ILARIS® (canakinumab) Not Cost Effective For Prevention of Cardiovascular Disease

MedicalResearch.com Interview with:

Thomas S. G. Sehested MD Department of Cardiology Copenhagen University Hospital Gentofte

Dr. Sehested

Thomas S. G. Sehested MD
Department of Cardiology
Copenhagen University Hospital Gentofte

Jenny Bjerre, MD Department of Cardiology Copenhagen University Hospital Herlev and Gentofte Copenhagen, Denmark Department of Health Research and Policy Stanford University School of Medicine Stanford, California

Dr. Bjerre

 
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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Critical Illness Linked To Brain Changes Associated with Cognitive Decline

MedicalResearch.com Interview with:

Keenan Walker, PhD Johns Hopkins University School of Medicine  Baltimore

Dr. Walker

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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Artificial Antibody Knocks Out Kidney Inflammation

MedicalResearch.com Interview with:

Michael P. Madaio, MD Sydenstricker Professor and Chairman Department of Medicine Medical College of Georgia at  Augusta University

Dr. Madaio

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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Secret Relationship of Regulatory T cells, Tregs, on Basophils

MedicalResearch.com Interview with:
“Basophil” by GreenFlames09 is licensed under CC BY 2.0Jagadeesh 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.  Continue reading

Inflammatory Cells That Suppress Skin Allergic Reactions Identified

MedicalResearch.com Interview with:
elstarNidhi Malhotra PhD

Boston Children’s Hospital
Division 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.  Continue reading

Effect of Adalimumab on Visual Functioning in Patients With Noninfectious Uveitis

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 SheppardUveitis 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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Beta-Blockers Reduce Heart Attack Size By Limiting Inflammation

MedicalResearch.com Interview with:

Borja Ibáñez MD Spanish National Centre for Cardiovascular Research Madrid

Dr. Ibáñez

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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Protective Bacteria May Reverse Inflammation In Some Forms of IBD

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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Inflammasomes Might Be Involved in Making You Sleep More When Sick or Sleep Deprived

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. 

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Anti–HIV Drug Candidate Prevents Intestinal Inflammation

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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pH Sensing Molecules May Play a Role in Initiating Inflammatory Bowel Disorders

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. Ruiz

MedicalResearch.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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Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis

MedicalResearch.com Interview with:

Dr. Jeri Nieves PhD Director of bone density testing New York's Helen Hayes Hospital

Dr. Jeri Nieves

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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Inflammatory Molecule Links Metabolic Environment and Innate Immunity

MedicalResearch.com Interview with:

David Underhill, PhD Professor of Biomedical Sciences Research scientist, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Cedars-Sinai

Dr. David Underhill

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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Inflammation Caused By Mosquito Bites Helps Viral Infections Spread

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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Inflammation Factors in How Obesity Influences Prostate Cancer Progression

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

Dr. Zeigler-Johnson

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.)

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Intestinal Bacteria May Decrease Cancer Risk By Reducing Inflammation

MedicalResearch.com Interview with:

Robert H. Schiestl PhD Department 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, California

Dr. Robert Schiestl

Robert H. Schiestl PhD
Department 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, California

Medical 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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No Evidence of Anti-Inflammatory Mediator Increase From Fish Oil Ingestion

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 PennsylvaniaMedicalResearch.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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Modern Wireless Devices May Cause Excessive Oxidative Stress In Humans

Prof. Igor Yakymenko Laboratory of Biophysics, Institute of Experimental Pathology, Oncology and Radiobiology NAS of UkraineMedicalResearch.com Interview with:
Prof. Igor Yakymenko

Laboratory of Biophysics, Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine

Medical Research: What is the background for this study? What are the main findings?

Prof. Yakymenko: We know a lot about both health effects and metabolic effects of radiofrequency radiation (RFR) today, including mutagenic and carcinogenic effects. For example, epidemiological studies over the world indicate that 5 years of cell phone use 20 min per day increase risk of acoustic neuroma 3 times. Or, for example, 4 years of cell phone use 1 hour or more per day increase risk of some kinds of brain tumors, including glioma, 3-5 times. But it was not understandable the primary mechanisms of such effects. In our study we had analyzed about 100 recent studies on metabolic effects of radiofrequency radiation, including our own experimental data, and demonstrated that oxidative/free radical effects are mandatory feature of RFR exposure of living cells. Moreover, the chronic radiofrequency radiation exposure can produce chronic oxidative stress in living cells as a first step for possible development of bulk of hazardous health effects.

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Gene Expression Signatures May Help Differentiate Sepsis From Non-Infectious Inflammation

MedicalResearch.com Interview with:
Timothy E Sweeney, MD PhD
Resident, General Surgery
Postdoc, Khatri Lab, Bioinformatics
Stanford University

Medical Research: What is the background for this study? What are the main findings?

