MedicalResearch.com Interview with:
A/Prof. Joshua Ooi, PhD
Head, Regulatory T-cell Therapies
Translational Research Facility
Clinical Sciences at Monash Health,
Monash University
MedicalResearch.com: What is the background for this study?Response: In 2017, we published a landmark Nature paper showing that people who are protected from autoimmune disease have specialized molecules on immune cells. These specific molecules are missing in patients that develop autoimmune disease.
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MedicalResearch.com Interview with:
Samir Mitragotri Ph.D.
Hiller Professor of Bioengineering
Hansjorg Wyss Professor of Biologically Inspired Engineering
Area Chair, Bioengineering
Core Faculty Member, Wyss Institute for Biologically Inspired Engineering
Harvard John A. Paulson School Of Engineering And Applied Sciences
MedicalResearch.com: What is the background for this study?Response: Traumatic brain injury (TBI) has a heavy burden on the world, affecting ~70 million people globally each year. Despite its prevalence, there are no clinically approved treatments beyond symptom management. There is an urgent need to develop effective therapies to alleviate the damage caused by TBI.
MedicalResearch.com: What do macrophages typically do?
As part of the innate immune system, macrophages migrate to areas of injury to eat pathogens or debris and manage inflammation in response to injury or infection. However, in the majority of cases of TBI, there is no actual infection from a foreign pathogen, leading to excessive inflammation that spreads damage beyond the initial impact.
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MedicalResearch.com Interview with:
Dr. Alexis C. Wood
United States Department of Agriculture (USDA)/ARS
Children’s Nutrition Research Center
Baylor College of Medicine, TX
MedicalResearch.com: What is the background for this study?Response: We know (we think!) that what we eat has a big influence on our health. However, discovering which foods influence our health, and how, is highly challenging. Research investigating this topic should be seen as an on-going process as new results and new study methods emerge, and as the food environment shifts.
Red meat is often considered a food that should be minimized in diets designed to support good health. This may seem surprising as red meat is a good source of protein and many other nutrients, but the advice to limit red meat intake is based on several large-scale studies showing associations between red meat consumption and the development of conditions such as type 2 diabetes, and other cardiovascular disease risk related factors. However, newer research, with different designs or approaches, has struggled to conclusively support this association; for example, in studies where the amount of red meat in people’s diet is manipulated, we do not see the expected increases in risk. Other studies have suggested that any associations between red meat intake and chronic disease may reflect confounding effects by adiposity – that is, the increased risk of disease really reflects the increased risk associated with a higher BMI.
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MedicalResearch.com Interview with:
Myrsini Kaforou, PhD
Senior Lecturer in Bioinformatics
Department of Infectious Disease
Imperial College London
MedicalResearch.com: What is the background for this study?Response: Children very often present to hospital and clinics with fever, but fever is a non-specific disease symptom. The identification of the cause of fever poses a great challenge for the clinical teams worldwide. The available diagnostic tests are neither quick or accurate enough to fully base decisions on, such as withholding or administering antibiotics.
For example, cultures may take days or even weeks to provide a result.
In our research group, we are working on novel approach; instead of trying to identify the causative pathogen, which is often inaccurate or impossible, we are studying the genes in the patient's blood that are "switched on" or "switched off" during the infection or the disease in general. Using computational/bioinformatics methods, we are able to identify out of thousands of genes, the combinations of genes, "the biosignatures" for each disease. In the past we had shown that this approach works to distinguish bacterial from viral infection, or tuberculosis disease from other conditions that mimic its symptoms. But with this work we have shown for the first time that a single set of genes, a "single gene panel" can be used to discriminate between 6 broad and/or 18 specific infectious or inflammatory conditions that cause fever in children.
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MedicalResearch.com Interview with:
Ellen H. Lee, MD
Incident Command System Surveillance and Epidemiology Section
New York City Department of Health and Mental Hygiene
Long Island City, New YorkMedicalResearch.com: What is the background for this study? Response: Published reports of the COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) have described higher proportions of cases among Black and Hispanic children. However, case series are limited by the lack of population-level data, which could help provide context for the racial/ethnic distribution of cases described in these reports.
