tbuckley/cabot-search huggingface dataset:
Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production
Authors: Douglas Kuperman, Brian Schofield, Marsha Wills-Karp, Michael J. Grusby
Journal: The Journal of Experimental Medicine (1998)

The pleiotropic cytokine interleukin 4 (IL-4) has been shown to regulate many processes thought to be important in the allergic diathesis. To determine the mechanism(s) by which IL-4 mediates allergic airway responses to inhaled allergens, we compared the effects of antigen sensitization and challenge on the development of allergic airway responses in mice in which the gene for the signal transducer and activator of transcription factor 6 (Stat6) was disrupted to those of their wild-type littermates. Strikingly, Stat6-deficient mice failed to develop airway hyperresponsiveness (AHR), which was observed in their wild-type littermates after allergen provocation. Moreover, antigen-induced increases in mucus-containing cells were found to be completely Stat6 dependent. Consistent with the lack of Th2 cytokine responses in Stat6-deficient mice, no ovalbumin-specific immunoglobulin (Ig)E was detected in their serum. In contrast, Stat6 signaling only partially mediated antigen-induced eosinophilia with no role in vascular adhesion molecule 1 expression. These results indicate that Stat6 signal transduction is critical in the development of allergen-induced AHR and that agents that specifically inhibit this pathway may provide a novel strategy for the treatment of allergic disorders.
The efficacy of a combination of ondansetron, methyiprednisolone and metopimazine in patients previously uncontrolled with a dual antiemetic treatment in cisplatin-based chemotherapy
Authors: B. Lebeau, A. Depierre, M. Giovannini, A. Rivière, L. Kaluzinski, B. Votan, M. Hédouin, H. d'Allens
Journal: Annals of Oncology (1997)
Sleep-wake abnormalities in patients with cirrhosis
Authors: Sara Montagnese, Cristiano De Pittà, Michele De Rui, Michela Corrias, Matteo Turco, Carlo Merkel, Piero Amodio, Rodolfo Costa, Debra J. Skene, Angelo Gatta
Journal: Hepatology (2013)

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed.
Borrelia Outer Membrane Surface Proteins and Transmission Through the Tick
Authors: Thomas J. Templeton
Journal: The Journal of Experimental Medicine (2004)

Pathogens of the bacterial genus Borrelia differ from fellow spirochetes, Treponema and Leptospira , in their use of arthropod vectors for transmission between warm-blooded hosts.The agents of relapsing fever, Borrelia recurrentis and Borrelia hermsii , are transmitted by lice and fast-feeding soft ticks, respectively, whereas the Lyme disease spirochete, Borrelia burgdorferi ( Bb ), is transmitted to human hosts via the hard-shelled tick, Ixodes (1, 2).The evolutionary adaptation to both arthropod and warm-blooded hosts involved the invention of repertoires of outer membrane surface proteins, largely lipoproteins, conferring the ability to adhere, recognize, and respond to mammalian and arthropod tissues.As described in this issue by Yang et al., the most robust model to date for Bb lipoprotein function are two plasmid-encoded genes, paralog siblings OspA and OspB , encoding prominently expressed outer envelope lipoproteins (3), which function during the passage of borreliae within the tick vector midgut (4).In turn, a third gene encoding the lipoprotein OspC is essential for egress to the tick salivary glands (5).Here I will give a brief introduction to Borrelia biology, describe the tremendous capacity and complexity of borrelial lipoprotein repertoires, and then focus on new studies and methodologies being brought to bear on understanding Bb Osp lipoprotein function during tick transmission.A Brief Natural History of Ticks and Borrelia.Ticks, like all biting (hematophagous) arthropods, routinely salivate into their food.Hematophagous arthropods possess pronounced salivary glands secreting numerous bioactive molecules that aid in blood pool formation and delivery, including anticoagulants, antiplatelet factors, vasodilators, histamine blockers, and in the case of the prolonged-feeding ticks, attachment cement (6, 7).As a consequence, and of concern to human and animal health, tick salivary secretion is also the route of transmission for pathogens such as the bacteria Rickettsia and Borrelia , apicomplexan protozoans Theileria and Babesia , as well as numerous viruses.Ixodes ticks take a blood meal, which can last several days, during each of their larval, nymph, and adult stages.Bb transmission is typically initiated by spirochete ingestion and midgut colonization during a larval stage feed on an infected mammalian
Relation between T cell number and epithelial HLA class II expression quantified by image analysis in normal and inflamed human gastric mucosa.
Authors: K Valnes, H S Huitfeldt, P Brandtzaeg
Journal: Gut (1990)

