tbuckley/cabot-search huggingface dataset:
THE COURSE AND TREATMENT OF LUPUS NEPHRITIS
Authors: Gerald B. Appel, M.D, Anthony Valeri, M.D
Journal: Annual Review of Medicine (1994)

▪ Abstract Renal involvement by systemic lupus is variable; some patients have minimal clinical and histologic involvement, whereas others have fulminant renal failure and severe proliferative renal lesions on biopsy. The World Health Organization (WHO) classification has greatly aided in the study of lupus nephritis. This classification defines six major patterns of renal involvement, each with characteristic clinical correlates and a typical course and prognosis. Transformations from one pattern of lupus nephritis to another may occur, and there may also be prominent involvement of the tubulointerstitial compartment and vasculature. Treatment of the renal lesions may be directed at the individual class of lupus nephritis. Thus patients with mesangial involvement (WHO Class II) do not require therapy directed at their kidney lesions. Many patients with biopsies showing focal proliferative disease (WHO Class III) and all patients whose biopsies show diffuse proliferative lesions (WHO Class IV) require vigorous treatment, which has included high-dose daily and alternate-day corticosteroids, azathioprine, i.v. pulse methylprednisolone, plasmapheresis, total lymphoid irradiation, cyclosporine, and oral and i.v. cyclophosphamide. Controlled trials have yielded reasonable evidence for the safety and efficacy of some treatments, whereas others have been used only in uncontrolled studies. When used judiciously, such vigorous therapy can improve the renal survival of patients with severe lupus nephritis.
Coeliac disease: emerging in China?
Authors: J. Wu, B. Xia, B. M. E. von Blomberg, C. Zhao, X. W. Yang, J. B. A. Crusius, A. S. Pena
Journal: Gut (2010)

We read with interest the leading article by Hunt and van Heel on recent advances in coeliac disease (CD) genetics.1 They suggested that further investigation of the coeliac-associated single nucleotide polymorphisms (SNPs) in other populations was needed. Our recent work may help to push this research work in the Chinese population. Here we report on a serological screening for CD in China. CD has been historically considered to be absent in the Far East (China, Japan, Korea, Malaysia, etc.).2 However, since the major known risk factors for CD are common in China, we used serological tests for immunoglobulin G (IgG) antigliadin antibodies (AGAs) and IgA antitissue transglutaminase antibodies (tTGs) to screen for CD in high risk patients,3 …
Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination
Authors: Hye-Young Park, Heounjeong Go, Ha Rim Song, Suhyeon Kim, Geun-Hyoung Ha, Yoon-Kyung Jeon, Ji-Eun Kim, Ho Lee, Hyeseong Cho, Ho Chul Kang, Hee-Young Chung, Chul-Woo Kim, Doo Hyun Chung, Chang-Woo Lee
Journal: Journal of Clinical Investigation (2014)

The signal-responsive E3 ubiquitin ligase pellino 1 (PELI1) regulates TLR and T cell receptor (TCR) signaling and contributes to the maintenance of autoimmunity; however, little is known about the consequence of mutations that result in upregulation of PELI1. Here, we developed transgenic mice that constitutively express human PELI1 and determined that these mice have a shorter lifespan due to tumor formation. Constitutive expression of PELI1 resulted in ligand-independent hyperactivation of B cells and facilitated the development of a wide range of lymphoid tumors, with prominent B cell infiltration observed across multiple organs. PELI1 directly interacted with the oncoprotein B cell chronic lymphocytic leukemia (BCL6) and induced lysine 63-mediated BCL6 polyubiquitination. In samples from patients with diffuse large B cell lymphomas (DLBCLs), PELI1 expression levels positively correlated with BCL6 expression, and PELI1 overexpression was closely associated with poor prognosis in DLBCLs. Together, these results suggest that increased PELI1 expression and subsequent induction of BCL6 promotes lymphomagenesis and that this pathway may be a potential target for therapeutic strategies to treat B cell lymphomas.
Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin
Authors: William Vermi, Elena Riboldi, Valerie Wittamer, Francesca Gentili, Walter Luini, Simona Marrelli, Annunciata Vecchi, Jean-Denis Franssen, David Communi, Luisa Massardi, Marina Sironi, Alberto Mantovani, Marc Parmentier, Fabio Facchetti, Silvano Sozzani
Journal: The Journal of Experimental Medicine (2005)

