MedicalResearch.com: Medical Research Exclusive Interviews January 28 2015

MedicalResearch.com
Exclusive Interviews with Medical Research and
Health Care Researchers from Major and Specialty Medical
Research Journals and Meetings
Editor: Marie Benz, MD
info@medicalresearch.com
January 28 2015
For Informational Purposes Only: Not for Specific Medical Advice.

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Brain Functions May Be Affected By Chronic High Salt Intake
MedicalResearch.com Interview with:
Charles Bourque PhD
James McGill Professor Centre for Research in Neuroscience
Montreal General Hospital Montreal QC, Canada
• Medical Research: What is the background for this study? What are the main findings?
Dr. Bourque: Previous work has established that there is a link between a high level of dietary
salt intake and the development of hypertension. In particular, so-called “salt-sensitive”
individuals display increases in blood pressure that correlate with significantly increased
levels of serum sodium concentration. Increased sodium levels are known to cause an
excitation of vasopressin (VP)-releasing neurons of the hypothalamus. We therefore tested
the hypothesis that this increase can contribute to the increase in blood pressure associated
with high sodium intake in rats.
• Medical Research: What should clinicians and patients take away from your report?
• Dr. Bourque: Our study shows that a high degree of salt ingestion can cause significant
biochemical changes within the brain that can alter the balance between well-defined
excitatory and inhibitory circuits in a manner that leads to impaired centrally-mediated
homeostasis and cardiovascular pathology. When it comes to hypertension, much of the
focus has been placed previously on peripheral factors such as vasomotor tone, vascular
resistance and renal deficits. Our work shows that changes in the function of brain circuits
can also play an important role in this disease. Changes in central function associated with
salt intake may go beyond those we discovered in the VP neurons of the hypothalamus. It is
therefore possible that other brain functions may be affected by chronic high salt intake.
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

Brain Functions May Be Affected By Chronic High Salt Intake
Charles Bourque PhD
James McGill Professor Centre for Research in Neuroscience
Montreal General Hospital Montreal QC, Canada
• Medical Research: What recommendations do you have for future research as a result of
this study?
• Dr. Bourque: First and foremost, we must determine if similar changes can be observed in
patients identified as salt-sensitive individuals. There are well-established protocols for
testing sodium-sensitive and baroreceptor pathways in humans, so this is a goal that is
possible in the near term.
• Second, it will be important to investigate if these effects can be fully reversed by lowering
salt intake and, if so, determine if individuals become sensitized to subsequent exposures to
salt.
• Lastly, experiments on animals should increase our understanding of the biochemical
mechanisms that link serum sodium levels to KCC2 expression in VP neurons, and determine
of other central processes are affected by high salt intake.
• Citation:
• Katrina Y. Choe, Su Y. Han, Perrine Gaub, Brent Shell, Daniel L. Voisin, Blayne A. Knapp,
Philip A. Barker, Colin H. Brown, J. Thomas Cunningham, Charles W. Bourque. High Salt Intake
Increases Blood Pressure via BDNF-Mediated Downregulation of KCC2 and Impaired
Baroreflex Inhibition of Vasopressin Neurons. Neuron, 2015; DOI:
10.1016/j.neuron.2014.12.048

First Trial of PTSD Treatment in Psychosis
David P.G. van den Berg PhD student
Clinical Psychologist Cognitive behavioural therapist Parnassia Psychiatric Institute
Early Detection and Intervention Team (EDIT) Zoutkeetsingel, The Netherlands
• Response: The last decade it has become clear that many people with psychotic disorders suffered severe
childhood trauma. These experiences enhance chances of developing psychosis, but also result in
comorbid posttraumatic stress disorder (PTSD). PTSD is highly prevalent in patients with psychotic
disorders and negatively influences prognosis and wellbeing. Prolonged Exposure (PE) and Eye Movement
Desensitization and Reprocessing (EMDR) are highly effective treatments and recommended as first choice
treatments in PTSD guidelines worldwide. Although there is no evidence to support this, patients with
psychosis are excluded from PTSD treatment due to fear of destabilization or psychotic decompensation.
Moreover, psychosis is the most used exclusion criterion in PTSD trials. This is the first randomized clinical
trial (RCT) of the efficacy of PTSD treatment in psychosis.
• In this RCT 155 patients with a psychotic disorder and comorbid PTSD were randomly assigned to PE,
EMDR or Waiting List (WL). In the treatment conditions participants received 8 sessions of 90-minutes
therapy. Standard protocols were used. Treatment was not preceded by stabilizing psychotherapeutic
interventions or skills training. The first session comprised psycho-education about PTSD and target
selection. In sessions 2 to 8 traumas were treated, starting with the most distressing experience. Baseline,
post-treatment and 6-month follow-up assessments were made. Participants in both PE and EMDR
showed greater reduction of PTSD symptoms than those in WL. Between group effect sizes were large.
About sixty percent of the participants in the treatment groups achieved loss of diagnosis. Treatment
effects were maintained at six-month follow-up for both PE and EMDR. Treatments did not result in
serious adversities.
• Response: Trauma is an important factor in psychosis. Both trauma history and PTSD symptoms should be
assessed in patients with psychotic disorders. In case of a comorbid PTSD, standard evidence based
protocols can be used effectively and safely. Both treatment effects and dropout rates are similar to those
in PTSD samples without psychosis. At least one in eight patients with psychotic disorder has
posttraumatic stress disorder. There is no need to exclude these people from effective trauma treatments.

First Trial of PTSD Treatment in Psychosis
David P.G. van den Berg PhD student
Clinical Psychologist Cognitive behavioural therapist Parnassia Psychiatric Institute
Early Detection and Intervention Team (EDIT) Zoutkeetsingel, The Netherlands
this study?
• Response: Another research group should replicate these finding. We especially advocate the
use of ‘exposure based’ treatments in this patient group. Future trials may want to extend
the number of sessions, since for many participants eight sessions were too little (most
participants suffered severe and multiple childhood trauma). Lastly, future studies may want
to include a supportive condition to differentiate between the specific therapeutic effects of
the target treatments and factors such as hope and attention.
• Citation:
• van den Berg DG, de Bont PM, van der Vleugel BM, et al. Prolonged Exposure vs Eye
Movement Desensitization and Reprocessing vs Waiting List for Posttraumatic Stress Disorder
in Patients With a Psychotic Disorder: A Randomized Clinical Trial. JAMA Psychiatry. Published
online January 21, 2015. doi:10.1001/jamapsychiatry.2014.2637.

Sleeping On Stomach May Increase Risk of Death in Epilepsy
James Tao, MD, Ph.D
Assistant Professor Director, EEG Lab
Department of Neurology, The University of Chicago
Dr. Tao: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in
patients with chronic uncontrolled epilepsy. Patients often died in sleep, in bed, and
unwitnessed. They were often found in prone position. These circumstances of SUDEP are
remarkably similar to those of sudden infant death syndrome (SIDS). In our study, we found
that 73% of 253 SUDEP patients were died in prone position. These findings suggest that
sudden unexpected death in epilepsy may share the mechanisms similar to SIDS.
• Dr. Tao: Stomach sleep may increase the risk of sudden unexpected death in epilepsy.
this study?
• Dr. Tao: Patients with epilepsy should avoid stomach sleep, and “Back is the Best”.
• Citation:
• Association of prone position with sudden unexpected death in epilepsy
Jennifer A. Liebenthal, MD, Shasha Wu, MD, PhD, Sandra Rose, MD, John S. Ebersole, MD
and James X. Tao, MD, PhD
• Published online before print January 21, 2015, doi: 10.1212/WNL.0000000000001260
Neurology 10.1212/WNL.0000000000001260

