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- Predictors of Mortality in Pediatric Patients on Venoarterial Extracorporeal Membrane Oxygenation.Punn R, Axelrod DM, Sherman-Levine S, Roth SJ, Tacy TAPediatr Crit Care Med
- Lifespan maturation and degeneration of human brain white matter.Yeatman JD, Wandell BA, Mezer AANat Commun
- Targeting SUMOylation Cascade for Diabetes Management.Sireesh D, Bhakkiyalakshmi E, Ramkumar KM, Kumar SR, Jennifer PA, Rajaguru P, Paulmurugan RCurr Drug Targets
- Lynch Syndrome Screening Should Be Considered for All Patients With Newly Diagnosed Endometrial Cancer.Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TAAm J Surg Pathol
- Inflammatory Cytokines and the Lymphatic Endothelium.Rockson SGLymphat Res Biol
- The potential for vertical bone regeneration via maxillary periosteal elevation.Mouraret S, Von Kaeppler E, Bardet C, Hunter DJ, Chaussain C, Bouchard P, Helms JAJ Clin Periodontol
- Do Girls Have a Nutritional Disadvantage Compared with Boys? Statistical Models of Breastfeeding and Food Consumption Inequalities among Indian Siblings.Fledderjohann J, Agrawal S, Vellakkal S, Basu S, Campbell O, Doyle P, Ebrahim S, Stuckler DPLoS One
- In utero arsenic exposure and fetal immune repertoire in a US pregnancy cohort.Nadeau KC, Li Z, Farzan S, Koestler D, Robbins D, Fei DL, Malipatlolla M, Maecker H, Enelow R, Korrick S, Karagas MRClin Immunol
- Recent technological updates and clinical applications of induced pluripotent stem cells.Diecke S, Jung SM, Lee J, Ju JHKorean J Intern Med
- Genome-wide map of regulatory interactions in the human genome.Heidari N, Phanstiel DH, He C, Grubert F, Jahanbanian F, Kasowski M, Zhang MQ, Snyder MPGenome Res
- ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes.Boxer LD, Barajas B, Tao S, Zhang J, Khavari PAGenes Dev
- Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.Conrad C, Lymp J, Thompson V, Dunn C, Davies Z, Chatfield B, Nichols D, Clancy J, Vender R, Egan ME, Quittell L, Michelson P, Antony V, Spahr J, Rubenstein RC, Moss RB, Herzenberg LA, Goss CH, Tirouvanziam RJ Cyst Fibros
- Urine electrolyte composition and diuretic therapy in heart failure: back to the future?Pao AC, Chertow GMCirc Heart Fail
- Correspondence of Plasma and Salivary Cortisol Patterns in Women with Breast Cancer.Zeitzer JM, Nouriani B, Neri E, Spiegel DNeuroendocrinology
- Glucocorticoids Increase Excitotoxic Injury and Inflammation in the Hippocampus of Adult Male Rats.Sorrells SF, Munhoz CD, Manley NC, Yen S, Sapolsky RMNeuroendocrinology
- Balanced SSFP Dixon imaging with banding-artifact reduction at 3 Tesla.Quist B, Hargreaves BA, Daniel BL, Saranathan MMagn Reson Med
- The capacity of neural crest-derived stem cells for ocular repair.Liu B, Hunter DJ, Smith AA, Chen S, Helms JABirth Defects Res C Embryo Today
- Millisecond Flashes of Light Phase Delay the Human Circadian Clock during Sleep.Zeitzer JM, Fisicaro RA, Ruby NF, Heller HCJ Biol Rhythms
- Heritability estimates on Hodgkin's lymphoma: a genomic- versus population-based approach.Thomsen H, da Silva Filho MI, Försti A, Fuchs M, Ponader S, von Strandmann EP, Eisele L, Herms S, Hofmann P, Sundquist J, Engert A, Hemminki KEur J Hum Genet
- Pilot study of vibration stimulation on neurological rehabilitation.Sui J, Shull P, Ji LBiomed Mater Eng
- Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis.Rothenberg ME, Wen T, Greenberg A, Alpan O, Enav B, Hirano I, Nadeau K, Kaiser S, Peters T, Perez A, Jones I, Arm JP, Strieter RM, Sabo R, Gunawardena KAJ Allergy Clin Immunol
- A system for multi-locus chromosomal integration and transformation-free selection marker rescue.Siddiqui MS, Choksi A, Smolke CDFEMS Yeast Res
- Israel-Gaza conflict.Ahmed Q, Avidan AY, Ciechanover A, Shechtman D, Zajfman D, Reichman U, Kornberg R, Hershko A, Lavie PLancet
- South America: Citation databases omit local journals.Alperin JPNature
- Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou ELancet
- Clinical profile and prognostic value of anemia at the time of admission and discharge among patients hospitalized for heart failure with reduced ejection fraction: findings from the EVEREST trial.Mentz RJ, Greene SJ, Ambrosy AP, Vaduganathan M, Subacius HP, Swedberg K, Maggioni AP, Nodari S, Ponikowski P, Anker SD, Butler J, Gheorghiade MCirc Heart Fail
- CD81 and hepatitis C virus (HCV) infection.Fénéant L, Levy S, Cocquerel LViruses
- Trends in pharmacotherapy in patients referred to a bipolar specialty clinic, 2000-2011.Hooshmand F, Miller S, Dore J, Wang PW, Hill SJ, Portillo N, Ketter TAJ Affect Disord
- Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls.Reynolds-May MF, Kenna HA, Marsh W, Stemmle PG, Wang P, Ketter TA, Rasgon NLBipolar Disord
- Clinical assessment of lurasidone benefit and risk in the treatment of bipolar I depression using number needed to treat, number needed to harm, and likelihood to be helped or harmed.Citrome L, Ketter TA, Cucchiaro J, Loebel AJ Affect Disord
- Dynamic recognition of the mRNA cap by Saccharomyces cerevisiae eIF4E.O'Leary SE, Petrov A, Chen J, Puglisi JDStructure
- Costimulation-adhesion blockade is superior to cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation.Huber BC, Ransohoff JD, Ransohoff KJ, Riegler J, Ebert A, Kodo K, Gong Y, Sanchez-Freire V, Dey D, Kooreman NG, Diecke S, Zhang WY, Odegaard J, Hu S, Gold JD, Robbins RC, Wu JCStem Cells
Predictors of Mortality in Pediatric Patients on Venoarterial Extracorporeal Membrane Oxygenation.