Epithelial expression of HLA class II determinants and the number of lamina propria and intraepithelial T cells were quantified in gastric body mucosa by means of paired immunofluorescence staining which was subjected to computerised image analysis. In normal mucosa, epithelial HLA-DR expression was virtually absent. A significantly increased expression was seen in simple chronic gastritis, most extensively in the isthmus zone, where a positive reaction was seen in 34% of the epithelial area when the gastritis was of low degree and in 85% when it was of moderate severity. The most extensive HLA-DR expression was found in moderate 9stump gastritis9 28 to 32 years after Billroth II resections. In these patients the epithelial area in the foveolar and isthmus zones showed 83% and 92% positive responses, respectively. The HLA subregion products were expressed in a differential manner (DR greater than DP greater than DQ). The number of both intraepithelial and lamina propria T cells increased significantly with increasing severity of gastritis, and the fraction of putative memory T cells was also raised. Correlation analyses showed a positive relation between the epithelial expression of HLA-DR and the intraepithelial as well as the lamina propria density of T cell. These results suggest a biological link between T cells, aberrant HLA-DR expression, and gastritis, although the pathogenic importance of this relation is unknown. Enhanced epithelial presentation of autoantigens or luminal antigens, or both leading to increased activation of T cells is one possible explanation.
Antineutrophil Cytoplasmic Antibodies and the Churg–Strauss Syndrome
Authors: Régis Sablé-Fourtassou, Pascal Cohen, Alfred Mahr, Christian Pagnoux, Luc Mouthon, David Jayne, Daniel Blockmans, Jean-François Cordier, Philippe Delaval, Xavier Puechal, Dominique Lauque, Jean-François Viallard, Abdelkader Zoulim, Loïc Guillevin
Journal: Annals of Internal Medicine (2005)

Background: Since testing for antineutrophil cytoplasmic antibodies (ANCA) became available for routine evaluation, no large homogeneous cohort of patients with the Churg–Strauss syndrome has been studied. Objective: To define the clinical and biological characteristics of newly diagnosed Churg–Strauss syndrome, according to the presence or absence of ANCA. Design: Cross-sectional analysis of manifestations of participants who were enrolled in treatment trials between December 1995 and December 2002. Setting: Multicenter study in 63 clinical centers in France, Belgium, Latvia, and the United Kingdom, coordinated by the French Vasculitis Study Group. Participants: 112 patients with Churg–Strauss syndrome that was recently diagnosed on the basis of current classifications. Measurements: The authors compared principal demographic, clinical, and laboratory features according to ANCA status at diagnosis. Results: The authors detected ANCA in 43 (38%) patients. Positive ANCA status at diagnosis was associated with renal involvement, peripheral neuropathy, and biopsy-proven vasculitis, whereas negative ANCA status was associated with heart disease and fever. Limitations: The authors assessed ANCA by immunofluorescence, but they did not assess ANCA centrally or systematically retest if ANCA was undetected at diagnosis. Conclusions: Phenotypically, ANCA-positive and ANCA-negative Churg–Strauss syndrome might differ. The association of ANCA positivity with clinical symptoms that indicate inflammation and necrosis of small vessels might characterize a predominantly vasculitic pattern of the Churg–Strauss syndrome. *For a list of members of the French Vasculitis Study Group, see the Appendix.
Aberrant IgA1 Glycosylation Is Inherited in Familial and Sporadic IgA Nephropathy
Authors: Ali G. Gharavi, Zina Moldoveanu, Robert J. Wyatt, Catherine V. Barker, Susan Y. Woodford, Richard P. Lifton, Jiri Mestecky, Jan Novak, Bruce A. Julian
Journal: Journal of the American Society of Nephrology (2008)