Physical Activity Critical To Global World Health
Philipe de Souto Barreto (PhD)
Toulouse University Hospital (CHU Toulouse)
Gérontopole of Toulouse – Head of Department: Prof Bruno Vellas
Dr. Barreto: This study discusses about the importance of physical activity for health promotion
globally. The main argument is that, since physical activity is associated to health benefits in a dose-
response manner, even less than the currently recommended amounts of physical activity, i.e., 150
minutes of moderate-to-vigorous physical activity per week or equivalent, will be associated to
health promotion. Therefore, from a global health perspective, it would be interesting to promote
small increments in physical activity among those who are fully sedentary.
• Dr. Barreto: The “take home message” of this article is that, regarding the associations between
physical activity and health, “every little bit counts, and more is often better”.
• Medical Research: What recommendations do you have for future research as a result of this
study?
• Dr. Barreto: In my opinion, future research on the topic of physical activity and health promotion
should focus on two main aspects: revisiting current public health guidelines on physical activity in
order to confirm, refine or modify current public health messages, and increasing public awareness
on sedentary behaviours, which constitutes a different concept from physical activity.
• Citation:
• Global health agenda on non-communicable diseases: has WHO set a smart goal for physical
activity?
• Philipe de Souto Barreto, researcher
• MJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h23 (Published 21 January 2015) Cite this as: BMJ
2015;350:h23

New Potential Diabetes Drug Target Identified
Dr. Holger Rehmann
Department of Molecular Cancer Research
UMC Utrecht The Netherlands
Dr. Rehmann: We have developed a chemical modified version of the second messenger
cAMP, Sp-8-BnT-cAMPS that allows selective activation of Epac2, a protein that augments
glucose induced insulin secretion.
• The second messenger cAMP activates a couple of receptor proteins, which controls such
divergent physiological effects as gene transcription, pacemaker activity, olfaction, and cell
adhesion. Almost any cell responses in one or the other way to cAMP and thus selective
action on only one cAMP receptor would be a requirement for a drug to induce specific
effects.
• The study confirms that it is possible to pharmacologically discriminate between structurally
highly related cAMP receptors. And indeed, Sp-8-BnT-cAMPS augments glucose induced
insulin secretion in primary human islets. Epac2 is thus a putative target for the development
of an antidiabetic drug.

New Potential Diabetes Drug Target Identified
Dr. Holger Rehmann
Department of Molecular Cancer Research
UMC Utrecht The Netherlands
• Dr. Rehmann To be clear, what we have done is rather basic research without impact on daily
clinical routine. The future has to show whether or not activation of Epac2 is a therapeutic option.
study?
• Dr. Rehmann: We are now able to activate Epac2 selectively with Sp-8-BnT-cAMPS. This is a
putative starting point for the development of an antidiabetic drug. I believe the focus should be
twofold:
• – The pharmacokinetic properties of Sp-8-BnT-cAMPS are not optimal. This needs clear
improvement or alternatively the development of a small molecule unrelated to cAMP.
• – We do not fully understand the physiological function of Epac2. Sp-8-BnT-cAMPS will be a
useful tool to analyse Epac2 mediated effects. This is not just an academic problem of
understanding how Epac2 exactly impinges on insulin secretion. As more we know on the
physiology as easier we can predict unwanted side effects or would at least be aware for what to
watch out. The value of Epac2 as a therapeutic target needs to be evaluated.
• Citation:
• Structure-Guided Design of Selective Epac1 and Epac2 Agonists
Schwede F1, Bertinetti D2, Langerijs CN3, Hadders MA4, Wienk H5, Ellenbroek JH6, de Koning EJ7, Bos
JL8, Herberg FW2, Genieser HG1, Janssen RA3, Rehmann H8.
PLoS Biol. 2015 Jan 20;13(1):e1002038. doi: 10.1371/journal.pbio.1002038.
eCollection 2015.

Infections After Heart Surgery Differ By Type of Surgery
Keita Morikane, Director
Division of Clinical Laboratory and Infection Control
Yamagata University Hospital
• Response: The risk factors for surgical site infection following cardiac
surgery is extensively investigated, but those specifically of open
heart surgery or coronary artery bypass remains unknown. The main
findings were that the risk factors between the two types of cardiac
surgery were considerably different.
• Response: The result of this study will enhance risk stratification and
adjustment of the incidence of surgical site infections when comparing
between hospitals, surgeons, and other specific groups
study?
• Response: There are many more unknown differences in the risk factors for
surgical site infection following various types of operation. Using the
large cohort of surveillance data in each countries, the differences
will be further investigated
• Citation:
• Differences in risk factors associated with surgical site infections
following two types of cardiac surgery in Japanese patients
Journal of Hospital Infection, 01/13/2015
Morikane K, et al.

Walking Groups Demonstrate Wide Ranging Health Benefits
Sarah Hanson
Norwich Medical School
University of East Anglia
Response: Physical inactivity is a global problem. Walking is an easy way to increase physical activity. One
way to increase physical activity may be through the use of outdoor walking groups. Walking groups are
increasingly popular but until now we have not known if there are wider health benefits from walking
groups, apart from increasing physical activity.
• Medical Research: What was the study method?
• Response: A systematic review and meta-analysis of outdoor walking group interventions found 42 studies
which met the eligibility criteria. These studies involved 1,843 participants in 14 countries doing
approximately 74,000 hours of walking.
• Medical Research: What are the main findings?
• Response: This systematic review has given us the evidence that outdoor group walking have wide ranging
health benefits. Participants had a wide range of long term conditions, including arthritis, dementia,
diabetes, fibromyalgia, obesity/overweight, mental health issues, and Parkinson’s disease.
• Meta-analysis showed statistically significant reductions in mean difference for systolic blood pressure -
3.72mmHg (-5.28 to -2.17) and diastolic blood pressure -3.14mmHg (-4.15 to -2.13); resting heart rate -
2.88bpm (-4.13 to -1.64); body fat -1.31% (-2.10 to -0.52), body mass index -0.71kg/m² (-1.19 to -0.23),
total cholesterol -0.11mmol/L (-0.22 to -0.01) and statistically significant mean increases in VO₂ max of
2.66 ml/kg/min (1.67 to 3.65), the SF-36 (physical functioning) score 6.02 (0.51 to 11.53) and a 6 minute
walk time of 79.6 metres (53.37, 105.84). A standardised mean difference showed a reduction in
depression scores with an effect size of -0.67 (-0.97 to -0.38). The evidence was less clear for other
outcomes such as waist circumference fasting glucose, SF36 (mental health) and serum lipids such as HDL.
There were no notable adverse side effects reported in any of the studies.

Walking Groups Demonstrate Wide Ranging Health Benefits
Sarah Hanson
Norwich Medical School
University of East Anglia
• Medical Research: What does this mean for clinicians and for patients?
• Response: Walking groups are effective and safe with good adherence and wide ranging
physical and psychological health benefits. They could be a promising intervention as an
adjunct to other healthcare or as a proactive health-promoting activity.
• This provides clinicians with evidence of a further effective option to recommend to those
patients who would benefit from increasing moderate physical activity.
• Citation:
• Is there evidence that walking groups have health benefits? A systematic review and meta-
analysis
• Sarah Hanson, Andy Jones
• Br J Sports Med bjsports-2014-094157Published Online First: 19 January 2015
doi:10.1136/bjsports-2014-094157

No Benefit of Omega-3 acid Supplements for Exercise-Induced Bronchoconstriction in Asthma
John Brannan PhD
Firestone Institute for Respiratory Health at St Joseph’s Healthcare & McMaster University, Hamilton, Ontario, Canada
Medical Research: What is the background for this study?
Response: The use of omega-3 acid supplements as treatments for allergic diseases including
asthma is controversial. Studies by investigators from Indiana University in the USA have
repeatedly demonstrated a beneficial effect of high dose omega-3 fatty acid supplements over 3
weeks in attenuating exercise-induced bronchoconstriction (EIB) similar or possibly better in
potency to what may be expected with a regular inhaled corticosteroids. The study by Brannan et
al. attempted to validate these findings by using inhaled mannitol, a bronchial provocation test
that was derived from the understanding of exercise-induced bronchoconstriction and which has
demonstrated experimentally to be a useful model for exercise-induced bronchoconstriction. All
pharmacotherapies that modify exercise-induced bronchoconstriction can modify the airway
sensitivity to inhaled mannitol in persons with asthma, thus it was of interest to see if an
‘alternative’ treatment that demonstrated efficacy in exercise-induced bronchoconstriction could
too modify the airway response to mannitol.

