tbuckley/cabot-search huggingface dataset:
Cytomegalovirus-Responsive γδ T Cells
Authors: Thomas Bachelet, Lionel Couzi, Vincent Pitard, Xavier Sicard, Claire Rigothier, Sébastien Lepreux, Jean-François Moreau, Jean-Luc Taupin, Pierre Merville, Julie Déchanet-Merville
Journal: Journal of the American Society of Nephrology (2014)

Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large γδ T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive γδ T cells express the Fcγ-receptor CD16, suggesting that γδ T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16(pos) γδ T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating γδ T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced γδ T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced γδ T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.
CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab
Authors: K. Miyazaki, M. Yamaguchi, R. Suzuki, Y. Kobayashi, A.M. Maeshima, N. Niitsu, D. Ennishi, J.-i. Tamaru, K. Ishizawa, M. Kashimura, Y. Kagami, K. Sunami, H. Yamane, M. Nishikori, H. Kosugi, T. Yujiri, R. Hyo, N. Katayama, T. Kinoshita, S. Nakamura
Journal: Annals of Oncology (2011)
A randomised, double-blind, sham-controlled study of granulocyte/monocyte apheresis for moderate to severe Crohn's disease
Authors: Bruce E Sands, Seymour Katz, Douglas C Wolf, Brian G Feagan, Tao Wang, Lisa-Marie Gustofson, Cindy Wong, Margaret K Vandervoort, Stephen Hanauer
Journal: Gut (2012)

<h3>Objectives</h3> Activated granulocytes and monocytes may contribute to the pathogenesis of Crohn9s disease (CD). In small, uncontrolled studies, granulocyte/monocyte apheresis (GMA) has shown promise in treating CD. We conducted a randomised, double-blind study to compare GMA with a sham procedure in patients with moderate to severe CD. <h3>Design</h3> Patients with active CD as defined by a Crohn9s Disease Activity Index (CDAI) of 220–450 were randomly allocated in a 2:1 ratio to treatment with GMA using the Adacolumn Apheresis System (JIMRO, Takasaki, Japan) or sham apheresis. Ten apheresis sessions were scheduled over a 9-week period, and efficacy was evaluated at week 12. The primary end point was the proportion of patients achieving clinical remission (CDAI score ≤150 without use of prohibited drugs). <h3>Results</h3> Clinical remission was achieved by 17.8% of patients in the GMA group (n=157) compared with 19.2% of those in the sham control group (n=78) (absolute difference −1.4% (95% CI−12.8% to 8.5%), p=0.858). Clinical response (defined as a ≥100-point decrease in CDAI) was achieved by 28.0% and 26.9% of patients in the GMA and sham groups, respectively (p=1.000). The two treatments produced similar changes from baseline in CDAI and quality of life, as well as in disease severity assessed endoscopically. The incidence and types of adverse events did not differ between groups. <h3>Conclusions</h3> GMA was well tolerated, but this study did not demonstrate its effectiveness over a sham procedure in inducing clinical remission or response in patients with moderate to severe CD. <h3>Clinical trial registration number</h3> Clinical Trials.gov identifier NCT00162942.
c-FLIP Mediates Resistance of Hodgkin/Reed-Sternberg Cells to Death Receptor–induced Apoptosis
Authors: Stephan Mathas, Andreas Lietz, Ioannis Anagnostopoulos, Franziska Hummel, Burkhard Wiesner, Martin Janz, Franziska Jundt, Burkhard Hirsch, Korinna Jöhrens-Leder, Hans-Peter Vornlocher, Kurt Bommert, Harald Stein, Bernd Dörken
Journal: The Journal of Experimental Medicine (2004)

