tbuckley/cabot-search huggingface dataset:
Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15.
Authors: R A Seder, K H Grabstein, J A Berzofsky, J F McDyer
Journal: The Journal of Experimental Medicine (1995)

Cytokines have been shown to be powerful regulators of the immune response. In this study, we analyze the effect that the newly recognized cytokine interleukin (IL)-15 has on proliferation and cytokine induction using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells from patients infected with human immunodeficiency virus (HIV) who are at various stages in their disease. We observed that IL-15 enhances the proliferative response in a dose-dependent manner from PBMCs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toxoid, or HIV-specific antigen. The effects of exogenous IL-15 are substantially diminished by adding a neutralizing antibody to the beta chain of the IL-2 receptor. Moreover, the ability of IL-15 to increase proliferation is enhanced by the presence of endogenous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2, IL-4, and interferon (IFN)-gamma induction from PBMC's or CD4+ T cells in response to mitogen or tetanus toxoid was also examined. This was compared to the effect that exogenous IL-2 and IL-12 had under the same conditions. Addition of IL-2 or IL-15 to short-term in vitro cultures of either PBMCs or CD4+ T cells had little effect on IL-2, IL-4, or IFN-gamma production. By contrast, IL-12 caused substantial enhancement of both IL-2 and IFN-gamma production from these cultures. The role that endogenous cytokines have on IFN-gamma induction was also studied. Addition of a neutralizing antibody to the alpha chain of the IL-2 receptor or IL-12 to antigen stimulated cultures caused a striking decrease in IFN-gamma production. Neutralization of endogenous IL-15 also resulted in diminished IFN-gamma production from cultures stimulated with mitogen. IL-4 and IFN-gamma protein production by PBMCs and CD4+ T cells stimulated with mitogen was assessed to see if we could detect a specific bias of cytokine production. Small amounts of IL-4 were detected from CD4+ T cells but not PBMCs from most individuals tested. IFN-gamma and IL-2, however, were also produced from these same cultures. These results further elucidate the mechanism of cytokine regulation in HIV-infected individuals, and they provide evidence that IL-15 may be a useful immune modulator.
DNA sequence analysis of I-Ak beta mutants reveals serologically immunodominant region.
Authors: B N Beck, L R Pease, M P Bell, J M Buerstedde, A E Nilson, G G Schlauder, D J McKean
Journal: The Journal of Experimental Medicine (1987)

We have produced a series of in vitro serologically selected cell lines that express mutant I-Ak molecules. In this report we describe the DNA sequence analysis of the Ak beta gene of four cell lines that express serologically altered Ak beta polypeptides in association with wild-type Ak alpha polypeptides. Each of the major serologic epitopes on the Ak beta polypeptide has been altered in one or more of the four mutants. In addition, the four mutants exhibit a broad spectrum of functional defects when used to stimulate a panel of T hybridomas of various specificities. The DNA sequence analysis revealed that each mutant had sustained a single nucleotide substitution resulting in a single amino acid substitution. All four independent substitutions occurred within or near the third of the four variable regions defined in the beta 1 domain of the A beta polypeptide by allelic comparisons. These data strongly suggest that the third variable region is the major determinant of alloantigenicity on the Ak beta polypeptide.
PTU-008 A reproducible, clinically-relevant, intensively-managed, pig model of acute liver failure for testing of therapies aimed to prolong survival
Authors: K Lee, C Palacios Jimenez, H Alibhai, Y-M Chang, P Leckie, S Priestnall, R Mookerjee, R Jalan, N Davies
Journal: Gut (2012)

