tbuckley/cabot-search huggingface dataset:
Gut Microbiota-Dependent Trimethylamine <i>N</i> -Oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease
Authors: W.H. Wilson Tang, Zeneng Wang, David J. Kennedy, Yuping Wu, Jennifer A. Buffa, Brendan Agatisa-Boyle, Xinmin S. Li, Bruce S. Levison, Stanley L. Hazen
Journal: Circulation Research (2014)

Trimethylamine-N-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis.To both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction.We first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, <60 mL/min per 1.73 m(2)). Median TMAO level among CKD subjects was 7.9 μmol/L (interquartile range, 5.2-12.4 μmol/L), which was markedly higher (P<0.001) than in non-CKD subjects (n=3166). Within CKD subjects, higher (fourth versus first quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. After adjustments for traditional risk factors, high-sensitivity C-reactive protein, estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio, 1.93; 95% confidence interval, 1.13-3.29; P<0.05). TMAO provided significant incremental prognostic value (net reclassification index, 17.26%; P<0.001 and differences in area under receiver operator characteristic curve, 63.26% versus 65.95%; P=0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction.Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.
Mechanisms That Regulate Macrophage Burden in Atherosclerosis
Authors: Gwendalyn J Randolph
Journal: Circulation Research (2014)

Mononuclear phagocytes (MPs) relevant to atherosclerosis include monocytes, macrophages, and dendritic cells. A decade ago, studies on macrophage behavior in atherosclerotic lesions were often limited to quantification of total macrophage area in cross-sections of plaques. Although technological advances are still needed to examine plaque MP populations in an increasingly dynamic and informative manner, innovative methods to interrogate the biology of MPs in atherosclerotic plaques developed in the past few years point to several mechanisms that regulate the accumulation and function of MPs within plaques. Here, I review the evolution of atherosclerotic plaques with respect to changes in the MP compartment from the initiation of plaque to its progression and regression, discussing the roles that recruitment, proliferation, and retention of MPs play at these different disease stages. Additional work in the future will be needed to better distinguish macrophages and dendritic cells in plaque and to address some basic unknowns in the field, including just how cholesterol drives accumulation of macrophages in lesions to build plaques in the first place and how macrophages as major effectors of innate immunity work together with components of the adaptive immune response to drive atherosclerosis. Answers to these questions are sought with the goal in mind of reversing disease where it exists and preventing its development where it does not.
Severe oral lichen planus: treatment with an aromatic retinoid (etretinate)
Authors: KJELL HERSLE, HAKAN MOBACKEN, KENT SLOBERG, HOLGER THILANDER
Journal: British Journal of Dermatology (1982)

Journal Article Severe oral lichen planus: treatment with an aromatic retinoid (etretinate) Get access KJELL HERSLE, KJELL HERSLE The Department of Dermatology, Faculty of Medicine, University of Goteborg, Sweden Search for other works by this author on: Oxford Academic Google Scholar HÅKAN MOBACKEN, HÅKAN MOBACKEN The Department of Dermatology, Faculty of Medicine, University of Goteborg, Sweden Dr Hakan Mobacken, Department of Dermatology, Sahlgren's Hospital, 8–413 45 Göteborg, Sweden. Search for other works by this author on: Oxford Academic Google Scholar KENT SLOBERG, KENT SLOBERG The Department of Oral Surgery, Faculty of Odontology, University of Goteborg, Sweden Search for other works by this author on: Oxford Academic Google Scholar HOLGER THILANDER HOLGER THILANDER The Department of Oral Surgery, Faculty of Odontology, University of Goteborg, Sweden Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 106, Issue 1, 1 January 1982, Pages 77–80, https://doi.org/10.1111/j.1365-2133.1982.tb00904.x Published: 01 January 1982 Article history Accepted: 05 March 1981 Published: 01 January 1982
Parsimony and the triple-system model of concepts
Authors: Safa Zaki, Joe Cruz
Journal: Behavioral and Brain Sciences (2010)