John Brannan PhD
Medical Research: What are the main findings?
Response: The main findings were, to our surprise, there was no benefit of high dose omega-3
fatty acid supplements on bronchial hyperresponsiveness to mannitol over 3 weeks. This was
associated with no changes in airway inflammation (sputum eosinophils), lung function or asthma
symptom control. We also found no benefit on resting urinary mast cell metabolites, in contrast
to the findings in studies showing a benefit of omega-3 fatty acids on EIB. Our findings suggest
that omega-3 supplements in tissues may not be able to penetrate tissue and/or modify the
substrate flow of eicosanoids in tissue such as the airways of the asthmatic. We did observed the
expected reductions in blood triglycerides which suggests that these doses of omega-3s can
modify metabolism in the blood or to some extent tissues that are highly perfused.

John Brannan PhD
• Response: This prospective randomised placebo-controlled study demonstrated no efficacy of omega-3 fatty acid
supplements on bronchial hyperresponsiveness and airway inflammation in persons with active symptomatic asthma and
who were either taking regular inhaled corticosteroids, or beta2 agonists alone, for management of their asthma symptoms.
Further, the lack of efficacy on airway sensitivity to mannitol adds doubt to the usefulness of this therapy on attenuating EIB
when either used alone or in combination with regular inhaled corticosteroids. In addition, as inhaled mannitol is a
standardised bronchial provocation test used to identify the presence of active asthma, in those that have a positive
mannitol test it would be clear that omega-3 supplements would have no benefit in treating their asthma.
• Medical Research: What recommendations do you have for future research as a result of this study?
• Response: The current studies by the Indiana University group using both exercise and eucapnic voluntary hyperpnea (like
mannitol, another surrogate test to identify EIB) should be validated by other groups. These studies used either very
mild exercise-induced bronchoconstriction or possibly a sub-optimal stimulus to provoke EIB. Studies evaluating drugs in EIB
require a standardised optimal exercise stimulus as well as participants with significant and reproducible exercise-induced
bronchoconstriction. This would aid in confirming this negative finding. It should be noted that recently negative findings on
the effects of omega-3s in relation to cardioprotective effects have surfaced to raise doubt on the effects of omega-3 fatty
acids as a treatment in cardiovascular disease, sustaining the controversy but suggesting the beneficial effects of omega-3s
may not be as significant as initially proposed.
• Citation:
• The Effect of Omega-3 Fatty Acids on Bronchial Hyperresponsiveness, Sputum Eosinophilia, and Mast Cell Mediators in
Asthma
•
John D. Brannan, PhD; Johan Bood, PhD; Ahmad Alkhabaz, MD; David Balgoma, PhD; Joceline Otis, BSc; Ingrid Delin, BSc;
Barbro Dahlén, MD, PhD; Craig E. Wheelock, PhD; Parameswaran Nair, MD, PhD; Sven-Erik Dahlén, MD, PhD; Paul M.
O’Byrne, MB
Chest. 2014. doi:10.1378/chest.14-1214

Potential Drug Targets To Prevent Hypoglycemia in Diabetics Identified
Martin G. Myers, Jr., M.D., M.P.H.
Director, Michigan Diabetes Research & Training Center
Marilyn H. Vincent Professor of Diabetes Research and
Department of Pharmacology, University of Cambridge, Cambridg
Dr. Myers: Diabetic people who take insulin to treat their diabetes are at risk of low blood
sugar, which can cause serious consequences (including death). This risk increases as blood
sugar control improves, and so this risk limits the ability to control blood sugar. The body has
a system (the counter-regulatory response) that acts to prevent blood sugar from going too
low, but this is often impaired in diabetic patients.
• We identified a brain circuit that senses and responds to falling blood sugar, and which acts
to increase blood sugar. Furthermore, we showed that the hormone leptin modulates the
sensitivity of this circuit, and identified the neurotransmitter (CCK) that acts in this circuit to
increase blood sugar. Thus, we have identified several potential drug targets that could be
used to prevent or treat low blood sugar in insulin-treated diabetics. If we are able to
pharmacologically modulate the activity of this brain circuit, it could improve the treatment
of these patients.

Potential Drug Targets To Prevent Hypoglycemia in Diabetics Identified
Martin G. Myers, Jr., M.D., M.P.H.
Director, Michigan Diabetes Research & Training Center
Marilyn H. Vincent Professor of Diabetes Research and
Department of Pharmacology, University of Cambridge, Cambridg
this study?
• Dr. Myers: There are two main things that we need to do with this information.
• First, we need to better understand how we might target this counter-regulatory system for
pharmacotherapy.
• Second, we need to understand the nature of the neurons that this prototype circuits
interacts with, as the other neurons within this circuit will certainly be very important to
study as we seek to understand why diabetic patients often mount an inadequate counter-
regulatory response to low blood sugar, and because these other neurons could also be
targets for therapy
• Citation:
• Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy
balance
• Jonathan N Flak,Christa M Patterson,Alastair S Garfield,Giuseppe D’Agostino,Paulette B
Goforth,Amy K Sutton, Paige A Malec,Jenny-Marie T Wong,Mark Germani,Justin C
Jones,Michael Rajala, Leslie Satin, Christopher J Rhodes, David P Olson Robert T Kennedy,
Lora K Heisler & Martin G Myers Jr Nature Neuroscience 17,1744–1750 (2014)
doi:10.1038/nn.3861

Opioids Commonly Taken By Women of Childbearing Age
Dr. Jennifer Lind PharmD, MPH
Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, CDC
• Medical Research: What is the background for this study?
Dr. Lind: CDC researchers published a new study estimating the proportion of women aged
15-44 years who filled a prescription for opioid pain medications. Opioids are prescribed by
healthcare providers to treat moderate to severe pain. They are also found in some
prescription cough medications. Opioids include medications like codeine, oxycodone,
hydrocodone, or morphine. For this study, researchers used data from two large insurance
claims datasets—one on Medicaid and one on private insurance—and looked at data from
2008-2012.
Dr. Lind: Opioid medications are widely used among women of reproductive age in the
United States, regardless of insurance type. On average, more than a third (39 percent) of
women aged 15-44 years enrolled in Medicaid, and more than one fourth (28 percent) of
those with private insurance filled a prescription for an opioid pain medication each year
during 2008-2012. Taking these medications early in pregnancy, often before women know
they are pregnant, can increase the risk for some birth defects (such as spina bifida) and
other poor pregnancy outcomes (such as preterm birth or low birth weight).

