tbuckley/cabot-search huggingface dataset:
Do childhood respiratory infections continue to influence adult respiratory morbidity?
Authors: S. C. Dharmage, B. Erbas, D. Jarvis, M. Wjst, C. Raherison, D. Norbäck, J. Heinrich, J. Sunyer, C. Svanes
Journal: European Respiratory Journal (2008)

The aim of the present study was to examine the influence of childhood respiratory infections on adult respiratory health. In 1992–1994, the European Community Respiratory Health Survey recruited community based samples of 20–44-yr-old people from 48 centres in 22 countries. Study participants completed questionnaires and underwent lung function testing. On average, 8.9 yrs later, 29 centres re-investigated their samples using similar methods. Mixed effects models comprising an estimate for the random variation between centres were used to evaluate the relevant associations. In total, 9,175 patients participated in both studies, of whom 10.9% reported serious respiratory infections (SRI) before 5 yrs of age and 2.8% reported hospitalisation for lung disease (HLD) before 2 yrs if age. SRI was associated with current wheeze (odds ratio (OR) 1.9, 95% confidence interval (CI) 1.7–2.2), asthma (OR 2.5, 95% CI 2.2–3.1), and lower forced expiratory volume in one second (FEV 1 ; 89 mL; 95% CI 54–126), forced vital capacity (FVC; 49 mL; 95% CI 8–90) and FEV 1 /FVC ratio (−1.2%; 95% CI −1.8– −0.6). Childhood respiratory infections were also associated with new asthma (OR 1.5, 95% CI 1.03–2.0), new wheeze (OR 1.5, 95% CI 1.0–2.4) and persistent wheeze (OR 2.2, 95% CI 1.4–3.6) but not with a decline in lung function. Similar findings were observed for HDL. These associations were significantly consistent across centres. SRI was associated with lower FEV 1 when excluding ever asthmatics and current wheezers. The impact of early infections was significantly larger in subjects exposed to maternal or active smoking. The impact of childhood respiratory infections on the respiratory system may not only last into adulthood but also influence development and persistence of adult respiratory morbidity.
ALTERATIONS IN THE BLOOD COAGULATION SYSTEM INDUCED BY BACTERIAL ENDOTOXIN
Authors: Donald G. McKay, Sandor S. Shapiro
Journal: The Journal of Experimental Medicine (1958)

The intravenous injection of bacterial endotoxins alter the coagulation system of rabbits' blood in vivo. Twenty-four hours after the first injection the fibrinogen level rises to twice normal values. The second injection at this time causes a 30 to 40 per cent decrease in fibrinogen content in 4 hours. Twenty hours later it again rises to twice normal values. A marked decrease in whole blood coagulation times in silicone occurs 4 hours after both injections but rises to normal values 24 hours following each injection. The circulating platelets drop from average levels of 300,000/c.mm. to 150,000/c.mm. after the first injection. The platelets remain at this low level and decrease to less than 100,000 after the second injection. During this time no fibrinolytic or fibrinogenolytic activity can be detected. Also, there is no significant change in the one stage prothrombin times or antithrombin titres. The marked decrease in circulating fibrinogen at the time when intracapillary thrombi are formed suggests that the "hyaline" thrombi of the generalized Shwartzman reaction are composed, in part, of fibrin. There appears to be a relationship between the level of circulating fibrinogen at the time of injection of bacterial endotoxin and the extent of the thrombosis. The higher the preinjection fibrinogen level, the more extensive is the thrombosis. There is also a relationship between the amount of fibrinogen loss and the extent of thrombosis after the injection. The more extensive the thrombosis the greater is the postinjection decrease in circulating fibrinogen. A comparison between the response of the hemostatic mechanism to tissue thromboplastin and bacterial endotoxin indicates that the latter acts in a unique manner and not by way of a simple "thromboplastic" activity. From the hematological standpoint, "preparation" for the generalized Shwartzman reaction is accompanied by an increased circulating fibrinogen, leukocytosis, and thrombocytopenia.
Toluene Diisocyanate Enhances Substance P in Sensory Neurons Innervating the Nasal Mucosa
Authors: DAWN D. HUNTER, BRIAN E. SATTERFIELD, JUN HUANG, JEFFREY S. FEDAN, RICHARD D. DEY
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Inhalation of irritants, such as toluene diisocyanate (TDI), stimulates substance P (SP) release from peripheral processes of sensory neurons innervating the airways. The purpose of this study was to determine if TDI inhalation affects intraneuronal levels of SP and preprotachykinin (PPT) messenger RNA (mRNA) in the sensory neurons of the trigeminal ganglion (TG) which innervate the nasal epithelium. The nasal cavity of Fisher-344 rats was instilled with rhodamine-labeled latex microspheres. Ten days later, the rats were exposed to 60 ppb of 2,4-2,6-TDI vapor for 2 h. The TG were removed 1, 12, 24, 48, 72, and 96 h after TDI treatment and prepared for SP immunocytochemistry and PPT in situ hybridization. SP nerve fiber density in nasal epithelium was significantly increased 12, 24, and 48 h after TDI exposure. The proportion of microsphere-labeled cell bodies expressing high levels of SP immunoreactivity was decreased at 24 h but was increased above controls at 48 and 72 h. The proportion of microsphere-labeled cell bodies expressing high levels of PPT mRNA was increased above control levels at 24 and 48 h. The percentage of leukocytes observed in nasal lavage fluid was significantly increased 12, 24, 48, and 72 h after inhalation. These studies indicate that SP production in TG neurons projecting to the nasal epithelium is transiently increased after TDI exposure, suggesting that TDI inhalation not only causes SP release but also increased intraneuronal neuropeptide levels. Increased neuronal SP levels may be involved in maintaining neurogenic inflammation or the development of airway hyperresponsiveness. Hunter DD, Satterfield BE, Huang J, Fedan JS, Dey RD. Toluene diisocyanate enhances substance P in sensory neurons innervating the nasal mucosa.
A whole genome association study of mother-to-child transmission of HIV in Malawi
Authors: Bonnie R Joubert, Ethan M Lange, Nora Franceschini, Victor Mwapasa, Kari E North, Steven R Meshnick
Journal: Genome Medicine (2010)

