tbuckley/cabot-search huggingface dataset:
Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis
Authors: Jonathan D Rohrer, Jennifer M Nicholas, David M Cash, John van Swieten, Elise Dopper, Lize Jiskoot, Rick van Minkelen, Serge A Rombouts, M Jorge Cardoso, Shona Clegg, Miklos Espak, Simon Mead, David L Thomas, Enrico De Vita, Mario Masellis, Sandra E Black, Morris Freedman, Ron Keren, Bradley J MacIntosh, Ekaterina Rogaeva, David Tang-Wai, Maria Carmela Tartaglia, Robert Laforce, Fabrizio Tagliavini, Pietro Tiraboschi, Veronica Redaelli, Sara Prioni, Marina Grisoli, Barbara Borroni, Alessandro Padovani, Daniela Galimberti, Elio Scarpini, Andrea Arighi, Giorgio Fumagalli, James B Rowe, Ian Coyle-Gilchrist, Caroline Graff, Marie Fallström, Vesna Jelic, Anne Kinhult Ståhlbom, Christin Andersson, Håkan Thonberg, Lena Lilius, Giovanni B Frisoni, Giuliano Binetti, Michela Pievani, Martina Bocchetta, Luisa Benussi, Roberta Ghidoni, Elizabeth Finger, Sandro Sorbi, Benedetta Nacmias, Gemma Lombardi, Cristina Polito, Jason D Warren, Sebastien Ourselin, Nick C Fox, Martin N Rossor
Journal: The Lancet Neurology (2015)

Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia.
Hepatocyte‐targeted expression by integrase‐defective lentiviral vectors induces antigen‐specific tolerance in mice with low genotoxic risk
Authors: Janka Mátrai, Alessio Cantore, Cynthia C. Bartholomae, Andrea Annoni, Wei Wang, Abel Acosta-Sanchez, Ermira Samara-Kuko, Liesbeth De Waele, Ling Ma, Pietro Genovese, Martina Damo, Anne Arens, Kevin Goudy, Timothy C. Nichols, Christof von Kalle, Marinee K. L. Chuah, Maria Grazia Roncarolo, Manfred Schmidt, Thierry VandenDriessche, Luigi Naldini
Journal: Hepatology (2011)

Abstract Lentiviral vectors are attractive tools for liver-directed gene therapy because of their capacity for stable gene expression and the lack of preexisting immunity in most human subjects. However, the use of integrating vectors may raise some concerns about the potential risk of insertional mutagenesis. Here we investigated liver gene transfer by integrase-defective lentiviral vectors (IDLVs) containing an inactivating mutation in the integrase (D64V). Hepatocyte-targeted expression using IDLVs resulted in the sustained and robust induction of immune tolerance to both intracellular and secreted proteins, despite the reduced transgene expression levels in comparison with their integrase-competent vector counterparts. IDLV-mediated and hepatocyte-targeted coagulation factor IX (FIX) expression prevented the induction of neutralizing antibodies to FIX even after antigen rechallenge in hemophilia B mice and accounted for relatively prolonged therapeutic FIX expression levels. Upon the delivery of intracellular model antigens, hepatocyte-targeted IDLVs induced transgene-specific regulatory T cells that contributed to the observed immune tolerance. Deep sequencing of IDLV-transduced livers showed only rare genomic integrations that had no preference for gene coding regions and occurred mostly by a mechanism inconsistent with residual integrase activity. Conclusion: IDLVs provide an attractive platform for the tolerogenic expression of intracellular or secreted proteins in the liver with a substantially reduced risk of insertional mutagenesis. (Hepatology 2011;)
Temporal Risk Profile for Infectious and Noninfectious Complications of Hemodialysis Access
Authors: Pietro Ravani, Brenda W. Gillespie, Robert Ross Quinn, Jennifer MacRae, Braden Manns, David Mendelssohn, Marcello Tonelli, Brenda Hemmelgarn, Matthew James, Neesh Pannu, Bruce M. Robinson, Xin Zhang, Ronald Pisoni
Journal: Journal of the American Society of Nephrology (2013)

