tbuckley/cabot-search huggingface dataset:
Inflammation induced conformational changes in Z alpha-1 antirypsin promotes lung Z-AT cell damage
Authors: Sam Alam, Karthik Santhanakrishnan, Jasvir Parmar, Sabina Janciauskiene, Ravi Mahadeva
Journal: European Respiratory Journal (2013)

Severe deficiency of the major anti-elastase α1-antitrypsin (AT) due to the Z (Glu342Lys) variant (Z-AT) is the commonest genetic reason for the development of COPD. There is however, significant variability in disease expression in Z-AT homozygotes. We postulated that Z-AT are prone to exaggerated lung damage compared to normal AT (M-AT) during LPS infection. Lung epithelial (A549 and NHBE) cells transfected with human M-AT or Z-AT (M-AT/Z-AT cells) were treated with LPS(20ng). Plasma native AT (N-AT,0.3mg/ml) was used to probe the effect of LPS. At 24h LPS Z-AT cells was compared to M-AT (unless stated) using ELISA, immunoblot or RT-PCR. Z-AT had significantly increased secretion of TNF-α; (mean±SEM) 87±5pg/ml vs. 28±2, IL-6; 296±52pg/ml vs. 40±10, IL-8; 14215±2857pg/ml vs. 1743±227 and MCP-1; 20769±1769pg/ml vs. 3025±161 and their respective mRNA at 0.5h, P
Progressive Multifocal Leukoencephalopathy after Natalizumab Monotherapy
Authors: Hans Lindå, Anders von Heijne, Eugene O. Major, Caroline Ryschkewitsch, Johan Berg, Tomas Olsson, Claes Martin
Journal: New England Journal of Medicine (2009)

We describe progressive multifocal leukoencephalopathy (PML) caused by infection with human polyomavirus JC virus in a patient with multiple sclerosis who was treated with natalizumab. The first PML symptoms appeared after 14 monthly infusions of the drug. Magnetic resonance imaging (MRI) showed a presumed multiple sclerosis lesion, and JC virus DNA was not detected on polymerase-chain-reaction (PCR) assay of cerebrospinal fluid. The patient's symptoms worsened, and the diagnosis of PML was established with a more sensitive quantitative PCR assay after 16 infusions of natalizumab. Plasma exchange was used to accelerate clearance of natalizumab. Approximately 3 weeks after plasma exchange, an immune-reconstitution inflammatory syndrome appeared. JC virus DNA was no longer detectable on quantitative PCR assay, and the patient's symptoms improved.
Insights into idiopathic pulmonary fibrosis in the real world
Authors: Vincent Cottin, Wim Wuyts
Journal: European Respiratory Journal (2015)

Idiopathic pulmonary fibrosis (IPF) is a relentless fibrotic disorder leading to an irreversible damage of the lungs, chronic respiratory failure, and death after a median of 3 years following the diagnosis [1]. The landscape in IPF has recently been profoundly modified in a number of ways. The disease process, once considered as a chronic inflammation and treated with anti-inflammatory and immunosuppressive drugs, is now viewed as uncontrolled wound healing resulting from injury to the alveolar epithelium [2]. Epidemiological studies have showed that IPF is more common than previously appreciated in the elderly population [3], with rising prevalence and mortality [4, 5]. The role of tobacco smoking is better appreciated [6]. The underlying genetic predisposition to IPF is progressively unveiled [7]. International evidence-based guidelines [8] have clarified the diagnostic approach and criteria, making large clinical studies possible, with the joined efforts of academic centres, the pharmaceutical industry, clinicians, and patients. Two antifibrotic drugs, pirfenidone and nintedanib [9–12], were recently demonstrated to reduce the progression of disease in a well-designed randomised controlled trials, and are now available to treat this dreadful disease. However, much remains to be done, before progression of IPF is controlled and the disease can be cured. Prospective cohorts such as INSIGHTS-IPF are complementary to clinical trials in idiopathic pulmonary fibrosis <http://ow.ly/NLvfX>
Oral adsorbent AST-120 ameliorates tubular injury in chronic renal failure patients by reducing proteinuria and oxidative stress generation
Authors: Tsukasa Nakamura, Eiichi Sato, Nobuharu Fujiwara, Yasuhiro Kawagoe, Tsukasa Suzuki, Yoshihiko Ueda, Sho-ichi Yamagishi
Journal: Metabolism (2010)
Residual sleepiness in obstructive sleep apnoea: phenotype and related symptoms
Authors: C. Vernet, S. Redolfi, V. Attali, E. Konofal, A. Brion, E. Frija-Orvoen, M. Pottier, T. Similowski, I. Arnulf
Journal: European Respiratory Journal (2011)

