MedicalResearch.com Interview with:
Marie Crandall, MD, MPH, FACS
Associate Professor of Surgery
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
Medical Research: What is the background for this study? What are the main findings?
Dr. Crandall: While the association between alcohol and interpersonal violence has been well established, research has been divided with respect to the direct effect of proximity to an establishment with a liquor license and violence. We used geographic regression analysis, which is a type of multivariate regression including geography as a variable, to examine the association between proximity to an establishment with a liquor license, such as a liquor store or tavern, and gun violence in Chicago.
We utilized our state trauma registry and geocoded 11,744 gunshot wounds that occurred between 1999-2009. On the assumption that different neighborhoods might experience risk differently, we used a combination of ordinary least squares and geographic regression analysis to identify homogenous areas with similar risk. We used sociodemographic variables as covariates in the analysis.
We found that the impact of proximity to an establishment with a liquor license and occurrence of gunshot wounds varied markedly by neighborhood. The areas of highest risk were found to have enormous associations, Odds Ratios (OR) greater than 500. These areas also tended to be more socioeconomically distressed areas of the city.
MedicalResearch.com Interview with:
Katherine Jones, M.A.
Research Associate, Department of Research
The American College of Obstetricians and Gynecologists
Department of Psychology, American University
Medical Research: What is the background for this study? What are the main findings?
Response: It is well evidenced that breastfeeding is highly advantageous for the mother, child, and society. Benefits to breastfeeding may be significantly larger for minority women as they are disproportionately affected by numerous adverse health outcomes. The benefits of breastfeeding may help mitigate some of these negative health consequences, and thus, also bridge larger gaps in racial and ethnic health disparities. This article aimed to review the literature on racial and ethnic disparities in breastfeeding rates and practices, conduct a systematic review of breastfeeding interventions, address barriers to breastfeeding among minority women, and provide obstetrician-gynecologists (ob-gyns) with recommendations on how they can help improve rates among minority women.
Overall, racial and ethnic minority women continue to have lower breastfeeding rates than white women in the United States, with African American women having the lowest rates of breastfeeding initiation and continuation among to all women. Minority women report several unique barriers to breastfeeding, including lack of access to information that promotes and supports breastfeeding, lack of work and cultural acceptance and support, language and literacy barriers, acculturation, and historical, sociopolitical, and economic challenges. Results from the systematic review of breastfeeding interventions among minority women indicated that breastfeeding-specific clinic appointments, enhanced breastfeeding programs, group prenatal education, peer counseling, and hospital policy changes significantly improve breastfeeding initiation, duration, and exclusivity.
MedicalResearch.com Interview with:
Dr. Jeanne Tie
Medical Oncologist | Royal Melbourne and Western Hospital
Research Fellow
Walter and Eliza Hall Institute of Medical Research
Parkville, VIC
Medical Research: What is the background for this study?
Dr. Tie: The increasing number of active agents available to treat metastatic colorectal cancer has resulted in an ever-improving life expectancy in this group of patients. However, the ability to expose patients with metastatic colorectal cancer to all effective anti-cancer treatment, particularly 3rd line treatment and beyond, is increasingly challenging in routine practice as some patients’ condition deteriorate too rapidly and do not live long enough to enjoy the benefit of these additional therapies. This is partly due to the current imaged-based method of assessing treatment response with the Response Evaluation Criteria in Solid Tumors (RECIST), which is usually performed every 8-12 weeks during the course of treatment. This means that for non-responders to treatment, several weeks to months will elapse before a switch to alternative therapy will be made. Conceptually, if a patient’s response to treatment could be made earlier, such as with a blood test, then an earlier switch to an alternative treatment can be made, minimizing the side-effects of the ineffective therapy and providing the opportunity for a more effective one. Currently, blood biomarkers add little to imaging-based assessment, with CEA lacking sensitivity and specificity.
Colorectal cancer is characterised by several recurrently mutated genes and advances in genomics and molecular technologies have now enabled rapid detection and quantification of these cancer-specific mutations in patient’s circulation (circulating tumor DNA - ctDNA). Previous studies have demonstrated that ctDNA can be detected in a high proportion of patients with advanced cancer. In this study, we describe the potential role of ctDNA as an early predictor of treatment response in patients with treatment naïve metastatic colorectal cancer (mCRC) undergoing chemotherapy and as a marker of disease bulk that could complement RECIST measurement.
MedicalResearch.com Interview with:
Perry N Halkitis, Ph.D., M.S., MPH
Professor of Applied Psychology
Global Public Health, and Population Health/Medicine
New York University.
Medical Research: What is the background for this study?