<h3>Introduction</h3> Hospitalisations from acetaminophen poisoning are increasing (1999, n=39 045; 2010, n=52 707. UK, NHS admissions). For the most serious cases there are no effective therapies to assist recovery or prolong survival apart from liver transplantation, which remains a limited resource. We report a clinically-relevant, intensively-managed, model of ALF, which mimics the human condition and has a predictable survival time, for testing of new potential therapies. <h3>Methods</h3> Nine, 30–40 kg, female pigs were anaesthetised and instrumented for continuous monitoring and management of respiratory and cardiovascular systems and acid-base and electrolyte status, using standardised intensive care protocols and intermittent positive pressure ventilation. Intracranial pressure (ICP) was monitored but not treated. Six animals were induced to ALF with acetaminophen administered via an oroduodenal tube: a loading dose of 0.25 g/kg was followed by hourly doses of 0.5–4.0 g adjusted according to serum acetaminophen concentrations. At irreversible ALF (defined as prothrombin time &gt;3 times normal), continuous renal replacement therapy (CRRT) was initiated. Three animals acted as controls with initiation of CRRT at 20 h and termination at 40 h. <h3>Results</h3> Following onset of acetaminophen dosing, peak serum acetaminophen concentrations of 367±30 mg/l were achieved at 12 h and irreversible ALF at 19.3±1.8 h. Death occurred predictably 12.6±2.7 h after irreversible ALF. Development of ALF was associated with progressive hypotension (p&lt;0.001) and metabolic acidosis (p=0.001), not observed in controls. Mean arterial pressure (MAP) was maintained with aggressive fluid therapy, noradrenaline and terlipressin. Metabolic acidosis was corrected successfully with bicarbonate and CRRT. In ALF, there was significant (p&lt;0.001) rise in ICP compared to controls with sudden marked increase prior to death: at study end, ICP in ALF and controls was 41.2±8.6 mm Hg and 22.7±2.5 mm Hg respectively. Death was preceded by abrupt increase in central venous pressure, fall in MAP and bradycardia. Histopathology confirmed moderate to marked acute centrilobular to midzonal hepatocyte degeneration and necrosis in ALF. <h3>Conclusion</h3> A predictable model of ALF, with death due to multi-organ failure, has been successfully validated for translational studies for therapies designed to prolong survival in man. <h3>Competing interests</h3> None declared.
Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression
Authors: Lu Yao, Chang Han, Kyoungsub Song, Jinqiang Zhang, Kyu Lim, Tong Wu
Journal: Cancer Research (2015)

Abstract Prostaglandin E2 (PGE2) is a proinflammatory lipid mediator that promotes cancer growth. The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes oxidation of the 15(S)-hydroxyl group of PGE2, leading to its inactivation. Therefore, 15-PGDH induction may offer a strategy to treat cancers that are driven by PGE2, such as human cholangiocarcinoma. Here, we report that omega-3 polyunsaturated fatty acids (ω-3 PUFA) upregulate 15-PGDH expression by inhibiting miR-26a and miR-26b, thereby contributing to ω-3 PUFA-induced inhibition of human cholangiocarcinoma cell growth. Treatment of human cholangiocarcinoma cells (CCLP1 and TFK-1) with ω-3 PUFA (DHA) or transfection of these cells with the Fat-1 gene (encoding Caenorhabditis elegans desaturase, which converts ω-6 PUFA to ω-3 PUFA) significantly increased 15-PGDH enzymes levels, but with little effect on the activity of the 15-PGDH gene promoter. Mechanistic investigations revealed that this increase in 15-PGDH levels in cells was mediated by a reduction in the expression of miR-26a and miR-26b, which target 15-PGDH mRNA and inhibit 15-PGDH translation. These findings were extended by the demonstration that overexpressing miR-26a or miR-26b decreased 15-PGDH protein levels, reversed ω-3 PUFA-induced accumulation of 15-PGDH protein, and prevented ω-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. We further observed that ω-3 PUFA suppressed miR-26a and miR-26b by inhibiting c-myc, a transcription factor that regulates miR-26a/b. Accordingly, c-myc overexpression enhanced expression of miR-26a/b and ablated the ability of ω-3 PUFA to inhibit cell growth. Taken together, our results reveal a novel mechanism for ω-3 PUFA-induced expression of 15-PGDH in human cholangiocarcinoma and provide a preclinical rationale for the evaluation of ω-3 PUFA in treatment of this malignancy. Cancer Res; 75(7); 1388–98. ©2015 AACR.
Anti-tumour necrosis factor alpha monoclonal antibody therapy for recalcitrant cerebral vasculitis in a patient with Behcet's syndrome
Authors: G Licata
Journal: Annals of the Rheumatic Diseases (2003)

