tbuckley/cabot-search huggingface dataset:
Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis
Authors: Christina Charles-Schoeman, Yuen Yin Lee, Victor Grijalva, Sogol Amjadi, John FitzGerald, Veena K Ranganath, Mihaela Taylor, Maureen McMahon, Harold E Paulus, Srinivasa T Reddy
Journal: Annals of the Rheumatic Diseases (2012)

Reverse cholesterol transport (RCT) is a major antiatherogenic function of high density lipoprotein (HDL). In the current work, the authors evaluated whether the RCT capacity of HDL from rheumatoid arthritis (RA) patients is impaired when compared to healthy controls.HDL was isolated from 40 patients with RA and 40 age and sex matched healthy controls. Assays of cholesterol efflux, HDL's antioxidant function and paraoxanase-1 (PON-1) activity were performed as described previously. Plasma myeloperoxidase (MPO) activity was assessed by a commercially available assay.Mean cholesterol efflux capacity of HDL was not significantly different between RA patients (40.2% ± 11.1%) and controls (39.5% ± 8.9%); p=0.75. However, HDL from RA patients with high disease activity measured by a disease activity score using 28 joint count (DAS28>5.1), had significantly decreased ability to promote cholesterol efflux compared to HDL from patients with very low disease activity/clinical remission (DAS28<2.6). Significant correlations were noted between cholesterol efflux and the DAS28 (r=-0.39, p=0.01) and erythrocyte sedimentation rate, (r=-0.41, p=0.0009). Higher plasma MPO activity was associated with worse HDL function (r=0.41/p=0.009 (antioxidant capacity); r=0.35, p=0.03 (efflux)). HDL's ability to promote cholesterol efflux was modestly but significantly correlated with its antioxidant function (r=-0.34, p=0.03).The cholesterol efflux capacity of HDL is impaired in RA patients with high disease activity and is correlated with systemic inflammation and HDL's antioxidant capacity. Attenuation of HDL function, independent of HDL cholesterol levels, may suggest a mechanism by which active RA contributes to increased cardiovascular (CV) risk.
Investigating intracerebral haemorrhage
Authors: D. Wilson, M. E. Adams, F. Robertson, M. Murphy, D. J. Werring
Journal: BMJ (2015)

#### The bottom line

A 49 year old, right handed woman presented with sudden left upper and lower limb weakness. Examination confirmed left hemiparesis with Medical Research Council (MRC) grade 3/5 power in the upper limb and 0/5 power in the lower limb. She had been diagnosed with relapsing-remitting multiple sclerosis but had been stable (without relapses) for over a year. Computed tomography (CT) on admission revealed a right frontal intracerebral haemorrhage (fig 1A⇓).



Fig 1 A: Non-contrast computed tomography (CT) head scan revealing acute intracerebral haemorrhage within the right frontal lobe (white arrow) with surrounding oedema (white arrowhead). B: T2 weighted magnetic resonance imaging (MRI) of brain of a patient with intracerebral haemorrhage taken two days after admission confirms a lesion in the left side of the midbrain in the region of the left crus cerebri (white arrow); it shows a peripheral T2 hypointense rim with heterogeneous internal signal, typical of a …
The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans
Authors: Fadila Benhamed, Pierre-Damien Denechaud, Maud Lemoine, Céline Robichon, Marthe Moldes, Justine Bertrand-Michel, Vlad Ratziu, Lawrence Serfaty, Chantal Housset, Jacqueline Capeau, Jean Girard, Hervé Guillou, Catherine Postic
Journal: Journal of Clinical Investigation (2012)

Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element–binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.
Capping and adenosine metabolism. Genetic and pharmacologic studies.
Authors: J Braun, F S Rosen, E R Unanue
Journal: The Journal of Experimental Medicine (1980)

Capping of membrane Ig was studied in lymphocytes treated with agents that interfere with adenosine metabolism. Treatment of murine or human B cells with combinations of coformycin, an inhibitor of adenosine deaminase, homocysteine, and adenosine impaired Ig capping. Inhibition of capping was also produced by 3-deazaadenosine, a specific inhibitor of adenosylhomocysteine hydrolase. The inhibitors did not affect capping of the Thy-1 antigen or membrane sites reactive with antilymphocyte antibodies. Two patients with a hereditary deficiency in adenosine deaminase had impairment of Ig capping. Such an impairment was not found in lymphocytes of two other patients who had undergone successful bone marrow transplantation. It is known that the addition of a calcium ionophore results in activation of microfilament function and in disruption of Ig caps. The ionophore effect was not inhibited by the agents mentioned above. Our results suggest that the inhibition of Ig capping during aberrant adenosine metabolism may be caused by a methylation defect preceding the contracticle event that produces membrane reorganization.
TCT-139 Prognosis and Incidence of Acute kidney Injury According to the Valve Academic Research Consortium after Transcatheter Aortic Valve Implantation
Authors: marc bedossa, vincent auffret, dominique boulmier, erwan donal, jean philippe Verhoye, gienvitto ruggieri, herve le breton
Journal: Journal of the American College of Cardiology (2012)
Obstructive sleep apnoea is associated with decreased insulin sensitivity in females
Authors: J. Theorell-Haglöw, C. Berne, C. Janson, E. Lindberg
Journal: European Respiratory Journal (2008)

