tbuckley/cabot-search huggingface dataset:
Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk
Authors: Fleur Lien, Alexandre Berthier, Emmanuel Bouchaert, Céline Gheeraert, Jeremy Alexandre, Geoffrey Porez, Janne Prawitt, Hélène Dehondt, Maheul Ploton, Sophie Colin, Anthony Lucas, Alexandre Patrice, François Pattou, Hélène Diemer, Alain Van Dorsselaer, Christophe Rachez, Jelena Kamilic, Albert K. Groen, Bart Staels, Philippe Lefebvre
Journal: Journal of Clinical Investigation (2014)

The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis.
Complementation of Lymphotoxin α Knockout Mice with Tumor Necrosis Factor–expressing Transgenes Rectifies Defective Splenic Structure and Function
Authors: Lena Alexopoulou, Manolis Pasparakis, George Kollias
Journal: The Journal of Experimental Medicine (1998)

Lymphotoxin (LT)α knockout mice, as well as double LTα/tumor necrosis factor (TNF) knockout mice, show a severe splenic disorganization with nonsegregating T/B cell zones and complete absence of primary B cell follicles, follicular dendritic cell (FDC) networks, and germinal centers. In contrast, as shown previously and confirmed in this study, LTβ-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks. We show here that similar to the splenic phenotype of LTβ-deficient mice, complementation of LTα knockout mice with TNF-expressing transgenes leads to a p55 TNF receptor–dependent restoration of B/T cell zone segregation and a partial preservation of primary B cell follicles, FDC networks, and germinal centers. Notably, upon lipopolysaccharide challenge, LTα knockout mice fail to produce physiological levels of TNF both in peritoneal macrophage supernatants and in their serum, indicating a coinciding deficiency in TNF expression. These findings suggest that defective TNF expression contributes to the complex phenotype of the LTα knockout mice, and uncover a predominant role for TNF and its p55 TNF receptor in supporting, even in the absence of LTα, the development and maintenance of splenic B cell follicles, FDC networks, and germinal centers.
Mechanical matching of the left ventricle with the arterial system in exercising dogs.
Authors: K Hayashida, K Sunagawa, M Noma, M Sugimachi, H Ando, M Nakamura
Journal: Circulation Research (1992)

We investigated how changes in ventricular contractility and arterial properties associated with exercise influence the energy transmission from the left ventricle to the arterial system. On six chronically instrumented dogs preconditioned to run on a treadmill, we imposed exercise loads of various degrees by altering the speed and slope of the treadmill (up to 7 km/hr and 20% slope). We evaluated ventricular contractility by end-systolic elastance (Ees) and arterial properties in terms of the effective arterial elastance (Ea). Ea was estimated by the ratio of mean aortic pressure to stroke volume. With exercise, Ees significantly increased from 7.6 +/- 1.7 to 10.9 +/- 2.6 mm Hg/ml (p less than 0.005), and Ea tended to increase from 4.9 +/- 1.4 to 6.7 +/- 1.8 mm Hg/ml (p = 0.068), whereas the ratio of Ea to Ees remained fairly constant (from 0.69 +/- 0.26 to 0.63 +/- 0.21, NS). The mechanical optimality index, defined as the ratio of stroke work to its theoretically derived maximal value, was 0.93 +/- 0.07 at rest and 0.92 +/- 0.08 at peak exercise. Similarly, the metabolic optimality index, defined as the ratio of cardiac oxygen consumption to stroke work conversion efficiency and its theoretical maximal value, was 0.98 +/- 0.02 at rest and 0.99 +/- 0.01 at peak exercise (NS). We conclude that external work of the left ventricle of these dogs was at a near maximal level for a given preload during exercise as well as at rest without compromising the conversion efficiency of metabolic energy to stroke work.
Platelet Adenine Nucleotide "Storage Pool Deficiency" In Thrombocytopenic Absent Radii Syndrome
Authors: H. James Day
Journal: JAMA (1972)

