tbuckley/cabot-search huggingface dataset:
Omic personality: implications of stable transcript and methylation profiles for personalized medicine
Authors: Rubina Tabassum, Ambily Sivadas, Vartika Agrawal, Haozheng Tian, Dalia Arafat, Greg Gibson
Journal: Genome Medicine (2015)

Personalized medicine is predicated on the notion that individual biochemical and genomic profiles are relatively constant in times of good health and to some extent predictive of disease or therapeutic response. We report a pilot study quantifying gene expression and methylation profile consistency over time, addressing the reasons for individual uniqueness, and its relation to N = 1 phenotypes. Whole blood samples from four African American women, four Caucasian women, and four Caucasian men drawn from the Atlanta Center for Health Discovery and Well Being study at three successive 6-month intervals were profiled by RNA-Seq, miRNA-Seq, and Illumina Methylation 450 K arrays. Standard regression approaches were used to evaluate the proportion of variance for each type of omic measure among individuals, and to quantify correlations among measures and with clinical attributes related to wellness. Longitudinal omic profiles were in general highly consistent over time, with an average of 67 % variance in transcript abundance, 42 % in CpG methylation level (but 88 % for the most differentiated CpG per gene), and 50 % in miRNA abundance among individuals, which are all comparable to 74 % variance among individuals for 74 clinical traits. One third of the variance could be attributed to differential blood cell type abundance, which was also fairly stable over time, and a lesser amount to expression quantitative trait loci (eQTL) effects. Seven conserved axes of covariance that capture diverse aspects of immune function explained over half of the variance. These axes also explained a considerable proportion of individually extreme transcript abundance, namely approximately 100 genes that were significantly up-regulated or down-regulated in each person and were in some cases enriched for relevant gene activities that plausibly associate with clinical attributes. A similar fraction of genes had individually divergent methylation levels, but these did not overlap with the transcripts, and fewer than 20 % of genes had significantly correlated methylation and gene expression. People express an "omic personality" consisting of peripheral blood transcriptional and epigenetic profiles that are constant over the course of a year and reflect various types of immune activity. Baseline genomic profiles can provide a window into the molecular basis of traits that might be useful for explaining medical conditions or guiding personalized health decisions.
Response to Comment on “Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells”
Authors: Naohiro Egawa, Shiho Kitaoka, Kayoko Tsukita, Motoko Naitoh, Kazutoshi Takahashi, Takuya Yamamoto, Fumihiko Adachi, Takayuki Kondo, Keisuke Okita, Isao Asaka, Takashi Aoi, Akira Watanabe, Yasuhiro Yamada, Asuka Morizane, Jun Takahashi, Takashi Ayaki, Hidefumi Ito, Katsuhiro Yoshikawa, Satoko Yamawaki, Shigehiko Suzuki, Dai Watanabe, Hiroyuki Hioki, Takeshi Kaneko, Kouki Makioka, Koichi Okamoto, Hiroshi Takuma, Akira Tamaoka, Kazuko Hasegawa, Takashi Nonaka, Masato Hasegawa, Akihiro Kawata, Minoru Yoshida, Tatsutoshi Nakahata, Ryosuke Takahashi, Maria C. N. Marchetto, Fred H. Gage, Shinya Yamanaka, Haruhisa Inoue
Journal: Science Translational Medicine (2013)

Our work and the study of Bilican et al. highlight the need for complementary assays to detect subtle phenotypic differences between control and mutant induced pluripotent stem cell lines.
Regulation of Endothelial Matrix Metalloproteinase-2 by Hypoxia/Reoxygenation
Authors: Yaara Ben-Yosef, Nitza Lahat, Sarah Shapiro, Haim Bitterman, Ariel Miller
Journal: Circulation Research (2002)