The New York City (NYC) Department of Health and Mental Hygiene required reporting of all possible cases of MIS-C among NYC residents, and for cases meeting MIS-C criteria, applied population denominators to calculate MIS-C incidence rates stratified by race/ethnicity. To help characterize the burden of severe COVID-19 disease in NYC, we also calculated COVID-19 hospitalization rates stratified by race/ethnicity.
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MedicalResearch.com Interview with:
Dr. Douglas Maslin, MPhil, MB BCHir
Dermatologist and Pharmacologist
Addenbrooke's Hospital
Cambridge, UK
MedicalResearch.com: What is the background for this study? Response: I’d like to answer this question in three parts:
Firstly, the background to Evelo and the therapeutic EDP1815: Evelo is developing orally administered biologic medicines based on a new understanding of how systemic inflammation is controlled. Evelo’s medicines are selected for their ability to modulate the small intestinal axis, or SINTAX, a network of anatomical and functional connections that has evolved to connect the small intestine with the rest of the body. SINTAX links small intestinal mucosal immunology with systemic inflammation and is now accessible with oral medicines. This inflammatory control pathway may enable a new class of products which are effective, safe, and can be manufactured affordably at large scale.
EDP1815 is a non-live pharmaceutical preparation of a strain of the bacterium Prevotella histicola isolated from the duodenum of a human donor. Its pharmacodynamic effect is through interactions with the immune cells within the small intestine and it has no systemic absorption. These local interactions in the small intestine then downregulate systemic inflammation. In fact, the inflammatory control afforded by targeting the small intestinal axis appears to result in the coordinated downregulation of multiple inflammatory pathways without immunosuppression, mimicking the body’s normal physiological processes of inflammation resolution.
Secondly, there is the key and exciting background pre-clinical data on EDP1815 – the details of which have been published today at the EADV conference. For example, oral administration of EDP1815 to mice has been shown to lead to striking therapeutic effects in in vivo models of delayed-type hypersensitivity, imiquimod-induced skin inflammation, fluorescein isothiocyanate cutaneous hypersensitivity, collagen-induced arthritis, and experimental acute encephalomyelitis (EAE).
The consistency of effect and dose shows that EDP1815 can coordinately resolve systemic inflammation across TH1, TH2 and TH17 pathways. This suggests the potential for clinical benefit across multiple diseases.
And, thirdly, there is the clinical unmet need for an oral, safe, effective treatment specifically for mild and moderate psoriasis patients, who have very limited treatment options outside of the poorly tolerated topical therapies, and these patients are reported to be dissatisfied with treatment options and therefore are often under-treated.
These three points explain the background to EDP1815 and the reason for progressing forward into the phase 1b in psoriasis.
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MedicalResearch.com Interview with:
Prof. Michael Glogauer, D.D.S., Ph.D
Faculty of Dentistry, University of Toronto
Toronto, ON Canada
MedicalResearch.com: What is the background for this study? Response: Periodontal disease (PD) affects between 20% and 50% of the global population, with growing evidence supporting its association with other inflammatory diseases, including heart disease, arthritis, and diabetes.
Several studies have shown how untreated periodontal disease leads to increased medical care costs for nonoral conditions, including patient hospitalization rates. The interaction of inflammatory diseases with PD suggests a shared, underlying pathology that may be exploited to better manage patients and reduce the economic burden. However, the mechanisms through which these diseases interact are unclear.
In periodontal disease, tissue and bone destruction in the mouth is driven by elevated recruitment of white blood cells called polymorphonuclear neutrophils (PMNs), which are activated by the oral disease and recruited from the circulation to sites of inflammation.(more…)
MedicalResearch.com Interview with:
David E. Leaf, MD, MMSc, FASN
Assistant Professor of Medicine, Harvard Medical School
Director of Clinical and Translational Research in Acute Kidney Injury
Division of Renal Medicine, Brigham and Women's Hospital
MedicalResearch.com: What is the background for this study? Response: The data for this study were derived from a multicenter cohort study of over 4,000 critically ill patients with COVID-19 admitted to ICUs at 68 sites across the US, as part of the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID). STOP-COVID was initiated by David E. Leaf, MD, MMSc and Shruti Gupta, MD, MPH, from the Division of Renal Medicine at Brigham and Women’s Hospital and Harvard Medical School. It was initiated in March, 2020 as an unfunded, grassroots network, and now includes over 400 collaborators from 68 sites across the US.
