tbuckley/cabot-search huggingface dataset:
P169 Tiotropium is effective in patients with severe asthma without evidence of chronic obstructive pulmonary disease
Authors: Dmg Halpin, Ed Bateman, P Moroni-Zentgraf, M Engel, H Schmidt, Ham Kerstjens
Journal: Thorax (2013)

<h3>Rationale</h3> Given the known effectiveness of tiotropium in chronic obstructive pulmonary disease (COPD) and the significant benefit observed in COPD patients with concomitant features of asthma, it is relevant to investigate whether patients included in the recent large trials of tiotropium in asthma can be confidently considered to have asthma alone. <h3>Methods</h3> Baseline characteristics were analysed for patients enrolled in two replicate Phase III, randomised, double-blind, placebo-controlled, parallel-group studies of tiotropium in asthma patients symptomatic despite treatment with inhaled corticosteroids plus long-acting beta agonists (Kerstjens <i>et al</i>. NEJM 2012). The entry criteria were: age 18–75 years; asthma diagnosed before the age of 40 years; =5-year history of asthma; score of =1.5 in the Asthma Control Questionnaire (ACQ) 7; and life-long non-smokers or ex-smokers (&lt;10 pack-years). Patients were also required to have persistent airflow limitation. Asthma diagnosis was confirmed in line with current Global Initiative for Asthma guidelines. Patients with a diagnosis of COPD or other lung disease were excluded from the studies. <h3>Results</h3> 912 patients were enrolled: 456 received add-on treatment with tiotropium and 456 received placebo. Mean age of the study population was 53.0 years; 37.6% of patients were aged =50 years. Mean age at diagnosis of asthma was 22.7 (range 0–44) years. Median duration of asthma was 28.0 (range 5–72) years, with 76.5% of patients having asthma for =20 years before enrolment. The majority of patients (75.9%) were life-long non-smokers; 24.1% were ex-smokers with a median number of pack-years of only 5.0. Mean ACQ score was 2.6 (range 1–5). Mean immunoglobulin E was 1210 µmol/L. The mean ( ± SD) bronchodilator response to salbutamol was 217 ± 217 mL. <h3>Conclusions</h3> The age of onset, duration of symptoms, lack of smoking, allergic status and bronchodilator response provide reasonable certainty that the patients enrolled in these studies had asthma and not COPD. Features compatible with COPD were thus more likely to reflect the effects of long-standing severe persistent asthma than the alternative diagnosis, and the efficacy demonstrated by tiotropium to represent improvement of asthma.
FDA faces regulatory challenges with new approaches to medicine
Authors: B. Roehr
Journal: BMJ (2014)

Bob Roehr looks at how medicine is changing and what it means for the regulators

The US Food and Drug Administration (FDA) faces unprecedented regulatory challenges not just with new products but with entirely new fields of activity that are likely to transform medicine in the decades to come. Among them are stem cell therapies, commensal microbial transplants, and personalized genetic testing. They are rapidly evolving and much remains unknown, or at least not definitively proven.

That uncertainty plays to the tension between emphasizing safety and affording opportunity for treatment that is at the core of the agency’s responsibility. Another often less apparent tension playing out is that between regulating interstate commerce, which is the legal basis for FDA authority, and the practice of medicine, which, to the extent that it is regulated, is the responsibility of state government.

The FDA regulatory paradigm historically is the model of infectious disease where a single drug targets an invading pathogen. Once that invader is neutralized, the body reverts to a normal state. But these new fields are characterized by the complexity of the intervention itself and its effect on the patient. The agency is struggling to understand and adapt to these new interventions.

One example occurred in November 2013 when the FDA told 23andMe to stop marketing its direct to consumer genetic testing services.1 It said that the company had failed to provide information necessary for approval and that consumers might misinterpret the information provided.

The company’s response, in an email to their clients, suggested that the FDA should have used a different regulatory pathway. It hinted that the disagreement was fundamental, not amenable to compromise, and might need to be resolved through the courts.

