tbuckley/cabot-search huggingface dataset:
Blood Eosinophils to Direct Corticosteroid Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease
Authors: Mona Bafadhel, Susan McKenna, Sarah Terry, Vijay Mistry, Mitesh Pancholi, Per Venge, David A. Lomas, Michael R. Barer, Sebastian L. Johnston, Ian D. Pavord, Christopher E. Brightling
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous.Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations.Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms.There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04).The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.
p53 Is Renoprotective after Ischemic Kidney Injury by Reducing Inflammation
Authors: Timothy A. Sutton, Takashi Hato, Erik Mai, Momoko Yoshimoto, Sarah Kuehl, Melissa Anderson, Henry Mang, Zoya Plotkin, Rebecca J. Chan, Pierre C. Dagher
Journal: Journal of the American Society of Nephrology (2012)

In the rat, p53 promotes tubular apoptosis after ischemic AKI. Acute pharmacologic inhibition of p53 is protective in this setting, but chronic inhibition enhances fibrosis, demonstrating that the role of p53 in ischemic AKI is incompletely understood. Here, we investigated whether genetic absence of p53 is also protective in ischemic AKI. Surprisingly, p53-knockout mice (p53(-/-)) had worse kidney injury, compared with wild-type mice, and exhibited increased and prolonged infiltration of leukocytes after ischemia. Acute inhibition of p53 with pifithrin-α in wild-type mice mimicked the observations in p53(-/-) mice. Chimeric mice that lacked p53 in leukocytes sustained injury similar to p53(-/-) mice, suggesting an important role for leukocyte p53 in ischemic AKI. Compared with wild-type mice, a smaller proportion of macrophages in the kidneys of p53(-/-) and pifithrin-α-treated mice after ischemic injury were the anti-inflammatory M2 phenotype. Ischemic kidneys of p53(-/-) and pifithrin-α-treated mice also showed reduced expression of Kruppel-like factor-4. Finally, models of peritonitis in p53(-/-) and pifithrin-α-treated mice confirmed the anti-inflammatory role of p53 and its effect on the polarization of macrophage phenotype. In summary, in contrast to the rat, inflammation characterizes ischemic AKI in mice; leukocyte p53 is protective by reducing the extent and duration of this inflammation and by promoting the anti-inflammatory M2 macrophage phenotype.
Childhood functional gastrointestinal disorders
Authors: A Rasquin-Weber, P E Hyman, S Cucchiara, D R Fleisher, J S Hyams, P J Milla, A Staiano
Journal: Gut (1999)

This is the first attempt at defining criteria for functional gastrointestinal disorders (FGIDs) in infancy, childhood, and adolescence. The decision-making process was as for adults and consisted of arriving at consensus, based on clinical experience. This paper is intended to be a quick reference. The classification system selected differs from the one used in the adult population in that it is organized according to main complaints instead of being organ-targeted. Because the child is still developing, some disorders such as toddler's diarrhea (or functional diarrhea) are linked to certain physiologic stages; others may result from behavioral responses to sphincter function acquisition such as fecal retention; others will only be recognizable after the child is cognitively mature enough to report the symptoms (e.g., dyspepsia). Infant regurgitation, rumination, and cyclic vomiting constitute the vomiting disorders. Abdominal pain disorders are classified as: functional dyspepsia, irritable bowel syndrome (IBS), functional abdominal pain, abdominal migraine, and aerophagia. Disorders of defecation include: infant dyschezia, functional constipation, functional fecal retention, and functional non-retentive fecal soiling. Some disorders, such as IBS and dyspepsia and functional abdominal pain, are exact replications of the adult criteria because there are enough data to confirm that they represent specific and similar disorders in pediatrics. Other disorders not included in the pediatric classification, such as functional biliary disorders, do occur in children; however, existing data are insufficient to warrant including them at the present time. For these disorders, it is suggested that, for the time being, clinicians refer to the criteria established for the adult population.
Establishment of a cell line from a hepatocellular carcinoma from a patient with hemochromatosis
Authors: Garwin K. Sing, Raymond Pace, Sharon Prior, Janet S.D. Scott, Paul Shield, Nicole Martin, Jeffrey Searle, Cameron Battersby, Lawrie W. Powell, Graham W.E. Cooksley
Journal: Hepatology (1994)

