Recent Stanford Publications in PubMed
- Learning the Structure of Biomedical Relationships from Unstructured Text.Percha B, Altman RBPLoS Comput Biol
- Potential Adverse Effects of Anesthesia in Children-Reply.Psaty BM, Platt R, Altman RBJAMA
- Outpatient Pharmacy Expenditures for Children With Serious Chronic Illness in California, 2010-2012.Swenson SM, Chamberlain LJ, Sanders LM, Sundaram V, Wise PHJAMA
- Obstetric Sepsis: Focus on the 3-Hour Bundle.Brown KN, Arafeh JMJ Perinat Neonatal Nurs
- Association of Anxiety Symptoms in Offspring of Bipolar Parents with Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype.Park MH, Sanders E, Howe M, Singh M, Hallmayer J, Kim E, Chang KJ Child Adolesc Psychopharmacol
- Motion Analysis for Microsurgical Training: Objective Measures of Dexterity, Economy of Movement, and Ability.McGoldrick RB, Davis CR, Paro J, Hui K, Nguyen D, Lee GKPlast Reconstr Surg
- Long-Term Outcomes of Rectosigmoid Neocolporrhaphy in Male-to-Female Gender Reassignment Surgery.Morrison SD, Satterwhite T, Grant DW, Kirby J, Laub DR, VanMaasdam JPlast Reconstr Surg
- Validation of a Skin-Lesion Image-Matching Algorithm Based on Computer Vision Technology.Chen RH, Snorrason M, Enger SM, Mostafa E, Ko JM, Aoki V, Bowling JTelemed J E Health
- Low expression of chloride channel accessory 1 predicts a poor prognosis in colorectal cancer: The question is still open.ShahidSales S, Mobarhan MG, Ghasemi F, Gholamin S, Avan ACancer
- Nullspace Sampling with Holonomic Constraints Reveals Molecular Mechanisms of Protein Gαs.Pachov DV, van den Bedem HPLoS Comput Biol
- Quantitative analysis of the myelin g-ratio from electron microscopy images of the macaque corpus callosum.Stikov N, Campbell JS, Stroh T, Lavelée M, Frey S, Novek J, Nuara S, Ho MK, Bedell BJ, Dougherty RF, Leppert IR, Boudreau M, Narayanan S, Duval T, Cohen-Adad J, Picard PA, Gasecka A, Côté D, Pike GBData Brief
- Best practices for evaluating single nucleotide variant calling methods for microbial genomics.Olson ND, Lund SP, Colman RE, Foster JT, Sahl JW, Schupp JM, Keim P, Morrow JB, Salit ML, Zook JMFront Genet
- Corrigendum: Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example.Goldstein BA, Knowles JW, Salfati E, Ioannidis JP, Assimes TLFront Genet
- Turn-taking: a case study of early gesture and word use in answering WHERE and WHICH questions.Clark EV, Lindsey KLFront Psychol
- Evaluation of sodium nitroprusside for controlled hypotension in children during surgery.Drover DR, Hammer GB, Barrett JS, Cohane CA, Reece T, Zajicek A, Schulman SRFront Pharmacol
- Physical biology of human brain development.Budday S, Steinmann P, Kuhl EFront Cell Neurosci
- Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells.Wu B, Wei S, Petersen N, Ali Y, Wang X, Bacaj T, Rorsman P, Hong W, Südhof TC, Han WProc Natl Acad Sci U S A
- Identification and characterization of an injury-induced skeletal progenitor.Marecic O, Tevlin R, McArdle A, Seo EY, Wearda T, Duldulao C, Walmsley GG, Nguyen A, Weissman IL, Chan CK, Longaker MTProc Natl Acad Sci U S A
- Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin.Wong YH, Lee CM, Xie W, Cui B, Poo MMProc Natl Acad Sci U S A
- Contribution of Lateral Column Lengthening to Correction of Forefoot Abduction in Stage IIb Adult Acquired Flatfoot Deformity Reconstruction.Chan JY, Greenfield ST, Soukup DS, Do HT, Deland JT, Ellis SJFoot Ankle Int
- Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN).Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MRDiabetes Care
- Approach to MR Imaging of the Elbow and Wrist: Technical Aspects and Innovation.Johnson D, Stevens KJ, Riley G, Shapiro L, Yoshioka H, Gold GEMagn Reson Imaging Clin N Am
- Management of advanced prostate cancer.von Eyben F, Kiljunen T, Kangasmaki A, Kairemo K, von Eyben R, Joensuu TAnn Oncol
- Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model.Dash R, Kim PJ, Matsuura Y, Ikeno F, Metzler S, Huang NF, Lyons JK, Nguyen PK, Ge X, Wong Po Foo C, McConnell MV, Wu JC, Yeung AC, Harnish P, Yang PCJ Am Heart Assoc
- Reply to M.H. Kanter et al.Rhoads KF, Patel MI, Ma Y, Schmidt LAJ Clin Oncol
- Infections of the CNS: Restless legs syndrome-current therapies and management of augmentation.Trenkwalder C, Winkelmann J, Inoue Y, Paulus WNat Rev Neurol
- Enculturating science: Community-centric design of behavior change interactions for accelerating health impact.Kumar V, Kumar A, Ghosh AK, Samphel R, Yadav R, Yeung D, Darmstadt GLSemin Perinatol
- Asteroid Risk Assessment: A Probabilistic Approach.Reinhardt JC, Chen X, Liu W, Manchev P, Paté-Cornell MERisk Anal
- Immune checkpoint blockade in patients with melanoma metastatic to the brain.Di Giacomo AM, Margolin KSemin Oncol
- G Protein-coupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs).Li L, Homan KT, Vishnivetskiy SA, Manglik A, Tesmer JJ, Gurevich VV, Gurevich EVJ Biol Chem
- Initial results of endoscopic gastrocutaneous fistula closure in children using an over-the-scope clip.Wright R, Abrajano C, Koppolu R, Stevens M, Nyznyk S, Chao S, Bruzoni M, Wall JJ Laparoendosc Adv Surg Tech A
- Quality improvement in neonatal digital radiography: implementing the basic quality improvement tools.Eslamy HK, Newman B, Weinberger ESemin Ultrasound CT MR
- Cystic lung lesions in newborns and young children: differential considerations and imaging.Newman B, Caplan JSemin Ultrasound CT MR
- Microalgal lipids biochemistry and biotechnological perspectives.Bellou S, Baeshen MN, Elazzazy AM, Aggeli D, Sayegh F, Aggelis GBiotechnol Adv
- Use of the plasma triglyceride/high-density lipoprotein cholesterol ratio to identify cardiovascular disease in hypertensive subjects.Salazar MR, Carbajal HA, Espeche WG, Aizpurúa M, Leiva Sisnieguez CE, Leiva Sisnieguez BC, March CE, Stavile RN, Balbín E, Reaven GMJ Am Soc Hypertens
- A pediatric case of T-cell prolymphocytic leukemia.Mitton B, Coutre S, Willert J, Schlis K, Porteus M, Kharbanda S, Agarwal-Hashmi RPediatr Blood Cancer
- Scoring respiratory events in sleep medicine: who is the driver--biology or medical insurance?Thomas RJ, Guilleminault C, Ayappa I, Rapoport DMJ Clin Sleep Med
- Critical function of a Chlamydomonas reinhardtii putative polyphosphate polymerase subunit during nutrient deprivation.Aksoy M, Pootakham W, Grossman ARPlant Cell
- Transient partial permeabilization with saponin enables cellular barcoding prior to surface marker staining.Behbehani GK, Thom C, Zunder ER, Finck R, Gaudilliere B, Fragiadakis GK, Fantl WJ, Nolan GPCytometry A
- Primary amine stabilization of a dicopper(III) bis(μ-oxo) species: modeling the ligation in pMMO.Citek C, Lin BL, Phelps TE, Wasinger EC, Stack TDJ Am Chem Soc
- Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress.Myers AJ, Williams L, Gatt JM, McAuley-Clark EZ, Dobson-Stone C, Schofield PR, Nemeroff CBJ Psychiatr Res
- Large-scale detection of metals with a small set of fluorescent DNA-like chemosensors.Yuen LH, Franzini RM, Tan SS, Kool ETJ Am Chem Soc
- Predictors of outcome at 1 year in adolescents with DSM-5 restrictive eating disorders: report of the national eating disorders quality improvement collaborative.Forman SF, McKenzie N, Hehn R, Monge MC, Kapphahn CJ, Mammel KA, Callahan ST, Sigel EJ, Bravender T, Romano M, Rome ES, Robinson KA, Fisher M, Malizio JB, Rosen DS, Hergenroeder AC, Buckelew SM, Jay MS, Lindenbaum J, Rickert VI, Garber A, Golden NH, Woods ERJ Adolesc Health
- The brassinosteroid signaling network-a paradigm of signal integration.Wang W, Bai MY, Wang ZYCurr Opin Plant Biol
- Patterning and processes: how stomatal development defines physiological potential.Dow GJ, Bergmann DCCurr Opin Plant Biol
- Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer.Efstathiou E, Titus M, Wen S, Hoang A, Karlou M, Ashe R, Tu SM, Aparicio A, Troncoso P, Mohler J, Logothetis CJEur Urol
- Cell elongation is regulated through a central circuit of interacting transcription factors in the Arabidopsis hypocotyl.Oh E, Zhu JY, Bai MY, Arenhart RA, Sun Y, Wang ZYElife
- The relationship between serial [(18) F]PBR06 PET imaging of microglial activation and motor function following stroke in mice.Lartey FM, Ahn GO, Ali R, Rosenblum S, Miao Z, Arksey N, Shen B, Colomer MV, Rafat M, Liu H, Alejandre-Alcazar MA, Chen JW, Palmer T, Chin FT, Guzman R, Loo BW, Graves EMol Imaging Biol
- Noninvasive reporter gene imaging of human Oct4 (pluripotency) dynamics during the differentiation of embryonic stem cells in living subjects.Ahn BC, Parashurama N, Patel M, Ziv K, Bhaumik S, Yaghoubi SS, Paulmurugan R, Gambhir SSMol Imaging Biol
- IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis.Adamopoulos IE, Suzuki E, Chao CC, Gorman D, Adda S, Maverakis E, Zarbalis K, Geissler R, Asio A, Blumenschein WM, Mcclanahan T, De Waal Malefyt R, Gershwin ME, Bowman EPAnn Rheum Dis
Learning the Structure of Biomedical Relationships from Unstructured Text.