It is “a culture clash between Silicon Valley, with its devotion to libertarianism and self-knowledge, and …
THE INTESTINAL ORIGIN OF ECLAMPSIA
Authors: R. C. Brown
Journal: BMJ (1930)

examlples of a low kidney reserve do not, I think, tend to showi, further nmanifestation of a like niature in suLbsequeiit pregnancies.The consideration of the cases under review bears out this conclusion.The answer to the sec(ond questioni is in the affirmliative.If thje conditioii of-hronic neplhritis cani definitely be estaoblished, it is, 1I tlintik, certain that the kidniey will slhowv a progressive deteriorationi in subsequent possible
Identification of a Novel Tumor-Associated Antigen, Cadherin 3/P-Cadherin, as a Possible Target for Immunotherapy of Pancreatic, Gastric, and Colorectal Cancers
Authors: Katsunori Imai, Shinya Hirata, Atsushi Irie, Satoru Senju, Yoshiaki Ikuta, Kazunori Yokomine, Michiko Harao, Mitsuhiro Inoue, Takuya Tsunoda, Shuichi Nakatsuru, Hidewaki Nakagawa, Yusuke Nakamura, Hideo Baba, Yasuharu Nishimura
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To establish cancer immunotherapy, it is important to identify the tumor-associated antigens (TAA) that are strongly expressed in the tumor cells but not in the normal cells. In this study, to establish an effective anticancer immunotherapy, we tried to identify the useful TAA of pancreatic cancer. Experimental Design: Based on a previous genome-wide cDNA microarray analysis of pancreatic cancer, we focused on cadherin 3 (CDH3)/P-cadherin as a novel candidate TAA for anticancer immunotherapy. To identify the HLA-A2 (A*0201)–restricted CTL epitopes of CDH3, we used HLA-A2.1 (HHD) transgenic mice (Tgm). Furthermore, we examined the cytotoxicity against the tumor cells in vitro and in vivo of CTLs specific to CDH3 induced from HLA-A2–positive healthy donors and cancer patients. Results: CDH3 was overexpressed in the majority of pancreatic cancer and various other malignancies, including gastric and colorectal cancers, but not in their noncancerous counterparts or in many normal adult tissues. In the experiment using HLA-A2.1 Tgm, we found that the CDH3-4655-663 (FILPVLGAV) and CDH3-7757-765 (FIIENLKAA) peptides could induce HLA-A2–restricted CTLs in Tgm. In addition, peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A2–positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both CDH3 and HLA-A2. Furthermore, the adoptive transfer of the CDH3-specific CTLs could inhibit the tumor growth of human cancer cells engrafted into nonobese diabetic/severe combined immunodeficiency mice. Conclusions: These results suggest that CDH3 is a novel TAA useful for immunotherapy against a broad spectrum of cancers, including pancreatic cancer.
Hyperlipidaemia due to isotretinoin and etretinate: possible mechanisms and consequences
Authors: J. MARSDEN
Journal: British Journal of Dermatology (1986)

Journal Article Hyperlipidaemia due to isotretinoin and etretinate: possible mechanisms and consequences Get access J. MARSDEN J. MARSDEN Department of Dermatology, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 114, Issue 4, 1 April 1986, Pages 401–407, https://doi.org/10.1111/j.1365-2133.1986.tb02842.x Published: 01 April 1986
Molecular Control of Cortical Dendrite Development
Authors: Kristin L. Whitford, Paul Dijkhuizen, Franck Polleux, Anirvan Ghosh
Journal: Annual Review of Neuroscience (2002)

▪ Abstract Dendritic morphology has a profound impact on neuronal information processing. The overall extent and orientation of dendrites determines the kinds of input a neuron receives. Fine dendritic appendages called spines act as subcellular compartments devoted to processing synaptic information, and the dendritic branching pattern determines the efficacy with which synaptic information is transmitted to the soma. The acquisition of a mature dendritic morphology depends on the coordinated action of a number of different extracellular factors. Here we discuss this evidence in the context of dendritic development in the cerebral cortex. Soon after migrating to the cortical plate, neurons extend an apical dendrite directed toward the pial surface. The oriented growth of the apical dendrite is regulated by Sema3A, which acts as a dendritic chemoattractant. Subsequent dendritic development involves signaling by neurotrophic factors and Notch, which regulate dendritic growth and branching. During postnatal development the formation and stabilization of dendritic spines are regulated in part by patterns of synaptic activity. These observations suggest that extracellular signals play an important role in regulating every aspect of dendritic development and thereby exert a critical influence on cortical connectivity.
Failure to demonstrate complement activation during bronchial challenge test
Authors: O Michel, J Duchateau, R Sergysels
Journal: European Respiratory Journal (1988)

