tbuckley/cabot-search huggingface dataset:
Adaptive redundancy, denominator neglect, and the base-rate fallacy
Authors: Christopher R. Wolfe
Journal: Behavioral and Brain Sciences (2007)

Abstract Homo sapiens have evolved a dual-process cognitive architecture that is adaptive but prone to systematic errors. Fuzzy-trace theory predicts that nested or overlapping class-inclusion relations create processing interference, resulting in denominator neglect: behaving as if one ignores marginal denominators in a 2 × 2 table. Ignoring marginal denominators leads to fallacies in base-rate problems and conjunctive and disjunctive probability estimates.
Investigation and management of uveitis
Authors: C. M. Guly, J. V. Forrester
Journal: BMJ (2010)

#### Summary points

Uveitis is estimated to account for 10% of blindness in people of working age in the Western world.1 A retrospective review of patients attending a uveitis clinic in the United Kingdom found that 70% of patients had visual impairment (visual acuity 6/18 or worse) and half of these patients had bilateral visual impairment.2 Acute anterior uveitis, which is the most common form of uveitis in the UK, usually has a good visual outcome, but other forms of uveitis have a poorer visual prognosis.

Uveitis is associated with many systemic diseases, including sarcoidosis, juvenile idiopathic arthritis, Behcet’s syndrome, and infectious diseases such as tuberculosis. For patients with systemic disease a management approach that involves collaboration with other specialties is important. In about half of cases, no systemic association is found and uveitis is presumed to be autoimmune.3 The introduction of biological treatments for many autoimmune conditions, and intravitreal injection of drugs for some eye diseases, has led to several of these treatments being used in patients with uveitis, despite limited evidence from randomised trials to support their use. This review discusses recent advances in the diagnosis of uveitis, ocular imaging, and treatments. It does not cover uveitis induced by ocular surgery.

Uveitis describes a group of intraocular inflammatory disorders that may be related to infection or …
Why Review Articles on the Health Effects of Passive Smoking Reach Different Conclusions
Authors: Deborah E. Barnes
Journal: JAMA (1998)

