tbuckley/cabot-search huggingface dataset:
Cerebral microcirculation shear stress levels determine<i>Neisseria meningitidis</i>attachment sites along the blood–brain barrier
Authors: Emilie Mairey, Auguste Genovesio, Emmanuel Donnadieu, Christine Bernard, Francis Jaubert, Elisabeth Pinard, Jacques Seylaz, Jean-Christophe Olivo-Marin, Xavier Nassif, Guillaume Duménil
Journal: The Journal of Experimental Medicine (2006)

Neisseria meningitidis is a commensal bacterium of the human nasopharynx. Occasionally, this bacterium reaches the bloodstream and causes meningitis after crossing the blood–brain barrier by an unknown mechanism. An immunohistological study of a meningococcal sepsis case revealed that neisserial adhesion was restricted to capillaries located in low blood flow regions in the infected organs. This study led to the hypothesis that drag forces encountered by the meningococcus in the bloodstream determine its attachment site in vessels. We therefore investigated the ability of N. meningitidis to bind to endothelial cells in the presence of liquid flow mimicking the bloodstream with a laminar flow chamber. Strikingly, average blood flows reported for various organs strongly inhibited initial adhesion. As cerebral microcirculation is known to be highly heterogeneous, cerebral blood velocity was investigated at the level of individual vessels using intravital imaging of rat brain. In agreement with the histological study, shear stress levels compatible with meningococcal adhesion were only observed in capillaries, which exhibited transient reductions in flow. The flow chamber assay revealed that, after initial attachment, bacteria resisted high blood velocities and even multiplied, forming microcolonies resembling those observed in the septicemia case. These results argue that the combined mechanical properties of neisserial adhesion and blood microcirculation target meningococci to transiently underperfused cerebral capillaries and thus determine disease development.
Extracorporeal membrane oxygenation as bridge in patients with non-iatrogenic massive hemoptysis
Authors: Jee-Hong Yoo, Hong Mo Kang, Cheon Woong Choi, Myung Jae Park, Jong Hoo Lee
Journal: European Respiratory Journal (2012)

Despite advanced technologies in intensive care, massive hemoptysis can cause death in a small subset of patients. In special, extensive bleeding, hypoxia, decreased pulmonary function and/or other comorbidities make it more difficult or impossible to perform bronchoscopy, arterial embolisation or resectional surgery. Extracorporeal membrane oxygenation (ECMO) is expected to provide adequate gas exchange, to reduce ventilator-induced lung injury and, eventually, to improve outcome in patients with respiratory and circulatory failture. However, it is not sure whether it is beneficial or not to perform ECMO in unstable patients with non-iatrogenic massive hemoptysis. The case applying ECMO to patients with iatrogenic massive hemoptysis is also very rare. A male with medical history of pulmonary tuberculosis received mechanically ventilator support because of severe community acquired pneumonia. As he abruptly showed severe hypoxemia and hypotension due to massive hemoptysis, ECMO was instituted. We herein describe detailed course of our case, helping physicians make a decision to initiate ECMO in patients with non-iartrogenic massive hemoptysis.
Adjuvant Treatment With a Glycoprotein IIb/IIIa Receptor Inhibitor Increases the Therapeutic Window for Low-Dose Tissue Plasminogen Activator Administration in a Rat Model of Embolic Stroke
Authors: Li Zhang, Zheng Gang Zhang, Ruilan Zhang, Daniel Morris, Mei Lu, Barry S. Coller, Michael Chopp
Journal: Circulation (2003)