Using this data, we used a ‘target trial emulation’ approach to examine whether early administration of the monoclonal antibody, tocilizumab, reduces mortality in critically ill patients with COVID-19. Target trial emulation, a novel method of analyzing observational data, is the idea of simulating a randomized control trial to reduce bias.(more…)
MedicalResearch.com Interview with:
Alvaro Moreira, MD
Assistant Professor, Department of Pediatrics
Co-Director Neonatal Nutrition and Bone Institute
UT Health San Antonio
MedicalResearch.com: What is the background for this study? Response: Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome, is a new dangerous childhood disease that is temporally associated with coronavirus disease 2019 (COVID-19).
We conducted a systematic review to communicate the typical presentation and outcomes of children diagnosed with this hyperinflammatory condition.(more…)
MedicalResearch.com Interview with:
Sacha Gnjatic, PhD
Associate Director of the Human Immune Monitoring Center
Associate Professor of Medicine, Oncological Sciences and Pathology
Icahn School of Medicine at Mount Sinai
Member of the Precision Immunology Institute and The Tisch Cancer Institute
Mount Sinai
MedicalResearch.com: What is the background for this study? Would you explain what is meant by cytokine/cytokines?Response: COVID-19 is a disease where inflammation is suspected to play a large role in pathogenicity, possibly more so than the tissue damage created by the virus alone. Cytokines are small soluble proteins that are produced by both immune cells and cells from tissues, and many play a role in signaling such inflammation, to alert of tissue damage or infection. Among these cytokines, interleukin-6 (IL-6), IL-8, IL-1beta, and Tumor Necrosis Factor alpha (TNF-a) have been well established as important markers of pathogenic inflammation. Drugs that counteract these cytokines are routinely use in various inflammatory disease, from rheumatoid arthritis to plaque psoriasis and Crohn’s disease. When the initial wave of SARS-CoV-2 infection hit our hospitals in New York, we therefore wondered whether these cytokines were associated with COVID-19 disease severity and outcome, and hoped that a rapid test to detect them in blood could be useful to make clinical decisions about treatment. We were able to analyze a very large number of patient samples (>1400) in a period of one month, and confirmed our findings in a second smaller cohort.
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MedicalResearch.com Interview with:
Kip Connor, Ph.D.
Harvard Medical School
Associate Professor of Ophthalmology
Department of Ophthalmology
Massachusetts Eye and Ear
MGH ECOR Ophthalmology Representative
Associate Scientist
MedicalResearch.com: What is the background for this study? Response: Classically, the retina and the central nervous system (CNS) have long been considered immunoprivileged sites within the body. This is not to say that these sites lack immunity; rather, they are capable of exhibiting a contained yet modifiable form of immunological response. Indeed, an intricate immune surveillance system exists within the retina that can interact with the retinal cellular milieu both during development and in response to injury or disease. While activation of this surveillance system can help protect and repair the delicate neural tissue of the retina in certain disease states, over-activation of this system can exacerbate disease pathology, thereby worsening vision loss.
Microglia are the resident immune cells of the central nervous system, including the retina, and are thought to function acutely in the homeostatic maintenance of the neuro-retinal microenvironment. However in chronic conditions, like autoimmune uveitis, we hypothesized that microglia become neurodegenerative.
In our current study we show for the first time a role for microglia in directing the initiation of this autoimmune disease by orchestrating the inflammatory response within the retina through the retinal vessels.
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MedicalResearch.com Interview with:
Dr. George Dangas MD PhD
Professor of Medicine, CardiologyMount Sinai Health System
MedicalResearch.com: What is the background for this study? Response: Widespread use of statins targeted to decrease levels of low density lipoprotein cholesterol (LDL-C) below 70mg/dL are recommended by guidelines. However, residual cholesterol risk may only be one part of the residual risk equation. Indeed, Biological inflammation has long been known as a pathophysiological mechanism of atherosclerosis and the recent CANTOS trial opened new therapeutic perspective by demonstrating that inflammation modulation via selective interleukin-1β inhibition could result in improved diagnosis in patients with coronary artery disease.