IgA nephropathy (IgAN) is a complex trait determined by genetic and environmental factors. Most IgAN patients exhibit a characteristic undergalactosylation of the O-glycans of the IgA1 hinge region, which promotes formation and glomerular deposition of immune complexes. It is not known whether this aberrant glycosylation is the result of an acquired or inherited defect, or whether the presence of aberrant IgA1 glycoforms alone can produce IgAN. A newly validated lectin enzyme-linked immunosorbent assay (ELISA) was used to determine the serum level of galactose-deficient IgA1 (Gd-IgA1) in a cohort of 89 IgAN patients and 266 of their relatives. High Gd-IgA1 levels (> or =95th percentile for controls) were observed in all 5 available patients with familial IgAN, in 21 of 45 (47%) of their at-risk relatives (assuming autosomal dominant inheritance), and in only 1 of 19 (5%) of unrelated individuals who married into the family. This provides evidence that abnormal IgA1 glycosylation is an inherited rather than acquired trait. Similarly, Gd-IgA1 levels were high in 65 of 84 (78%) patients with sporadic IgAN and in 50 of 202 (25%) blood relatives. Heritability of Gd-IgA1 was estimated at 0.54 (P = 0.0001), and segregation analysis suggested the presence of a major dominant gene on a polygenic background. Because most relatives with abnormal IgA1 glycoforms were asymptomatic, additional cofactors must be required for IgAN to develop. The fact that abnormal IgA1 glycosylation clusters in most but not all families suggests that measuring Gd-IgA1 may help distinguish patients with different pathogenic mechanisms of disease.
Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma
Authors: Michael A. Postow, Margaret K. Callahan, Christopher A. Barker, Yoshiya Yamada, Jianda Yuan, Shigehisa Kitano, Zhenyu Mu, Teresa Rasalan, Matthew Adamow, Erika Ritter, Christine Sedrak, Achim A. Jungbluth, Ramon Chua, Arvin S. Yang, Ruth-Ann Roman, Samuel Rosner, Brenna Benson, James P. Allison, Alexander M. Lesokhin, Sacha Gnjatic, Jedd D. Wolchok
Journal: New England Journal of Medicine (2012)

The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system. Ipilimumab is a monoclonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). We report a case of the abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy. Temporal associations were noted: tumor shrinkage with antibody responses to the cancer-testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. (Funded by the National Institutes of Health and others.).
Centrilobular Liver Necrosis Induced by Hypoxia in Chronic Ethanol-Fed Rats
Authors: Samuel W. French, Nancy C. Benson, Piera S. Sun
Journal: Hepatology (1984)

Rats fed ethanol from 21 to 130 days were subjected to one or more episodes of hypoxia (6% O 2 ) in order to determine if ethanol predisposed to centrilobular liver necrosis induced by hypoxia. Pair-fed control rats were fed the diet regimen in parallel with the ethanol-fed rats through an indwelling gastric cannula. The diet and ethanol were fed continuously 24 hr per day so as to maintain high blood alcohol levels in the ethanol-fed rats. Serum enzyme levels, SGOT and SGPT were measured before and after the hypoxic episodes as an indicator of centrilobular necrosis. Animal livers were studied for centrilobular necrosis by light and electron microscopy. Necrosis was documented to be present when flocculent densities were found in hepatocytic mitochondria or the plasma membrane permitted lanthanum entrance into the cell. The results showed that ethanol feeding to maintain high blood alcohol levels did increase the propensity of the liver to undergo centrilobular necrosis when the rats were subjected to hypoxia (1 hr 45 min to 5 hr 30 min). Centrilobular necrosis was observed in the ethanol-fed rats only. Serum enzyme levels (SGPT and SGOT) rose to very high levels in these rats when they were permitted to die of hypoxia. Serum sediment from the ethanol-fed rats contained numerous cell fragments and free organelles. Since the plasma membranes were missing along the sinusoidal face of centrilobular hepatocytes and microbodies were present, it was concluded that the cell fragments in the blood had originated from necrotic hepatocytes.
Human herpes virus-8 associated primary effusion lymphoma of the pleural cavity in HIV-negative elderly men
Authors: V Ascoli, CC Scalzo, C Danese, K Vacca, A Pistilli, F Lo Coco
Journal: European Respiratory Journal (1999)

Human herpes virus-8 (HHV-8)-associated primary effusion lymphoma (PEL) is an unusual lymphoma confined to the body cavities, which primarily affects human immunodeficiency virus (HIV)-positive men at high risk for Kaposi's sarcoma (KS). We describe two HIV-negative elderly Italian men, who developed pleural HHV-8-positive PEL in association with other diseases (systemic hypertension, colonic carcinoma, chronic obstructive airways disease, dilated cardiomyopathy), but without KS. Thoracic computed tomography revealed unilateral pleural effusion and pleural thickening. Thoracentesis disclosed large lymphoma cells, with no T- or B-cell associated antigens, clonal rearrangement of the immunoglobulin heavy chain gene and the presence of HHV-8 but not Epstein-Barr virus deoxyribonucleic acid sequences. Our cases differ from most pleural effusion lymphomas, in that they are non-acquired immunodeficiency syndrome-related. This highlights the possible human herpes virus-8-associated primary effusion lymphoma risk among elderly human immunodeficiency virus-negative patients, particularly Italians, in whom human herpes virus-8 seroprevalence rates and incidence of classic Kaposi's sarcoma are high.
Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis
Authors: C. E. Ramsden, D. Zamora, B. Leelarthaepin, S. F. Majchrzak-Hong, K. R. Faurot, C. M. Suchindran, A. Ringel, J. M. Davis, J. R. Hibbeln
Journal: BMJ (2013)

