tbuckley/cabot-search huggingface dataset:
A randomized controlled trial to compare the safety and effectiveness of doxycycline (200 mg daily) with oral prednisolone (0·5 mg kg−1 daily) for initial treatment of bullous pemphigoid: a protocol for the Bullous Pemphigoid Steroids and Tetracyclines (B
Authors: J.R. Chalmers, F. Wojnarowska, G. Kirtschig, A.J. Nunn, D.J. Bratton, J. Mason, K.A. Foster, D. Whitham, H.C. Williams
Journal: British Journal of Dermatology (2015)

Bullous pemphigoid (BP) is the most common autoimmune blistering disease in older people, and is associated with significant morbidity and mortality. Oral corticosteroids are usually effective but the side-effects are thought to contribute to the high morbidity and mortality rate. Treatment with oral tetracyclines may be effective but high-quality, randomized controlled trials (RCTs) are needed to confirm this.To compare the effectiveness and safety of two strategies for treating BP.This is a two-arm, parallel group, 52-week RCT comparing doxycycline with prednisolone for initial treatment of BP. Dose is fixed for the initial 6 weeks of treatment (doxycycline 200 mg daily; prednisolone 0.5 mg kg(-1) daily), after which it can be adjusted according to need. A total of 256 patients with BP will be recruited in the U.K. and Germany.The primary outcomes are: (i) effectiveness (assessor-blinded blister count at 6 weeks) and (ii) safety [proportion of patients experiencing ≥ grade 3 adverse events (i.e. severe, life: threatening or fatal) related to trial medication during the year of follow-up]. Primary effectiveness analysis will be an assessment of whether doxycycline can be considered noninferior to prednisolone after 6 weeks of treatment. Primary safety analysis is a superiority analysis at 12 months. Secondary outcomes include longer-term assessment of effectiveness, relapse rates, the proportion of patients experiencing any grade of adverse events related to treatment, quality of life and cost-effectiveness.The trial will provide good evidence for whether the strategy of starting BP treatment with doxycycline is a useful alternative to prednisolone.
Leukocyte, Rather than Tumor-produced SPARC, Determines Stroma and Collagen Type IV Deposition in Mammary Carcinoma
Authors: Sabina Sangaletti, Antonella Stoppacciaro, Cristiana Guiducci, Maria Rosaria Torrisi, Mario P. Colombo
Journal: The Journal of Experimental Medicine (2003)

Secreted protein, acidic and rich in cysteine (SPARC), also known as osteonectin or BM-40, is a Ca2+-binding matricellular glycoprotein involved in development, wound healing, and neoplasia. However, the role of SPARC in tumors is ill defined mostly because it is expressed by both tumor and stromal cells, especially inflammatory cells. We analyzed the respective roles of host- and tumor-derived SPARC in wild-type and congenic SPARC knockout (SPARC−/−) mice on a BALB/c genetic background injected into the mammary fat pad with SPARC-producing mammary carcinoma cells derived from c-erB2 transgenic BALB/c mice. Reduced tumor growth but massive parenchyma infiltration, with large areas of necrosis and impaired vascularization were observed in SPARC−/− mice. Immunohistochemical analysis showed a defect in collagen type IV deposition in the stroma of lobular tumors from SPARC−/− mice. Chimeric mice expressing SPARC only in bone marrow–derived cells were able to organize peritumoral and perilobular stroma, whereas reciprocal chimeras transplanted with bone marrow from SPARC−/− mice developed tumors with less defined lobular structures, lacking assembled collagen type IV and with a parenchyma heavily infiltrated by leukocytes. Together, the data indicate that SPARC produced by host leukocytes, rather than the tumor, determines the assembly and function of tumor-associated stroma through the organization of collagen type IV.
Acute abdominal pain in systemic lupus erythematosus: factors contributing to recurrence of lupus enteritis
Authors: Y G Kim, H K Ha, S S Nah, C-K Lee, H-B Moon, B Yoo
Journal: Annals of the Rheumatic Diseases (2006)