Among the consequences resulting from the exposure of endothelial cells (ECs) to ischemia/reperfusion is angiogenesis, involving degradation of vascular basement membrane and extracellular matrix. Matrix metalloproteinase (MMP)-2, a member of the MMP family, partakes in this process. MMP-2, secreted as a proenzyme, undergoes activation through interaction with membrane type (MT)1-MMP and the endogenous tissue inhibitor of MMPs (TIMP)-2. Although hypoxia and reoxygenation (H/R) are major constituents of ischemia/reperfusion processes, their direct effects on endothelial MMP-2 have been scarcely investigated. This study examined the in vitro effects of H/R on human macrovascular ECs (EAhy 926). The level of MMP-2 mRNA (Northern blot) and protein (zymography, ELISA) and the mRNA of its activator (MT1-MMP) and inhibitor (TIMP-2) were analyzed. Short (6-hour) hypoxia inhibited the mRNA expression of MMP-2, MT1-MMP, and TIMP-2, culminating in reduced latent and active MMP-2 protein. Prolonged (24-hour) hypoxia further suppressed MT1-MMP and TIMP-2 mRNA, whereas it enhanced MMP-2 mRNA and enzyme secretion (after 48-hour hypoxia). Reoxygenation did not influence the inhibited TIMP-2 but upregulated MMP-2 and MT1-MMP mRNA expression, leading to enhanced secretion of active MMP-2 protein. These results demonstrate H/R-mediated modulation of EC MMP-2 at both transcriptional and posttranscriptional levels. Prolonged hypoxia of ECs appears to enhance MMP-2 production and secretion, whereas reoxygenation further increases its level. These H/R-mediated effects on MMPs have the potential of enabling EC migration and possible angiogenesis.
Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study) [see comments]
Authors: T Koster, FR Rosendaal, E Briet, FJ van der Meer, LP Colly, PH Trienekens, SR Poort, PH Reitsma, JP Vandenbroucke
Journal: Blood (1995)
Functional evaluation of the lung resection candidate
Authors: CT Bolliger, AP Perruchoud
Journal: European Respiratory Journal (1998)

Advances in operative technique and perioperative care have considerably reduced surgical morbidity and mortality after pulmonary resections. Various single and combined parameters of functional operability have been proposed to assess the surgical risk. Pulmonary function tests adequately assess the pulmonary risk, and baseline or stress electrocardiography, echocardiography and nuclear cardiac studies assess the cardiac risk. Patients with normal or only slightly impaired pulmonary function (forced expiratory volume in one second (FEV1) and transfer factor of the lung for carbon monoxide (TL,CO) &gt; or = 80% of predicted) and no cardiovascular risk factors can undergo pulmonary resections up to a pneumonectomy without further investigation. For others, exercise testing, pulmonary split-function studies, or a combination of these two methods are recommended. Exercise testing, most frequently performed as a symptom-limited test with the measurement of maximal oxygen uptake (V'O2,max), assesses both the pulmonary and cardiovascular reserves. A V'O2,max of &lt;10 mL.kg(-1).min(-1) is generally considered prohibitive for any resection, a value of &gt;20 mL.kg(-1).min(-1) or &gt;75% of predicted normal, safe for major resections. Split-function studies are radionuclide-based estimations of the predicted postoperative (ppo) values of various parameters. The currently used ppo-parameters are FEV1-ppo, TL,CO-ppo and, most recently, V'O2,max-ppo. Suggested cut-off values for safe resection are: for FEV1-ppo and TL,CO-ppo &gt; or = 40% pred; and for V'O2,max &gt; or = 35% pred, combined with an absolute value of &gt; or = 10 mL.kg(-1).min(-1). The lowest acceptable ppo-values will still have to be established by additional prospective studies. In the long-term, resections involving not more than one lobe usually lead to an early functional deficit followed by later recovery. The permanent functional loss in pulmonary function is small (&lt; or = 10%) and exercise capacity is only slightly reduced or not at all. Pneumonectomy, on the other hand, leads to an early permanent loss of about 33% in pulmonary function and 20% in exercise capacity. Thus, pulmonary function tests alone overestimate the functional loss after lung resection.
Mitochondrial Reprogramming Induced by CaMKIIδ Mediates Hypertrophy Decompensation
Authors: B. Daan Westenbrink, Haiyun Ling, Ajit S. Divakaruni, Charles B.B. Gray, Alexander C. Zambon, Nancy D. Dalton, Kirk L. Peterson, Yusu Gu, Scot J. Matkovich, Anne N. Murphy, Shigeki Miyamoto, Gerald W. Dorn, Joan Heller Brown
Journal: Circulation Research (2015)

Sustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca(2+)/calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation.To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq.Compared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion.Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.
The match day use of ultrasound during professional football finals matches
Authors: Phillip James, Tim Barbour, Ian Stone
Journal: British Journal of Sports Medicine (2010)

Objectives To describe the use of ultrasound by a professional Australian rules football team in the immediate pregame period to guide local anaesthetic injections, during game time to assess injuries and to guide local anaesthetic injections, and postmatch to assess injuries and to guide therapeutic injections. Methods The use of match day ultrasound was documented during four finals matches. Local anaesthetic injections were considered effective if players played without pain and experienced no complication from the injection. The results of the diagnostic scans were assessed against subsequent clinical progress and correlation with any follow-up imaging. Therapeutic injections were considered effective if there was clinical improvement and the player was able to play in subsequent weeks without restriction. Results Pregame, a total of 11 ultrasound guided local anaesthetic injections were performed on eight players, with a further local anaesthetic during a game. All injections achieved good pain relief without any complication. A single diagnostic scan on one player during a game showed no acute muscle tear, the player successfully completed the game. Postgame, a total of four ultrasound guided steroid injections were performed on three players and all players played in the next match. The injections achieved good therapeutic results. The therapeutic injections given immediately postgame, maximised the recovery period available to the players. Conclusions Ultrasound proved useful in guiding local anaesthetic before and during matches and also therapeutic injections after matches. Ultrasound had a limited role in the assessment of injuries during a game.
Reinstitutionalisation in mental health care: comparison of data on service provision from six European countries
Authors: Stefan Priebe, Alli Badesconyi, Angelo Fioritti, Lars Hansson, Reinhold Kilian, Francisco Torres-Gonzales, Trevor Turner, Durk Wiersma
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To establish whether reinstitutionalisation is occurring in mental health care and, if so, with what variations between western European countries. <b>Design</b> Comparison of data on changes in service provision. <b>Setting</b> Six European countries with different traditions of mental health care that have all experienced deinstitutionalisation since the 1970s—England, Germany, Italy, the Netherlands, Spain, and Sweden. <b>Outcome measures</b> Changes in the number of forensic hospital beds, involuntary hospital admissions, places in supported housing, general psychiatric hospital beds, and general prison population between 1990-1 and 2002-3. <b>Results</b> Forensic beds and places in supported housing have increased in all countries, whereas changes in involuntary hospital admissions have been inconsistent. The number of psychiatric hospital beds has been reduced in five countries, but only in two countries does this reduction outweigh the number of additional places in forensic institutions and supported housing. The general prison population has substantially increased in all countries. <b>Conclusions</b> Reinstitutionalisation is taking place in European countries with different traditions of health care, although with significant variation between the six countries studied. The precise reasons for the phenomenon remain unclear. General attitudes to risk containment in a society, as indicated by the size of the prison population, may be more important than changing morbidity and new methods of mental healthcare delivery.
Designing a Randomized Clinical Trial to Evaluate Personalized Medicine: A New Approach Based on Risk Prediction
Authors: S. G. Baker, D. J. Sargent
Journal: JNCI Journal of the National Cancer Institute (2010)

