tbuckley/cabot-search huggingface dataset:
14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans
Authors: R. Tamisier, J.L. Pépin, J. Rémy, J.P. Baguet, J.A. Taylor, J.W. Weiss, P. Lévy
Journal: European Respiratory Journal (2010)

Obstructive sleep apnoea syndrome (OSAS) causes nocturnal chronic intermittent hypoxia (IH) that contributes to excess cardiovascular morbidity. To explore the consequences of IH, we used our recently developed model of nocturnal IH in healthy humans to characterise the profile of this blood pressure increase, to determine if it is sustained and to explore potential physiological mechanisms. We performed 24-h ambulatory monitoring of blood pressure in 12 healthy subjects before and after 2 weeks of IH exposure. We also assessed systemic haemodynamics, muscle sympathetic nerve activity (MSNA), ischaemic calf blood flow responses and baroreflex gain. We obtained blood samples for inflammatory markers before, during and after exposure. IH significantly increased daytime ambulatory blood pressure after a single night of exposure (3 mmHg for mean and diastolic) and further increased daytime pressures after 2 weeks of exposure (8 mmHg systolic and 5 mmHg diastolic). Mean ± sd MSNA increased across the exposure (17.2 ± 5.1 versus 21.7 ± 7.3 bursts·min⁻¹; p < 0.01) and baroreflex control of sympathetic outflow declined from -965.3 ± 375.1 to -598.4 ± 162.6 AIU·min⁻¹ ·mmHg⁻¹ (p < 0.01). There were no evident changes in either vascular reactivity or systemic inflammatory markers. These data are the first to show that the arterial pressure rise is sustained throughout the waking hours beyond the acute phase immediately after exposure. Moreover, they may suggest that sympathoactivation induced by IH likely contributes to blood pressure elevation and may derive from reduced baroreflex inhibition. These mechanisms may reflect those underlying the blood pressure elevation associated with OSAS.
NF-κB in Cancer: A Matter of Life and Death
Authors: Bharat B. Aggarwal, Bokyung Sung
Journal: Cancer Discovery (2011)

Abstract Activation of NF-κB has been linked to various cellular processes in cancer, including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance, and radioresistance. Although acute inflammation mediates innate and humoral immunity, chronic inflammation has been linked to tumorigenesis. Thus, inhibition of NF-κB has therapeutic potential in sensitization of tumors to chemotherapeutic agents; however, generalized suppression of NF-κB can result in serious host toxicity with minimum effect on the tumor. Cancer Discovery; 1(6); 469–71. ©2011 AACR. Commentary on Enzler et al., p. 496.
Involvement of Artemis in nonhomologous end-joining during immunoglobulin class switch recombination
Authors: Likun Du, Mirjam van der Burg, Sergey W. Popov, Ashwin Kotnis, Jacques J.M. van Dongen, Andrew R. Gennery, Qiang Pan-Hammarström
Journal: The Journal of Experimental Medicine (2008)

DNA double-strand breaks (DSBs) introduced in the switch (S) regions are intermediates during immunoglobulin class switch recombination (CSR). These breaks are subsequently recognized, processed, and joined, leading to recombination of the two S regions. Nonhomologous end-joining (NHEJ) is believed to be the principle mechanism involved in DSB repair during CSR. One important component in NHEJ, Artemis, has however been considered to be dispensable for efficient CSR. In this study, we have characterized the S recombinational junctions from Artemis-deficient human B cells. Sμ–Sα junctions could be amplified from all patients tested and were characterized by a complete lack of “direct” end-joining and a remarkable shift in the use of an alternative, microhomology-based end-joining pathway. Sμ–Sγ junctions could only be amplified from one patient who carries “hypomorphic” mutations. Although these Sμ–Sγ junctions appear to be normal, a significant increase of an unusual type of sequential switching from immunoglobulin (Ig)M, through one IgG subclass, to a different IgG subclass was observed, and the Sγ–Sγ junctions showed long microhomologies. Thus, when the function of Artemis is impaired, varying modes of CSR junction resolution may be used for different S regions. Our findings strongly link Artemis to the predominant NHEJ pathway during CSR.
Modulation of Cystatin A Expression in Human Airway Epithelium Related to Genotype, Smoking, COPD, and Lung Cancer
Authors: Marcus W. Butler, Tomoya Fukui, Jacqueline Salit, Renat Shaykhiev, Jason G. Mezey, Neil R. Hackett, Ronald G. Crystal
Journal: Cancer Research (2011)