Resistance to death receptor–mediated apoptosis is supposed to be important for the deregulated growth of B cell lymphoma. Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin's lymphoma (cHL), resist CD95-induced apoptosis. Therefore, we analyzed death receptor signaling, in particular the CD95 pathway, in these cells. High level CD95 expression allowed a rapid formation of the death-inducing signaling complex (DISC) containing Fas-associated death domain–containing protein (FADD), caspase-8, caspase-10, and most importantly, cellular FADD-like interleukin 1β–converting enzyme-inhibitory protein (c-FLIP). The immunohistochemical analysis of the DISC members revealed a strong expression of CD95 and c-FLIP overexpression in 55 out of 59 cases of cHL. FADD overexpression was detectable in several cases. Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane. Elevated c-FLIP expression in HRS cells depends on nuclear factor (NF)-κB. Despite expression of other NF-κB–dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis. Therefore, c-FLIP is a key regulator of death receptor resistance in HRS cells.
GPR48 Increases Mineralocorticoid Receptor Gene Expression
Authors: Jiqiu Wang, Xiaoying Li, Yingying Ke, Yan Lu, Feng Wang, Nengguang Fan, Haiyan Sun, Huijie Zhang, Ruixin Liu, Jun Yang, Lei Ye, Mingyao Liu, Guang Ning
Journal: Journal of the American Society of Nephrology (2011)

Aldosterone and the mineralocorticoid receptor (MR) are critical to the maintenance of electrolyte and BP homeostasis. Mutations in the MR cause aldosterone resistance known as pseudohypoaldosteronism type 1 (PHA1); however, some cases consistent with PHA1 do not exhibit known gene mutations, suggesting the possibility of alternative genetic variants. We observed that G protein-coupled receptor 48 (Gpr48/Lgr4) hypomorphic mutant (Gpr48(m/m)) mice had hyperkalemia and increased water loss and salt excretion despite elevated plasma aldosterone levels, suggesting aldosterone resistance. When we challenged the mice with a low-sodium diet, these features became more obvious; the mice also developed hyponatremia and increased renin expression and activity, resembling a mild state of PHA1. There was marked renal downregulation of MR and its downstream targets (e.g., the α-subunit of the amiloride-sensitive epithelial sodium channel), which could provide a mechanism for the aldosterone resistance. We identified a noncanonical cAMP-responsive element located in the MR promoter and demonstrated that GPR48 upregulates MR expression via the cAMP/protein kinase A pathway in vitro. Taken together, our data demonstrate that GPR48 enhances aldosterone responsiveness by activating MR expression, suggesting that GPR48 contributes to homeostasis of electrolytes and BP and may be a candidate gene for PHA1.
Reduced activity of Na(+)-K+ ATPase of pancreatic islets in chronic renal failure
Authors: S M Hajjar, G Z Fadda, P Thanakitcharu, M Smogorzewski, S G Massry
Journal: Journal of the American Society of Nephrology (1992)

The activity of Na(+)-K+ ATPase of pancreatic islets modulates their insulin secretion. The study presented here examined the activity of this enzyme in pancreatic islets of chronic renal failure (CRF) rats in an effort to further delineate the mechanisms of impaired insulin secretion in CRF. The Vmax of Na(+)-K+ ATPase, but not its Km, and the ATP content are significantly reduced in islets of CRF rats that have elevated levels of parathyroid hormone (PTH). These derangements are prevented by prior parathyroidectomy of CRF rats (low blood levels of PTH) or by their treatment with the calcium channel blocker verapamil; these latter rats have sustained elevation of blood levels of PTH. The data indicate that the chronic excess blood levels of PTH in CRF initiates events (augmented entry of calcium) that lead to the reduction in ATP content and in Vmax of Na(+)-K+ ATPase of pancreatic islets. Reducing the blood levels of PTH by parathyroidectomy or blocking the action of PTH on calcium entry into cells by verapamil prevents these derangements. The results suggest that chronic inhibition of Na(+)-K+ ATPase may participate in the processes underlying the impaired insulin secretion in CRF.
Migraine and Risk of Cardiovascular Disease in Women
Authors: Tobias Kurth, J. Michael Gaziano, Nancy R. Cook, Giancarlo Logroscino, Hans-Christoph Diener, Julie E. Buring
Journal: JAMA (2006)