Dr. Halkitis: The P18 Cohort Study is a prospective cohort study of gay, bisexual and other young men who have sex with men (YMSM) which seeks to examine the development of health behaviors as these young men transition from adolescent to adulthood. Officially named “Syndemic Production among Emergent Adult Men”, this study was funded by the National Institute on Drug Abuse from 2009-2014 and renewed on March 1, 2014 for an additional five years.
The original aims of the study were as follows:
MedicalResearch.com Interview with:
Michelle Schmiegelow, MD, PhD-student
Hjertemedicinsk Forskning
Gentofte Universitetshospital
Hellerup
Medical Research: What is the background for this study?
Dr. Schmiegelow: Obesity has become a worldwide epidemic, but the excess cardiovascular risk observed in obese individuals may primarily be attributable to metabolic mediators, rather than obesity per se. Several studies conducted in primarily non-Hispanic white populations suggest that obese individuals without the metabolic syndrome, defined as metabolically healthy obese, have a cardiovascular risk similar to that of normal weight metabolically healthy individuals.
We used prospectively collected data from the Women’s Health Initiative studies to evaluate whether obesity unaccompanied by metabolic abnormalities was associated with increased risk of cardiovascular disease (CVD) across racial/ethnic subgroups in postmenopausal women. Additionally, we examined whether the use of the metabolic syndrome to define the metabolically healthy obese applied to the various racial/ethnic subgroups by quantifying the number and type of metabolic syndrome components.
All women were classified by obesity level and metabolic health status at baseline. The women were thus categorized according to body mass index (BMI, kg/m2) into normal weight (BMI 18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (30.0 kg/m2) women. Metabolic health status was first defined by presence of the metabolic syndrome (yes/no), and second by number of metabolic syndrome components. In accordance with the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute we defined the metabolic syndrome as any two of the following (criteria for women): increased waist circumference ≥80 cm; increased level of triglycerides ≥150 mg/dL (≥1.7 mM); decreased level of HDL-C <50 mg/dL (<1.3 mM); increased blood pressure with either systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, or treatment with antihypertensive drugs; and impaired fasting serum glucose ≥100 mg/dL (6.1 mM).
Medical Research: What are the main findings?
Dr. Schmiegelow: The study population comprised 14,364 women without diabetes or prior cardiovascular disease. The women had a median age of 64 years (interquartile range 57–69), and 47% were white, 36% were black and 18% were Hispanic. Over a median follow-up of 13 years (interquartile range 12–14 years), 1,101 women (7.7%) had a first cardiovascular event.
The main findings of this study were that metabolic abnormalities appeared to confer more cardiovascular risk among black women than among white women. Consistent with other studies, among white women without the metabolic syndrome, obesity was not associated with increased cardiovascular risk compared with normal weight women. Conversely, black overweight and black obese women had increased cardiovascular risk compared with normal weight black women without the metabolic syndrome, even in absence of the metabolic syndrome.
According to number of metabolic syndrome components, black overweight or obese women with just two metabolic abnormalities had increased risk of cardiovascular disease, although they would be considered “metabolically healthy” based on the standard definition, particularly since one of these abnormalities were abdominal obesity for 79% of overweight and 98% of obese women, irrespective of race/ethnicity. White obese women with three metabolic abnormalities did not have a statistically significantly increased cardiovascular risk compared with normal weight metabolically healthy women. Thus, cardiovascular disease risk appeared to be elevated in black women by the presence of only two or three metabolic abnormalities to a degree that would require four or more metabolic abnormalities among white women. These findings did not appear to be driven by any particular combination of metabolic abnormalities.
MedicalResearch.com Interview with:
Dr. Hope M. Tiesman MSPH, PhD
CDC, Atlanta
Medical Research: What is the background for this study? What are the main findings?
Dr. Tiesman: The authors regularly monitor non-occupational injury trends, including the recent and significant increase in suicide rates. This finding led the authors to consider how these non-occupational trends impacted the workplace. We used data for two large national surveillance systems. We obtained data on workplace suicides from the Bureau of Labor Statistics' Census of Fatal Occupational Injury (CFOI) which compiles data on all fatal work-related injuries in the US. We obtained data on non-workplace suicides from the CDC's Web-Based Injury Statistics Query and Reporting System or WISQARS. WISQARS data are compiled using national death certificate data. From here we calculated suicide rates and compared trends across workplace and non-workplace suicides as well as examined the socio-demographics and occupational characteristics of those who chose suicide in the workplace.