Vascular access complications are a major cause of morbidity in patients undergoing hemodialysis, and determining how the risks of different complications vary over the life of an access may benefit the design of prevention strategies. We used data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) to assess the temporal profiles of risks for infectious and noninfectious complications of fistulas, grafts, and tunneled catheters in incident hemodialysis patients. We used longitudinal data to model time from access placement or successful treatment of a previous complication to subsequent complication and considered multiple accesses per patient and repeated access complications using baseline and time-varying covariates to obtain adjusted estimates. Of the 7769 incident patients identified, 7140 received at least one permanent access. During a median follow-up of 14 months (interquartile range, 7-22 months), 10,452 noninfectious and 1131 infectious events (including 551 hospitalizations for sepsis) occurred in 112,085 patient-months. The hazards for both complication types declined over time in all access types: They were 5-10 times greater in the first 3-6 months than in later periods after access placement or a remedial access-related procedure. The hazards declined more quickly with fistulas than with grafts and catheters (P<0.001; Weibull regression). These data indicate that risks for noninfectious and infectious complications of the hemodialysis access decline over time with all access types and suggest that prevention strategies should target the first 6 months after access placement or a remedial access-related procedure.
Portal hypertension in chronic hepatitis: relationship to morphological changes.
Authors: D J van Leeuwen, S C Howe, P J Scheuer, S Sherlock
Journal: Gut (1990)

Various anatomical factors were examined which might provide passive resistance to portal venous flow and so cause portal hypertension. Methods included the measurement of portal pressure (WHVPG) in cirrhotic and non-cirrhotic patients, morphological assessment by semiquantitative grading of severity of disease, calculation of hepatocyte size indices, and assessment of volume density of hepatocytes, sinusoids, Disse9s space and Disse9s space collagen by electron microscopy. The wedged hepatic venous pressure gradient increased with progression of disease and portal hypertension was present before histologically detectable cirrhosis had developed. With increasing progression of disease towards cirrhosis, the relationship between individual and aggregated features and the WHVPG diminished and lost statistical significance. Hepatocyte size increased with progression of histological changes and correlated significantly with increase of WHVPG, both in non-alcoholic and alcoholic patients. Disse9s space collagen was increased significantly in non-alcoholic chronic active hepatitis compared with patients with near-normal liver. No significant decrease of sinusoidal space was found. Multiple factors rather than any single feature influence the development of portal hypertension.
Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice
Authors: Ji Zhou, Geoff H. Werstuck, Šárka Lhoták, A. B. Lawrence de Koning, Sudesh K. Sood, Gazi S. Hossain, Jan Møller, Merel Ritskes-Hoitinga, Erling Falk, Sanjana Dayal, Steven R. Lentz, Richard C. Austin
Journal: Circulation (2004)

A causal relation between hyperhomocysteinemia (HHcy) and accelerated atherosclerosis has been established in apolipoprotein E-deficient (apoE-/-) mice. Although several cellular stress mechanisms have been proposed to explain the atherogenic effects of HHcy, including oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, their association with atherogenesis has not been completely elucidated.ApoE-/- mice were fed a control or a high-methionine (HM) diet for 4 (early lesion group) or 18 (advanced lesion group) weeks to induce HHcy. Total plasma homocysteine levels and atherosclerotic lesion size were significantly increased in early and advanced lesion groups fed the HM diet compared with control groups. Markers of ER stress (GRP78/94, phospho-PERK), oxidative stress (HSP70), and inflammation (phospho-IkappaB-alpha) were assessed by immunohistochemical staining of these atherosclerotic lesions. GRP78/94, HSP70, and phospho-IkappaB-alpha immunostaining were significantly increased in the advanced lesion group fed the HM diet compared with the control group. HSP47, an ER-resident molecular chaperone involved in collagen folding and secretion, was also increased in advanced lesions of mice fed the HM diet. GRP78/94 and HSP47 were predominantly localized to the smooth muscle cell-rich fibrous cap, whereas HSP70 and phospho-IkappaB-alpha were observed in the lipid-rich necrotic core. Increased HSP70 and phospho-IkappaB-alpha immunostaining in advanced lesions of mice fed the HM diet are consistent with enhanced carotid artery dihydroethidium staining. Interestingly, GRP78/94 and phospho-PERK were markedly increased in macrophage foam cells from early lesions of mice fed the control or the HM diet.Multiple cellular stress pathways, including ER stress, are associated with atherosclerotic lesion development in apoE-/- mice.
Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine
Authors: Ruben A. Mesa, David Loegering, Heather L. Powell, Karen Flatten, Sonnet J. H. Arlander, Nga T. Dai, Michael P. Heldebrant, Benjamin T. Vroman, B. Douglas Smith, Judith E. Karp, Cynthia J. Ten Eyck, Charles Erlichman, Scott H. Kaufmann, Larry M. Karnitz
Journal: Blood (2005)
Emergence of a hypervirulent carbapenem-resistant Klebsiella pneumoniae isolate from clinical infections in China
Authors: Yawei Zhang, Ji Zeng, Wenen Liu, Feng Zhao, Zhidong Hu, Chunjiang Zhao, Qi Wang, Xiaojuan Wang, Hongbin Chen, Henan Li, Feifei Zhang, Shuguang Li, Bin Cao, Hui Wang
Journal: Journal of Infection (2015)
Arbitration and the internal market
Authors: M Forsythe
Journal: BMJ (1994)

