tbuckley/cabot-search huggingface dataset:
Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group
Authors: M Rudwaleit, A G Jurik, K-G A Hermann, R Landewe, D van der Heijde, X Baraliakos, H Marzo-Ortega, M Ostergaard, J Braun, J Sieper
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Background:</h3> Magnetic resonance imaging (MRI) of sacroiliac joints has evolved as the most relevant imaging modality for diagnosis and classification of early axial spondyloarthritis (SpA) including early ankylosing spondylitis. <h3>Objectives:</h3> To identify and describe MRI findings in sacroiliitis and to reach consensus on which MRI findings are essential for the definition of sacroiliitis. <h3>Methods:</h3> Ten doctors (two radiologists and eight rheumatologists) from the ASAS/OMERACT MRI working group reviewed and discussed in three workshops MR images depicting sacroiliitis associated with SpA and other conditions which may mimic SpA. Descriptions of the pathological findings and technical requirements for the appropriate acquisition were formulated. In a consensual approach MRI findings considered to be essential for sacroiliitis were defined. <h3>Results:</h3> Active inflammatory lesions such as bone marrow oedema (BMO)/osteitis, synovitis, enthesitis and capsulitis associated with SpA can be detected by MRI. Among these, the clear presence of BMO/osteitis was considered essential for defining active sacroiliitis. Structural damage lesions such as sclerosis, erosions, fat deposition and ankylosis can also be detected by MRI. At present, however, the exact place of structural damage lesions for diagnosis and classification is less clear, particularly if these findings are minor. The ASAS group formally approved these proposals by voting at the annual assembly. <h3>Conclusions:</h3> For the first time, MRI findings relevant for sacroiliitis have been defined by consensus by a group of rheumatologists and radiologists. These definitions should help in applying correctly the imaging feature "active sacroiliitis by MRI" in the new ASAS classification criteria for axial SpA.
A silent cause of sudden cardiac death especially in sport: congenital coronary artery anomalies
Authors: Sharleen F Hill, Mary N Sheppard
Journal: British Journal of Sports Medicine (2013)

Aim To raise awareness of congenital coronary artery anomalies (CCAAs) as an important cause of sudden cardiac death (SCD) in athletes, we describe a cohort of the malignant subset. Defining the key anatomical features for the cardiologist and pathologist to be aware of and detailing a systematic approach to examining the coronary arteries at autopsy. Methods Retrospective non-case-controlled analysis of 2304 cases of SCD referred by pathologists between 1994 and January 2012. Results 31 (1.3%) of the 2304 cases of SCD had CCAAs; 24 men (77%) and 7 women (23%), mean age 28 years (range 16 months–63 years). In 15 cases (48%), SCD occurred during or immediately after physical exertion. Cardiac symptoms were documented to have occurred in only seven patients (23%) prior to SCD. The anomaly had been identified by the referring pathologist in only 11 of the 31 cases (35%). Conclusions CCAAs are a rare and mostly benign entity, but a subset has the potential to be fatal without any forewarning. In a significant proportion of cases identified in this large cohort, the victim was under exertion at the time of death, highlighting the relevance of this anomaly to the sports and exercise medicine community.
Ischemia/reperfusion-induced apoptosis: connecting nitric oxide and cell cycle regulators
Authors: C PIGNATTI, C STEFANELLI
Journal: Cardiovascular Research (2003)

See article by Maejima et al. [1] (pages 308–320) in this issue. 