Chemerin is a chemotactic agent that was recently identified as the ligand of ChemR23, a serpentine receptor expressed by activated macrophages and monocyte-derived dendritic cells (DCs). This paper shows that blood plasmacytoid and myeloid DCs express functional ChemR23. Recombinant chemerin induced the transmigration of plasmacytoid and myeloid DCs across an endothelial cell monolayer. In secondary lymphoid organs (lymph nodes and tonsils), ChemR23 is expressed by CD123+ plasmacytoid DCs and by CD1a+ DC-SIGN+ DCs in the interfollicular T cell area. ChemR23+ DCs were also observed in dermis from normal skin, whereas Langerhans cells were negative. Chemerin expression was selectively detected on the luminal side of high endothelial venules in secondary lymphoid organs and in dermal endothelial vessels of lupus erythematosus skin lesions. Chemerin+ endothelial cells were surrounded by ChemR23+ plasmacytoid DCs. Thus, ChemR23 is expressed and functional in plasmacytoid DCs, a property shared only by CXCR4 among chemotactic receptors. This finding, together with the selective expression of the cognate ligand on the luminal side of high endothelial venules and inflamed endothelium, suggests a key role of the ChemR23/chemerin axis in directing plasmacytoid DC trafficking.
Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis.
Authors: D L Bratton, Q Hamid, M Boguniewicz, D E Doherty, J M Kailey, D Y Leung
Journal: Journal of Clinical Investigation (1995)

Evidence suggesting that prolonged effector cell survival may contribute to perpetuation of inflammation prompted us to ask whether monocyte macrophages, the predominate inflammatory cell in the lesion of chronic atopic dermatitis (AD), exhibit enhanced survival in AD. Cultures of peripheral blood monocytes from patients with chronic AD, psoriasis, and from normal (NL) donors were examined for morphologic features and DNA fragmentation characteristic of cells undergoing the process of apoptosis (programmed cell death). Cultures of AD monocytes exhibited a significantly lower incidence of apoptosis than did cultures of NL monocytes (45 vs 68%, P < 0.01), or psoriatic monocytes (45 vs 80%, P < 0.01). Furthermore, AD monocytes were unresponsive to both IL-1, an inhibitor of apoptosis, and IL-4, an enhancer of apoptosis, in comparison to cultured NL monocytes. Of note, GM-CSF in a concentration-dependent fashion, decreased the incidence of apoptosis in NL monocyte cultures and rendered them unresponsive to these cytokines. These findings suggested that GM-CSF may enhance monocyte survival in AD. In support of this hypothesis, AD monocyte cultures produced fivefold more GM-CSF than did cultures of NL monocytes or psoriatic monocytes (P < 0.05). Additionally, there was a significantly greater number of GM-CSF mRNA expressing cells detected by in situ hybridization in biopsies of lesions of chronic AD than in acute AD or NL skin (P < 0.05). Finally, NL monocytes incubated with supernatants obtained from monocytes of AD patients exhibited significant inhibition of apoptosis, an effect that could be ablated by a neutralizing antibody to GM-CSF. Taken together, these data strongly suggest that increased production of GM-CSF by cells from patients with AD inhibits monocyte apoptosis and may contribute to the chronicity of this inflammatory disease.
The effect of airway alkalization by nebulized sodium bicarbonate on airway blood flow
Authors: Adrian Kis, Laura Andrea Toth, Laszlo Kunos, Szilvia Vasas, Gyorgy Losonczy, Eliana Mendes, Adam Wanner, Gabor Horvath
Journal: European Respiratory Journal (2012)

Background:  The airway acidifies in a variety of inflammatory lung diseases as measured by exhaled breath condensate (EBC). We have demonstrated in vitro that alkalization improves absorption of cationic bronchodilators, such as albuterol and tiotropium, both in airway epithelia and smooth muscle cells; however, the rationale of airway alkalization therapy is not fully understood.   Objective:  The purpose of the study was to determine the effect of nebulized sodium bicarbonate (NaHCO 3 ) solution on airway vascular smooth muscle function.   Methods:  Ten healthy non-smoker volunteers participated in the study. To assay airway pH, EBC was collected pre- and post-administration of 4.2% NaHCO 3  (pH=8.4). NaHCO 3  induced CO 2  production was evaluated with a real-time mass spectrometer gas analyzer by measuring Phase 1 and end-tidal CO 2  levels during normal breathing, and breath-hold maneuvers for 5 and 15 sec. Airway vascular smooth muscle responses were assessed by measuring airway blood flow (Q aw ).   Results:  After NaHCO 3  administration for 15 min using a heated ultrasonic nebulizer, EBC pH increased from 7.54±0.2 to 8.07±0.09 units (p 2  levels during normal breathing, and breath-hold maneuvers for 5 and 15 sec were not significantly different, suggesting no excessive CO 2  generation from the breakdown of inhaled NaHCO 3 . NaHCO 3  nebulization resulted in an increase of mean Q aw  from 33.9±3.8 to 48.7±5.5 μl/min/ml (p   Conclusion:  Nebulized NaHCO 3  can increase airway pH without significant effects on exhaled CO 2  levels in healthy subjects. NaHCO 3  induced increase in Q aw , together with elevated airway pH, could improve absorption of inhaled cationic bronchodilators.
Reply to Harnad
Authors: B. F. Skinner
Journal: Behavioral and Brain Sciences (1984)

