all based on biocuration. Biological databases are used extensively by life science researchers, as online encyclopedias, as aids in the interpretation of new experimental data and as golden standards for the development of new bioinformatics algorithms. Although manual curation has been assumed to be highly accurate, we are aware of only one previous study of biocuration accuracy. We assessed the accuracy of EcoCyc and CGD by manually selecting curated assertions within randomly chosen EcoCyc and CGD gene pages and by then validating that the data found in the referenced publications supported those assertions. A database assertion is considered to be in error if that assertion could not be found in the publication cited for that assertion. We identified 10 errors in the 633 facts that we validated across the two databases, for an overall error rate of 1.58%, and individual error rates of 1.82% for CGD and 1.40% for EcoCyc. These data suggest that manual curation of the experimental literature by Ph.D-level scientists is highly accurate. Database URL: http://ecocyc.org/, http://www.candidagenome.org//
PMID: 24923819 [PubMed - indexed for MEDLINE]
Risk of subsequent cancers in renal cell carcinoma survivors with a family history.
Eur J Cancer. 2014 Aug;50(12):2108-18
Authors: Chen T, Fallah M, Sundquist K, Liu H, Hemminki K
BACKGROUND: This study aimed at elucidating the effect of family history on the development of subsequent cancers in renal cell carcinoma (RCC) survivors and aimed at assessing whether the interactions between risks of subsequent cancers in RCC survivors and familial risk of subsequent cancer are additive or multiplicative interactions.
METHODS: A population-based cohort (Swedish Family-Cancer Database) of 14,267 RCC patients diagnosed in 1990-2010 was followed for cancer incidence. Standardised incidence ratios (SIRs) were calculated for subsequent cancers in RCC survivors and in RCC survivors with a family history of subsequent cancer. Familial risk of subsequent cancer was calculated for individuals with family history of specific cancer, compared to those without.
RESULTS: For subsequent hemangioblastoma (HB) in RCC survivors, drastically elevated risk was observed for the effect of family history of HB [SIR=777 (95% confidence interval (CI): 160-2270)] and of family history of RCC [378 (46-1367)]. Colorectal, lung, prostate and RCCs favoured additive interactions between risk of subsequent cancers in RCC survivors and familial risk, while endocrine glands, nervous system and urinary bladder cancers favoured multiplicative interactions.
CONCLUSIONS: Risks of subsequent HB in RCC survivors were tremendously modified by family history of RCC or HB, which may resemble characteristics of von Hippel-Lindau syndrome and show the power of present approach to detect heritable cancer clusters. Additive or multiplicative interactions found for colorectal, lung, prostate, endocrine glands, nervous system, urinary bladder and RCCs might raise awareness among clinicians and RCC survivors with a family history of seven cancers about elevated risks of subsequent those cancers.
PMID: 24923229 [PubMed - indexed for MEDLINE]
Hepatitis C virus infection and coronary artery disease risk: a systematic review of the literature.
Dig Dis Sci. 2014 Jul;59(7):1586-93
Authors: Wong RJ, Kanwal F, Younossi ZM, Ahmed A
BACKGROUND AND AIMS: While hepatitis C virus (HCV) infection has been implicated in increasing the risk of coronary artery disease (CAD), conflicting reports exist regarding this association. We performed a systematic review to further investigate this association.
METHODS: We conducted a PubMed search of original research articles from January 1, 1995 to June 30, 2013 to identify case-control and cohort studies evaluating the association between HCV and CAD using keyword terms ["hepatitis c" or "HCV"] and ["coronary artery disease" or "heart disease" or "atherosclerosis."] The primary CAD-related endpoints included myocardial infarction, congestive heart failure, need for coronary artery bypass grafting, or transluminal percutaneous coronary angioplasty. Binary outcomes are reported as odds ratios (OR) with 95 % confidence interval (CI).
RESULTS: We identified five studies (four cohort studies and one case-control study) that met our inclusion criteria. A significant association between HCV and CAD was demonstrated in one cohort study (adjusted HR 1.27; 95 % CI 1.22-1.31). One cohort study demonstrated a decreased risk of CAD associated with HCV (adjusted OR 0.74; 95 % CI 0.71-0.76). The remaining studies did not find a significant association between HCV and risk of CAD.