Platelet aggregation and fibrin deposition are key events leading to microvascular thrombosis and progressive impairment of downstream microvascular perfusion after stroke. We tested the hypothesis that inhibition of platelet function with a GP IIb/IIIa receptor antagonist would increase the efficacy and safety and increase the time window for thrombolytic therapy for stroke with full- and half-dose tissue plasminogen activator (tPA).Rats were subjected to embolic middle cerebral artery occlusion. Four hours after ischemia, rats were treated with 7E3 F(ab')2 (6 mg/kg) in combination with tPA at doses of 10 and 5 mg/kg, tPA alone at a dose of 10 or 5 mg/kg, 7E3 F(ab')2 (6 mg/kg) alone, or saline. Combination treatment with 7E3 F(ab')2 and tPA (full- or half-dose) significantly (P<0.05) reduced infarct volume and neurological deficits compared with saline-treated rats. However, treatment with 7E3 F(ab')2 or tPA (full- or half-dose) alone did not reduce infarct volume. Quantitative measurements of cerebral microvessels perfused by FITC-dextran revealed that combination treatment with 7E3 F(ab')2 and full-dose tPA significantly (P<0.05) increased the percentage of FITC-dextran-perfused vessels compared with saline and full-dose tPA-treated rats. In addition, treatment with 7E3 F(ab')2 in combination with full-dose tPA significantly (P<0.05) decreased microvascular platelet accumulation and matrix metalloproteinase 9 immunoreactivity and protected against loss of collagen IV immunoreactivity.Combination treatment with 7E3 F(ab')2 with full- and half-dose tPA at 4 hours after ischemia significantly reduces infarct volume and improves neurological outcome. Enhancement of patency and integrity of cerebral microvessels most likely contributes to the benefits observed with this combination therapy.
Cyclosporin A pharmacokinetics in liver transplant recipients in relation to biliary T-tube clamping and liver dysfunction.
Authors: N V Naoumov, J M Tredger, C M Steward, J G O'Grady, J Grevel, A Niven, B Whiting, R Williams
Journal: Gut (1989)

Cyclosporin A pharmacokinetics were studied after oral (4-14 mg/kg body weight) and intravenous dosing (1.5-3.5 mg/kg) in 13 orthotopic liver transplant recipients before and after permanent clamping of the biliary T-tube. After T-tube clamping, cyclosporin A absorption was faster and more complete with the mean time of peak concentration, tmax, reduced to around three hours from around six hours and mean bioavailability rising from only 16.6% (n = 13) to 30% in the entire group (n = 11 after clamping) or to 35% after excluding two patients who developed severe cholestasis after the preclamping study. Bioavailability in these two patients fell below 8% and to around 1% in a further patient with severe graft dysfunction. Clamping reduced the metabolic clearance of cyclosporin A by only 25% from a mean before clamping of 2.9 ml/min/kg to 2.3 ml/min/kg (n = 11). Oral cyclosporin A becomes a reliable means of maintaining therapeutic drug concentrations only after bioavailability increases in association with T-tube clamping and in the absence of severe liver dysfunction or cholestasis.
Antagonistic Effects of Aspirin and Folic Acid on Inflammation Markers and Subsequent Risk of Recurrent Colorectal Adenomas
Authors: Gloria Y F Ho, Xiaonan Xue, Mary Cushman, Gail McKeown-Eyssen, Robert S Sandler, Dennis J Ahnen, Elizabeth L Barry, Fred Saibil, Robert S Bresalier, Thomas E Rohan, John A Baron
Journal: JNCI Journal of the National Cancer Institute (2009)

The Aspirin/Folate Polyp Prevention Trial found that aspirin, but not folic acid, reduced recurrence of colorectal adenomas. This study examined whether treatment effects on inflammation markers explained the trial results. The trial had a factorial design with three aspirin (placebo, 81, and 325 mg/d) and two folic acid (placebo and 1 mg/d) groups. There were 884 subjects who had colonoscopic evaluation for adenomas at year 3 and plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), soluble TNF receptor type II (sTNF-R2), and IL-1 receptor antagonist (IL-1Ra) measured at baseline and year 3. Among individuals not receiving folic acid, there was a 4% decrease (mean ratio of year 3 to baseline levels = 0.96, 95% confidence interval [CI] = 0.82 to 1.14) in CRP for a period of 3 years in the 325 mg of aspirin group vs a 20% increase (mean ratio = 1.20, 95% CI = 1.03 to 1.41) in the placebo group ( P = .027). By contrast, the reverse was observed among individuals who also received folic acid ( Pinteraction = .013). Changes in inflammation markers were not associated with adenoma recurrence. Low-dose aspirin (325 mg/d) is beneficial in stabilizing CRP levels, which may be abrogated by folate. Nevertheless, inflammation markers do not mediate the chemopreventive effect of aspirin on colorectal adenomas.
23 PEGINTERFERON ALFA-2B AND RIBAVIRIN FOR HEPATITIS C RECURRENCE POST ORTHOTOPIC LIVER TRANSPLANTATION (OLT): FINAL RESULTS FROM THE PROTECT STUDY
Authors: F.D. Gordon, R.S. Brown, P. Kwo, R.J. Ghalib, J. Crippin, H. Vargas, K. Brown, T. Schiano, X. Yu, E. Chaudhri, L. Pedicone
Journal: Journal of Hepatology (2010)
Locus on Chromosome 6p Linked to Elevated HDL Cholesterol Serum Levels and to Protection Against Premature Atherosclerosis in a Kindred With Familial Hypercholesterolemia
Authors: Samuel Canizales-Quinteros, Carlos A. Aguilar-Salinas, Eduardo Reyes-Rodríguez, Laura Riba, Maribel Rodríguez-Torres, Salvador Ramírez-Jiménez, Adriana Huertas-Vázquez, Verónica Fragoso-Ontiveros, Alejandro Zentella-Dehesa, José L. Ventura-Gallegos, Gerardo Vega-Hernández, Angelina López-Estrada, Moisés Aurón-Gómez, Francisco Gómez-Pérez, Juan Rull, Nancy J. Cox, Graeme I. Bell, Maria Teresa Tusié-Luna
Journal: Circulation Research (2003)

Heterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic disorder leading to premature coronary heart disease (CHD), usually before 60 years of age. We studied an extended multigenerational kindred with FH linked to chromosome 1p32 in which atherosclerotic complications were either delayed or prevented in individuals with elevated HDL cholesterol (HDL-C) levels or hyperalphalipoproteinemia (HA). Premature CHD was observed in FH individuals without HA. The study of this family established that the HA trait in the family also followed an autosomal dominant mode of inheritance with a pattern of segregation independent from FH. We identified a locus on chromosome 6 linked to elevated HDL-C levels (HA) in this family. Haplotype analysis refined the localization to a 7.32-cM interval (73 to 80 cM from pter) flanked by markers D6S1280 and D6S1275. Parametric 2-point and multipoint analyses yielded maximum LOD scores of 3.05 and 3.17, respectively. This finding was confirmed with a nonparametric multipoint score of 3.78 (P=0.0009). We propose that this locus, linked to elevated HDL-C levels, confers protection against premature CHD within an FH context.
Terbutaline as powder inhalation from Bricanyl Turbuhaler compared to terbutaline as nebulizer solution in severe chronic airways obstruction
Authors: NC Hansen
Journal: European Respiratory Journal (1989)

Twenty two adults with severe chronic airways obstruction--FEV1 from 14 to 57% of predicted--participated on two consecutive days in an open cross over comparison of inhalation of 2 mg terbutaline powder by Bricanyl Turbuhaler and 5 mg terbutaline by a conventional jet nebulizer (Pari Inhalierboy). All participants were domiciliary users of nebulized terbutaline previous to inclusion in this study. The mean (SD) maximal increase in FEV1 within the 60 minutes following inhalation by Turbuhaler and by Pari Inhalierboy was 27% (15%) and 28% (15%). The mean (SD) maximal increase in FVC was 30% (20%) and 29% (16%). The differences were not statistically significant. All participants were able to produce inspiratory flows high enough to use the Turbuhaler. The study suggests that it will be possible to replace the use of nebulizers with powder inhalations, as far as the bronchodilating effects are concerned.
Protein Function, Connectivity, and Duplicability in Yeast
Authors: Anuphap Prachumwat, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2005)

Protein-protein interaction networks have evolved mainly through connectivity rewiring and gene duplication. However, how protein function influences these processes and how a network grows in time have not been well studied. Using protein-protein interaction data and genomic data from the budding yeast, we first examined whether there is a correlation between the age and connectivity of yeast proteins. A steady increase in connectivity with protein age is observed for yeast proteins except for those that can be traced back to Eubacteria. Second, we investigated whether protein connectivity and duplicability vary with gene function. We found a higher average duplicability for proteins interacting with external environments than for proteins localized within intracellular compartments. For example, proteins that function in the cell periphery (mainly transporters) show a high duplicability but are lowly connected. Conversely, proteins that function within the nucleus (e.g., transcription, RNA and DNA metabolisms, and ribosome biogenesis and assembly) are highly connected but have a low duplicability. Finally, we found a negative correlation between protein connectivity and duplicability.
Does suppression of HBV replication by antiviral therapy confer the same benefit as host immune control of HBV?
Authors: Suna Yapali, Anna S Lok
Journal: Gut (2014)