Cardiomyocytes are able to divide throughout the fetal period of life and continue to increase in cell number up to the first 2-3 days after birth. Thereafter, they undergo terminal differentiation. Although in certain pathological conditions, such as myocardial infarction, cardiomyocyte proliferation has been observed also in the adult heart [2], postnatal cardiomyocytes are normally irreversibly withdrawn from the cell cycle, resulting in the loss of their regenerative capacity. In response to some stimuli, such as increased overload and ischemia, cardiac myocytes can grow by hypertrophy, which is accompanied by the upregulation of protein synthesis [3]. Hypertrophic and mitogenic stimuli share similar intracellular responses, such as multiple second messenger systems and induction of various immediate-early genes. Actually, serum stimulation of neonatal, terminally-differentiated cardiomyocytes, similarly to what happens in proliferating cells, upregulates some of the cell cycle regulators such as G1 cyclins and associated cyclin-dependent kinases (cdks), which are required for the induction of cardiac hypertrophy [4].

The cdk enzymes are members of a conserved family of serine/threonine kinases whose activity is dependent on the presence of activating subunits known as cyclins. The abundance of specific cyclins increases during phases of the cell cycle in which they are required, thus regulating cell cycle progression. Such a control system operates at the level of checkpoints that occur at the G1/S phase boundary, in the S phase, and during the G2/M phases. For example, cdk2 binds cyclin A or E at the transition G1/S of the cycle and the complex may phosphorylate specific proteins, thus allowing the cell cycle processes to continue. Whereas cyclin binding is required for cdk kinase activity, other proteins can inhibit the enzymatic activity of cyclin/cdk complexes and prevent cell cycle progression. The p21 … 

*Corresponding author. Tel.: +39-51-2091203; fax: +39-51-2091224. claudio.stefanelli{at}unibo.it
A Live-Attenuated Listeria Vaccine (ANZ-100) and a Live-Attenuated Listeria Vaccine Expressing Mesothelin (CRS-207) for Advanced Cancers: Phase I Studies of Safety and Immune Induction
Authors: Dung T. Le, Dirk G. Brockstedt, Ran Nir-Paz, Johannes Hampl, Shruti Mathur, John Nemunaitis, Daniel H. Sterman, Raffit Hassan, Eric Lutz, Bentley Moyer, Martin Giedlin, Jana-Lynn Louis, Elizabeth A. Sugar, Alice Pons, Andrea L. Cox, Jordana Levine, Aimee Luck Murphy, Peter Illei, Thomas W. Dubensky, Joseph E. Eiden, Elizabeth M. Jaffee, Daniel A. Laheru
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses and activation and recruitment of natural killer (NK) and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T-cell responses against mesothelin-expressing murine tumors. These two phase I studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively. Experimental Design: A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1 × 106, 3 × 107, or 3 × 108 colony-forming units (cfu). CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic, or ovarian cancers. Seventeen subjects received up to 4 doses of 1 × 108, 3 × 108, 1 × 109, or 1 × 1010 cfu. Results: A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1 × 109 cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, listeriolysin O and mesothelin-specific T-cell responses were detected and 37% of subjects lived ≥15 months. Conclusions: ANZ-100 and CRS-207 administration was safe and resulted in immune activation. Clin Cancer Res; 18(3); 858–68. ©2011 AACR.
Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production
Authors: Ekaterina Y. Shishova, Janis M. Stoll, Baran A. Ersoy, Sudeep Shrestha, Erez F. Scapa, Yingxia Li, Michele W. Niepel, Ya Su, Linda A. Jelicks, Gregory L. Stahl, Marcie A. Glicksman, Roger Gutierrez-Juarez, Gregory D. Cuny, David E. Cohen
Journal: Hepatology (2011)

Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp-/- mice are protected against diet-induced increases in hepatic glucose production and that small molecule inhibition of PC-TP recapitulates this phenotype. Pctp-/- and wildtype mice were subjected to high-fat feeding and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high-fat diet-induced increases in hepatic glucose production were markedly attenuated in Pctp-/- mice. Small molecule inhibitors of PC-TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high-fat-fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC-TP, displaced phosphatidylcholines from the lipid binding site, and increased the thermal stability of the protein. Administration of the optimized inhibitor to wildtype mice attenuated hepatic glucose production associated with high-fat feeding, but had no activity in Pctp-/- mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin-sensitizing agents, the inhibitor promoted insulin-independent phosphorylation of key insulin signaling molecules.These findings suggest PC-TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance.
Dropping Out of Mental Health Treatment: Patterns and Predictors Among Epidemiological Survey Respondents in the United States and Ontario
Authors: Mark J. Edlund, Philip S. Wang, Patricia A. Berglund, Stephen J. Katz, Elizabeth Lin, Ronald C. Kessler
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The authors interviewed individuals treated for self-described mental health problems in the preceding year to examine patterns and predictors associated with dropping out of treatment. METHOD: Subjects were drawn from respondents to community epidemiological surveys carried out in representative samples of the United States and Ontario populations. Dropouts were those who had left mental health treatment during the prior year for reasons other than symptom improvement. The surveys also assessed potential dropout correlates: sociodemographic characteristics, attitudes about mental health care, disorder type, provider type, and treatment received. RESULTS: The proportion of dropouts did not significantly differ between the United States (19.2%) and Ontario (16.9%), nor did the effects of the predictors differ significantly between the two samples. Sociodemographic characteristics associated with treatment dropout included low income, young age, and, in the United States, lacking insurance coverage for mental health treatment. Patient attitudes associated with dropout included viewing mental health treatment as relatively ineffective and embarrassment about seeing a mental health provider. Respondents who received both medication and talk therapy were less likely to drop out than those who received single-modality treatments. CONCLUSIONS: Mental health treatment dropout is a serious problem, especially among patients who have low income, are young, lack insurance, are offered only single-modality treatments, and have negative attitudes about mental health care. Cost-effective interventions targeting these groups are needed to increase the proportion of patients who complete an adequate course of treatment.
A Simple Hierarchical Approach to Modeling Distributions of Substitution Rates
Authors: Sergei L. Kosakovsky Pond, Simon D. W. Frost
Journal: Molecular Biology and Evolution (2004)

Genetic sequence data typically exhibit variability in substitution rates across sites. In practice, there is often too little variation to fit a different rate for each site in the alignment, but the distribution of rates across sites may not be well modeled using simple parametric families. Mixtures of different distributions can capture more complex patterns of rate variation, but are often parameter-rich and difficult to fit. We present a simple hierarchical model in which a baseline rate distribution, such as a gamma distribution, is discretized into several categories, the quantiles of which are estimated using a discretized beta distribution. Although this approach involves adding only two extra parameters to a standard distribution, a wide range of rate distributions can be captured. Using simulated data, we demonstrate that a "beta-" model can reproduce the moments of the rate distribution more accurately than the distribution used to simulate the data, even when the baseline rate distribution is misspecified. Using hepatitis C virus and mammalian mitochondrial sequences, we show that a beta- model can fit as well or better than a model with multiple discrete rate categories, and compares favorably with a model which fits a separate rate category to each site. We also demonstrate this discretization scheme in the context of codon models specifically aimed at identifying individual sites undergoing adaptive or purifying evolution.
Relationship between quality of life and clinical status in asthma: a factor analysis
Authors: E.F. Juniper, M.E. Wisniewski, F.M. Cox, A.H. Emmett, K.E. Nielsen, P.M. O'Byrne
Journal: European Respiratory Journal (2004)

Many studies have shown that correlation between clinical asthma status and asthma-specific quality of life is only weak to moderate. However, this relationship has never been explored to determine whether the weakness is due to noise of measurement or whether quality of life is a distinct component of asthma health status. With a database from three clinical trials (n=763), factor analysis was used to explore the relationships between quality of life, measured by the Asthma Quality of Life Questionnaire (AQLQ), and conventional measures of asthma clinical status (symptoms, airway calibre and rescue β 2 ‐agonist use). The analysis revealed that although patients with severe, poorly controlled asthma tend to have worse quality of life than milder, well-controlled patients, overall asthma health status has four components (factors): asthma-specific quality of life; airway calibre; daytime symptoms and daytime β 2 ‐agonist use, and night-time symptoms and night-time β 2 ‐agonist use. The clean loading of all 21 outcomes onto four distinct and clinically identifiable factors suggests that, although some weakness of correlation between clinical indices and quality of life may be due to noise of measurement, it is mainly attributable to asthma health status being composed of distinct components.
Clinical and pharmacologic analysis of hyperfractionated daily oral etoposide.
Authors: H Minami, Y Ando, S Sakai, K Shimokata
Journal: Journal of Clinical Oncology (1995)