However, the prevalence and impact of a residual inflammatory biological syndrome in patients with controlled cholesterol risk is unclear. (more…)
MedicalResearch.com Interview with:
Alan Nelson, MPAS, PhD
Division of Primary Care and Population Health, Department of Medicine
Stanford University School of Medicine
Stanford, CaliforniaMedicalResearch.com: What is the background for this study? Response: The past research literature has provided relatively little information on the appropriate level of concern regarding non-steroidal anti-inflammatory drugs (NSAIDs) and kidney disease risk among younger, apparently healthy patients. Clinicians are generally most concerned about the effects of these medications on the kidneys among patients with existing renal impairment and persons at risk for it, especially older patients.
Given that NSAID use appears to be high and rising in the US, we were interested in developing evidence on this topic in a population of working-age adults.
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MedicalResearch.com Interview with:
Thomas S. G. Sehested MD
Department of Cardiology
Copenhagen University Hospital Gentofte
Jenny Bjerre, MD
Department of Cardiology
Copenhagen University
Department of Health Research and Policy
Stanford University School of Medicine
Stanford, California
MedicalResearch.com: What is the background for this study? Response: n 2017, the results from the much-awaited Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial were published, confirming the inflammatory hypothesis, i.e. that targeting inflammation can reduce cardiovascular disease. The trial tested the monoclonal antibody canakinumab in a population of post-myocardial infarction patients with elevated inflammation markers (hs-CRP). Canakinumab is currently used for rare diseases and carries an orphan drug price: the 150mg dose used in CANTOS costs approximately $73,000 per year.
Due to the high prevalence of cardiovascular disease, millions of patients could potentially be eligible for treatment with this high-priced anti-inflammatory drug. Therefore, we wanted to investigate the cost-effectiveness for canakinumab for secondary prevention of cardiovascular disease, using the reported results from CANTOS.
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MedicalResearch.com Interview with:
Keenan Walker, PhD
Johns Hopkins University School of Medicine
Baltimore
MedicalResearch.com: What is the background for this study? What are the main findings?Response: This study was conducted in response to anecdotal accounts and scientific evidence which suggests that major medical conditions, such as critical illness and severe infections, can have a long-term neurological effect on some individuals.
There are quite a few studies to date which have found that critical illnesses, such as severe sepsis, are associated with long-term cognitive impairment. Based on this evidence, we wanted to figure out to what degree critical illness and major infection may affect later brain structure and to determine whether the structural changes associated with these events were similar to those observed in Alzheimer’s disease.
Our main finding was that individuals who had one or more critical illness or major infection major infection during the decades leading up to older adulthood were more likely to have smaller brain volumes in brain regions most vulnerable to Alzheimer's disease.
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MedicalResearch.com Interview with:
Michael P. Madaio, MD
Sydenstricker Professor and Chairman
Department of Medicine
Medical College of Georgia at
Augusta University
MedicalResearch.com: What is the background for this study? Response: Glomerulonephritis is a inflammatory disease of the kidney. Glomeruli are the filtering units in the kidney. This is most often immunologically mediated and are autoimmune.
Most therapies are directed at inhibiting the Immune/autoimmune process (immunotherapy) systemically.
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MedicalResearch.com Interview with:
Jagadeesh BAYRY, DVM, PhD, HDR
Scientist CRCN/Associate Professor-INSERM
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1138
Centre de Recherche des Cordeliers
PARIS , FRANCE
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Basophils are rare granulocytes that are important for the protection against helminth parasites. In addition, basophils mediate T helper 2 responses, support B cell differentiation, and thus establish a vital link between innate and adaptive immunity. Although rare in number, basophils are implicated in various pathological conditions due to the fact that they undergo rapid activation in response to a wide range of stimuli they receive. These stimuli induce the release of diverse immune mediators including cytokines and mediators of hypersensitivity reactions histamine and leukotriene. Basophils are well known for their pathogenic role in allergic diseases. Recent data also advocate basophils in the pathogenesis of autoimmune and other inflammatory diseases. Therefore, considering the impact of dysregulated functions of basophils on the immune response in various diseases, we deliberated that it is essential to understand the regulatory mechanisms by which basophils are kept in check.
Among immunoregulatory cells, CD4+CD25+FoxP3+ regulatory T cells (Tregs) have been widely studied for their role in immune tolerance and in the maintenance of immune homeostasis. Tregs modulate autoimmune and inflammatory responses by exerting direct suppressive effects on various immune cells including dendritic cells, T cells, macrophages, monocytes, B cells, neutrophils, natural killer cells, and mast cells. In view of emerging reports on the role of basophils in various pathological conditions, we investigated if Tregs are able to control the activation and functions of basophils.