Objective.—To determine whether the conclusions of review articles on the health effects of passive smoking are associated with article quality, the affiliations of their authors, or other article characteristics.Data Sources.—Review articles published from 1980 to 1995 were identified through electronic searches of MEDLINE and EMBASE and from a database of symposium proceedings on passive smoking.Article Selection.—An article was included if its stated or implied purpose was to review the scientific evidence that passive smoking is associated with 1 or more health outcomes. Articles were excluded if they did not focus specifically on the health effects of passive smoking or if they were not written in English.Data Extraction.—Review article quality was evaluated by 2 independent assessors who were trained, followed a written protocol, had no disclosed conflicts of interest, and were blinded to all study hypotheses and identifying characteristics of articles. Article conclusions were categorized by the 2 assessors and by one of the authors. Author affiliation was classified as either tobacco industry affiliated or not, based on whether the authors were known to have received funding from or participated in activities sponsored by the tobacco industry. Other article characteristics were classified by one of the authors using predefined criteria.Data Synthesis.—A total of 106 reviews were identified. Overall, 37% (39/106) of reviews concluded that passive smoking is not harmful to health; 74% (29/39) of these were written by authors with tobacco industry affiliations. In multiple logistic regression analyses controlling for article quality, peer review status, article topic, and year of publication, the only factor associated with concluding that passive smoking is not harmful was whether an author was affiliated with the tobacco industry (odds ratio, 88.4; 95% confidence interval, 16.4-476.5; P<.001).Conclusions.—The conclusions of review articles are strongly associated with the affiliations of their authors. Authors of review articles should disclose potential financial conflicts of interest, and readers of review articles should consider authors' affiliations when deciding how to judge an article's conclusions.
Low dose warfarin treatment for calcinosis in patients with systemic sclerosis
Authors: T Cukierman
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To evaluate the effect of low doses of warfarin in patients with systemic sclerosis with disseminated subcutaneous calcinosis. <b>Methods:</b> Three patients with disseminated subcutaneous calcinosis were treated with low doses of warfarin for 1 year. Subcutaneous calcinotic lesions, coagulation blood parameters, and the tendency for bleeding were followed up during the year. <b>Results:</b> Two of the patients, who had newly diagnosed, diffuse, and relatively small calcinotic lesions, responded to warfarin treatment, with complete resolution of the calcinosis. The other patient, with larger and longer standing calcinotic lesions, did not respond to warfarin treatment. None of the three patients showed a prolongation of prothrombin time or partial thromboplastin time, nor did any have an increased tendency for bleeding. <b>Conclusions:</b> Low dose warfarin may serve as an effective treatment for calcinosis in a selected group of patients who have small and relatively new onset calcinosis. This treatment does not prolong the coagulation of blood and there is no increased tendency for bleeding.
Chronic Chlamydia pneumoniae infection in patients with symptomatic atherothrombosis
Authors: P. Halfon, N. Limal, G. Penaranda, H. Khiri, D. Sene, M. Andreu, J.M. Feryn, M. Rotily, R. Serra, J.C. Piette, P. Cacoub
Journal: Journal of Infection (2005)
Insulinoma-Associated 1 Has a Panneurogenic Role and Promotes the Generation and Expansion of Basal Progenitors in the Developing Mouse Neocortex
Authors: Lilla M. Farkas, Christiane Haffner, Thomas Giger, Philipp Khaitovich, Katja Nowick, Carmen Birchmeier, Svante Pääbo, Wieland B. Huttner
Journal: Neuron (2008)
Isodeoxyelephantopin, a Novel Sesquiterpene Lactone, Potentiates Apoptosis, Inhibits Invasion, and Abolishes Osteoclastogenesis through Suppression of Nuclear Factor-κB (NF-κB) Activation and NF-κB-Regulated Gene Expression
Authors: Haruyo Ichikawa, Mangalam S. Nair, Yasunari Takada, D.B. Alan Sheeja, M.A. Suresh Kumar, Oommen V. Oommen, Bharat B. Aggarwal
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Deoxyelephantopin (ESD) and isodeoxyelephantopin (ESI) are two sesquiterpene lactones derived from the medicinal plant Elephantopus scaber Linn. (Asteraceae). Although they are used for the treatment of a wide variety of proinflammatory diseases, very little is known about their mechanism of action. Because most genes that control inflammation are regulated by activation of the transcription factor nuclear factor-κB (NF-κB), we postulated that ESD and ESI mediate their activities through modulation of the NF-κB activation pathway. Experimental Design: We investigated the effect of ESI and ESD on NF-κB activation by electrophoretic mobility shift assay and NF-κB-regulated gene expression by Western blot analysis. Results: We found that ESI suppressed NF-κB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-κB activation was blocked. ESI did not interfere with the binding of NF-κB to DNA but rather inhibited IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-κB-regulated, proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of apoptosis induced by TNF and suppression of TNF-induced invasion and receptor activator of NF-κB ligand-induced osteoclastogenesis. Conclusion: Our results indicate that ESI inhibits NF-κB activation and NF-κB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.
Notch 1–Deficient Common Lymphoid Precursors Adopt a B Cell Fate in the Thymus
Authors: Anne Wilson, H. Robson MacDonald, Freddy Radtke
Journal: The Journal of Experimental Medicine (2001)