Abstract The cathepsin inhibitor Cystatin A (CSTA) has antiapoptotic properties linked with neoplastic changes in squamous cell epithelium, where it has been proposed as a diagnostic and prognostic marker of lung cancer. Notably, cystatin A is upregulated in dysplastic epithelium, prompting us to hypothesize that it might be modulated in chronic obstructive pulmonary disease (COPD), a small airway epithelial (SAE) disorder that is a risk factor for non–small cell lung cancer (NSCLC) in a subset of smokers. Here we report that genetic variation, smoking, and COPD can all elevate levels of CSTA expression in lung small airway epithelia, with still further upregulation in squamous cell carcinoma (SCC), an NSCLC subtype. We examined SAE gene expression in 178 individuals, including healthy nonsmokers (n = 60), healthy smokers (n = 82), and COPD smokers (n = 36), with corresponding large airway epithelium (LAE) data included in a subset of subjects (n = 52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were found to associate with its expression in SAE. Levels were higher in COPD smokers than in healthy smokers, who, in turn, had higher levels than nonsmokers. CSTA gene expression in LAE was also smoking-responsive. Using publicly available NSCLC expression data we also found that CSTA was upregulated in SCC versus LAE and downregulated in adenocarcinoma versus smoke-exposed SAE. All phenotypes were associated with different proportional expression of CSTA to cathepsins. Our findings establish that genetic variability, smoking, and COPD all influence CSTA expression, as does SCC, supporting the concept that CSTA may make pivotal contributions to NSCLC pathogenesis in both early and late stages of disease development. Cancer Res; 71(7); 2572–81. ©2011 AACR.
The Roles of Prolactin, Growth Hormone, Insulin-Like Growth Factor-I, and Thyroid Hormones in Lymphocyte Development and Function: Insights from Genetic Models of Hormone and Hormone Receptor Deficiency*
Authors: Kenneth Dorshkind, Nelson D. Horseman
Journal: Endocrine Reviews (2000)

An extensive literature suggesting that PRL, GH, IGF-I, and thyroid hormones play an important role in immunity has evolved. Because the use of one or more of these hormones as immunostimulants in humans is being considered, it is of critical importance to resolve their precise role in immunity. This review addresses new experimental evidence from analysis of lymphocyte development and function in mice with genetic defects in expression of these hormones or their receptors that calls into question the presumed role played by some of these hormones and reveals unexpected effects of others. These recent findings from the mutant mouse models are integrated and placed in context of the wider literature on endocrine-immune system interactions. The hypothesis that will be developed is that, with the exception of a role for thyroid hormones in B cell development, PRL, GH, and IGF-I are not obligate immunoregulators. Instead, they apparently act as anabolic and stress-modulating hormones in most cells, including those of the immune system.
Flip-Flop Lung. An Unusual Etiology of Bronchiectasis
Authors: Deborah R. Liptzin, Leland L. Fan, Paul C. Stillwell, Kimberly A. Dannull, Michael F. Fadell, David A. Partrick, Megan K. Dishop
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

A 14-year-old female presented to a pulmonary clinic with a 1-year history of recurrent right lower lobe pneumonia.Spirometry, immunologic, rheumatologic, cystic fibrosis, primary ciliary dyskinesia, and fungal assessments were unrevealing.Bronchoscopy showed right lower lobe pus that was not cleared by the procedure (Figure 1A).Bronchoalveolar lavage revealed 237,390,000 white blood cells (97% neutrophils) and grew Streptococcus anginosus.Initial computed tomography scan revealed right lower lobe airspace disease with fluid-filled bronchiectasis (Figure 1B).After prolonged treatment with amoxicillin/clavulanate, dornase alfa, and airway clearance, the fluid resolved, unveiling saccular bronchiectasis (Figure 1C).Gross pathology after right lower lobe resection confirmed saccular bronchiectasis (Figure 1D, filled arrow), and revealed a crumpled plastic tag labeled "ladies flip flop USA size 5-6" (Figure 1D, open arrow; Figure 1E).Afterwards, her mother recalled that she "used to chew on stuff."The patient remembered wearing the sandals 4 years prior, but had no recollection of aspirating the tag.
Outcome of Congestive Heart Failure in Elderly Persons: Influence of Left Ventricular Systolic Function: The Cardiovascular Health Study
Authors: John S. Gottdiener
Journal: Annals of Internal Medicine (2002)