More than 300,000 children are newly infected with HIV each year, predominantly through mother-to-child transmission (HIV MTCT). Identification of host genetic traits associated with transmission may more clearly explain the mechanisms of HIV MTCT and further the development of a vaccine to protect infants from infection. Associations between transmission and a selection of genes or single nucleotide polymorphisms (SNP)s may give an incomplete picture of HIV MTCT etiology. Thus, this study employed a genome-wide association approach to identify novel variants associated with HIV MTCT. We conducted a nested case-control study of HIV MTCT using infants of HIV(+) mothers, drawn from a cohort study of malaria and HIV in pregnancy in Blantyre, Malawi. Whole genome scans (650,000 SNPs genotyped using Illumina genotyping assays) were obtained for each infant. Logistic regression was used to evaluate the association between each SNP and HIV MTCT. Genotype results were available for 100 HIV(+) infants (at birth, 6, or 12 weeks) and 126 HIV(-) infants (at birth, 6, and 12 weeks). We identified 9 SNPs within 6 genes with a P-value < 5 × 10-5 associated with the risk of transmission, in either unadjusted or adjusted by maternal HIV viral load analyses. Carriers of the rs8069770 variant allele were associated with a lower risk of HIV MTCT (odds ratio = 0.27, 95% confidence interval = 0.14, 0.51), where rs8069770 is located within HS3ST3A1, a gene involved in heparan sulfate biosynthesis. Interesting associations for SNPs located within or near genes involved in pregnancy and development, innate immunological response, or HIV protein interactions were also observed. This study used a genome-wide approach to identify novel variants associated with the risk of HIV MTCT in order to gain new insights into HIV MTCT etiology. Replication of this work using a larger sample size will help us to differentiate true positive findings.
Comparison of Negative Pressure Wound Therapy Using Vacuum-Assisted Closure With Advanced Moist Wound Therapy in the Treatment of Diabetic Foot Ulcers
Authors: Peter A. Blume, Jodi Walters, Wyatt Payne, Jose Ayala, John Lantis
Journal: Diabetes Care (2008)

OBJECTIVE—The purpose of this study was to evaluate safety and clinical efficacy of negative pressure wound therapy (NPWT) compared with advanced moist wound therapy (AMWT) to treat foot ulcers in diabetic patients. RESEARCH DESIGN AND METHODS—This multicenter randomized controlled trial enrolled 342 patients with a mean age of 58 years; 79% were male. Complete ulcer closure was defined as skin closure (100% reepithelization) without drainage or dressing requirements. Patients were randomly assigned to either NPWT (vacuum-assisted closure) or AMWT (predominately hydrogels and alginates) and received standard off-loading therapy as needed. The trial evaluated treatment until day 112 or ulcer closure by any means. Patients whose wounds achieved ulcer closure were followed at 3 and 9 months. Each study visit included closure assessment by wound examination and tracings. RESULTS—A greater proportion of foot ulcers achieved complete ulcer closure with NPWT (73 of 169, 43.2%) than with AMWT (48 of 166, 28.9%) within the 112-day active treatment phase (P = 0.007). The Kaplan-Meier median estimate for 100% ulcer closure was 96 days (95% CI 75.0–114.0) for NPWT and not determinable for AMWT (P = 0.001). NPWT patients experienced significantly (P = 0.035) fewer secondary amputations. The proportion of home care therapy days to total therapy days for NPWT was 9,471 of 10,579 (89.5%) and 12,210 of 12,810 (95.3%) for AMWT. In assessing safety, no significant difference between the groups was observed in treatment-related complications such as infection, cellulitis, and osteomyelitis at 6 months. CONCLUSIONS—NPWT appears to be as safe as and more efficacious than AMWT for the treatment of diabetic foot ulcers.
Leptin receptor polymorphisms and lung function decline in COPD
Authors: N. N. Hansel, L. Gao, N. M. Rafaels, R. A. Mathias, E. R. Neptune, C. Tankersley, A. V. Grant, J. Connett, T. H. Beaty, R. A. Wise, K. C. Barnes
Journal: European Respiratory Journal (2009)

Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina TM GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p&lt;0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.
Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction
Authors: Hilaire C. Lam, Suzanne M. Cloonan, Abhiram R. Bhashyam, Jeffery A. Haspel, Anju Singh, J. Fah Sathirapongsasuti, Morgan Cervo, Hongwei Yao, Anna L. Chung, Kenji Mizumura, Chang Hyeok An, Bin Shan, Jonathan M. Franks, Kathleen J. Haley, Caroline A. Owen, Yohannes Tesfaigzi, George R. Washko, John Quackenbush, Edwin K. Silverman, Irfan Rahman, Hong Pyo Kim, Ashfaq Mahmood, Shyam S. Biswal, Stefan W. Ryter, Augustine M.K. Choi
Journal: Journal of Clinical Investigation (2013)

Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1+/- or Map1lc3B-/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6-/Y) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1-/-, Map1lc3B-/-, and Hdac6-/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.
HER-2/neu Gene Amplification and Response to Paclitaxel in Patients With Metastatic Breast Cancer
Authors: G. E. Konecny, C. Thomssen, H. J. Luck, M. Untch, H.-J. Wang, W. Kuhn, H. Eidtmann, A. d. Bois, S. Olbricht, D. Steinfeld, V. Mobus, G. v. Minckwitz, S. Dandekar, L. Ramos, G. Pauletti, M. D. Pegram, F. Janicke, D. J. Slamon
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: HER-2/neu overexpressionappears to be associated with improved response to anthracycline-based chemotherapy, but its association with response to taxane-based chemotherapy is unclear. In this retrospective subset analysis of patients with metastatic breast cancer enrolled in a randomized treatment trial, we investigated the response of patients with known HER-2/neu status to treatment with taxane-based epirubicin–paclitaxel (ET) chemotherapy compared with treatment with epirubicin–cyclophosphamide (EC) chemotherapy. Methods: HER-2/neu status (positive [i.e., HER-2/neu amplification] or negative [i.e., no HER-2/neu amplification]) of archival specimens of primary tumors from 297 patients with metastatic breast cancer was determined by use of fluorescence in situ hybridization. Associations between HER-2/neu status and the efficacy of randomly assigned chemotherapy (ET versus EC) were investigated. All statistical tests were two-sided. Results : Patients with HER-2/neu–positive tumors had a statistically significantly greater objective response rate than patients with HER-2/neu–negative tumors to treatment with ET (76% versus 50%, respectively; P = .005) but not to treatment with EC (46% versus 33%; P = .130). The objective response rate associated with ET was greater than that associated with EC for both HER-2/neu–positive tumors (76% versus 46%; P = .004) and HER-2/neu–negative tumors (50% versus 33%; P = .002). However, the improvement in the objective response rate associated with ET, compared with that associated with EC, was greater for patients with HER-2/neu–positive tumors (adjusted odds ratio [OR] = 3.64, 95% confidence interval [CI] = 1.48 to 8.92; P = .005) than for patients with HER-2/neu–negative tumors (adjusted OR = 1.92, 95% CI = 1.01 to 3.64; P = .046). Among patients with HER-2/neu–positive tumors, those who received ET had better progression-free survival and overall survival than those who received EC (for progression-free survival, adjusted relative risk [RR] = 0.65, 95% CI = 0.42 to 1.02; P = .062; for overall survival, adjusted RR = 0.60, 95% CI = 0.36 to 1.02; P = .059). However, among patients with HER-2/neu–negative tumors, those who received ET and those who received EC had similar progression-free survival and overall survival. Conclusions: HER-2/neu amplification does not adversely influence response to first-line chemotherapy with either ET or EC. Furthermore, a taxane-containing regimen such as ET may provide a preferential benefit to patients with HER-2/neu–positive tumors.
Correlation between clinical features of systemic lupus erythematosus and levels of antihistone antibodies of the IgG, IgA, and IgM isotypes.
Authors: N R Gompertz, D A Isenberg, B M Turner
Journal: Annals of the Rheumatic Diseases (1990)