<h3>To the Editor.—</h3> A hemorrhagic diathesis has been described in patients with a platelet functional defect characterized by prolonged bleeding time, normal platelet counts, and abnormal platelet aggregation. The latter is characterized by a poor or absent aggregation with low concentrations of collagen and absence of secondary aggregation with adenosine diphosphate (ADP) and adrenaline.<sup>1</sup>Most of these patients are devoid of other defects and the bleeding disorder has been classified as thrombopathia or thrombocytopathia, terms that are confusing and inaccurate. Similar platelet abnormalities have been found in albinos,<sup>2,3</sup>in one case of Wiskott-Aldrich syndrome,<sup>4</sup>in the Hermansky-Pudlak syndrome,<sup>5</sup>and in some cases of connective tissue disease.<sup>6</sup>Some of these patients have a deficient storage pool of adenine nucleotides and serotonin, and the abnormality has been referred to as "storage pool deficiency" (SPD).<sup>1</sup>This deficiency may be more common than realized, as is evidenced by
Activation of NFAT Signaling in Podocytes Causes Glomerulosclerosis
Authors: Yinqiu Wang, George Jarad, Piyush Tripathi, Minggui Pan, Jeanette Cunningham, Daniel R. Martin, Helen Liapis, Jeffrey H. Miner, Feng Chen
Journal: Journal of the American Society of Nephrology (2010)

Mutant forms of TRPC6 can activate NFAT-dependent transcription in vitro via calcium influx and activation of calcineurin. The same TRPC6 mutants can cause FSGS, but whether this involves an NFAT-dependent mechanism is unknown. Here, we generated mice that allow conditional induction of NFATc1. Mice with NFAT activation in nascent podocytes in utero developed proteinuria and glomerulosclerosis postnatally, resembling FSGS. NFAT activation in adult mice also caused progressive proteinuria and FSGS. Ultrastructural studies revealed podocyte foot process effacement and deposition of extracellular matrix. NFAT activation did not initially affect expression of podocin, synaptopodin, and nephrin but reduced their expression as glomerular injury progressed. In contrast, we observed upregulation of Wnt6 and Fzd9 in the mutant glomeruli before the onset of significant proteinuria, suggesting a potential role for Wnt signaling in the pathogenesis of NFAT-induced podocyte injury and FSGS. These results provide in vivo evidence for the involvement of NFAT signaling in podocytes, proteinuria, and glomerulosclerosis. Furthermore, this study suggests that NFAT activation may be a key intermediate step in the pathogenesis of mutant TRPC6-mediated FSGS and that suppression of NFAT activity may contribute to the antiproteinuric effects of calcineurin inhibitors.
The Impact of Clone Size on the Prognostic Value of Chromosome Aberrations by Fluorescence <i>In Situ</i> Hybridization in Multiple Myeloma
Authors: Gang An, Zengjun Li, Yu-Tzu Tai, Chirag Acharya, Qian Li, Xiaoqi Qin, Shuhua Yi, Yan Xu, Xiaoyan Feng, Chengwen Li, Jiawei Zhao, Lihui Shi, Meirong Zang, Shuhui Deng, Weiwei Sui, Mu Hao, Dehui Zou, Yaozhong Zhao, Junyuan Qi, Tao Cheng, Kun Ru, Jianxiang Wang, Kenneth C Anderson, Lugui Qiu
Journal: Clinical Cancer Research (2015)

Accumulating evidence indicates that intratumor heterogeneity is prevalent in multiple myeloma and that a collection of multiple, genetically distinct subclones are present within the myeloma cell population. It is not clear whether the size of clonal myeloma populations harboring unique cytogenetic abnormalities carry any additional prognostic value.We analyzed the prognostic impact of cytogenetic aberrations by fluorescence in situ hybridization at different cutoff values in a cohort of 333 patients with newly diagnosed myeloma and 92 patients with relapsed myeloma.We found that nearly all IgH-related arrangements were observed in a large majority of the purified plasma cells; however, 13q deletion, 17p deletion, and 1q21 amplification appeared in different percentages within the malignant plasma cell population. Based on the size of subclones carrying these cytogenetic aberrations, the patients were divided into four groups: 0%-10%, 10.5%-20%, 20.5%-50%, and >50%. Receiver-operating characteristics analysis was applied to determine the optimal cutoff value with the greatest differential survival and showed that the most powerful clone sizes were 10% for 13q deletion, 50% for 17p deletion, and 20% for 1q21 gains, which provided the best possible cutoffs for predicting poor outcomes.Our study indicated that the impact of clone size on prognostic value varies between specific genetic abnormalities. Prognostic value was observed for even a subgroup of plasma cells harboring the cytogenetic aberration of 13q deletion and 1q21 gains; however, 17p deletion displayed the most powerful cutoff for predicting survival only if the predominant clones harbored the abnormality.
A noninvasive algorithm to exclude pre-capillary pulmonary hypertension
Authors: D. Bonderman, P. Wexberg, A.M. Martischnig, H. Heinzl, M-B. Lang, R. Sadushi, N. Skoro-Sajer, I.M. Lang
Journal: European Respiratory Journal (2010)