A. What is the current status of theory in radical behaviorism? Radical behaviorism is antitheoretical in the sense that it attacks and rejects traditional explanations of behavior in terms of internal initiating causes. It is anti-creationist. It turns instead, as Darwin did, to the selection of presumably random variations by contingencies of survival (ethology) and contingencies of reinforcement (the experimental analysis of behavior). In that analysis, rate of responding is taken as a basic datum and studied as a function of many contingencies of reinforcement. The results are factual, not theoretical. The analysis has “matured” by successfully analyzing more and more complex arrangements of variables. If rate of responding is taken as a measure of probability of response, an element of theory no doubt arises, and theory may be necessary in interpreting facts about behavior which are out of reach of precise prediction and control. As in modern astronomy, a laboratory science of behavior will continue, I believe, to give the best possible explanation of facts beyond experimental control – events in the world at large in the case of behavior, the waves and particles reaching the earth from outer space in the case of astronomy. The depth and breadth of both fields depend not upon improvements in theory but upon success in the analysis of presumably similar phenomena where some degree of prediction and control is possible.
Activity-Dependent Proteolytic Cleavage of Neuroligin-1
Authors: Kunimichi Suzuki, Yukari Hayashi, Soichiro Nakahara, Hiroshi Kumazaki, Johannes Prox, Keisuke Horiuchi, Mingshuo Zeng, Shun Tanimura, Yoshitake Nishiyama, Satoko Osawa, Atsuko Sehara-Fujisawa, Paul Saftig, Satoshi Yokoshima, Tohru Fukuyama, Norio Matsuki, Ryuta Koyama, Taisuke Tomita, Takeshi Iwatsubo
Journal: Neuron (2012)
Senior medical staff need to be included in severe asthma
Authors: B R. O'Driscoll
Journal: BMJ (2003)

EDITOR—Rees has drawn attention to the importance and usefulness of the new asthma guidelines, but he questioned the necessity of adding the authors' view that senior medical staff should be consulted in a situation where there is clear evidence of benefit (use of intravenous magnesium for severe asthma).1

As a member of the …
Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats
Authors: T Kondo, K Obata, K Miyoshi, J Sakurai, J Tanaka, H Miwa, K Noguchi
Journal: Gut (2009)

Transient receptor potential (TRP)A1, a member of the TRP family of ion channels, has been proposed to function in diverse sensory processes, including thermosensation and pain. However, TRPA1 has not been directly implicated in stomach mechanosensation, and its contribution to acute visceral pain from this organ is unknown. Here, we investigated the expression of TRPA1 in primary sensory afferents and its involvement in visceral hypersensitivity in rats.We examined TRPA1 expression in the dorsal root ganglion (DRG), nodose ganglion (NG), and stomach of rats by using immunohistochemistry. Electromyographic responses to gastric distention (GD) were recorded from the acromiotrapezius muscle in TRPA1 knockdown rats and in control rats.TRPA1 was predominantly expressed with sensory neuropeptides in DRG and NG neurons, and in nerve fibres in the rat stomach. Gastric distention induced the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in DRG and NG neurons 2 min after stimulation, and most of the phosphorylated-ERK1/2-labelled DRG neurons were TRPA1-positive neurons. Intrathecal injection of TRPA1 antisense attenuated the visceromotor response, and suppressed ERK1/2 activation in the DRG, but not NG, neurons produced by GD. Furthermore, intrathecal and intraperitoneal injections of the TRPA1 inhibitor HC-03003 suppressed the response to noxious GD.The activation of TRPA1 in DRG neurons by noxious GD may be involved in acute visceral pain. Our findings point to the potential blockade of TRPA1 in primary afferents as a new therapeutic target for the reduction of visceral hypersensitivity.
Rates of Medical Errors and Preventable Adverse Events Among Hospitalized Children Following Implementation of a Resident Handoff Bundle
Authors: Amy J. Starmer, Theodore C. Sectish, Dennis W. Simon, Carol Keohane, Maireade E. McSweeney, Erica Y. Chung, Catherine S. Yoon, Stuart R. Lipsitz, Ari J. Wassner, Marvin B. Harper, Christopher P. Landrigan
Journal: JAMA (2013)