ABSTRACT We describe the establishment and characterization of a novel hepatoma cell line. This cell line, designated RBHF–1, was established from a hepatocellular carcinoma of a 67–yr–old man with a history of genetic hemochromatosis. At this writing, the cells have been maintained in RPMI–1640 tissue–culture medium and fetal calf serum without any additional supplements for 30 mo. The cells form colonies on soft agar and are not tumorigenic in nude mice. The cell line is polymorphic and displays characteristics of mature hepatocytes by synthesizing albumin, α2–macroglobulin, fibronectin and α–fetoprotein. Cytogenetic analysis shows multiple chromosomal aberrations, with a consistent deletion in the long arm and deletions or rearrangements in the short arm of chromosome 1. There is no evidence for hepatitis B or hepatitis C virus infection of the cell line. The cells contain no detectable intracellular iron after staining with Perls' stain. Unlike other hepatoma cell lines, there is no detectable binding of epidermal growth factor to RBHF–1 cells. This is the first cell line to be established from a patient with hemochromatosis, and it provides a potentially important model for the study of hepatocyte transformation in association with iron overload. (Hepatology 1994;20:74-81.)
Prognostic Significance of Endothelial Dysfunction in Hypertensive Patients
Authors: Francesco Perticone, Roberto Ceravolo, Arturo Pujia, Giorgio Ventura, Saverio Iacopino, Angela Scozzafava, Alessandro Ferraro, Massimo Chello, Pasquale Mastroroberto, Paolo Verdecchia, Giuseppe Schillaci
Journal: Circulation (2001)

Background — Forearm endothelial dysfunction, characterized by an impaired vasodilating response to acetylcholine (ACh), may be associated with several cardiovascular risk factors, including essential hypertension. Although the prognostic value of coronary endothelial dysfunction has been demonstrated, that of forearm endothelial dysfunction is still unknown. Methods and Results — Endothelium-dependent and -independent vasodilation was investigated in 225 never-treated hypertensive patients (age, 35 to 54 years) by intra-arterial infusion of increasing doses of ACh and sodium nitroprusside. Patients were divided into tertiles on the basis of their increase in ACh-stimulated forearm blood flow (FBF) from basal: group 1, from 30% to 184%; group 2, from 185% to 333%; and group 3, from 339% to 760% increase from basal. During a mean follow-up of 31.5 of months (range, 4 to 84 months), there were 29 major adverse events at the cardiac (n=19), cerebrovascular (n=9), or peripheral vascular (n=1) level. Events included myocardial infarction, angina, coronary revascularization procedures, stroke, transient cerebral ischemic attack, and aortoiliac occlusive disease. Event rate per 100 patient-years was 8.17, 4.34, and 2.02 in the first, second, and third tertiles of peak percent increase in FBF during ACh infusion. The excess risk associated with an FBF increase in the first tertile was significant (relative risk, 2.084; 95% CI, 1.25 to 3.48; P =0.0049) after controlling for individual risk markers, including 24-hour ambulatory blood pressure. Conclusions — Our data suggest that forearm endothelial dysfunction is a marker of future cardiovascular events in patients with essential hypertension.
The effect of age, sex, obesity and posture on upper airway size
Authors: SE Martin, R Mathur, I Marshall, NJ Douglas
Journal: European Respiratory Journal (1997)

Most patients with sleep apnoea/hypopnoea syndrome (SAHS) are middle-aged men. As there are conflicting data on the effects of age and gender on upper airway calibre, we tested the hypothesis that increasing age and the male sex predispose to upper airway narrowing in normal subjects. We measured upper airway calibre using acoustic reflection in 60 men and 54 women (median 35, range 16-74 yrs) both seated and supine. All upper airway dimensions, except oropharyngeal junction (OPJ), decreased with increasing age in both men and women (r &gt; -0.24, p &lt; or = 0.05) while supine (r2 &gt; 0.06). Men had greater changes in airway area at OPJ on lying down (mean (SEM) 0.5 (0.1), 0.2 (0.1) cm2; p &lt; 0.02). Men had greater body mass indices (mean (SD) 26 (4), 24 (4) kg.m-2; p = 0.04), and larger neck circumferences (mean (SD) 38 (3), 33 (2) cm; p &lt; 0.0001) than women. For any body mass index, neck circumference was larger in men than women (p &lt; 0.001). This study shows that upper airway size decreases with increasing age in both men and women, and that men have greater upper airway collapsibility on lying down at oropharyngeal junction than women.
Post-Transplant Lymphoproliferative Disorders
Authors: Stephen Gottschalk, Cliona M. Rooney, Helen E. Heslop
Journal: Annual Review of Medicine (2004)

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after hematopoietic stem cell or solid organ transplantation. The majority of PTLD is of B-cell origin and associated with Epstein-Barr virus (EBV). During the past decade progress has been made in better understanding the pathogenesis of PTLD, and early detection strategies, such as serial measurement of EBV-DNA load in peripheral blood samples, have assisted in the identification of high-risk patients. In addition, novel immunotherapies have been developed, including the use of monoclonal antibodies and adoptive transfer of EBV-specific T cells. Despite these advances, it remains a major challenge to define indications for preemptive therapies for PTLD and to integrate novel therapeutic approaches with conventional therapies.
Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma
Authors: Diego F. Calvisi, Federico Pinna, Floriana Meloni, Sara Ladu, Rossella Pellegrino, Marcella Sini, Lucia Daino, Maria M. Simile, Maria R. De Miglio, Patrizia Virdis, Maddalena Frau, Maria L. Tomasi, Maria A. Seddaiu, Maria R. Muroni, Francesco Feo, Rosa M. Pascale
Journal: Cancer Research (2008)

Abstract Sustained activation of extracellular signal-regulated kinase (ERK) has been detected previously in numerous tumors in the absence of RAS-activating mutations. However, the molecular mechanisms responsible for ERK-unrestrained activity independent of RAS mutations remain unknown. Here, we evaluated the effects of the functional interactions of ERK proteins with dual-specificity phosphatase 1 (DUSP1), a specific inhibitor of ERK, and S-phase kinase-associated protein 2 (SKP2)/CDC28 protein kinase 1b (CKS1) ubiquitin ligase complex in human hepatocellular carcinoma (HCC). Levels of DUSP1, as assessed by real-time reverse transcription–PCR and Western blot analysis, were significantly higher in tumors with better prognosis (as defined by the length of patients' survival) when compared with both normal and nontumorous surrounding livers, whereas DUSP1 protein expression sharply declined in all HCC with poorer prognosis. In the latter HCC subtype, DUSP1 inactivation was due to either ERK/SKP2/CKS1-dependent ubiquitination or promoter hypermethylation associated with loss of heterozygosity at the DUSP1 locus. Noticeably, expression levels of DUSP1 inversely correlated with those of activated ERK, as well as with proliferation index and microvessel density, and directly with apoptosis and survival rate. Subsequent functional studies revealed that DUSP1 reactivation led to suppression of ERK, CKS1, and SKP2 activity, inhibition of proliferation and induction of apoptosis in human hepatoma cell lines. Taken together, the present data indicate that ERK achieves unrestrained activity during HCC progression by triggering ubiquitin-mediated proteolysis of its specific inhibitor DUSP1. Thus, DUSP1 may represent a valuable prognostic marker and ERK, CKS1, or SKP2 potential therapeutic targets for human HCC. [Cancer Res 2008;68(11):4192–200]
The Consequences of Toxic Shock Syndrome in an 18-Month-Old Boy with 20% Scalds
Authors: T C Davis, N K Griffin
Journal: Journal of the Royal Society of Medicine (1996)

Toxic shock syndrome may complicate burns and scalds in young children 1,2 . However, it can occur in the district general hospital setting, where early recognition of the prodromal features to facilitate early therapy will depend on the knowledge and training of paediatricians and casualty staff.
Transcriptional Autoregulation by BRCA1
Authors: Adriana De Siervi, Paola De Luca, Jung S. Byun, Li Jun Di, Temesgen Fufa, Cynthia M. Haggerty, Elba Vazquez, Cristian Moiola, Dan L. Longo, Kevin Gardner
Journal: Cancer Research (2010)

Abstract The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult. Cancer Res; 70(2); 532–42
Blocking Angiotensin II Synthesis/Activity Preserves Glomerular Nephrin in Rats with Severe Nephrosis
Authors: ARIELA BENIGNI, SUSANNA TOMASONI, ELENA GAGLIARDINI, CARLA ZOJA, JAMES A. GRUNKEMEYER, RAGHU KALLURI, GIUSEPPE REMUZZI
Journal: Journal of the American Society of Nephrology (2001)

Angiotensin-converting enzyme inhibitors restore size-selective dysfunction of the glomerular barrier in experimental animals and humans with proteinuric nephropathies, although the structural and molecular determinants of such an effect are not completely understood. This study used an accelerated model of experimental nephrosis to assess nephrin gene and protein expression in the kidney and the possible modulating effect of drugs that block angiotensin II (AII) synthesis/activity. Passive Heymann nephritis (PHN) and control animals were studied at day 7, month 4, and month 8. Additional PHN rats were treated with lisinopril or AII receptor blocker L-158,809 and studied at 8 mo. Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury. An intense signal of nephrin mRNA was detected in glomeruli of control animals mainly restricted to podocytes. In PHN rats, nephrin staining progressively and remarkably decreased with time. Lisinopril and L-158,809 fully prevented the decrease in nephrin transcripts to levels comparable to those of control rats. Consistent with nephrin mRNA expression, immunostaining of the protein showed a progressive decrease in kidneys from PHN rats that was completely abolished by lisinopril and L-158,809. In summary, progressive renal injury was associated with downregulation of nephrin gene that was totally prevented by angiotensin-converting enzyme inhibitor and AII receptor blocker, suggesting that renoprotection afforded by drugs that interfere with AII synthesis/activity was related to an effect on nephrin assembly.
Germinal centers are free for all
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2007)