Pediatr Crit Care Med. 2014 Sep 16;
Authors: Punn R, Axelrod DM, Sherman-Levine S, Roth SJ, Tacy TA
OBJECTIVES:: Currently, there are no established echocardiographic or hemodynamic predictors of mortality after weaning venoarterial extracorporeal membrane oxygenation in children. We wished to determine which measurements predict mortality.
DESIGN:: Over 3 years, we prospectively assessed six echo and six hemodynamic variables at 3-5 circuit rates while weaning extracorporeal membrane oxygenation flow. Hemodynamic measurements were heart rate, inotropic score, arteriovenous oxygen difference, pulse pressure, oxygenation index, and lactate. Echo variables included shortening/ejection fraction, outflow tract Doppler-derived stroke distance (velocity-time integral), degree of atrioventricular valve regurgitation, longitudinal strain (global longitudinal strain), and circumferential strain (global circumferential strain).
SETTING:: Cardiovascular ICU at Lucille Packard Children's Hospital Stanford, CA.
SUBJECTS:: Patients were stratified into those who died or required heart transplant (Gr1) and those who did not (Gr2). For each patient, we compared the change for each variable between full versus minimum extracorporeal membrane oxygenation flow for each group.
MEASUREMENTS AND MAIN RESULTS:: We enrolled 21 patients ranging in age from 0.02 to 15 years. Five had dilated cardiomyopathy, and 16 had structural heart disease with severe ventricular dysfunction. Thirteen of 21 patients (62%) comprised Gr1, including two patients with heart transplants. Eight patients constituted Gr2. Gr1 patients had a significantly greater increase in oxygenation index (35% mean increase; p < 0.01) off extracorporeal membrane oxygenation compared to full flow, but no change in velocity-time integral or arteriovenous oxygen difference. In Gr2, velocity-time integral increased (31% mean increase; p < 0.01), with no change in arteriovenous oxygen difference or oxygenation index. Pulse pressure increased modestly with flow reduction only in Gr1 (p < 0.01).
CONCLUSION:: Failure to augment velocity-time integral or an increase in oxygenation index during the extracorporeal membrane oxygenation weaning is associated with poor outcomes in children. We propose that these measurements should be performed during extracorporeal membrane oxygenation wean, as they may discriminate who will require alternative methods of circulatory support for survival.
PMID: 25230312 [PubMed - as supplied by publisher]
Lifespan maturation and degeneration of human brain white matter.
Nat Commun. 2014;5:4932
Authors: Yeatman JD, Wandell BA, Mezer AA
Properties of human brain tissue change across the lifespan. Here we model these changes in the living human brain by combining quantitative magnetic resonance imaging (MRI) measurements of R1 (1/T1) with diffusion MRI and tractography (N=102, ages 7-85). The amount of R1 change during development differs between white-matter fascicles, but in each fascicle the rate of development and decline are mirror-symmetric; the rate of R1 development as the brain approaches maturity predicts the rate of R1 degeneration in aging. Quantitative measurements of macromolecule tissue volume (MTV) confirm that R1 is an accurate index of the growth of new brain tissue. In contrast to R1, diffusion development follows an asymmetric time-course with rapid childhood changes but a slow rate of decline in old age. Together, the time-courses of R1 and diffusion changes demonstrate that multiple biological processes drive changes in white-matter tissue properties over the lifespan.
PMID: 25230200 [PubMed - as supplied by publisher]
Targeting SUMOylation Cascade for Diabetes Management.
Curr Drug Targets. 2014 Sep 15;
Authors: Sireesh D, Bhakkiyalakshmi E, Ramkumar KM, Kumar SR, Jennifer PA, Rajaguru P, Paulmurugan R
Post-translational modifications (PTMs) play important roles in regulating protein stability, trafficking, folding conformation, and functional activity. Small ubiquitin-like modifier (SUMO) protein mediates a distinct type of PTM called SUMOylation in which through a series of enzymatically-catalyzed reactions, the SUMO protein is covalently ligated to the target protein and modify its activities. SUMOylation regulates many cellular processes like transcription, the maintenance of the ion gradient across the cell membrane, stress response, autoimmunity, etc. Several target proteins of SUMOylation are involved in the biological pathways related to various human diseases; just a few to highlight here are cardiovascular diseases, diabetes, cancer, and neurodegenerative disorders. This review mainly focuses on the SUMOylation process, regulatory roles of SUMOylation in diabetes, and prospects of developing novel anti-diabetic drugs targeting SUMOylation process.
PMID: 25230117 [PubMed - as supplied by publisher]
Lynch Syndrome Screening Should Be Considered for All Patients With Newly Diagnosed Endometrial Cancer.