Current guidelines recommend right heart catheterisation (RHC) in symptomatic patients at risk of pre-capillary pulmonary hypertension (PH) with echocardiographic systolic pulmonary artery pressures ≥36 mmHg. Growing awareness for PH, a high prevalence of post-capillary PH and the inability to distinguish between pre- and post-capillary PH by echocardiography have led to unnecessary RHCs. The aim of our study was to assess whether standard noninvasive diagnostic procedures are able to safely exclude pre-capillary PH. Data from 251 patients referred for suspicion of pre-capillary PH were used to develop a noninvasive diagnostic decision tree. A prospectively collected data set of 121 consecutive patients was utilised for temporal validation. According to the decision tree, patients were stratified by the presence or absence of an electrocardiographic right ventricular strain pattern (RVS) and serum N-terminal brain natriuretic peptide (NT-proBNP) levels below and above 80 pg·mL −1 . In the absence of RVS and elevated NT-proBNP, none of the patients in the prospective validation cohort were diagnosed with pre-capillary PH by RHC. Combining echocardiography with the diagnostic algorithm increased specificity to 19.3% (p = 0.0009), while sensitivity remained at 100%. Employing ECG and NT-proBNP on top of echocardiography helps recognise one false positive case per five patients referred with dyspnoea and echocardiographic suspicion of PH, while not missing true pre-capillary PH.
Changes in Intra-Abdominal Visceral Fat and Serum Leptin Levels in Patients With Obstructive Sleep Apnea Syndrome Following Nasal Continuous Positive Airway Pressure Therapy
Authors: Kazuo Chin, Kouichi Shimizu, Takaya Nakamura, Noboru Narai, Hiroaki Masuzaki, Yoshihiro Ogawa, Michiaki Mishima, Takashi Nakamura, Kazuwa Nakao, Motoharu Ohi
Journal: Circulation (1999)

Background —Obstructive sleep apnea syndrome (OSAS) is a common disorder in obese subjects. Visceral fat accumulation (VFA) is a better predictor of coronary heart disease than body mass index. Leptin is a hormone involved in the control of body weight and fat distribution. The effect of nasal continuous positive airway pressure (NCPAP) treatment on VFA and serum leptin levels in OSAS patients has not been known. Methods and Results —VFA and subcutaneous fat accumulation (SFA) were assessed by CT before and after NCPAP treatment in 22 OSAS patients (mean apnea and hypopnea index &gt;50 episodes/h). Serum leptin levels of another 21 OSAS patients were measured before and after 3 to 4 days of NCPAP to gain insight into the mechanism by which NCPAP affects fat distribution. VFA and SFA decreased significantly after 6 months of NCPAP treatment (236±16 to 182±14cm 2 , P =0.0003 and 215±21 to 189±18 cm 2 , P =0.003, respectively). VFA decreased significantly in the body weight reduction group (n=9, P &lt;0.01) and the no body weight reduction group (n=13, P &lt;0.03). In contrast, SFA changed significantly in the body weight reduction group only ( P &lt;0.01). Leptin levels decreased significantly following 3 to 4 days of NCPAP ( P &lt;0.01), whereas body weight, fasting insulin, and cortisol levels did not change significantly. Conclusions —Correction of sleep disordered breathing by NCPAP may be used to reduce VFA in OSAS patients. OSAS may have significant effects on the serum leptin levels.
Incidence of occupational latent tuberculosis infection in South African healthcare workers
Authors: Shahieda Adams, Rodney Ehrlich, Roslynn Baatjies, Richard N. van Zyl-Smit, Qonita Said-Hartley, Rodney Dawson, Keertan Dheda
Journal: European Respiratory Journal (2015)