In order to demonstrate a possible complement activation during early bronchospastic reaction in asthma, we have measured plasmatic C3d (a split product of C3) and the C3d/C3 index, both of which are sensitive indices of complement activation. Twenty-nine allergenic bronchial challenge tests were accomplished, with an absence of response in six cases, an early reaction in sixteen cases and a dual reaction in seven cases. Changes in plasmatic C3d or C3d/C3 five min after an early reaction, or five min after the last dose of allergen (in the six cases without bronchial response) were insignificant. However, complement activation in the lungs during asthmatic reaction cannot be completely excluded without studies using the bronchoalveolar technique.
Multiple thoracic osteophytes presenting as mediastinal mass
Authors: A. Sykes, R. Badiger, J. Wort, S. Copley
Journal: Thorax (2007)

A 59-year-old builder presented to the accident and emergency department with a 4-week history of intermittent central chest pain. He was a lifelong non-smoker, had no asbestos or tuberculosis exposures, and had no cardiac risk factors. The …
Excretion and metabolism of catecholamines by the isolated perfused rat kidney.
Authors: P Silva, L Landsberg, A Besarab
Journal: Journal of Clinical Investigation (1979)

The excretion and metabolism of labeled epinephrine and norepinephrine by the isolated, perfused rat kidney were studied. The excretion of both catecholamines significantly exceeded the amount filtered, thus providing direct evidence of net tubular secretion. Renal clearance of epinephrine was significantly greater than that of norepinephrine. Tubular secretion was a linear function of the concentration of unbound catecholamine in the medium with no demonstrable tubular maximum at the concentrations studied. The isolated kidney removed catecholamines from the medium by metabolism as well as excretion in the urine. O-Methylation was the major metabolic route and O-methylated metabolites were rapidly excreted and concentrated in urine. Preferential excretion and metabolism of epinephrine were confirmed in double-label experiments in which [14C]epinephrine and [3H]norepinephrine were perfused together. The ratio of 14C:3H in urine exceeded that in perfusion medium for total radioactivity as well as for catecholamines and O-methylated amines. The present study thus provides direct evidence for (a) net tubular secretion of epinephrine and norepinephrine with a direct relationship between secretion and medium concentration; (b) significant renal metabolism of both epinephrine and norepinephrine with O-methylation as the major metabolic route; and (c) preferential excretion and metabolism of epinephrine.
Improvement in Oncology Practice Performance Through Voluntary Participation in the Quality Oncology Practice Initiative
Authors: Joseph O. Jacobson, Michael N. Neuss, Kristen K. McNiff, Pamela Kadlubek, Leroy R. Thacker, Frank Song, Peter D. Eisenberg, Joseph V. Simone
Journal: Journal of Clinical Oncology (2008)

The Quality Oncology Practice Initiative (QOPI) became available to all American Society of Clinical Oncology member physicians in 2006 as a voluntary medical oncology practice-based quality measurement and improvement project. QOPI assesses practice performance for a series of evidence- and consensus-based process measures, relying on practices to complete structured chart reviews and submit data via a secure Web-based portal.This analysis focused on the 71 practices that participated in both the March and September 2006 data collections (7,624 charts abstracted in March and 10,240 in September). Among 33 measures common to both collections, five measures were closely correlated, and 28 are included in the final analysis. Composite scores were created for six different domains of care. Statistical significance was tested on both absolute changes and relative changes (relative failure reduction) of quality measures from baseline to follow-up and between the lower quartile and all other quartiles.Practice performance on individual measures varied between 18.8% and 98.6%. Mean overall performance as measured by a composite score increased from 78.7% in March to 82.3% in September (P < .05). Improvement was most marked among practices originally performing in the bottom quartile. Using a composite score, the absolute and relative performance for the bottom quartile improved by 27% and 35%, respectively, statistically superior to that of all others.Practices that participated in QOPI demonstrated improved performance in self-reported process measures, with the greatest improvement demonstrated in initially low-performing practices.
Effectiveness of Gastric Bypass Surgery in a Patient With Familial Partial Lipodystrophy
Authors: Kristina M. Utzschneider, Dace L. Trence
Journal: Diabetes Care (2006)