<h3>Summary</h3> <i>De novo</i> genetic mutations represent a major contributor to pediatric disease, including autism spectrum disorders (ASD), congenital heart disease, and muscular dystrophies<sup>1,2</sup>, but there are currently no methods to prevent or predict them. These mutations are classically thought to occur either at low levels in progenitor cells or at the time of fertilization<sup>1,3</sup> and are often assigned a low risk of recurrence in siblings<sup>4,5</sup>. Here, we directly assess the presence of <i>de novo</i> mutations in paternal sperm and discover abundant, germline-restricted mosaicism. From a cohort of ASD cases, employing single molecule genotyping, we found that four out of 14 fathers were germline mosaic for a putatively causative mutation transmitted to the affected child. Three of these were enriched or exclusively present in sperm at high allelic fractions (AF; 7-15%); and one was recurrently transmitted to two additional affected children, representing clinically actionable information. Germline mosaicism was further assessed by deep (&gt;90x) whole genome sequencing of four paternal sperm samples, which detected 12/355 transmitted <i>de novo</i> single nucleotide variants that were mosaic above 2% AF, and more than two dozen additional, non-transmitted mosaic variants in paternal sperm. Our results demonstrate that germline mosaicism is an underestimated phenomenon, which has important implications for clinical practice and in understanding the basis of human disease. Genetic analysis of sperm can assess individualized recurrence risk following the birth of a child with a <i>de novo</i> disease, as well as the risk in any male planning to have children.
Intracellular Na <sup>+</sup> Concentration Is Elevated in Heart Failure But Na/K Pump Function Is Unchanged
Authors: Sanda Despa, Mohammed A. Islam, Christopher R. Weber, Steven M. Pogwizd, Donald M. Bers
Journal: Circulation (2002)

Background — Intracellular sodium concentration ([Na + ] i ) modulates cardiac contractile and electrical activity through Na/Ca exchange (NCX). Upregulation of NCX in heart failure (HF) may magnify the functional impact of altered [Na + ] i . Methods and Results — We measured [Na + ] i by using sodium binding benzofuran isophthalate in control and HF rabbit ventricular myocytes (HF induced by aortic insufficiency and constriction). Resting [Na + ] i was 9.7±0.7 versus 6.6±0.5 mmol/L in HF versus control. In both cases, [Na + ] i increased by ≈2 mmol/L when myocytes were stimulated (0.5 to 3 Hz). To identify the mechanisms responsible for [Na + ] i elevation in HF, we measured the [Na + ] i dependence of Na/K pump–mediated Na + extrusion. There was no difference in V max (8.3±0.7 versus 8.0±0.8 mmol/L/min) or K m (9.2±1.0 versus 9.9±0.8 mmol/L in HF and control, respectively). Therefore, at measured [Na + ] i levels, the Na/K pump rate is actually higher in HF. However, resting Na + influx was twice as high in HF versus control (2.3±0.3 versus 1.1±0.2 mmol/L/min), primarily the result of a tetrodotoxin-sensitive pathway. Conclusions — Myocyte [Na + ] i is elevated in HF as a result of higher diastolic Na + influx (with unaltered Na/K-ATPase characteristics). In HF, the combined increased [Na + ] i , decreased Ca 2+ transient, and prolonged action potential all profoundly affect cellular Ca 2+ regulation, promoting greater Ca 2+ influx through NCX during action potentials. Notably, the elevated [Na + ] i may be critical in limiting the contractile dysfunction observed in HF.
Early numerical representations and the natural numbers: Is there really a complete disconnect?
Authors: Stella F. Lourenco, Susan C. Levine
Journal: Behavioral and Brain Sciences (2008)