Handoff miscommunications are a leading cause of medical errors. Studies comprehensively assessing handoff improvement programs are lacking.To determine whether introduction of a multifaceted handoff program was associated with reduced rates of medical errors and preventable adverse events, fewer omissions of key data in written handoffs, improved verbal handoffs, and changes in resident-physician workflow.Prospective intervention study of 1255 patient admissions (642 before and 613 after the intervention) involving 84 resident physicians (42 before and 42 after the intervention) from July-September 2009 and November 2009-January 2010 on 2 inpatient units at Boston Children's Hospital.Resident handoff bundle, consisting of standardized communication and handoff training, a verbal mnemonic, and a new team handoff structure. On one unit, a computerized handoff tool linked to the electronic medical record was introduced.The primary outcomes were the rates of medical errors and preventable adverse events measured by daily systematic surveillance. The secondary outcomes were omissions in the printed handoff document and resident time-motion activity.Medical errors decreased from 33.8 per 100 admissions (95% CI, 27.3-40.3) to 18.3 per 100 admissions (95% CI, 14.7-21.9; P < .001), and preventable adverse events decreased from 3.3 per 100 admissions (95% CI, 1.7-4.8) to 1.5 (95% CI, 0.51-2.4) per 100 admissions (P = .04) following the intervention. There were fewer omissions of key handoff elements on printed handoff documents, especially on the unit that received the computerized handoff tool (significant reductions of omissions in 11 of 14 categories with computerized tool; significant reductions in 2 of 14 categories without computerized tool). Physicians spent a greater percentage of time in a 24-hour period at the patient bedside after the intervention (8.3%; 95% CI 7.1%-9.8%) vs 10.6% (95% CI, 9.2%-12.2%; P = .03). The average duration of verbal handoffs per patient did not change. Verbal handoffs were more likely to occur in a quiet location (33.3%; 95% CI, 14.5%-52.2% vs 67.9%; 95% CI, 50.6%-85.2%; P = .03) and private location (50.0%; 95% CI, 30%-70% vs 85.7%; 95% CI, 72.8%-98.7%; P = .007) after the intervention.Implementation of a handoff bundle was associated with a significant reduction in medical errors and preventable adverse events among hospitalized children. Improvements in verbal and written handoff processes occurred, and resident workflow did not change adversely.
Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979–2011
Authors: Christine Rungoe, Ebbe Langholz, Mikael Andersson, Saima Basit, Nete M Nielsen, Jan Wohlfahrt, Tine Jess
Journal: Gut (2013)

<h3>Introduction</h3> Treatment possibilities have changed in inflammatory bowel disease (IBD). We assessed changes in medical treatment and surgery over time and impact of medications on risk of surgery in a population-based cohort. <h3>Methods</h3> 48 967 individuals were diagnosed with IBD (Crohn9s disease (CD), 13 185; ulcerative colitis (UC), 35 782) during 1979–2011. Cumulative probability of receiving 5-aminosalicylic acids (5-ASA), topical, oral corticosteroids, thiopurines, and tumour necrosis factor-α (TNF-α) blockers, and of first minor or major surgery according to period of diagnosis, was estimated. Medication use and risk of surgery was examined by Cox regression. <h3>Results</h3> 5-year cumulative probability of first major surgery decreased from 44.7% in cohort (1979–1986) to 19.6% in cohort (2003–2011) (p &lt; 0.001) for CD, and from 11.7% in cohort (1979–1986) to 7.5% in cohort (2003–2011) (p &lt; 0.001) for UC. Minor surgery risk decreased significantly in CD. From cohort (1995–2002) to cohort (2003–2011), a significant increase in use of thiopurines and TNF-α blockers was observed, paralleled by a significant decrease in use of 5-ASA and corticosteroids. Comparing use of azathioprine (or oral corticosteroids) to never-use, no convincing surgery-sparing effect was found. Comparing use in 3+ months of a given drug with use &lt;3 months, only 3+ months use of oral corticosteroids reduced the risk of surgery in patients with disease duration of &gt;1 year. <h3>Conclusions</h3> Parallel to an increasing use of thiopurines and TNF-α blockers in IBD over time, a persistent significant decrease in surgery rates was observed along with a significant decrease in use of 5-ASA and corticosteroids. However, no convincing surgery-sparing effect of newer medications was found.
Endothelial dysfunction in response to psychosocial stress in monkeys.
Authors: W B Strawn, G Bondjers, J R Kaplan, S B Manuck, D C Schwenke, G K Hansson, C A Shively, T B Clarkson
Journal: Circulation Research (1991)