PLoS Comput Biol. 2015 Jul;11(7):e1004216
Authors: Percha B, Altman RB
The published biomedical research literature encompasses most of our understanding of how drugs interact with gene products to produce physiological responses (phenotypes). Unfortunately, this information is distributed throughout the unstructured text of over 23 million articles. The creation of structured resources that catalog the relationships between drugs and genes would accelerate the translation of basic molecular knowledge into discoveries of genomic biomarkers for drug response and prediction of unexpected drug-drug interactions. Extracting these relationships from natural language sentences on such a large scale, however, requires text mining algorithms that can recognize when different-looking statements are expressing similar ideas. Here we describe a novel algorithm, Ensemble Biclustering for Classification (EBC), that learns the structure of biomedical relationships automatically from text, overcoming differences in word choice and sentence structure. We validate EBC's performance against manually-curated sets of (1) pharmacogenomic relationships from PharmGKB and (2) drug-target relationships from DrugBank, and use it to discover new drug-gene relationships for both knowledge bases. We then apply EBC to map the complete universe of drug-gene relationships based on their descriptions in Medline, revealing unexpected structure that challenges current notions about how these relationships are expressed in text. For instance, we learn that newer experimental findings are described in consistently different ways than established knowledge, and that seemingly pure classes of relationships can exhibit interesting chimeric structure. The EBC algorithm is flexible and adaptable to a wide range of problems in biomedical text mining.
PMID: 26219079 [PubMed - as supplied by publisher]
Potential Adverse Effects of Anesthesia in Children-Reply.
JAMA. 2015 Jul 28;314(4):409
Authors: Psaty BM, Platt R, Altman RB
PMID: 26219066 [PubMed - as supplied by publisher]
Outpatient Pharmacy Expenditures for Children With Serious Chronic Illness in California, 2010-2012.
JAMA. 2015 Jul 28;314(4):405-407
Authors: Swenson SM, Chamberlain LJ, Sanders LM, Sundaram V, Wise PH
PMID: 26219060 [PubMed - as supplied by publisher]
Obstetric Sepsis: Focus on the 3-Hour Bundle.
J Perinat Neonatal Nurs. 2015 Jul-Sep;29(3):213-221
Authors: Brown KN, Arafeh JM
Early recognition and treatment of sepsis are key to decreasing maternal and fetal morbidity and mortality. Timing is critical, and early intervention is associated with improved outcomes. The perinatal provider is in a unique position to identify risk factors, perform assessments, and implement the first 3 hours of the sepsis bundle. Early detection and management combined with careful assessment can assist in providing evidence-based care and moving the patient to a higher level of care when warranted.
PMID: 26218814 [PubMed - as supplied by publisher]
Association of Anxiety Symptoms in Offspring of Bipolar Parents with Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype.
J Child Adolesc Psychopharmacol. 2015 Jul 28;
Authors: Park MH, Sanders E, Howe M, Singh M, Hallmayer J, Kim E, Chang K
OBJECTIVE: Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status.
METHODS: A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC).
RESULTS: Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group.
CONCLUSIONS: This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype.
PMID: 26218602 [PubMed - as supplied by publisher]
Motion Analysis for Microsurgical Training: Objective Measures of Dexterity, Economy of Movement, and Ability.
Plast Reconstr Surg. 2015 Aug;136(2):231e-240e
Authors: McGoldrick RB, Davis CR, Paro J, Hui K, Nguyen D, Lee GK
BACKGROUND: Evaluation of skill acquisition in microsurgery has traditionally relied on subjective opinions of senior faculty, but is shifting toward early competency-based training using validated models. No objective measures of dexterity, economy of movement, and ability exist. The authors propose a novel video instrument motion analysis scoring system to objectively measure motion.
METHODS: Video of expert microsurgeons was analyzed and used to develop a resident motion analysis scoring system based on a mathematical model. Motion analysis scores were compared to blinded, global rating scores of the same videos using the Stanford Microsurgery and Resident Training scale.
RESULTS: Eighty-five microsurgical anastomoses from 16 residents ranging from postgraduate years 1 through 6 were analyzed. Composite motion analysis scores for each segmented video correlated positively to arterial anastomotic experience (rho, +0.77; p < 0.001). Stanford Microsurgery and Resident Training scale interrater reliability was consistent between expert assessors, and mean composite motion analysis overall performance and Stanford scores were well matched for each level of experience. Composite motion analysis scores correlated significantly with combined Stanford Microsurgery and Resident Training [instrument handling (rho, +0.66; p < 0.01), efficiency (rho, +0.59; p < 0.01), suture handling (rho, +0.83; p < 0.001), operative flow (rho, +0.67; p < 0.001), and overall performance (rho, +89; p < 0.001)] motion components of the scale.
CONCLUSIONS: Instrument motion analysis provides a novel, reliable, and consistent objective assessment for microsurgical trainees. It has an associated cost, but is timely, repeatable, and senior physician independent, and exposes patients to zero risk.
PMID: 26218398 [PubMed - as supplied by publisher]
Long-Term Outcomes of Rectosigmoid Neocolporrhaphy in Male-to-Female Gender Reassignment Surgery.
Plast Reconstr Surg. 2015 Aug;136(2):386-394
Authors: Morrison SD, Satterwhite T, Grant DW, Kirby J, Laub DR, VanMaasdam J
BACKGROUND: Favorable outcomes of rectosigmoid neocolporrhaphy have previously been reported. Unfortunately, rectosigmoid transfers are still perceived negatively, usually relegated to secondary vaginoplasties. This study aims to provide an objective investigation into the safety and efficacy of rectosigmoid neocolporrhaphy for vaginoplasty in male-to-female transsexual patients.
METHODS: A retrospective review was performed on male-to-female patients who had undergone rectosigmoid neocolporrhaphy performed by the senior author. Patient data including demographics, medical history, complications, and the need for revision surgery were obtained. Direct inquires were conducted to determine patients' level of satisfaction with appearance, sexual function, and ease of postoperative recovery.
RESULTS: Eighty-three patients were included over the course of 22 years, with an average clinical follow-up of 2.2 years (83 patients) and phone interview follow-up of 23 years (21 patients). Overall, the patients were healthy, with minimal comorbidities. Forty-eight patients (58 percent) had complications, but the majority (83.3 percent) were minor and consisted mainly of introital stricture or excessive protrusion of the corpus spongiosum. Smoking was associated with higher complication rates (p = 0.05), especially stricture formation. Excessive mucorrhea occurred in 28.6 percent but resolved after the first year. Overall patient satisfaction with appearance and sexual function was high.
CONCLUSIONS: This study is one of the largest and longest reported series of rectosigmoid transfers for vaginoplasty in transsexual patients. Rectosigmoid neocolporrhaphies have many times been recommended for secondary or revision surgery when other techniques, such as penile inversion, have failed. However, the authors believe the rectosigmoid transfer is safe and efficacious, and it should be offered to male-to-female patients for primary vaginoplasty.
CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
PMID: 26218383 [PubMed - as supplied by publisher]
Validation of a Skin-Lesion Image-Matching Algorithm Based on Computer Vision Technology.
Telemed J E Health. 2015 Jul 28;
Authors: Chen RH, Snorrason M, Enger SM, Mostafa E, Ko JM, Aoki V, Bowling J
BACKGROUND: Melanoma incidence is increasing globally, but consistently accurate skin-lesion classification methods remain elusive. We developed a simple software system to classify potentially all types of skin lesions. In the current study, we evaluated the system's ability to identify melanomas with a diameter of 10 mm or larger.