Opioids Commonly Taken By Women of Childbearing Age
Dr. Jennifer Lind PharmD, MPH
Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, CDC
• Dr. Lind: CDC encourages women to speak to their healthcare provider to determine the safest
treatment for their pain. If an opioid is determined to be deemed necessary, we encourage women
to ask about the lowest effective dose, shortest amount of time possible to be on treatment and to
discuss effective birth control methods to decrease the likelihood of becoming pregnant while on
the opioid medication. Healthcare providers should discuss the potential risks and benefits of
opioid medication use with women of reproductive age, prior to prescribing.
study?
• Dr. Lind: More research is needed to understand the effects of pain management medications in
pregnancy. A better understanding of opioid use just before and during early pregnancy can help
inform strategies to reduce unnecessary prescribing of opioids. CDC’s Treating for Two initiative
aims to fill these gaps in knowledge. Treating for Two aims to expand research and develop
guidance for treating conditions during pregnancy. This information will allow women and their
healthcare providers to make informed decisions about treating health conditions, like pain, during
pregnancy.
• Citation:
• Opioid Prescription Claims Among Women of Reproductive Age — United States, 2008–2012
• Elizabeth C. Ailes, PhD1, April L. Dawson, MPH1, Jennifer N. Lind, PharmD1, Suzanne M. Gilboa,
PhD1, Meghan T. Frey, MPH1, Cheryl S. Broussard, PhD1, Margaret A. Honein, PhD1
• MMWR Weekly January 23, 2015 / 64(02);37-41

Syngap1 Gene Mutation Linked To Intellectual Disability, Schizophrenia andAutism
Gavin Rumbaug
Professor (Associate)
The Scripps Research Institute
Medical Research: What is the background for this study? What are the main findings?
Response: We have developed a genetic approach that protects animal models against a type of
genetic disruption that causes intellectual disability, including serious memory impairments and
altered anxiety levels. The findings focus on treating the effects of mutations to a gene known
as Syngap1. In our new study, we examined the effect of damaging Syngap1 mutations during
development and found that the mutations disrupt a critical period of neuronal growth—a period
between the first and third postnatal weeks in mouse models. We found that a certain type of
cortical neuron grows too quickly in early development, which then leads to the premature
formation of certain types of neural circuits. These findings help explain why genetic treatments
in adult mice are not very effective.

Gavin Rumbaug
• Response: Damaging mutations in Syngap1 that reduce the number of functional proteins
are one of the more common causes of sporadic intellectual disability and are associated
with schizophrenia and autism spectrum disorder. Early estimates suggest that these non-
inherited genetic mutations account for 1-2% percent of these intellectual disability cases.
Sporadic intellectual disability affects approximately one percent of the worldwide
population, suggesting that tens of thousands of individuals with intellectual disability may
carry damaging Syngap1 mutations without knowing it.
• It is important to find these patients with these mutations. The only way currently known to
identify Syngap1 patients is through gene sequencing. So, if a patient has idiopathic
intellectual disability, it’s a good idea to have their genes sequenced. Even if they do not have
Syngap1 mutations (there would be about a ~1-2% chance; higher if the patient also has
some form of epilepsy), there is a good chance that they will receive information about other
mutations that will help with a diagnosis. The next generation of treatments for
developmental brain disorders will be heavily influenced by the specific genetic make-up of
each patient. Thus, it’s very important to have this genetic information in hand.

Gavin Rumbaug
this study?
• Response: Our model shows that the early developmental period is the critical time to treat
this type of genetic disorder, so our hope is that these studies will eventually lead to a
therapy specifically designed for patients with psychiatric disorders caused by
damaging Syngap1 mutations. As a result of these studies, we are now developing a drug-
screening program to look for drug-like compounds that could restore levels
of Syngap1 protein in defective neurons. As personalized medicine advances, such a therapy
could ultimately be tailored to patients based on their specific genotype.
• Citation:
• Syngap1 Haploinsufficiency Damages a Postnatal Critical period of Pyramidal Cell Structural
Maturation Linked to Cortical Circuit Assembly
• Massimiliano Aceti, Thomas K. Creson, Thomas Vaissiere, Camilo Rojas, Wen-Chin Huang, Ya-
Xian Wang, Ronald S. Petralia, Damon T. Page, Courtney A. Miller, Gavin Rumbaugh
• Biological Psychiatry (Impact Factor: 9.47). 08/2014; DOI: 10.1016/j.biopsych.2014.08.001

Novel Compound May Shut Down Pancreatic and Triple Negative Breast CancerCells
Dr. Patrick Griffin PhD
Professor and Chairman Department of Molecular Therapeutics Director of the Translational Research Institute
Scripps Research Institute, Jupiter, Florida
• MedicalResearch.com: What is the background for this study? What are the main findings?
• Dr. Griffin: We identified a novel synthetic compound known as SR1848 that sharply inhibits
the activity and expression of “liver receptor homolog-1” or LRH-1, a protein that plays an
important role in the progression of breast and pancreatic cancers.
• Our new study shows that SR1848 removes LRH1 from DNA, shutting down expression of
LRH-1 target genes, and halts cell proliferation. It’s a novel compound that appears to be a
promising chemical scaffold for fighting tumors that are non-responsive to standard
therapies.
• MedicalResearch.com: What should clinicians and patients take away from your report?
• Dr. Griffin: LRH-1 has been implicated in the proliferation and metastasis of estrogen
receptor-positive breast cancers and the more difficult to treat estrogen receptor-negative
breast cancers. Our new findings suggest that repressing LRH-1 could be useful in treating the
more aggressive triple-negative breast cancer subtype where therapies are currently so
limited.

Novel Compound May Shut Down Pancreatic and Triple Negative Breast CancerCells
Dr. Patrick Griffin PhD
Professor and Chairman Department of Molecular Therapeutics Director of the Translational Research Institute
Scripps Research Institute, Jupiter, Florida
• MedicalResearch.com: What recommendations do you have for future research as a result
of this study?
• Dr. Griffin: Our new compound also appears attractive as a potential therapeutic because of
its lack of impact on cells that do not express LRH1, which could mean few potential side
effects.
• Citation:
• Antiproliferation activity of a small molecule repressor of liver receptor homolog 1.
• Mol Pharmacol. 2015 Feb;87(2):296-304. doi: 10.1124/mol.114.095554. Epub 2014 Dec 3.

Signal For Development of Atopic Dermatitis – Eczema – Seen In Early Infancy
Dr. Alan Irvine, MD
Professor in Dermatology
Department of Clinical Medicine Trinity College Dublin
Response: Atopic diseases include atopic dermatitis (AD, also know as eczema), food allergy, allergic
rhinitis and asthma. The prevalence of these diseases has increased in recent decades causing
considerable morbidity in childhood. The putative “Atopic March” refers to the typical sequence of clinical
manifestation of atopic disease, usually initiated by atopic dermatitis from early infancy.
• Parental atopy is an independent risk factor for development of atopic disease. The genetic mechanisms
and inheritance pattern of atopic diseases are not fully elucidated but recent candidate gene studies and
Genome Wide Association Studies (GWAS) have yielded some insights. The most widely replicated and
most significant gene to influence atopic dermatitis is Filaggrin (FLG). Filaggrin is a filament binding protein
in the stratum Corneum. FLG loss-of-function mutations (FLG mut) occur in 10% of Europeans, imparting
an increased risk of atopic dermatitis, food allergy and asthma. The overall increase in risk of atopic
dermatitis conferred by a single FLG loss-of-function mutation is approximately 3.3, with a significant
additional and independent effect conferred by intragenic copy number variations in FLG. Importantly FLG
mutations increase the risk of developing asthma only in the presence of atopic dermatitis.
• While loss-of-function mutations in the skin barrier protein filaggrin (FLG) are a major risk for atopic
dermatitis, the pathogenic sequence of disturbances in skin barrier function prior to or during the early
development of atopic dermatitis is not fully understood. A more detailed understanding of these events
is needed to develop a clearer picture of disease pathogenesis. A robust, non-invasive test to identify
babies at high risk of atopic dermatitis would be important in planning early intervention and/or
prevention studies.
• We found that raised transepidermal water loss at birth and at two months in asymptomatic infants
predates the development of atopic dermatitis. This signal is independent of FLG status and parental
atopy.