Several important findings to highlight. Across the 8-yr timeframe, we found that workplace suicide rates remained relatively stable, even somewhat decreasing that it is until 2007 when a large and significant jump in rates was found. This was in contrast with non-workplace suicide rates which increased over the entire study period. Men had signifıcantly higher workplace suicide rates compared to women and generally, as age increased, so did workplace suicide rates. Those aged between 65 and 74 years had the highest suicide rate of all workers which was also a bit different from non-workplace suicide rates. Finally, we found that those in protective service occupations, such as police and firefighters, had the highest workplace suicide rates, followed closely by those in farming/fishing/and forestry occupations. These occupations have been associated with higher overall suicide rates in prior studies. A somewhat novel finding was that those in automotive maintenance and repair occupations also had significantly higher workplace suicide rates.
MedicalResearch.com Interview with:
David F. Penson, MD, MPH
Hamilton and Howd Chair in Urologic Oncology
Professor and Chair, Department of Urologic Surgery
Director, Center for Surgical Quality and Outcomes Research
Vanderbilt University Medical Center
Nashville, TN 37232-2765
Medical Research: What is the background for this editorial? What are the main findings?
Response: This editorial discusses the implication of the recent removal of the PSA data from the seer-medicare dataset. It reviews the significance of the action: specifically what it means for prior publications that used this information to address clinical research questions in prostate cancer. It makes the point that, while these datasets are powerful, researchers have stretched the limits of what they can do too far. Simply put, we cant always guarantee that the clinical data collected in administrative datasets will necessarily be accurate so we need to be more selective in how we use these data and not simply run analyses on the data just because it is easy.
MedicalResearch.com Interview with:
Thomas M. Gill, M.D
Humana Foundation Professor of Medicine (Geriatrics)
Professor of Epidemiology and of Investigative Medicine
Director Yale Program on Aging and Yale Center for Disability and Disabling Disorders
Director, Yale Training Program in Geriatric Clinical Epidemiology and Aging-Related Research
Medical Research: What is the background for this study? What are the main findings?h
Response: Understanding the disabling process at the end of life is essential for informed decision-making among older persons, their families, and their physicians.
We know from prior research that the course of disability at the end of life does not follow a predictable pattern for most older persons. This raises the question about what is driving the development and progression of disability at the end of life.
We identified six distinct trajectories of disability in the last year of life, ranging from the least disabled to most disabled. We found that the course of disability in the last year of life closely tracked the monthly prevalence of hospitalization for each of the six trajectories.
MedicalResearch.com Interview with:
Wendong Li, Ph.D.
Assistant professor of psychological sciences
Department of Psychological Sciences
Kansas State University
Manhattan, KS
Medical Research: What is the background for this study? What are the main findings?
Dr. Wen-Dong Li: There has been a "nature versus nurture" debate in leadership: Are leaders born or made? In academia, research on trait theories of leadership has shown that important individual characteristics such as personality traits are predictive of whether one is a leader or not (leadership role occupancy or emergence). One author of this paper, Dr. Arvey conducted twin studies showing that about 30% of the individual differences in leadership is attributable to individual differences in their genetic makeup. But so far, little research has examined whether specific genes are involved and no research has examined the pathways linking genes to leadership.
This is where this research came in. We found that a dopamine transporter gene, DAT1 was involved in genetic influences on leadership role occupancy, but through two opposing pathways. One pathway is through proactive personality: DAT1 10-repeat allele was negatively related to proactive personality, which in turn was positively associated with leadership role occupancy. The negative indirect effect was significant. On the other hand, DAT1 was positively related to (moderate) rule breaking, which was positively associated with leadership role occupancy. The overall relationship between DAT1 and leadership was not significant. Thus we call it a mixed blessing because the two opposing mechanisms offset each other.
MedicalResearch.com Interview with:
Rik Ossenkoppele PhD.
Postdoctoral researcher
UCSF Memory and Aging Center
MedicalResearch: What is the background for this study?
Dr. Ossenkoppele: Since 2004, several PET tracers have been developed that measure fibrillar amyloid-β plaques, a neuropathological hallmark of Alzheimer’s disease (AD). Through visual assessment by a nuclear medicine physician or quantitative cut-points, the presence or absence of amyloid-β pathology can be determined in the living human brain. The FDA, in support of the clinical application of amyloid imaging, has recently approved three of these PET tracers. A proportion of patients with other types of dementia then Alzheimer’s disease that harbor cerebral amyloid-β pathology, however, potentially limits the clinical utility of amyloid imaging. When ordering clinical amyloid PET scans and correctly interpreting the significance of amyloid PET results, clinicians need to understand the prevalence of amyloid-positivity across different types of dementia. It is also important to be aware of the relationships of amyloid-positivity prevalence and demographic (e.g. age and sex), cognitive and genetic (e.g. presence of the AD-risk allele apolipoprotein E [APOE] ε4) factors. Most amyloid PET studies to date come from single centers with modest sample sizes. We therefore conducted a meta-analysis with individual participant data from 29 cohorts worldwide, including 1359 patients with clinically diagnosed Alzheimer’s disease and 538 patients with non-AD dementia. We also included 1849 healthy controls with amyloid PET data, and an independent sample of 1369 AD patients with autopsy data from the NACC database.