Background: Most persons with congestive heart failure are elderly, and many elderly persons with congestive heart failure have normal left ventricular systolic function. Objective: To evaluate the relationship between left ventricular systolic function and outcome of congestive heart failure in elderly persons. Design: Population-based longitudinal study of coronary heart disease and stroke. Setting: Four U.S. sites: Forsyth County, North Carolina; Sacramento County, California; Allegheny County, Pennsylvania; and Washington County, Maryland. Participants: 5888 persons who were at least 65 years of age and were recruited from the community. Measurements: Total mortality and cardiovascular morbidity and mortality. Results: Of 5532 participants, 269 (4.9%) had congestive heart failure. Among these, left ventricular function was normal in 63%, borderline decreased in 15%, and overtly impaired in 22%. The mortality rate was 25 deaths per 1000 person-years in the reference group (no congestive heart failure and normal left ventricular function at baseline); 154 deaths per 1000 person-years in participants with congestive heart failure and impaired left ventricular systolic function; 87 and 115 deaths per 1000 person-years in participants with congestive heart failure and normal or borderline systolic function, respectively; and 89 deaths per 1000 person-years in persons with impaired left ventricular function but no congestive heart failure. Although the risk for death from congestive heart failure was lower in persons with normal systolic function than in those with impaired function, more deaths were associated with normal systolic function because more persons with heart failure fall into this category. Conclusions: Community-dwelling elderly persons, especially those with impaired left ventricular function, have a substantial risk for death from congestive heart failure. However, more deaths occur from heart failure in persons with normal systolic function because left ventricular function is more often normal than impaired in elderly persons with heart failure.
Intestinal alkaline phosphatase preserves the normal homeostasis of gut microbiota
Authors: M. S. Malo, S. N. Alam, G. Mostafa, S. J. Zeller, P. V. Johnson, N. Mohammad, K. T. Chen, A. K. Moss, S. Ramasamy, A. Faruqui, S. Hodin, P. S. Malo, F. Ebrahimi, B. Biswas, S. Narisawa, J. L. Millan, H. S. Warren, J. B. Kaplan, C. L. Kitts, E. L. Hohmann, R. A. Hodin
Journal: Gut (2010)

The intestinal microbiota plays a critical role in maintaining human health; however, the mechanisms governing the normal homeostatic number and composition of these microbes are largely unknown. Previously it was shown that intestinal alkaline phosphatase (IAP), a small intestinal brush border enzyme, functions as a gut mucosal defence factor limiting the translocation of gut bacteria to mesenteric lymph nodes. In this study the role of IAP in the preservation of the normal homeostasis of the gut microbiota was investigated.Bacterial culture was performed in aerobic and anaerobic conditions to quantify the number of bacteria in the stools of wild-type (WT) and IAP knockout (IAP-KO) C57BL/6 mice. Terminal restriction fragment length polymorphism, phylogenetic analyses and quantitative real-time PCR of subphylum-specific bacterial 16S rRNA genes were used to determine the compositional profiles of microbiotas. Oral supplementation of calf IAP (cIAP) was used to determine its effects on the recovery of commensal gut microbiota after antibiotic treatment and also on the colonisation of pathogenic bacteria.IAP-KO mice had dramatically fewer and also different types of aerobic and anaerobic microbes in their stools compared with WT mice. Oral supplementation of IAP favoured the growth of commensal bacteria, enhanced restoration of gut microbiota lost due to antibiotic treatment and inhibited the growth of a pathogenic bacterium (Salmonella typhimurium).IAP is involved in the maintenance of normal gut microbial homeostasis and may have therapeutic potential against dysbiosis and pathogenic infections.
Effect of Exogenous Adenosine Triphosphate on the Metabolic State of the Excised Hypothermic Dog Heart
Authors: MARGITA FEDELEŠOVÁ, ATTILA ZIEGELHÖFFER, ERNST-GEORG KRAUSE, ALBERT WOLLENBERGER
Journal: Circulation Research (1969)