Am J Surg Pathol. 2014 Sep 16;
Authors: Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA
Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Mutation carriers are at substantially increased risk of developing cancers of the colorectum and endometrium, among others. Given recent recommendations for universal, cost-effective screening of all patients with newly diagnosed colorectal cancer using MMR protein immunohistochemistry, we evaluated MMR protein expression in a series of endometrial cancers in the general population. A total of 605 consecutive cases of primary endometrial cancer at a single institution (1997 to 2013) were evaluated regardless of age, family history, or histologic features. Evaluation methods consisted of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2, followed by DNA methylation analysis for cases with MLH1/PMS2 deficiency. Germline mutation testing was performed on a subset of cases. Forty MMR-deficient, nonmethylated endometrial cancers were identified: 3 MLH1/PMS2 and 37 MSH6/MSH2 protein deficiencies. Only 25% occurred in women below 50 years of age (range, 39 to 88 y), 1 of which was in a risk-reducing hysterectomy specimen. Only 15% of patients had a prior history of carcinoma, including only 2 patients with prior colorectal carcinoma. Most (80%) of the endometrial cancers were purely endometrioid; there were 2 mixed endometrioid/mucinous, 1 mucinous, 1 serous, 2 clear cell, and 2 carcinosarcoma cases. When grading was applicable, 40% of the endometrial malignancies were FIGO grade 1, 34% grade 2, and 26% grade 3. Thirteen percent arose in the lower uterine segment, and 23% had tumor-infiltrating lymphocytes. Of the tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated tumor morphology, or location in the lower uterine segment). These data suggest that a significant number of LS-associated endometrial carcinomas are missed using clinical, histologic, and locational screening parameters and provide support for universal screening of all newly diagnosed endometrial cancers.
PMID: 25229768 [PubMed - as supplied by publisher]
Inflammatory Cytokines and the Lymphatic Endothelium.
Lymphat Res Biol. 2014 Sep;12(3):123
Authors: Rockson SG
PMID: 25229431 [PubMed - as supplied by publisher]
The potential for vertical bone regeneration via maxillary periosteal elevation.
J Clin Periodontol. 2014 Sep 17;
Authors: Mouraret S, Von Kaeppler E, Bardet C, Hunter DJ, Chaussain C, Bouchard P, Helms JA
BACKGROUND: While many studies have been performed on the characteristics and regenerative capacity of long bone periosteum, the craniofacial periosteum remains poorly understood.
AIM: The aim of this study was to investigate the potential for a maxillary periosteum tunneling procedure to induce vertical alveolar bone regeneration.
MATERIALS AND METHODS: We employed a murine injury model that activates skeletal stem cells in the periosteum without overtly damaging the underlying cortical bone, preserving the integrity of the long bone and maxilla, and avoiding the introduction of pathological motion at the injury site. Further, we introduced a collagen sponge to serve as a scaffold, providing the necessary space for vertical bone regeneration.
RESULTS: Periosteal elevation alone resulted in bone formation in the tibia and delayed bone resorption in the maxilla. With the presence of the collagen sponge, new bone formation occurred in the maxilla.
CONCLUSIONS: Periosteal response to injury varies with anatomical location, so conclusions from long bone studies should not be extrapolated for craniofacial applications. Murine maxillary periosteum has the osteogenic potential to induce vertical alveolar bone regeneration. This article is protected by copyright. All rights reserved.
PMID: 25229322 [PubMed - as supplied by publisher]
Do Girls Have a Nutritional Disadvantage Compared with Boys? Statistical Models of Breastfeeding and Food Consumption Inequalities among Indian Siblings.
PLoS One. 2014;9(9):e107172
Authors: Fledderjohann J, Agrawal S, Vellakkal S, Basu S, Campbell O, Doyle P, Ebrahim S, Stuckler D
BACKGROUND: India is the only nation where girls have greater risks of under-5 mortality than boys. We test whether female disadvantage in breastfeeding and food allocation accounts for gender disparities in mortality.
METHODS AND FINDINGS: Secondary, publicly available anonymized and de-identified data were used; no ethics committee review was required. Multivariate regression and Cox models were performed using Round 3 of India's National Family and Health Survey (2005-2006; response rate = 93.5%). Models were disaggregated by birth order and sibling gender, and adjusted for maternal age, education, and fixed effects, urban residence, household deprivation, and other sociodemographics. Mothers' reported practices of WHO/UNICEF recommendations for breastfeeding initiation, exclusivity, and total duration (ages 0-59 months), children's consumption of 24 food items (6-59 months), and child survival (0-59 months) were examined for first- and secondborns (n = 20,395). Girls were breastfed on average for 0.45 months less than boys (95% CI: = 0.15 months to 0.75 months, p = 0.004). There were no gender differences in breastfeeding initiation (OR = 1.04, 95% CI: 0.97 to 1.12) or exclusivity (OR = 1.06, 95% CI: 0.99 to 1.14). Differences in breastfeeding cessation emerged between 12 and 36 months in secondborn females. Compared with boys, girls had lower consumption of fresh milk by 14% (95% CI: 79% to 94%, p = 0.001) and breast milk by 21% (95% CI: 70% to 90%, p<0.000). Each additional month of breastfeeding was associated with a 24% lower risk of mortality (OR = 0.76, 95% CI: 0.73 to 0.79, p<0.000). Girls' shorter breastfeeding duration accounted for an 11% increased probability of dying before age 5, accounting for about 50% of their survival disadvantage compared with other low-income countries.
CONCLUSIONS: Indian girls are breastfed for shorter periods than boys and consume less milk. Future research should investigate the role of additional factors driving India's female survival disadvantage.
PMID: 25229235 [PubMed - as supplied by publisher]
In utero arsenic exposure and fetal immune repertoire in a US pregnancy cohort.
Clin Immunol. 2014 Sep 13;
Authors: Nadeau KC, Li Z, Farzan S, Koestler D, Robbins D, Fei DL, Malipatlolla M, Maecker H, Enelow R, Korrick S, Karagas MR
Arsenic has wide-ranging effects on human health and there is evidence that it alters the immune response by influencing CD4+/CD8+ T cell ratios, IL-2 cytokine levels, and the expression of immune-response genes. We investigated the impact of in utero environmental arsenic exposure on immune development and function in newborns participating in a pregnancy cohort in New Hampshire, U.S., where arsenic levels have exceeded the current EPA maximum contaminant level of 10μg/L. Our results showed that maternal urinary arsenic concentrations were inversely related to absolute total CD45RA+CD4+ cord blood CD69+ T cell counts (N=116, p=0.04) and positively associated with CD45RA+CD69- CD294+ cell counts (p=0.01). In placental samples (N=70), higher in utero urinary arsenic concentrations were positively associated with expression of IL1β (p=0.03). These data provide evidence that relatively low-level arsenic exposure in utero may alter the fetal immune system and lead to immune dysregulation.