In contrast to the central dogma on Tregs as immunosuppressors, we discovered that human basophils are refractory to Treg-mediated suppression. On the contrary, we found that Tregs stimulate resting basophils to induce the expression of activation markers CD69, CD203c, and CD13, and release cytokines IL-4, IL-8, and IL-13. Treg-induced activation of basophils involves IL-3 and STAT5 but was not contact-dependent. These results provide evidence of direct positive effects that human Tregs have on basophil activation and reveal a previously unrecognized feature of this cell subset well known for immunosuppressive functions.(more…)
MedicalResearch.com Interview with:
Nidhi Malhotra PhDBoston Children's HospitalDivision of Allergy and Immunology
Senior Scientist at Elstar Therapeutics Inc.
MedicalResearch.com: What is the background for this study? What are the main findings?Response: Allergies such as Atopic Dermatitis (AD) are rampant in the industrialized nations. Why are we more predisposed to developing hypersensitive reactions to innocuous proteins (allergens) is not well understood. To gain better understanding and to develop better therapies, we need to first delve deeper into how our immune system regulates homeostasis in tissues such as skin. The main cell types that thwart inflammatory reactions are known as regulatory T cells. These cells are generated in thymus and reside in secondary lymphoid tissues but they are also prominent at tissue sites such as in dermal layer of skin. In this study, I focused on understanding how Tregs resident in skin are distinct from the Tregs in secondary lymphoid organs such as lymph nodes (LNs). I uncovered that functioning of Tregs in skin is underpinned by a distinct set of genes. One main gene that I found to be highly expressed in skin Tregs but not in LN Tregs is Rora, which encodes for the transcription factor ROR alpha (RORa).
This observation was intriguing as previous studies had elucidated the requirement of RORa in the development of inflammatory type-2 innate lymphoid cells (ILC2s) and it has been considered the antagonizing RORa functioning would curb allergic responses. However, I observed that Tregs require RORa to suppress allergic responses. In particular, RORa regulates the expression of a TNF receptor family member DR3, which binds to the cytokine TL1A. TL1A has a role in enhancing suppressive activity of Tregs while also enhancing type-2 cytokine production from ILC2s. Hence, in the absence of DR3 in Tregs, we believe more TL1A is available to ILC2s resulting in unrestrained allergic responses.(more…)
MedicalResearch.com Interview with:
Andrew Dick FRSB FMedSci
Professor of Ophthalmology
Bristol Eye Hospital, University of Bristol, Bristol, England
National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital, Institute of Ophthalmology, University College London, London, England and
John Sheppard, MD
President, Virginia Eye Consultants
Professor of Ophthalmology, Eastern Virginia Medical School
MedicalResearch.com: What should readers take away from your report?Dr. Andrew Dick:These findings demonstrate that adalimumab is associated with clinically meaningful improvements in visual functioning for patients with non-infectious intermediate uveitis, posterior uveitis, and panuveitis. The emphasis of this work is that for the first time in uveitis we have seen patient reported outcome benefit of a biologic treatment. This analysis supports the use of adalimumab as a promising new treatment option, having demonstrated improvements in both clinical and visual functioning outcomes in patients with active and inactive uveitis.
Dr. John Sheppard: Uveitis has a substantial effect on individuals’ physical, professional, psychological, avocational and social functioning in day-to-day life. Adalimumab, an anti-inflammatory drug that binds to tumor necrosis factor, was recently approved for the treatment of non-infectious intermediate uveitis, posterior uveitis, and panuveitis. It is the first systemic therapy specifically approved for uveitis. The analyses in this study provide evidence that patients with noninfectious uveitis treated with adalimumab experience significant and clinically meaningful improvements in vision-related quality of life, compared with those who received placebo.
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MedicalResearch.com Interview with:Borja Ibáñez MD
Spanish National Centre for Cardiovascular Research
Madrid
MedicalResearch.com: What is the background for this study? What are the main findings?Response: Acute myocardial infarction (heart attack) is a severe condition responsible for thousands of deaths every year and with important long-term consequences for survivors. Best treatment for acute myocardial infarction is a rapid coronary reperfusion.