![Graphic][1] 

The offspring of two types of B cell clones (red and yellow) are present in several germinal centers (numbered) in a human lymph node (blue). Germinal centers (GCs)—the sites of antibody development—are not exclusive niches for rookie B cells. They are also open to
Biological monitoring of particulate matter accumulated in the lungs of urban asthmatic children in the Tel Aviv Metropolitanian Area
Authors: Elizabeth Fireman, Daria Bliznuk, Yehuda Schwarz, Ruth Soferman, Shmuel Kivity
Journal: European Respiratory Journal (2013)

Background: Lung inflammation from exposure to air-borne particulate matter (PM) may be responsible for morbidity in asthma. But several studies using environmental monitoring data showed inconsistent results. We evaluated the capability of induced sputum (IS) technology to biologically monitor particulate matter in the lungs of urban asthmatic children.

Methods: We collected clinical, demographic, biological and environmental monitoring data on 136 children referred for asthma evaluations. The study participants were divided into two groups according to IS eosinophil counts of <3% (non-inflammatory) and ≥3% (inflammatory).

Results : Particles (ranges 0-2.5 µm and 0-5 µm) in biologic monitoring comprised a strong risk factor for eosinophilic inflammation in IS (≥3%).Children with >80% of particles (0-2.5 µm) out of the total particulate matter accumulated in the airways display the highest OR 10.7 (CI=2.052-56.4 p = 0.005) to induced eosinophilic inflammation. Heme oxygenase-1 (HO-1) enzyme levels in IS positively correlated with % eosinophils and with particles in IS ranged between 2-3 μm. The level of HO-1 enzyme activity and FEV1/FVC in children with <3% eosinophils, but not ≥3%, were positively and significantly correlated, showing a protective effect of HO-1 in this group.

Conclusions : Accumulation of particulate matter involves oxidative stress pathways and is a risk factor for developing eosinophilic inflammation in asthmatic children. IS can biologically monitor this process.
Serum leptin concentration, obesity, and insulin resistance in Western Samoans: cross sectional study
Authors: P. Zimmet, A. Hodge, M. Nicolson, M. Staten, M. de Courten, J. Moore, A. Morawiecki, J. Lubina, G. Collier, G. Alberti, G. Dowse
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objective</b>: To measure serum leptin concentrations in the Polynesian population of Western Samoa and to examine epidemiological associations of leptin with anthropometric, demographic, behavioural, and metabolic factors in this population with a high prevalence of obesity and non-insulin dependent diabetes mellitus. <b>Design</b>: Cross sectional study, leptin concentration being measured in a subgroup of a population based sample. <b>Subjects</b>: 240 Polynesian men and women aged 28–74 years were selected to cover the full range of age, body mass index, and glucose tolerance. <b>Main outcome measurements</b>: Serum leptin, insulin, and glucose concentrations; anthropometric measures; physical activity; and area of residence. <b>Results</b>: Leptin concentrations were correlated with body mass index (r = 0.80 in men, 0.79 in women) and waist circumference (r = 0.82 in men, 0.78 in women) but less so with waist to hip ratio. At any body mass index, leptin concentration was higher in women than men (geometric mean adjusted for body mass index 15.3 v 3.6 pg/1, P&lt;0.001). Leptin concentration also correlated with fasting insulin concentration (r = 0.63 in men, 0.64 in women) and insulin concentration 2 hours after a glucose load (r = 0.58 in men, 0.52 in women). These associations remained significant after controlling for body mass index; effects of physical activity and of rural or urban living on leptin concentration were eliminated after adjusting for obesity, except values remained high in urban men. 78% of variance in leptin was explained by a model including fasting insulin concentration, sex, body mass index, and a body mass index by sex interaction term. Similar results were obtained if waist circumference replaced body mass index. <b>Conclusions</b>: The strong relation of leptin with obesity is consistent with leptin production being proportional to mass of adipose tissue. The relation with insulin independent of body mass index suggests a possible role for leptin in insulin resistance or hyperinsulinaemia. <h3>Key messages</h3> They were also strongly correlated with serum insulin concentrations even after adjusting for obesity in both sexes Concentrations were higher in women than men, even at the same body mass index or waist circumference Resistance to the effects of leptin may be important in human obesity Leptin may simply reflect the size of adipose tissue stores, but the independent association with insulin concentration suggests a possible role in insulin resistance or hyperinsulinaemia