Dr. Sweeney: Sepsis is defined as the presence of systemic inflammation due to infection. Systemic inflammation can be caused from many things, such as trauma, surgery, thrombosis, autoimmunity, etc. It can also be caused by infection. On the other hand, infection does not necessarily cause systemic inflammation, either:  a person can get a minor infection, like strep throat, and not have a systemic response. It’s the intersection of severe inflammation (a syndrome called SIRS) with infection that defines sepsis.

In general surgery, we frequently see patients after traumatic injury or surgery who are having an inflammatory response (ie, fevers, fast heart rate, high white blood cell count, etc). But it’s not clear whether this inflammatory response is a reaction to the trauma or surgery, or whether there might be an infection brewing that is causing the reaction. Identifying the inflammatory response doesn’t require many special tests– it’s easy to spot. So we know which patients have inflammation and which do not. What is difficult is determining the root cause of the inflammation, and, in particular, whether there is an infection present that needs treatment with antibiotics.

Current diagnostics for infection (not sepsis) are either slow (like blood cultures, which can take 24-72 hours to return) or not highly accurate (like procalcitonin). We sought to define a better test that could specifically differentiate between people with sterile inflammation, and people with inflammation due to infection (sepsis). By integrating gene expression data from multiple publicly available cohorts, we were able to find a set of 82 genes that are significantly differently expressed between these two groups. We then used an algorithm called a greedy forward search to find a subset of 11 genes that were most diagnostic for sepsis.

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Deficient Calcium Channels Weaken Immune Response To Chronic Infections

Dr. Ludovic Desvignes. PhD. Assistant Professor, Departments of Medicine and Pathology NYU Langone Medical CenterMedicalResearch.com Interview
Dr. Ludovic Desvignes PhD.
Assistant Professor, Departments of Medicine and Pathology
NYU Langone Medical Center

MedicalResearch: What is the background for this study?

Dr. Desvignes: This study is the result of a collaboration at NYU Langone Medical Center, between the laboratories of Dr. Stefan Feske and Dr. Joel Ernst, my mentor. Dr. Feske and colleagues had developed a mouse model of rare, inherited mutations he had identified in infants. These mutations occur in the genes for STIM1 and ORAI1, which are crucial for calcium flux in cells of the immune system. The young patients affected by these mutations suffer from severe, recurrent and chronic infections that often cause death before their first birthday. In particular, some of these patients cannot control infection with BCG, which is a normally innocuous strain of mycobacteria administered to protect against tuberculosis (TB). TB is a chronic infection and one of the leading causes of infection-related death worldwide. Going into this study, Dr. Feske and colleagues knew that without functional calcium channels, immune cells do not function properly. However, they did not fully understand how these channels contribute to immune responses to infectious pathogens in a living organism and in particular, for pathogens that cause chronic infections such as TB. This is why Dr. Ernst and I collaborated with Dr. Feske and provided him with our clinical and research expertise in TB.

MedicalResearch: What are the main findings?

Dr. Desvignes: Dr. Feske’s mice are genetically engineered to lack STIM1 in a certain type of immune cells, known as T cells or T lymphocytes. We infected these mice with Mycobacterium tuberculosis, the bacterium causing TB. Mycobacterium tuberculosis causes chronic infection by manipulating the immune system even in healthy people. The first very surprising result of our study was that mice lacking calcium flux in T cells handled acute TB fairly well. Only during the chronic phase of infection did they become unable to control mycobacterial growth and developed a strong inflammation in their lungs, which was due to an infiltration by different types of immune cells, including T cells. We discovered that the accumulation of STIM1-deficient T cells in the lungs resulted from the cells’ inability to die, which is a normal mechanism to limit an immune response and prevent excessive inflammation.

Another immune control mechanism that failed in the absence of STIM1 is mediated by a subset of T cells called induced regulatory T cells, or iTreg cells. These cells are essential to prevent normal immune responses from going “overboard” by suppressing the functions of other immune cells, including T cells. We found that calcium signals are required for the development of iTreg cells and that their numbers were strongly reduced in the lungs of infected STIM1-deficient mice. We therefore think that the lack of iTreg cells in the absence of STIM1 contributes to the severe lung inflammation in chronic TB.

The third finding that really surprised us was that T cells accumulating in the lungs of STIM1-deficient mice produced large amounts of a protein called interferon gamma. While interferon gamma is required to control Mycobacterium tuberculosis, it is also a very potent promoter of inflammation and too much of it can lead to tissue damage. Dr. Feske and colleagues had previously observed that calcium fluxes promote the production of interferon gamma in T cells cultured in vitro and we expected the STIM1-deficient T cells to be defective in the production of that protein. During chronic TB, however, calcium signaling turned out to be not only dispensable for the production of interferon gamma by T cells but it was actually required to limit its production and thus, to control inflammation.