Dr. Alan Irvine, MD
• Response: A signal for the development of atopic dermatitis/eczema is seen at 2 days and
again at 2 months in asymptomatic infants. In other words the pathway to atopic dermatitis
/eczema starts in some infants very shortly after birth. This is a needed mechanistic insight.
• The clinical relevance of these insights is that interventions to potentially prevent atopic
dermatitis could be targeted towards such infants, especially in families at high risk, such as
those with a strong family history of these diseases. Early intervention, including intensive
moisturizing therapies have come into focus recently and many studies are ongoing. Our
findings, using the simple, painless test will help target those interventions to those most
likely to benefit form them

Dr. Alan Irvine, MD
• MedicalResearch.com: What recommendations do you have for future research as a result
of this study?
• Response: Insights into the pathogenesis of atopic dermatitis have highlighted the role of skin
barrier dysfunction. This paper reinforces the fact that these changes occur very early, these
changes need to be better understood with further mechanistic work.
• Targeted intervention studies should be performed using our findings to identify those
children most in need of intervention. This will make interventions more efficient and cost
effective.
• Citation:
• Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months
predates and predicts atopic dermatitis at 1 year
• Journal of Allergy and Clinical Immunology
Available online 22 January 2015
Maeve Kelleher | Audrey Dunn-Galvin | Jonathan O’B. Hourihane | Deirdre Murray | Linda E.
Campbell | W.H. Irwin McLean | Alan D. Irvine

Diagnosis of Celiac Disease in Older Children Tripled Over 20 Years
Dr Laila J Tata PhD
Associate Professor in Epidemiology Faculty of Medicine & Health Sciences
University of Nottingham
• Response: Over the last decades there has been increased clinical awareness of coeliac
disease (CD) partially because of improvements in the accuracy and availability of diagnostic
tests, however, we do not have current estimates of actual celiac disease diagnoses in
children and it is important to know whether diagnostic patterns vary socioeconomic
group. Funded by CORE/Coeliac UK and conducted at the University of Nottingham, this
study analysed 2,063,421 children aged less than 18 years who were registered with general
practices (primary care doctors) across the United Kingdom contributing to their routine
electronic health records to The Health Improvement Network (THIN) database between
1993 and 2012. The study found 1,247 children were diagnosed with coeliac disease,
corresponding to about 1 new case in every 10,000 children each year. Girls consistently had
more diagnoses than boys and whilst the incidence of new celiac disease cases among
children up to age 2 years remained stable over time, diagnoses in older children almost
tripled over the past 20 years. Moreover, the study found a socioeconomic gradient in celiac
disease diagnoses, such that children living in less socioeconomically deprived areas were
about twice as likely to be diagnosed as those from more deprived areas. This pattern held
for boys and girls and for all ages.

Dr Laila J Tata PhD
• Response: Clinicians should ensure they implement the most recent diagnostic guidelines
and procedures to obtain a diagnosis of celiac disease The gap in childhood diagnosis
between the most and least socioeconomically deprived children could be due to different
risk factors predisposing to celiac disease , however, there is limited evidence for this thus far.
Another likely possibility is that ascertainment of disease varies, so awareness campaigns for
clinicians and the general population may help to implement strategies for case-finding in all
children and reduce this inequality.

Dr Laila J Tata PhD
this study?
• Response: Whilst we assessed patterns of diagnosis only, we are now assessing patient
interactions with primary care doctors before their diagnosis to determine if the inequality in
childhood celiac disease found is related to lack of seeking medical care or to differences in
diagnostic investigations and testing by doctors. Future studies should also investigate other
possible explanations for this gradient by exploring the association between exposures to
different specific risk factors that may alter predisposition to the occurrence of CD between
socioeconomic groups.
• Citation:
• Socioeconomic variation in the incidence of childhood coeliac disease in the UK
Fabiana Zingone, Joe West, Colin J Crooks, Kate M Fleming, Timothy R Card, Carolina Ciacci,
Laila J Tata
• Arch Dis Child archdischild-2014-307105Published Online First: 22 January 2015
doi:10.1136/archdischild-2014-307105

Nightcall PCI Procedures Don’t Affect Cardiologists’ Daytime Outcomes
Herbert Aronow, MD
St Joseph Mercy, Ann Arbor, MI
Dr. Aronow: Psychomotor and cognitive performance may be impaired by sleep
deprivation. Interventional cardiologists perform emergent, middle-of-the-night procedures,
and may be sleep-deprived as a consequence. Whether performance of middle-of-the-night
percutaneous coronary intervention (PCI) procedures impacts outcomes associated with PCI
procedures performed the following day is not known.
• Dr. Aronow: In a large registry study of ~ 1.5 million patients who underwent PCI in the US,
we found that the incidence of bleeding or death following daytime PCI procedures, was no
different in the hands of operators who had performed similar procedures the night before
than in the hands of operators who had not. A number of other adverse procedural
outcomes were also no different between groups. These findings suggest that our current
system of providing life saving middle-of-the-night cardiovascular care does not jeopardize
the safety of PCI procedures performed under the light of day.

Nightcall PCI Procedures Don’t Affect Cardiologists’ Daytime Outcomes
Herbert Aronow, MD
St Joseph Mercy, Ann Arbor, MI
this study?
• Dr. Aronow: Future research should focus on factors that impact outcomes associated with
middle-of-the-night PCI procedures.
• Citation:
• Aronow HD, Gurm HS, Blankenship JC, et al. Middle-of-the-night percutaneous coronary
intervention and its association with percutaneous coronary intervention outcomes the next
day. JACC Cardiovasc Interv. 2015; 8:49-56.

Epigenetic Control Protein Allows Melanoma Cells To Metatasize
Prof Lukas Sommer. Ph.D.
Cell and Developmental Biology University of Zurich Institute of Anatomy
Zurich Switzerland
• MedicalResearch: What is the background for this study? What are the main findings?
• Prof. Lukas Sommer: Melanoma, the most aggressive of all skin cancers, is often fatal for
patients due to the pronounced formation of metastases. Up to date, a melanoma’s rampant
growth was mainly attributed to genetic causes, such as mutations in certain genes. However,
we now reveal that so-called epigenetic factors also play a crucial role in the formation of
metastases in malignant skin cancer. Epigenetic factors do not influence the gene sequence
directly, but rather cause certain genes and chromosomal segments to be packed in different
densities – and thus make them accessible for reading. In our study we identified “EZH2” as
an epigenetic control protein found very frequently in malignant melanoma cells compared
to normal cells. In these cells, “EZH2” controls genes that govern both tumor growth and
genes that are important for the formation of metastases. We exploited this central position
of EZH2 to combat the cancer by using a pharmacological inhibitor to suppress the activity of
EZH2. As a result, we were able to prevent the growth and malignant spread of the cancer in
an animal model and in human melanoma cells.

Zurich Switzerland
• MedicalResearch: What should clinicians and patients take away from your report?
• Prof. Lukas Sommer: Various cancer drugs have been developed that target signaling
pathways activated by genetic alterations in tumor cells. Some of these drugs have recorded
astonishingly positive results in the clinic and are able to prolong the lives of seriously sick
patients. Unfortunately, however, in most cases a kind of resistance develops: Eventually, the
cancer cells no longer respond to the drug and the tumor spreads again. Evidently, the cancer
cells have found new ways to grow. We believe that, depending on the prevalent conditions,
cancer cells are able to “read” different genes and use them to their own end. Epigenetic
control mechanisms such as the one identified in our study are likely key players in this
process. Thus, combinatorial treatments that include targeting of epigenetic control proteins
such as “EZH2” might open up new possibilities for future cancer treatments.

Zurich Switzerland
• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Prof. Lukas Sommer: An imminent research question arising from our study is whether
development of resistance to currently used anti-cancer drugs in melanoma indeed involves
epigenetic regulation. Could we prevent cancer cells from using alternative ways to grow by
blocking epigenetic factors such as “EZH2”? This remains to be shown in future studies.
• Citation:
• The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of
distinct tumour suppressors
• Nat Commun. 2015 Jan 22;6:6051. doi: 10.1038/ncomms7051.
• Zingg D1, Debbache J1, Schaefer SM1, Tuncer E1, Frommel SC2, Cheng P3, Arenas-Ramirez N4,
Haeusel J1, Zhang Y1, Bonalli M1, McCabe MT5, Creasy CL5, Levesque MP3, Boyman O4,
Santoro R2, Shakhova O6, Dummer R3, Sommer L1.