MATERIALS AND METHODS: The skin-lesion classification system is composed of a proprietary database of nearly 12,000 diagnosed skin-lesion images and a computer algorithm based on the principles of content-based image retrieval. The algorithm compares characteristics of new skin-lesion images with images in the database to identify the nearest-match diagnosis.
RESULTS: Nearly all classification accuracy measures for this new system exceeded 90%, with results for sensitivity of 90.4% (95% confidence interval, 85.6-93.7%), specificity of 91.5% (85.4-95.2%), positive predictive value of 94.5% (90.4-96.9%), negative predictive value of 85.5% (78.7-90.4%), and overall classification accuracy of 90.8% (87.2-93.4%).
CONCLUSIONS: The image-matching algorithm performed with high accuracy for the classification of larger melanomas. Furthermore, the system does not require a dermoscope or any other specialized hardware; any close-focusing camera will do. This system has the potential to be an inexpensive and accurate tool for the evaluation of skin lesions in ethnically and geographically diverse populations.
PMID: 26218353 [PubMed - as supplied by publisher]
Low expression of chloride channel accessory 1 predicts a poor prognosis in colorectal cancer: The question is still open.
Cancer. 2015 Jul 28;
Authors: ShahidSales S, Mobarhan MG, Ghasemi F, Gholamin S, Avan A
PMID: 26218330 [PubMed - as supplied by publisher]
Nullspace Sampling with Holonomic Constraints Reveals Molecular Mechanisms of Protein Gαs.
PLoS Comput Biol. 2015 Jul;11(7):e1004361
Authors: Pachov DV, van den Bedem H
Proteins perform their function or interact with partners by exchanging between conformational substates on a wide range of spatiotemporal scales. Structurally characterizing these exchanges is challenging, both experimentally and computationally. Large, diffusional motions are often on timescales that are difficult to access with molecular dynamics simulations, especially for large proteins and their complexes. The low frequency modes of normal mode analysis (NMA) report on molecular fluctuations associated with biological activity. However, NMA is limited to a second order expansion about a minimum of the potential energy function, which limits opportunities to observe diffusional motions. By contrast, kino-geometric conformational sampling (KGS) permits large perturbations while maintaining the exact geometry of explicit conformational constraints, such as hydrogen bonds. Here, we extend KGS and show that a conformational ensemble of the α subunit Gαs of heterotrimeric stimulatory protein Gs exhibits structural features implicated in its activation pathway. Activation of protein Gs by G protein-coupled receptors (GPCRs) is associated with GDP release and large conformational changes of its α-helical domain. Our method reveals a coupled α-helical domain opening motion while, simultaneously, Gαs helix α5 samples an activated conformation. These motions are moderated in the activated state. The motion centers on a dynamic hub near the nucleotide-binding site of Gαs, and radiates to helix α4. We find that comparative NMA-based ensembles underestimate the amplitudes of the motion. Additionally, the ensembles fall short in predicting the accepted direction of the full activation pathway. Taken together, our findings suggest that nullspace sampling with explicit, holonomic constraints yields ensembles that illuminate molecular mechanisms involved in GDP release and protein Gs activation, and further establish conformational coupling between key structural elements of Gαs.
PMID: 26218073 [PubMed - as supplied by publisher]
Quantitative analysis of the myelin g-ratio from electron microscopy images of the macaque corpus callosum.
Data Brief. 2015 Sep;4:368-73
Authors: Stikov N, Campbell JS, Stroh T, Lavelée M, Frey S, Novek J, Nuara S, Ho MK, Bedell BJ, Dougherty RF, Leppert IR, Boudreau M, Narayanan S, Duval T, Cohen-Adad J, Picard PA, Gasecka A, Côté D, Pike GB
We provide a detailed morphometric analysis of eight transmission electron micrographs (TEMs) obtained from the corpus callosum of one cynomolgus macaque. The raw TEM images are included in the article, along with the distributions of the axon caliber and the myelin g-ratio in each image. The distributions are analyzed to determine the relationship between axon caliber and g-ratio, and compared against the aggregate metrics (myelin volume fraction, fiber volume fraction, and the aggregate g-ratio), as defined in the accompanying research article entitled 'In vivo histology of the myelin g-ratio with magnetic resonance imaging' (Stikov et al., NeuroImage, 2015).
PMID: 26217818 [PubMed]
Best practices for evaluating single nucleotide variant calling methods for microbial genomics.
Front Genet. 2015;6:235
Authors: Olson ND, Lund SP, Colman RE, Foster JT, Sahl JW, Schupp JM, Keim P, Morrow JB, Salit ML, Zook JM
Innovations in sequencing technologies have allowed biologists to make incredible advances in understanding biological systems. As experience grows, researchers increasingly recognize that analyzing the wealth of data provided by these new sequencing platforms requires careful attention to detail for robust results. Thus far, much of the scientific Communit's focus for use in bacterial genomics has been on evaluating genome assembly algorithms and rigorously validating assembly program performance. Missing, however, is a focus on critical evaluation of variant callers for these genomes. Variant calling is essential for comparative genomics as it yields insights into nucleotide-level organismal differences. Variant calling is a multistep process with a host of potential error sources that may lead to incorrect variant calls. Identifying and resolving these incorrect calls is critical for bacterial genomics to advance. The goal of this review is to provide guidance on validating algorithms and pipelines used in variant calling for bacterial genomics. First, we will provide an overview of the variant calling procedures and the potential sources of error associated with the methods. We will then identify appropriate datasets for use in evaluating algorithms and describe statistical methods for evaluating algorithm performance. As variant calling moves from basic research to the applied setting, standardized methods for performance evaluation and reporting are required; it is our hope that this review provides the groundwork for the development of these standards.
PMID: 26217378 [PubMed]
Corrigendum: Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example.
Front Genet. 2015;6:231
Authors: Goldstein BA, Knowles JW, Salfati E, Ioannidis JP, Assimes TL
[This corrects the article on p. 254 in vol. 5, PMID: 25136350.].
PMID: 26217377 [PubMed - as supplied by publisher]
Turn-taking: a case study of early gesture and word use in answering WHERE and WHICH questions.
Front Psychol. 2015;6:890
Authors: Clark EV, Lindsey KL
When young children answer questions, they do so more slowly than adults and appear to have difficulty finding the appropriate words. Because children leave gaps before they respond, it is possible that they could answer faster with gestures than with words. In this study, we compare gestural and verbal responses from one child between the ages of 1;4 and 3;5, to adult Where and Which questions, which can be answered with gestures and/or words. After extracting all adult Where and Which questions and child answers from longitudinal videotaped sessions, we examined the timing from the end of each question to the start of the response, and compared the timing for gestures and words. Child responses could take the form of a gesture or word(s); the latter could be words repeated from the adult question or new words retrieved by the child. Or responses could be complex: a gesture + word repeat, gesture + new word, or word repeat + new word. Gestures were the fastest overall, followed successively by word-repeats, then new-word responses. This ordering, with gestures ahead of words, suggests that the child knows what to answer but needs more time to retrieve any relevant words. In short, word retrieval and articulation appear to be bottlenecks in the timing of responses: both add to the planning required in answering a question.
PMID: 26217253 [PubMed]
Evaluation of sodium nitroprusside for controlled hypotension in children during surgery.
Front Pharmacol. 2015;6:136
Authors: Drover DR, Hammer GB, Barrett JS, Cohane CA, Reece T, Zajicek A, Schulman SR
PURPOSE: (1) To define the onset and offset of the blood-pressure-lowering effects of sodium nitroprusside (SNP) for use in developing instructions for dose titration in children undergoing a surgical or medical procedure, and (2) to assess the safety of SNP administration in pediatric patients requiring controlled reduction of blood pressure.
METHODS: We conducted a randomized, double-blind, parallel-group, dose-ranging, effect-controlled, multicenter study of intravenous (IV) infusions of SNP in pediatric patients <17 years, who required controlled hypotension for at least 2 h while undergoing a surgical or medical procedure. A blinded SNP dose of 0.3, 1, 2, or 3 μg/kg/min was infused for 30 min, followed by open-label administration for at least 90 min. Both infusions were titrated to effect.
RESULTS: The final intent-to-treat group comprised 203 patients. Significant reductions in mean arterial pressure (MAP) from baseline were observed for all four doses at 20 and 25 min after the start of infusion (p ≤ 0.009 and p ≤ 0.010 for each time, respectively). Overall, 98.5% of the patients achieved the target MAP; 72.9% first achieved the target MAP during the blinded infusion. The mean infusion rate at target MAP was 1.07 μg/kg/min.
CONCLUSION: We determined that 0.3 μg/kg/m is a reasonable starting dose for SNP in pediatric patients requiring controlled hypotension. The infusion rate can then be increased to achieve the desired reduction in blood pressure. On the basis of our results, we found an average infusion rate of 1 μg/kg/min might be appropriate. Of note, no cyanide toxicity was reported, and no measureable cyanide levels were detected in any blood samples obtained during the study. http://clinicaltrials.gov/show/NCT00135668.