<b>Objective</b> To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death. <b>Design</b> Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data. <b>Setting</b> Ambulatory, coronary care clinic in Sydney, Australia. <b>Participants</b> 458 men aged 30-59 years with a recent coronary event. <b>Interventions</b> Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups. <b>Outcome measures</b> All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group. <b>Results</b> The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% <i>v</i> 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% <i>v</i> 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% <i>v</i> 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07). <b>Conclusions</b> Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats. <b>Trial registration</b> Clinical trials NCT01621087.
Endothelial Nitric Oxide Synthase Variants in Cystic Fibrosis Lung Disease
Authors: Hartmut Grasemann, Karin Storm van's Gravesande, Rainer Büscher, Nicola Knauer, Eric S. Silverman, Lyle J. Palmer, Jeffrey M. Drazen, Felix Ratjen
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Variants in the genes encoding for the nitric oxide synthases may act as disease modifier loci in cystic fibrosis, affecting both an individual's nitric oxide level and pulmonary function. In this study, the 894G/T variant in exon 7 of the endothelial nitric oxide synthase gene was related to exhaled nitric oxide and pulmonary function in 70 cystic fibrosis patients who were aged 14.8 +/- 6.9 years (mean +/- SD), with a FEV1 of 69.4 +/- 24.8% predicted. Although there was no association between endothelial nitric oxide synthase genotypes and exhaled nitric oxide in males, nitric oxide levels were significantly higher in female cystic fibrosis patients with an 894T mutant allele, compared with female patients homozygous for the 894G wild-type allele (7.0 +/- 4.4 versus 3.6 +/- 1.9 parts per billion, p = 0.02). Furthermore, in female patients, colonization of airways with Pseudomonas aeruginosa was significantly (p < 0.05) less frequent when carrying an 894T mutant allele as compared with wild type. These data suggest that the 894T variant in the endothelial nitric oxide synthase gene is associated with increased airway nitric oxide formation in female cystic fibrosis patients, possibly affecting colonization of airways with P. aeruginosa.
Effect of firmness of mattress on chronic non-specific low-back pain: randomised, double-blind, controlled, multicentre trial
Authors: Francisco M Kovacs, Víctor Abraira, Andrés Peña, José Gerardo Martín-Rodríguez, Manuel Sánchez-Vera, Enrique Ferrer, Domingo Ruano, Pedro Guillén, Mario Gestoso, Alfonso Muriel, Javier Zamora, María Teresa Gil del Real, Nicole Mufraggi
Journal: The Lancet (2003)
New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone.
Authors: P M Yen, A Sugawara, S Refetoff, W W Chin
Journal: Journal of Clinical Investigation (1992)

Generalized resistance to thyroid hormone (GRTH) is a syndrome of hyposensitivity to triiodothyronine (T3) that displays autosomal dominant inheritance. The genetic defect commonly lies in the ligand-binding domain of one of the TR beta alleles. Since there are two major thyroid hormone receptor (TR) isoforms, TR alpha and TR beta, it is not known how the mutant receptor mediates a dominant negative effect. Previously, we showed that T3 caused dissociation of TR homodimers and TR alpha/TR beta dimers from several thyroid hormone response elements (TREs). Hence, we used the electrophoretic mobility shift assay to compare the effect of T3 on the DNA binding of mutant TR beta-1 (Mf-1) from a kindred with GRTH with normal TR beta. Mf-1 bound better as a homodimer than TR beta, but dissociated from DNA only at high T3 concentrations. Both receptors heterodimerized with nuclear auxiliary proteins. They also dimerized with TR alpha and with each other. Surprisingly, T3 disrupted the DNA binding of the Mf-1/TR isoform dimers. Thus, mechanisms for the dominant negative effect by mutant TRs likely involve either increased binding to TREs by mutant homodimers that cannot bind T3 (hence cannot dissociate from DNA) and/or the formation of inactive mutant TR/nuclear protein heterodimers.
Long-term follow-up of “stent-like” (≤ 30% diameter stenosis post) angioplasty: A case for provisional stenting
Authors: Patrick W. Serruys, Aida J. Azar, Ulrich Sigwart, Wolfgang Rutsch, Peter De Jaegere, Ferdinand Klemenij, Pim de Feyter, Paul van den Heuvel, Bernard de Bruyne, Victor Legrand
Journal: Journal of the American College of Cardiology (1996)