PURPOSE The antitumor effect of etoposide is increased by maintaining a low blood level, whereas high peak levels may cause myelotoxicity. We investigated whether a constant low blood level could be obtained by the administration of oral etoposide three times daily. PATIENTS AND METHODS Nineteen patients with non-small-cell lung cancer were treated with oral etoposide (25 mg three times daily for 21 days) as monotherapy or in combination with cisplatin 80 mg/m2. A pharmacokinetic model that predicted the mean blood concentration (Cmean) was developed in the 10 patients on etoposide monotherapy and validated in the nine patients on combination chemotherapy. Pharmacodynamic relationships were evaluated in each group. RESULTS Etoposide dose per body-surface area ranged from 45 to 63 mg/m2/d (median, 53), but did not correlate with plasma level. Cmean was 1.1 +/- 0.3 micrograms/mL. Peak concentrations ranged from 0.6 to 2.5 micrograms/mL. The intrapatient coefficient of variation for plasma etoposide concentrations was 22% +/- 10%. Cmean was accurately estimated as follows: Cmean = 0.098 + 0.413 x C0 + 0.458 x C2 (r = .97, P = .0001), where C0 and C2 represent concentrations before and 2 hours after administration. This model was unbiased (mean predictive error [MPE], 0.0 microgram/mL) and precise (root mean square error [RMSE], 0.1 microgram/mL). Leukopenia was the major toxicity. The surviving fraction of leukocytes (SF; nadir count/pretreatment count) was correlated to Cmean as follows: SF = 0.87 - 0.34 x Cmean (r = .67, P = .03) in the monotherapy group and SF = 0.64 - 0.33 x Cmean (R = .77, P = .03) in the combination chemotherapy group. Two and four patients treated with monotherapy and combination chemotherapy showed responses, respectively. All responders had a Cmean &gt; or = 1.0 microgram/mL. CONCLUSION Hyperfractionated oral etoposide achieveda stable plasma level that could be predicted by measurement at only two times.
IL-4–producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells
Authors: Irah L. King, Markus Mohrs
Journal: The Journal of Experimental Medicine (2009)

Interleukin (IL)-4 is the quintessential T helper type 2 (Th2) cytokine produced by CD4+ T cells in response to helminth infection. IL-4 not only promotes the differentiation of Th2 cells but is also critical for immunoglobulin (Ig) G1 and IgE isotype-switched antibody responses. Despite the IL-4–mediated link between Th2 cells and B lymphocytes, the location of IL-4–producing T cells in the lymph nodes is currently unclear. Using IL-4 dual reporter mice, we examined the Th2 response and IL-4 production in the draining mesenteric lymph nodes during infection with the enteric nematode Heligmosomoides polygyrus. We show that although IL-4–competent Th2 cells are found throughout the B and T cell areas, IL-4–producing Th2 cells are restricted to the B cell follicles and associate with germinal centers. Consistent with their localization, IL-4 producers express high levels of CXCR5, ICOS, PD-1, IL-21, and BCL-6, a phenotype characteristic of T follicular helper (Tfh) cells. Although IL-4 was dispensable for the generation of Th2 and Tfh cells, its deletion resulted in defective B cell expansion and maturation. Our report reveals the compartmentalization of Th2 priming and IL-4 production in the lymph nodes during infection, and identifies Tfh cells as the dominant source of IL-4 in vivo.
Thymic T Cell Development and Progenitor Localization Depend on CCR7
Authors: Ana Misslitz, Oliver Pabst, Gabriele Hintzen, Lars Ohl, Elisabeth Kremmer, Howard T. Petrie, Reinhold Förster
Journal: The Journal of Experimental Medicine (2004)