PMID: 26217225 [PubMed]
Physical biology of human brain development.
Front Cell Neurosci. 2015;9:257
Authors: Budday S, Steinmann P, Kuhl E
Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales-from phenomena on the cellular level toward form and function on the organ level-to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.
PMID: 26217183 [PubMed]
Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells.
Proc Natl Acad Sci U S A. 2015 Jul 27;
Authors: Wu B, Wei S, Petersen N, Ali Y, Wang X, Bacaj T, Rorsman P, Hong W, Südhof TC, Han W
Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca(2+). Ca(2+) then binds to synaptotagmin-7 as a major Ca(2+) sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment is ameliorated by glucagon-like peptide-1 (GLP-1) or by GLP-1 receptor agonists, which improve glucose homeostasis. However, the mechanism by which GLP-1 receptor agonists boost insulin secretion remains unclear. Here, we report that GLP-1 stimulates protein kinase A (PKA)-dependent phosphorylation of synaptotagmin-7 at serine-103, which enhances glucose- and Ca(2+)-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca(2+)-triggered exocytosis, whereas a phospho-inactive synaptotagmin-7 mutant disrupts GLP-1 potentiation of insulin secretion. Our findings thus suggest that synaptotagmin-7 is directly activated by GLP-1 signaling and may serve as a drug target for boosting insulin secretion. Moreover, our data reveal, to our knowledge, the first physiological modulation of Ca(2+)-triggered exocytosis by direct phosphorylation of a synaptotagmin.
PMID: 26216970 [PubMed - as supplied by publisher]
Identification and characterization of an injury-induced skeletal progenitor.
Proc Natl Acad Sci U S A. 2015 Jul 27;
Authors: Marecic O, Tevlin R, McArdle A, Seo EY, Wearda T, Duldulao C, Walmsley GG, Nguyen A, Weissman IL, Chan CK, Longaker MT
The postnatal skeleton undergoes growth, remodeling, and repair. We hypothesized that skeletal progenitor cells active during these disparate phases are genetically and phenotypically distinct. We identified a highly potent regenerative cell type that we term the fracture-induced bone, cartilage, stromal progenitor (f-BCSP) in the fracture callus of adult mice. The f-BCSP possesses significantly enhanced skeletogenic potential compared with BCSPs harvested from uninjured bone. It also recapitulates many gene expression patterns involved in perinatal skeletogenesis. Our results indicate that the skeletal progenitor population is functionally stratified, containing distinct subsets responsible for growth, regeneration, and repair. Furthermore, our findings suggest that injury-induced changes to the skeletal stem and progenitor microenvironments could activate these cells and enhance their regenerative potential.
PMID: 26216955 [PubMed - as supplied by publisher]
Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin.
Proc Natl Acad Sci U S A. 2015 Jul 27;
Authors: Wong YH, Lee CM, Xie W, Cui B, Poo MM
Brain-derived neurotrophic factor (BDNF) is known to modulate synapse development and plasticity, but the source of synaptic BDNF and molecular mechanisms regulating BDNF release remain unclear. Using exogenous BDNF tagged with quantum dots (BDNF-QDs), we found that endocytosed BDNF-QDs were preferentially localized to postsynaptic sites in the dendrite of cultured hippocampal neurons. Repetitive neuronal spiking induced the release of BDNF-QDs at these sites, and this process required activation of glutamate receptors. Down-regulating complexin 1/2 (Cpx1/2) expression eliminated activity-induced BDNF-QD secretion, although the overall activity-independent secretion was elevated. Among eight synaptotagmin (Syt) isoforms examined, down-regulation of only Syt6 impaired activity-induced BDNF-QD secretion. In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6. Thus, neuronal activity could trigger the release of endosomal BDNF from postsynaptic dendrites in a Cpx- and Syt6-dependent manner, and endosomes containing BDNF may serve as a source of BDNF for activity-dependent synaptic modulation.
PMID: 26216953 [PubMed - as supplied by publisher]
Contribution of Lateral Column Lengthening to Correction of Forefoot Abduction in Stage IIb Adult Acquired Flatfoot Deformity Reconstruction.
Foot Ankle Int. 2015 Jul 27;
Authors: Chan JY, Greenfield ST, Soukup DS, Do HT, Deland JT, Ellis SJ
BACKGROUND: Correction of forefoot abduction in stage IIb adult acquired flatfoot likely depends on the amount of lateral column lengthening (LCL) performed, although this represents only one aspect of a successful reconstruction. The purpose of this study was to evaluate the correlation between common reconstructive variables and the observed change in forefoot abduction.
METHODS: Forty-one patients who underwent flatfoot reconstruction involving an Evans-type LCL were assessed retrospectively. Preoperative and postoperative anteroposterior (AP) radiographs of the foot at a minimum of 40 weeks (mean, 2 years) after surgery were reviewed to determine correction in forefoot abduction as measured by talonavicular coverage (TNC) angle, talonavicular uncoverage percent, talus-first metatarsal (T-1MT) angle, and lateral incongruency angle. Fourteen demographic and intraoperative variables were evaluated for association with change in forefoot abduction including age, gender, height, weight, body mass index, as well as the amount of LCL and medializing calcaneal osteotomy performed, LCL graft type, Cotton osteotomy, first tarsometatarsal fusion, flexor digitorum longus transfer, spring ligament repair, gastrocnemius recession and any one of the modified McBride/Akin/Silver procedures.
RESULTS: Two variables significantly affected the change in lateral incongruency angle. These were weight (P = .04) and the amount of LCL performed (P < .001). No variables were associated with the change in TNC angle, talonavicular uncoverage percent, or T-1MT angle. Multivariate regression analysis revealed that LCL was the only significant predictor of the change in lateral incongruency angle. The final regression model for LCL showed a good fit (R(2) = 0.70, P < .001). Each millimeter of LCL corresponded to a 6.8-degree change in lateral incongruency angle.
CONCLUSION: Correction of forefoot abduction in flatfoot reconstruction was primarily determined by the LCL procedure and could be modeled linearly. We believe that the lateral incongruency angle can serve as a valuable preoperative measurement to help surgeons titrate the proper amount of correction performed intraoperatively.
LEVEL OF EVIDENCE: Level III, retrospective comparative study.
PMID: 26216884 [PubMed - as supplied by publisher]
Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN).
Diabetes Care. 2015 Jul 27;
Authors: Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR
OBJECTIVE: This study was conducted to determine if type 1 diabetes is associated with an increased risk of fracture across the life span.
RESEARCH DESIGN AND METHODS: This population-based cohort study used data from The Health Improvement Network (THIN) in the U.K. (data from 1994 to 2012), in which 30,394 participants aged 0-89 years with type 1 diabetes were compared with 303,872 randomly selected age-, sex-, and practice-matched participants without diabetes. Cox regression analysis was used to determine hazard ratios (HR) for incident fracture in participants with type 1 diabetes.
RESULTS: A total of 334,266 participants, median age 34 years, were monitored for 1.9 million person-years. HR were lowest in males and females age <20 years, with HR 1.14 (95% CI 1.01-1.29) and 1.35 (95% CI 1.12-1.63), respectively. Risk was highest in men 60-69 years (HR 2.18 [95% CI 1.79-2.65]), and in women 40-49 years (HR 2.03 [95% CI 1.73-2.39]). Lower extremity fractures comprised a higher proportion of incident fractures in participants with versus those without type 1 diabetes (31.1% vs. 25.1% in males, 39.3% vs. 32% in females; P < 0.001). Secondary analyses for incident hip fractures identified the highest HR of 5.64 (95% CI 3.55-8.97) in men 60-69 years and the highest HR of 5.63 (95% CI 2.25-14.11) in women 30-39 years.
CONCLUSIONS: Type 1 diabetes was associated with increased risk of incident fracture that began in childhood and extended across the life span. Participants with type 1 diabetes sustained a disproportionately greater number of lower extremity fractures. These findings have important public health implications, given the increasing prevalence of type 1 diabetes and the morbidity and mortality associated with hip fractures.
PMID: 26216874 [PubMed - as supplied by publisher]
Approach to MR Imaging of the Elbow and Wrist: Technical Aspects and Innovation.
Magn Reson Imaging Clin N Am. 2015 Aug;23(3):355-66
Authors: Johnson D, Stevens KJ, Riley G, Shapiro L, Yoshioka H, Gold GE
Wrist and elbow MR imaging technology is advancing at a dramatic rate. Wrist and elbow MR imaging is performed at medium and higher field strengths with more specialized surface coils and more variable pulse sequences and postprocessing techniques. High field imaging and improved coils lead to an increased signal-to-noise ratio and increased variety of soft tissue contrast options. Three-dimensional imaging is improving in terms of usability and artifacts. Some of these advances have challenges in wrist and elbow imaging, such as postoperative patient imaging, cartilage mapping, and molecular imaging. This review considers technical advances in hardware and software and their clinical applications.