We define personalized medicine as the administration of treatment to only persons thought most likely to benefit, typically those at high risk for mortality or another detrimental outcome. To evaluate personalized medicine, we propose a new design for a randomized trial that makes efficient use of high-throughput data (such as gene expression microarrays) and clinical data (such as tumor stage) collected at baseline from all participants. Under this design for a randomized trial involving experimental and control arms with a survival outcome, investigators first estimate the risk of mortality in the control arm based on the high-throughput and clinical data. Then investigators use data from both randomization arms to estimate both the effect of treatment among all participants and among participants in the highest prespecified category of risk. This design requires only an 18.1% increase in sample size compared with a standard randomized trial. A trial based on this design that has a 90% power to detect a realistic increase in survival from 70% to 80% among all participants, would also have a 90% power to detect an increase in survival from 50% to 73% in the highest quintile of risk.
Surfer wipe out by predator fish
Authors: G M M J Kerkhoffs, J W op den Akker, E R Hammacher
Journal: British Journal of Sports Medicine (2003)

Needlefish injuries, commonly reported in the Indo-Pacific region, have not been previously reported along the European coastlines. This case report describes a penetrating injury to the heel of a professional surfer during competition off the Portuguese coast. Diagnostic as well as therapeutic recommendations are made.
The Miracle at St Alfege's: seventy years on
Authors: M. D O'Brien
Journal: Journal of the Royal Society of Medicine (2007)

Smith calls for a coordinated campaign to instigate change and asks who will take the lead. 4Among medical students, this position is being taken up by Medsin's Global Health Advocacy Project (www.medsin.org/ghap). 5 This student group, whose annual conference last month attracted some 400 student delegates and included Lancet editor Richard Horton as a guest lecturer, forms a strong body of internationally aware future health professionals.GHAP members at various medical schools are writing to their course lecturers and authors of popular undergraduate
Role of Nitric Oxide in the Renal Hemodynamic Response to Unilateral Nephrectomy
Authors: David H. Sigmon, Edgard Gonzalez-Feldman, Maria A. Cavasin, D’Anna L. Potter, William H. Beierwaltes
Journal: Journal of the American Society of Nephrology (2004)

Reduction of renal mass by unilateral nephrectomy results in an immediate increase in renal blood flow (RBF) to the remnant kidney, followed by compensatory renal hypertrophy. Whether the increase in RBF after unilateral nephrectomy is mediated by nitric oxide (NO) was tested. It was found that immediately after nephrectomy, blood flow to the remaining kidney increased by 8% (P < 0.01), and inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) blocked the increase in RBF. In addition, 2 d after nephrectomy, there was a 49% increase in RBF (corrected per gram of kidney weight), a 25% increase at 7 and 14 d, and a 16% increase after 28 d. Acute inhibition of NO synthesis with L-NAME in uninephrectomized rats caused a greater decrease in RBF on days 2 and 7 compared with controls, whereas by 14 and 28 d, the response to L-NAME was similar to controls. Urinary excretion of cyclic guanosine monophosphate, a marker for renal NO production, increased 2.5-fold by 2 d after uninephrectomy (P < 0.005) and remained at this level through 28 d. Pretreating rats chronically with a subpressor dose of L-NAME beginning 2 d before nephrectomy blocked the increase in RBF seen at 2 and 7 d and retarded the renal hypertrophy that should have developed by 7 d. It is concluded that after unilateral nephrectomy, immediate and sustained increases in RBF are mediated at least in part by NO. The hypertrophic response to unilateral nephrectomy may be partially initiated by the signal of hemodynamic changes.
Osteogenic protein-1 mRNA expression is selectively modulated after acute ischemic renal injury.
Authors: M M Almanzar, K S Frazier, P H Dube, A I Piqueras, W K Jones, M F Charette, A L Paredes
Journal: Journal of the American Society of Nephrology (1998)