Migraine with aura has been associated with an adverse cardiovascular risk profile and prothrombotic factors that, along with migraine-specific physiology, may increase the risk of vascular events. Although migraine with aura has been associated with increased risk of ischemic stroke, an association with cardiovascular disease (CVD) and, specifically, coronary events remains unclear.To evaluate the association between migraine with and without aura and subsequent risk of overall and specific CVD.Prospective cohort study of 27,840 US women aged 45 years or older who were participating in the Women's Health Study, were free of CVD and angina at study entry (1992-1995), and who had information on self-reported migraine and aura status, and lipid measurements. This report is based on follow-up data through March 31, 2004.The primary outcome measure was the combined end point of major CVD (first instance of nonfatal ischemic stroke, nonfatal myocardial infarction, or death due to ischemic CVD); other measures were first ischemic stroke, myocardial infarction, coronary revascularization, angina, and death due to ischemic CVD.At baseline, 5125 women (18.4%) reported any history of migraine; of the 3610 with active migraine (migraine in the prior year), 1434 (39.7%) indicated aura symptoms. During a mean of 10 years of follow-up, 580 major CVD events occurred. Compared with women with no migraine history, women who reported active migraine with aura had multivariable-adjusted hazard ratios of 2.15 (95% confidence interval [CI], 1.58-2.92; P<.001) for major CVD, 1.91 (95% CI, 1.17-3.10; P = .01) for ischemic stroke, 2.08 (95% CI, 1.30-3.31; P = .002) for myocardial infarction, 1.74 (95% CI, 1.23-2.46; P = .002) for coronary revascularization, 1.71 (95% CI, 1.16-2.53; P = .007) for angina, and 2.33 (95% CI, 1.21-4.51; P = .01) for ischemic CVD death. After adjusting for age, there were 18 additional major CVD events attributable to migraine with aura per 10 000 women per year. Women who reported active migraine without aura did not have increased risk of any vascular events or angina.In this large, prospective cohort of women, active migraine with aura was associated with increased risk of major CVD, myocardial infarction, ischemic stroke, and death due to ischemic CVD, as well as with coronary revascularization and angina. Active migraine without aura was not associated with increased risk of any CVD event.
Sphincter denervation in anorectal incontinence and rectal prolapse.
Authors: A G Parks, M Swash, H Urich
Journal: Gut (1977)

Biopsies of the external anal sphincter, puborectalis, and levator ani muscles have been examined in 24 women and one man with long-standing anorectal incontinence, 18 of whom also had rectal prolapse, and in two men with rectal prolapse alone. In 16 of the women anorectal incontinence was of unknown cause, but in eight there was a history of difficult labour. Similar biopsies were examined in six control subjects. In all the incontinent patients there was histological evidence of denervation, which was most prominent in the external anal sphincter muscle biopsies, and least prominent in the levator ani muscles. Myopathic features, which were thought to be secondary, were present in the more abnormal biopsies. There were severe histological abnormalities in small nerves supplying the external anal sphincter muscle in the three cases in which material was available for study. We suggest that idiopathic anorectal incontinence may be the result of denervation of the muscles of the anorectal sling, and of the anal sphincter mechanism. This could result from entrapment or stretch injury of the pudendal or perineal nerves occurring as a consequence of rectal descent induced during repeated defaecation straining, or from injuries to these nerves associated with childbirth.
Treatment of acute stroke.
Authors: M S Ali
Journal: BMJ (1984)