Upon reperfusion, all inflammatory cells and mediators accumulated in the circulation during the infarction process, enter into the myocardium and causes an extra damage to the heart. Activated neutrophils play a critical role in this damage occurring upon reperfusion. The final size of infarction is the main determinant for mortality and long-term morbidity. The possibility of limiting the extent of infarcted tissue is of paramount importance.
Betablockers have been used in patients for more than 4 decades, mainly to treat arrhythmias and high blood pressure. Recently the same group of investigators demonstrated that the very early administration (i.e. during ambulance transfer to the hospital) of the betablocker “metoprolol” was able to reduce the size of infarction in patients. The mechanism by which metoprolol was protective in patients suffering a myocardial infarction was unknown.
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MedicalResearch.com Interview with:
Justin E. Wilson, Ph.D On behalf of the authors
Research Assistant Professor - Laboratory of Jenny Ting
Department of Genetics
Lineberger Comprehensive Cancer Center
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599
MedicalResearch.com: Could you provide me with some background on this project? Why did you decide to do this research project? What prior work led up to this latest paper?Response: Previous work from our lab and others discovered two major points about NLRP12:
a) NLRP12 suppresses inflammation in response to bacterial components
b) NLRP12 provides protection against the inflammatory bowel disease colitis and colitis-associated colon cancer (i.e., Nlrp12-defcient mice have greater colon inflammation and inflammation-driven colon cancer).
Therefore, we wanted to know if Nlrp12 was regulating inflammation in the colon by responding to the trillions of intestinal microbes collective referred to as the microbiome. Mounting evidence also indicates that the immune system both responds to and influences the composition of the intestinal microbiome during intestinal health and disease, and we hypothesized that NLRP12 could be one of the important immune components during this process. Moreover, we were also interested in this topic because targeting the microbiome to treat inflammatory disorders and other diseases is an attractive method that has many advantages over immune suppression.
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MedicalResearch.com Interview with: Mark Robert Zielinski, MD
Department of Psychiatry
Harvard Medical School and Veterans Affairs Boston Healthcare System
West Roxbury, MA 02132
MedicalResearch.com: What is the background for this study?
Response: Anecdotally, people have known that the immune system and sleep are related. In the last several decades this relationship has been systematically investigated. This work led to important findings that several molecules that enhance inflammation including interleukin-1 beta regulate sleep. Interleukin-1 beta is known to increase sleep and sleep intensity after sleep loss and in response to pathogens. However, it was unknown how these effects are connected. Interestingly, the NLRP3 inflammasome is a protein complex that senses changes in the local environment and subsequently activates pro-inflammatory molecules including interleukin-1 beta. Therefore, we wanted to see if the NLRP3 inflammasome is involved in sleep regulation.(more…)
MedicalResearch.com Interview with:
Prof. Jamal Tazi
Director, Institute for Molecular Genetics
CNRS and University of Montpellier and Executive Committee Member
ABIVAX
MedicalResearch.com: What is the background for this study?Response: Its long been established that people with HIV, even those treated successfully with antiretroviral treatment, exhibit significantly higher levels of chronic inflammation than HIV-negative people. The causes of this inflammation are many – ongoing viral replication, often in the so-called viral reservoirs, leaky gut syndrome, concomitant viral infections (eg CMV, hepatitis etc).
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MedicalResearch.com Interview with: Cheryl de Valliere, PhD
University Hospital Zurich
Division of Gastroenterology and Hepatology
Zurich Switzerland
and co-authors
Gerhard Rogler, Jesus Cosin Roger, Pedro A. RuizMedicalResearch.com: What is the background for this study?Response: Inflammatory Bowel Disease (IBD), including ulcerative colitis and Crohn’s disease, gives rise to chronic relapsing inflammation of the gastrointestinal (GI) tract, resulting in a disruption of the epithelial barrier function and exacerbated innate and adaptive immune responses. One of the most important features under these inflammatory conditions is the presence of hypoxic areas where oxygen levels are lower than in normal tissue. It has been widely reported that the main transcription factor regulating cellular responses to hypoxia, hypoxia inducible factor (HIF)-1, is significantly induced in patients with IBD compared with healthy subjects. Furthermore, hypoxia is not only linked to inflammation, but also influences the local tissue pH, leading to an reduction of the pH in the inflamed mucosa compared with the non-inflamed one.