Depot Birth Control May Be Linked With Greater HIV Acquisition in Women
Charles Morrison PhD
FHI 360 Clinical Sciences
Durham, North Carolina
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Morrison: The possible connection between hormonal contraception and HIV acquisition has
been an open question for 25 years. Some studies have suggested that there is an increased risk
associated with hormonal contraception, particularly with the 3-month injectable contraceptive
called depot-medroxyprogesterone acetate (DMPA). Other studies have found that no such risk
exists.
• The World Health Organization (WHO) has held several technical consultations on this subject.
WHO’s current guidelines state that “because of the inconclusive nature of the body of evidence on
the possible increased risk of HIV acquisition, women using progestogen-only injectable
contraception should be strongly advised to also always use condoms, male or female, and other
HIV preventive measures.”
• Two meta-analyses focusing on hormonal contraception and HIV acquisition have recently been
published. One of them, FHI 360’s collaborative study, is an individual participant data meta-
analysis. It found that users of injectable DMPA were 50 percent more likely to become infected
with HIV than women not using hormonal contraceptives. For women using a different injectable
progestin, norethisterone enanthate (NET-EN), or combined oral contraceptives (COC), the study
investigators did not find a significantly increased risk of acquiring HIV compared to those who
were not using hormonal contraceptives. Furthermore, DMPA users were 43 percent and 32
percent more likely to become infected with HIV compared to oral contraceptives users and NET-EN
users, respectively.
• It is important to point out a key secondary finding. The associations between hormonal
contraception and risk of becoming infected with HIV were attenuated in studies that had a lower
risk of methodological bias compared to those with higher risk of bias. This suggests that some of
the risk found to be associated with hormonal contraception in fact may be attributed to inherent
flaws in the nonrandomized studies themselves.

• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Morrison: This meta-analysis contributes to the growing body of evidence that
demonstrates that depot-medroxyprogesterone acetate may be associated with an increased
risk of HIV acquisition compared to women not using hormonal contraceptives and women
using other types of hormonal contraceptives including oral contraceptives and NET-EN.
However, because of the observational nature of the data in all the studies included in the
meta-analysis, we need to be cautious about changing guidelines and counseling based on
the study. Thus, women in regions with high HIV prevalence should be made aware that the
use of DMPA may or may not increase their susceptibility to HIV acquisition, and should be
advised to use condoms and take other HIV prevention measures.

• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Dr. Morrison: The WHO has called for higher-quality evidence to inform policy makers,
clinicians and women on this issue. The most robust evidence would be provided by a
randomized trial of hormonal contraception and HIV acquisition. Such a randomized trial is
now in the preparatory stages by a consortium that includes FHI 360, WHO, the Wits
Reproductive Health and HIV Institute (WRHI) and the University of Washington.
• Citation:
• Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data
Meta-analysis
• Morrison CS1, Chen PL2, Kwok C2, Baeten JM3, Brown J4, Crook AM5, Van Damme L6, Delany-
Moretlwe S7, Francis SC8, Friedland BA9, Hayes RJ8, Heffron R3, Kapiga S8, Karim QA10, Karpoff
S11, Kaul R12, McClelland RS3, McCormack S4, McGrath N13, Myer L14, Rees H7, van der Straten
A15, Watson-Jones D16, van de Wijgert JH17, Stalter R1, Low N18.
• PLoS Med. 2015 Jan 22;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. eCollection
2015.

Coronary Heart Disease Deaths Fall Due to Population Decreases in Blood Pressure and Cholesterol
Dr. Maria Guzman-Castillo
Department of Public Health and Policy
University of Liverpool, Liverpool, UK
Dr. Guzman-Castillo: The UK has experienced a remarkable 60% reduction in coronary heart
disease (CHD) mortality since the 1970s. However CHD remains the leading cause of premature
death.
• The aim of our study was to analyse the recent falls in coronary heart disease mortality and
quantify the relative contributions from preventive medications and from population-wide changes
in blood pressure and cholesterol levels, particularly exploring the potential effects on
socioeconomic inequalities, an aspect not well explored in the past.
• Our study found that, approximately 22,500 fewer deaths were attributable to reductions in blood
pressure and cholesterol in the English population between 2000-2007.
• The substantial decline in blood pressure was responsible for approximately 13,000 fewer deaths.
Approximately 1,800 fewer deaths came from medications and some 11,200 fewer deaths from
population-wide changes. Reduction in population blood pressure fewer deaths in the most
deprived quintile compared with the most affluent.
• Reduction in cholesterol resulted in substantially smaller gains, approximately 7,400 fewer deaths;
approximately 5,300 fewer deaths were attributable to statin use and approximately 2,100 DPPs to
population-wide changes. Interestingly, statins prevented more deaths in the most affluent quintile
compared with the most deprived. Conversely, population-wide changes in cholesterol prevented
threefold more deaths in the most deprived quintile compared with the most affluent.

Coronary Heart Disease Deaths Fall Due to Population Decreases in Blood Pressure and Cholesterol
Dr. Maria Guzman-Castillo
Department of Public Health and Policy
University of Liverpool, Liverpool, UK
• Dr. Guzman-Castillo: Severely limited health care budgets are now forcing planning systems
to consider how best to allocate future resources. Our results strengthen the case for greater
emphasis on preventive approaches, but focusing on population based policies to reduce
blood pressure and cholesterol, targeting primarily our diets. Such strategies might be more
powerful, rapid, cost-effective, and more equitable than relying mostly on lipid lowering
medications.
this study?
• Dr. Guzman-Castillo: It is important to replicate these findings in other populations and over
different time periods, to understand better the role of statins on primary prevention of
cardiovascular disease. Also, to explore what is the optimal combination of strategies,
including both population level and high-risk approaches, to maximize population gains while
reducing the pressure on already overstressed health systems.
• Citation:
• Guzman-Castillo, R. Ahmed, N. Hawkins, S. Scholes, E. Wilkinson, J. Lucy, S. Capewell, M.
O’Flaherty, R. Raine, M. Bajekal. The contribution of primary prevention medication and
dietary change in coronary mortality reduction in England between 2000 and 2007: a
modelling study. BMJ Open, 2015; 5 (1): e006070
DOI: 10.1136/bmjopen-2014-006070

Expired Medicaid Payment Bump Had Increased New Patient Appointment Availability
MedicalResearch.com Interview with: Daniel Polsky PhD
Executive Director, Leonard Davis Institute of Health Economics
Professor of Medicine and Health Care Management
Perelman School of Medicine and the Wharton School University of Pennsylvania
Dr. Polsky: The Medicaid Fee bump, a provision of the Affordable Care Act (ACA), raised
Medicaid payments to Medicare levels in 2013 and 2014 for selected services and providers
expired on January 1, 2015 before policymakers had much empirical evidence about its
effects. The federally funded increase in reimbursements was aimed at expanding access to
primary care for the growing number of Medicaid enrollees. The reimbursement increase
expired at the end of 2014 in most states. We found that this policy worked to increase the
number of providers offering primary care appointments to Medicaid patients. The Medicaid
pay bump was associated with a 7.7 percentage points increase in new patient appointment
availability without longer wait times. This increase in availability was largest in the states
where primary care physicians received the largest increase in their Medicaid
reimbursements.
• Dr. Polsky: Physician participation in Medicaid is largely a function of reimbursement
levels. When levels are increased from the low levels that have existed in many states,
physicians are more likely to participate.