Familial partial lipodystrophy (FPL) is associated with loss of subcutaneous fat in the extremities but preservation, or increase, of fat in the face, neck, and trunk. Patients with FPL manifest marked insulin resistance and develop diabetes and hypertriglyceridemia that are often very difficult to manage with pharmacologic agents, the current standard of therapy for FPL. Roux-en-Y gastric bypass (RYGB), a surgical procedure that leads to marked weight loss in morbidly obese subjects, improves insulin sensitivity (1,2) and reverses (3) or prevents diabetes (4). This is the first report of RYGB in a patient with FPL that resulted in unanticipated dramatic improvement in the metabolic control of her lipodystrophy.

The patient is a 55-year-old Caucasian woman with FPL who underwent a laparoscopic RYGB for treatment of severe gastroesophageal reflux disease and gastroparesis, failing standard medical therapy. She reported a history of truncal obesity and thin extremities throughout her life. She was diagnosed with FPL type 1 based on physical exam findings of distal loss of subcutaneous fat in her extremities with excess fat in her chin and face and marked abdominal obesity. Her medical problems included poorly controlled type 2 diabetes, hypertriglyceridemia with a history of recurrent pancreatitis, coronary artery disease, hypertension, depression, and asthma. Her family history was significant for early coronary artery disease in her mother. …
Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat.
Authors: M P Bendeck, N Zempo, A W Clowes, R E Galardy, M A Reidy
Journal: Circulation Research (1994)

We have characterized matrix metalloproteinase expression in the rat carotid artery after two forms of arterial injury, balloon catheter denudation and nylon filament denudation. Gelatinolytic enzymes with molecular masses of 70 and 62 kD were produced constitutively in the rat carotid. Production of an 88-kD gelatinase was induced after balloon catheter injury, and proteinase production continued during the period of migration of smooth muscle cells from the media to the intima, from 6 hours to 6 days after balloon catheter injury. In addition, a marked increase in 62-kD gelatinolytic activity was observed between 4 and 14 days after arterial injury. Gelatinase activities (88 and 62 kD) were also increased after nylon filament denudation but were markedly less after this injury than after balloon catheter injury. These results suggested a correlation between gelatinase activity and smooth muscle cell migration after arterial injury. Administration of a metalloproteinase inhibitor after balloon catheter injury resulted in a 97% reduction in the number of smooth muscle cells migrating into the intima. Therefore, we hypothesize that gelatinase expression directly facilitates smooth muscle cell migration within the media and into the intima. These results suggest that gelatinases are involved in the vascular smooth muscle cell activation and neointimal formation that characterize arterial tissue remodeling after injury.
Association between health-related quality of life and consultation for respiratory symptoms: results from the DIMCA programme
Authors: G van den Boom, MP Rutten-van Molken, PR Tirimanna, CP van Schayck, H Folgering, C van Weel
Journal: European Respiratory Journal (1998)

In general practice, diagnosis of chronic obstructive pulmonary disease (COPD) is hampered by underpresentation. A substantial proportion of subjects experiencing respiratory complaints do not consult their general practitioner (GP). In this study, the relationship between disease-specific quality of life and presentation of respiratory symptoms to a GP is investigated. A random sample from the general population (undiagnosed subjects) was screened for symptoms and objective signs of COPD (n=1,155). The lung function of subjects with symptoms of COPD was monitored for 6 months. During this period, 48 new COPD patients with a persistently reduced lung function (forced expiratory volume in one second (FEV1) less than or equal to the predicted value minus 2 SD) were detected. A disease-specific quality-of-life questionnaire (chronic respiratory questionnaire (CRQ)) was administered and clinical and GP consultation data were collected. Multivariate analysis showed that quality-of-life impairments due to dyspnoea and fatigue and variability in lung function (bronchial hyperresponsiveness, reversibility and peak expiratory flow rate variability) were related to medical consultation. Only 31% of the newly detected patients reported that they had ever visited their GP for respiratory complaints. A similarly low percentage was found in the rest of the sample (26%). It is concluded that the mere presence of respiratory symptoms or a (gradually) reduced lung function is insufficient reason for patients to seek medical help. Subjects are more likely to consult their general practitioner once their quality of everyday life is affected or they experience variability in lung function.
cAMP/PKA antagonizes thrombin-induced inactivation of endothelial myosin light chain phosphatase: role of CPI-17
Authors: Muhammad Aslam, Frauke V. Härtel, Muhammad Arshad, Dursun Gündüz, Yaser Abdallah, Heinrich Sauer, Hans Michael Piper, Thomas Noll
Journal: Cardiovascular Research (2010)