The characteristics of residual excessive sleepiness (RES), defined by an Epworth score &gt;10 in adequately treated apnoeic patients, are unknown. 40 apnoeic patients, with (n = 20) and without (n = 20) RES, and 20 healthy controls underwent clinical interviews, cognitive and biological tests, polysomnography, a multiple sleep latency test, and 24-h sleep monitoring. The marked subjective sleepiness in the RES group (mean± sd score 16.4±3) contrasted with moderately abnormal objective measures of sleepiness (90% of patients with RES had daytime sleep latencies &gt;8 min). Compared with patients without RES, the patients with RES had more fatigue, lower stage N3 percentages, more periodic leg movements (without arousals), lower mean sleep latencies and longer daytime sleep periods. Most neuropsychological dimensions (morning headaches, memory complaints, spatial memory, inattention, apathy, depression, anxiety and lack of self-confidence) were not different between patients with and without RES, but gradually altered from controls to apnoeic patients without and then with RES. RES in apnoeic patients differs markedly from sleepiness in central hypersomnia. The association between RES, periodic leg movements, apathy and depressive mood parallels the post-hypoxic lesions in noradrenaline, dopamine and serotonin systems in animals exposed to intermittent hypoxia.
The Private Practice of Community Psychiatry
Authors: WARREN T. VAUGHAN, DONALD E. NEWMAN, ALLAN LEVY, SAMUEL MARTY
Journal: American Journal of Psychiatry (1973)

The successful incorporation of the private practice of psychiatry into a system of community mental health care was attributable to several factors. They included an affluent catchment area; support from hospital administration and staff, private mental health practitioners, and a state-county finance program; and attempts to eliminate schisms that have traditionally separated private and public sectors of psychiatry. The success of this program has implications for the development of mental health services in the 1970s.
Sleep Characteristics, Mental Health, and Diabetes Risk
Authors: Edward J. Boyko, Amber D. Seelig, Isabel G. Jacobson, Tomoko I. Hooper, Besa Smith, Tyler C. Smith, Nancy F. Crum-Cianflone
Journal: Diabetes Care (2013)

Research has suggested that a higher risk of type 2 diabetes associated with sleep characteristics exists. However, studies have not thoroughly assessed the potential confounding effects of mental health conditions associated with alterations in sleep.We prospectively assessed the association between sleep characteristics and self-reported incident diabetes among Millennium Cohort Study participants prospectively followed over a 6-year time period. Surveys are administered approximately every 3 years and collect self-reported data on demographics, height, weight, lifestyle, features of military service, sleep, clinician-diagnosed diabetes, and mental health conditions assessed by the PRIME-MD Patient Health Questionnaire and the PTSD Checklist-Civilian Version. Statistical methods for longitudinal data were used for data analysis.We studied 47,093 participants (mean 34.9 years of age; mean BMI 26.0 kg/m2; 25.6% female). During 6 years of follow-up, 871 incident diabetes cases occurred (annual incidence 3.6/1,000 person-years). In univariate analyses, incident diabetes was significantly more likely among participants with self-reported trouble sleeping, sleep duration<6 h, and sleep apnea. Participants reporting incident diabetes were also significantly older, of nonwhite race, of higher BMI, less likely to have been deployed, and more likely to have reported baseline symptoms of panic, anxiety, posttraumatic stress disorder, and depression. After adjusting for covariates, trouble sleeping (odds ratio 1.21 [95% CI 1.03-1.42]) and sleep apnea (1.78 [1.39-2.28]) were significantly and independently related to incident diabetes.Trouble sleeping and sleep apnea predict diabetes risk independent of mental health conditions and other diabetes risk factors.
Requirement of aquaporin-1 for NaCl-driven water transport across descending vasa recta
Authors: Thomas L. Pallone, Aurélie Edwards, Tonghui Ma, Erik P. Silldorff, A.S. Verkman
Journal: Journal of Clinical Investigation (2000)