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Antioxidants May Have Mixed Effect on Aging

Dr. Jeremy Van Raamsdonk Laboratory of Aging and Neurodegenerative Disease (LAND), Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, Department of Translational Science and Molecular Medicine, Department of Genetics, Michigan State University, East Lansing, Michigan, Department of Biology, McGill University, Montreal, Quebec, CanadaMedicalResearch.com Interview with:
Dr. Jeremy Van Raamsdon PhD
Laboratory of Aging and Neurodk egenerative Disease (LAND),
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, Deptment of Translational Science and Molecular Medicine, Department of Genetics, Michigan State University, East Lansing, Michigan,Dep. of Biology, McGill University, Montreal, Quebec, Canada

Medical Research: What is the background for this study? What are the main findings?

Dr. Van Raamsdonk : The free radical theory of aging is one of the most widely accepted theories of aging. This theory suggests that reactive oxygen species (ROS), which are also known as free radicals, cause a type of damage, called oxidative damage, that accumulates over time to cause the functional decline associated with aging. ROS have also been proposed to play a role in many diseases including neurodegenerative disorders such as Parkinson’s disease and Huntington’s disease.

However, recent work has demonstrated that ROS are not necessarily detrimental. ROS perform functional roles in the body and thus it is possible to have too little ROS. We previously showed that increasing ROS by decreasing the levels of an antioxidant enzyme called superoxide dismutase (SOD) does not decrease lifespan even when all of the SOD genes are removed. We also showed that in some cases treatment with an antioxidant, such as Vitamin C, can lead to decreased lifespan. This finding is consistent with human clinical trials in which it has not been possible to show a beneficial effect of antioxidants on longevity.

In this paper we further examine the relationship between ROS and aging. We use a simple genetic model organism, the worm Caenorhabditis elegans, which has been used extensively in aging research, to determine how location impacts the effect of ROS on lifespan. We used a genetic approach to increase the levels of ROS in different parts of a cell and found that location is crucial in determining the effect of ROS on lifespan. Mildly increasing the levels of ROS in the mitochondria increases lifespan, while increasing ROS in the cytoplasm has the opposite effect of decreasing lifespan.

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Study Examines Chronic Inflammation of Traumatic Brain Injury

Alan I Faden, M.D. David S. Brown Professor in Trauma Professor, Departments of Anesthesiology, Anatomy & Neurobiology, Neurosurgery, and Neurology Director, Center for Shock, Trauma & Anesthesiology Research (STAR) University of Maryland School of MedicineMedicalResearch.com Interview with:
Alan I Faden, M.D.
David S. Brown Professor in Trauma
Professor, Departments of Anesthesiology, Anatomy & Neurobiology, Neurosurgery, and Neurology
Director, Center for Shock, Trauma & Anesthesiology Research (STAR) University of Maryland School of Medicine

Medical Research: What is the background for this study? What are the main findings?

Dr. Faden: Accumulating clinical and pre-clinical research data indicate that traumatic brain injury (TBI) can lead to chronic progressive neurodegeneration. In this regard, most attention has focused on the connections between TBI and with Alzheimer disease (AD) or Chronic Traumatic Encephalopathy (CTE). However, recent epidemiological studies raise questions about the association between TBI and AD, and CTE is likely a less common end-stage result resulting from complex pathobiological changes. In contrast, both older and newer studies underscore that traumatic brain injury can cause chronic neuroinflammation that leads to chronic neurodegeneration. In contrast to AD and CTE, the latter condition appears to be potentially treatable, even long after injury. Our paper critically assesses the mechanisms and treatment of chronic post traumatic neurodegeneration.

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Link Between Inflammation and Breast Cancer Explored

Dr. Jorge Morales-Montor Departamento de Inmunología Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México México City MéxicoMedicalResearch.com Interview with:
Dr. Jorge Morales-Montor
Departamento de Inmunología
Instituto de Investigaciones Biomédicas
Universidad Nacional Autónoma de México
México City México

MedicalResearch: What is the background for this study?

Dr. Morales-Montor: Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped in several protein families referred as tumour necrosis factors, interleukins, interferons and colony stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis and metastasis, all phenomena in which cytokines are prominent players. The data we have hitherto let us suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer related disorders.

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Cesarean Delivery May Increase Risk of Childhood Inflammatory Diseases

Professor of Pediatrics Hans Bisgaard, MD, DMSc Copenhagen Prospective Studies on Asthma in Childhood Herlev and Gentofte Hospital, University of Copenhagen, Denmark.