Machery's dismissive position on parsimony requires that we examine especially carefully the data he provides as evidence for his complex triple-system account. We use the prototype-exemplar debate as an example of empirical findings which may not, in fact, support a multiple-systems account. We discuss the importance of considering complexity in scientific theory.
Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias
Authors: K. Kuwano, N. Nakashima, I. Inoshima, N. Hagimoto, M. Fujita, M. Yoshimi, T. Maeyama, N. Hamada, K. Watanabe, N. Hara
Journal: European Respiratory Journal (2003)

Lung epithelial cells are a primary target for reactive oxygen species (ROS). ROS can cause oxidative deoxyribonucleic acid modification, such as 8-hydroxy-deoxyguanosine (8-OHdG). A human homologue of the MutT protein (hMTH1) prevents this modification. Mitochondria are the most important cellular source of ROS and may be susceptible to oxidative damage. The purpose of this study is to investigate oxidative stress and mitochondrial damage in lung epithelial cells from idiopathic interstitial pneumonias (IIPs). The authors analysed 8-OHdG, hMTH1, and mitochondrial proteins on lung specimens from 13 patients with IIPs consisted of eight patients with usual interstitial pneumonia and five patients with nonspecific interstitial pneumonia using Western blot analysis and immunohistochemistry. Immunoreactivity for 8-OHdG and hMTH1 was significantly increased in the lung epithelial cells from patients with IIPs compared with controls. The expression of hMTH1 was localised in the nuclear and cytoplasmic, but not the mitochondrial, fraction of lung homogenates. Immunoreactivity for mitochondrial protein and cytochrome c oxidase complex subunit IV was increased in the lung epithelial cells from patients with IIPs compared with controls. The current study concludes that oxidative stress may participate in epithelial cell damage in idiopathic interstitial pneumonia, and that increased mitochondrial mass may associate with increased reactive oxygen species production in idiopathic interstitial pneumonia.
Coronary Microvascular Pericytes Are the Cellular Target of Sunitinib Malate–Induced Cardiotoxicity
Authors: Vishnu Chintalgattu, Meredith L. Rees, James C. Culver, Aditya Goel, Tilahu Jiffar, Jianhu Zhang, Kenneth Dunner, Shibani Pati, James A. Bankson, Renata Pasqualini, Wadih Arap, Nathan S. Bryan, Heinrich Taegtmeyer, Robert R. Langley, Hui Yao, Michael E. Kupferman, Mark L. Entman, Mary E. Dickinson, Aarif Y. Khakoo
Journal: Science Translational Medicine (2013)

Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact platelet-derived growth factor receptor (PDGFR) signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anticancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.
Entecavir vs. lamivudine in chronic hepatitis B patients with severe acute exacerbation and hepatic decompensation
Authors: Chien-Hung Chen, Chih-Lang Lin, Tsung-Hui Hu, Chao-Hung Hung, Po-Lin Tseng, Jing-Houng Wang, Juan-Yu Chang, Sheng-Nan Lu, Rong-Nan Chien, Chuan-Mo Lee
Journal: Journal of Hepatology (2014)
Do large volume spacer devices reduce the systemic effects of high dose inhaled corticosteroids?
Authors: P H Brown, G Blundell, A P Greening, G K Crompton
Journal: Thorax (1990)

When used in high doses, inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal axis. The influence of the mode of drug inhalation on the degree of this suppression is not clear. Hypothalamo-pituitary-adrenal function was assessed by measurement of 0900 h serum cortisol concentrations, a short tetracosactrin test, and 24 hour urine free cortisol excretion in 48 adults with asthma taking 1500-2500 micrograms beclomethasone dipropionate daily via a metered dose aerosol. Twelve patients had hypothalamo-pituitary-adrenal suppression, as judged by subnormal results from at least two of the three tests or (in one patient) by an abnormal insulin stress test response. These patients then changed to inhaling the same dose of beclomethasone dipropionate through a 750 ml spacer device (Volumatic). The endocrine tests were repeated from nine days to eight weeks later in 10 patients. Comparison with initial values showed that adding the spacing device caused an increase in the median 0900 h cortisol concentration from 126 nmol/l to 398 nmol/l, in the post-tetracosactrin cortisol concentration from 402 nmol/l to 613 nmol/l and in 24 hour urine free cortisol excretion from 54 nmol to 84 nmol. The rise in serum cortisol concentration in response to tetracosactrin did not change. Evidence of persisting hypothalamo-pituitary-adrenal axis suppression was present in only four of the 10 patients; the most pronounced improvements in function tended to occur in those who had never required long term oral corticosteroids. The results from this uncontrolled study suggest that asthmatic patients taking high dose beclomethasone dipropionate may minimise adverse effects by using a large volume spacer device.
Mental time travel in the rat: Dissociation of recall and familiarity
Authors: Madeline J. Eacott, Alexander Easton
Journal: Behavioral and Brain Sciences (2007)