What we first need to do is to define more precisely the prevalence of genital chlamydial infections in different populations.This does not require the use of new, highly sensitive diagnostic methods.Relatively insensitive, cheap, but nevertheless specific detection procedures can be used if their performance features are known accurately enough.Furthermore, urine samples may facilitate detection of urogenital chlamydial infections in population based prevalence studies."Once the overall prevalence has been defined accurately enough to provide a dependable baseline for future reference then more sensitive diagnostic tests can be applied on an individual basis in the context of a well designed and evaluated programme of screening, treatment, and contact tracing.The newer, more sensitive tests are not cheap-these include polymerase or ligase chain reactions.8The alternative to this approach is to give antibiotics to women in perceived high risk groups5 without testing for chlamydial infection-an approach recognised generally as poor medicine and carrying the risk of undertreatment and the emergence of organisms resistant to antibiotics.Vaccination may eventually be feasible,'2 but preliminary results suggest that effective protection will be difficult to achieve.The Swedish experience suggests that vaccination may be indicated only as an adjunct to case finding, diagnosis, and treatment in the highest risk groups.The targets in the Health of the Nation include a reduction in sexually transmitted infections, with gonococcal disease being used as a marker; the aim is to reduce its incidence by 20% by 1995.'3This may be achievable with little effort, since the disease is already declining-but a similar decline in the incidence of genital chlamydial infections will surely not be achieved unless there is adequate financial support for the active programme I have outlined.Steps should be taken now.In the long term they will pay for themselves.
Wild-Type <i>KRAS</i> Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer
Authors: Rafael G. Amado, Michael Wolf, Marc Peeters, Eric Van Cutsem, Salvatore Siena, Daniel J. Freeman, Todd Juan, Robert Sikorski, Sid Suggs, Robert Radinsky, Scott D. Patterson, David D. Chang
Journal: Journal of Clinical Oncology (2008)

Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.
LMNA mutations in atypical Werner's syndrome
Authors: Lishan Chen, Lin Lee, Brian A Kudlow, Heloisa G Dos Santos, Olav Sletvold, Yousef Shafeghati, Eleanor G Botha, Abhimanyu Garg, Nancy B Hanson, George M Martin, I Saira Mian, Brian K Kennedy, Junko Oshima
Journal: The Lancet (2003)
Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161
Authors: Jenny M Mjösberg, Sara Trifari, Natasha K Crellin, Charlotte P Peters, Cornelis M van Drunen, Berber Piet, Wytske J Fokkens, Tom Cupedo, Hergen Spits
Journal: Nature Immunology (2011)
714 HBSAG LEVELS DURING THE FIRST 24 WEEKS OF PEGINTERFERON ALFA-2A [40KD] (PEGASYS) TREATMENT IN PATIENTS WITH HBEAG-NEGATIVE CHRONIC HEPATITIS B: THE PERSEAS COHORT
Authors: I. Goulis, E. Akriviadis, S. Karatapanis, M. Deutsch, G. Dalekos, M. Raptopoulou-Gigi, C. Drakoulis, G. Bakalos, G. Papatheodoridis
Journal: Journal of Hepatology (2011)
Antibodies against acetaldehyde-modified protein epitopes in human alcoholics
Authors: Onni Niemelä, Felix Klajner, Hector Orrego, Eva Vidins, Laurence Blendis, Yedy Israel
Journal: Hepatology (1987)