Deletion of AQP1 in mice results in diminished urinary concentrating ability, possibly related to reduced NaCl- and urea gradient–driven water transport across the outer medullary descending vasa recta (OMDVR). To quantify the role of AQP1 in OMDVR water transport, we measured osmotically driven water permeability in vitro in microperfused OMDVR from wild-type, AQP1 heterozygous, and AQP1 knockout mice. OMDVR diameters in AQP1–/– mice were 1.9-fold greater than in AQP1+/+ mice. Osmotic water permeability (Pf) in response to a 200 mM NaCl gradient (bath > lumen) was reduced about 2-fold in AQP1+/– mice and by more than 50-fold in AQP1–/– mice. Pf increased from 1015 to 2527 μm/s in AQP1+/+ mice and from 22 to 1104 μm/s in AQP1–/– mice when a raffinose rather than an NaCl gradient was used. This information, together with p-chloromercuribenzenesulfonate inhibition measurements, suggests that nearly all NaCl-driven water transport occurs by a transcellular route through AQP1, whereas raffinose-driven water transport also involves a parallel, AQP1-independent, mercurial-insensitive pathway. Interestingly, urea was also able to drive water movement across the AQP1-independent pathway. Diffusional permeabilities to small hydrophilic solutes were comparable in AQP1+/+ and AQP1–/– mice but higher than those previously measured in rats. In a mathematical model of the medullary microcirculation, deletion of AQP1 resulted in diminished concentrating ability due to enhancement of medullary blood flow, partially accounting for the observed urine-concentrating defect.
Targeting Mucosal Sites by Polymeric Immunoglobulin Receptor-directed Peptides
Authors: Kendra D. White, J. Donald Capra
Journal: The Journal of Experimental Medicine (2002)

Polymeric immunoglobulins provide first line humoral defense at mucosal surfaces to which they are specifically transported by the polymeric immunoglobulin receptor (pIgR) on mucosal and glandular epithelial cells. Previous studies from our laboratory suggested that amino acids 402–410 of the Cα3 domain of dimeric IgA (dIgA) represented a potential binding site for the pIgR. Here by binding human secretory component to overlapping decapeptides of Cα3, we confirm these residues and also uncover an additional site. Furthermore, we show that the Cα3 motif appears to be sufficient to direct transport of green fluorescent protein through the pIgR-specific cellular transcytosis system. An alternative approach identified phage peptides, selected from a library by the in vitro Madin Darby Canine Kidney transcytosis assay, for pIgR-mediated transport through epithelial cells. Some transcytosis-selected peptides map to the same 402–410 pIgR-binding Cα3 site. Further in vivo studies document that at least one of these peptides is transported in a rat model measuring hepatic bile transport. In addition to identifying small peptides that are both bound and transported by the pIgR, this study provides evidence that the pIgR-mediated mucosal secretion system may represent a means of targeting small molecule therapeutics and genes to mucosal epithelial cells.
Quality control: a necessary, but sometimes overlooked, tool for improving respiratory medicine
Authors: R. Farre, D. Navajas
Journal: European Respiratory Journal (2009)

he importance of quality control in both general and respiratory medicine has increased in parallel with the complexity of healthcare provision.Only a few decades ago, the respiratory physician and/or scientist had a very limited number of diagnostic and therapeutic tools available and, moreover, medical practice was based almost exclusively on the personal interaction between doctor and patient.Consequently, at that time the quality of the respiratory healthcare depended entirely on the professional competence of the doctor.Although nowadays the relationship between physician and patient undoubtedly still lies at the heart of respiratory medical practice, the quality of the medical service received by the patient also depends on many other participants in a complex healthcare network: various medical specialists, lung function technicians, nurses, respiratory therapists, social workers and administrative staff.Accordingly, several quality control programmes are applied in order to avoid, or at least to reduce, errors in diagnosis, improper performance of procedures, errors in medication, and failure to supervise or monitor care or recognise complications associated with treatment [1].
Comparative Effectiveness of Lifestyle Intervention Efforts in the Community
Authors: Gretchen A. Piatt, Miriam C. Seidel, Robert O. Powell, Janice C. Zgibor
Journal: Diabetes Care (2012)