PMID: 26216768 [PubMed - in process]
Management of advanced prostate cancer.
Ann Oncol. 2015 Jul 27;
Authors: von Eyben F, Kiljunen T, Kangasmaki A, Kairemo K, von Eyben R, Joensuu T
PMID: 26216387 [PubMed - as supplied by publisher]
Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model.
J Am Heart Assoc. 2015;4(7)
Authors: Dash R, Kim PJ, Matsuura Y, Ikeno F, Metzler S, Huang NF, Lyons JK, Nguyen PK, Ge X, Wong Po Foo C, McConnell MV, Wu JC, Yeung AC, Harnish P, Yang PC
BACKGROUND: The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri-infarct region (PIR) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese-enhanced magnetic resonance imaging [MEMRI]), myocardial scar (delayed gadolinium enhancement MRI), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.
METHODS AND RESULTS: Twelve adult swine underwent ischemia-reperfusion injury. Digital subtraction of MEMRI-negative myocardium (intrainfarct region) from delayed gadolinium enhancement MRI-positive myocardium (PIR and intrainfarct region) clearly delineated the PIR in which the MEMRI-positive signal reflected PIR viability. Human amniotic mesenchymal stem cells (hAMSCs) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine PIR. Immediately following hAMSC delivery, MEMRI demonstrated an increased PIR viability signal compared with control. Direct PIR viability remained higher in hAMSC-treated hearts for >6 weeks. Increased PIR viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and hAMSC engraftment, as confirmed by immunocytochemistry. Increased MEMRI and positron emission tomography reporter gene signal in the intrainfarct region and the PIR correlated with sustained functional augmentation (global and regional) within the hAMSC group (mean change, left ventricular ejection fraction: hAMSC 85±60%, control 8±10%; P<0.05) and reduced chamber dilatation (left ventricular end-diastole volume increase: hAMSC 24±8%, control 110±30%; P<0.05).
CONCLUSIONS: The positron emission tomography reporter gene signal of hAMSC engraftment correlates with the improved MEMRI signal in the PIR. The increased MEMRI signal represents PIR viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real-time method of tracking PIR viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.
PMID: 26215972 [PubMed - in process]
Reply to M.H. Kanter et al.
J Clin Oncol. 2015 Jul 27;
Authors: Rhoads KF, Patel MI, Ma Y, Schmidt LA
PMID: 26215958 [PubMed - as supplied by publisher]
Infections of the CNS: Restless legs syndrome-current therapies and management of augmentation.
Nat Rev Neurol. 2015 Jul 28;
Authors: Trenkwalder C, Winkelmann J, Inoue Y, Paulus W
Idiopathic restless legs syndrome (RLS) can severely affect quality of life and disturb sleep, so that pharmacological treatment is necessary, especially for elderly patients. Treatment guidelines recommend initiation of therapy with dopamine agonists (pramipexole, ropinirole or the rotigotine transdermal patch, all approved in most countries) or α-2-δ ligands (gabapentin enacarbil, approved in the USA and Japan), depending on the country and availability. Where approved, opioids (prolonged release oxycodone-naloxone, approved in Europe) are also recommended as a second-line therapy for severe RLS. Several iron formulations can be effective but are not yet approved for RLS therapy, whereas benzodiazepines and other anticonvulsants are not recommended or approved. Less is known about effective management of RLS that is associated with other conditions, such as uraemia or pregnancy. Furthermore, very little data are available on the management of RLS when first-line treatment fails or patients experience augmentation. In this Review, we summarize state-of-the-art therapies for RLS in the context of the diagnostic criteria and available guidelines, based on knowledge ranging from Class I evidence for the treatment of idiopathic RLS to Class IV evidence for the treatment of complications such as augmentation. We consider therapies, including combination therapies, that are used in clinical practice for long-term management of RLS, despite a lack of trials and approval, and highlight the need for practical long-term evaluation of current trials.
PMID: 26215616 [PubMed - as supplied by publisher]
Enculturating science: Community-centric design of behavior change interactions for accelerating health impact.
Semin Perinatol. 2015 Jul 24;
Authors: Kumar V, Kumar A, Ghosh AK, Samphel R, Yadav R, Yeung D, Darmstadt GL
Despite significant advancements in the scientific evidence base of interventions to improve newborn survival, we have not yet been able to "bend the curve" to markedly accelerate global rates of reduction in newborn mortality. The ever-widening gap between discovery of scientific best practices and their mass adoption by families (the evidence-practice gap) is not just a matter of improving the coverage of health worker-community interactions. The design of the interactions themselves must be guided by sound behavioral science approaches such that they lead to mass adoption and impact at a large scale. The main barrier to the application of scientific approaches to behavior change is our inability to "unbox" the "black box" of family health behaviors in community settings. The authors argue that these are not black boxes, but in fact thoughtfully designed community systems that have been designed and upheld, and have evolved over many years keeping in mind a certain worldview and a common social purpose. An empathetic understanding of these community systems allows us to deconstruct the causal pathways of existing behaviors, and re-engineer them to achieve desired outcomes. One of the key reasons for the failure of interactions to translate into behavior change is our failure to recognize that the content, context, and process of interactions need to be designed keeping in mind an organized community system with a very different worldview and beliefs. In order to improve the adoption of scientific best practices by communities, we need to adapt them to their culture by leveraging existing beliefs, practices, people, context, and skills. The authors present a systems approach for community-centric design of interactions, highlighting key principles for achieving intrinsically motivated, sustained change in social norms and family health behaviors, elucidated with progressive theories from systems thinking, management sciences, cross-cultural psychology, learning and social cognition, and the behavioral sciences. These are illustrated through a case study of designing effective interactions in Shivgarh, India, that led to rapid and substantial changes in newborn health behaviors and reduction in NMR by half over a span of 16 months.
PMID: 26215599 [PubMed - as supplied by publisher]
Asteroid Risk Assessment: A Probabilistic Approach.
Risk Anal. 2015 Jul 28;
Authors: Reinhardt JC, Chen X, Liu W, Manchev P, Paté-Cornell ME
Following the 2013 Chelyabinsk event, the risks posed by asteroids attracted renewed interest, from both the scientific and policy-making communities. It reminded the world that impacts from near-Earth objects (NEOs), while rare, have the potential to cause great damage to cities and populations. Point estimates of the risk (such as mean numbers of casualties) have been proposed, but because of the low-probability, high-consequence nature of asteroid impacts, these averages provide limited actionable information. While more work is needed to further refine its input distributions (e.g., NEO diameters), the probabilistic model presented in this article allows a more complete evaluation of the risk of NEO impacts because the results are distributions that cover the range of potential casualties. This model is based on a modularized simulation that uses probabilistic inputs to estimate probabilistic risk metrics, including those of rare asteroid impacts. Illustrative results of this analysis are presented for a period of 100 years. As part of this demonstration, we assess the effectiveness of civil defense measures in mitigating the risk of human casualties. We find that they are likely to be beneficial but not a panacea. We also compute the probability-but not the consequences-of an impact with global effects ("cataclysm"). We conclude that there is a continued need for NEO observation, and for analyses of the feasibility and risk-reduction effectiveness of space missions designed to deflect or destroy asteroids that threaten the Earth.
PMID: 26215051 [PubMed - as supplied by publisher]
Immune checkpoint blockade in patients with melanoma metastatic to the brain.
Semin Oncol. 2015 Jun;42(3):459-65
Authors: Di Giacomo AM, Margolin K
Metastatic disease to the brain is a frequent manifestation of melanoma and is associated with a very poor outcome. Systemic therapy with cytotoxic chemotherapy provide only a minimal benefit, while surgery and radiotherapy provide in some patients local control but they less frequently affect the overall outcome of melanoma brain metastases (MBM). The advent of active systemic drugs has revolutioned the care of metastatic melanoma, but this benefit has not been translated into intracranial activity. However, since 2010 the anti-CTLA-4 antibody ipilimumab and the BRAF inhibitors, dabrafenib and vemurafenib, have demonstrated initial signs of efficacy in active brain metastases. This chapter reviews the available data and rationale for ongoing and future trials of immune checkpoint-based combination therapy.
PMID: 25965364 [PubMed - indexed for MEDLINE]
G Protein-coupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs).
J Biol Chem. 2015 Apr 24;290(17):10775-90
Authors: Li L, Homan KT, Vishnivetskiy SA, Manglik A, Tesmer JJ, Gurevich VV, Gurevich EV
G protein-coupled receptor (GPCR) kinases (GRKs) play a key role in homologous desensitization of GPCRs. It is widely assumed that most GRKs selectively phosphorylate only active GPCRs. Here, we show that although this seems to be the case for the GRK2/3 subfamily, GRK5/6 effectively phosphorylate inactive forms of several GPCRs, including β2-adrenergic and M2 muscarinic receptors, which are commonly used as representative models for GPCRs. Agonist-independent GPCR phosphorylation cannot be explained by constitutive activity of the receptor or membrane association of the GRK, suggesting that it is an inherent ability of GRK5/6. Importantly, phosphorylation of the inactive β2-adrenergic receptor enhanced its interactions with arrestins. Arrestin-3 was able to discriminate between phosphorylation of the same receptor by GRK2 and GRK5, demonstrating preference for the latter. Arrestin recruitment to inactive phosphorylated GPCRs suggests that not only agonist activation but also the complement of GRKs in the cell regulate formation of the arrestin-receptor complex and thereby G protein-independent signaling.
PMID: 25770216 [PubMed - indexed for MEDLINE]
Initial results of endoscopic gastrocutaneous fistula closure in children using an over-the-scope clip.
J Laparoendosc Adv Surg Tech A. 2015 Jan;25(1):69-72
Authors: Wright R, Abrajano C, Koppolu R, Stevens M, Nyznyk S, Chao S, Bruzoni M, Wall J
Gastrocutaneous fistula (GCF) occurs commonly in pediatric patients after removal of long-term gastrostomy tubes. Although open repair is generally successful, endoscopic approaches may offer benefits in terms of incisional complications, postoperative pain, and procedure time. In addition, endoscopic approaches may offer particular benefit in patients with varied degrees of skin irritation or erosion surrounding a GCF, making surgical repair difficult, or patients with significant comorbidities, making minimal intervention and anesthesia time preferable. Over-the-scope (OSC) clips are a new technology that enables endoscopic closure of intestinal fistulas up to 2 cm in diameter. Six pediatric patients underwent endoscopic GCF closure using OSC clips under Institutional Review Board approval. The procedure was technically successful in 5 of 6 cases with an average operating time of 29 minutes. The technical failure required an open revision, whereas all other patients reported full healing of the GCF site at 1 month. All successful cases were performed as outpatients without postoperative narcotics. In addition, all patients reported high satisfaction with the procedure and cosmetic results. Endoscopic GCF closure using an OSC clip is technically feasible in the pediatric population. Based on limited cases with a 1-month follow-up, the functional and cosmetic results of technically successful cases are excellent. Endoscopic GCF closure is a potential alternative to standard surgical closure in patients with skin irritation or erosion and/or significant comorbidities.
PMID: 25531644 [PubMed - indexed for MEDLINE]
Quality improvement in neonatal digital radiography: implementing the basic quality improvement tools.
Semin Ultrasound CT MR. 2014 Dec;35(6):608-26
Authors: Eslamy HK, Newman B, Weinberger E
A quality improvement (QI) program may be implemented using the plan-do-study-act cycle (as a model for making improvements) and the basic QI tools (used to visually display and analyze variation in data). Managing radiation dose has come to the forefront as a safety goal for radiology departments. This is especially true in the pediatric population, which is more radiosensitive than the adult population. In this article, we use neonatal digital radiography to discuss developing a QI program with the principle goals of decreasing the radiation dose, decreasing variation in radiation dose, and optimizing image quality.
PMID: 25454055 [PubMed - indexed for MEDLINE]
Cystic lung lesions in newborns and young children: differential considerations and imaging.
Semin Ultrasound CT MR. 2014 Dec;35(6):571-87
Authors: Newman B, Caplan J
Numerous diverse entities produce cystic lung changes in neonates and young children. This review provides an evidence-based, age-appropriate, differential diagnostic framework to use when confronted with pulmonary cystic changes. The categories of diseases that have been discussed include congenital cystic bronchopulmonary malformations, neoplastic conditions, infections, collagen or soft tissue abnormalities, and mimics of cystic lung disease. An understanding of the pathophysiology, imaging appearance, and demographics of these entities is essential in guiding optimal care. Important educational points include differentiating bronchopulmonary malformations from neoplasms and the management and surveillance of lung cysts in young children.
PMID: 25454053 [PubMed - indexed for MEDLINE]
Microalgal lipids biochemistry and biotechnological perspectives.
Biotechnol Adv. 2014 Dec;32(8):1476-93
Authors: Bellou S, Baeshen MN, Elazzazy AM, Aggeli D, Sayegh F, Aggelis G
In the last few years, there has been an intense interest in using microalgal lipids in food, chemical and pharmaceutical industries and cosmetology, while a noteworthy research has been performed focusing on all aspects of microalgal lipid production. This includes basic research on the pathways of solar energy conversion and on lipid biosynthesis and catabolism, and applied research dealing with the various biological and technical bottlenecks of the lipid production process. In here, we review the current knowledge in microalgal lipids with respect to their metabolism and various biotechnological applications, and we discuss potential future perspectives. The committing step in fatty acid biosynthesis is the carboxylation of acetyl-CoA to form malonyl-CoA that is then introduced in the fatty acid synthesis cycle leading to the formation of palmitic and stearic acids. Oleic acid may also be synthesized after stearic acid desaturation while further conversions of the fatty acids (i.e. desaturations, elongations) occur after their esterification with structural lipids of both plastids and the endoplasmic reticulum. The aliphatic chains are also used as building blocks for structuring storage acylglycerols via the Kennedy pathway. Current research, aiming to enhance lipogenesis in the microalgal cell, is focusing on over-expressing key-enzymes involved in the earlier steps of the pathway of fatty acid synthesis. A complementary plan would be the repression of lipid catabolism by down-regulating acylglycerol hydrolysis and/or β-oxidation. The tendency of oleaginous microalgae to synthesize, apart from lipids, significant amounts of other energy-rich compounds such as sugars, in processes competitive to lipogenesis, deserves attention since the lipid yield may be considerably increased by blocking competitive metabolic pathways. The majority of microalgal production occurs in outdoor cultivation and for this reason biotechnological applications face some difficulties. Therefore, algal production systems need to be improved and harvesting systems need to be more effective in order for their industrial applications to become more competitive and economically viable. Besides, a reduction of the production cost of microalgal lipids can be achieved by combining lipid production with other commercial applications. The combined production of bioactive products and lipids, when possible, can support the commercial viability of both processes. Hydrophobic compounds can be extracted simultaneously with lipids and then purified, while hydrophilic compounds such as proteins and sugars may be extracted from the defatted biomass. The microalgae also have applications in environmental biotechnology since they can be used for bioremediation of wastewater and to monitor environmental toxicants. Algal biomass produced during wastewater treatment may be further valorized in the biofuel manufacture. It is anticipated that the high microalgal lipid potential will force research towards finding effective ways to manipulate biochemical pathways involved in lipid biosynthesis and towards cost effective algal cultivation and harvesting systems, as well.
PMID: 25449285 [PubMed - indexed for MEDLINE]
Use of the plasma triglyceride/high-density lipoprotein cholesterol ratio to identify cardiovascular disease in hypertensive subjects.
J Am Soc Hypertens. 2014 Oct;8(10):724-31
Authors: Salazar MR, Carbajal HA, Espeche WG, Aizpurúa M, Leiva Sisnieguez CE, Leiva Sisnieguez BC, March CE, Stavile RN, Balbín E, Reaven GM
This analysis evaluated the hypothesis that the plasma triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) concentration ratio can help identify patients with essential hypertension who are insulin-resistant, with the cardiovascular disease (CVD) risk profile associated with that defect. Data from a community-based study developed between 2003 and 2012 were used to compare CVD risk factors and outcome. Plasma TG/HDL-C cut-points of 2.5 (women) and 3.5 (men) subdivided normotensive (n = 574) and hypertensive (n = 373) subjects into "high" and "low" risk groups. Metabolic syndrome criteria (MetS) were also used to identify "high" and "low" risk groups. The baseline cardio-metabolic profile was significantly more adverse in 2003 in "high" risk subgroups, irrespective of BP classification or definition of risk (TG/HDL-C ratio vs. MetS criteria). Crude incidence of combined CVD events increased across risk groups, ranging from 1.9 in normotensive-low TG/HDL-C subjects to 19.9 in hypertensive-high TG/HDL-C ratio individuals (P for trends <.001). Adjusted hazard ratios for CVD events also increased with both hypertension and TG/HDL-C. Comparable findings were seen when CVD outcome was predicted by MetS criteria. The TG/HDL-C concentration ratio and the MetS criteria identify to a comparable degree hypertensive subjects who are at greatest cardio-metabolic risk and develop significantly more CVD.
PMID: 25418494 [PubMed - indexed for MEDLINE]
A pediatric case of T-cell prolymphocytic leukemia.
Pediatr Blood Cancer. 2015 Jun;62(6):1061-2
Authors: Mitton B, Coutre S, Willert J, Schlis K, Porteus M, Kharbanda S, Agarwal-Hashmi R
T-cell Prolymphocytic Leukemia (T-PLL) is a rare entity, and to date has never been reported in children. Here, we describe the first pediatric case of T-PLL in a 16-year old male and review his clinical course through treatment. He underwent therapy with alemtuzumab and pentostatin, which was successful in inducing initial remission. He then underwent an allogeneic matched sibling stem cell transplant following a myeloablative conditioning regimen and remains disease-free 1.5 years after diagnosis.
PMID: 25417638 [PubMed - indexed for MEDLINE]
Scoring respiratory events in sleep medicine: who is the driver--biology or medical insurance?
J Clin Sleep Med. 2014 Nov 15;10(11):1245-7
Authors: Thomas RJ, Guilleminault C, Ayappa I, Rapoport DM
PMID: 25325601 [PubMed - indexed for MEDLINE]
Critical function of a Chlamydomonas reinhardtii putative polyphosphate polymerase subunit during nutrient deprivation.
Plant Cell. 2014 Oct;26(10):4214-29
Authors: Aksoy M, Pootakham W, Grossman AR
Forward genetics was used to isolate Chlamydomonas reinhardtii mutants with altered abilities to acclimate to sulfur (S) deficiency. The ars76 mutant has a deletion that eliminates several genes, including VACUOLAR TRANSPORTER CHAPERONE1 (VTC1), which encodes a component of a polyphosphate polymerase complex. The ars76 mutant cannot accumulate arylsulfatase protein or mRNA and shows marked alterations in levels of many transcripts encoded by genes induced during S deprivation. The mutant also shows little acidocalcisome formation compared with wild-type, S-deprived cells and dies more rapidly than wild-type cells following exposure to S-, phosphorus-, or nitrogen (N)-deficient conditions. Furthermore, the mutant does not accumulate periplasmic L-amino acid oxidase during N deprivation. Introduction of the VTC1 gene specifically complements the ars76 phenotypes, suggesting that normal acidocalcisome formation in cells deprived of S requires VTC1. Our data also indicate that a deficiency in acidocalcisome function impacts trafficking of periplasmic proteins, which can then feed back on the transcription of the genes encoding these proteins. These results and the reported function of vacuoles in degradation processes suggest a major role of the acidocalcisome in reshaping the cell during acclimation to changing environmental conditions.
PMID: 25281687 [PubMed - indexed for MEDLINE]
Transient partial permeabilization with saponin enables cellular barcoding prior to surface marker staining.
Cytometry A. 2014 Dec;85(12):1011-9
Authors: Behbehani GK, Thom C, Zunder ER, Finck R, Gaudilliere B, Fragiadakis GK, Fantl WJ, Nolan GP
Fluorescent cellular barcoding and mass-tag cellular barcoding are cytometric methods that enable high sample throughput, minimize inter-sample variation, and reduce reagent consumption. Previously employed barcoding protocols require that barcoding be performed after surface marker staining, complicating combining the technique with measurement of alcohol-sensitive surface epitopes. This report describes a method of barcoding fixed cells after a transient partial permeabilization with 0.02% saponin that results in efficient and consistent barcode staining with fluorescent or mass-tagged reagents while preserving surface marker staining. This approach simplifies barcoding protocols and allows direct comparison of surface marker staining of multiple samples without concern for variations in the antibody cocktail volume, antigen-antibody ratio, or machine sensitivity. Using this protocol, cellular barcoding can be used to reliably detect subtle differences in surface marker expression.
PMID: 25274027 [PubMed - indexed for MEDLINE]
Primary amine stabilization of a dicopper(III) bis(μ-oxo) species: modeling the ligation in pMMO.
J Am Chem Soc. 2014 Oct 15;136(41):14405-8
Authors: Citek C, Lin BL, Phelps TE, Wasinger EC, Stack TD
Here we report the formation of the first examples of dicopper(III) bis(μ-oxo) complexes ligated by the primary amines, propylenediamine, and N,N,-dimethyl propylenediamine. Stabilization of these new compounds is effected at -125 °C by "core capture"- introduction of exogenous ligand to a preformed dicopper(III) bis(μ-oxo) complex supported by the peralkylated tetramethyl propylenediamine. Primary amine ligation in these compounds matches the single primary amine coordination of the putative active site of particulate methane monooxygenase (pMMO) and polysaccharide monooxygenase. Reactivity studies presented here show primary amine ligated cores are competent oxidants, capable of activating C-H bonds by an H-atom abstraction mechanism. Trends in spectroscopy, structure, and reactivity provide hints to the potential role of primary amine ligation in pMMO: increased substrate accessibility to the redox active orbitals of the Cu2O2 core and greater stabilization of the oxidant without attenuation of oxidizing power.
PMID: 25268334 [PubMed - indexed for MEDLINE]
Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress.
J Psychiatr Res. 2014 Dec;59:93-100
Authors: Myers AJ, Williams L, Gatt JM, McAuley-Clark EZ, Dobson-Stone C, Schofield PR, Nemeroff CB
BACKGROUND: Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression.
METHODS: In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples.
RESULTS: A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associated with differences in DASS scores with one SNP (rs139832701) showing significant association or a trend towards association for all three measures. Several OXTR SNPs were correlated with alterations in OXTR RNA expression and rs3831817 replicated across both sets of tissues.
CONCLUSIONS: These results support the hypothesis that the oxytocin system plays a role in the pathophysiology of mood and anxiety disorders.
PMID: 25262417 [PubMed - indexed for MEDLINE]
Large-scale detection of metals with a small set of fluorescent DNA-like chemosensors.
J Am Chem Soc. 2014 Oct 15;136(41):14576-82
Authors: Yuen LH, Franzini RM, Tan SS, Kool ET
An important advantage of pattern-based chemosensor sets is their potential to detect and differentiate a large number of analytes with only few sensors. Here we test this principle at a conceptual limit by analyzing a large set of metal ion analytes covering essentially the entire periodic table, employing fluorescent DNA-like chemosensors on solid support. A tetrameric "oligodeoxyfluoroside" (ODF) library of 6561 members containing metal-binding monomers was screened for strong responders to 57 metal ions in solution. Our results show that a set of 9 chemosensors could successfully discriminate the 57 species, including alkali, alkaline earth, post-transition, transition, and lanthanide metals. As few as 6 ODF chemosensors could detect and differentiate 50 metals at 100 μM; sensitivity for some metals was achieved at midnanomolar ranges. A blind test with 50 metals further confirmed the discriminating power of the ODFs.
PMID: 25255102 [PubMed - indexed for MEDLINE]
Predictors of outcome at 1 year in adolescents with DSM-5 restrictive eating disorders: report of the national eating disorders quality improvement collaborative.
J Adolesc Health. 2014 Dec;55(6):750-6
Authors: Forman SF, McKenzie N, Hehn R, Monge MC, Kapphahn CJ, Mammel KA, Callahan ST, Sigel EJ, Bravender T, Romano M, Rome ES, Robinson KA, Fisher M, Malizio JB, Rosen DS, Hergenroeder AC, Buckelew SM, Jay MS, Lindenbaum J, Rickert VI, Garber A, Golden NH, Woods ER
PURPOSE: The National Eating Disorders Quality Improvement Collaborative evaluated data of patients with restrictive eating disorders to analyze demographics of diagnostic categories and predictors of weight restoration at 1 year.
METHODS: Fourteen Adolescent Medicine eating disorder programs participated in a retrospective review of 700 adolescents aged 9-21 years with three visits, with DSM-5 categories of restrictive eating disorders including anorexia nervosa (AN), atypical AN, and avoidant/restrictive food intake disorder (ARFID). Data including demographics, weight and height at intake and follow-up, treatment before intake, and treatment during the year of follow-up were analyzed.
RESULTS: At intake, 53.6% met criteria for AN, 33.9% for atypical AN, and 12.4% for ARFID. Adolescents with ARFID were more likely to be male, younger, and had a longer duration of illness before presentation. All sites had a positive change in mean percentage median body mass index (%MBMI) for their population at 1-year follow-up. Controlling for age, gender, duration of illness, diagnosis, and prior higher level of care, only %MBMI at intake was a significant predictor of weight recovery. In the model, there was a 12.7% change in %MBMI (interquartile range, 6.5-19.3). Type of treatment was not predictive, and there were no significant differences between programs in terms of weight restoration.
CONCLUSIONS: The National Eating Disorders Quality Improvement Collaborative provides a description of the patient population presenting to a national cross-section of 14 Adolescent Medicine eating disorder programs and categorized by DSM-5. Treatment modalities need to be further evaluated to assess for more global aspects of recovery.
PMID: 25200345 [PubMed - indexed for MEDLINE]
The brassinosteroid signaling network-a paradigm of signal integration.
Curr Opin Plant Biol. 2014 Oct;21:147-53
Authors: Wang W, Bai MY, Wang ZY
Many hormonal and environmental signals regulate common cellular and developmental processes in plants. While the molecular pathways that transduce these signals have each been studied in detail, how these pathways are wired into regulatory networks to provide the coordinated responses has remained an outstanding question. Recent studies of the brassinosteroid signaling network have revealed extensive signal integration through direct interactions between components of different signaling pathways. In particular, a circuit of interacting transcription regulators integrates many signaling pathways to enable coordinated and coherent regulation of seedling morphogenesis by hormonal and environmental signals. The recent studies support an emerging theme that complex networks of highly integrated signaling pathways underlie the high levels of developmental plasticity and environmental adaptability of plants.