A family of pH-sensing G-protein coupled receptors (GPCRs), including the receptor T-cell death-associated gene 8 (TDAG8) and the ovarian cancer G-protein coupled receptor 1 (OGR1 or GPR68), play an important role in physiological pH homeostasis. At low extracellular pH, second messenger signaling pathways are activated by protons binding to the histidine residues located on the extracellular region of the receptor. Recent studies have reported a link between IBD and this family of pH-sensing receptors. Indeed, TDAG8 has been identified as an IBD risk gene and we have previously reported an increased expression of OGR1 in patients with IBD compared with healthy subjects.
To better understand the basic mucosal inflammatory mechanisms, and foster the development of new treatment options (e.g. pH receptor blockers and OGR1 antagonists) for chronic mucosal inflammatory diseases, we investigated the effects of hypoxia on pH-sensing OGR1 in the intestinal mucosa and associated cells.
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MedicalResearch.com Interview with:Dr. Jeri Nieves PhD
Director of bone density testing
New York's Helen Hayes Hospital
MedicalResearch.com: What is the background for this study? What are the main findings?Response: Amyotrophic lateral sclerosis (ALS) is a devastating severe neurodegenerative disorder that causes progressive muscle atrophy, paralyses, and eventual respiratory failure.
Our objective was to evaluate the associations between nutrition and severity of ALS around the time of diagnosis. This was a cross-sectional analysis of data from a multicenter cohort of 302 patients with ALS. We assessed nutrient intake using a modified Block Food Frequency Questionnaire. The outcomes were respiratory function (measured using percentage forced vital capacity; FVC%) and functional performance measured by ALS Functional Rating Scale–Revised (ALSFRS-R), both considered important indicators of the severity of ALS. Results of the regression analysis were that higher intakes of antioxidants and carotenes from vegetable intake were associated with higher ALSFRS-R scores or better %FVC.
We used a novel analysis to evaluate the diet as a whole and found that higher intakes of antioxidants, fiber from grains, vegetables, fruit, eggs, fish, and poultry were all associated with higher function in patients with ALS. However, milk and lunch meats were associated with lower measures of function. These consistent results from two different statistical analyses indicate that diet may help minimize the severity of ALS. Perhaps these findings point to the role of oxidative stress in ALS severity.
In summary, increased consumption of antioxidant nutrients, foods high in carotenoids and fiber, vegetables and fruits, poultry and fish are associated with better function around the time of ALS diagnosis.
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MedicalResearch.com Interview with:David Underhill, PhD
Professor of Biomedical Sciences
Research scientist, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
Cedars-Sinai
Los Angeles, CA
MedicalResearch.com: What is the background for this study?Response: “Innate immunity” is the body’s natural resistance to microbial infection and stands in contrast to “adaptive immunity,” which is the body’s learned response to infection (e.g. antibodies and vaccines). In the standard model of innate immunity that has emerged over the last several decades, scientists have come to understand that the human genome encodes many “receptors” that have evolved as sensors for specific common microbial molecules, such as bacterial or viral DNA or components of bacterial or fungal cell walls. The job of these receptors is to survey the environment (skin, blood, etc.) for potentially dangerous microbes and initiate inflammatory responses if they are found. These activities are essential for defense against infection, and people and animals with defects in these sensors or the responses they trigger can be susceptible to infection.
My laboratory has been interested for more than a decade in identifying these innate sensors and the microbial targets that they recognize. In this study, we were looking for the sensor that allows white blood cells (e.g. macrophages and dendritic cells) to detect Gram-positive bacterial cell walls and trigger a specific inflammatory response: secretion of the potent inflammatory mediator interleukin-1β (IL-1β).
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MedicalResearch.com Interview with: Clive McKimmie PhD
Research Fellow,
Virus Host Interaction Team (VHIT),
University of Leeds
St James’ University Hospital
Leeds UK
MedicalResearch.com: What is the background for this study?Response: With the rapid spread of Zika in the Americas, attention has been drawn to this group of neglected mosquito-borne viral infections. The Zika virus is not alone in causing problems, others such as dengue and chikungunya viruses are infecting millions of people each year. Yet there’s little doctors can do to help people who get sick.
When mosquitoes bite you they can transmit these disease causing viruses. We don’t understand what happens during the early stages of infection very well. However, it is known that the mosquito bite itself somehow helps the virus to infect your body.