Acetaldehyde, the primary metabolite of ethanol, binds covalently to proteins forming condensation products which have been recently shown to be immunogenic. To assess whether an antibody response against acetaldehyde-modified protein epitopes is associated with alcoholic liver disease, the serum immunoreactivity against proteins modified in vitro by acetaldehyde and against the corresponding unmodified proteins was measured by an enzyme-linked immunosorbent assay in 58 alcoholics with varying degrees of liver damage. Alcoholics showed significantly higher titers against protein-acetaldehyde conjugates than against the unmodified protein, independent of the nature of the carrier protein. The highest titers occurred in alcoholic hepatitis patients. Sera of patients with chronic hepatitis of nonalcoholic origin and of healthy controls also reacted with acetaldehyde conjugates, but their titers were significantly lower than those in alcoholic hepatitis patients. Our data support the idea that binding of acetaldehyde to proteins in humans generates antigenic determinants which trigger a corresponding immune response against such epitopes and suggest that this humoral immune response may be implicated in autoantibody formation and liver damage associated with excessive alcohol consumption.
Age-dependent deficiency of B lymphocyte lineage precursors in NZB mice.
Authors: H Jyonouchi, P W Kincade, K S Landreth, G Lee, R A Good, M E Gershwin
Journal: The Journal of Experimental Medicine (1982)

Adult NZB mice (greater than 15 wk old) have very few bone marrow cells that can give rise to sIg+ clonable B cells during liquid culture. This deficiency corresponds to extremely low numbers of cells with cytoplasmic but not surface mu chains of IgM and reduced numbers of cells bearing a high molecular weight B-lineage antigen. Depletion of Thy-1-bearing cells and appropriate mixing experiments did not provide evidence either that suppressor cells are responsible for this phenomenon or that accessory cells are defective in NZB mice. Nor did it seem that B cells were being produced in extramedullary sites. B cell precursors were detectable in very young NZB mice, exceeded control values at 4-5 wk of age, and then declined rapidly. In contrast, these persisted for greater than 1 yr in normal BALB/c, DBA/2, and CBA/H mice. It appears possible that intermediate stages in B-lineage differentiation become prematurely exhausted through an accelerated aging process in NZB mice. These chronological changes have implications for understanding the sequence of events that lead to B lymphocyte formation and the processes that normally regulate it.
Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury
Authors: Kenichi Imahashi, Hideo Kusuoka, Katsuji Hashimoto, Jun Yoshioka, Hitoshi Yamaguchi, Tsunehiko Nishimura
Journal: Circulation Research (1999)

Abstract —To elucidate the role of intracellular Na + kinetics during ischemia and reperfusion in postischemic contractile dysfunction, intracellular Na + concentration ([Na + ] i ) was measured in isolated perfused rat hearts using 23 Na nuclear magnetic resonance spectroscopy. The extension of the ischemic period from 9 minutes to 15, 21, and 27 minutes (at 37°C) increased [Na + ] i at the end of ischemia from 270.0±10.4% of preischemic level (mean±SE, n=5) to 348.4±12.0% (n=5), 491.0±34.0% (n=7), and 505.3±12.1% (n=5), respectively, whereas the recovery of developed pressure worsened with the prolongation of the ischemic period (95.1±4.2%, 84.3±1.2%, 52.8±13.7%, and 16.9±6.4% of preischemic level). The kinetics of [Na + ] i recovery during reperfusion was analyzed by the fitting of a monoexponential function. When the hearts were reperfused with low–[Ca] o (0.15 mmol/L) solution, the time constants of the recovery (τ) after 15-minute (8.07±0.85 minutes, n=5) and 21-minute ischemia (6.44±0.90, n=5) were significantly extended, with better functional recovery (98.5±1.4% for 15-minute [ P &lt;0.05]; 98.0±1.0% for 21-minute [ P &lt;0.05]) compared with standard reperfusion ([Ca] o =2.0 mmol/L, τ=3.58±0.28 minutes for 15-minute [ P &lt;0.0001]; τ=3.02±0.20 for 21-minute [ P &lt;0.0001]). A selective inhibitor of Na + /Ca 2+ exchanger also decelerated the [Na + ] i recovery, which suggests that the recovery reflects the Na + /Ca 2+ exchange activity. In contrast, high-[Ca] o reperfusion (5 mmol/L) accelerated the [Na + ] i recovery after 9-minute ischemia (τ=2.48±0.11 minute, n=5 [ P &lt;0.0001]) and 15-minute ischemia (τ=2.10±0.07, n=6 [ P &lt;0.05]), but functional recovery deteriorated only in the hearts with 15-minute ischemia (29.8±9.4% [ P &lt;0.05]). [Na + ] i recovery after 27-minute ischemia was incomplete and decelerated by low-[Ca] o reperfusion, with limited improvement of functional recovery (42.5±7.9%, n=5 [ P &lt;0.05]). These results indicate that intracellular Na + accumulation during ischemia is the substrate for reperfusion injury and that the [Na + ] i kinetics during reperfusion, which is coupled with Ca 2+ influx, also determines the degree of injury.
Quantitative ultrasonography in rheumatoid arthritis: evaluation of inflammation by Doppler technique
Authors: E Qvistgaard
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> To evaluate ultrasonographic methods, including the Doppler technique, as measures of synovial inflammation in finger joints of patients with rheumatoid arthritis. <h3>METHODS</h3> Ultrasonography was performed with a high frequency transducer (13 MHz). Evaluation of the sonographic data was conducted by two independent observers and included measurement of synovial area and thickness (grey tone ultrasound), vascularisation (power/colour Doppler), and indices of the intra- and extrasynovial arterial flow (spectral Doppler). The flow pattern was estimated by the indices of pulsatility (PI) and resistance (RI). <h3>RESULTS</h3> The sonographic measurements of joint space were reproducible with intraobserver, intraclass correlation coefficients (ICC) 0.82–0.97 (p&lt;0.0001) and interobserver ICC 0.81 (p&lt;0.0001). The mean (SD) fraction of the synovium vascularised in the patients was 0.15 (0.15). The synovial blood flow was characterised by a diastolic flow—that is, the flow persisting during the diastole. The mean (SD) PI was 1.92 (1.18) and RI 0.70 (0.13). The estimated vascular fraction correlated with the erythrocyte sedimentation rate (ESR) (<i>r</i><sub>s</sub>=0.53, p=0.03). The relative Pi (rPi), an estimate of an abnormally low resistance to vascularisation, correlated with both ESR (<i>r</i><sub>s</sub>=−0.557, p&lt;0.05) and Health Assessment Questionnaire score (<i>r</i><sub>s</sub>=−0.584, p&lt;0.05). After an injection of contrast Levovist the vascular fraction increased, while no difference in PI and RI was observed. <h3>CONCLUSION</h3> Ultrasonography is a reliable tool for estimating the size of the joint space and the synovial activity measured by the degree of vascularisation and pattern of flow. Ultrasonography may be useful in monitoring the synovial inflammation in rheumatoid arthritis.
Isolated interventricular septal tuberculoma causing complete heart block.
Authors: C Wren, P G Stovin
Journal: Thorax (1982)

