tbuckley/cabot-search huggingface dataset:
Functional Genomic Annotation of Genetic Risk Loci Highlights Inflammation and Epithelial Biology Networks in CKD
Authors: Nora Ledo, Yi-An Ko, Ae-Seo Deok Park, Hyun-Mi Kang, Sang-Youb Han, Peter Choi, Katalin Susztak
Journal: Journal of the American Society of Nephrology (2014)

Genome-wide association studies (GWASs) have identified multiple loci associated with the risk of CKD. Almost all risk variants are localized to the noncoding region of the genome; therefore, the role of these variants in CKD development is largely unknown. We hypothesized that polymorphisms alter transcription factor binding, thereby influencing the expression of nearby genes. Here, we examined the regulation of transcripts in the vicinity of CKD-associated polymorphisms in control and diseased human kidney samples and used systems biology approaches to identify potentially causal genes for prioritization. We interrogated the expression and regulation of 226 transcripts in the vicinity of 44 single nucleotide polymorphisms using RNA sequencing and gene expression arrays from 95 microdissected control and diseased tubule samples and 51 glomerular samples. Gene expression analysis from 41 tubule samples served for external validation. 92 transcripts in the tubule compartment and 34 transcripts in glomeruli showed statistically significant correlation with eGFR. Many novel genes, including ACSM2A/2B, FAM47E, and PLXDC1, were identified. We observed that the expression of multiple genes in the vicinity of any single CKD risk allele correlated with renal function, potentially indicating that genetic variants influence multiple transcripts. Network analysis of GFR-correlating transcripts highlighted two major clusters; a positive correlation with epithelial and vascular functions and an inverse correlation with inflammatory gene cluster. In summary, our functional genomics analysis highlighted novel genes and critical pathways associated with kidney function for future analysis.
Inducible Co-Stimulatory Molecule Ligand Is Protective during the Induction and Effector Phases of Crescentic Glomerulonephritis
Authors: Dragana Odobasic, A. Richard Kitching, Timothy J. Semple, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2006)

The inducible co-stimulatory molecule (ICOS)/ICOS ligand (ICOSL) co-stimulatory pathway is critical in T cell activation, differentiation, and effector function. Its role was investigated in a model of Th1-driven crescentic glomerulonephritis (GN). GN was induced by sensitizing mice to sheep globulin (day 0) and challenging them with sheep anti-mouse glomerular basement membrane antibody (Ab; day 10). Disease and immune responses were assessed on day 20. For testing the role of ICOSL in the induction of GN, control or anti-ICOSL mAb were administered from days 0 to 8. For examining the role of ICOSL in the effector phase of GN, treatment lasted from days 10 to 18. Blockade of ICOSL during the induction of GN increased glomerular accumulation of CD4+ T cells and macrophages and augmented renal injury. These results correlated with attenuated splenocyte production of protective Th2 cytokines IL-4 and IL-10 and decreased apoptosis of splenic CD4+ T cells. ICOSL was upregulated within glomeruli of mice with GN. Inhibition of ICOSL during the effector phase of GN enhanced glomerular T cell and macrophage accumulation and augmented disease, without affecting the systemic immune response (cytokine production, T cell apoptosis/proliferation, Ab levels). Increased presence of leukocytes in glomeruli of mice that received anti-ICOSL mAb was associated with enhanced cellular proliferation and upregulation of P-selectin and intercellular adhesion molecule-1 within glomeruli. These studies demonstrate that ICOSL is protective during the induction of GN by augmenting Th2 responses and CD4+ T cell apoptosis. They also show that ICOSL is upregulated in nephritic glomeruli, where it locally reduces accumulation of T cells and macrophages and attenuates renal injury.
The Natural History of the Systemic Inflammatory Response Syndrome (SIRS)
Authors: M. Sigfrido Rangel-Frausto, Didier Pittet, Michele Costigan, Taekyu Hwang, Charles S. Davis, Richard P. Wenzel
Journal: JAMA (1995)

Define the epidemiology of the four recently classified syndromes describing the biologic response to infection: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock.Prospective cohort study with a follow-up of 28 days or until discharge if earlier.Three intensive care units and three general wards in a tertiary health care institution.Patients were included if they met at least two of the criteria for SIRS: fever or hypothermia, tachycardia, tachypnea, or abnormal white blood cell count.Development of any stage of the biologic response to infection: sepsis, severe sepsis, septic shock, end-organ dysfunction, and death.During the study period 3708 patients were admitted to the survey units, and 2527 (68%) met the criteria for SIRS. The incidence density rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857, 804, and 542 episodes per 1000 patient-days, respectively, and 671, 495, and 320 per 1000 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 649 (26%) developed sepsis, 467 (18%) developed severe sepsis, and 110 (4%) developed septic shock. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria (two, three, or all four) that the patients met. As the population of patients progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS, sepsis, severe sepsis, and septic shock: 7%, 16%, 20%, and 46%, respectively. Of interest, we also observed equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations.This prospective epidemiologic study of SIRS and related conditions provides, to our knowledge, the first evidence of a clinical progression from SIRS to sepsis to severe sepsis and septic shock.
Disease progression in patients with thin cutaneous melanomas
Authors: N. Nicolaou, A. Morris, R. Motley
Journal: British Journal of Dermatology (2004)

Sir, We read with great interest the paper by Schmid‐Wendtner et al.1 regarding disease progression in patients with thin cutaneous melanomas. In this paper thorough follow‐up and skin examination was recommended in a subgroup of patients with thin tumours: male patients with lentigo maligna melanoma or acrolentigenous melanoma located in the head and neck region. We were surprised that when the histological findings were reviewed there was no mention of any assessment of histological regression in the primary melanomas. In a study by Guitart et al.2 examining the histological characteristics of metastasizing thin melanomas, those with extensive regression represented a group at higher risk for the development of metastases. The poorer prognosis of thin melanomas associated with histological regression has been shown in other studies.3–5 Histological regression is a potential confounding variable and we would be most interested to ascertain whether the authors have considered evidence of histological regression to be an important prognostic factor in their study.
Total IgE Level is Associated with Anti-Ascaris Specific IgE but not with Stool Parasites or Blood Eosinophilia in Young Allergic Patients in a Tropical Region (Recife - Brazil)
Authors: D. Medeiros, A.R. Silva, J.A. Rizzo, M.E. Motta, E. Sarinho
Journal: Journal of Allergy and Clinical Immunology (2006)
Symptomatic Hyponatremia During Treatment of Dehydrating Diarrheal Disease With Reduced Osmolarity Oral Rehydration Solution
Authors: Nur H. Alam, Mohammed Yunus, Abu S. G. Faruque, Niklaus Gyr, Samima Sattar, Shahanaz Parvin, Jamal U. Ahmed, Mohammed A. Salam, David A. Sack
Journal: JAMA (2006)

Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recommended the use of a single formulation (sodium, 90 mEq/L; potassium, 20 mEq/L; chloride, 98 mEq/L; citrate, 290 mg/dL; glucose, 2000 mg/dL [111 mmol/L]; and osmolarity, 311 mOsm/L) of oral rehydration solution (ORS) for prevention and treatment of dehydration from diarrheal diseases due to any cause, including cholera, irrespective of patient's age. 1 The use of this ORS contributed to the dramatic global reduction in deaths from diarrheal diseases since that time. 2 The main limitation of this ORS, however, is that it neither reduces stool volume nor diarrhea duration, 3 2 factors that are considered important for its acceptance by mothers and health care workers.There has also been concern that the solution, which
Differential cytology of bronchoalveolar lavage fluid in normal children
Authors: F Ratjen, M Bredendiek, M Brendel, J Meltzer, U Costabel
Journal: European Respiratory Journal (1994)

Bronchoalveolar lavage (BAL) is increasingly used in the assessment of pulmonary diseases in children. However, reference values for cellular and non-cellular constituents of BAL fluid in children are lacking. We have studied the differential cytology of BAL fluid in 48 children aged 3-16 years (mean age +/- SD 7.9 +/- 3.5 yrs) undergoing elective surgery for nonpulmonary illnesses. A flexible bronchoscope (Pentax 3.5 or 4.9 mm) was wedged in the middle lobe or one of its segments. BAL was performed with 3x1 ml-kg-1 body weight of normal saline warmed to body temperature. The first sample was studied separately; subsequent samples were pooled for analysis. The mean recovery was 58 +/- 15%. Significantly more granulocytes and less lymphocytes were found in the first, as compared to the pooled, sample. Total cell counts were highly variable and ranged from 0.5-57.1 x 10(4) ml-1. Macrophages were the predominant cell type, with a mean percentage of 81.2 +/- 12.7%. The relative proportion of lymphocytes was higher than that reported in most studies of adult volunteers (16.1 +/- 2.4%). No age dependency was observed for either cell type. The mean percentage of granulocytes was 2.5 +/- 3.3%. Absolute granulocyte counts were significantly higher in children under 8 yrs of age. This study provides the first reference data on BAL differential cytology in children without pulmonary disease and will be the basis for future investigations of BAL in paediatric lung diseases.
Recent developments in treatments targeting castration-resistant prostate cancer bone metastases
Authors: Y. Loriot, C. Massard, K. Fizazi
Journal: Annals of Oncology (2012)

Prostate cancer is the most common male cancer and one of the top causes of male cancer-related death. Most patients with prostate cancer respond to initial androgen deprivation therapy before progressing to castration-resistant prostate cancer (CRPC) and eventually developing bone metastases. Growth of prostate cancer metastases in the bone microenvironment produces numerous factors that disrupt the dynamic equilibrium of osteogenesis and osteolysis existing in healthy bone, leading to progressive morbidity, poor quality of life, and increased treatment costs.
Yersinia pestis and the Plague of Justinian 541–543 AD: a genomic analysis
Authors: David M Wagner, Jennifer Klunk, Michaela Harbeck, Alison Devault, Nicholas Waglechner, Jason W Sahl, Jacob Enk, Dawn N Birdsell, Melanie Kuch, Candice Lumibao, Debi Poinar, Talima Pearson, Mathieu Fourment, Brian Golding, Julia M Riehm, David J D Earn, Sharon DeWitte, Jean-Marie Rouillard, Gisela Grupe, Ingrid Wiechmann, James B Bliska, Paul S Keim, Holger C Scholz, Edward C Holmes, Hendrik Poinar
Journal: The Lancet Infectious Diseases (2014)
Effects of Caffeine on Intermittent Hypoxia in Infants Born Prematurely
Authors: Lawrence M. Rhein, Nicole R. Dobson, Robert A. Darnall, Michael J. Corwin, Tim C. Heeren, Christian F. Poets, Betty L. McEntire, Carl E. Hunt, Henrietta Bada, Wally Carlo, Larry Consenstein, Mary Lucia Gregory, Karen Hendricks-Munoz, Deborah Hoy, Nilima Karamchandani, Judith M. Klarr, Praveen Kumar, Corinne L. Leach, Joan Richardson, Ted S. Rosenkrantz, Robert D. White
Journal: JAMA Pediatrics (2014)

Preterm infants have immature respiratory control and resulting intermittent hypoxia (IH). The extent of IH after stopping routine caffeine treatment and the potential for reducing IH with extended caffeine treatment are unknown.To determine (1) the frequency of IH in premature infants after discontinuation of routine caffeine treatment and (2) whether extending caffeine treatment to 40 weeks' postmenstrual age (PMA) reduces IH.A prospective randomized clinical study was conducted at 16 neonatal intensive care units in the United States, with an 18-month enrollment period. Preterm infants (<32 weeks' gestation) previously treated with caffeine were randomized to extended caffeine treatment or usual care (controls) at a PMA of at least 34 weeks but less than 37 weeks. Continuous pulse oximeter recordings were obtained through 40 weeks' PMA. Oximeter data were analyzed by persons masked to patient group.Continued treatment with caffeine.Number of IH events and seconds with less than 90% hemoglobin oxygen saturation (Sao2) per hour of recording.Our analysis included 95 preterm infants. In control infants, the mean (SD) time at less than 90% Sao2 at 35 and 36 weeks' PMA was 106.3 (89.0) and 100.1 (114.6) s/h, respectively. The number of IH events decreased significantly from 35 to 39 weeks' PMA (P = .01). Extended caffeine treatment reduced the mean time at less than 90% Sao2 by 47% (95% CI, -65% to -20%) to 50.9 (48.1) s/h at 35 weeks and by 45% (95% CI, -74% to -17%) to 49.5 (52.1) s/h at 36 weeks.Substantial IH persists after discontinuation of routine caffeine treatment and progressively decreases with increasing PMA. Extended caffeine treatment decreases IH in premature infants.clinicaltrials.gov Identifier: NCT01875159.
Apolipoprotein E (ApoE), a novel heparin-binding protein inhibits the development of Kaposi's sarcoma-like lesions in BALB/c nu/nu mice.
Authors: P J Browning, D D Roberts, V Zabrenetzky, J Bryant, M Kaplan, R H Washington, A Panet, R C Gallo, T Vogel
Journal: The Journal of Experimental Medicine (1994)