The aim of the present study was to assess associations between obstructive sleep apnoea and insulin sensitivity in a population-based sample of females. In total, 400 females aged 20–70 yrs underwent a full-night polysomnography, fasting blood sampling, measurement of anthropometric variables and oral glucose tolerance test with measurement of the insulin response (n = 358). The apnoea/hypopnoea index (AHI) was calculated from the results of the polysomnography. From the results of the oral glucose tolerance test, an insulin sensitivity index (ISI) was calculated. Females with an AHI &lt;5 (n = 119) had a mean± sd ISI of 8.3±3.8, whereas females with an AHI ≥30 (n = 34) had an ISI of 6.2±4.0. Nocturnal minimal saturation was independently associated with decreased insulin sensitivity when controlling for age, waist/hip ratio, level of physical activity, smoking and alcohol consumption (95% confidence interval (CI) 0.004–0.14). When adjusting for confounders, the AHI was associated with increased fasting and 2-h insulin levels (95% CI 0.14–0.99 and 95% CI 0.28–6.47, respectively). Obstructive sleep apnoea was found to be independently associated with decreased insulin sensitivity in the present population-based sample of females.
Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer
Authors: G Lindgren
Journal: Gut (2002)

Background and aims: Polypectomy in the colon has been shown to prevent colorectal cancer in both the general population and in familial colorectal cancer. Individuals with a family history of colorectal cancer have an increased risk of the disease. Over a period of 10 years, 304 subjects at risk were included in ongoing surveillance with regular colonoscopies. To compile the medical findings and experience generated during this period, a retrospective cross sectional study was performed. Subjects: Subjects were classified into three family groups: families with hereditary non-polyposis colorectal cancer (HNPCC); families with hereditary colorectal cancer (HCC, non-Lynch syndrome); and a third group of families with only empirical risk estimates based on a family history of two close relatives (TCR) with colorectal cancer. Methods: The risk population was studied with regard to age at onset, prevalence, number, cancer risk, size, dysplasia, and distribution of adenomas. A comparison was made within the family groups and with a reference group representing the general population. Results: In total, 195 adenomas and six cancers were detected among 85 individuals. The relative risk of having an adenoma in the whole risk population compared with the general population was 2.6. Subjects from TCR families had most adenomas and HNPCC subjects had the least. A shift from proximal adenomas to distal carcinomas in families with HCC and TCR suggested a higher cancer risk in distal adenomas in these syndromes. HNPCC families showed a younger age at onset and adenomas with a higher degree of dysplasia. In HNPCC, there was a similar localisation of adenomas and carcinomas, suggesting a high risk of cancer in all adenomas. Conclusions: There was clear overrepresentation of adenomas in all three family types compared with the reference population. In HNPCC, we found earlier onset of adenomas and faster progression to cancer. Families with HCC, and even more so TCR subjects, had a later onset and lower risk of cancer from proximal adenomas. Based on these results, surveillance protocols in Sweden have been revised.
Rheumatic fever: autoantibodies against a variety of cardiac, nuclear, and streptococcal antigens.
Authors: Q.G Eichbaum, E.J Hughes, J.E Epstein, D.W Beatty
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To measure antibody titres to cardiac, nuclear, and streptococcal antigens in different groups of rheumatic fever (n = 60) and control subjects (n = 80) with the aim of identifying cross reactive antigens of potential laboratory diagnostic value. METHODS--Enzyme linked immunosorbent assays (ELISA), immunocytochemical, and electrophoretic techniques were used to measure titres of antibodies to a variety of cardiac, nuclear, and streptococcal antigens in seven groups comprising patients with rheumatic fever and control subjects. RESULTS--Increased concentrations of antibodies to several streptococcal and cardiac antigens, in addition to increased IgA and IgG levels, were noted in sera from patients with acute rheumatic fever and chronic rheumatic heart disease. Autoantibodies to nuclear antigens were evident in three rheumatic fever sera. CONCLUSION--Although we were unable to identify any unique cross reactivity between cardiac and streptococcal antigens, these results demonstrate that there is an exaggerated humoral response to several cardiac, nuclear and streptococcal antigens in patients with rheumatic fever.
INT 0123 (Radiation Therapy Oncology Group 94-05) Phase III Trial of Combined-Modality Therapy for Esophageal Cancer: High-Dose Versus Standard-Dose Radiation Therapy
Authors: Bruce D. Minsky, Thomas F. Pajak, Robert J. Ginsberg, Thomas M. Pisansky, James Martenson, Ritsuko Komaki, Gordon Okawara, Seth A. Rosenthal, David P. Kelsen
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare the local/regional control, survival, and toxicity of combined-modality therapy using high-dose (64.8 Gy) versus standard-dose (50.4 Gy) radiation therapy for the treatment of patients with esophageal cancer. PATIENTS AND METHODS: A total of 236 patients with clinical stage T1 to T4, N0/1, M0 squamous cell carcinoma or adenocarcinoma selected for a nonsurgical approach, after stratification by weight loss, primary tumor size, and histology, were randomized to receive combined-modality therapy consisting of four monthly cycles of fluorouracil (5-FU) (1,000 mg/m2/24 hours for 4 days) and cisplatin (75 mg/m2 bolus day 1) with concurrent 64.8 Gy versus the same chemotherapy schedule but with concurrent 50.4 Gy. The trial was stopped after an interim analysis. The median follow-up was 16.4 months for all patients and 29.5 months for patients still alive. RESULTS: For the 218 eligible patients, there was no significant difference in median survival (13.0 v 18.1 months), 2-year survival (31% v 40%), or local/regional failure and local/regional persistence of disease (56% v 52%) between the high-dose and standard-dose arms. Although 11 treatment-related deaths occurred in the high-dose arm compared with two in the standard-dose arm, seven of the 11 deaths occurred in patients who had received 50.4 Gy or less. CONCLUSION: The higher radiation dose did not increase survival or local/regional control. Although there was a higher treatment-related mortality rate in the patients assigned to the high-dose radiation arm, it did not seem to be related to the higher radiation dose. The standard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy is 50.4 Gy.
Targeting cell motility in pulmonary arterial hypertension
Authors: Roxane Paulin, Jolyane Meloche, Audrey Courboulin, Caroline Lambert, Alois Haromy, Antony Courchesne, Pierre Bonnet, Steeve Provencher, Evangelos D. Michelakis, Sébastien Bonnet
Journal: European Respiratory Journal (2013)

