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"human challenge"

Peter Jatlow, Gerald Valentine, Ralitza Gueorguieva, Haleh Nadim, Ran Wu, Stephanie S O'Malley, Mehmet Sofuoglu
Objectives: Menthol is often added to cigarettes and e-cigarette solutions for its cooling and anti-irritant effects, and may contribute to development of nicotine dependence, particularly in vulnerable populations such as adolescents, and among African Americans. Menthol is rapidly metabolized to menthol glucuronide (MG) with little or no unconjugated menthol measurable in venous blood. Human challenge studies of the effects of inhaled menthol, and of its interactions with nicotine, would benefit from a quantitative measure of acute menthol exposure...
January 2018: Tobacco Regulatory Science
Alastair Proudfoot, Andrew Bayliffe, Cecilia M O'Kane, Tracey Wright, Adrian Serone, Philippe Jean Bareille, Vanessa Brown, Umar I Hamid, Younan Chen, Robert Wilson, Joanna Cordy, Peter Morley, Ruud de Wildt, Stuart Elborn, Matthew Hind, Edwin R Chilvers, Mark Griffiths, Charlotte Summers, Daniel Francis McAuley
BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects...
January 29, 2018: Thorax
Jae-Keun Park, Alison Han, Lindsay Czajkowski, Susan Reed, Rani Athota, Tyler Bristol, Luz Angela Rosas, Adriana Cervantes-Medina, Jeffery K Taubenberger, Matthew J Memoli
Influenza virus hemagglutinin (HA) surface glycoprotein is currently the primary target of licensed influenza vaccines. Recently, broadly reactive antibodies that target the stalk region of the HA have become a major focus of current novel vaccine development. These antibodies have been observed in humans after natural infection with influenza A virus, but the data are limited. Using samples and data from the uniquely controlled setting of an influenza A/H1N1 virus human challenge study of healthy volunteers, we performed a secondary analysis that for the first time explores the role of anti-HA stalk antibody as a human correlate of protection...
January 23, 2018: MBio
Rob J W Arts, Simone J C F M Moorlag, Boris Novakovic, Yang Li, Shuang-Yin Wang, Marije Oosting, Vinod Kumar, Ramnik J Xavier, Cisca Wijmenga, Leo A B Joosten, Chantal B E M Reusken, Christine S Benn, Peter Aaby, Marion P Koopmans, Hendrik G Stunnenberg, Reinout van Crevel, Mihai G Netea
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity...
January 10, 2018: Cell Host & Microbe
Laura K Mueller, Johanna Simon, Christine Rosenauer, Volker Mailaender, Svenja Morsbach, Katharina Landfester
Nanomaterials are interesting candidates for applications in medicine as drug delivery or diagnostic agents. For a safe application, they have to be evaluated in vitro and in vivo models to finally be translated to human clinical trials. However, often, those transfer processes fail and it is not completely understood whether in vitro models leading to these animal models can reliably be compared to the situation in humans. Especially, the interaction of nanomaterials with components from different blood plasma sources is difficult to compare and the outcomes of those interactions with respect to body distribution and cell uptake are unclear...
December 29, 2017: Biomacromolecules
Vijayaprasad Gopichandran
An ethics panel, convened by the National Institute of Health and other research bodies in the USA, disallowed researchers from the Johns Hopkins University and University of Vermont from performing controlled human infection of healthy volunteers to develop a vaccine against Zika virus infection. The members published their ethical analysis and recommendations in February 2017. They have elaborated on the risks posed by human challenge with Zika virus to the volunteers and other uninvolved third parties and have systematically analysed the social value of such a human challenge experiment...
October 31, 2017: Indian Journal of Medical Ethics
E R Job, M Schotsaert, L I Ibañez, A Smet, T Ysenbaert, K Roose, M Dai, C A M de Haan, H Kleanthous, T U Vogel, X Saelens
There is increasing evidence to suggest that antibodies directed toward influenza A virus (IAV) neuraminidase (NA) are an important correlate of protection against influenza in humans. Moreover, the potential of NA-specific antibodies to provide broader protection than conventional hemagglutinin (HA) antibodies has been recognized. Here, we describe the isolation of two monoclonal antibodies, N1-7D3 and N1-C4, directed toward the N1 NA. N1-7D3 binds to a conserved linear epitope in the membrane-distal, carboxy-terminal part of the NA and reacted with the NA of seasonal H1N1 isolates ranging from 1977 to 2007 and the 2009 H1N1pdm virus, as well as A/Vietnam/1194/04 (H5N1)...