Abstract We examine and reject the claim that the past-directed aspect of mental time travel (episodic memory) is unique to humans. Recent work in our laboratory with rats has demonstrated behaviours that resemble “remember, know” judgements about past occasions. Similar to human episodic memory, we can also demonstrate a dissociation in the neural basis of recollection and familiarity in nonhumans.
A phase II study of nilotinib administered to imatinib resistant and intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP)
Authors: G. Rosti, P. le Coutre, K. Bhalla, F. Giles, G. Ossenkoppele, A. Hochhaus, N. Gattermann, A. Haque, A. Weitzman, M. Baccarani, H. Kantarjian
Journal: Journal of Clinical Oncology (2007)

7007 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib. The objective of this phase II open-label study was to evaluate the safety and efficacy of nilotinib in imatinib-resistant or -intolerant CML-CP pts Methods: Imatinib-resistance was defined using standard criteria and had failed imatinib &gt;/= 600mg/day. Imatinib intolerance was defined as intolerant symptoms and lack of MCyR. Primary endpoint was MCyR determined by conventional ITT analysis. Planned nilotinib dose was 400mg BID with escalation to 600mg BID for inadequate responses Results: 316 pts were enrolled and included for safety analysis; efficacy results are from 279 pts with at least 6 mos of follow up. 221 (70%) pts were imatinib-resistant and 95 (30%) were imatinib- intolerant. Median duration of CML was 58 mos; median prior imatinib use was 33 mos. 227 (73%) pts had prior imatinib dose &gt;/= 600mg/day. Treatment with nilotinib is ongoing for 221 (70%) pts. 95 (30%) pts have discontinued treatment (41 for AEs, 32 for disease progression). Median duration of nilotinib exposure was 247 days; overall median average dose intensity was 797mg/day. Median cumulative duration of dose interruptions was 19 days. MCyR was achieved in 145 (52%), 96 (34%) were complete and 49 (18%) partial. Median time to MCyR was 2.8 mos. CHR was achieved in 137/185 (74%) pts without baseline CHR. Median time to CHR was 1.0 mos. Response rates were similar in imatinib- resistant and -intolerant pts. After 10 mos of follow up, the median duration of CHR and MCyR has not been reached. The most frequent Grade 3/4 laboratory abnormalities included thrombocytopenia in (29%), neutropenia in (28%), and asymptomatic lipase elevation in (15%) pts. Rare (&lt;1%) pleural effusion, pericardial effusion, or pulmonary edema were observed. Requirements for growth factors and platelet transfusions were minimal. Conclusions: Nilotinib resulted in significant response rates in pts with imatinib-resistant or -intolerant CML-CP and excellent tolerability as indicated by high dose intensity, favorable rates of myelosuppression, and no serious episodes of fluid retention. No significant financial relationships to disclose.
Rapid Increase in Breast Magnetic Resonance Imaging Use
Authors: Natasha K. Stout, Larissa Nekhlyudov, Lingling Li, Elisabeth S. Malin, Dennis Ross-Degnan, Diana S. M. Buist, Marjorie A. Rosenberg, Marina Alfisher, Suzanne W. Fletcher
Journal: JAMA Internal Medicine (2013)