We have recently reported that Notch 1, a member of the Notch multigene family, is essential for the development of murine T cells. Using a mouse model in which Notch 1 is inactivated in bone marrow (BM) precursors we have shown that B cells instead of T cells are found in the thymus of BM chimeras. However, it is not clear whether these B cells develop by default from a common lymphoid precursor due to the absence of Notch 1 signaling, or whether they arise as a result of perturbed migration of BM-derived B cells and/or altered homeostasis of normal resident thymic B cells. In this report we show that Notch 1–deficient thymic B cells resemble BM B cells in phenotype and turnover kinetics and are located predominantly in the medulla and corticomedullary junction. Peripheral blood lymphocyte analysis shows no evidence of recirculating Notch1−/− BM B cells. Furthermore, lack of T cell development is not due to a failure of Notch1−/− precursors to home to the thymus, as even after intrathymic reconstitution with BM cells, B cells instead of T cells develop from Notch 1–deficient precursors. Taken together, these results provide evidence for de novo ectopic B cell development in the thymus, and support the hypothesis that in the absence of Notch 1 common lymphoid precursors adopt the default cell fate and develop into B cells instead.
Drug-Induced Long QT in Adult Psychiatric Inpatients: The 5-Year Cross-Sectional ECG Screening Outcome in Psychiatry Study
Authors: François R. Girardin, Marianne Gex-Fabry, Patricia Berney, Dipen Shah, Jean-Michel Gaspoz, Pierre Dayer
Journal: American Journal of Psychiatry (2013)

Routine electrocardiograms of 6,790 patients admitted to a Swiss public psychiatric hospital over 5 years showed the likelihood of a long QT interval increases if a patient taking certain medications has hypokalemia, hepatitis C, HIV, or abnormal T wave morphology.
Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer
Authors: Jennifer A Morrison, Laura A Pike, Sharon B Sams, Vibha Sharma, Qiong Zhou, Jill J Severson, Aik-Choon Tan, William M Wood, Bryan R Haugen
Journal: Molecular Cancer (2014)

Thyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells. Microarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo. Using microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model. Our findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in the transition from differentiated to advanced thyroid cancer. These studies underscore the potential of TXNIP as a novel therapeutic target and prognostic indicator in advanced thyroid cancer.
Promotion of colorectal cancer growth and metastasis by the LIM and SH3 domain protein 1
Authors: L. Zhao, H. Wang, C. Liu, Y. Liu, X. Wang, S. Wang, X. Sun, J. Li, Y. Deng, Y. Jiang, Y. Ding
Journal: Gut (2010)

LIM and SH3 protein 1 (LASP-1), initially identified from a cDNA library of metastatic axillary lymph nodes of breast cancer patients, is a specific focal adhesion protein involved in numerous biological and pathological processes. The overexpression of LASP-1 has been described in several types of cancers, but the role of LASP-1 in colorectal cancer (CRC) is unknown. In a previous study, comparative proteomic analysis was performed and LASP-1 was identified as a CRC-associated protein in those patients with CRC.Using immunohistochemistry, we analysed LASP-1 protein expression in 126 clinicopathologically characterised CRC cases. Using gene transfection and RNA interference, we investigated the effects of LASP-1 overexpression and depletion on tumor cellular behavior in vitro and in vivo. Using 2-D DIGE, we analysed the effect of the presence and absence of LASP-1 gene on protein expression profiles of CRC cells.Overexpression of LASP-1 was found in metastatic CRC tissues (p=0.002), and its expression level was closely correlated with overall survival of patients with CRC (p=0.002). RNA interference-mediated silencing of the LASP-1 gene in SW620 CRC cells inhibited cell proliferation and migration significantly. However, gene transfection-mediated overexpression of LASP-1 in SW480 CRC cells resulted in aggressive phenotypes of cancer cells and promoted cancer growth and metastasis. Furthermore, both overexpression and silencing of the LASP-1 gene caused a very similar protein expression pattern in different CRC cell lines. The identified LASP-1-modulated proteins, including some key cellular molecules, were involved in various biological processes.The results show that LASP-1 might be a promising target in the treatment of patients with CRC with growth and metastasis of CRC.
Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog
Authors: M SCHOENMAKERS, C RAMAKERS, J VANOPSTAL, J LEUNISSEN, C LONDONO, M VOS
Journal: Cardiovascular Research (2003)