T cell differentiation in the adult thymus depends on sequential interactions between lymphoid progenitors and stromal cells found in distinct regions of the cortex and medulla. Therefore, migration of T cell progenitors through distinct stromal environments seems to be a crucial process regulating differentiation and homeostasis inside the thymus. Here we show that CCR7-deficient mice are distinguished by a disturbed thymic architecture, impaired T cell development, and decreased numbers of the thymocytes. Analysis of developing double negative (CD4−CD8−) pool of wild-type thymus reveals that CCR7 expression is restricted to a CD25intCD44+ subpopulation. Correspondingly, CCR7 deficiency results in an accumulation of this population in mutant thymus. Furthermore, immunohistology shows that in CCR7-deficient mice CD25+CD44+ cells accumulate at the cortico-medullary junction, suggesting that CCR7 signaling regulates the migration of early progenitors toward the outer thymic cortex, thereby continuing differentiation. Results obtained from mixed bone marrow chimeras support this view, since the development of CCR7-deficient thymocytes is also disturbed in a morphologically intact thymus. Thus, our findings establish an essential role for CCR7 in intrathymic migration and proper T cell development.
The clinical spectrum of epidermolysis bullosa simplex
Authors: H.M. Horn, M.J. Tidman
Journal: British Journal of Dermatology (2000)

As part of the U.K. National Epidermolysis Bullosa Register, we have systematically recorded clinical information on 130 (77%) of the 168 known Scottish epidermolysis bullosa simplex (EBS) sufferers. Three subtypes of EBS were recognized: Dowling-Meara (EBS-DM), Weber-Cockayne (EBS-WC) and Köbner (EBS-Kb), seen in 5%, 42% and 53% of patients, respectively. As there is considerable overlap between EBS-WC and EBS-Kb, with both phenotypes frequently seen within the same pedigree, EBS-WC is best regarded as a milder variant of EBS-Kb rather than a separate disorder. Improvement with age is common in all variants of EBS, but is not invariable. Pain due to acral blistering in EBS-Kb/EBS-WC has a more marked impact on life-style than the blisters of EBS-DM. Oral blistering, nail involvement and aplasia cutis congenita occur in all EBS subtypes and laryngeal involvement is a feature of EBS-DM. Seasonal variation is not seen in EBS-DM but is common in EBS-Kb/EBS-WC.
Molecular genetics of atrial fibrillation
Authors: Samir B Damani, Eric J Topol
Journal: Genome Medicine (2009)

Atrial fibrillation (AF) is the most common persistent cardiac dysrhythmia and the number one cause of arrhythmia-related hospitalizations. In addition, AF is a major contributor to stroke. With life expectancies increasing, the growing global disability from AF has crippling implications for society. Several family studies have shown a strong polygenetic predisposition for AF but, so far, most of the linkage analysis and candidate gene studies have discovered only monogenic, rare, deleterious mutations. Recent breakthroughs in high-throughput genotyping technology have allowed improved scanning of the genome with greater statistical power to detect susceptibility alleles for AF. Using this technology, a region on 4q25 has now been identified and validated in thousands of cases as a common susceptibility factor for AF with an odds ratio of over 3.0 for homozygotes. The Paired-like homeodomain transcription factor 2 (PITX2) gene, which is involved in embryonic cardiac development, has now been identified as the causal variant for the 4q25 susceptibility locus. Additional susceptibility variants are anticipated that will have direct ramifications for prognosis and treatment of this highly pervasive and clinically significant disorder.