Pulmonary artery smooth muscle cells (PASMC), in pulmonary arterial hypertension (PAH), contribute to obliterative vascular remodelling and are characterised by enhanced proliferation, suppressed apoptosis and, a much less studied, increased migration potential. One of the major proteins that regulate cell migration is focal adhesion kinase (FAK), but its role in PAH is not fully understood. We hypothesised that targeting cell migration by FAK inhibition may be a new therapeutic strategy in PAH. In vivo , inhalation of FAK-siRNA (n=5) or oral delivery of PF-228 (FAK inhibitor PF-573 228; n=5) inhibited rat monocrotaline induced PAH, improving the haemodynamics, vascular remodelling (media thickness), and right ventricular hypertrophy. In vitro , FAK was activated in PAH human lungs (n=8) or PASMC when compared to those form healthy subjects (Western blot, n=5), in a Src-dependent manner, as it was reversed by the specific Src inhibitor PP2. The degree of FAK phosphorylation at Y576 correlated positively with pulmonary vascular resistance in PAH patients. FAK inhibition (siRNA, PF-228 and PP2) in PAH-PASMCs induced a fivefold increase in apoptosis (percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling), a 2.5-fold decrease in proliferation (%Ki67), an 18% decrease in cell migration (colorimetric assay) and a 50% decrease in cell invasion (wound healing). Suppressing PASMC migration by FAK inhibition inhibits PAH progression and may open a new therapeutic window in PAH.
Systemic Administration of PRO051 in Duchenne's Muscular Dystrophy
Authors: Nathalie M. Goemans, Mar Tulinius, Johanna T. van den Akker, Brigitte E. Burm, Peter F. Ekhart, Niki Heuvelmans, Tjadine Holling, Anneke A. Janson, Gerard J. Platenburg, Jessica A. Sipkens, J.M. Ad Sitsen, Annemieke Aartsma-Rus, Gert-Jan B. van Ommen, Gunnar Buyse, Niklas Darin, Jan J. Verschuuren, Giles V. Campion, Sjef J. de Kimpe, Judith C. van Deutekom
Journal: New England Journal of Medicine (2011)

Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes. The present phase 1-2a study aimed to assess the safety, pharmacokinetics, and molecular and clinical effects of systemically administered PRO051.We administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients, with each of four possible doses (0.5, 2.0, 4.0, and 6.0 mg per kilogram of body weight) given to 3 patients. Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points. All patients subsequently entered a 12-week open-label extension phase, during which they all received PRO051 at a dose of 6.0 mg per kilogram per week. Safety, pharmacokinetics, serum creatine kinase levels, and muscle strength and function were assessed.The most common adverse events were irritation at the administration site and, during the extension phase, mild and variable proteinuria and increased urinary α(1)-microglobulin levels; there were no serious adverse events. The mean terminal half-life of PRO051 in the circulation was 29 days. PRO051 induced detectable, specific exon-51 skipping at doses of 2.0 mg or more per kilogram. New dystrophin expression was observed between approximately 60% and 100% of muscle fibers in 10 of the 12 patients, as measured on post-treatment biopsy, which increased in a dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the 12-week extension phase, there was a mean (±SD) improvement of 35.2±28.7 m (from the baseline of 384±121 m) on the 6-minute walk test.Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment. (Funded by Prosensa Therapeutics; Netherlands National Trial Register number, NTR1241.).
Variable Tidal Volumes Improve Lung Protective Ventilation Strategies in Experimental Lung Injury
Authors: Peter M. Spieth, Alysson R. Carvalho, Paolo Pelosi, Catharina Hoehn, Christoph Meissner, Michael Kasper, Matthias Hübler, Matthias von Neindorff, Constanze Dassow, Martina Barrenschee, Stefan Uhlig, Thea Koch, Marcelo Gama de Abreu
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Noisy ventilation with variable Vt may improve respiratory function in acute lung injury.To determine the impact of noisy ventilation on respiratory function and its biological effects on lung parenchyma compared with conventional protective mechanical ventilation strategies.In a porcine surfactant depletion model of lung injury, we randomly combined noisy ventilation with the ARDS Network protocol or the open lung approach (n = 9 per group).Respiratory mechanics, gas exchange, and distribution of pulmonary blood flow were measured at intervals over a 6-hour period. Postmortem, lung tissue was analyzed to determine histological damage, mechanical stress, and inflammation. We found that, at comparable minute ventilation, noisy ventilation (1) improved arterial oxygenation and reduced mean inspiratory peak airway pressure and elastance of the respiratory system compared with the ARDS Network protocol and the open lung approach, (2) redistributed pulmonary blood flow to caudal zones compared with the ARDS Network protocol and to peripheral ones compared with the open lung approach, (3) reduced histological damage in comparison to both protective ventilation strategies, and (4) did not increase lung inflammation or mechanical stress.Noisy ventilation with variable Vt and fixed respiratory frequency improves respiratory function and reduces histological damage compared with standard protective ventilation strategies.
Treatment with Nasal CPAP Decreases Automobile Accidents in Patients with Sleep Apnea
Authors: LARRY FINDLEY, CAROL SMITH, JOANNA HOOPER, MICHAEL DINEEN, PAUL M. SURATT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We studied 50 consecutive patients to test the hypothesis that successful treatment of obstructive sleep apnea with nasal continuous positive airway pressure (nasal CPAP) will decrease automobile accidents in patients with sleep apnea. Thirty-six (72%) of the patients reported using nasal CPAP regularly during 2 yr. Fourteen patients reported they had not used CPAP during 2 yr. The patients with sleep apnea in this study had a higher automobile crash rate than all drivers in the state of Colorado (0.07 versus 0.01 crash per driver per year, p < 0.02). Patients who were treated with nasal CPAP had a lower crash rate while being treated than before treatment (0.07 versus 0 crash per driver per year, p < 0.03). Untreated patients with sleep apnea continued to have a high crash rate (0.07 crash per driver before and after diagnosis). Drivers with sleep apnea were reluctant to report their automobile crashes, for the drivers in this study reported only one-third of the crashes in which they were involved. This is the first study to confirm with traffic records that patients with sleep apnea have fewer automobile crashes while being treated with nasal CPAP. Findley L, Smith C, Hooper J, Dineen M, Suratt PM. Treatment with nasal CPAP decreases automobile accidents in patients with sleep apnea.
Hepatocyte turnover and regeneration: Virtually a virtuoso performance
Authors: Malcolm R. Alison, Wey-Ran Lin
Journal: Hepatology (2011)

The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.