Breast magnetic resonance imaging (MRI) is highly sensitive for detecting breast cancer. Low specificity, cost, and little evidence regarding mortality benefits, however, limit recommendations for its use to high-risk women. How breast MRI is actually used in community settings is unknown.To describe breast MRI trends and indications in a community setting.Retrospective cohort study at a not-for-profit health plan and multispecialty group medical practice in New England of 10,518 women aged 20 years and older enrolled in the health plan for at least 1 year who had at least 1 breast MRI between January 1, 2000, and December 31, 2011.Breast MRI counts were obtained from claims data. Clinical indication (screening, diagnostic evaluation, staging or treatment, or surveillance) was determined using a prediction model developed from electronic medical records on a subset of participants. Breast cancer risk status was assessed using claims data and, for the subset, also through electronic medical record review. RESULTS; Breast MRI use increased more than 20-fold from 6.5 per 10,000 women in 2000 to 130.7 per 10,000 in 2009. Use then declined and stabilized to 104.8 per 10,000 by 2011. Screening and surveillance, rare indications in 2000, together accounted for 57.6% of MRI use by 2011; 30.1% had a claims-documented personal history and 51.7% a family history of breast cancer, whereas 3.5% of women had a documented genetic mutation. In the subset of women with electronic medical records who received screening or surveillance MRIs, only 21.0% had evidence of meeting American Cancer Society (ACS) criteria for breast MRI. Conversely, only 48.4% of women with documented deleterious genetic mutations received breast MRI screening.Breast MRI use increased steeply over 10 years and then stabilized, especially for screening and surveillance among women with family or personal history of breast cancer; most women receiving screening and surveillance breast MRIs lacked documented evidence of meeting ACS criteria, and many women with mutations were not screened. Efforts are needed to ensure that breast MRI use and documentation are focused on those women who will benefit most.
Cartilaginous airway wall dimensions and airway resistance in cystic fibrosis lungs
Authors: H.A.W.M. Tiddens, L.P. Koopman, R.K. Lambert, W.m Elliott, W.C.j Hop, T.w van der Mark, W.j de Boer, J.C. de Jongste
Journal: European Respiratory Journal (2000)

It is not clear how airway pathology relates to the severity of airflow obstruction and increased bronchial responsiveness in cystic fibrosis (CF) patients. The aim of this study was to measure the airway dimensions of CF patients and to estimate the importance of these dimensions to airway resistance using a computational model. Airway dimensions were measured in lungs obtained from CF patients who had undergone lung transplantation (n=12), lobectomy (n=1), or autopsy (n=4). These dimensions were compared to those of airways from lobectomy specimens from 72 patients with various degrees of chronic obstructive pulmonary disease (COPD). The airway dimensions of the CF and COPD patients were introduced into a computational model to study their effect on airway resistance. The inner wall and smooth muscle areas of peripheral CF airways were increased 3.3- and 4.3-fold respectively compared to those of COPD airways. The epithelium was 53% greater in height in peripheral CF airways. The sensitivity and maximal plateau resistance of the computed dose/response curves were substantially increased in the CF patients compared to COPD patients. The changes in airway dimensions of cystic fibrosis patients probably contribute to the severe airflow obstruction, and to increased bronchial responsiveness, in these patients.
Defective Angiogenesis in the Inflammatory Granulation Tissue in Histidine Decarboxylase–deficient Mice but not in Mast Cell–deficient Mice
Authors: Ajoy Kumar Ghosh, Noriyasu Hirasawa, Hiroshi Ohtsu, Takehiko Watanabe, Kazuo Ohuchi
Journal: The Journal of Experimental Medicine (2002)