MedicalResearch: What are the main findings?
Dr. Ossenkoppele: In patients clinically diagnosed with Alzheimer’s disease, the prevalence of amyloid-positivity decreased from 93% at age 50 to 79% at age 90. The drop in amyloid-positivity was most prominent in older Alzheimer’s disease patients who did not carry an APOE ε4 allele (~1/3 of these patients had a negative amyloid PET scan). This most likely reflects a mix of
1) clinical misdiagnoses (i.e. non-AD pathology causing an AD phenotype),
2) false negative PET scans (i.e. abundance of cerebral amyloid pathology that is not detected by PET), and
3) possibly elder patients need less amyloid pathology (sub-threshold levels for PET) to reach the stage of dementia due to age-related reductions in cognitive resilience (“cognitive reserve theory”) or simultaneous presence of multiple pathologies (“double-hit theory”).
The relatively high rate of amyloid-negative Alzheimer’s disease patients highlights the necessity of biomarker-informed patient selection for Alzheimer’s disease clinical trials.
In most patients clinically diagnosed with non-AD, the prevalence of amyloid-positivity increased with aging and was ~18% higher in APOE ε4 carriers. Presence of amyloid pathology in non-AD dementia may reflect
1) clinical misdiagnosis (i.e. AD pathology is the causative pathology), or
2) comorbid pathologies, where amyloid may be secondary to other pathologies that are actually driving the clinical presentation. Interestingly, patients with a clinical diagnosis of non-AD dementia who harbored cerebral amyloid pathology showed lower Mini-Mental State Examination scores (measure of global cognition), suggesting that amyloid-β is not just an innocent bystander.
MedicalResearch.com Interview with:
Robert Wong, M.D., M.S.
Attending Physician, Gastroenterology & Hepatology
Director, GI Research
Highland Hospital I A member of Alameda Health System
Oakland, CA 94602
Medical Research: What is the background for this study? What are the main findings?
Dr. Wong: The main findings are that despite the stabilizing prevalence of metabolic syndrome, a large proportion of U.S. adults affected with metabolic still raises concern, especially given the significant health consequences associated with this syndrome. In additional to cardiovascular disease, metabolic syndrome also increases the risk of concurrent nonalcoholic fatty liver disease, often considered the hepatic manifestation of metabolic syndrome. Many studies, including work that our group has completed suggests that nonalcoholic fatty liver disease will soon become the leading etiology of chronic liver disease in the U.S. Furthermore, our finding that metabolic syndrome increases with increasing age, reflects the increased risk for metabolic syndrome associated diseases such as hypertension, diabetes, and dyslipidemia with older age. This is important to recognize given the aging population of the U.S.
MedicalResearch.com Interview with:
Jeff Bridge, Ph.D
Center for Innovation in Pediatric Practice
Principal Investigator
The Research Institute at Nationwide Children's Hospital
Medical Research: What is the background for this study?
Dr. Bridge: Suicide is a leading cause of death among children younger than 12 years. Suicide rates in this age group have remained steady overall for the past 20 years, but this is the first national study to observe higher suicide rates among black children compared to white children. Little is known about the epidemiology of suicide in this age group, as prior research has typically excluded children younger than 10 years old and investigated trends only within specific older age groups.
Medical Research: What are the main findings?
Dr. Bridge: We found that suicide ranked 14th as a cause of death among 5- to 11-year old black children in 1993-97 but rose to 9th in 2008-12. For white children, suicide ranked 12th in 1993-97 and 11th in 2008-12. Rates have remained stable in Hispanic and non-Hispanic children. The findings in this study highlight an emerging racial disparity in the epidemiology of childhood suicide.
MedicalResearch.com Interview with:
Josep Rodés-Cabau MD
Quebec Heart and Lung Institute,
Quebec City, QC, Canada
Medical Research: What is the background for this study? What are the main findings?
Dr. Rodés-Cabau: Hemolysis is the breakdown of red blood cells (RBC) in the body. There are many different causes of hemolysis, however a common cause is when RBCs traverse foreign substances, such as inserted heart valve prostheses. The biological interaction between the RBC and a foreign substance may cause RBC lysis/destruction. Furthermore, in the setting of turbulent blood flow, such as when a prosthetic heart valve is starting to leak, the degree of hemolysis could reflect the severity and duration of this leak. In the absence of valve leaks, hemolysis rates and severity may simply reflect how biocompatible a foreign/prosthetic valve is within the body. The lower the hemolysis rate and severity, the more biocompatible the valve/foreign body.