Solutions of adenosine triphosphate (ATP) were injected into the left coronary artery of isolated nonperfused dog hearts kept for 30 to 180 minutes at temperatures varying from 4 to 34°C. The amount of ATP administered varied from 0.5 to 7 µmoles/g heart. The left ventricles of the ATP-treated hearts had a higher content of adenine nucleotides and of phosphocreatine than did the left ventricles of control hearts not exposed to ATP. This effect was temperature-dependent and was maximal at 14°C. Glycogen disappearance in the hypothermic myocardial tissue was markedly slowed in a dose-dependent fashion by the administration of ATP. Injections of adenine and adenosine were without effect. An analysis of the intra- and extracellular distribution of simultaneously administered adenosine-8 -14 C-triphosphate and adenosine triphosphate-α- 32 P shows that the injected ATP was mainly split into ADP, AMP, adenosine, and inorganic phosphate and indicates that a minor percentage of these fission products entered the myocardial cells, some of the ADP and AMP being rephosphorylated there to ATP. The results suggest that intravascular introduction of ATP into the arrested hypothermic heart might help in the survival of the organ.
Influenza-like illness in residential care homes: a study of the incidence, aetiological agents, natural history and health resource utilisation
Authors: D S Hui, J Woo, E Hui, A Foo, M Ip, K-W To, E S C Cheuk, W-Y Lam, A Sham, P K S Chan
Journal: Thorax (2008)

<h3>Background:</h3> Influenza-like illness (ILI) among elderly people living in residential care homes (RCHEs) is a common cause for hospitalisation. A study was undertaken to examine the incidence, underlying aetiology, natural history and associated healthcare resource utilisation related to ILI in the RCHE population. <h3>Methods:</h3> A prospective study of ILI in four RCHEs in Shatin, Hong Kong was conducted from April 2006 to March 2007. Each RCHE was monitored daily for the occurrence of ILI and followed up until resolution of illness or death. Clinical features were recorded and sputum, nasopharyngeal aspirate, blood and urine specimens were examined for underlying aetiology. <h3>Results:</h3> 259 episodes of ILI occurred in 194 subjects, with mild peaks in winter and summer, over a sustained level throughout the year. The infectious agent was identified in 61.4% of all episodes, comprising bacterial infection in 53.3% and viral in 46.7%. Multiple infections occurred in 16.2% of subjects. The most frequent organism was <i>Streptococcus pneumoniae</i>, followed by respiratory syncytial virus, <i>Pseudomonas aeruginosa</i>, metapneumovirus and parainfluenza virus types 1 and 3. Clinical features did not vary according to the underlying aetiology, the common presenting features being a decrease in general condition, cognitive and functional deterioration, and withholding of food in addition to fever and respiratory symptoms. Overall, mortality at 1 month/discharge was 9.7%. Infection with methicillin-resistant <i>Staphylococcus aureus</i>, low body mass index and poor function predisposed to mortality. No association was observed between influenza vaccination status and underlying aetiology, clinical features or outcome. <h3>Conclusions:</h3> The clinical presentation of ILI is non-specific and is mainly due to bacterial and viral infections other than influenza in the RCHE population.
Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice
Authors: Roja Barikbin, Daniel Neureiter, Jan Wirth, Annette Erhardt, Dorothee Schwinge, Johannes Kluwe, Christoph Schramm, Gisa Tiegs, Gabriele Sass
Journal: Hepatology (2011)

Induction or overexpression of the heme-degrading enzyme, heme oxygenase 1 (HO-1), has been shown to protect mice from liver damage induced by acute inflammation. We have investigated the effects of HO-1 induction in a mouse model of chronic liver inflammation and fibrogenesis with progression to hepatocellular carcinoma (HCC) (Mdr2ko; FVB.129P2-Abcb4(tm1Bor)). HO-1 was induced in vivo by treatment with cobalt protoporphyrin IX, starting at week 5 or 12 of mice lifespan, and continued for 7 weeks. Our results showed that HO-1 induction reduced liver damage and chronic inflammation by regulating immune cell infiltration or proliferation as well as tumor necrosis factor receptor signaling. Fibrosis progression was significantly reduced by HO-1 induction in mice with mild, as well as established, portal and lobular fibrosis. HO-1 induction significantly suppressed hepatic stellate cell activation. During established fibrosis, HO-1 induction was able to revert portal inflammation and fibrosis below levels observed at the start of treatment. Moreover, hepatocellular proliferation and signs of dysplasia were decreased after HO-1 induction.Induction of HO-1 interferes with chronic inflammation and fibrogenesis and, in consequence, might delay progression to HCC.
Transmyocardial Laser Revascularization Remodels the Intrinsic Cardiac Nervous System in a Chronic Setting
Authors: R.C. Arora, G.M. Hirsch, K. Hirsch, J.A. Armour
Journal: Circulation (2001)