PMID: 25229165 [PubMed - as supplied by publisher]
Recent technological updates and clinical applications of induced pluripotent stem cells.
Korean J Intern Med. 2014 Sep;29(5):547-557
Authors: Diecke S, Jung SM, Lee J, Ju JH
Induced pluripotent stem cells (iPSCs) were first described in 2006 and have since emerged as a promising cell source for clinical applications. The rapid progression in iPSC technology is still ongoing and directed toward increasing the efficacy of iPSC production and reducing the immunogenic and tumorigenic potential of these cells. Enormous efforts have been made to apply iPSC-based technology in the clinic, for drug screening approaches and cell replacement therapy. Moreover, disease modeling using patient-specific iPSCs continues to expand our knowledge regarding the pathophysiology and prospective treatment of rare disorders. Furthermore, autologous stem cell therapy with patient-specific iPSCs shows great propensity for the minimization of immune reactions and the provision of a limitless supply of cells for transplantation. In this review, we discuss the recent updates in iPSC technology and the use of iPSCs in disease modeling and regenerative medicine.
PMID: 25228828 [PubMed - as supplied by publisher]
Genome-wide map of regulatory interactions in the human genome.
Genome Res. 2014 Sep 16;
Authors: Heidari N, Phanstiel DH, He C, Grubert F, Jahanbanian F, Kasowski M, Zhang MQ, Snyder MP
Increasing evidence suggests that interactions between regulatory genomic elements play an important role in regulating gene expression. We generated a genome-wide interaction map of regulatory elements in human cells (ENCODE tier 1 cells, K562, GM12878) using Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) experiments targeting six broadly distributed factors. Bound regions covered 80% of DNase I hypersensitive sites including 99.7% of TSS and 98% of enhancers. Correlating this map with ChIP-seq and RNA-seq data sets revealed cohesin, CTCF, and ZNF143 as key components of three-dimensional (3D) chromatin structure and revealed how distal chromatin state affects gene transcription. Comparison of interactions between cell types revealed that enhancer-promoter interactions were highly cell-type specific. Construction and comparison of distal and proximal regulatory networks revealed stark differences in structure and biological function. Proximal binding events are enriched at genes with housekeeping functions while distal binding events interact with genes involved in dynamic biological processes including response to stimulus. This study reveals new mechanistic and functional insights into regulatory region organization in the nucleus.
PMID: 25228660 [PubMed - as supplied by publisher]
ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes.
Genes Dev. 2014 Sep 15;28(18):2013-26
Authors: Boxer LD, Barajas B, Tao S, Zhang J, Khavari PA
ZNF750 controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes, a role underscored by pathogenic ZNF750 mutations in cancer and psoriasis. How ZNF750 accomplishes these dual gene regulatory impacts is unknown. Here, we characterized ZNF750 as a transcription factor that binds both the progenitor and differentiation genes that it controls at a CCNNAGGC DNA motif. ZNF750 interacts with the pluripotency transcription factor KLF4 and chromatin regulators RCOR1, KDM1A, and CTBP1/2 through conserved PLNLS sequences. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) and gene depletion revealed that KLF4 colocalizes ∼10 base pairs from ZNF750 at differentiation target genes to facilitate their activation but is unnecessary for ZNF750-mediated progenitor gene repression. In contrast, KDM1A colocalizes with ZNF750 at progenitor genes and facilitates their repression but is unnecessary for ZNF750-driven differentiation. ZNF750 thus controls differentiation in concert with RCOR1 and CTBP1/2 by acting with either KDM1A to repress progenitor genes or KLF4 to induce differentiation genes.
PMID: 25228645 [PubMed - in process]
Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.
J Cyst Fibros. 2014 Sep 13;
Authors: Conrad C, Lymp J, Thompson V, Dunn C, Davies Z, Chatfield B, Nichols D, Clancy J, Vender R, Egan ME, Quittell L, Michelson P, Antony V, Spahr J, Rubenstein RC, Moss RB, Herzenberg LA, Goss CH, Tirouvanziam R
PURPOSE: To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways.
METHODS: A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24weeks. Endpoints: primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV1 and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF.
RESULTS: Lung function (FEV1 and FEF25-75%) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log10 HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14).
CONCLUSIONS: NAC recipients maintained their lung function while placebo recipients declined (24week FEV1 treatment effect=150mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.
PMID: 25228446 [PubMed - as supplied by publisher]
Urine electrolyte composition and diuretic therapy in heart failure: back to the future?
Circ Heart Fail. 2014 Sep;7(5):697-8
Authors: Pao AC, Chertow GM
PMID: 25228317 [PubMed - in process]
Correspondence of Plasma and Salivary Cortisol Patterns in Women with Breast Cancer.
Neuroendocrinology. 2014 Sep 10;
Authors: Zeitzer JM, Nouriani B, Neri E, Spiegel D
Introduction: The 'diurnal slope' of salivary cortisol has been used as a measure of stress and circadian function in a variety of reports with several detailing its association with cancer progression. The relationship of this slope, typically a negative value from high morning concentrations to low evening concentrations, to the underlying daily variation in total plasma cortisol throughout the 24-hour cycle, however, has never been reported. Methods: To examine the relationship between diurnal salivary cortisol slope and the underlying pattern of plasma cortisol in individuals with cancer, we examined a cohort of women with advanced breast cancer (n = 97) who had saliva and plasma collected during a modified 24-hour, constant posture protocol. Results: We found that steepness of the diurnal slope of salivary cortisol was correlated with the amplitude of plasma cortisol rhythm when the slope was calculated from samples taken at wake+30 min and 9PM (r = -0.29, p > 0.05). Other variants of salivary slope calculations were not significantly correlated with the amplitude of the plasma cortisol rhythm. Diurnal salivary cortisol slope steepness was not correlated with the time between habitual waking and the computed circadian peak of cortisol, but there was a correlation between diurnal slope steepness and the time between habitual waking and the time of the awakening spike of morning cortisol (r's<-0.23, p's<0.05). Conclusion: It therefore appears that in women with advanced breast cancer, diurnal salivary cortisol slope primarily represents aspects of the cortisol awakening response in relation to evening levels more than the circadian rhythm of total plasma cortisol. © 2014 S. Karger AG, Basel.