Expired Medicaid Payment Bump Had Increased New Patient Appointment Availability
MedicalResearch.com Interview with: Daniel Polsky PhD
Executive Director, Leonard Davis Institute of Health Economics
Professor of Medicine and Health Care Management
Perelman School of Medicine and the Wharton School University of Pennsylvania
this study?
• Dr. Polsky: We focused on behavior of practices that already participate in the Medicaid
program. We did not study whether the policy increased the number of newly participating
Medicaid providers. This would be an important area of future research.
• Citation:
• Appointment Availability after Increases in Medicaid Payments for Primary Care
• Daniel Polsky, Ph.D., Michael Richards, M.D., Ph.D., Simon Basseyn, B.A., Douglas Wissoker,
Ph.D., Genevieve M. Kenney, Ph.D., Stephen Zuckerman, Ph.D., and Karin V. Rhodes, M.D.
This article was published on January 21, 2015, at NEJM.org
DOI: 10.1056/NEJMsa1413299

Interval Breast Cancer More Aggressive Than Mammogram Detected Tumors
Dr Jingmei Li
Department of Medical Epidemiology and Biostatistics
Karolinska Institutet Stockholm, Sweden
Response: Some cancers, such as interval breast cancers, which are detected within two
years of a negative mammogram, are associated with more aggressive tumour characteristics
and worse prognosis. As women with interval cancers were twice as likely to have a personal
of family history of breast cancer, it is likely that there exist inherited variants that predispose
a woman to the more aggressive form of the disease. Our study is one of the first to show
empirical evidence that screen-detected and interval cancers are different genetically and are
two distinct subtypes.
• Response: When aggressive breast cancers get diagnosed, it may be too advanced for
effective treatment. Germline genetic markers can be used to overcome this situation
because they do not measure a tumour-derived product and can be informative years before
cancer develops. In addition, such a discovery is important for women who might develop
interval cancer in the future, as mammography screening does not benefit them.

Interval Breast Cancer More Aggressive Than Mammogram Detected Tumors
Dr Jingmei Li
Department of Medical Epidemiology and Biostatistics
Karolinska Institutet Stockholm, Sweden
this study?
• Response: Although we have shown that screen-detected and interval cancers are different,
we haven’t identified any specific genetic variant that can discriminate between them. The
next step will be to identify genetic variants which can discriminate between screen-detected
and interval cancers.
• Citation:
• Li, J. Holm, J. Bergh, M. Eriksson, H. Darabi, L. S. Lindström, S. Törnberg, P. Hall, and K. Czene
• Breast cancer genetic risk profile is differentially associated with interval and screen-detected
breast cancers Ann Oncol first published online December 8, 2014
doi:10.1093/annonc/mdu565

Improved DNA Repair May Help Bowhead Whales Live 200 Years
Joao Pedro de Magalhaes, PhD
Institute of Integrative Biology Biosciences Building, Room 245
University of Liverpool UK
• Response: Our understanding of species differences in longevity (e.g., why can mice not live more
than 5 years or dogs more than 30, yet bats can live over 40 years, humans over a century and
bowheads over two centuries) is very poor and thus our findings provide novel candidate genes and
mechanisms for future studies. The candidate genes we found with evidence of bowhead-specific
functions may play a role in the exceptional longevity and disease resistance of these animals. In
particular, we discovered changes in bowhead genes related to cell cycle, DNA repair, cancer, and
aging that suggest alterations that may be biologically-relevant. So my own view is that this points
toward improved DNA repair and cell cycle regulation mechanisms to prevent DNA damage
accumulation during the lifescourse which in turn promotes longevity and resistance to age-related
diseases like cancer.
• Response: There’s no immediate applications. But by identifying novel maintenance and repair
mechanisms we hope to learn what is the secret for living longer, healthier lives and may be able
apply this knowledge to improve human health and preserve human life. Long-term we may be
able to discover ways of fine tuning longevity assurance mechanisms based on findings from long-
lived species like bowheads, for example by identifying longevity genes that we could then
manipulate therapeutically. As such, this is a different approach in biomedical research. Most
research on human diseases is usually based on animal models that develop the disease under
study at a higher incidence and rate than normal. The use of disease-resistant organisms to identify
genes, mechanisms and processes that protect against (rather than cause) disease is an unexplored
paradigm.

Improved DNA Repair May Help Bowhead Whales Live 200 Years
Joao Pedro de Magalhaes, PhD
Institute of Integrative Biology Biosciences Building, Room 245
University of Liverpool UK
this study?
• Response: Mouse studies I think would be ideal to determine if these genes emerging from
the bowhead genome can protect against age-related diseases or even promote
longevity. for example, creating mice with bowhead genes and assaying for longevity and/or
cancer would help elucidate the importance to longevity and disease resistance of our
findings. But as you imagine these are expensive studies and at the moment we do not have
the funds yet to perform this line of work.
• Citation:
• Insights into the Evolution of Longevity from the Bowhead Whale Genome
• Cell Rep 2015 Jan;10(1):112-22
• Michael Keane, Jeremy Semeiks, Andrew E Webb, Yang I Li, Víctor Quesada, Thomas Craig,
Lone Bruhn Madsen, Sipko van Dam, David Brawand, Patrícia I Marques, Pawel Michalak, Lin
Kang, Jong Bhak, Hyung-Soon Yim, Nick V Grishin, Nynne Hjort Nielsen, Mads Peter Heide-
Jørgensen, Elias M Oziolor, Cole W Matson, George M Church, Gary W Stuart, John C Patton, J
Craig George, Robert Suydam, Knud Larsen, Carlos López-Otín, , John W Bickham, Bo
Thomsen, João Pedro de Magalhães
Jan 2015

Health Care Waste in Landfills May Promote Antibiotic ResistanceMedicalResearch.com Interview with:
Prof.Thiago César Nascimento
Departamento de Enfermagem Básica
Faculdade de EnfermagemLaboratório de Fisiologia e Genética Molecular Bacteriana
Universidade Federal de Juiz de Fora
Medical Research: What is the background for this study? What are the main findings?
Response: Preliminarily, we observed a high incidence of coagulase-
negative Staphylococcus strains (CoNS) recovered from the leachate of the health care waste in
an untreated sanitary landfill. As Staphylococcus sp. especially oxacillin or methicillin-resistant
CoNS remains as important putative pathogenic bacteria regarding human and other animals, in
this study we investigated the antimicrobial susceptibility patterns and the occurrence of
the mecA gene. In conclusion, our results raise issues related to the viability of putative
pathogenic bacteria resistant to important antimicrobial drugs carrying important resistance
markers in untreated healthcare waste in sanitary landfills.These risks regarding the potential
spread of leachate from sanitary landfills due to human and animal activities, or even due to
weather phenomena, such as torrential rains and floods, should be considered. Our results
address a phenomenon related to the incorrect healthcare waste management in Brazil and in
other geographical regions. Taking into account environmental health, more
conscientious policies should be considered by authorities to avoid the disposal of healthcare
waste without any further treatment.

• Response: A fact to be considered for both health professionals and patients is incorrect
segregation at the time of generation what most often leads to a greater production of
infectious biological waste. Particularly in relation to clinicians, the irrational use of
antibiotics mainly associated with their improper disposal would also be an issue to consider.
One of the greatest healthcare waste problems to be addressed is the presence of putative
pathogens. The selective pressure of antibiotics and other medicines, as well as chemical
compounds commonly discharged as healthcare residues, can lead to the proliferation of
these pathogens. These organisms, mainly bacteria, may show antimicrobial resistance and
are potential contaminants for hospital surfaces and materials.

this study?
• Response: Whereas the incorrect waste management can be a similar reality in other
geographical regions, I believe that further studies should be conducted in order to point out
the impact in these regions. As noted in our study,the viability of putative pathogenic
bacteria resistant to important antimicrobial drugs carrying important resistance markers in
untreated heatlhcare waste in sanitary landfills, should also be investigated in future studies.
• Citation:
• Potential spread of multidrug-resistant coagulase-negative staphylococci through
healthcare waste.
• Thiago César Nascimento, Vânia Lúcia da Silva, Alessandra Barbosa Ferreira-Machado,
Cláudio Galuppo Diniz
The Journal of Infection in Developing Countries 2014
• Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil

Travelers May Spread Antibiotic Resistance
MedicalResearch.com Interview with: Anu Kantele, MD PhD
Associate Professor, Department of Medicine, University of Helsinki
Specialist of Infectious Diseases, Helsinki University Hospital
Head of Travel Clinic, Aava Medical Centre
• Dr. Kantele: Increasing antimicrobial resistance is considered a serious global threat for
modern medicine. Resistance is rapidly surging in regions with poor hygiene and uncontrolled
use of antibiotics. Resistant bacteria are gradually spreading from there to countries in which
the prevalence has thus far been low.
• Our study was conducted among 430 healthy Finnish travelers visiting warm countries
(tropical /subtropical regions). The volunteers provided stool samples before and after travel
and filled in questionnaires. The stools were analyzed for multidrugresistant bacteria (not
only so called ESBL bacteria but also CPE bacteria which are even more resistant).
• None of the travelers had CPE strains in their stools before or after their journey. 1% carried
ESBL before travel, and 21% acquired a strain while overseas. The risk was greatest in the
Indian subcontinent and almost similar in Southeast Asia. In Africa, it proved to be increased
but did not reach such a high level. Two factors amplified the risk significantly: travellers’
diarrhea and use of antibiotics. Among the entire study population, ESBL was found in 11% of
those staying healthy, 22% of those with diarrhea, and 37% of those who took antibiotics for
their diarrhea. In the Indian subcontinent, the respective figures were 23%, 47%, and 80%,
and in Southeast Asia 14%, 32%, and 69%.