Case reportA 66-year-old man, seen in 1971 after a presyncopal episode, was found to have a heart rate of 32 beats per minute.His ECG showed complete heart block with narrow QRS complexes.After two Adams-Stokes attacks in hospital a temporary pacemaker was inserted.He had previously been well with no history of tuber- culosis nor of contact with tuberculosis.Investigation
The absorption, distribution, metabolism and excretion (ADME) of single oral doses of AZD5069, a novel CXCR2 antagonist, in healthy male volunteers
Authors: Tim Mant, Heather Wray, Marie Cullberg, Bengt Larsson
Journal: European Respiratory Journal (2012)

BACKGROUND:  AZD5069 is a CXC chemokine receptor-2 (CXCR2) antagonist with potential as a novel COPD treatment. Initial studies have indicated an acceptable safety profile for AZD5069. This study characterised the ADME of a single oral dose of AZD5069.   METHODS:  In this phase I, open-label, non-comparative, single centre study, healthy male volunteers received a single oral dose of 120 mg [ 14 C]AZD5069. Blood and urine samples (for radioactivity analysis, metabolite profiling, identification and bioanalysis of AZD5069) and faeces samples (for radioactivity analysis and metabolite profiling) were collected. Safety and tolerability were also assessed.   RESULTS  :  Subjects (n=6) were white males (aged 50–65 years, mean BMI 25.6 kg/m 2 ). The mean recovery of radioactivity in urine and faeces was 100% (range 98–103% [65% in urine, 35% in faeces]). 6.7% of the AZD5069 dose was recovered unmetabolised in urine. AZD5069 was rapidly absorbed and the apparent terminal elimination half-life was 10 hours. There were no deaths, serious adverse events (AEs) or withdrawals due to AEs. Four subjects reported 6 AEs, with headache the most commonly observed event. There were no clinically significant safety and tolerability findings, other than the expected reversible reduction in circulating neutrophil numbers.   CONCLUSION:  Absorption of AZD5069 was rapid. Complete recovery of radioactivity was attained, with the majority being excreted in the urine. Only a small fraction was renally excreted as parent drug, suggesting that metabolism is the primary route of elimination. No safety concerns were identified.