An attempt was made to define the correlation between the clinical features of systemic lupus erythematosus and levels of circulating antihistone antibodies of the IgG, IgA, and IgM isotypes. Serum antibody levels were determined by enzyme linked immunosorbent assay (ELISA) on serial blood samples (n = 4) from 25 patients, representing five subgroups: (a) renal disease; (b) central nervous system disorders; (c) skin and joint disease only; (d) serositis; and (e) deep venous thrombosis with or without spontaneous abortion. The levels of antihistone antibodies of each isotype varied widely from patient to patient, but antibody levels in the four samples from each patient correlated closely. A close correlation between levels of IgG and IgA antihistone antibodies was found but there was no correlation between these isotypes and IgM antihistone antibodies. In individual patients no simple correlation between disease activity and antihistone antibody levels was established, but levels of antihistone antibodies of the IgG and IgA isotypes were significantly higher in those patients in whom the disease was consistently more active.
Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial
Authors: Giulio G Stefanini, Bindu Kalesan, Patrick W Serruys, Dik Heg, Pawel Buszman, Axel Linke, Thomas Ischinger, Volker Klauss, Franz Eberli, William Wijns, Marie-Claude Morice, Carlo Di Mario, Roberto Corti, Diethmar Antoni, Hae Y Sohn, Pedro Eerdmans, Gerrit-Anne van Es, Bernhard Meier, Stephan Windecker, Peter Jüni
Journal: The Lancet (2011)
Homotypic Gap Junctional Communication Associated with Metastasis Suppression Increases with PKA Activity and Is Unaffected by PI3K Inhibition
Authors: Thomas M. Bodenstine, Kedar S. Vaidya, Aimen Ismail, Benjamin H. Beck, Leah M. Cook, Anne R. Diers, Aimee Landar, Danny R. Welch
Journal: Cancer Research (2010)

Loss of gap junctional intercellular communication (GJIC) between cancer cells is a common characteristic of malignant transformation. This communication is mediated by connexin proteins that make up the functional units of gap junctions. Connexins are highly regulated at the protein level and phosphorylation events play a key role in their trafficking and degradation. The metastasis suppressor breast cancer metastasis suppressor 1 (BRMS1) upregulates GJIC and decreases phosphoinositide-3-kinase (PI3K) signaling. On the basis of these observations, we set out to determine whether there was a link between PI3K and GJIC in tumorigenic and metastatic cell lines. Treatment of cells with the well-known PI3K inhibitor LY294002, and its structural analogue LY303511, which does not inhibit PI3K, increased homotypic GJIC; however, we found the effect to be independent of PI3K/AKT inhibition. We show in multiple cancer cell lines of varying metastatic capability that GJIC can be restored without enforced expression of a connexin gene. In addition, while levels of connexin 43 remained unchanged, its relocalization from the cytosol to the plasma membrane was observed. Both LY294002 and LY303511 increased the activity of protein kinase A (PKA). Moreover, PKA blockade by the small molecule inhibitor H89 decreased the LY294002/LY303511-mediated increase in GJIC. Collectively, our findings show a connection between PKA activity and GJIC mediated by PI3K-independent mechanisms of LY294002 and LY303511. Manipulation of these signaling pathways could prove useful for antimetastatic therapy.
Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study
Authors: W. Brugger, J. Hirsch, F. Grünebach, R. Repp, P. Brossart, W. Vogel, H.-G. Kopp, M.G. Manz, M. Bitzer, G. Schlimok, M. Kaufmann, A. Ganser, K. Fehnle, M. Gramatzki, L. Kanz
Journal: Annals of Oncology (2004)
Surgery for primary CNS lymphoma? Challenging a paradigm
Authors: M. Weller, P. Martus, P. Roth, E. Thiel, A. Korfel
Journal: Neuro-Oncology (2012)

The standard of care for primary central nervous system lymphoma (PCNSL) is systemic chemotherapy with or without whole brain radiotherapy or intrathecal chemotherapy. In contrast to treatment for other brain tumors, efforts at resection are discouraged. This is a secondary analysis of the German PCNSL Study Group-1 trial, a large randomized phase III study comprising 526 patients with PCNSL. Progression-free survival (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.10-1.74; P = .005) and overall survival (HR: 1.33; 95% CI: 1.04-1.70; P = .024) were significantly shorter in biopsied patients compared with patients with subtotal or gross total resections. This difference in outcome was not due to age or Karnofsky performance status (KPS). When controlled for the number of lesions, the HR of biopsy versus subtotal or gross total resection remained unchanged for progression-free survival (HR = 1.37; P = .009) but was smaller for overall survival (HR = 1.27; P = .085). This analysis of the largest PCNSL trial ever performed challenges the traditional view that the extent of resection has no prognostic impact on this disease. Therefore, we propose to reconsider the statement that efforts at resection should be discouraged, at least if resection seems safe, as is often the case in treatment of single PCNSL lesions.