Cardiovascular disease occurs in ESRD patients at rates that are far higher than is seen in the general population, and cardiovascular deaths account for the majority of deaths among dialysis patients. Abnormal mineral metabolism is a novel cardiovascular risk factor among dialysis patients. Recently published results demonstrated that even with good control of BP and anemia, conventional hemodialysis is associated with significant left ventricular hypertrophy (LVH); however, daily hemodialysis was associated with a significant reduction in LV mass index (LVMI). Furthermore, it was shown that control of serum phosphorus correlates with the reduction in LVMI. These data suggest a novel mechanism for the deleterious effect of elevated serum phosphorus on cardiovascular outcomes among hemodialysis patients: LVH. Other investigators have noted an association of hyperphosphatemia and LVH; however, this study was the first to demonstrate that improvement in serum phosphorus is associated with reduction in LVM. In addition, it is shown that daily hemodialysis is an effective modality in improving serum phosphorus through significantly improved phosphorus removal. Elevated serum phosphorus leads to vascular calcification, which can lead to LVH by decreasing vascular compliance. However, our study showed an improvement in LVMI during a 12-mo period. Because vascular calcification is unlikely to remit over this time period, it is proposed that serum phosphorus has a reversible, cardiotoxic effect that leads to LVH that can be reversed successfully with good control of serum phosphorus.
Endogenous and Natural Complement Inhibitor Attenuates Myocardial Injury and Arterial Thrombogenesis
Authors: Vasile I. Pavlov, Mikkel-Ole Skjoedt, Ying Siow Tan, Anne Rosbjerg, Peter Garred, Gregory L. Stahl
Journal: Circulation (2012)

Coagulation disorders and reperfusion of ischemic myocardium are major causes of morbidity and mortality. Lectin pathway initiation complexes are composed of multimolecular carbohydrate recognition subcomponents and 3 lectin pathway-specific serine proteases. We have recently shown that the lectin pathway-specific carbohydrate recognition subcomponent mannose-binding lectin plays an essential role in the pathophysiology of thrombosis and ischemia/reperfusion injury. Thus, we hypothesized that the endogenous mannose-binding lectin (MBL)/ficolin-associated protein-1 (MAP-1) that inhibits complement activation in vitro also could be an in vivo regulator by attenuating myocardial schema/reperfusion injury and thrombogenesis when used at pharmacological doses in wild-type mice.In 2 mouse models, MAP-1 preserves cardiac function, decreases infarct size, decreases C3 deposition, inhibits MBL deposition, and prevents thrombogenesis. Furthermore, we demonstrate that MAP-1 displaces MBL/ficolin-associated serine protease (MASP)-1, MASP-2, and MASP-3 from the MBL complex.Our results suggest that the natural, endogenous inhibitor MAP-1 effectively inhibits lectin pathway activation in vivo. MAP-1 at pharmacological doses represents a novel therapeutic approach for human diseases involving the lectin pathway and its associated MASPs.
Hidradenitis suppurativa—an androgen—dependent condition
Authors: P.S. Mortimer, Mary A. Gales, R.A. Moore, R.P.R. Dawber
Journal: British Journal of Dermatology (1985)

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of apocrine glands: poral occlusion and added bacterial infection are important aetiological factors but the underlying cause remains unknown. Published animal work shows the apocrine gland to be hormone dependent. A similar mechanism is suggested in man by the failure of HS to appear before puberty and its frequent association with acne vulgaris and other androgen‐dependent conditions. Forty‐two patients with HS have been clinically and biochemically assessed for signs of increased androgen activity. Plasma total testosterone (T) sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS), prolactin, FSH, LH and 17‐β‐oestradiol were measured and compared with groups of normal female controls (n = 25) and subjects with idiopathic hirsutes (n = 37). Nineteen patients with no medical contra‐indications were randomly allocated to a double‐blind within‐patient crossover trial comparing ethinyloestradiol (50 μg) and cyproterone acetate (CPA) (50 mg in a reverse sequential regimen) with ethinyloestradiol (50 mg and levonorgestrel (500 μg) (EU/50). Treatments were sequential for 12 months with crossover at 6 months. Patients were assessed by clinical grading. Results demonstrate total testosterone and T/SHBG (index of free testosterone) to be significantly higher than normal controls in the HS group (P < 0·01) as well as the hirsutes group (P < 0·01). Treatment with CPA demonstrated significant improvement as compared to EU/50. Seven of the 19 patients were ultimately clear of the disease. We propose clinical criteria, including the presence of comedones, associated acne and pilonidal sinus, for establishing the diagnosis of HS. Early recognition is important for satisfactory control of the disease.
CDK1 Regulates Mediator of DNA Damage Checkpoint 1 during Mitotic DNA Damage
Authors: Bing Yu, W. Brian Dalton, Vincent W. Yang
Journal: Cancer Research (2012)