CONCLUSIONS: The current systematic review demonstrates that the association between HCV and CAD remains unclear. We need more large, long-term cohort studies with clear definitions of patient population and endpoints to better ascertain the association between HCV and CAD.
PMID: 24894512 [PubMed - indexed for MEDLINE]
Narcolepsy is a common phenotype in HSAN IE and ADCA-DN.
Brain. 2014 Jun;137(Pt 6):1643-55
Authors: Moghadam KK, Pizza F, La Morgia C, Franceschini C, Tonon C, Lodi R, Barboni P, Seri M, Ferrari S, Liguori R, Donadio V, Parchi P, Cornelio F, Inzitari D, Mignarri A, Capocchi G, Dotti MT, Winkelmann J, Lin L, Mignot E, Carelli V, Plazzi G
We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.
PMID: 24727570 [PubMed - indexed for MEDLINE]
GigaDB: promoting data dissemination and reproducibility.
Database (Oxford). 2014;2014:bau018
Authors: Sneddon TP, Zhe XS, Edmunds SC, Li P, Goodman L, Hunter CI
Often papers are published where the underlying data supporting the research are not made available because of the limitations of making such large data sets publicly and permanently accessible. Even if the raw data are deposited in public archives, the essential analysis intermediaries, scripts or software are frequently not made available, meaning the science is not reproducible. The GigaScience journal is attempting to address this issue with the associated data storage and dissemination portal, the GigaScience database (GigaDB). Here we present the current version of GigaDB and reveal plans for the next generation of improvements. However, most importantly, we are soliciting responses from you, the users, to ensure that future developments are focused on the data storage and dissemination issues that still need resolving. Database URL: http://www.gigadb.org.
PMID: 24622612 [PubMed - indexed for MEDLINE]
Safe application of topical negative pressure dressings to exposed brain before definitive reconstruction.
J Plast Reconstr Aesthet Surg. 2014 Aug;67(8):e204-5
Authors: Davis CR, Mitsala G, Malcolm G, Orlando A
PMID: 24593941 [PubMed - indexed for MEDLINE]
Isoniazid hepatotoxicity requiring liver transplantation.
Dig Dis Sci. 2014 Jul;59(7):1370-4
Authors: Sheen E, Huang RJ, Uribe LA, Nguyen MH
PMID: 24573717 [PubMed - indexed for MEDLINE]
On-chip separation and analysis of RNA and DNA from single cells.
Anal Chem. 2014 Feb 18;86(4):1953-7
Authors: Shintaku H, Nishikii H, Marshall LA, Kotera H, Santiago JG
The simultaneous analysis of RNA and DNA of single cells remains a challenge as these species have very similar physical and biochemical properties and can cross-contaminate each other. Presented is an on-chip system that enables selective lysing of single living cells, extraction, focusing, and absolute quantification of cytoplasmic RNA mass and its physical separation from DNA in the nucleus using electrical lysing and isotachophoresis (ITP). This absolute quantitation is performed without enzymatic amplification in less than 5 min. The nucleus is preserved, and its DNA fluorescence signal can be measured independently. We demonstrate the technique using single mouse lymphocyte cells, for which we extracted an average of 14.1 pg of total RNA per cell. We also demonstrate correlation analysis between the absolute amount of RNA and relative amount of DNA, showing heterogeneity associated with cell cycles. The technique is compatible with fractionation of DNA and RNA and with downstream assays of each.
PMID: 24499009 [PubMed - indexed for MEDLINE]
An anti-inflammatory NOD-like receptor is required for microglia development.
Cell Rep. 2013 Dec 12;5(5):1342-52
Authors: Shiau CE, Monk KR, Joo W, Talbot WS
Microglia are phagocytic cells that form the basis of the brain's immune system. They derive from primitive macrophages that migrate into the brain during embryogenesis, but the genetic control of microglial development remains elusive. Starting with a genetic screen in zebrafish, we show that the noncanonical NOD-like receptor (NLR) nlrc3-like is essential for microglial formation. Although most NLRs trigger inflammatory signaling, nlrc3-like acts cell autonomously in microglia precursor cells to suppress unwarranted inflammation in the absence of overt immune challenge. In nlrc3-like mutants, primitive macrophages initiate a systemic inflammatory response with increased proinflammatory cytokines and actively aggregate instead of migrating into the brain to form microglia. NLRC3-like requires both its pyrin and NACHT domains, and it can bind the inflammasome component apoptosis-associated speck-like protein. Our studies suggest that NLRC3-like may regulate the inflammasome and other inflammatory pathways. Together, these results demonstrate that NLRC3-like prevents inappropriate macrophage activation, thereby allowing normal microglial development.