There are many different brands and generations of prosthetic heart valves that have been implanted in humans during the prior decades. The early-generation surgically implanted valves caused quite severe hemolysis requiring re-operation when possible. Modern-day surgical heart valves now have superior designs and rarely cause significant hemolysis. Nevertheless the rates of sub-clinical (or biochemical) hemolysis are around 30% for modern-day mechanical heart valves.
Nowadays, certain patients are eligible to undergo transcatheter aortic valve implantation (TAVI), a revolutionary means of valve replacement without the need for open heart surgery. However to-date, the biocompatibility of these new transcatheter heart valves has not been tested in humans in vivo. We systematically evaluated hemolysis rates and its associated factors in a large consecutive series of patients undergoing TAVI at the Quebec Heart & Lung Institute, Quebec, Canada.
We found that the rate of transcatheter heart valve hemolysis was 15%, lower than that reported for modern-day mechanical surgically implanted valves. No patient demonstrated severe hemolysis. The presence of a size mismatch between the patient and transcatheter valve (termed prosthesis patient mismatch) significantly associated with the likelihood of hemolysis. Indirect measurements of wall shear stress also associated with hemolysis rates.
MedicalResearch.com Interview with:
Christophe Tzourio, MD, PhD
Professor of Epidemiology
University of Bordeaux
Medical Research: What is the background for this study? What are the main findings?
Dr. Tzourio: The efficacy of lipid-lowering drugs (LLD) - which include statins and fibrates - to reduce the risk of coronary events and stroke has already been demonstrated in randomized trials. However, these trials were performed on highly selected patients, usually of middle-age (50-70 yrs) and with a history of cardiovascular disease or a high vascular profile. There is therefore currently no indication on the benefit of these drugs in elderly individuals of the general population without a past-history of cardiovascular disease and guidelines do not recommend the use of lipid-lowering drugs in elderly individuals without clinical atherosclerotic disease.
As there are not randomized trials in non-selected individuals in this age category, observational population-based cohorts are therefore the only alternative to study the impact of lipid-lowering drugs on the risk of cardiovascular diseases in the elderly.
We analyzed data from the Three-City study, a community-based cohort in 7484 elderly individuals (mean age 74 years), followed-up during 9 years, without known history of vascular disease at baseline. We observed a one third decrease in the risk of stroke in lipid lowering drug users (hazard ratio 0.66, 0.49 to 0.90) compared with non-users. Reduction in stroke risk was similar for the statin and fibrate groups. No protective effect was seen on the risk of coronary heart disease.
MedicalResearch.com Interview with:
Lao Saal, M.D. Ph.D.
Head, Translational Oncogenomics Unit
Assistant Professor
Department of Oncology and Pathology
Lund University Cancer Center
Lund, Sweden
Medical Research: What is the background for this study?
Dr. Saal: About a quarter of women diagnosed with primary (non-metastatic) breast cancer will unfortunately progress and later be found to have metastatic spread, which can occur many years to even a decade or more after the first diagnosis. At this point, the prognosis after identification of metastatic breast cancer is very poor. Metastatic disease is typically diagnosed only after it has grown large enough to cause symptoms, be noticed on exam, or be detectable by imaging. It is thought that early detection of metastasis has the potential to lead to better outcomes because therapies could be modified when the metastasis is still very small. Moreover, a very sensitive and specific test that could identify patients who appear "cancer-free" could also be useful. Essentially all cancers have unstable genomes, where chromosomes physically break and are reassembled incorrectly and thus the normal sequence is altered. Importantly, DNA material from cancer cells can be found in the blood circulation and therefore this circulating tumor DNA has the potential to be a cancer biomarker.
Medical Research: What are the main findings?
Dr. Saal: Eleonor Olsson, a PhD student in my lab who defends her thesis next week, and Christof Winter, a postdoc bioinformatician in my group, were the first authors of the paper. In our study we tested whether periodic monitoring of circulating tumor DNA (ctDNA) in blood plasma samples, taken before surgery for primary breast cancer and at multiple timepoints after surgery, could identify the metastastic spread, and whether the quantity of ctDNA was associated to patient outcome. We analyzed a retrospective cohort of 20 patients, who had enrolled many years ago in a separate epidemiological study run by Helena Jernström in our department, wherein the appropriate blood plasma samples had been biobanked and tumor tissue was available and we had long-term clinical follow-up information.
As far as we are aware, our study is the first to show the potential for serial ctDNA monitoring in the context of primary breast cancer. We found that our ctDNA blood tests could discriminate patients with eventual metastasis from those with long‐term disease‐free survival with 93% sensitivity and 100% specificity. Furthermore, ctDNA‐based detection of metastatic disease preceded clinical detection for 86% of patients by an average 11 months and in some cases by 3 years. In all of the patients who had long-term disease-free survival, we did not detect any ctDNA in any timepoints after surgery. Lastly, the measured quantity of ctDNA was a significant predictor of outcome: for each doubling of the ctDNA level, the odds ratio for metastasis was 2.1 and the odds ratio for death was 1.3. An interesting anecdote -- one patient we studied had bilateral breast cancer and we found that it was the right-side tumor (which actually had more favorable clinical characteristics) that gave rise to the metastasis and not the left-side tumor.
MedicalResearch.com Interview with:
Dr. Linnea A. Polgreen, Ph.D.
Assistant Professor, Health Services Research
Department of Pharmacy Practice and Science
Iowa City, IA
Medical Research: What is the background for this study? What are the main findings?
Dr. Polgreen: Many patients with hypertension are unaware that they have hypertension. Furthermore, a substantial number of patients diagnosed with hypertension are poorly controlled. Unfortunately there is no point-of-care test to diagnose hypertension. For most patients with multiple to moderate hypertension, multiple measurements are needed over time to confirm the diagnosis. This need to obtain multiple measurement often delays the diagnosis of hypertension, and delays potential for changes in therapy for those who are diagnosed but poorly controlled. Patients are routinely reminded to check their blood pressure measurements at home. However, these measurements often do not occur or are not collected in a timely fashion. Recently electronic medical records (EMRs) have built portals for patients to enter data such as blood pressure measurements, but it is unclear how effective these portals will be for diagnosing and treating high blood pressure.We studied 121 patients with at least one high blood pressure measurement in the past year and randomized them to three groups.
MedicalResearch.com Interview with:
Interview of Candice Contet, Ph.D.
Assistant Professor
The Scripps Research Institute, La Jolla, CA
MedicalResearch: What is the background for this study?
Dr. Contet: Alcohol changes the activity of numerous proteins in the brain. One of them is an ion channel found in neurons, the G-protein activated inwardly rectifying potassium (GIRK) channel. It is however unknown whether the ability of alcohol to open GIRK channels matters for its effects in vivo, i.e. how tipsy we feel or how motivated we are to drink alcohol. To address this question, we studied mice that are lacking one of the components of GIRK channels, the GIRK3 subunit. These mice behave normally in the absence of alcohol, and we sought to determine whether they respond differently to alcohol.
MedicalResearch: What are the main findings?
Dr. Contet: We found that the absence of GIRK3 did not impact how fast the mice clear alcohol from their body nor how sensitive they are to alcohol intoxication. Alcohol reduced their motor coordination, made them sleepy and lowered their body temperature to the same extent as in normal mice. GIRK3-deficient mice also drank as much alcohol as normal mice when they were given continuous access to alcohol, a situation in which mice sporadically drink throughout the day but rarely get intoxicated. By contrast, when mice are given access to alcohol only for a couple hours per day at a specific time of the day, they drink to the point of intoxication. Under these conditions, which emulate “binge drinking”, the GIRK3-deficient mice drank more than normal mice.
The next step was to locate the region of the brain responsible for the effect of GIRK3 on binge drinking. We turned our attention to the mesocorticolimbic dopaminergic pathway, a neural circuit that facilitates reward seeking. This pathway originates in an area of the midbrain called the ventral tegmental area (VTA) and releases the neurotransmitter dopamine in two forebrain areas: the ventral striatum and the prefrontal cortex. Alcohol, like other drugs of abuse, activates this pathway. When we reintroduced GIRK3 in the VTA of GIRK3-deficient mice, their alcohol intake dropped down to normal levels. Increasing the levels of GIRK3 in the VTA of normal mice reduced their alcohol consumption even further. We concluded that GIRK3 in the VTA keeps binge drinking in check: the more GIRK3, the less binge drinking.
We then wanted to understand how GIRK3 controls binge drinking: do the GIRK3-deficient mice drink more because alcohol is more rewarding to them, or because more alcohol is needed for them to experience the same level of reward? To answer this question, we measured the activity of VTA neurons in brain slices. Alcohol usually make VTA neurons fire more – but in the absence of GIRK3, these neurons were completely insensitive to alcohol, even at a very high concentration. We also measured the levels of dopamine in the ventral striatum. Injecting mice with a moderate dose of alcohol usually causes a rise in dopamine levels – but again, GIRK3-deficient mice were completely unresponsive.
These results may seem paradoxical. If the canonical “reward pathway” of the brain cannot be activated by alcohol, these mice should not have any motivation to drink alcohol. But the mesocorticolimbic dopaminergic pathway is not the only brain circuit responsible for the rewarding properties of alcohol, and we think that GIRK3-deficient mice end up drinking more alcohol to activate alternative circuits more strongly than normal mice would.