reuil et al reported on a patient with Erdheim-Chester disease. 1 We would like to add our experience in a patient who had a good response to steroids.A 46 year old housewife, born in Maceio (Brazil), complained of pain in her legs for a period of eight months, which interfered with her sleep; there were no constitutional symptoms, such as weight loss, asthenia, or fever.On physical examination, there was no systemic involvement or bone inflammation, except for tenderness on palpation of both tibiae.An x ray examination showed bilateral and symmetrical cortical osteosclerosis of the diaphysial regions of the tibiae, which was better illustrated with magnetic resonance imaging (MRI) which showed a low signal on T 1 and a high signal on T 2 of the medullar canal (fig 1).Bone scintigraphy showed intense hypercapitation at the upper and medial regions of the right tibia and the medial region of the left tibia (fig 2).Other MR images (brain, thorax, and abdomen) were normal.A bone biopsy showed only osteosclerosis, which has been described in this disease. 2 She was treated with steroids for six months (prednisone 20 mg/day) and responded well, being asymptomatic and receiv-ing no treatment since December 2000.As bone pain is the first symptom of this xanthogranulomatosis, rheumatologists should be able to recognise the disease in an early phase when treatment gives a better outcome.. . . .
Limited posterior left atrial cryoablation in patients with chronic atrial fibrillation undergoing valvular heart surgery
Authors: Fiorenzo Gaita, Roberto Gallotti, Leonardo Calò, Eric Manasse, Riccardo Riccardi, Lucia Garberoglio, Francesco Nicolini, Marco Scaglione, Paolo Di Donna, Domenico Caponi, Giorgio Franciosi
Journal: Journal of the American College of Cardiology (2000)
Magnetic Resonance Imaging of the Upper Airway in Children with Down Syndrome
Authors: ELIZABETH C. UONG, JOSEPH M. McDONOUGH, CATHERINE E. TAYAG-KIER, HUAQING ZHAO, JOHN HASELGROVE, SOROUSH MAHBOUBI, RICHARD J. SCHWAB, ALLAN I. PACK, RAANAN ARENS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

As compared with control subjects, children with Down syndrome have different size and shape relationships among tissues composing the upper airway, which may predispose them to obstructive sleep apnea (OSA). We hypothesized that Down syndrome children without OSA have similar subclinical differences. We used magnetic resonance imaging to study the upper airway in 11 Down syndrome children without OSA (age, 3.2 ± 1.4 yr) and in 14 control subjects (age, 3.3 ± 1.1 yr). Sequential T1- and T2-weighted spin-echo axial and sagittal images were obtained. We found a smaller airway volume in subjects with Down syndrome (1.4 ± 0.4 versus 2.3 ± 0.8 cm3 in controls, p < 0.005). Subjects with Down syndrome had a smaller mid- and lower face skeleton. They had a shorter mental spine–clivus distance (5.7 ± 0.6 versus 6.2 ± 0.4 cm, p < 0.05), hard palate length (3.2 ± 0.4 versus 3.7 ± 0.2 cm, p < 0.005), and mandible volume (11.5 ± 3.7 versus 16.9 ± 2.9 cm3, p < 0.0005). Adenoid and tonsil volume was significantly smaller in the subjects with Down syndrome. However, the tongue, soft-palate, pterygoid, and parapharyngeal fat pads were similar to those of control subjects. This study shows that Down syndrome children without OSA do not have increased adenoid or tonsillar volume; reduced upper airway size is caused by soft tissue crowding within a smaller mid- and lower face skeleton.
Extracellular adenosine regulates naive T cell development and peripheral maintenance
Authors: Caglar Cekic, Duygu Sag, Yuan-Ji Day, Joel Linden
Journal: The Journal of Experimental Medicine (2013)

Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A2A receptor (A2AR) gene, Adora2a, and show that either global A2AR deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A2AR signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K)–AKT pathway, thereby reducing IL-7Rα down-regulation and naive T cell apoptosis. Patterns of IL-7Rα expression on T cells in chimeric mice reconstituted with Adora2a+/+ and Adora2a−/− bone marrow cells suggest that decreased IL-7Rα in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A2AR expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7Rα expression. Therefore, A2AR signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery.
A Medical Interviewing Course: Objectives, Techniques, and Assessment
Authors: DAVID W. CLINE, JUDITH N. GARRARD
Journal: American Journal of Psychiatry (1973)