Bacterial DNA contains unmethylated CpG dinucleotides and is a potent ligand for TLR9. Bacterial DNA has been claimed the active ingredient in bacterial lysates used for immunotherapy. Whereas the detection of viral DNA by TLR9 expressed in plasmacytoid dendritic cells (PDCs) with subsequent IFN-α production is well defined, the role of bacterial DNA during microbial infection is less clear. In fact, IFN-α is not a hallmark of antibacterial immune responses. Unlike in mice, TLR9 expression in humans is restricted to PDCs and B cells; thus, conclusions from murine models of infection have limitations. In this study, we demonstrate that lysates of heat-killed <i>Escherichia coli</i> containing bacterial DNA induced IFN-α in isolated PDCs but not in the mixed cell populations of human PBMCs. Depletion of monocytes restored IFN-α secretion by PDCs within PBMCs. We found that monocyte-derived IL-10 and PGs contribute to monocyte-mediated inhibition of IFN-α release in PDCs. We conclude that human PDCs can be stimulated by bacterial DNA via TLR9; however, in the physiological context of mixed-cell populations, PDC activation is blocked by factors released from monocytes stimulated in parallel by other components of bacterial lysates such as LPS. This functional repression of PDCs by concomitantly stimulated monocytes avoids production of antiviral IFN-α during bacterial infection and thus explains how the innate immune system is enabled to distinguish bacterial from viral CpG DNA and thus to elicit the appropriate responses despite the presence of CpG DNA in both types of infection.
Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets
Authors: Adam J. Kimple, Dustin E. Bosch, Patrick M. Giguère, David P. Siderovski
Journal: Pharmacological Reviews (2011)

Because G-protein coupled receptors (GPCRs) continue to represent excellent targets for the discovery and development of small-molecule therapeutics, it is posited that additional protein components of the signal transduction pathways emanating from activated GPCRs themselves are attractive as drug discovery targets. This review considers the drug discovery potential of two such components: members of the "regulators of G-protein signaling" (RGS protein) superfamily, as well as their substrates, the heterotrimeric G-protein α subunits. Highlighted are recent advances, stemming from mouse knockout studies and the use of "RGS-insensitivity" and fast-hydrolysis mutations to Gα, in our understanding of how RGS proteins selectively act in (patho)physiologic conditions controlled by GPCR signaling and how they act on the nucleotide cycling of heterotrimeric G-proteins in shaping the kinetics and sensitivity of GPCR signaling. Progress is documented regarding recent activities along the path to devising screening assays and chemical probes for the RGS protein target, not only in pursuits of inhibitors of RGS domain-mediated acceleration of Gα GTP hydrolysis but also to embrace the potential of finding allosteric activators of this RGS protein action. The review concludes in considering the Gα subunit itself as a drug target, as brought to focus by recent reports of activating mutations to GNAQ and GNA11 in ocular (uveal) melanoma. We consider the likelihood of several strategies for antagonizing the function of these oncogene alleles and their gene products, including the use of RGS proteins with Gα<sub>q</sub> selectivity.
Assignment of three Chinese xeroderma pigmentosum patients to complementation group C and one to group E
Authors: None Han, None Hara, None Ayaki, None Wang, None Sun, None You, None Zhang, None Qiang, None Ikenaga
Journal: British Journal of Dermatology (1998)

Four Chinese patients with xeroderma pigmentosum (XP), who had different degrees of skin symptoms, were tested for their genetic complementation groups. Skin fibroblasts obtained from the patients were used for complementation analysis done by a cell-fusion technique. Three of the patients belonged to group C and one, who had the mildest cutaneous manifestations, to group E. This is the first report of a group E XP patient in China. Our present findings together with previous reports suggest that group C XP is more common in China, similar to the distribution among Caucasian XP patients but markedly different from the Japanese distribution.
Relationship between Exhaled Nitric Oxide and Mucosal Eosinophilic Inflammation in Children with Difficult Asthma, after Treatment with Oral Prednisolone
Authors: DONALD N. R. PAYNE, IAN M. ADCOCK, NICOLA M. WILSON, TIM OATES, MICHAEL SCALLAN, ANDREW BUSH
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Exhaled nitric oxide (FE(NO)) has been proposed as a noninvasive marker of airway inflammation in asthma, and may reflect airway eosinophilia. We examined the relationship between FE(NO) and eosinophilic inflammation in endobronchial biopsies from 31 children with difficult asthma (mean age [range] 11.9 [6-17] yr), following 2 wk of prednisolone (40 mg/d). Endobronchial biopsy was also performed in seven children without asthma. Biopsy eosinophils were detected using antibody to major basic protein, and point-counting used to derive an "eosinophil score." FE(NO) readings and suitable biopsies for analysis were both obtained in 21 of 31 children with asthma. Adherence to prednisolone was demonstrated in 17 of these 21. Within this group, there was a correlation between FE(NO) and eosinophil score (r = 0.54, p = 0.03). The relationship was strongest in patients with persistent symptoms after prednisolone, in whom FE(NO) > 7 ppb was associated with a raised eosinophil score. For all patients, FE(NO) < 7 ppb was associated with an eosinophil score within the nonasthmatic range, regardless of symptoms. We propose that FE(NO) is associated with eosinophilic inflammation in children with difficult asthma, following prednisolone, and may help in identifying patients in whom persistent symptoms are associated with airway eosinophilia.
Exercise-induced airways constriction
Authors: B. G. Simonsson, B-E. Skoogh, B. Ekstrom-Jodal
Journal: Thorax (1972)