OBJECTIVE To determine the comparative effectiveness of three lifestyle intervention modalities in decreasing risk for diabetes. RESEARCH DESIGN AND METHODS Five hundred and fifty-five individuals (86.1% female, 95.1% white, and 55.8% obese) from eight rural communities were screened for BMI ≥25 kg/m2 and waist circumference &amp;gt;40 inches in men and &amp;gt;35 inches in women. Communities with their eligible participants (n = 493; mean age 51 years, 87.6% female, 94.1% Caucasian) were assigned to four Group Lifestyle Balance (GLB) intervention groups: face to face (FF) (n = 119), DVD (n = 113), internet (INT) (n = 101), and self-selection (SS) (n = 101). SS participants chose the GLB modality. GLB is a comprehensive lifestyle behavior–change program. RESULTS A marked decline was observed in weight after the intervention in all groups (FF −12.5 lbs, P = 0.01; DVD −12.2 lbs, P &amp;lt; 0.0001; INT −13.7 lbs, P &amp;lt; 0.0001; and SS −14 lbs, P &amp;lt; 0.0001). Participants in SS experienced the largest average weight loss. Weight loss was sustained in &amp;gt;90% of participants in each group at 6 months (FF 90.7%, DVD 90.9%, INT 92.1%, and SS 100%). All groups experienced improvements in the proportion of participants with CVD risk factors. The proportion of individuals with CVD risk factors remained steady between 3 and 6 months in all groups and never returned back to baseline. All associations remained after multivariate adjustment. CONCLUSIONS Despite the modality, the GLB intervention was effective at decreasing weight and improving CVD risk factor control. SS and FF participants experienced greater improvements in outcomes compared with other groups, establishing the importance of patient-centered decision making and a support network for successful behavior change.
Changes in function and morphology of normal human skin: evaluation using optical coherence tomography
Authors: J. Welzel, C. Reinhardt, E. Lankenau, C. Winter, H.H. Wolff
Journal: British Journal of Dermatology (2004)

Background Optical coherence tomography (OCT) is a noninvasive morphological method for investigating human skin. It allows high-resolution in vivo imaging of inflammatory skin diseases and tumours. Because it is a newly developed method, systematic studies on standardization and on evaluation of factors influencing the representation of the skin have not yet been performed. Objectives In this study, normal human skin was treated with various external stimuli which induce changes of function and morphology. Changes in stratum corneum thickness as well as changes induced by pigmentation, oedema and erythema were investigated using OCT. Methods Healthy skin of human volunteers was treated with tape stripping, ultraviolet A irradiation, water, histamine, nicotinic acid and various ointments. Results In the tape stripping experiment, the thickness of the horny layer was quantified and monitored. Pigmentation increased the light attenuation of the tissue, whereas hydration and erythema led to a slight decrease of scattering. Topical treatment of the skin gave a nonspecific increase of penetration depth of the light due to the lower reflectivity of the surface. Conclusions There are various physiological conditions which influence optical properties of the skin. These parameters should be considered when performing standardized OCT studies.
Neutrophil chemotaxis in granulomatosis with polyangiitis (Wegener’s) and idiopathic pulmonary fibrosis
Authors: A.G. Richter, G.D. Perkins, A. Chavda, E. Sapey, L. Harper, D.R. Thickett
Journal: European Respiratory Journal (2011)