Recombinant apolipoprotein E-3 (ApoE-3), expressed in Escherichia coli, was purified and used in an in vitro and an in vivo model system for acquired immunodeficiency syndrome-associated Kaposi's sarcoma (AIDS-KS). This protein blocked cell proliferation and chemotaxis of AIDS-KS cells in response to activated lymphocyte conditioned medium (AL-CM) and oncostatin M (OSM). ApoE-3 also inhibited the formation of neoangiogenic lesions induced in BALB/c nu/nu mice by AIDS-KS cells. These findings represent a novel and potentially less toxic therapeutic approach for the treatment of AIDS-KS.
Dysregulation in level of goal and action identification across psychological disorders
Authors: Edward Watkins
Journal: Clinical Psychology Review (2010)

Goals, events, and actions can be mentally represented within a hierarchical framework that ranges from more abstract to more concrete levels of identification. A more abstract level of identification involves general, superordinate, and decontextualized mental representations that convey the meaning of goals, events, and actions, "why" an action is performed, and its purpose, ends, and consequences. A more concrete level of identification involves specific and subordinate mental representations that include contextual details of goals, events, and actions, and the specific "how" details of an action. This review considers three lines of evidence for considering that dysregulation of level of goal/action identification may be a transdiagnostic process. First, there is evidence that different levels of identification have distinct functional consequences and that in non-clinical samples level of goal/action identification appears to be regulated in a flexible and adaptive way to match the level of goal/action identification to circumstances. Second, there is evidence that level of goal/action identification causally influences symptoms and processes involved in psychological disorders, including emotional response, repetitive thought, impulsivity, problem solving and procrastination. Third, there is evidence that the level of goal/action identification is biased and/or dysregulated in certain psychological disorders, with a bias towards more abstract identification for negative events in depression, GAD, PTSD, and social anxiety.
BUBR1 deficiency results in abnormal megakaryopoiesis
Authors: Qi Wang, Tongyi Liu, Yuqiang Fang, Suqing Xie, Xuan Huang, Radma Mahmood, Gita Ramaswamy, Kathleen M Sakamoto, Zbigniew Darzynkiewicz, Ming Xu, Wei Dai
Journal: Blood (2003)
Process versus outcome in hypertension: a positive result.
Authors: R B Haynes, E S Gibson, D W Taylor, C D Bernholz, D L Sackett
Journal: Circulation (1982)

We studied the association between the outcome of antihypertensive care and three items of that care among 230 hypertensive steelworkers who were referred to 83 physicians. The first item was the decision to treat some patients but not others: 63% of the patients were prescribed antihypertensive drugs and the mean decrease in their diastolic blood pressure (DBP) was greater than that among untreated patients (12.2 +/- 0.84 vs 7.8 +/- 0.83 mm Hg [+/- SEM], p less than 0.001). The second item was the vigor of prescribed medication: Patients prescribed more vigorous treatments had lower DBP (p less than 0.005). Third, patient compliance was related to achieving a goal DBP of less than 90 mm Hg (p less than 0.05) and the product of prescribed vigor and compliance was highly associated with DBP response (p less than 0.0001). These results stand in contrast to those of previous studies that failed to detect associations between various other items of the care process and the outcome of antihypertensive care.
Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment
Authors: Zhihong Zeng, Yue Xi Shi, Twee Tsao, YiHua Qiu, Steven M. Kornblau, Keith A. Baggerly, Wenbin Liu, Katti Jessen, Yi Liu, Hagop Kantarjian, Christian Rommel, David A. Fruman, Michael Andreeff, Marina Konopleva
Journal: Blood (2012)
Abstract P095: Preterm Delivery and Incident Metabolic Syndrome: A 25-year Prospective Study of CARDIA Women
Authors: Janet M Catov, Andrew Althouse, Cora Lewis, Upasna Goswami, Emily Harville, Erica Gunderson
Journal: Circulation (2014)

Introduction: Women who deliver preterm births have excess risk for cardiovascular disease and diabetes later in life, perhaps related to metabolic dysregulation. Previous studies, however, have not evaluated how the pre-pregnancy metabolic status, other pregnancy characteristics and post pregnancy weight gain may be involved. Hypothesis: We hypothesized that women who delivered preterm births would have excess risk of incident metabolic syndrome (MetS) compared to women with term births independent of their pre-pregnancy metabolic profile, parity and other risk factors. Methods: We studied 1,246 women (50% Black; 624 of 1,246) in the Coronary Artery Risk Development in Young Adults (CARDIA study) who had at least one singleton birth between baseline (1985-1986) and year 25, and no MetS before pregnancy. Blood pressure, lipids, and anthropometrics were measured at baseline and at up to 7 subsequent exams. We ascertained incident MetS cases using the National Cholesterol Education Program Adult Treatment Panel III criteria and estimated the relative hazards (RH) of MetS in women with 1 or more preterm births (&lt;37 weeks, n=306) versus 1 (n=558) and 2 or more (n=382) term births (≥37 weeks) using complementary log-log models adjusted for race, age, education, smoking, time-varying parity and pre-pregnancy metabolic syndrome components. Gestational diabetes mellitus (GDM), self-reported hypertension during pregnancy, and time dependent weight gain were considered as potential mediators. Results: Of 338 incident MetS cases in 17,212 person years, the crude incidence rate among women with preterm birth was higher than among those with 1, but not 2 or more term births (24.2, 14.4, and 32.2, respectively). After adjustment for covariates, however, including time-varying parity, the adjusted RH (95%CI) for incident MetS was 1.89 (1.24, 2.89) for women with preterm vs. term births. Additional adjustment for GDM or hypertension during pregnancy only modestly affected this estimate, but accounting for time-varying weight gain attenuated it to be non-significant (adj HR 1.42 (0.92, 2.21). Increased waist circumference (18.1 ± 12.3 vs. 15.9 ± 11.9 cm, p&lt;0.01) and increased systolic blood pressure (13.6 ± 18.3 vs. 6.6 ± 12.5 mmHg, p&lt;0.01) were the MetS components that changed the most from baseline to year 25 among women with preterm vs. term births. Conclusions: In conclusion, women with a history of preterm birth have an almost two-fold increased risk of incident MetS compared to those with term births after 25 years of follow up. This was independent of the pre-pregnancy metabolic status, other complications and time dependent parity. It was explained, in part, by post pregnancy weight gain.
Role of Ca <sub>V</sub> β Subunits, and Lack of Functional Reserve, in Protein Kinase A Modulation of Cardiac Ca <sub>V</sub> 1.2 Channels
Authors: Jayalakshmi Miriyala, Trang Nguyen, David T. Yue, Henry M. Colecraft
Journal: Circulation Research (2008)

Protein kinase A (PKA)-mediated enhancement of L-type calcium currents (I(Ca,L)) is essential for sympathetic regulation of the heartbeat and is the classic example of channel regulation by phosphorylation, and its loss is a common hallmark of heart failure. Mechanistic understanding of how distinct Ca(V) channel subunits contribute to PKA modulation of I(Ca,L) has been intensely pursued yet remains elusive. Moreover, critical features of this regulation such as its functional reserve (the surplus capacity available for modulation) in the heart are unknown. Here, we use an overexpression paradigm in heart cells to simultaneously identify the impact of auxiliary Ca(V)betas on PKA modulation of I(Ca,L) and to gauge the functional reserve of this regulation in the heart. Ca(V)1.2 channels containing wild-type beta(2a) or a phosphorylation-deficient mutant (beta(2a,AAA)) were equally upregulated by PKA, discounting a necessary role for beta phosphorylation. Nevertheless, channels reconstituted with beta(2a) displayed a significantly diminished PKA response compared with other beta isoforms, an effect explainable by a uniquely higher basal P(o) of beta(2a) channels. Overexpression of all betas increased basal current density, accompanied by a concomitant decrease in the magnitude of PKA regulation. Scatter plots of fold increase in current against basal current density revealed an inverse relationship that was conserved across species and conformed to a model in which a large fraction of channels remained unmodified after PKA activation. These results redefine the role of beta subunits in PKA modulation of Ca(V)1.2 channels and uncover a new design principle of this phenomenon in the heart, vis à vis a limited functional reserve.
MIP-1α level in nasopharyngeal aspirates at the first wheezing episode predicts recurrent wheezing
Authors: Kazuko Sugai, Hirokazu Kimura, Yumiko Miyaji, Hiroyuki Tsukagoshi, Masakazu Yoshizumi, Tomomi Sasaki-Sakamoto, Satoko Matsunaga, Yumi Yamada, Jun-ichi Kashiwakura, Masahiro Noda, Masanori Ikeda, Kunihisa Kozawa, Akihide Ryo, Shigemi Yoshihara, Hiromitsu Ogata, Yoshimichi Okayama
Journal: Journal of Allergy and Clinical Immunology (2015)