Abstract Cells engage sophisticated programs of DNA damage response (DDR) and repair to guard against genetic mutations. Although there is significant knowledge concerning DDR in interphase cells, much less is known about these processes in mitosis. Direct interaction between MDC1, a master DDR organizer, and a marker of DNA damage, histone γH2AX, is required to trigger robust repair. Here we show that the DNA damage-induced interaction between MDC1 and γH2AX is attenuated in mitosis. Furthermore, inhibition in the activity of the core mitotic regulator CDK1, either by pharmacologic inhibition or siRNA attenuation, enhances MDC1–γH2AX colocalization in mitosis. Our findings offer key new insights into how DDR is controlled during mitosis. Cancer Res; 72(21); 5448–53. ©2012 AACR.
Hypoxia Is Present in Murine Atherosclerotic Plaques and Has Multiple Adverse Effects on Macrophage Lipid Metabolism
Authors: Sajesh Parathath, Stephanie L. Mick, Jonathan E. Feig, Victor Joaquin, Lisa Grauer, David M. Habiel, Max Gassmann, Lawrence B. Gardner, Edward A. Fisher
Journal: Circulation Research (2011)

Human atherosclerotic plaques contain large numbers of cells deprived of O(2). In murine atherosclerosis, because the plaques are small, it is controversial whether hypoxia can occur.To examine if murine plaques contain hypoxic cells, and whether hypoxia regulates changes in cellular lipid metabolism and gene expression in macrophages.Aortic plaques from apolipoprotein-E-deficient mice were immunopositive for hypoxia-inducible transcription factor (HIF-1α) and some of its downstream targets. Murine J774 macrophages rendered hypoxic demonstrated significant increases in cellular sterol and triglycerides. The increase in sterol content in hypoxic macrophages correlated with elevated 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase activity and mRNA levels. In addition, when macrophages were incubated with cholesterol complexes, hypoxic cells accumulated 120% more cholesterol, predominately in the free form. Cholesterol-efflux assays showed that hypoxia significantly decreased efflux mediated by ATP-binding cassette subfamily A member 1 (ABCA1), whose sub cellular localization was altered in both J774 and primary macrophages. Furthermore, in vivo expression patterns of selected genes from cells in hypoxic regions of murine plaques were similar to those from J774 and primary macrophages incubated in hypoxia. The hypoxia-induced accumulation of sterol and decreased cholesterol efflux was substantially reversed in vitro by reducing the expression of the hypoxia-inducible transcription factor, HIF-1α.Hypoxic regions are present in murine plaques. Hypoxic macrophages have increased sterol content due to the induction of sterol synthesis and the suppression of cholesterol efflux, effects that are in part mediated by HIF-1α.
Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity
Authors: Sanjay Rajagopalan, Emily C. Somers, Robert D. Brook, Christine Kehrer, Dana Pfenninger, Emily Lewis, Anjan Chakrabarti, Bruce C. Richardson, Eric Shelden, W. Joseph McCune, Mariana J. Kaplan
Journal: Blood (2004)
Comment on ‘Diagnostic delay in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: results from the Danish nationwide DANBIO registry’
Authors: Ernst Feldtkeller, Martin Rudwaleit
Journal: Annals of the Rheumatic Diseases (2014)

Sørensen and Hetland state in their article1 and in their reply to a comment by Sykes et al 2 a dramatic decrease of the delay in diagnosis for patients with ankylosing spondylitis since the year 2000. The results of their study can be summarised in the following way:
Gut, inflammation and osteoporosis: basic and clinical concepts
Authors: H. Tilg, A. R. Moschen, A. Kaser, A. Pines, I. Dotan
Journal: Gut (2008)

Chronic inflammatory disorders such as inflammatory bowel diseases (IBD) affect bone metabolism and are frequently associated with the presence of osteoporosis. Bone loss is regulated by various mediators of the immune system such as the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), IL-6, or interferon-gamma. TNF-α, a master cytokine in human IBD, causes bone erosions in experimental models and these effects are exerted by osteoclasts. Other TNF-related cytokines such as receptor activator of nuclear factor kappa B (RANK), its ligand, RANKL, and osteoprotegerin are important mediators in inflammatory processes in the gut and are critically involved in the pathophysiology of bone loss. The awareness and early diagnosis of osteoporosis in states of chronic inflammation, together with applied therapies such as bisphosphonates, may be beneficial in inflammation-associated osteoporosis. Although several mechanisms may contribute to osteoporosis in patients with IBD and coeliac disease, inflammation as an important factor has so far been neglected. As key inflammatory mediators in IBD such as TNF-α are involved in the disease process both in gut and bone, we hypothesise that neutralisation of TNF-α could prove an efficient strategy in the treatment of inflammation-related osteoporosis in the future.