Prospective trials have demonstrated that transmyocardial laser revascularization (TMLR) imparts symptomatic relief to patients with refractory angina. Because peak clinical effectiveness of TMLR is usually delayed by several months, it has been proposed that ventricular denervation is one mechanism whereby TMLR imparts symptomatic relief. We have demonstrated that TMLR does not denervate the heart in the acute setting, nor does it modify the intrinsic cardiac nervous system (ICNS) in the acute setting. However, the long-term effects of TMLR on the ICNS remain unknown.A holmium:yttrium-aluminum-garnet laser created 20 channels through the anterolateral left ventricular free wall of 10 dogs. Four weeks later, the function of cardiac sensory inputs to the ICNS was studied by applying veratridine (7.5 micromol/L) to ventricular sensory fields. Chronotropic and inotropic responses elicited by cardiac sympathetic or parasympathetic efferent neurons stimulated electrically (10 Hz, 4 V, 4 ms) or chemically (nicotine 5 to 20 microgram/kg IV) were also assessed. Chemical activation of epicardial sensory neurites with veratridine elicited expected ICNS excitatory responses. Electrical stimulation of sympathetic and parasympathetic efferent neurons induced expected altered cardiac responses. In contrast, the responsiveness of the ICNS to systemically administered nicotine was obtunded.Although chronic TMLR does not affect cardiac afferent or extracardiac efferent neuronal function, it does "remodel" the ICNS so that its responsiveness to a known potent chemical agonist (ie, nicotine) becomes obtunded. Remodeling of the ICNS may account in part for the delayed symptomatic relief that TMLR imparts to patients with refractory angina.
Is patellofemoral joint osteoarthritis an under-recognised outcome of anterior cruciate ligament reconstruction? A narrative literature review
Authors: Adam G Culvenor, Jill L Cook, Natalie J Collins, Kay M Crossley
Journal: British Journal of Sports Medicine (2012)

Patellofemoral joint (PFJ) osteoarthritis (OA) is a prevalent disease capable of being a potent source of knee symptoms. Although anterior cruciate ligament (ACL) injury and reconstruction (ACLR) are well-established risk factors for the development of tibiofemoral joint OA, PFJ OA after ACL reconstruction has gone largely unrecognised. This is despite the high prevalence of anterior knee pain after ACLR, which can reduce the capacity for physical activity and quality of life. The susceptibility of the PFJ to degenerative change after ACLR may have implications for current rehabilitation strategies. This review summarises the evidence describing the prevalence of PFJ OA after ACLR and examines why this compartment may be at increased risk of early onset OA after ACLR. Strategies that address the modifiable factors for risk of PFJ OA may aid in alleviating joint loads and symptoms for people after ACLR.
Peroxynitrite-induced α-actinin nitration and contractile alterations in isolated human myocardial cells
Authors: A BORBELY, A TOTH, I EDES, L VIRAG, J PAPP, A VARRO, W PAULUS, J VANDERVELDEN, G STIENEN, Z PAPP
Journal: Cardiovascular Research (2005)

Peroxynitrite-mediated myocardial protein nitration has been associated with a depressed cardiac pump function. In the present study, an attempt was made to elucidate the molecular background of peroxynitrite-evoked alterations in the human myocardium.Isometric force generation was measured in permeabilized human ventricular myocytes and biochemical methods were employed to identify the proteins affected by peroxynitrite-induced nitrotyrosine formation.The maximal Ca(2+)-activated isometric force (pCa=4.75) decreased to zero with increasing concentrations of peroxynitrite in a concentration-dependent manner (IC50: 55+/-4 microM; based on a total of 75 myocytes). However, there were no differences before and after the application of 50 microM peroxynitrite in the Ca(2+)-sensitivity of force production (pCa50: 5.89+/-0.02 and 5.86+/-0.04), in the steepness of the Ca(2+)-force relationship (nHill: 2.22+/-0.11 and 2.42+/-0.25), and in the actin-myosin turnover kinetics (k(tr) at saturating [Ca2+]: 1.14+/-0.03 1/s and 1.05+/-0.07 1/s) (P>0.05). Nevertheless, 50 muM peroxynitrite greatly deteriorated the cross-striation pattern and induced a slight, but significant, increase in the passive force component (from 2.1+/-0.1 to 2.5+/-0.2 kN/m2; n=57 cells), reflecting ultrastructural alterations. Western immunoblots revealed that 50 microM peroxynitrite selectively induced the nitration of a protein with an apparent molecular mass of about 100 kDa. Subsequent immunoprecipitation assays identified this nitrated protein as alpha-actinin, a major Z-line protein.These results suggest alpha-actinin as a novel target for peroxynitrite in the human myocardium; its nitration induces a contractile dysfunction, presumably by decreasing the longitudinal transmission of force between adjacent sarcomeres.