Airway conductance was measured in a body plethysmograph at different lung volumes before and after graded exercise. In 14 out of 19 patients, mostly asthmatics, airway conductance fell significantly after exercise. These subjects also showed other signs of an increased bronchial reactivity to different stimuli, including forced breathing, hyperventilation, and cold air, but they had no exogenous allergy. The exercise-induced bronchoconstriction could be blocked by atropine in six of the nine patients tested. Exercise-induced bronchoconstriction in patients with clinical and physiological evidence of increased airway reactivity thus seems to be primarily mediated via a vagal reflex, probably from hyperresponsive airway mechanoreceptors reacting to increased ventilatory flow or lung distension. No relation was found between PaCO<sub>2</sub> or pH and the severity of airways constriction. Cromoglycic acid failed to block the exercise reaction in five of the six hyperreactive patients tested. In addition to or following the vagal reflex a disturbed relation between beta and alpha receptors in bronchial muscles or a release of humoral spasmogens may contribute to the progression of post-exercise airways constriction.
Interpreting neuroscience and explaining the mind
Authors: Ian Gold, Daniel Stoljar
Journal: Behavioral and Brain Sciences (1999)

Although a wide variety of questions were raised about different aspects of the target article, most of them fall into one of five categories each of which deals with a general question. These questions are (1) Is the radical neuron doctrine really radical? (2) Is the trivial neuron doctrine really trivial? (3) Were we sufficiently critical of the radical neuron doctrine? (4) Is there a distinction to be drawn at all between the two doctrines? and (5) How does our argument bear on related issues in the ontology of mind? Our replies to the objections and observations presented are organized around these five questions.
Management and outcome of pregnancy in autoimmune hepatitis
Authors: M A Heneghan, S M Norris, J G O'Grady, P M Harrison, I G McFarlane
Journal: Gut (2001)

There is a paucity of data in the literature on the risks associated with, and optimal management of, pregnancy in patients with autoimmune hepatitis (AIH).To assess maternal and fetal outcomes in relation to clinical management of pregnancy in a large cohort of patients with well defined AIH.A review of all known pregnancies in 162 females with definite AIH attending our clinics between 1983 and 1998, with respect to treatment, natural history, and outcome.Thirty one live births (one twin) resulted from 35 pregnancies in 18 women (seven with cirrhosis). Median age at conception was 28 years (range 18-36). Two patients presented with AIH de novo during pregnancy. At conception, in 15 pregnancies patients had been receiving azathioprine alone or (in nine) with prednisolone, in seven prednisolone alone, and in one cyclosporin. Fetal loss at > or =20 weeks' gestation occurred in two instances. Flares in disease activity occurred during four pregnancies and within three months of delivery in a further four. Among the 31 children born (median follow up 10 years) only two abnormalities have been identified: Perthes' disease in one and severe mental and physical handicap in a second who was born prematurely following decompensation of the mother's liver disease. Neither mother was receiving azathioprine.Successful completion of pregnancy is a realistic expectation for patients with well controlled AIH. Treatment options vary, but azathioprine appears to be generally safe and without adverse outcomes for mother or baby. Vigilance is required, however, and patients need to be monitored carefully during pregnancy and for several months post partum.