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MedicalResearch.com Interview with:
Charnita Zeigler-Johnson, Ph.D., M.P.H.
Assistant Professor
Division of Population Sciences
Department of Medical Oncology
Thomas Jefferson University
Philadelphia, PA 19107
Medical Research: What is the background for this study?
Dr. Zeigler-Johnson: Obesity has been associated with poor prostate cancer outcomes, included advanced disease at diagnosis, increased risk for cancer recurrence, and risk for mortality. One possible link in the relationship between obesity and prostate cancer progression is inflammation. Obesity produces a state of systemic chronic low-grade inflammation which may contribute to the underlying biology of the tumor microenvironment. The presence of immune cells (T-cells and macrophages) in the tumor microenvironment may indicate aggressive tumors that are likely to metastasize. The goal of this study was to examine prostate cancer tissue to characterize differences in immune cells within the tumor microenvironment by obesity status and cancer severity. We studied tumor samples from 63 non-obese and 36 obese prostate cancer patients.
Medical Research: What are the main findings?Dr. Zeigler-Johnson: We found that T-cell and macrophage counts in the tumor did not differ by patient obesity status. However, macrophage (CD68) counts were higher among men diagnosed with higher tumor grade (Gleason Score 7-10). We also found that T-cell (CD8) counts were associated with quicker time to prostate cancer recurrence (indicated by detectable prostate specific antigen levels after treatment.)(more…)
MedicalResearch.com Interview with:
Robert H. Schiestl PhDDepartment of Environmental Health Sciences, Fielding School of Public Health,
Department of Pathology
Department of Radiation Oncology
Geffen School of Medicine
University of California Los Angeles,
Los Angeles, CaliforniaMedical Research: What is the background for this study? What are the main findings?
Dr. Schiestl: When we moved from Harvard to UCLA 13 years ago, after 6 years at UCLA our Atm mouse colony lived significantly 4 fold longer and the frequency of DNA deletions was 4.5 fold reduced and the latency of lymphoma 2.5 fold different. Ultimately we identified the reason behind this as a difference in the intestinal bacteria. The Atm deficient mice are hypersensitive to inflammation and the bacteria reduced inflammation. Then I isolated the most prevalent bacterium among the health beneficial bacteria and this bacterium by itself called Lactobacillus johnsonii 456 reduced genotoxicity and all markers of inflammation.
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MedicalResearch.com Interview with:
Carsten C. Skarke MD
Research Assistant Professor of Medicine
McNeil Fellow in Translational Medicine
Institute for Translational Medicine and Therapeutics
Perelman School of Medicine
University of Pennsylvania
Medical Research: What is the background for this study? What are the main findings?
Dr. Skarke: A growing body of publications suggests anti-inflammatory actions of fish oils. These health benefits are proposed to emerge from lipids called specialized pro-resolving mediators, (SPMs), which can be formed from omega-3 polyunsaturated fatty acids found in fish. A limitation to date, though, in this field is that there is little evidence of their formation in humans. And the cases where presence of these lipids is reported in humans, less rigorous analytical approaches, such as enzyme immunoassay (EIA), radioimmunoassay (RIA) or mass spectrometry without internal authentic standards, have been used. Thus, the specific aim for our study was to use state-of-the-art mass spectrometry to identify and quantify these specialized pro-resolving mediators.
Several aspects of our study design set us apart from what was done in previous studies.
First, we biased our ability to detect SPMs formed in healthy volunteers by giving fish oil in high doses which had been previously shown to influence blood pressure and platelet aggregation under placebo-controlled conditions.
Second, we also looked at lower doses of fish oil, those more commonly consumed by the general public, for the formation of SPMs during an acute inflammatory response and its resolution.
Third, we relied in our measurements of SPMs on authentic internal standards. These deuterated lipids, d4-resolvin E1 for example, facilitate distinct identification of the naturally formed lipid.
And fourth, we achieved very low limit of detection levels, below 10 pg/ml for resolvin E1, for example.
The surprising finding of our studies is that we failed to detect a consistent signal of SPM formation in urine or plasma of healthy volunteers who had taken fish oil. Even more surprising was that we found no alteration in the formation of SPMs during the resolution of inflammation. These results let us question the relevance of endogenous specialized pro-resolving mediators to the putative anti-inflammatory effects of fish oils in humans.
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