Abstract The proposal of Rips et al. is motivated by discontinuity and input claims. The discontinuity claim is that no continuity exists between early (nonverbal) numerical representations and natural number. The input claim is that particular experiences (e.g., cardinality-related talk and object-based activities) do not aid in natural number construction. We discuss reasons to doubt both claims in their strongest forms.
Targeting Activin Receptor-Like Kinase 1 Inhibits Angiogenesis and Tumorigenesis through a Mechanism of Action Complementary to Anti-VEGF Therapies
Authors: Dana D. Hu-Lowe, Enhong Chen, Lianglin Zhang, Katherine D. Watson, Patrizia Mancuso, Patrick Lappin, Grant Wickman, Jeffrey H. Chen, Jianying Wang, Xin Jiang, Karin Amundson, Ronald Simon, Andreas Erbersdobler, Simon Bergqvist, Zheng Feng, Terri A. Swanson, Brett H. Simmons, John Lippincott, Gerald F. Casperson, Wendy J. Levin, Corrado Gallo Stampino, David R. Shalinsky, Katherine W. Ferrara, Walter Fiedler, Francesco Bertolini
Journal: Cancer Research (2011)

Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin(+) perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.
Molecular mechanisms are involved in ethanol mediated lung endothelial barrier dysfunction
Authors: Umapathy Siddaramappa, Alexander Verin
Journal: European Respiratory Journal (2011)

Recent studies have uncovered a significant but previously unknown correlation between alcohol (ethanol) abuse and the risk of acute respiratory distress syndrome (ARDS) (1). Despite studies aimed at improving outcomes in patients with ARDS, the mortality remains high at > 40%. For those who abuse alcohol, the mortality is even higher, at 65% (2) and, therefore, alcohol abuse causes tens of thousands of excess deaths annually. One of the important functions of lung endothelium is to provide a barrier against the penetration of bacterial toxins in the circulation and endothelial junctional proteins act as a structural barrier against the paracellular permeation (3). We hypothesized that excessive alcohol could negatively regulate the integrity of the lung endothelial barrier and increases the risk during bacterial infections. Our novel preliminary data using human lung microvascular endothelial cells (HLMVEC) demonstrate that ethanol dose-dependently disrupts the EC barrier properties as evidenced by Electric Cell-Substrate Impedance Sensing (ECIS) based transendothelial electrical resistance measurement. Pretreatment of the HLMVEC with LPS and subsequent challenge with ethanol disrupts the tight junctional proteins and increased phosphorylation of Myosin light chain compared to LPS or ethanol alone treatment suggesting an increased damage to the endothelium when one takes alcohol during bacterial infection. We showed that ethanol inhibit the endothelial wound healing process.   References:   1Prout, M et al, 2007. Expert Rev Respir Med 1:197-207.  2Boe, D.M et al, 2009. J Leukoc Biol 86:1097-1104.  3Vandenbroucke, E. et al, 2008. Ann N Y Acad Sci 1123:134-145.
A Case of Abnormal Cardiac Position (Levoposition)
Authors: G. G. ROWE, L. W. PAUL
Journal: Circulation (1959)

Dextroposition and levoposition are both believed to be forms of cardiac malposition that arise in early fetal life. It is believed that this is the first case of levoposition reported. When cardiac positions are grossly abnormal, special investigations are required to establish normality of cardiac function, since usual criteria for physical findings, electrocardiographic data, and radiographic determination of size and shape may not be applicable.
Single Nucleotide Polymorphisms of <i>RecQ1</i>, <i>RAD54L</i>, and <i>ATM</i> Genes Are Associated With Reduced Survival of Pancreatic Cancer
Authors: Donghui Li, Marsha Frazier, Douglas B. Evans, Kenneth R. Hess, Christopher H. Crane, Li Jiao, James L. Abbruzzese
Journal: Journal of Clinical Oncology (2006)

Our goal was to determine whether single nucleotide polymorphisms (SNPs) in DNA repair genes influence the clinical outcome of pancreatic cancer.
Left Ventricular Morphology and Function in Patients with Atherosclerotic Renovascular Disease
Authors: Julian R. Wright, Ala’a E. Shurrab, Anne Cooper, Paul R. Kalra, Robert N. Foley, Philip A. Kalra
Journal: Journal of the American Society of Nephrology (2005)

Atherosclerotic renovascular disease (ARVD) is associated with heart disease. There has been no systematic study of cardiac structure and function in patients with this condition. In this study, the epidemiology of cardiac changes and their relationship to renal function, renovascular anatomy, and BP are delineated. With the use of a cross-sectional design, 79 patients with ARVD and 50 control patients without ARVD underwent echocardiography and 24-h ambulatory BP monitoring. Clinical and biochemical data were collected. Results were analyzed according to renal function, residual renal artery patency, and unilateral or bilateral ARVD. Only 4 (5.1%) patients with ARVD had normal cardiac structure and function. Patients with ARVD (age 70.7 +/- 7.5 yr; estimated GFR 36 +/- 19 ml/min) had significantly more cardiovascular comorbidity (77.2 versus 42.0%; P < 0.001), greater prevalence of left ventricular (LV) hypertrophy (78.5 versus 46.0%; P < 0.001) and LV diastolic dysfunction (74.6 versus 40.0%; P < 0.001), and greater LV mass index (183 +/- 74 versus 116 +/- 33 g/m2; P < 0.001) and LV end-diastolic volume index (82 +/- 35 versus 34 +/- 16 ml/m2; P < 0.001) than control subjects. BP was similar for both patient groups. For patients with ARVD, neither renal function nor renal artery patency predicted a difference in echocardiographic or ambulatory BP monitoring parameters. Patients with bilateral ARVD had greater LV mass index and LV dilation than patients with unilateral disease. Patients with ARVD exhibit a high prevalence of cardiac morphologic and functional abnormalities at early stages of renal dysfunction. Such patients must be identified early in their disease course to allow risk factor modification.
Cranio-Carpo-Tarsal Dysplasia
Authors: F. Clarke Fraser
Journal: JAMA (1970)

The features of whistling face syndrome as it appeared in a father were compared with those found in his infant son. The syndrome is inherited as an autosomal dominant trait. Sporadic cases presumably represent fresh mutations, and will transmit the mutant gene to about half of their children. Siblings of sporadic cases, on the other hand, will have a very low risk of being affected.
Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection
Authors: Marcus Altfeld, Eric S. Rosenberg, Raj Shankarappa, Joia S. Mukherjee, Frederick M. Hecht, Robert L. Eldridge, Marylyn M. Addo, Samuel H. Poon, Mary N. Phillips, Gregory K. Robbins, Paul E. Sax, Steve Boswell, James O. Kahn, Christian Brander, Philip J.R. Goulder, Jay A. Levy, James I. Mullins, Bruce D. Walker
Journal: The Journal of Experimental Medicine (2001)

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.
Effect of Apolipoprotein E4 Allele on Plasma LDL Cholesterol Response to Diet Therapy in Type 2 Diabetic Patients
Authors: Mieko Saito, Masaaki Eto, Hayami Nitta, Yukiko Kanda, Makoto Shigeto, Katsura Nakayama, Kazuhito Tawaramoto, Fumiko Kawasaki, Shinji Kamei, Kenji Kohara, Masafumi Matsuda, Michihiro Matsuki, Kohei Kaku
Journal: Diabetes Care (2004)