The authors describe a course for teaching medical interviewing skills to medical students. Course components included a programmed manual, observing a skilled interviewer, role-playing exercises, programmed medical interviewing films, and interviewing patients. The majority of the course was conducted in a small-group setting during a one-week period. Student participation was emphasized in course planning and discussion groups and as learners and teachers. Students and instructors rated the course as above average to excellent. The students showed a significant learning gain in medical interviewing techniques.
THE INTERRELATIONSHIPS OF THE CARDIOVASCULAR, RENAL AND ELECTROLYTE EFFECTS OF INTRAVENOUS DIGOXIN IN CONGESTIVE HEART FAILURE 1
Authors: Ludwig W. Eichna, Saul J. Farber, Adolph R. Berger, David P. Earle, Bertha Rader, Edmund Pellegrino, Roy E. Albert, J. Deaver Alexander, Harry Taube, Sol Youngwirth
Journal: Journal of Clinical Investigation (1951)
GOLD 2011 disease severity classification in COPDGene: a prospective cohort study
Authors: MeiLan K Han, Hana Muellerova, Douglas Curran-Everett, Mark T Dransfield, George R Washko, Elizabeth A Regan, Russell P Bowler, Terri H Beaty, John E Hokanson, David A Lynch, Paul W Jones, Antonio Anzueto, Fernando J Martinez, James D Crapo, Edwin K Silverman, Barry J Make
Journal: The Lancet Respiratory Medicine (2012)
Arsenic Trioxide Affects Signal Transducer and Activator of Transcription Proteins through Alteration of Protein Tyrosine Kinase Phosphorylation
Authors: Meir Wetzler, Michael T. Brady, Erin Tracy, Zhang-Rong Li, Kathleen A. Donohue, Kieran L. O'Loughlin, Yijun Cheng, Amir Mortazavi, Amy A. McDonald, Padmaja Kunapuli, Paul K. Wallace, Maria R. Baer, John K. Cowell, Heinz Baumann
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Arsenic trioxide decreases proliferation of acute myeloid leukemia (AML) cells, but its precise mechanism of action is unknown. Experimental Design: We studied the effect of arsenic trioxide on patient samples and the AML cell line HEL, which, like leukemic blasts from 50% of AML cases, has constitutively activated signal transducer and activator of transcription (STAT) proteins. Results: Arsenic trioxide induced mitotic arrest starting at 24 hours and significant cell death at 48 hours. These events were preceded by an arsenic trioxide dose-dependent down-regulation of activated STAT proteins starting at 6 hours. We hypothesized that arsenic trioxide inhibits protein tyrosine kinases (PTK), which, among others, phosphorylate and activate STATs. We therefore studied arsenic trioxide effects on Janus kinases and on three oncogenic PTKs that are known to activate STATs [FLT3, ZNF198/fibroblast growth factor receptor 1 (FGFR1), and BCR/ABL]. Arsenic trioxide reduced STAT3 activation by Janus kinases, altered phosphorylation and electrophoretic mobility of ZNF198/fibroblast growth factor receptor 1, reduced kinase protein level, and decreased STAT3 protein phosphorylation. Arsenic trioxide also reduced the phosphorylation of BCR/ABL and FLT3 with corresponding decreased STAT5 phosphorylation. Conclusions: These results suggest a selective activity of arsenic trioxide on PTKs and will assist in developing clinical trials in AML.
Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening
Authors: Ah-Fong Hoo, Lena P Thia, The Thanh Diem Nguyen, Andrew Bush, Jane Chudleigh, Sooky Lum, Deeba Ahmed, Ian Balfour-Lynn, Siobhan B Carr, Richard J Chavasse, Kate L Costeloe, John Price, Anu Shankar, Colin Wallis, Hilary A Wyatt, Angela Wade, Janet Stocks
Journal: Thorax (2012)