The presence of antineutrophil cytoplasmic antibodies in granulomatosis with polyangiitis (Wegener’s) (GPA) implicates the neutrophil as a key effector cell. Previous studies have reported elevated neutrophil counts in the lung, although the determinants of neutrophil chemotaxis in the GPA lung are unknown. Bronchoalveolar lavage fluid (BALF) cell counts, myeloperoxidase (MPO) and chemokines were measured in 27 patients with GPA, 20 disease controls with idiopathic pulmonary fibrosis (IPF) and six healthy controls. CXC chemokine ligand (CXCL)8, interleukin (IL)-1β, epithelial neutrophil-activating protein 78, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor were measured by ELISA. The neutrophil chemotactic potential of BALF was investigated using the under-agarose method, and specific antibodies were used to examine the role of CXCL8 and IL-1β. GPA BALF had an increased neutrophil percentage, and elevated MPO, CXCL8 and G-CSF concentrations compared with healthy controls. Chemotaxis of control neutrophils towards BALF from patients with active (p=0.006) and remission (p=0.077) GPA, and IPF (p=0.001) patients was increased compared with normal controls. BALF-induced chemotaxis correlated with BALF IL-1β (r=0.761, p=0.001) and CXCL8 (r=0.640, p=0.012) in GPA, and was inhibited by anti-CXCL8 (85%; p&lt;0.001) and anti-IL-1β (69%; p&lt;0.001). Our study confirms a neutrophilia and pro-inflammatory alveolar milieu that persists in clinical remission. CXCL8 and IL-1β appear to play important roles in the neutrophil chemotactic response to BALF.
Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses
Authors: Di Liu, Weifeng Shi, Yi Shi, Dayan Wang, Haixia Xiao, Wei Li, Yuhai Bi, Ying Wu, Xianbin Li, Jinghua Yan, Wenjun Liu, Guoping Zhao, Weizhong Yang, Yu Wang, Juncai Ma, Yuelong Shu, Fumin Lei, George F Gao
Journal: The Lancet (2013)
<i>O</i> 6-Methylguanine DNA Methyltransferase Deficiency and Response to Temozolomide-Based Therapy in Patients with Neuroendocrine Tumors
Authors: Matthew H. Kulke, Jason L. Hornick, Christine Frauenhoffer, Susanne Hooshmand, David P. Ryan, Peter C. Enzinger, Jeffrey A. Meyerhardt, Jeffrey W. Clark, Keith Stuart, Charles S. Fuchs, Mark S. Redston
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Recent studies suggest that temozolomide has activity in neuroendocrine tumors. Low levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), are associated with sensitivity to temozolomide in other tumor types. We evaluated the prevalence of MGMT deficiency in neuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide-based regimens. Experimental Design: The prevalence of MGMT deficiency, measured by immunohistochemistry, was assessed in 97 archival neuroendocrine tumor specimens. Rates of treatment response and survival were next evaluated in a cohort of 101 consecutive neuroendocrine tumor patients who had received treatment with a temozolomide-based regimen at one of three institutions. MGMT expression was directly correlated with treatment response in 21 patients who had available tumor tissue and response data. Results: In archival specimens, MGMT deficiency was observed in 19 of 37 (51%) pancreatic neuroendocrine tumors and 0 of 60 (0%) carcinoid tumors (P &amp;lt; 0.0001). In the clinical cohort, 18 of 53 (34%) patients with pancreatic neuroendocrine tumors but only 1 of 44 (2%) patients with carcinoid tumors (P &amp;lt; 0.001) experienced a partial or complete response to temozolomide-based therapy. Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide, 4 of 5 patients with MGMT-deficient tumors (all pancreatic neuroendocrine tumors) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment (P = 0.001). Conclusions: MGMT deficiency, measured by immunohistochemistry, is more common in pancreatic neuroendocrine tumors than in carcinoid tumors as is treatment response to temozolomide-based therapy. Absence of MGMT may explain the sensitivity of some pancreatic neuroendocrine tumors to treatment.
Central Nervous System Metastases in Patients with HER2-Positive Metastatic Breast Cancer: Incidence, Treatment, and Survival in Patients from registHER
Authors: Adam M. Brufsky, Musa Mayer, Hope S. Rugo, Peter A. Kaufman, Elizabeth Tan-Chiu, Debu Tripathy, Iulia Cristina Tudor, Lisa I. Wang, Melissa G. Brammer, Mona Shing, Marianne Ulcickas Yood, Denise A. Yardley
Journal: Clinical Cancer Research (2011)

Abstract Purpose: registHER is a prospective, observational study of 1,023 newly diagnosed HER2-positive metastatic breast cancer (MBC) patients. Experimental Design: Baseline characteristics of patients with and without central nervous system (CNS) metastases were compared; incidence, time to development, treatment, and survival after CNS metastases were assessed. Associations between treatment after CNS metastases and survival were evaluated. Results: Of the 1,012 patients who had confirmed HER2-positive tumors, 377 (37.3%) had CNS metastases. Compared with patients with no CNS metastases, those with CNS metastases were younger and more likely to have hormone receptor–negative disease and higher disease burden. Median time to CNS progression among patients without CNS disease at initial MBC diagnosis (n = 302) was 13.3 months. Treatment with trastuzumab, chemotherapy, or surgery after CNS diagnosis was each associated with a statistically significant improvement in median overall survival (OS) following diagnosis of CNS disease (unadjusted analysis: trastuzumab vs. no trastuzumab, 17.5 vs. 3.8 months; chemotherapy vs. no chemotherapy, 16.4 vs. 3.7 months; and surgery vs. no surgery, 20.3 vs. 11.3 months). Although treatment with radiotherapy seemed to prolong median OS (13.9 vs. 8.4 months), the difference was not significant (P = 0.134). Results of multivariable proportional hazards analyses confirmed the independent significant effects of trastuzumab and chemotherapy (HR = 0.33, P &amp;lt; 0.001; HR = 0.64, P = 0.002, respectively). The effects of surgery and radiotherapy did not reach statistical significance (P = 0.062 and P = 0.898, respectively). Conclusions: For patients with HER2-positive MBC evaluated in registHER, the use of trastuzumab, chemotherapy, and surgery following CNS metastases were each associated with longer survival. Clin Cancer Res; 17(14); 4834–43. ©2011 AACR.
Target cells of Epstein-Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma
Authors: Judith M Timms, Andrew Bell, Joanne R Flavell, Paul G Murray, Alan B Rickinson, Alexandra Traverse-Glehen, Françoise Berger, Henri-Jacques Delecluse
Journal: The Lancet (2003)