OBJECTIVE—The aim of this study was to investigate the effect of apolipoprotein (apo)E4 allele on plasma LDL cholesterol response to calorie-restricted diet therapy in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—Twenty-four diabetic patients with the apoE3/3 genotype and 11 diabetic patients with the apoE4/3 genotype were recruited. Participants were hospitalized for calorie-restricted diet therapy (25.0 kcal · kg body wt−1 · day−1) for 14 days. Body weight, fasting plasma glucose (FPG) levels, and plasma lipid levels on hospital days 1 and 14 were compared between the two apoE genotype groups. RESULTS—There were no significant differences in baseline FPG levels, HbA1c levels, BMI, and plasma levels of total cholesterol, triglyceride, and HDL cholesterol between the two apoE genotype groups, but baseline plasma levels of LDL cholesterol were significantly higher in the apoE4/3 group than in the apoE3/3 group. Body weight decreased slightly and FPG levels decreased significantly after diet therapy in both apoE genotype groups. In the apoE3/3 group, only plasma levels of triglyceride decreased significantly after diet therapy, whereas in the apoE4/3 group, plasma levels of triglyceride, total cholesterol, and LDL cholesterol decreased significantly after diet therapy. The decrease (percentage of change) in total cholesterol (−16.3 vs. −6.6%) and LDL cholesterol (−15.6 vs. −0.7%) after diet therapy was significantly greater in the apoE4/3 group than in the apoE3/3 group. CONCLUSIONS—Calorie-restricted diet therapy is more effective in reducing plasma LDL cholesterol in type 2 diabetic patients with the apoE4 allele.
THE RELATION OF OXYGEN SUPPLY TO WATER MOVEMENT AND TO UREA FORMATION IN SURVIVING LIVER TISSUE
Authors: Eugene L. Opie
Journal: The Journal of Experimental Medicine (1961)

Liver slices have been immersed during periods up to 4 hours at 38°C. in Krebs-Ringer solution with bicarbonate buffer and exposed to varied oxygen supply in the presence of carbon dioxide equal to that of venous blood. Water movement, urea, and amino acid formation by the liver tissue have been measured. Water contents of surviving liver tissue diminishes with increased oxygen supply, but during life the maximum limit of oxygen is determined by that brought by the arterial blood and has an approximate partial pressure of 100 mm. Hg. Urea formation by liver slices is increased by increased oxygen supply but does not occur with anoxia. Osmotic pressure within liver cells is maintained in part by amino acids and related substances, and in part by electrolytes. Diminished osmotic pressure and loss of water is explainable by oxidation of nitrogenous substances with formation of urea which leaves the cells. These changes within a limited range of variation are adjustable to functional needs.
Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells
Authors: Matthias Lochner, Caspar Ohnmacht, Laura Presley, Pierre Bruhns, Mustapha Si-Tahar, Shinichiro Sawa, Gérard Eberl
Journal: The Journal of Experimental Medicine (2010)

The programmed development of lymph nodes and Peyer’s patches during ontogeny requires lymphoid tissue inducer (LTi) cells that express the nuclear hormone receptor RORγt. After birth, LTi cells in the intestine cluster into cryptopatches, the precursors of isolated lymphoid follicles (ILFs), which are induced to form by symbiotic bacteria and maintain intestinal homeostasis. We show that in RORγt-deficient mice, which lack LTi cells, programmed lymphoid tissues, ILFs, and Th17 cells, bacterial containment requires the generation of large numbers of tertiary lymphoid tissues (tLTs) through the activity of B cells. However, upon epithelial damage, these mice develop severe intestinal inflammation characterized by extensive recruitment of neutrophils and IgG+ B cells, high expression of activation-induced deaminase in tLTs, and wasting disease. The pathology was prevented by antibiotic treatment or inhibition of lymphoid tissue formation and was significantly decreased by treatment with intravenous immunoglobulin G (IVIG). Our data show that intestinal immunodeficiency, such as an absence in RORγt-mediated proinflammatory immunity, can be compensated by increased lymphoid tissue genesis. However, this comes at a high cost for the host and can lead to a deregulated B cell response and aggravated inflammatory pathology.
Diagnosis and management of alveolar proteinosis: the role of electron microscopy.
Authors: J F Costello, D C Moriarty, M A Branthwaite, M Turner-Warwick, B Corrin
Journal: Thorax (1975)

The diagnosis and management of three cases of pulmonary alveolar proteinosis are described. The electron microscopic appearances of lung biopsy material, lung washings, and sputum and the value of this method of sputum examination in extremely ill patients are demonstrated. The practical details of controlled volume bronchial lavage are described and the good clinical and physiological response of patients reported. The findings have been compared with those of experimental pulmonary alveolar proteinosis, and the pathogenesis of the condition is discussed.