The test-specific incidence of latent tuberculosis infection (LTBI) in healthcare workers from sub-Saharan Africa is unknown. 505 healthcare workers from South Africa were screened at baseline, and after 12 months, with a questionnaire, the tuberculin skin test (TST), and two T-cell assays (T-SPOT.TB and QuantiFERON-TB Gold-In-Tube). Test-specific conversion rates were calculated. The prevalence of presumed LTBI at baseline was 84, 69 and 62% using the TST, QuantiFERON-TB Gold-In-Tube and T-SPOT.TB, respectively. The annual test-specific conversion rate, depending on the cut-off point used, was as follows: TST 38%; QuantiFERON-TB Gold-In-Tube 13–22%; and T-SPOT.TB 18–22%. Annual reversion rates were 4, 7 and 16%, respectively. The annual TST conversion rate was significantly higher than that derived from published local community-based data (IRR 3.53, 95% CI 1.81–6.88). Factors associated with conversion (any test) included healthcare sector of employment, counselling of tuberculosis patients, and a baseline positive TST (for T-SPOT.TB). The annual rate of tuberculosis infection in South African healthcare workers was very high, irrespective of the testing method used, and may be explained by occupational exposure, as the rate was considerably higher than non-healthcare workers from the same community. Collectively, these data support the need for implementation of tuberculosis-specific infection control measures in Africa.
Imaging in lung cancer: recent advances in PET-CT and screening
Authors: D. R. Baldwin
Journal: Thorax (2011)

Lung cancer is probably the most intensely imaging dependent sub-specialty within respiratory medicine. Historically chest physicians have had close involvement with imaging. The development of mass miniature chest radiographs is attributed to Manuel Dias de Abreu, a Brazillian pulmonologist1 and in conjunction with providing a tuberculosis service, chest physicians have reported mass miniature chest radiographs, independent of radiologists. Although the latter is now neither appropriate or indeed the case, in lung cancer, chest physicians along with other clinicians within the cancer multidisciplinary team (MDT) rely heavily on imaging and, aided by the accessibility of images afforded by the Picture Archiving and Communication System (PACS) are becoming increasingly expert. Furthermore, chest physicians are using imaging more for their own diagnostic and therapeutic procedures; in particular transthoracic and endobronchial ultrasound. It is axiomatic therefore that a radiologist who is firmly committed to the cancer MDT makes an enormous contribution to an effective care pathway. Thus any new development in imaging will have a considerable impact on lung cancer clinicians' clinical practice whether they deal principally with diagnosis and staging (chest physicians and radiologists) or treatment (oncologists and thoracic surgeons).

Over the last 10 years there have been important developments in the lung cancer care pathway from early diagnosis through diagnosis and staging and to treatment, many of these driven by improved imaging. It is necessary to have a clear idea about the performance of an imaging test (or any test) to understand how a result should influence management. A self-evident point about imaging tests is that because they do not sample tissue, they tend to yield a greater number of false positive and false negative results and therefore have a lower specificity and negative predictive value compared with minimally invasive tests. Indeed, as imaging tests improve their sensitivity the place of tests …
Duration of RT-PCR positivity in severe acute respiratory syndrome
Authors: C. M. Chu, W. S. Leung, V. C. C. Cheng, K. H. Chan, A. W. N. Lin, V. L. Chan, J. Y. M. Lam, K. S. Chan, K. Y. Yuen
Journal: European Respiratory Journal (2005)

Severe acute respiratory syndrome (SARS) is a highly infectious respiratory infection with a high mortality. The duration of infectivity is unknown. The RT-PCR positivity for SARS-associated coronavirus (SARS-CoV) was followed in 45 virologically confirmed SARS patients. Serial RT-PCRs for SARS-CoV were performed in the nasopharyngeal aspirate, stool and urine of 45 SARS patients who survived until discharge. All patients had at least one site that was positive for SARS-CoV on presentation. Time to RT-PCR conversion was studied in all patients. There were 15 males (33.3%) and 30 females (66.7%), with a mean± sd age of 40.7±14.7 yrs. The median (range) time of RT-PCR conversion was 30 days (2–81). On discharge from the hospital, 18 (40%) remained RT-PCR positive in at least one site. For patients with positive RT-PCR on discharge, the median (range) time to RT-PCR conversion after discharge was 13 days (2–60). A significant proportion of severe acute respiratory syndrome patients remained RT-PCR positive for severe acute respiratory syndrome-associated coronavirus for a substantial duration after discharge. The clinical significance is unknown and this finding merits further study. It is prudent to advise patients to adhere to strict personal hygiene on discharge until RT-PCR becomes negative.
Excellent Outcome With Reduced Treatment in Infants With Nonmetastatic and Unresectable Neuroblastoma Without <i>MYCN</i> Amplification: Results of the Prospective INES 99.1
Authors: Hervé Rubie, Bruno De Bernardi, Mary Gerrard, Adela Canete, Ruth Ladenstein, Jérôme Couturier, Peter Ambros, Caroline Munzer, Andrew D.J. Pearson, Alberto Garaventa, Penelope Brock, Victoria Castel, Dominique Valteau-Couanet, Keith Holmes, Andrea Di Cataldo, Bénédicte Brichard, Véronique Mosseri, Catalina Marquez, Dominique Plantaz, Luca Boni, Jean Michon
Journal: Journal of Clinical Oncology (2010)