MedicalResearch.com Interview with:
C. Munro Cullum, PhD, ABPP
Professor of Psychiatry and Neurology & Neurotherapeutics
Pamela Blumenthal Distinguished Professor of Clinical Psychology
Chief of Psychology , Director of Neuropsychology
Univ. of Texas Southwestern Medical Center Dallas, TX
Medical Research: What is the background for this study? What are the main findings?
Dr. Cullum: My colleague and principal investigator of the study, Dr. John Hart and I have been interested in the acute and longer-term effects of traumatic brain injury for years, and because of my roles in the Alzheimer’s Disease Center and the Texas Institute for Brain Injury and Repair at the University of Texas Southwestern Medical Center, it seemed like a natural to begin studying older individuals with and without cognitive disorder who have a history of traumatic brain injury. Our main findings are two-fold:
First, we demonstrated that a history of concussion with loss of consciousness (which make up only about 10% of all concussions) was associated with smaller memory centers in the brain (the hippocampus) and lower memory results in our sample of retired professional football players. Concussions that did not result in loss of consciousness did not show that same strong association.
Second, our data suggest that patients with a clinical diagnosis of mild cognitive impairment (ie a memory disorder that does not grossly impair overall functioning but may lead to dementia) who also have a history of concussion with loss of consciousness show worse memory results and more brain atrophy than similar individuals diagnosed with mild cognitive impairment in the absence of a history of concussion.
MedicalResearch.com Interview with:
Kevin Yarasheski, PhD
Assistant Director, Biomedical Mass Spectrometry Research Facility
Professor of Medicine, Cell Biology & Physiology, Physical Therapy
Washington University School of Medicine
Medical Research: What is the background for this study?
Dr. Yarasheski: People living with HIV and taking combination antiretroviral therapy (cART) have successfully reduced the amount of HIV virus in their blood and have partially reconstituted their immune system (CD4+ T-cell count >250 cells/µL). Despite this, many still experience residual immune cell activation and inflammation that is believed to increase HIV morbidity (non-AIDS conditions e.g., CVD, T2DM, obesity, liver fat, bone loss, dementia) and mortality. Scientists are seeking safe and effective interventions for residual immune cell activation and inflammation, that have the potential to reduce non-AIDS complications that threaten quality and quantity of life among HIV infected adults.
We have been testing the safety and efficacy of sitagliptin in people living with HIV; a dipeptidyl peptidase 4 inhibitor that is FDA approved for treating T2DM, and appears to have favorable anti-inflammatory and immune modulatory properties that might specifically benefit people living with HIV and experiencing cardiometabolic complications associated with residual immune cell activation and inflammation.
Medical Research: What are the main findings?
Dr. Yarasheski: In a randomized, double-blinded, placebo controlled 8-wk trial, we found that sitagliptin had beneficial anti-inflammatory, immune regulatory, hematopoietic progenitor cell mobilizing, and glucose lowering effects in cART-treated virally suppressed HIV adults with impaired glucose tolerance. Sitagliptin improved glucose tolerance (a risk factor for CVD), reduced circulating and adipose-specific inflammatory markers (risk factors for obesity, T2DM, liver fat accumulation, and CVD), and increased the number of blood stem cells that can repair damage and inflammation in the vascular walls.
MedicalResearch.com Interview with:
Dr. Nina Kaminen-Ahola Ph.D.
Department of Medical Genetics
Faculty of Medicine
University of Helsinki
Helsinki, Finland
Medical Research: What is the background for this study?
Dr. Kaminen-Ahola: The beginning of embryonic development is vulnerable to the effects of external influences and disruption of these processes can have
long-term effects on development. Our previous study demonstrated, for
the first time, that alcohol exposure in early pregnancy can cause
permanent changes to the epigenetic regulation, gene function and the
appearance of mouse offspring. We discovered increased
DNA-methylation, transcriptional silencing of an epigenetically
sensitive allele Agouti viable yellow (Avy) and darker coat colour in
the offspring. In this study we wanted to see whether alcohol consumed
in early pregnancy causes long-term changes to the epigenome and gene
expression in hippocampus.
According to previous studies the phenotype of offspring in this mouse
model is highly variable, but reminiscent of human FAS with growth
restriction, similar structural changes to corresponding areas of the
face and skull, and hyperactivity. In this study we wanted to
determine the impact of alcohol on the structures of the central
nervous system.
Medical Research: What are the main findings?
Dr. Kaminen-Ahola: We observed that early exposure to alcohol caused subtle changes in the epigenome and altered the function of several genes in the
hippocampi of adolescent mice. We also detected alcohol-induced
alterations in the brain structure of adult offspring.