PMID: 25139830 [PubMed - indexed for MEDLINE]
Patterning and processes: how stomatal development defines physiological potential.
Curr Opin Plant Biol. 2014 Oct;21:67-74
Authors: Dow GJ, Bergmann DC
Stomata present an excellent opportunity for connecting scientific disciplines: they are governed by complex genetic controls and unique cell biology, while also possessing a large influence over plant productivity and relationships with the environment. For this reason, stomata have engaged scientists for many centuries and continue to be a central interest for many fields of research. Recent technological advances have enabled interdisciplinary studies of stomata that were previously out of reach, and as a result, we are beginning to realize new insights about stomatal biology that place them at the intersection of our changing world. This review is intended to describe these interdisciplinary connections, discuss the relevant scales at which they are having an influence, and highlight ways we can capitalize on such novel approaches. While we incorporate knowledge about molecular advances, this is not intended to be an extensive review of that field, but rather, we focus on how those systems inform plant physiology and are connected to global scales.
PMID: 25058395 [PubMed - indexed for MEDLINE]
Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer.
Eur Urol. 2015 Jan;67(1):53-60
Authors: Efstathiou E, Titus M, Wen S, Hoang A, Karlou M, Ashe R, Tu SM, Aparicio A, Troncoso P, Mohler J, Logothetis CJ
BACKGROUND: Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).
OBJECTIVE: To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.
DESIGN, SETTING, AND PARTICIPANTS: In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.
RESULTS AND LIMITATIONS: Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥ 50% and ≥ 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.
CONCLUSIONS: The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.
PATIENT SUMMARY: We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01091103.
PMID: 24882673 [PubMed - indexed for MEDLINE]
Cell elongation is regulated through a central circuit of interacting transcription factors in the Arabidopsis hypocotyl.
Authors: Oh E, Zhu JY, Bai MY, Arenhart RA, Sun Y, Wang ZY
As the major mechanism of plant growth and morphogenesis, cell elongation is controlled by many hormonal and environmental signals. How these signals are coordinated at the molecular level to ensure coherent cellular responses remains unclear. In this study, we illustrate a molecular circuit that integrates all major growth-regulating signals, including auxin, brassinosteroid, gibberellin, light, and temperature. Analyses of genome-wide targets, genetic and biochemical interactions demonstrate that the auxin-response factor ARF6, the light/temperature-regulated transcription factor PIF4, and the brassinosteroid-signaling transcription factor BZR1, interact with each other and cooperatively regulate large numbers of common target genes, but their DNA-binding activities are blocked by the gibberellin-inactivated repressor RGA. In addition, a tripartite HLH/bHLH module feedback regulates PIFs and additional bHLH factors that interact with ARF6, and thereby modulates auxin sensitivity according to developmental and environmental cues. Our results demonstrate a central growth-regulation circuit that integrates hormonal, environmental, and developmental controls of cell elongation in Arabidopsis hypocotyl.
PMID: 24867218 [PubMed - indexed for MEDLINE]
The relationship between serial [(18) F]PBR06 PET imaging of microglial activation and motor function following stroke in mice.
Mol Imaging Biol. 2014 Dec;16(6):821-9
Authors: Lartey FM, Ahn GO, Ali R, Rosenblum S, Miao Z, Arksey N, Shen B, Colomer MV, Rafat M, Liu H, Alejandre-Alcazar MA, Chen JW, Palmer T, Chin FT, Guzman R, Loo BW, Graves E
PURPOSE: Using [(18) F]PBR06 positron emission tomography (PET) to characterize the time course of stroke-associated neuroinflammation (SAN) in mice, to evaluate whether brain microglia influences motor function after stroke, and to demonstrate the use of [(18) F]PBR06 PET as a therapeutic assessment tool.
PROCEDURES: Stroke was induced by transient middle cerebral artery occlusion (MCAO) in Balb/c mice (control, stroke, and stroke with poststroke minocycline treatment). [18 F]PBR06 PET/CT imaging, rotarod tests, and immunohistochemistry (IHC) were performed 3, 11, and 22 days poststroke induction (PSI).
RESULTS: The stroke group exhibited significantly increased microglial activation, and impaired motor function. Peak microglial activation was 11 days PSI. There was a strong association between microglial activation, motor function, and microglial protein expression on IHC. Minocycline significantly reduced microglial activation and improved motor function by day 22 PSI.
CONCLUSION: [18 F]PBR06 PET imaging noninvasively characterizes the time course of SAN, and shows increased microglial activation is associated with decreased motor function.
PMID: 24865401 [PubMed - indexed for MEDLINE]
Noninvasive reporter gene imaging of human Oct4 (pluripotency) dynamics during the differentiation of embryonic stem cells in living subjects.
Mol Imaging Biol. 2014 Dec;16(6):865-76
Authors: Ahn BC, Parashurama N, Patel M, Ziv K, Bhaumik S, Yaghoubi SS, Paulmurugan R, Gambhir SS
PURPOSE: Human pluripotency gene networks (PGNs), controlled in part by Oct4, are central to understanding pluripotent stem cells, but current fluorescent reporter genes (RGs) preclude noninvasive assessment of Oct4 dynamics in living subjects.
PROCEDURES: To assess Oc4 activity noninvasively, we engineered a mouse embryonic stem cell line which encoded both a pOct4-hrluc (humanized renilla luciferase) reporter and a pUbi-hfluc2-gfp (humanized firefly luciferase 2 fused to green fluorescent protein) reporter.
RESULTS: In cell culture, pOct4-hRLUC activity demonstrated a peak at 48 h (day 2) and significant downregulation by 72 h (day 3) (p=0.0001). Studies in living subjects demonstrated significant downregulation in pOct4-hRLUC activity between 12 and 144 h (p = 0.001) and between 12 and 168 h (p = 0.0003). pOct4-hRLUC signal dynamics after implantation was complex, characterized by transient upregulation after initial downregulation in all experiments (n = 10, p = 0.01). As expected, cell culture differentiation of the engineered mouse embryonic stem cell line demonstrated activation of mesendodermal, mesodermal, endodermal, and ectodermal master regulators of differentiation, indicating potency to form all three germ layers.
CONCLUSIONS: We conclude that the Oct4-hrluc RG system enables noninvasive Oct4 imaging in cell culture and in living subjects.
PMID: 24845530 [PubMed - indexed for MEDLINE]
IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis.
Ann Rheum Dis. 2015 Jun;74(6):1284-92
Authors: Adamopoulos IE, Suzuki E, Chao CC, Gorman D, Adda S, Maverakis E, Zarbalis K, Geissler R, Asio A, Blumenschein WM, Mcclanahan T, De Waal Malefyt R, Gershwin ME, Bowman EP
BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease characterised by clinical features that include bone loss and epidermal hyperplasia. Aberrant cytokine expression has been linked to joint and skin pathology; however, it is unclear which cytokines are critical for disease initiation. Interleukin 17A (IL-17A) participates in many pathological immune responses; however, its role in PsA has not been fully elucidated.
OBJECTIVE: To determine the role of IL-17A in epidermal hyperplasia and bone destruction associated with psoriatic arthritis.
DESIGN: An in vivo gene transfer approach was used to investigate the role of IL-17A in animal models of inflammatory (collagen-induced arthritis) and non-inflammatory (receptor activator of NF-κB ligand (RANKL)-gene transfer) bone loss.
RESULTS: IL-17A gene transfer induced the expansion of IL-17RA(+)CD11b(+)Gr1(low) osteoclast precursors and a concomitant elevation of biomarkers indicative of bone resorption. This occurred at a time preceding noticeable joint inflammation, suggesting that IL-17A is critical for the induction of pathological bone resorption through direct activation of osteoclast precursors. Moreover, IL-17A induced a second myeloid population CD11b(+)Gr1(high) neutrophil-like cells, which was associated with cutaneous pathology including epidermal hyperplasia, parakeratosis and Munro's microabscesses formation.
CONCLUSIONS: Collectively, these data support that IL-17A can play a key role in the pathogenesis of inflammation-associated arthritis and/or skin disease, as observed in PsA.
PMID: 24567524 [PubMed - indexed for MEDLINE]
Access restricted to Stanford community
Can't find it?
Look if we have it in print:
- All Biomedical Resources
- Specialty Portals
- Obstetrics & Gynecology
- Biomedical Ethics
- Palliative Care
- Comparative Medicine
- Consumer Health
- Emergency Medicine
- Global Health
- Physical & Rehabilitation Med
- Infectious Diseases
- Internal Medicine
- LPCH Heart Center Nursing
- Reference Desk
- Medical Education
- Spiritual Care
- Multicultural Health
- Student IL Materials
- Classes & Tutorials
- Using the Library
- About Lane
- How To