To evaluate the efficacy of low-dose chemotherapy in infants with nonmetastatic and unresectable neuroblastoma (NB) without MYCN amplification.Infants with localized NB and no MYCN amplification were eligible in the SIOPEN Infant Neuroblastoma European Study 99.1 study. Primary tumor was deemed unresectable according to imaging defined risk factors. Diagnostic procedures and staging were carried out according to International Staging System recommendations. Children without threatening symptoms received low-dose cyclophosphamide (5 mg/kg/d × 5 days) and vincristine (0.05 mg/kg at day 1; CyV), repeated once to three times every 2 weeks until surgical excision could be safely performed. Children with either one threatening symptom or insufficient response to CyV were given carboplatin and etoposide (CaE), sometimes followed by vincristine, cyclophosphamide, and doxorubicin. No postoperative treatment was to be administered.Between December 1999 and April 2004, 120 infants were included in the study. Eighty-eight had no threatening symptoms and 79 received CyV. CaE was given to 49 of them because of insufficient response. Thirty-two children had threatening symptoms, 30 of whom received CaE. Anthracyclines were given to 46 children. Surgery was attempted in 102 patients, leading to gross surgical excision in 93. Relapse occurred in 12 patients (nine local and three metastatic). Five-year overall and event-free survivals were 99% ± 1% and 90% ± 3%, respectively, with a median follow-up of 6.1 years (range, 1.6 to 9.1).Low-dose chemotherapy without anthracyclines is effective in 62% of infants with an unresectable NB and no MYCN amplification, allowing excellent survival rates without jeopardizing their long-term outcome.
Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries
Authors: K. Chatzidionysiou, E. Lie, E. Nasonov, G. Lukina, M. L. Hetland, U. Tarp, C. Gabay, P. L. C. M. van Riel, D. C. Nordstrom, J. Gomez-Reino, K. Pavelka, M. Tomsic, T. K. Kvien, R. F. van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To assess the 6-month effectiveness of the first rituximab (RTX) course in rheumatoid arthritis (RA) and to identify possible predictors of response. <h3>Method</h3> 10 European registries submitted anonymised datasets (baseline, 3- and 6-month follow-up) from patients with RA who had started RTX, and datasets were pooled and analysed. Heterogeneity between countries was analysed by analysis of variance. Predictors of response were identified by logistic regression. <h3>Results</h3> 2019 patients were included (mean age/disease duration 53.8/12.1 years, 80.3% female, 85.6% rheumatoid factor (RF) positive and 76.8% (456/594 patients) anti-cyclic citrullinated peptide antibodies (anti-CCP) positive). For these patients an average of 2.7 disease-modifying antirheumatic drugs (DMARDs) (range 0–10) had failed, and RTX was given as the first biological agent in 36.6% of patients. There was significant heterogeneity between countries for several baseline characteristics, including the number of previous biological agents. Disease Activity Score based on 28 joint counts (DAS28) decreased from 5.8±1.4 at baseline to 4.2±1.4 at 6 months (p&lt;0.0001) and 22.2%/42.5% achieved European League Against Rheumatism (EULAR) good/moderate response. Larger 6-month improvement in DAS28 was observed in RF-positive and anti-CCP-positive versus seronegative patients. The following predictors of EULAR good response at 6 months were identified in a multivariate analysis: anti-CCP positivity (OR=2.86, p=0.003), number of previous DMARDs (OR=0.84, p=0.06), ≤1 previous biological agents (OR=1.89, p=0.04), baseline DAS28 level (OR=0.74, p=0.003). <h3>Conclusion</h3> In this large observational cohort of patients with RA treated with RTX, seropositive patients achieved significantly greater reductions in DAS28 at 6 months than seronegative patients. Effectiveness was best when RTX was used as the first biological agent or after failure of no more than one anti-tumour necrosis factor agent.