February 15, 2018: Journal of Virology
Joanna E Rimmer, Clayton Harro, David A Sack, Kawsar R Talaat, Ramiro L Gutierrez, Barbara DeNearing, Jessica Brubaker, Renee M Laird, Frédéric Poly, Alexander C Maue, Kayla Jaep, Ashley Alcala, Yelizaveta Mochalova, Christina L Gariepy, Subhra Chakraborty, Patricia Guerry, David R Tribble, Chad K Porter, Mark S Riddle
Background: Campylobacter species are a leading cause of diarrheal disease globally with significant morbidity. Primary prevention efforts have yielded limited results. Rifaximin chemoprophylaxis decreases travelers' diarrhea rates and may be suitable for high risk persons. We assessed the efficacy of rifaximin in the controlled human infection model (CHIM) for Campylobacter jejuni. Methods: Twenty-eight subjects were admitted to an inpatient facility and randomized to a twice daily dose of 550 mg rifaximin or placebo...
November 14, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Roberto Cuomo, Luca Grimaldi, Giuseppe Nisi, Cesare Brandi, Carlo D'Aniello
Median and Ulnar nerve palsy is a devastating condition that compromise hand function. A procedure of tendon transfer may be helpful to restore the movements by linking palsy muscles to other muscles able to contract. Scientific discoveries and technological innovations have profoundly changed this kind of surgery; studies on sarcomeres, for example, changed the concept of tensioning. To date we know that muscle strength and its contraction capacity depends on many factors (not only tensioning) such as sarcomeres length, cellular cytoskeleton and extracellular matrix composition: all of these factors interact together and in a ways not still fully understood, determining the complex concept of "movement...
November 2, 2017: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
Hans de Graaf, Diane Gbesemete, Andrew R Gorringe, Dimitri A Diavatopoulos, Kent E Kester, Saul N Faust, Robert C Read
INTRODUCTION: We summarise an ethically approved protocol for the development of an experimental human challenge colonisation model. Globally Bordetella pertussis is one of the leading causes of vaccine-preventable death. Many countries have replaced whole cell vaccines with acellular vaccines over the last 20 years during which pertussis appears to be resurgent in a number of countries in the developed world that boast high immunisation coverage. The acellular vaccine provides relatively short-lived immunity and, in contrast to whole cell vaccines, may be less effective against colonisation and subsequent transmission...
October 11, 2017: BMJ Open
Kathryn M Rodgers, Julia O Udesky, Ruthann A Rudel, Julia Green Brody
BACKGROUND: Many common environmental chemicals are mammary gland carcinogens in animal studies, activate relevant hormonal pathways, or enhance mammary gland susceptibility to carcinogenesis. Breast cancer's long latency and multifactorial etiology make evaluation of these chemicals in humans challenging. OBJECTIVE: For chemicals previously identified as mammary gland toxicants, we evaluated epidemiologic studies published since our 2007 review. We assessed whether study designs captured relevant exposures and disease features suggested by toxicological and biological evidence of genotoxicity, endocrine disruption, tumor promotion, or disruption of mammary gland development...
January 2018: Environmental Research
Nicholas A Feasey, Myron M Levine
No abstract text is available yet for this article.
December 2, 2017: Lancet
Smita Das, Ihn Kyung Jang, Becky Barney, Roger Peck, John C Rek, Emmanuel Arinaitwe, Harriet Adrama, Maxwell Murphy, Mallika Imwong, Clare L Ling, Stephane Proux, Warat Haohankhunnatham, Melissa Rist, Annette M Seilie, Amelia Hanron, Glenda Daza, Ming Chang, Tomoka Nakamura, Michael Kalnoky, Paul Labarre, Sean C Murphy, James S McCarthy, Francois Nosten, Bryan Greenhouse, Sophie Allauzen, Gonzalo J Domingo
Sensitive field-deployable diagnostic tests can assist malaria programs in achieving elimination. The performance of a new Alere™ Malaria Ag P.f Ultra Sensitive rapid diagnostic test (uRDT) was compared with the currently available SD Bioline Malaria Ag P.f RDT in blood specimens from asymptomatic individuals in Nagongera, Uganda, and in a Karen Village, Myanmar, representative of high- and low-transmission areas, respectively, as well as in pretreatment specimens from study participants from four Plasmodium falciparum -induced blood-stage malaria (IBSM) studies...