PMID: 24316075 [PubMed - indexed for MEDLINE]
Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia.
Cell Rep. 2013 Dec 12;5(5):1316-29
Authors: Loktev AV, Jackson PK
Human monogenic obesity syndromes, including Bardet-Biedl syndrome (BBS), implicate neuronal primary cilia in regulation of energy homeostasis. Cilia in hypothalamic neurons have been hypothesized to sense and regulate systemic energy status, but the molecular mechanism of this signaling remains unknown. Here, we report a comprehensive localization screen of 42 G-protein-coupled receptors (GPCR) revealing seven ciliary GPCRs, including the neuropeptide Y (NPY) receptors NPY2R and NPY5R. We show that mice modeling BBS disease or obese tubby mice fail to localize NPY2R to cilia in the hypothalamus and that BBS mutant mice fail to activate c-fos or decrease food intake in response to the NPY2R ligand PYY3-36. We find that cells with ciliary NPY2R show augmented PYY3-36-dependent cAMP signaling. Our data demonstrate that ciliary targeting of NPY receptors is important for controlling energy balance in mammals, revealing a physiologically defined ligand-receptor pathway signaling within neuronal cilia.
PMID: 24316073 [PubMed - indexed for MEDLINE]
Synthesis of modified Trichinella spiralis disaccharide epitopes and a comparison of their recognition by chemical mapping and saturation transfer difference NMR.
Carbohydr Res. 2014 Jan 13;383:1-13
Authors: Cui L, Ling CC, Sadowska J, Bundle DR
A rat monoclonal antibody 9D4 raised against the cell surface N-glycan of the parasite Trichinella spirallis protects rats against further infection. The terminal disaccharide β-d-Tyvp(1→3)β-d-GalNAcp (2) represents the immunodominant portion of the antigenic determinant. Chemical mapping of the antibody binding site by functional group modification employing monodeoxy and mono-O-methyl congeners identified key polar contacts and topography of the bound disaccharide. We report here a comparison of the chemical mapping studies with the antigen topography inferred from saturation transfer difference (STD) NMR experiments. During chemical mapping several congeners of compound 2 showed substantially enhanced binding. Pairing of these functional group modifications to create derivatives 6 and 7 did not show additive free energy gains and STD NMR data point to small variations in mode of binding as a probable cause. Improved syntheses of disaccharides 2-7 are reported.
PMID: 24239604 [PubMed - indexed for MEDLINE]
Evidence that duplications of 22q11.2 protect against schizophrenia.
Mol Psychiatry. 2014 Jan;19(1):37-40
Authors: Rees E, Kirov G, Sanders A, Walters JT, Chambert KD, Shi J, Szatkiewicz J, O'Dushlaine C, Richards AL, Green EK, Jones I, Davies G, Legge SE, Moran JL, Pato C, Pato M, Genovese G, Levinson D, Duan J, Moy W, Göring HH, Morris D, Cormican P, Kendler KS, O'Neill FA, Riley B, Gill M, Corvin A, Wellcome Trust Case Control Consortium, Craddock N, Sklar P, Hultman C, Sullivan PF, Gejman PV, McCarroll SA, O'Donovan MC, Owen MJ
A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.
PMID: 24217254 [PubMed - indexed for MEDLINE]
In vivo readout of CFTR function: ratiometric measurement of CFTR-dependent secretion by individual, identifiable human sweat glands.