• Medical Research: What is the significance of these findings?
• Dr. Kantele: Travelers colonized with resistant bacteria mostly remain unaware of the
situation, and the bacteria will disappear within months (or years, sometimes). However, if
these bacteria manage to cause an infection, many of the antibiotics commonly used will be
inefficacious. Infections with multidrugresistant bacteria tend to entail greater costs, longer
hospital stay and increased mortality. Furthermore, the bacteria may spread from
asymptomatic carriers to their close contacts, such as family members, and, eventually, reach
local hospitals. Over the course of time, resistant bacteria are bound to spread to low-
prevalence countries, and ultimately, across the globe.
• 100 million travelers are estimated to contract diarrhea each year. As obvious, with such large
numbers of people concerned, whether they take antibiotics for it or not is not at all
inconsequential. Treating diarrhea with antibiotics not only forwards the global spread of
antimicrobial resistance but also contributes to the local resistance in developing countries,
since the antibiotics used by travelers end up in the environment they visit.

• Dr. Kantele: They should learn to respect antibiotics and reserve them for situations where
they are really needed. Travelers’ diarrhea does not count among them: in more than 90% of
cases travelers’ diarrhea is mild /moderate and resolves spontaneously. Antibiotics may
shorten its duration (1.5 days on the average), yet may cause harm both to the individual and
his/her surroundings. The patient should drink enough fluids; if needed, non-antibiotic drugs
such as loperamide can be used to relieve symptoms. Antibiotics are warranted only in
severe diarrhea (high fever, poor condition etc).

• What recommendations do you have for future research as a result of this study?
• Dr. Kantele: Antibiotics are like a natural resource: we run the risk of losing them, because
we use them too carelessly across the globe. The situation calls for serious action all over:
improving hygiene and establishing reasonable antimicrobial policies in high risk regions;
surveillance of antimicrobial resistance, infection control at hospitals, development of new
antibiotics or other approaches to treating infections; devising vaccines etc. This study of
ours encourages further research into means of preventing the initial colonization, i.e.
identifying risk factors and developing approaches that provide protection against contracting
the bacteria.
• Citation:
• Anu Kantele, Tinja Lääveri, Sointu Mero, Katri Vilkman, Sari H. Pakkanen, Jukka Ollgren, Jenni
Antikainen, and Juha Kirveskari
• Antimicrobials Increase Travelers’ Risk of Colonization by Extended-Spectrum Betalactamase-
Producing Enterobacteriaceae Clin Infect Dis. first published online January 21, 2015
doi:10.1093/cid/ciu957

Sleep in Young Adults Important For Later Life Cognitive Function
Michael K. Scullin, Ph.D.
Principal Investigator of the Sleep Neuroscience & Cognition (SNaC) Laboratory and an Assistant Professor of Psychology & Neuroscience
Director Sleep Neuroscience and Cognition Laboratory Baylor University
Dr. Scullin: One of the purposes of sleep in healthy adults is to optimize cognitive functioning. When we
lose out on a few hours of sleep we tend not to be able to focus or think as well as when we get enough
sleep (typically 8 hours). Even more interesting is that particular aspects of sleep physiology—our deepest
levels of sleep known as slow wave sleep and rapid eye movement sleep—are essential to our brain’s
ability to take the information that we learn during the day and stabilize those memories so that we can
use them in the future.
• Sleep quantity and quality change markedly across the lifespan, though there are individual differences in
how much one’s sleep changes. Our work was concerned with the possible long-term repercussions of
cutting back on sleep and getting lower quality sleep (less slow wave sleep and rapid eye movement
sleep). We reviewed approximately 200 scientific articles on this topic and we found that the amount of
total sleep and the quality of that sleep is important to cognitive and memory functioning in young adults
and middle-aged adults and can even predict how well someone’s cognitive functioning will be decades
later. Thus, if you’re sleeping well when you are 40 then you are investing in preserving your mental
functioning at age 50.
• Dr. Scullin: Some of the most common symptoms of sleep disturbances include feeling sleepy during the
day, snoring at night, and waking up repeatedly in the middle of the night to use the bathroom. Sleep
problems should not be overlooked by either the clinician or the patient. Researchers have shown that not
getting enough sleep can exacerbate medical conditions. In our work, we found that not sleeping enough
and not getting enough rapid eye movement sleep could even predict how well one preserves their
mental functioning as they move into older age. Clinicians and patients should be aware that there are
many treatments for poor sleep, some that are pharmacological and others that involve simple habit
changes. You can learn about many of these treatment options on the National Sleep Foundation’s
website (http://sleepfoundation.org/).

Sleep in Young Adults Important For Later Life Cognitive Function
Michael K. Scullin, Ph.D.
Principal Investigator of the Sleep Neuroscience & Cognition (SNaC) Laboratory and an Assistant Professor of Psychology & Neuroscience
Director Sleep Neuroscience and Cognition Laboratory Baylor University
this study?
• Dr. Scullin: One of the trickiest issues in the field is in determining why sleep quantity and
quality change as we age. The answer is likely to that there are many factors contributing to
the changes in sleep, with some factors having physiological origins such as changes to our
internal biological clock, and other factors having psychological origins such as an increase in
life stressors in middle age. My opinion is that if we can do a better job of isolating why sleep
changes as we age then that will be the first step toward creating new interventions for
maintaining sleep quality, and thus also cognitive functioning, across the lifespan.
• Citation:
• Scullin, M. K. & Bliwise, D. L. (2015). Sleep, cognition, and normal aging: Integrating a half-
century of multidisciplinary research. Perspectives on Psychological Science, 10, 97-137.

Lupron May Preserve Some Cognitive Function in Women With Alzheimer’s Disease
Craig S. Atwood
Associate Professor, University of Wisconsin Madison, WI
Richard L. Bowen, M.D. Private Practice, Charleston, SC
• Response: Currently, there is no treatment for Alzheimer’s disease that halts or slows its
progression. Alzheimer’s disease is a neurodegenerative disorder resulting in memory loss
and impairments of behavioral, language and visuo-spatial skills. A growing body of
biological, preclinical and epidemiological data suggests that the age-related changes in
hormones of the hypothalamic-pituitary-gonadal (HPG) axis are a major etiological factor in
Alzheimer disease. The changes in these hormones include not only the decline in the sex
steroids, (i.e. 17-estradiol and testosterone), but the elevations in gonadotropin-releasing
hormone and luteinizing hormone. In particular there are encouraging epidemiological
studies involving the use of Lupron Depot which suppresses these hormones. In one such
study which included hundreds of thousands of patients it was found that men who had
prostate disease and were treated with Lupron Depot had a 34 to 55 percent decreased risk
of developing Alzheimer’s disease compared with prostate-cancer patients who didn’t
receive the drug.

Craig S. Atwood
• