tbuckley/cabot-search huggingface dataset:
Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis.
Authors: B L Riggs, H W Wahner, W L Dunn, R B Mazess, K P Offord, L J Melton
Journal: Journal of Clinical Investigation (1981)

Patterns of bone loss in the axial and the appendicular skeleton were studied in 185 normal volunteers (105 women and 82 men; age range, 20--89 yr) and in 76 women and 9 men with vertebral fractures due to osteoporosis. Bone mineral density was measured in vivo at the lumbar spine (predominantly trabecular bone) by dual photon absorptiometry and at the midradius (greater than 95% cortical bone) and distal radius (75% cortical and 25% trabecular bone) by single photon absorptiometry. In normal women, bone diminution from the vertebrae began in young adulthood and was linear. In the appendicular skeleton, bone diminution did not occur until age 50 yr, was accelerated from aged 51 to 65 yr, and then decelerated somewhat after age 65 yr. Overall bone diminution throughout life was 47% for the vertebrae, 30% for the midradius, and 39% for the distal radius. In normal men, vertebral and appendicular bone diminution with aging was minimal or insignificant. Mean bone mineral density was lower in patients with osteoporosis than in age- and sex-matched normal subjects at all three scanning sites, although spinal measurements discriminated best; however, there was considerable overlap. By age 65 yr, half of the normal women (and by age 85 yr, virtually all of them) had vertebral bone mineral density values below the 90th percentile of women with vertebral fractures and, thus, might be considered to have asymptomatic osteoporosis. For men, the degree of overlap was less. The data suggest that disproportionate loss of trabecular bone from the axial skeleton is a distinguishing characteristic of spinal osteoporosis.
CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence
Authors: Emma J. Petrie, Craig S. Clements, Jie Lin, Lucy C. Sullivan, Darryl Johnson, Trevor Huyton, Annie Heroux, Hilary L. Hoare, Travis Beddoe, Hugh H. Reid, Matthew C.J. Wilce, Andrew G. Brooks, Jamie Rossjohn
Journal: The Journal of Experimental Medicine (2008)

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A-HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a "lock and key" interaction is typical of innate receptor-ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.
Metabolic Phenotype in the Brothers of Women with Polycystic Ovary Syndrome
Authors: Susan Sam, Andrea D. Coviello, Yeon-Ah Sung, Richard S. Legro, Andrea Dunaif
Journal: Diabetes Care (2008)

Hyperandrogenemia, insulin resistance, and dyslipidemia demonstrate familial aggregation in the female first-degree relatives of women with polycystic ovary syndrome (PCOS), suggesting that these defects are heritable. Hyperandrogenemia also appears to be the male reproductive phenotype. We performed this study to test the hypothesis that brothers of women with PCOS have metabolic defects similar to those of their proband sisters.This was a prospective case-control study performed at four academic medical centers in the U.S. Fasting blood was obtained from 196 non-Hispanic white brothers of women with PCOS and 169 control men of age, BMI, and ethnicity comparable to those of brothers. A separate analysis was performed by study site to assess potential regional variations in metabolic parameters.Overall, brothers of women with PCOS had significantly higher total (P = 0.001) and LDL cholesterol (P = 0.01) as well as triglyceride levels (P = 0.01) compared with control men, although there were regional variations in these differences. There were significant positive correlations between brothers and their sisters with PCOS for total (rho = 0.2, P = 0.009) and LDL cholesterol (rho = 0.3, P = 0.001) and triglyceride (rho = 0.2, P = 0.05) levels. Brothers also had significantly higher fasting insulin levels and homeostatic index of insulin resistance (P = 0.02 for both comparisons) compared with control men.Brothers of women with PCOS have dyslipidemia as well as evidence for insulin resistance similar to that of their proband sisters with PCOS. These findings are consistent with the hypothesis that some metabolic abnormalities in PCOS are heritable and are not sex specific.
The MYC–WDR5 Nexus and Cancer
Authors: Lance R. Thomas, Audra M. Foshage, April M. Weissmiller, William P. Tansey
Journal: Cancer Research (2015)

Abstract The MYC oncogenes encode a family of transcription factors that feature prominently in cancer. MYC proteins are overexpressed or deregulated in a majority of malignancies and drive tumorigenesis by inducing widespread transcriptional reprogramming that promotes cell proliferation, metabolism, and genomic instability. The ability of MYC to regulate transcription depends on its dimerization with MAX, which creates a DNA-binding domain that recognizes specific sequences in the regulatory elements of MYC target genes. Recently, we discovered that recognition of target genes by MYC also depends on its interaction with WDR5, a WD40-repeat protein that exists as part of several chromatin-regulatory complexes. Here, we discuss how interaction of MYC with WDR5 could create an avidity-based chromatin recognition mechanism that allows MYC to select its target genes in response to both genetic and epigenetic determinants. We rationalize how the MYC–WDR5 interaction provides plasticity in target gene selection by MYC and speculate on the biochemical and genomic contexts in which this interaction occurs. Finally, we discuss how properties of the MYC–WDR5 interface make it an attractive point for discovery of small-molecule inhibitors of MYC function in cancer cells. Cancer Res; 75(19); 4012–5. ©2015 AACR.
Skp2 Overexpression Is Highly Representative of Intrinsic Biological Aggressiveness and Independently Associated with Poor Prognosis in Primary Localized Myxofibrosarcomas
Authors: Hsuan-Ying Huang, Hong-Yo Kang, Chien-Feng Li, Hock-Liew Eng, Shih-Cheng Chou, Ching-Nan Lin, Ching-Yeh Hsiung
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Two SCFSkp2 ubiquitin ligase–related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in posttranscriptional degradation of p27Kip1 tumor suppressor. We analyzed the prognostic utility of p27Kip1 and its interacting cell cycle regulators in myxofibrosarcomas. Experimental Design: Clinicopathologic features and tissue microarray–based immunohistochemical expression of p27Kip1, Skp2, Cks1, cyclin E, cyclin A, Ki-67, and minichromosome maintenance protein 2 (Mcm2) were assessed in 70 primary myxofibrosarcomas and correlated with clinical outcomes. Skp2 mRNA expression and the relationship between Skp2 and p27Kip1 proteins were examined in six cases by semiquantitative reverse transcription-PCR and Western blotting, respectively. Results: High indices of Skp2 (≥10%), cyclin A (≥10%), and Mcm2 (≥50%) were adverse prognosticators at the univariate level. Furthermore, co-overexpression of Skp2 and cyclin A identified highly lethal cases in the entire cohort [P &amp;lt; 0.0001 for disease-specific survival (DSS), P = 0.0004 for overall survival (OS)] and the lower-grade subset (Fédération Nationale des Centres de Lutte Contre le Cancer grade 1 and 2; P = 0.0006 for DSS, P = 0.0093 for OS). In multivariate analyses, Skp2 overexpression overshadowed most intrinsic clinicopathologic factors and independently correlated with worse metastasis-free survival (P = 0.0012), DSS (P = 0.0234), and OS (P = 0.0056). Notably, positive margins independently predicted inferior local recurrence-free survival (P = 0.0012) and also negatively affected metastasis-free survival (P = 0.0471), DSS (P = 0.0152), and OS (P = 0.0173). Reverse transcription-PCR showed up-regulation of Skp2 mRNA in four cases and Western blotting displayed a matched expression pattern of Skp2. Conclusions: Margin status and intrinsic property of myxofibrosarcomas both affect patient survival. Skp2 overexpression is highly representative of the biological aggressiveness of myxofibrosarcomas and plays an important prognostic role.
The health and development of children born to older mothers in the United Kingdom: observational study using longitudinal cohort data
Authors: A. G. Sutcliffe, J. Barnes, J. Belsky, J. Gardiner, E. Melhuish
Journal: BMJ (2012)

<b>Objective</b> To assess relations between children's health and development and maternal age. <b>Design</b> Observational study of longitudinal cohorts. <b>Setting</b> Millennium Cohort Study (a random sample of UK children) and the National Evaluation of Sure Start study (a random sample of children in deprived areas in England), 2001 to 2007. <b>Participants</b> 31 257 children at age 9 months, 24 781 children at age 3 years, and 22 504 at age 5 years. <b>Main outcome measures</b> Childhood unintentional injuries and hospital admissions (aged 9 months, 3 years, and 5 years), immunisations (aged 9 months and 3 years), body mass index, language development, and difficulties with social development (aged 3 and 5 years). <b>Results</b> Associations were independent of personal and family characteristics and parity. The risk of children having unintentional injuries requiring medical attention or being admitted to hospital both declined with increasing maternal age. For example, at three years the risk of unintentional injuries declined from 36.6% for mothers aged 20 to 28.6% for mothers aged 40 and hospital admissions declined, respectively, from 27.1% to 21.6%. Immunisation rates at nine months increased with maternal age from 94.6% for mothers aged 20 to 98.1% for mothers aged 40. At three years, immunisation rates reached a maximum, at 81.3% for mothers aged 27, being lower for younger and older mothers. This was linked to rates for the combined measles, mumps, and rubella immunisation because excluding these resulted in no significant relation with maternal age. An increase in overweight children at ages 3 and 5 years associated with increasing maternal age was eliminated once maternal body mass index was included as a covariate. Language development was associated with improvements with increasing maternal age, with scores for children of mothers aged 20 being lower than those of children of mothers aged 40 by 0.21 to 0.22 standard deviations at ages 3 and 4 years. There were fewer social and emotional difficulties associated with increasing maternal age. Children of teenage mothers had more difficulties than children of mothers aged 40 (difference 0.28 SD at age 3 and 0.16 SD at age 5). <b>Conclusion</b> Increasing maternal age was associated with improved health and development for children up to 5 years of age.
Comparison of the Profiles of Postoperative Systemic Hemodynamics and Oxygen Transport in Neonates After the Hybrid or the Norwood Procedure
Authors: Jia Li, Gencheng Zhang, Lee Benson, Helen Holtby, Sally Cai, Tilman Humpl, Glen S. Van Arsdell, Andrew N. Redington, Christopher A. Caldarone
Journal: Circulation (2007)

Background— After the Norwood procedure, early postoperative neonatal physiology is characterized by hemodynamic instability and imbalance of oxygen transport that is commonly attributed to surgical myocardial injury and a systemic inflammatory response to cardiopulmonary bypass (CPB). Because the Hybrid procedure (arterial duct stenting and bilateral pulmonary artery banding) avoids CPB, cardioplegic arrest, and circulatory arrest, we hypothesized that the Hybrid procedure is associated with superior postoperative hemodynamics and oxygen transport. Methods and Results— Oxygen consumption (VO 2 ) was continuously measured using respiratory mass spectrometry for 72 hours after Hybrid (n=6) and Norwood (n=13) procedures. Arterial, superior vena cava, and pulmonary venous blood gases and pressures were measured at 2- to 4-hour intervals to calculate systemic and pulmonary blood flows (Qs, Qp), and systemic vascular resistance (SVR), total pulmonary vascular resistance including pulmonary arterial band or B-T shunt (tPVR), cardiac output (CO), oxygen delivery (DO 2 ), and oxygen extraction ratio (ERO 2 ). Rate-pressure product was calculated as heart rate×systolic arterial pressure. When compared with the Norwood procedure, the early postoperative Hybrid patients had lower CO, higher SVR, and higher Qp:Qs ratios. In addition, the DO 2 and VO 2 were both lower in the Hybrids with higher ERO 2 and lactate levels. This early postoperative pattern reversed after 48 hours. Conclusions— Although Hybrid procedure avoids CPB and cardioplegic arrest, the early hemodynamic profile is not superior to the Norwood in terms of cardiac output and control of pulmonary blood flow. These data strongly suggest that a “hands off” approach to postoperative care in Hybrid patients may not be appropriate in patients with preoperative diminished myocardial function; and in such patients a Norwood-derived management strategy (afterload reduction and inotropic support) should be considered.
<sup>52</sup>Mn Production for PET/MRI Tracking Of Human Stem Cells Expressing Divalent Metal Transporter 1 (DMT1)
Authors: Christina M Lewis, Stephen A Graves, Reinier Hernandez, Hector F Valdovinos, Todd E Barnhart, Weibo Cai, Mary E Meyerand, Robert J Nickles, Masatoshi Suzuki
Journal: Theranostics (2014)

There is a growing demand for long-term in vivo stem cell imaging for assessing cell therapy techniques and guiding therapeutic decisions. This work develops the production of (52)Mn and establishes proof of concept for the use of divalent metal transporter 1 (DMT1) as a positron emission tomography (PET) and magnetic resonance imaging (MRI) reporter gene for stem cell tracking in the rat brain. (52)Mn was produced via proton irradiation of a natural chromium target. In a comparison of two (52)Mn separation methods, solvent-solvent extraction was preferred over ion exchange chromatography because of reduced chromium impurities and higher (52)Mn recovery. In vitro uptake of Mn-based PET and MRI contrast agents ((52)Mn(2+) and Mn(2+), respectively) was enhanced in DMT1 over-expressing human neural progenitor cells (hNPC-DMT1) compared to wild-type control cells (hNPC-WT). After cell transplantation in the rat striatum, increased uptake of Mn-based contrast agents in grafted hNPC-DMT1 was detected in in vivo manganese-enhanced MRI (MEMRI) and ex vivo PET and autoradiography. These initial studies indicate that this approach holds promise for dual-modality PET/MR tracking of transplanted stem cells in the central nervous system and prompt further investigation into the clinical applicability of this technique.
Factors Associated With Efficacy of Nurse-led Bowel Training of Patients With Chronic Constipation
Authors: Fareed Iqbal, Alan Askari, Franklin Adaba, Aliya Choudhary, Gregory Thomas, Brigitte Collins, Emile Tan, R John Nicholls, Carolynne J Vaizey
Journal: Clinical Gastroenterology and Hepatology (2015)
Benefits and risks of interferon therapy for hepatitis B
Authors: Robert Perrillo
Journal: Hepatology (2009)

Abstract Alpha interferon is the only licensed drug for hepatitis B with immunomodulatory as well as viral inhibitory properties. Potential advantages of interferon compared to nucleoside analogs include a lack of drug resistance, a finite and defined treatment course, and a higher likelihood for hepatitis B surface antigen (HBsAg) clearance. Approximately 30% of hepatitis B e antigen (HBeAg)-positive and 40% of HBeAg-negative cases have a sustained virological response (when defined as HBeAg seroconversion and/or hepatitis B virus (HBV) DNA levels below 20,000 copies/mL, respectively) 6 months after completion of a 48-week course of peginterferon alfa-2a These responses remain durable in 80% and 50% of cases, respectively, when evaluated several years later. Recent studies have shown that changes in HBsAg and HBeAg concentration during treatment predict sustained virological response and serial monitoring of HBsAg is helpful in predicting HBsAg clearance. HBeAg-positive patients with genotype A have higher rates of HBeAg and HBsAg clearance, whereas HBeAg-negative patients with genotype D have the lowest rate of response to interferon therapy. Long-term follow-up of virological responders to either standard alpha interferon or peginterferon has demonstrated a progressive increase in the rate of HBsAg clearance, particularly in patients who were initially HBeAg-positive. Future studies need to address if specific virological benchmarks during therapy can be used to tailor treatment duration. Conclusion: Peginterferon alfa has a place as first-line therapy of hepatitis B in patients who are carefully selected on the basis of pretreatment serum HBV DNA and aminotransferase levels, safety considerations, and viral genotype. (Hepatology 2009;49:S103–S111.)
Genetic studies in primary gout
Authors: J. O. Alvsaker
Journal: Journal of Clinical Investigation (1968)

The plasma levels of the urate-binding alpha(1)-alpha(2)-globulin, as determined by its urate-binding capacity, have been recorded in 19 individuals from two gouty kindreds. A significantly reduced binding capacity, accounting for 13-30% of the mean value obtained in healthy, unrelated control subjects, was found in all cases of gout and in the single case of essential hyperuricemia included in the present study. In addition, six apparently healthy members of one of these kindreds also exhibited this characteristic. The distribution of the characteristic in three subsequent generations from this kindred further supported the hypothesis that the reduced binding capacity was inherited as an autosomal trait for which affected subjects were heterozygous. Based on the present observation, the mechanisms of inheritance in primary gout are discussed with special emphasis on the possible cooperation of genetic and environmental factors.
Mechanism of activation of the NA+/H+ exchanger by arginine vasopressin in hepatocytes
Authors: Sawkat M. Anwer
Journal: Hepatology (1994)