<h3>Background</h3> Long-term benefits of newborn screening (NBS) for cystic fibrosis (CF) have been established with respect to nutritional status, but effects on pulmonary health remain unclear. <h3>Hypothesis</h3> With early diagnosis and commencement of standardised treatment, lung function at ∼3 months of age is normal in NBS infants with CF. <h3>Methods</h3> Lung clearance index (LCI) and functional residual capacity (FRC) using multiple breath washout (MBW), plethysmographic (pleth) FRC and forced expirations from raised lung volumes were measured in 71 infants with CF (participants in the London CF Collaboration) and 54 contemporaneous healthy controls age ∼3 months. <h3>Results</h3> Compared with controls, and after adjustment for body size and age, LCI, FRC<sub>MBW</sub> and FRC<sub>pleth</sub> were significantly higher in infants with CF (mean difference (95% CI): 0.5 (0.1 to 0.9), p=0.02; 0.4 (0.1 to 0.7), p=0.02 and 0.9 (0.4 to 1.3), p&lt;0.001, z-scores, respectively), while forced expiratory volume (FEV<sub>0.5</sub>) and flows (FEF<sub>25–75</sub>) were significantly lower (−0.9 (−1.3 to −0.6), p&lt;0.001 and −0.7 (−1.1 to −0.2), p=0.004, z-scores, respectively). 21% (15/70) of infants with CF had an elevated LCI (&gt;1.96 z-scores) and 25% (17/68) an abnormally low FEV<sub>0.5</sub> (below −1.96 z-scores). While only eight infants with CF had abnormalities of LCI and FEV<sub>0.5</sub>, using both techniques identified abnormalities in 35% (24/68). Hyperinflation (FRC<sub>pleth</sub> &gt;1.96 z-scores) was identified in 18% (10/56) of infants with CF and was significantly correlated with diminished FEF<sub>25–75</sub> (r=−0.43, p&lt;0.001) but not with LCI or FEV<sub>0.5</sub>. <h3>Conclusion</h3> Despite early diagnosis of CF by NBS and protocol-driven treatment in specialist centres, abnormal lung function, with increased ventilation inhomogeneity and hyperinflation and diminished airway function, is evident in many infants with CF diagnosed through NBS by 3 months of age.
Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy
Authors: Robert S. Rahimi, Amit G. Singal, Jennifer A. Cuthbert, Don C. Rockey
Journal: JAMA Internal Medicine (2014)

Hepatic encephalopathy (HE) is a common cause of hospitalization in patients with cirrhosis. Pharmacologic treatment for acute (overt) HE has remained the same for decades.To compare polyethylene glycol 3350-electrolyte solution (PEG) and lactulose treatments in patients with cirrhosis admitted to the hospital for HE. We hypothesized that rapid catharsis of the gut using PEG may resolve HE more effectively than lactulose.The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE.Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization.The primary end point was an improvement of 1 or more in HE grade at 24 hours, determined using the hepatic encephalopathy scoring algorithm (HESA), ranging from 0 (normal clinical and neuropsychological assessments) to 4 (coma). Secondary outcomes included time to HE resolution and overall length of stay.A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related.PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE.clinicaltrials.gov Identifier: NCT01283152.
Farnesoid X receptor–induced lysine‐specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity
Authors: Young‐Chae Kim, Sungsoon Fang, Sangwon Byun, Sunmi Seok, Byron Kemper, Jongsook Kim Kemper
Journal: Hepatology (2014)

Bile acids (BAs) function as endocrine signaling molecules that activate multiple nuclear and membrane receptor signaling pathways to control fed‐state metabolism. Since the detergent‐like property of BAs causes liver damage at high concentrations, hepatic BA levels must be tightly regulated. Bile acid homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary BA receptor, farnesoid X receptor, and small heterodimer partner, which inhibits BA synthesis by recruiting repressive histone‐modifying enzymes. Although histone modifiers have been shown to regulate BA‐responsive genes, their in vivo functions remain unclear. Here, we show that lysine‐specific histone demethylase1 (LSD1) is directly induced by BA‐activated farnesoid X receptor, is recruited to the BA synthetic genes Cyp7a1 and Cyp8b1 and the BA uptake transporter gene Ntcp , and removes a gene‐activation marker, trimethylated histone H3 lysine‐4, leading to gene repression. Recruitment of LSD1 was dependent on small heterodimer partner, and LSD1‐mediated demethylation of trimethylated histone H3 lysine‐4 was required for additional repressive histone modifications, acetylated histone 3 on lysine 9 and 14 deacetylation, and acetylated histone 3 on lysine 9 methylation. A BA overload, feeding 0.5% cholic acid chow for 6 days, resulted in adaptive responses of altered expression of hepatic genes involved in BA synthesis, transport, and detoxification/conjugation. In contrast, adenovirus‐mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum alanine aminotransferase and aspartate aminotransferase levels, and hepatic inflammation. Conclusion : This study identifies LSD1 as a novel histone‐modifying enzyme in the orchestrated regulation mediated by the farnesoid X receptor and small heterodimer partner that reduces hepatic BA levels and protects the liver against BA toxicity. (H epatology 2015;62:220‐231)