Activation of cAMP signalling abrogates thrombin-induced hyperpermeability. One of the mechanisms underlying this protective effect is the inactivation of endothelial contractile machinery, one of the major determinants of endothelial barrier function, mainly via the activation of myosin light chain phosphatase (MLCP). To date, the mechanisms of cAMP-mediated MLCP activation are only partially understood. Here the contribution of two cAMP effectors, PKA and Epac, in the regulation of endothelial contractile machinery and barrier function was studied. Endothelial contractile machinery and barrier function were analysed in cultured human umbilical vein endothelial cells (HUVEC). The cAMP analogues 8-CPT-cAMP and 6-Bnz-cAMP were used to activate Epac and PKA, respectively, and forskolin (FSK) was used to activate adenylyl cyclase. The cells were challenged by thrombin to inhibit MLCP via the RhoA/Rock pathway. Activation of either PKA or Epac partially blocked thrombin-induced hyperpermeability. Simultaneous activation of PKA and Epac had additive effects that were comparable to that of FSK. Activation of PKA but not Epac inhibited thrombin-induced phosphorylation of MLC and the MLCP regulatory subunit MYPT1, partly via inhibition of the RhoA/Rock pathway. FSK activated the MLCP catalytic subunit PP1 via dephosphorylation and dissociation of the PP1 inhibitory protein CPI-17. FSK blunted thrombin-induced CPI-17 phosphorylation, CPI-17/PP1 complex formation, and PP1 inactivation. Down-regulation of CPI-17 attenuated thrombin-induced hyperpermeability and abolished the antagonistic effect of the PKA activator, whereas the Epac activator retained its antagonistic effect. cAMP/PKA regulates the endothelial barrier via inhibition of the contractile machinery, mainly by the activation of MLCP via inhibition of CPI-17 and RhoA/Rock. The permeability-lowering effect of the cAMP/Epac pathway is independent of CPI-17.
Defective Sorting to Secretory Vesicles in Trans-Golgi Network Is Partly Responsible for Protein C Deficiency
Authors: Masao Naito, Jun Mimuro, Hitoshi Endo, Seiji Madoiwa, Kyo-ichi Ogata, Jiro Kikuchi, Teruko Sugo, Takanori Yasu, Yusei Kariya, Yuichi Hoshino, Yoichi Sakata
Journal: Circulation Research (2003)

Three thrombophilic patients with protein C (PC) deficiency were found to have independent mutations in the PC gene. These mutations resulted in single amino acid substitutions of R169W, R352W, and G376D in the affected PC molecules. These abnormal PC molecules were expressed in CHO-K1 cells in the presence or absence of vitamin K, and their synthesis, posttranslational modification, and secretion were studied. PC G376D was not secreted from the cells and was gradually degraded inside the cells. There was partial secretion of PC R169W and PC R352W, but most of these molecules were not secreted but were degraded intracellularly. On the basis of pulse-chase, immunofluorescence, and endo-β- N -acetylglucosaminidase H digestion experiments, the majority of wild-type PC molecules localize not in the Golgi apparatus but in the rough endoplasmic reticulum inside the cells. This suggests that wild-type PC molecules are secreted immediately after γ-carboxylation and modification at the Golgi apparatus. In contrast, the mutant PC molecules were retained inside the cells even after modification of oligosaccharides at the trans-Golgi apparatus, which was probably due to impaired conformation of the abnormal molecules. Data suggest that these abnormal PC molecules were not sorted to secretory vesicles in the trans-Golgi network because of conformational defects in addition to the transport defect from the rough endoplasmic reticulum to the Golgi apparatus and were degraded inside the cells, thereby resulting in a PC deficiency in the affected patients.