The current study was designed to evaluate the effects of a disrupted social environment on the endothelial integrity of various vascular segments in male cynomolgus monkeys (Macaca fascicularis). Each of 20 single-caged adult monkeys was fed a diet comparable to a person's ingestion of 240 mg cholesterol/day for a 10-week baseline period and then was introduced as a stranger into a four-member social group for 3 days. Half of the monkeys received a beta-adrenergic blocking agent (metoprolol) via subcutaneous implant 2 days before and during group housing. The social manipulation produced persistent sympathetic arousal as evidenced by significantly elevated heart rates among untreated monkeys (p less than 0.01) but not among their metoprolol-treated counterparts, whose heart rate declined (p less than 0.05). After the social manipulation, all monkeys were necropsied and evaluated for endothelial incorporation of immunoglobulin G (as an indicator of cell death), endothelial cell replication, the presence of adherent leukocytes, and arterial low density lipoprotein permeability and concentration. At branching sites in the thoracic aorta, immunoglobulin G incorporation and endothelial cell replication were significantly greater in untreated monkeys than in metoprolol-treated monkeys (p less than 0.01 for both analyses); no differences existed at nonbranch sites. Endothelial cell replication in the coronary arteries (where immunoglobulin G incorporation was not examined) was also greater among untreated than among metoprolol-treated monkeys. No significant differences were observed between treatment groups in arterial low density lipoprotein permeability or leukocyte adherence; estimates of arterial low density lipoprotein concentrations were higher among untreated than among metoprolol-treated monkeys, but only in the abdominal portion of the aorta. These results indicate that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial dysfunction, effects that may be prevented by treatment with a beta-adrenergic blocking agent.
T cells tamed by statins
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Cholesterol-lowering statin drugs, such as Lipitor and Zocor, have a fortuitous side effect: they ease T cell–driven autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). On page 401, Dunn and colleagues show that statins curb T cell activation by robbing the cells of isoprenoids, lipid intermediates formed during cholesterol biosynthesis.






Figure 1

Statins inhibit Th1 cells by reducing the intracellular isoprenoids required for Ras and RhoA function




The ability of statins to inhibit T cell proliferation has been appreciated for over a decade, but the mechanism was never fully understood. More recently, these drugs were shown to inhibit inflammatory T helper (Th)-1 responses and instead promote Th2 responses—a shift that protects mice against Th1-driven diseases such as RA and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.

A study in 2002 was the first to attribute the protective effect of statins in autoimmunity to a decrease in isoprenoids—lipids that attach to small GTP-binding proteins, allowing these proteins to associate with the cell membrane and transmit activating signals. In mice, interfering with the attachment of isoprenyl groups to the GTPase Rho in endothelial cells prevented T cells from crossing the blood–brain barrier on the road to causing EAE.

Dunn and colleagues now show that a similar mechanism is at play in EAE-causing T cells. T cells treated with atorvastatin (Lipitor) proliferated less and produced lower levels of the Th1 cytokine interferon (IFN)-γ compared with untreated cells. This inhibition was traced to defects in two GTP-binding proteins—Ras and RhoA—which failed to associate with the cell membrane in T cells from Lipitor-treated mice, thus preventing the activation of downstream signaling pathways required for T cell proliferation and the production of IFN-γ. Adding the relevant isoprenoids back to Lipitor-treated T cells reversed this effect.

Statins have a similar antiproliferative effect on tumor cells, an observation that prompted their testing as anticancer therapeutics. In fact, statins appear to have few drawbacks. So far, the use of these drugs has not been associated with either an increased incidence of Th2-driven diseases, such as asthma or allergies, or an increased risk of viral or bacterial infections that normally induce a protective Th1 response.