Objective: Left ventricular hypertrophy has been associated with the prolongation of QT-time, and an increased risk of ventricular arrhythmias. The renin angiotensin system has been implicated in the development of ventricular hypertrophy. At 5 weeks complete AV block (CAVB) in the dog, there is: (1) biventricular hypertrophy associated with a transient activation of components of the renin angiotensin system, (2) increased APD, more pronounced in the left than in the right ventricle leading to spatial dispersion of repolarization, and (3) enhanced susceptibility to drug-induced torsade de pointes arrhythmias. To investigate whether these remodeling processes develop in parallel, time dependency was assessed in absence or presence of the AT1 receptor-blocker Irbesartan. Methods and results: Dogs in sinus rhythm, 2 and 5 weeks CAVB were compared to dogs chronically treated with Irbesartan (30 mg/kg BID). Endocardial monophasic APD of left and right ventricle was measured and susceptibility to torsade de pointes was tested by infusing Dofetilide (0.025 mg/kg/5′). Hypertrophy was determined by relating heart-to-body weight at sacrifice. Left ventricular APD had increased more than right ventricular APD at 2 and 5 weeks CAVB, leading to an increase in spatial dispersion. At that time torsade de pointes were evocable in the majority of the dogs. Hypertrophy had only developed completely at 5 weeks CAVB. Irbesartan had no effect on electrical and structural parameters or on arrhythmogenicity. Conclusions: In the CAVB dog ventricular hypertrophy is not a prerequisite for electrical remodeling or drug-induced torsade de pointes, and the AT1-receptor has no dominant role in the completion of these remodeling processes.
CARD9 mediates Dectin-1–induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity
Authors: Xin-Ming Jia, Bing Tang, Le-Le Zhu, Yan-Hui Liu, Xue-Qiang Zhao, Sara Gorjestani, Yen-Michael S. Hsu, Long Yang, Jian-Hong Guan, Guo-Tong Xu, Xin Lin
Journal: The Journal of Experimental Medicine (2014)

Dectin-1 functions as a pattern recognition receptor for sensing fungal infection. It has been well-established that Dectin-1 induces innate immune responses through caspase recruitment domain-containing protein 9 (CARD9)-mediated NF-κB activation. In this study, we find that CARD9 is dispensable for NF-κB activation induced by Dectin-1 ligands, such as curdlan or Candida albicans yeast. In contrast, we find that CARD9 regulates H-Ras activation by linking Ras-GRF1 to H-Ras, which mediates Dectin-1-induced extracellular signal-regulated protein kinase (ERK) activation and proinflammatory responses when stimulated by their ligands. Mechanistically, Dectin-1 engagement initiates spleen tyrosine kinase (Syk)-dependent Ras-GRF1 phosphorylation, and the phosphorylated Ras-GRF1 recruits and activates H-Ras through forming a complex with CARD9, which leads to activation of ERK downstream. Finally, we show that inhibiting ERK activation significantly accelerates the death of C. albicans-infected mice, and this inhibitory effect is dependent on CARD9. Together, our studies reveal a molecular mechanism by which Dectin-1 induces H-Ras activation that leads to ERK activation for host innate immune responses against fungal infection.
In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus
Authors: Hiroyuki Kishimoto, Toru Kojima, Yuichi Watanabe, Shunsuke Kagawa, Toshiya Fujiwara, Futoshi Uno, Fuminori Teraishi, Satoru Kyo, Hiroyuki Mizuguchi, Yuuri Hashimoto, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara
Journal: Nature Medicine (2006)
Suboptimal activation of melanoma infiltrating lymphocytes (TIL) due to low avidity of TCR/MHC-tumor peptide interactions.
Authors: N Gervois, Y Guilloux, E Diez, F Jotereau
Journal: The Journal of Experimental Medicine (1996)