PLoS One. 2013;8(10):e77114
Authors: Wine JJ, Char JE, Chen J, Cho HJ, Dunn C, Frisbee E, Joo NS, Milla C, Modlin SE, Park IH, Thomas EA, Tran KV, Verma R, Wolfe MH
To assess CFTR function in vivo, we developed a bioassay that monitors and compares CFTR-dependent and CFTR-independent sweat secretion in parallel for multiple (~50) individual, identified glands in each subject. Sweating was stimulated by intradermally injected agonists and quantified by optically measuring spherical sweat bubbles in an oil-layer that contained dispersed, water soluble dye particles that partitioned into the sweat bubbles, making them highly visible. CFTR-independent secretion (M-sweat) was stimulated with methacholine, which binds to muscarinic receptors and elevates cytosolic calcium. CFTR-dependent secretion (C-sweat) was stimulated with a β-adrenergic cocktail that elevates cytosolic cAMP while blocking muscarinic receptors. A C-sweat/M-sweat ratio was determined on a gland-by-gland basis to compensate for differences unrelated to CFTR function, such as gland size. The average ratio provides an approximately linear readout of CFTR function: the heterozygote ratio is ~0.5 the control ratio and for CF subjects the ratio is zero. During assay development, we measured C/M ratios in 6 healthy controls, 4 CF heterozygotes, 18 CF subjects and 4 subjects with 'CFTR-related' conditions. The assay discriminated all groups clearly. It also revealed consistent differences in the C/M ratio among subjects within groups. We hypothesize that these differences reflect, at least in part, levels of CFTR expression, which are known to vary widely. When C-sweat rates become very low the C/M ratio also tended to decrease; we hypothesize that this nonlinearity reflects ductal fluid absorption. We also discovered that M-sweating potentiates the subsequent C-sweat response. We then used potentiation as a surrogate for drugs that can increase CFTR-dependent secretion. This bioassay provides an additional method for assessing CFTR function in vivo, and is well suited for within-subject tests of systemic, CFTR-directed therapeutics.
PMID: 24204751 [PubMed - indexed for MEDLINE]
Augmenting endogenous Wnt signaling improves skin wound healing.
PLoS One. 2013;8(10):e76883
Authors: Whyte JL, Smith AA, Liu B, Manzano WR, Evans ND, Dhamdhere GR, Fang MY, Chang HY, Oro AE, Helms JA
Wnt signaling is required for both the development and homeostasis of the skin, yet its contribution to skin wound repair remains controversial. By employing Axin2(LacZ/+) reporter mice we evaluated the spatial and temporal distribution patterns of Wnt responsive cells, and found that the pattern of Wnt responsiveness varies with the hair cycle, and correlates with wound healing potential. Using Axin2(LacZ/LacZ) mice and an ear wound model, we demonstrate that amplified Wnt signaling leads to improved healing. Utilizing a biochemical approach that mimics the amplified Wnt response of Axin2(LacZ/LacZ) mice, we show that topical application of liposomal Wnt3a to a non-healing wound enhances endogenous Wnt signaling, and results in better skin wound healing. Given the importance of Wnt signaling in the maintenance and repair of skin, liposomal Wnt3a may have widespread application in clinical practice.
PMID: 24204695 [PubMed - indexed for MEDLINE]
Protective effects of inhaled carbon monoxide in endotoxin-induced cholestasis is dependent on its kinetics.
Biochimie. 2014 Feb;97:173-80
Authors: Vanova K, Suk J, Petr T, Cerny D, Slanar O, Vreman HJ, Wong RJ, Zima T, Vitek L, Muchova L
Carbon monoxide (CO), a product of heme oxygenase (HMOX), has many beneficial biological functions and is a promising therapeutic agent for many pathological conditions. However, the kinetics of inhaled CO and its protective role in endotoxin-induced cholestasis is not fully known. Thus, our objective was to characterize the kinetics of inhaled CO and then investigate its use in early phase experimental endotoxin-induced cholestasis. Female Wistar rats were randomly divided into 4 groups: CON (control), LPS (lipopolysaccharide, 6 mg/kg), CO (250 ppm COx1h), and CO + LPS. Rats were sacrificed at 0-12 h after LPS administration. Tissues and blood were collected for liver injury markers and tissue CO distribution measurements. Livers were harvested for measurements of Hmox activity, Hmox1 mRNA expression, cytokines (IL10, IL6, TNF), and bile lipid and pigment transporters. Half-lives of CO in spleen, blood, heart, brain, kidney, liver, and lungs were 2.4 ± 1.5, 2.3 ± 0.8, 1.8 ± 1.6, 1.5 ± 1.2, 1.1 ± 1.1, 0.6 ± 0.3, 0.6 ± 0.2 h, respectively. CO treatment increased liver IL10 mRNA and decreased TNF expression 1 h after LPS treatment and prevented the down-regulation of bile acid and bilirubin hepatic transporters (Slc10a1, Abcb11, and Abcc2, p < 0.05), an effect closely related to the kinetics. The protective effect of CO against cholestatic liver injury persisted even 12 h after CO exposure, as shown by attenuation of serum cholestatic markers in CO-treated animals. CO exposure substantially attenuated endotoxin-induced cholestatic liver injury and was directly related to the kinetics of inhaled CO. This data underscores the importance of the kinetics of inhaled CO for the proper design of experimental and clinical studies of using CO as a treatment strategy.
PMID: 24148277 [PubMed - indexed for MEDLINE]
Resting ST amplitude: prognosis and normal values in an ambulatory clinical population.
Ann Noninvasive Electrocardiol. 2013 Nov;18(6):519-29
Authors: Zarafshar S, Wong M, Singh N, Aggarwal S, Adhikarla C, Froelicher VF
BACKGROUND: There is limited data describing ST segment amplitude in apparently healthy, asymptomatic populations. We analyzed ST amplitude in the standard resting electrocardiogram (ECG) in a large, multiethnic, stable, clinical population.
METHODS: We evaluated computerized ST amplitude measurements from the resting ECGs of 29,281 ambulatory outpatients collected between 1987 and 1999 at the Palo Alto, VA. With the PR interval as the isoelectric line, both elevation criteria (≥0.1 mV, ≥0.15 mV, and ≥0.2 mV) and depression criteria (≤-0.05 mV or ≤-0.1 mV), were applied. Cox-Hazard survival analysis techniques were used to demonstrate in which leads ST amplitude displacement was associated with cardiovascular (CV) death. To create a cohort without ECG patterns clearly associated with disease, we excluded ECGs with inverted T waves, wide QRS, or diagnostic Q waves and coded the remaining "normal" ECGs for ST elevation and depression to determine a normal range.
RESULTS: The only ST amplitudes that were significantly and independently associated with time to CV death when adjusted for age, gender, and ethnicity were ST depression in all of the lateral leads (I, V4 -V6 ). When isolated to the inferior leads, (II and AVF), no ST amplitude criteria were associated with CV death. Among the "normal ECG" subgroup the precordial leads exhibited the greatest median ST amplitudes and the most significant differences between the leads, genders and ethnicities.
CONCLUSIONS: Significant differences in ST amplitude were present in the precordial leads according to gender and ethnicity. This was particularly apparent when amplitude threshold were set for comparisons. Our findings provide the normal range for ST amplitude that when exceeded, should raise clinical concern.
PMID: 24147772 [PubMed - indexed for MEDLINE]
A novel engineered anti-CD20 tracer enables early time PET imaging in a humanized transgenic mouse model of B-cell non-Hodgkins lymphoma.
Clin Cancer Res. 2013 Dec 15;19(24):6820-9
Authors: Natarajan A, Hackel BJ, Gambhir SS
PURPOSE: The aim of this article was to evaluate the use of a novel engineered anti-CD20 protein based on the 10 kDa human fibronectin type 3 domain (FN3) and subsequently compare with (64)Cu-rituximab for positron emission tomography (PET) imaging of CD20.
EXPERIMENTAL DESIGN: The engineered FN3(CD20) and FN3(WT) were produced in Escherichia coli cells at 2 to 5 mg/L, conjugated to DOTA, labeled with (64)Cu, and used for PET imaging of huCD20 expression in B cells. Humanized transgenic mice and subcutaneously xenografted mice each received intravenous (64)Cu-FN3(CD20) or FN3(WT) (3.7 MBq/4 μg Do-FN3 in 200 μL PBS). Control group received a blocking dose (50-fold excess) of unconjugated FN3(CD20) two hours before radiotracer injection. PET imaging was carried out at 1 to 24 hours postinjections.
RESULTS: In vitro assay demonstrated FN3 binds CD20 with 20 nmol/L affinity on CD20-expressing cells. (64)Cu-FN3(CD20) showed clear, high-contrast visualization of huCD20-expressing B cells in the spleen of transgenic mice as early as 1 hour postinjection [38 ± 3% injected dose (ID)/g] and exhibited a spleen-to-blood ratio of 13 by 4 hours. This is higher uptake (P = 0.04) and 10-fold greater signal-to-background (P = 0.04) than the (64)Cu-rituximab antibody radiotracer. Tumor uptake (16.8 ± 1.6 vs. 5.6 ± 1.4%ID/g) and tumor:background ratios were superior for FN3CD20 relative to rituximab in xenograft studies as well.
CONCLUSIONS: The (64)Cu-Do-FN3(CD20) radiotracer represents a novel small, high-affinity binder for imaging human CD20, which may be well suited for B-cell non-Hodgkin's lymphoma imaging in patients at early time points.
PMID: 24097872 [PubMed - indexed for MEDLINE]
Talking to children matters: early language experience strengthens processing and builds vocabulary.
Psychol Sci. 2013 Nov 1;24(11):2143-52
Authors: Weisleder A, Fernald A
Infants differ substantially in their rates of language growth, and slow growth predicts later academic difficulties. In this study, we explored how the amount of speech directed to infants in Spanish-speaking families low in socioeconomic status influenced the development of children's skill in real-time language processing and vocabulary learning. All-day recordings of parent-infant interactions at home revealed striking variability among families in how much speech caregivers addressed to their child. Infants who experienced more child-directed speech became more efficient in processing familiar words in real time and had larger expressive vocabularies by the age of 24 months, although speech simply overheard by the child was unrelated to vocabulary outcomes. Mediation analyses showed that the effect of child-directed speech on expressive vocabulary was explained by infants' language-processing efficiency, which suggests that richer language experience strengthens processing skills that facilitate language growth.
PMID: 24022649 [PubMed - indexed for MEDLINE]
Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development.
Cardiovasc Res. 2014 Jan 1;101(1):120-9
Authors: Yang J, Zeini M, Lin CY, Lin CJ, Xiong Y, Shang C, Han P, Li W, Quertermous T, Zhou B, Chang CP
AIMS: Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin-NFAT signalling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries.
METHODS AND RESULTS: Using tissue-specific gene deletion, we found that calcineurin-NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 (Cnb1), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin-NFAT signals within a narrow time window at embryonic Day 12.5-13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2, whose gene product is critical for transducing transforming growth factor β (TGFβ)-Alk5 signalling to control coronary development.
CONCLUSION: Our findings demonstrate new spatiotemporal and molecular actions of calcineurin-NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin-NFAT integrates with TGFβ signalling during embryonic development.
PMID: 23946498 [PubMed - indexed for MEDLINE]
The immune system and inflammation in breast cancer.
Mol Cell Endocrinol. 2014 Jan 25;382(1):673-82
Authors: Jiang X, Shapiro DJ
During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.
PMID: 23791814 [PubMed - indexed for MEDLINE]
In vitro immunomodulation of a whole blood IFN-γ release assay enhances T cell responses in subjects with latent tuberculosis infection.
PLoS One. 2012;7(10):e48027
Authors: Gaur RL, Suhosk MM, Banaei N
BACKGROUND: Activation of innate immunity via pathogen recognition receptors (PRR) modulates adaptive immune responses. PRR ligands are being exploited as vaccine adjuvants and as therapeutics, but their utility in diagnostics has not been explored. Interferon-gamma (IFN-γ) release assays (IGRAs) are functional T cell assays used to diagnose latent tuberculosis infection (LTBI); however, novel approaches are needed to improve their sensitivity.
METHODS: In vitro immunomodulation of a whole blood IGRA (QuantiFERON®-TB GOLD In-Tube) with Toll-like receptor agonists poly(I:C), LPS, and imiquimod was performed on blood from subjects with LTBI and negative controls.
RESULTS: In vitro immunomodulation significantly enhanced the response of T cells stimulated with M. tuberculosis antigens from subjects with LTBI but not from uninfected controls. Immunomodulation of IGRA revealed T cell responses in subjects with LTBI whose T cells otherwise do not respond to in vitro stimulation with antigens alone. Similar to their in vivo functions, addition of poly(I:C) and LPS to whole blood induced secretion of inflammatory cytokines and IFN-α and enhanced the surface expression of antigen presenting and costimulatory molecules on antigen presenting cells.
CONCLUSIONS: In vitro immunomodulation of whole blood IGRA may be an effective strategy for enhancing the sensitivity of T cells for diagnosis of LTBI.
PMID: 23144722 [PubMed - indexed for MEDLINE]
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