We have analyzed the role of histamine in the angiogenesis of the granulation tissue in histidine decarboxylase–deficient (HDC−/−) mice, mast cell–deficient mice (WBB6F1-W/WV), and their corresponding wild-type mice (HDC+/+ and WBB6F1+/+). In HDC+/+ mice, subcutaneous implantation of a cotton thread in the dorsum induced granulation tissue formation with angiogenesis, while the topical injection of antivascular endothelial growth factor (VEGF) IgG strongly suppressed them. In HDC−/− mice which showed lower VEGF levels in the granulation tissue, there was notably less angiogenesis and granulation tissue formation than in HDC+/+ mice. The topical injection of histamine or the H2 agonist dimaprit rescued the defective angiogenesis and granulation tissue formation in HDC−/− mice. There was no significant difference in the granulation tissue formation and angiogenesis between WBB6F1-W/WV and WBB6F1+/+ mice. In addition, macrophages in the granulation tissue were found to express HDC. Our findings indicate that histamine derived from nonmast cells plays a significant role in the angiogenesis of the inflammatory granulation tissue.
Loss of Klotho Contributes to Kidney Injury by Derepression of Wnt/β-Catenin Signaling
Authors: Lili Zhou, Yingjian Li, Dong Zhou, Roderick J. Tan, Youhua Liu
Journal: Journal of the American Society of Nephrology (2013)

Aging is an independent risk factor for CKD, but the molecular mechanisms that link aging and CKD are not well understood. The antiaging protein Klotho may be an endogenous antagonist of Wnt/β-catenin signaling, which promotes fibrogenesis, suggesting that loss of Klotho may contribute to CKD through increased Wnt/β-catenin activity. Here, normal adult kidneys highly expressed Klotho in the tubular epithelium, but various models of nephropathy exhibited markedly less expression of Klotho. Loss of Klotho was closely associated with increased β-catenin in the diseased kidneys, suggesting an inverse correlation between Klotho and canonical Wnt signaling. In vitro, both full-length and secreted Klotho bound to multiple Wnts, including Wnt1, Wnt4, and Wnt7a. Klotho repressed gene transcription induced by Wnt but not by active β-catenin. Furthermore, Klotho blocked Wnt-triggered activation and nuclear translocation of β-catenin, as well as the expression of its target genes in tubular epithelial cells. Investigating potential mediators of Klotho loss in CKD, we found that TGF-β1 suppressed Klotho expression and concomitantly activated β-catenin; conversely, overexpression of Klotho abolished fibrogenic effects of TGF-β1. In two mouse models of CKD induced by unilateral ureteral obstruction or adriamycin, in vivo expression of secreted Klotho inhibited the activation of renal β-catenin and expression of its target genes. Secreted Klotho also suppressed myofibroblast activation, reduced matrix expression, and ameliorated renal fibrosis. Taken together, these results suggest that Klotho is an antagonist of endogenous Wnt/β-catenin activity; therefore, loss of Klotho may contribute to kidney injury by releasing the repression of pathogenic Wnt/β-catenin signaling.
Stressful Life Events and Previous Episodes in the Etiology of Major Depression in Women: An Evaluation of the “Kindling” Hypothesis
Authors: K S Kendler, L M Thornton, C O Gardner
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Although previous evidence has suggested that the etiologic role of stressful life events in major depression is reduced in recurrent versus first-onset cases, this question deserves reexamination because of potential methodological limitations of the previous studies. METHOD: Members of female-female twin pairs from a population-based registry (N=2,395), who were interviewed four times over a period of 9 years, formed a study group that contained 97,515 person-months and 1,380 onsets of major depression. Discrete-time survival, proportional hazards model, and piece-wise regression analyses were used to examine the interaction between life event exposure and number of previous depressive episodes in the prediction of episodes of major depression. RESULTS: For those with zero to nine previous depressive episodes, the depressogenic effect of stressful life events declined substantially with increasing episode number. However, the association between stressful life events and major depression was not substantially influenced by additional episodes. This pattern of results was robust to the addition of indices of event severity, measures of genetic risk, and restriction to independent stressful life events. The same pattern was also seen upon examining within-person changes in number of episodes. CONCLUSIONS: The association between previous number of depressive episodes and the pathogenic impact of stressful life events on major depression is likely causal and biphasic. Through approximately nine episodes, the association between stressful life event exposure and risk of major depression progressively declines but is largely unchanged with further episodes. These results are consistent with the kindling hypothesis but suggest a threshold at which the mind/brain is no longer additionally sensitized to the depressive state.