November 2017: American Journal of Tropical Medicine and Hygiene
Swati Puranik, Jason Kam, Pranav P Sahu, Rama Yadav, Rakesh K Srivastava, Henry Ojulong, Rattan Yadav
Humans require more than 20 mineral elements for healthy body function. Calcium (Ca), one of the essential macromineral, is required in relatively large quantities in the diet for maintaining a sound overall health. Young children, pregnant and nursing women in marginalized and poorest regions of the world, are at highest risk of Ca malnutrition. Elderly population is another group of people most commonly affected by Ca deficiency mainly in the form of osteoporosis and osteopenia. Improved dietary intake of Ca may be the most cost-effective way to meet such deficiencies...
2017: Frontiers in Plant Science
Jakob Busch-Petersen, Donald C Carpenter, Miriam Burman, James Foley, Gerald E Hunsberger, David J Kilian, Michael Salmon, Ruth J Mayer, John G Yonchuk, Ruth Tal-Singer
CXC chemokine receptor 2 (CXCR2) is a key receptor in the chemotaxis of neutrophils to sites of inflammation. The studies reported here describe the pharmacological characterization of danirixin, a CXCR2 antagonist in the diaryl urea chemical class. Danirixin has high affinity for CXCR2, with a negative log of the 50% inhibitory concentration (pIC50) of 7.9 for binding to Chinese hamster ovary cell (CHO)-expressed human CXCR2, and 78-fold selectivity over binding to CHO-expressed CXCR1. Danirixin is a competitive antagonist against CXCL8 in Ca(2+)-mobilization assays, with a KB (the concentration of antagonist that binds 50% of the receptor population) of 6...
August 2017: Journal of Pharmacology and Experimental Therapeutics
Azra Blazevic, Mei Xia, Aldin Turan, Janice Tennant, Daniel F Hoft
Despite the great effort to develop an effective vaccine against tuberculosis (TB) there is currently no reliable and safe human challenge model that can be used for in vivo evaluation of new TB vaccine candidates and/or elucidation of the mechanisms of TB protective immunity. In this study, five volunteers were challenged with BCG intradermally (ID). Swab specimens were collected at multiple time points from the vaccination site pre- and post-vaccination to quantitate mycobacterial shedding as a surrogate of in vivo mycobacterial immunity...
July 2017: Tuberculosis
Julia Korell, Bruce Green, John DeVincenzo, Dymphy Huntjens
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections, and is a major cause of hospital admissions and death in young children. Limited treatments currently exist that can prevent or minimise exacerbation of the disease. The aims of this work were: 1) to develop a population pharmacodynamic model to describe RSV kinetics (RSVK) in nasal lavage, 2) evaluate the impact of an investigational fusion inhibitor, JNJ-53718678, on RSVK, and 3) determine the relationship between RSVK and symptoms scores...
November 15, 2017: European Journal of Pharmaceutical Sciences
Lev Stimmer, Claire-Maëlle Fovet, Ché Serguera
Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods...
January 1, 2017: Veterinary Pathology
Stephanie Fresnay, Monica A McArthur, Laurence S Magder, Thomas C Darton, Claire Jones, Claire S Waddington, Christoph J Blohmke, Brian Angus, Myron M Levine, Andrew J Pollard, Marcelo B Sztein
Typhoid fever, caused by the human-restricted organism Salmonella enterica serovar Typhi (S. Typhi), constitutes a major global health problem. The development of improved attenuated vaccines is pressing, but delayed by the lack of appropriate preclinical models. Herein, we report that high levels of S. Typhi-responsive CD8+ T cells at baseline significantly correlate with an increased risk of disease in humans challenged with a high dose (~10(4) CFU) wild-type S. Typhi. Typhoid fever development was associated with higher multifunctional S...
2017: Frontiers in Immunology
Hazel C Dobinson, Malick M Gibani, Claire Jones, Helena B Thomaides-Brears, Merryn Voysey, Thomas C Darton, Claire S Waddington, Danielle Campbell, Iain Milligan, Liqing Zhou, Sonu Shrestha, Simon A Kerridge, Anna Peters, Zoe Stevens, Audino Podda, Laura B Martin, Flavia D'Alessio, Duy Pham Thanh, Buddha Basnyat, Stephen Baker, Brian Angus, Myron M Levine, Christoph J Blohmke, Andrew J Pollard
Background: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures...
April 15, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
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