Prof. Bisgaard

MedicalResearch.com Interview with:
Professor of Pediatrics Hans Bisgaard, MD, DMSc
Copenhagen Prospective Studies on Asthma in Childhood
Herlev and Gentofte Hospital,
University of Copenhagen, Denmark

Medical Research: What is the background for this study? What are the main findings?

Prof. Bisgaard: The purpose of this study was to look for a shared risk factor for immunological diseases which make its debut in childhood. During the recent decades a parallel increase in prevalence of immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have been observed in westernized countries. The rate of cesarean delivery has increased in the same period and has previously been associated with the development of some of these diseases. This study takes advantage of the unique and valuable nationwide registry data in Denmark to establish a large population based cohort (2 million term children) with 35 years of follow up (in the period 1977-2012). We found cesarean delivery to be a common risk factor for a range of childhood immunological diseases: asthma, juvenile arthritis, inflammatory bowel diseases, connective tissue disorders, immune deficiencies and leukemia, but with no association to psoriasis, celiac disease, and diabetes type 1.

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Healthy Lifestyle, Not Supplements, Linked to Longevity

Annlia Paganini Hill PhD Project Scientist Biostatistician and Epidemiologist Department of Neurology, School of Medicine University of California, Irvine, Irvine, CaliforniaMedicalResearch.com Interview with:
Annlia Paganini Hill PhD
Project Scientist Biostatistician and Epidemiologist
Department of Neurology, School of Medicine
University of California, Irvine, Irvine, California

Medical Research: What is the background for this study? What are the main findings?

Response: Free radicals are formed when one exercises and when the body converts food to energy. Environmental sources (e.g. smoke, air pollution, sunlight) also expose the body to free radicals. Free radicals can cause “oxidative stress” and damage cells. Oxidative stress is thought to play a role in a variety of diseases: cancer, cardiovascular disease, diabetes, Alzheimer’s disease, Parkinson’s disease, cataracts, and age-related macular degeneration.

Antioxidants are man-made or natural substances that may prevent or delay some types of cell damage. Antioxidants are found in many foods and are also available as dietary supplements. Vegetables and fruits are rich sources of antioxidants. There is good scientific evidence that eating a diet with lots of vegetables and fruits is healthful and lowers risks of certain diseases. However, it is unclear whether this is because of the antioxidants, something else in these foods, other foods in people’s diet, or other lifestyle choices.

While antioxidants have been shown to counteract oxidative stress in cells and animal studies, whether consuming large amounts of antioxidant supplements benefits human health is debated. Given the continued use of vitamin supplements by a large proportion of the population and the presumed safety of antioxidant supplementation, we assessed the relationship between antioxidant vitamin intake and all-cause mortality in older adults.

We examined these associations using data from the Leisure World Cohort Study, a study of nearly 14,000 residents of a California retirement community. In the early 1980s, participants (median age, 74 years) reported details on use of vitamin supplements and dietary intake of foods containing vitamins A and C. During followup (1981-2013), over 93% of participants had died (median age at death, 88 years).

Medical Research: What are the main findings?

Response: Previously, we had found that a number of factors were associated with lower risk of death in our cohort — not smoking, physical activity, moderate alcohol consumption, caffeine intake, ideal body mass index (neither too fat nor too thin), and no history of high blood pressure, angina, heart attack, stroke, diabetes, rheumatoid arthritis, or cancer .

Neither dietary nor supplemental intake of vitamins A, C or E were significantly associated with reduced mortality in this study once these other lifestyle behaviors and disease conditions were taken into account.

In Leisure World Cohort and in the general population, health-promoting habits often cluster; e.g. those who take vitamin supplements often exercise, do not smoke, and are not obese. Thus, these factors explain the observed association between longevity and vitamin supplements in our and previous studies.

Medical Research: What should clinicians and patients take away from your report?

Response: Antioxidant supplements should not be used to replace a nutritionally adequate diet. A healthful diet characterized by high amounts of fruits and vegetables, whole grains, and fish should be recommended to avoid nutritional deficiencies and to prevent chronic disease.

Additionally, other studies have shown that high-dose antioxidant supplements may even be harmful (increased risks of prostate cancer, hemorrhagic stroke, and lung cancer in smokers). And because antioxidant supplement may interact with other medications, use of supplements should be discussed with a health care provider.

Citation:

Antioxidant Vitamin Intake and Mortality: The Leisure World Cohort Study.

Paganini-Hill A, Kawas CH, Corrada MM.
Am J Epidemiol. 2014 Dec 29. pii: kwu294. [Epub ahead of print]