PMID: 25228297 [PubMed - as supplied by publisher]
Glucocorticoids Increase Excitotoxic Injury and Inflammation in the Hippocampus of Adult Male Rats.
Neuroendocrinology. 2014 Sep 10;
Authors: Sorrells SF, Munhoz CD, Manley NC, Yen S, Sapolsky RM
Background/Aims: Stress exacerbates neuron loss in many CNS injuries via the actions of adrenal glucocorticoid (GC) hormones. For some injuries, this GC-endangerment of neurons is accompanied by greater immune cell activation in the CNS, a surprising outcome given the potent immunosuppressive properties of GCs. Methods: To determine whether the effects of GCs on inflammation contribute to neuron death or result from it, we tested whether non-steroidal anti-inflammatory drugs could protect neurons from GCs during kainic acid excitotoxicity in adrenalectomized male rats. We next measured GC effects on (i) chemokine production (CCL2, CINC-1), (ii) signals that suppress immune activation (CX3CL1, CD22, CD200, and TGF-b), and (iii) NF-kB activity. Results: Concurrent treatment with minocycline but not indomethacin prevented GC-endangerment. GCs did not substantially affect CCL2, CINC-1, or baseline NF-kB activity, but they did suppress CX3CL1, CX3CR1, and CD22 expression in the hippocampus, factors that normally restrain inflammatory responses. Conclusions: These findings demonstrate that cellular inflammation is not necessarily suppressed by GCs in the injured hippocampus; instead, GCs may worsen hippocampal neuron death, at least in part, by increasing the neurotoxicity of CNS inflammation. © 2014 S. Karger AG, Basel.
PMID: 25228100 [PubMed - as supplied by publisher]
Balanced SSFP Dixon imaging with banding-artifact reduction at 3 Tesla.
Magn Reson Med. 2014 Sep 16;
Authors: Quist B, Hargreaves BA, Daniel BL, Saranathan M
PURPOSE: To develop a three-dimensional (3D) balanced steady-state free-precession (bSSFP) two-point Dixon method with banding-artifact suppression to offer robust high-resolution 3D bright-fluid imaging.
METHODS: A complex sum reconstruction that combines phase-cycled bSSFP images acquired at specific echo times for robust fat/water separation without banding was investigated and compared with a magnitude-based method. Bloch simulations using both single-peak and multiple-peak fat models were performed to predict the performance of these methods for a wide range of echo times and repetition times. The quality and degree of fat/water separation was evaluated in both simulations and using in vivo imaging.
RESULTS: Simulations predicted that both effective banding-artifact suppression and substantial improvements in fat/water separation are possible at echo times that are different from conventional echo times, enabling improved spatial resolution. Comparisons between various echo times and repetition times in vivo validated the improved fat/water separation and effective banding-artifact removal predicted by the simulations.
CONCLUSION: The proposed complex sum Dixon 3D bSSFP method is able to effectively separate fat and water at different sets of echo times, while removing banding-artifacts, providing a fast, high-resolution, T2 -like sequence without blurring. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.
PMID: 25227766 [PubMed - as supplied by publisher]
The capacity of neural crest-derived stem cells for ocular repair.
Birth Defects Res C Embryo Today. 2014 Sep 16;
Authors: Liu B, Hunter DJ, Smith AA, Chen S, Helms JA
Whether it is due to a particular epigenetic signature, or some other component of an embryonic differentiation program, accumulating evidence indicates that the origins of a stem cell has a profound impact on the potential of a tissue to regenerate and repair. Here, we focus on Müller glia, long considered the stem cells of the retina, and their surprising derivation from the neural crest. Whether the multipotent properties of a subset of Müller glia is associated with their neural crest origin remains a tantalizing possibility. Birth Defects Research (Part C), 2014. © 2014 Wiley Periodicals, Inc.
PMID: 25227475 [PubMed - as supplied by publisher]
Millisecond Flashes of Light Phase Delay the Human Circadian Clock during Sleep.
J Biol Rhythms. 2014 Sep 16;
Authors: Zeitzer JM, Fisicaro RA, Ruby NF, Heller HC
The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p < 0.05). Confirmation that the flashes penetrated the eyelids is presented by the occurrence of an evoked response in the EEG. Despite the robust effect on circadian timing, there were no large changes in either the amount or spectral content of sleep (p values > 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans.
PMID: 25227334 [PubMed - as supplied by publisher]
Heritability estimates on Hodgkin's lymphoma: a genomic- versus population-based approach.
Eur J Hum Genet. 2014 Sep 17;
Authors: Thomsen H, da Silva Filho MI, Försti A, Fuchs M, Ponader S, von Strandmann EP, Eisele L, Herms S, Hofmann P, Sundquist J, Engert A, Hemminki K
Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of Hodgkin's lymphoma (HL) and demonstrated the association of common genetic variation for this type of cancer. Such evidence for inherited genetic risk is also provided by the family history and the very high concordance between monozygotic twins. However, little is known about the genetic and environmental contributions. A common measure for describing the phenotypic variation due to genetics is the heritability. Using GWAS data on 906 HL cases by considering all typed SNPs simultaneously, we have calculated that the common variance explained by SNPs accounts for >35% of the total variation on the liability scale in HL (95% confidence interval 6-62%). These findings are consistent with similar heritability estimates of ∼0.40 (95% confidence interval 0.17-0.58) based on Swedish population data. Our estimates support the underlying polygenic basis for susceptibility to HL, and show that heritability based on the population data is somehow larger than heritability based on the genomic data because of the possibility of some missing heritability in the GWAS data. Besides that there is still major evidence for multiple loci causing HL on chromosomes other than chromosome 6 that need to be detected. Because of limited findings in prior GWASs, it seems worth checking for more loci causing susceptibility to HL.European Journal of Human Genetics advance online publication, 17 September 2014; doi:10.1038/ejhg.2014.184.
PMID: 25227146 [PubMed - as supplied by publisher]
Pilot study of vibration stimulation on neurological rehabilitation.
Biomed Mater Eng. 2014 Jan 1;24(6):2593-601
Authors: Sui J, Shull P, Ji L
Robot-assisted therapy has been proved effective for dyskinesia, and has many unique advantages compared with traditional treatment, such as repeatability, accuracy, objectivity. But some studies show that the effect of the robot-assisted rehabilitation for improving patients' activities of daily life (ADLs) is not obvious. This study introduces a novel auxiliary method-vibration stimulation combined with robots which may improve patients' ADLs. In controlled trials, two kinds of feedback-vibration and visual feedback are applied to prompt subjects for rehabilitation, and electromyographic signals (EMGs) and motion parameters are recorded in real time. Experimental results show that subjects' EMGs using vibration feedback are similar to healthy people, and characteristics of motion are closer to the theoretical value compared with control group. Vibration stimulation may serve as a kind of efficient auxiliary means to improve the efficiency of neurological rehabilitation.
PMID: 25226962 [PubMed - in process]
Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis.
J Allergy Clin Immunol. 2014 Sep 13;
Authors: Rothenberg ME, Wen T, Greenberg A, Alpan O, Enav B, Hirano I, Nadeau K, Kaiser S, Peters T, Perez A, Jones I, Arm JP, Strieter RM, Sabo R, Gunawardena KA
BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options.
OBJECTIVE: We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE.
METHODS: Patients (18-50 years) with proton pump inhibitor-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers.
RESULTS: Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo (P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated.
CONCLUSIONS: QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease-related transcripts in adults with EoE in a sustained manner.
PMID: 25226850 [PubMed - as supplied by publisher]
A system for multi-locus chromosomal integration and transformation-free selection marker rescue.
FEMS Yeast Res. 2014 Sep 16;
Authors: Siddiqui MS, Choksi A, Smolke CD
Yeast integrating plasmids (YIPs) are a versatile tool for stable integration in Saccharomyces cerevisiae. However, current YIP systems necessitate time- and labor-intensive methods for cloning and selection marker rescue. Here we describe the design, construction, and validation of a new YIP system capable of accelerating the stable integration of multiple expression constructs into different loci in the yeast S. cerevisiae. These "directed pop-out" plasmids enable a simple, two-step integration protocol that results in a scarless integration alongside a complete rescue of the selection marker. These plasmids combine three key features: a dedicated "YIPout" fragment directs a recombination event that rescues the selection marker while avoiding undesired excision of the target DNA sequence, a multi-fragment modular DNA assembly system simplifies cloning, and a new set of counterselectable markers enables serial integration followed by a transformation-free marker rescue event. We constructed and tested directed pop-out YIPs for integration of fluorescent reporter genes into four yeast loci. We validated our new YIP design by integrating three reporter genes into three different loci with transformation-free rescue of selection markers. These new YIP designs will facilitate the construction of yeast strains that express complex heterologous metabolic pathways. This article is protected by copyright. All rights reserved.
PMID: 25226817 [PubMed - as supplied by publisher]
Lancet. 2014 Aug 30;384(9945):e34-7
Authors: Ahmed Q, Avidan AY, Ciechanover A, Shechtman D, Zajfman D, Reichman U, Kornberg R, Hershko A, Lavie P
PMID: 25145777 [PubMed - indexed for MEDLINE]
South America: Citation databases omit local journals.
Nature. 2014 Jul 10;511(7508):155
Authors: Alperin JP
PMID: 25008513 [PubMed - indexed for MEDLINE]
Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.
Lancet. 2014 Aug 30;384(9945):766-81
Authors: Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E
BACKGROUND: In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013.
METHODS: We systematically identified surveys, reports, and published studies (n=1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n=19,244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs).
FINDINGS: Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m(2) or greater increased between 1980 and 2013 from 28·8% (95% UI 28·4-29·3) to 36·9% (36·3-37·4) in men, and from 29·8% (29·3-30·2) to 38·0% (37·5-38·5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23·8% (22·9-24·7) of boys and 22·6% (21·7-23·6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8·1% (7·7-8·6) to 12·9% (12·3-13·5) in 2013 for boys and from 8·4% (8·1-8·8) to 13·4% (13·0-13·9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down.
INTERPRETATION: Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene.
FUNDING: Bill & Melinda Gates Foundation.
PMID: 24880830 [PubMed - indexed for MEDLINE]
Clinical profile and prognostic value of anemia at the time of admission and discharge among patients hospitalized for heart failure with reduced ejection fraction: findings from the EVEREST trial.
Circ Heart Fail. 2014 May;7(3):401-8
Authors: Mentz RJ, Greene SJ, Ambrosy AP, Vaduganathan M, Subacius HP, Swedberg K, Maggioni AP, Nodari S, Ponikowski P, Anker SD, Butler J, Gheorghiade M
BACKGROUND: Anemia has been associated with worse outcomes in patients with chronic heart failure (HF). We aimed to characterize the clinical profile and postdischarge outcomes of hospitalized HF patients with anemia at admission or discharge.
METHODS AND RESULTS: An analysis was performed on 3731 (90%) of 4133 hospitalized HF patients with ejection fraction ≤40% enrolled in the Efficacy of Vasopressin Antagonist in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial with baseline hemoglobin data, comparing the clinical characteristics and outcomes (all-cause mortality and cardiovascular mortality or HF hospitalization) of patients with and without anemia (hemoglobin <12 g/dL for women and <13 g/dL for men) on admission or discharge/day 7. Overall, 1277 patients (34%) were anemic at baseline, which persisted through discharge in 73% and resolved in 27%; 6% of patients without baseline anemia developed anemia by discharge or day 7. Patients with anemia were older, with lower blood pressure, and higher creatinine and natriuretic peptide levels compared with those without anemia (all P<0.05). After risk adjustment, anemia at discharge, but not admission, was independently associated with increased all-cause mortality (hazard ratio, 1.30; 95% confidence interval, 1.05-1.60; P=0.015; and hazard ratio, 0.94; 95% confidence interval, 0.76-1.15; P=0.53, respectively) and cardiovascular mortality plus HF hospitalization early postdischarge (≤100 days; hazard ratio 1.73; 95% confidence interval, 1.37-2.18; P<0.001; and hazard ratio, 0.92; 95% confidence interval, 0.73-1.16; P=0.47, respectively). Neither baseline nor discharge anemia was associated with long-term cardiovascular mortality plus HF hospitalization (>100 days) on adjusted analysis (both P>0.1).
CONCLUSIONS: Among hospitalized HF patients with reduced ejection fraction, modest anemia at discharge but not baseline was associated with increased all-cause mortality and short-term cardiovascular mortality plus HF hospitalization.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00071331.
PMID: 24737459 [PubMed - indexed for MEDLINE]
CD81 and hepatitis C virus (HCV) infection.
Viruses. 2014 Feb;6(2):535-72
Authors: Fénéant L, Levy S, Cocquerel L
Hepatitis C Virus (HCV) infection is a global public health problem affecting over 160 million individuals worldwide. Its symptoms include chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV is an enveloped RNA virus mainly targeting liver cells and for which the initiation of infection occurs through a complex multistep process involving a series of specific cellular entry factors. This process is likely mediated through the formation of a tightly orchestrated complex of HCV entry factors at the plasma membrane. Among HCV entry factors, the tetraspanin CD81 is one of the best characterized and it is undoubtedly a key player in the HCV lifecycle. In this review, we detail the current knowledge on the involvement of CD81 in the HCV lifecycle, as well as in the immune response to HCV infection.
PMID: 24509809 [PubMed - indexed for MEDLINE]
Trends in pharmacotherapy in patients referred to a bipolar specialty clinic, 2000-2011.
J Affect Disord. 2014 Feb;155:283-7
Authors: Hooshmand F, Miller S, Dore J, Wang PW, Hill SJ, Portillo N, Ketter TA
OBJECTIVE: To assess mood stabilizer (MS) and second-generation antipsychotic (SGA) prescribing trends in bipolar disorder (BD) outpatients referred to a bipolar disorder specialty clinic over the past 12 years.
METHOD: BD outpatients referred to the Stanford University Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prescription rates for MSs and SGAs were compared during the first (2000-2005) and second (2006-2011) six years.
RESULTS: Among 597 BD patients (mean±SD age 35.4±8.6 years; 58.1% female; 40.7% Type I, 43.6% Type II, and 15.7% Type Not Otherwise Specified; taking 2.6±1.7 prescription psychotropic medications), lamotrigine, quetiapine, and aripiprazole usage more than doubled, from 14.7% to 37.2% (p<0.0001), 7.2% to 19.7% (p<0.0001), and 3.1% to 10.9% (p=0.0003), respectively, while olanzapine and risperidone use decreased by more than half from 15.0% to 6.6% (p=0.0043), and from 8.7% to 3.8% (p=0.039), respectively. SGA use increased from 34.1% to 44.8% (p=0.013), although MS use continued to be more common (in 65.2% for 2006-2011). Use of other individual MSs and SGAs and MSs as a class did not change significantly.
CONCLUSIONS: Over 12 years, in patients referred to a BD specialty clinic, lamotrigine, quetiapine, and aripiprazole use more than doubled, and olanzapine and risperidone use decreased by more than half. Tolerability (for lamotrigine, aripiprazole, olanzapine, and risperidone) more than efficacy (for quetiapine) differences may have driven these findings. Additional studies are needed to explore the relative influences of enhanced tolerability versus efficacy upon prescribing practices in BD patients.
PMID: 24314912 [PubMed - indexed for MEDLINE]
Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls.
Bipolar Disord. 2014 Feb;16(1):37-47
Authors: Reynolds-May MF, Kenna HA, Marsh W, Stemmle PG, Wang P, Ketter TA, Rasgon NL
OBJECTIVES: The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.
METHODS: Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.
RESULTS: Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.
CONCLUSIONS: Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.
PMID: 24262071 [PubMed - indexed for MEDLINE]
Clinical assessment of lurasidone benefit and risk in the treatment of bipolar I depression using number needed to treat, number needed to harm, and likelihood to be helped or harmed.
J Affect Disord. 2014 Feb;155:20-7
Authors: Citrome L, Ketter TA, Cucchiaro J, Loebel A
BACKGROUND: Prior to recent FDA approval of lurasidone for treatment of bipolar depression there were only two approved treatments for this condition (quetiapine and olanzapine-fluoxetine combination), and these were as likely to provide therapeutic benefit as adverse effects. We assessed the efficacy, safety, and tolerability of lurasidone for major depressive episodes associated with bipolar I disorder, using number needed to treat (NNT, for benefits), number needed to harm (NNH, for harms), and likelihood of being helped or harmed (LHH, ratio of NNH to NNT, for trade-offs between benefits vs. harms).