Interestingly, we also found out that in addition to hippocampus,
alcohol caused similar changes to gene function in two different
tissues of the infant mouse, bone marrow and the olfactory epithelium
of the snout.
These results support our hypothesis that early gestational ethanol
exposure alters the epigenetic reprogramming of the embryo, which
leads to alterations in gene regulation and embryonic development, and
causes life-long changes in brain structure, function, and behaviour.
MedicalResearch.com Interview with:
Jalal B. Andre, MD
Director of Neurological MRI
Harborview Medical Center
Assistant Professor of Radiology
University of Washington
Seattle, WA 98195-7115
Medical Research: What is the background for this study? What are the main findings?
Dr. Andre: Patient motion during clinical magnetic resonance (MR) examinations occurs frequently, can result in artifacts that degrade image quality, and has the potential to mask underlying pathology and affect patient care. Surprisingly, the frequency of motion artifacts in clinical MR examinations has been poorly documented in the literature, as has been the cost associated with obtaining such exams, specifically those that do not meet diagnostic criteria. To better quantify these observations, we performed a retrospective study evaluating the prevalence of motion artifacts during a randomly selected week of clinical MR examinations.
We devised a graded 5-tier scale to quantify patient motion, which incorporated the potential for clinical impact Using this scale, two neuroradiologists performed a consensus evaluation at a picture archiving and communication system station of 192 MR examinations performed during a single calendar week. This evaluation revealed that significant motion artifact (defined as artifact that could impact image interpretation and potentially change diagnosis) was present in 7.5% of outpatient and nearly 30% of inpatient and/or emergency department MR examinations, and that repeated sequences (subcomponents of an MR examination) were present in nearly 20% of completed MR examinations. In addition, we found that the specific imaged body part was less predictive of subsequent patient motion than was patient disposition (if they were imaged as a hospital inpatient and/or emergency department patient). Using a base-case cost estimate derived from fiscal year 2012 outpatient Medicare reimbursement rates and institutional cost estimates, our analysis suggested that a potential cost of $592 per hour could be lost in hospital revenue secondary to patient motion. Extrapolated over a calendar year, the cost of patient motion (as potential forgone institutional revenue) approached $115,000 per scanner per year.
MedicalResearch.com Interview with:
Michael B. Weinstock, MD
Professor of Emergency Medicine, Adjunct
Department of Emergency Medicine, The Ohio State University College of Medicine
Emergency Department Chairman and Director of Medical Education, Mt. Carmel St. Ann's Dept. of Emergency Medicine
Columbus, Ohio
Medical Research: What is the background for this study?
Response: Patients with potential cardiac ischemia are often admitted to the hospital even after a negative evaluation in the emergency department due to concern about missed MI, unstable angina, or potential for cardiac arrhythmia.
Medical Research: What are the main findings?
Response: Our study was different than previous studies and clinical decision rules; instead of looking at a 30 day marker, which is important to the cardiologist, ours looked at the risk of a Clinically Relevant Adverse Cardiac Event (CRACE) occurring during hospitalization. These events included inpatient STEMI, life-threatening arrhythmia, cardiac or respiratory arrest, or death. The study found only 4 of these events out of 7266 patients studied and of the 4, two were possibly iatrogenic, suggesting that after a negative ED evaluation (including 2 negative serial cardiac enzyme tests, non-ischemic and interpretable ECG, and nonconcerning vital signs) a patient can be safely sent home for an expedited cardiac outpatient evaluation.
MedicalResearch.com Interview with:
Ranjith Ramasamy MD
Assistant Professor of Urology
University of Miami
Medical Research: What is the background for this study?
Dr. Ramasamy: The association between testosterone supplementation therapy (TST) and thrombotic risk in elderly men remains controversial. We evaluated the prevalence of thrombotic events and all-cause mortality in men older than 65 years with hypogonadism treated with testosterone therapy. We compared men treated with testosterone to an age and comorbidity matched cohort of hypogonadal men not treated with testosterone supplementation therapy.
Medical Research: What are the main findings?
Dr. Ramasamy: No man who received testosterone supplementation therapy died, whereas 6 hypogonadal men who did not receive TST died (p=0.007). There were 4 thrombotic events (1 MI - myocardial infarction, 2 CVA/TIA - stroke, 1 PE - pulmonary embolism) in men who received testosterone supplementation therapy compared to 1 event (CVA/TIA) among men who did not receive TST (p = 0.8). All the events (except one death which took place at 6 months of follow–up) occurred 2 years or more after follow–up. Strengths of the study include long follow–up (>3 years), availability of serum testosterone levels before and after therapy and of a control group (hypogonadal men not treated with TST) for comparison. Limitations included retrospective study design, and a small sample size.