Coculture of melanoma cells and T cell clones derived from tumor-infiltrating lymphocytes (TIL) generally results in lysis of the antigen-bearing tumor cells but to inefficient proliferation and IL-2 secretion by responder T cells. This suboptimal activation is classically explained by an inability of tumor cells to provide costimulatory signals. Here we analyzed the responses to synthetic peptides of HLA-A2.1-restricted CTL clones specific for melanoma antigens MART-1 and NA17-A. We showed that peptide concentrations ranging from 1 pM to 10 nM efficiently sensitized the peptide transporter-deficient T2 cells to lysis. T2 cells pulsed with melanoma peptides also induced TIL proliferation and detectable secretion of IL-2, IFN-gamma and GM-CSF, but only for peptide concentrations 10- to 10,000-fold higher than those required for lysis. Hence this suggests that partial triggering of TIL clones by melanoma cells could be due to expression of appropriate MHC-peptide complexes at subthreshold levels. In support of this, we showed that melanoma cells, unable to trigger IL-2 secretion, developed this ability when incubated with the appropriate peptide. These results indicate that the level of antigens expressed on melanoma tumors critically affects TIL activation status and thus, the efficiency of specific immune reactions mediated by these cells.
The Impact of Intravenous Fat Emulsion Administration in Acute Lung Injury
Authors: Marilena E. Lekka, Stamatis Liokatis, Christos Nathanail, Vasiliki Galani, George Nakos
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The aim of this study was to evaluate the effect of parenteral nutrition containing medium- and long-chain triglycerides on the function of the respiratory system and to investigate mechanisms involved in this process. We studied 13 patients with acute respiratory distress syndrome (ARDS), 8 receiving lipid and 5 placebo, and 6 without ARDS, receiving lipid. Bronchoalveolar lavage (BAL) was performed before and 1 hour after administration of lipid or placebo. In patients with ARDS, lipid administration resulted in deterioration of oxygenation (Pa(O(2))/FI(O(2)): from 129 +/- 37 to 95 +/- 42), compliance of respiratory system (from 39.2 +/- 12 to 33.1 +/- 9.2 ml/cm H(2)O), and pulmonary vascular resistance (from 258 +/- 47 to 321 +/- 58 dyne x s x cm(-5)). In the BAL fluid of the same group, an increase in total protein and phospholipid concentrations, phospholipase activities, platelet-activating factor and neutrophils, as well as alterations in BAL lipid profile were observed. No significant changes were observed in the control or in the ARDS-Placebo groups. In conclusion, this study indicates that administration of medium- and long-chain triglycerides in patients with ARDS causes alterations in lung function and hemodynamics. Inflammatory cells, possibly activated by lipids, release phospholipase A(2) and platelet-activating factor, enhancing edema formation, inflammation, and surfactant alterations.
Frataxin deficiency unveils cell-context dependent actions of insulin-like growth factor I on neurons
Authors: Carolina Franco, Silvia Fernández, Ignacio Torres-Alemán
Journal: Molecular Neurodegeneration (2012)

Abstract Background Friedreich’s ataxia (FRDA) is a neurodegenerative disease caused by deficiency of the mitochondrial iron chaperone frataxin (Fxn). FRDA has no cure, but disease-modifying strategies to increase frataxin are under study. Because insulin-like growth factor I (IGF-I) has therapeutic effects in various types of cerebellar ataxia and exerts protective actions on mitochondrial function, we explored the potential Fxn-stimulating activity of this growth factor on brain cells. Results IGF-I normalized frataxin levels in frataxin-deficient neurons and astrocytes through its canonical Akt/mTOR signaling pathway. IGF-I also stimulated frataxin in normal astrocytes but not in normal neurons, whereas IGF-I stimulated the Akt/mTOR pathway in both types of cells. This cell context-dependent action of IGF-I on neurons suggested that the intrinsic regulation of Fxn in neurons is different than in astrocytes. Indeed, neurons express much higher levels of frataxin and are much more sensitive to Fxn deficiency than astrocytes; i.e.: only neurons die in the absence of frataxin. In addition, the half-life of frataxin is shorter in neurons than in astrocytes, while after blockade of the proteasome only neurons responded to IGF-I with an increase in frataxin levels. We also explore a potential therapeutic utility of IGF-I in FRDA-like transgenic mice (YG8R mice) and found that treatment with IGF-I normalized motor coordination in these moderately ataxic mice. Conclusion Exposure to IGF-I unveiled a cell-specific regulation of frataxin in neurons as compared to astrocytes. Collectively, these results indicate that IGF-I exerts cell-context neuroprotection in frataxin deficiency that maybe therapeutically effective.