METHODS: Data was collected from two 6-week multicenter, randomized, double-blind, placebo-controlled, flexibly-dosed acute bipolar I depression studies, one using lurasidone monotherapy at 20-60mg/d or 80-120mg/d, and the other using lurasidone 20-120mg/d adjunctive to lithium or valproate. The NNT or NNH was calculated for lurasidone vs. placebo for the following dichotomous outcomes: response (≥50% reduction from baseline on Montgomery Asberg Depression Rating Scale (MADRS) total score); remission (final MADRS total score ≤12); discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; and incidence of total cholesterol ≥240mg/dl, low-density lipoprotein cholesterol ≥160mg/dl, fasting triglycerides ≥200mg/dl and glucose ≥126mg/dl post-baseline.
RESULTS: NNT vs. placebo for response was 5 for lurasidone monotherapy (both dose ranges) and 7 for adjunctive therapy. NNT vs. placebo for remission for lurasidone monotherapy was 6 for 20-60mg/d and 7 for 80-120mg/d and 7 for adjunctive lurasidone. NNH vs. placebo for discontinuation due to an AE for lurasidone monotherapy was 642 for 20-60mg/d and -181 for 80-120mg/d, and for adjunctive lurasidone was -54 (negative NNH denotes an advantage for lurasidone). Lurasidone was not associated with any clinically meaningful mean weight or metabolic changes compared to placebo; NNH vs. placebo for weight gain ≥7% was 29 for 20-60mg/d and 5550 for 80-120mg/d and 42 for adjunctive lurasidone. The three most frequently occurring AEs with the largest difference in incidence for lurasidone vs. placebo were nausea, akathisia, and somnolence, with NNH values for lurasidone vs. placebo ranging from 11 (nausea with lurasidone monotherapy 80-120mg/d) to 130 (somnolence with lurasidone monotherapy 20-60mg/d). LHH was substantially and consistently >1 (indicating benefit being more likely than harm) when contrasting response or remission vs. AEs or weight gain.
LIMITATIONS: Additional studies, including longer-term and open-label, "real world" data is needed to confirm the results reported here.
CONCLUSIONS: NNT, NNH, and LHH help quantify relative benefits (efficacy) and harms (side effects), thus placing lurasidone findings in research studies into clinical perspective. Lurasidone, compared to other treatments approved for bipolar depression, yielded comparable benefits (all had single-digit NNT vs. placebo for response or remission), and less risk of harm (double-digit or greater NNHs with lurasidone compared to single-digit NNHs for sedation with quetiapine and for ≥7% weight gain with olanzapine-fluoxetine combination), and thus a substantially more favorable LHH (> or >>1) with lurasidone monotherapy and adjunctive therapy, compared to quetiapine and olanzapine-fluoxetine combination (LHH<or ~1).
PMID: 24246116 [PubMed - indexed for MEDLINE]
Dynamic recognition of the mRNA cap by Saccharomyces cerevisiae eIF4E.
Structure. 2013 Dec 3;21(12):2197-207
Authors: O'Leary SE, Petrov A, Chen J, Puglisi JD
Recognition of the mRNA 5' m⁷G(5')ppp(5')N cap is key to translation initiation for most eukaryotic mRNAs. The cap is bound by the eIF4F complex, consisting of a cap-binding protein (eIF4E), a "scaffold" protein (eIF4G), and an RNA helicase (eIF4A). As a central early step in initiation, regulation of eIF4F is crucial for cellular viability. Although the structure and function of eIF4E have been defined, a dynamic mechanistic picture of its activity at the molecular level in the eIF4F·mRNA complex is still unavailable. Here, using single-molecule fluorescence, we measured the effects of Saccharomyces cerevisiae eIF4F factors, mRNA secondary structure, and the poly(A)-binding protein Pab1p on eIF4E-mRNA binding dynamics. Our data provide an integrated picture of how eIF4G and mRNA structure modulate eIF4E-mRNA interaction, and uncover an eIF4G- and poly(A)-independent activity of poly(A)-binding protein that prolongs the eIF4E·mRNA complex lifetime.
PMID: 24183571 [PubMed - indexed for MEDLINE]
Costimulation-adhesion blockade is superior to cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation.
Stem Cells. 2013 Nov;31(11):2354-63
Authors: Huber BC, Ransohoff JD, Ransohoff KJ, Riegler J, Ebert A, Kodo K, Gong Y, Sanchez-Freire V, Dey D, Kooreman NG, Diecke S, Zhang WY, Odegaard J, Hu S, Gold JD, Robbins RC, Wu JC
RATIONALE: Human embryonic stem cell (hESC) derivatives are attractive candidates for therapeutic use. The engraftment and survival of hESC derivatives as xenografts or allografts require effective immunosuppression to prevent immune cell infiltration and graft destruction.
OBJECTIVE: To test the hypothesis that a short-course, dual-agent regimen of two costimulation-adhesion blockade agents can induce better engraftment of hESC derivatives compared to current immunosuppressive agents.
METHODS AND RESULTS: We transduced hESCs with a double fusion reporter gene construct expressing firefly luciferase (Fluc) and enhanced green fluorescent protein, and differentiated these cells to endothelial cells (hESC-ECs). Reporter gene expression enabled longitudinal assessment of cell engraftment by bioluminescence imaging. Costimulation-adhesion therapy resulted in superior hESC-EC and mouse EC engraftment compared to cyclosporine therapy in a hind limb model. Costimulation-adhesion therapy also promoted robust hESC-EC and hESC-derived cardiomyocyte survival in an ischemic myocardial injury model. Improved hESC-EC engraftment had a cardioprotective effect after myocardial injury, as assessed by magnetic resonance imaging. Mechanistically, costimulation-adhesion therapy is associated with systemic and intragraft upregulation of T-cell immunoglobulin and mucin domain 3 (TIM3) and a reduced proinflammatory cytokine profile.
CONCLUSIONS: Costimulation-adhesion therapy is a superior alternative to current clinical immunosuppressive strategies for preventing the post-transplant rejection of hESC derivatives. By extending the window for cellular engraftment, costimulation-adhesion therapy enhances functional preservation following ischemic injury. This regimen may function through a TIM3-dependent mechanism.
PMID: 24038578 [PubMed - indexed for MEDLINE]
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