Osteogenic protein-1 (OP-1) is a morphogenetic factor highly expressed in the kidney and involved in tissue repair and development. Homozygous OP-1-deficient mice die shortly after birth due mainly to arrest of renal growth and differentiation. Because postischemic injury involves several repair mechanisms, this study examined whether kidney OP-1 mRNA expression is modulated after ischemia. Acute ischemic renal injury was achieved in rats by unilateral clamping of the renal pedicle followed by reperfusion. Rats were killed at 3, 6, 12, 24, and 48 h and 7 d after reperfusion, and kidneys were microdissected and analyzed by histology and Northern and Western blots. Changes in OP-1 mRNA were determined by measuring the ratio of OP-1/glyceraldehyde 3-phosphate dehydrogenase signals for each OP-1 transcript (4.0 and 2.4 kb) from ischemic, opposite, and sham-operated rats. The OP-1 mRNA content for transcript 4.0 kb was fivefold lower in the whole ischemic kidney compared with that in sham animals 24 h after reperfusion. In the ischemic medulla, OP-1 mRNA was strikingly downregulated 20-fold when compared with the ischemic cortex. Results for transcript 2.4 kb and for the other time points were comparable. OP-1 mRNA expression was also affected in the opposite medulla compared with the sham medulla. However, only in the ischemic medulla was the relative OP-1 content significantly lower at all time points. Similar results were obtained when analyzing OP-1 protein by Western blot at 24 h after reperfusion. Seven days after reperfusion, the levels of OP-1 mRNA returned to baseline. In conclusion, kidney OP-1 mRNA and protein are selectively downregulated in the medulla after acute ischemic renal injury. OP-1 modulation may be a key element for kidney repair.
Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation
Authors: Scott R. Auerbach, Cedric Manlhiot, Sushma Reddy, Caroline Kinnear, Marc E. Richmond, Dorota Gruber, Brian W. McCrindle, Liyong Deng, Jonathan M. Chen, Linda J. Addonizio, Wendy K. Chung, Seema Mital
Journal: Journal of the American College of Cardiology (2009)
Environmental Genomics: A Tale of Two Fishes
Authors: G. Bucciarelli, M. Di Filippo, D. Costagliola, F. Alvarez-Valin, G. Bernardi, G. Bernardi
Journal: Molecular Biology and Evolution (2009)

The influence of the environment on two congeneric fishes, Gillichthys mirabilis and Gillichthys seta, that live in the Gulf of California at temperatures of 10-25 degrees C, and up to 42-44 degrees C, respectively, was addressed by analyzing their genomes. Compared with G. mirabilis, G. seta showed some striking features. Substitution rates in the mitochondrial genes were found to be extremely fast, in fact faster than in noncoding control regions (D-loops), from which a divergence time of less than 0.66-0.75 Mya could be estimated. In the nuclear genome, 1) both AT --> GC/GC --> AT and transversion: transition ratios in coding sequences (CDSs) were relatively high; moreover, the ratios of nonsynonymous/synonymous changes (Ka/Ks) suggested that some genes were under positive selection; 2) DNA methylation showed a very significant decrease; and 3) a GC-rich minisatellite underwent a 4-fold amplification in the gene-rich regions. All these observations clearly indicate that the environment (temperature and the accompanying hypoxia) can rapidly mold the nuclear as well as the mitochondrial genome. The stabilization of gene-rich regions by the amplification of the GC-rich minisatellite and by the GC increase in nuclear CDSs is of special interest because it provides a model for the formation of the GC-rich and gene-rich isochores of the genomes of mammals and birds.
A Community Mental Health Center Built Around a Private Practice
Authors: WINSTON COCHRAN
Journal: American Journal of Psychiatry (1969)

A group of Texas psychiatrists, working through a private, profit-making corporation, have been providing service to medically indigent patients by means of a contract arrangement since 1964; no federal funds are involved. During this period the group's private practice has increased substantially. The author believes the model he describes permits simultaneous pursuit of the goals of community service and fiscal success.