Arginine vasopressin has been shown to activate the Na+/H+ exchanger in hepatocytes by calcium/calmodulin-dependent processes. Whether this activation also involves protein kinase C and is associated with changes in the intracellular pH setpoint was investigated in this study. Changes in pHi and intracellular Ca++ concentration were measured with the fluorescent probes BCECF and quin-2, respectively. Intracellular pH recovery rate was calculated from time-dependent changes in intracellular pH in hepatocytes acid-loaded with sodium propionate. Arginine vasopressin, phorbol myristate acetate and thapsigargin stimulated intracellular pH recovery but did not increase basal intracellular pH. Arginine vasopressin and thapsigargin, but not phorbol myristol acetate, increased intracellular Ca++ concentration. The protein kinase C inhibitors staurosporine and calphostin C inhibited arginine vasopressin- and phorbol myristol acetate-induced, but not thapsigargin-induced, intracellular pH recovery. Neither staurosporine nor calphostin C affected arginine vasopressin- and thapsigargin-induced increases in intracellular Ca++ concentration, and no inhibitor affected basal intracellular pH recovery. Arginine vasopressin, phorbol myristol acetate and thapsigargin increased intracellular pH dependency of intracellular pH recovery without affecting intracellular pH setpoint. These results indicate that the activation of the Na+/H+ exchanger by arginine vasopressin is mediated both by Ca++/calmodulin and protein kinase C and may be due to enhanced interaction of H+ with the internal modifier site of the exchanger.
Secondary Pulmonary Hypertension in Chronic Heart Failure
Authors: Denzil L. Moraes, Wilson S. Colucci, Michael M. Givertz
Journal: Circulation (2000)

Abstract —Pulmonary vascular resistance is frequently elevated in patients with chronic left ventricular failure as a result of dysregulation of vascular smooth muscle tone and structural remodeling. The former is reversible over a period of minutes to days by pharmacological vasodilators, whereas the latter is relatively fixed and may resolve only slowly, over months to years. These abnormalities are due, at least in part, to pulmonary vascular endothelial dysfunction that results in impaired nitric oxide availability and increased endothelin expression. In patients with chronic heart failure, the resulting pulmonary hypertension directly affects right ventricular function and may affect exercise capacity, morbidity, and mortality. New treatment strategies, which include the use of agents that increase nitric oxide availability or oppose the actions of endothelin, may improve the structure and function of the pulmonary vasculature in patients with chronic heart failure.
A bacterial carbohydrate links innate and adaptive responses through Toll-like receptor 2
Authors: Qun Wang, Rachel M. McLoughlin, Brian A. Cobb, Marie Charrel-Dennis, Kathleen J. Zaleski, Douglas Golenbock, Arthur O. Tzianabos, Dennis L. Kasper
Journal: The Journal of Experimental Medicine (2006)

Commensalism is critical to a healthy Th1/Th2 cell balance. Polysaccharide A (PSA), which is produced by the intestinal commensal Bacteroides fragilis, activates CD4+ T cells, resulting in a Th1 response correcting the Th2 cell skew of germ-free mice. We identify Toll-like receptors as crucial to the convergence of innate and adaptive responses stimulated by PSA. Optimization of the Th1 cytokine interferon-γ in PSA-stimulated dendritic cell–CD4+ T cell co-cultures depends on both Toll-like receptor (TLR) 2 and antigen presentation. Synergy between the innate and adaptive responses was also shown when TLR2−/− mice exhibited impaired intraabdominal abscess formation in response to B. fragilis. Commensal bacteria, using molecules like PSA, potentially modulate the Th1/Th2 cell balance and the response to infection by coordinating both the innate and adaptive pathways.
Cellular action and interactions of arginine vasopressin in vascular smooth muscle
Authors: R W Schrier, V Briner, C Caramelo
Journal: Journal of the American Society of Nephrology (1993)

In recent years, much has been learned about the vascular action of arginine vasopressin (AVP) including (1) the structure, internalization, and recycling of the V1 AVP receptor; (2) the AVP postreceptor signaling events for the initial and sustained vascular smooth muscle cell contraction as well as the hormone's mitogenic effect; (3) the process of homologous and heterologous AVP desensitization in vascular smooth muscle cells; (4) the interaction of AVP with other vasoconstrictor and vasodilator hormones; (5) the vascular interaction of AVP with endothelial events; and (6) the vascular interactions that may occur with systemic acidemia or alkalemia as well as with ethanol. The various potential clinical and biochemical implications of these results are discussed briefly.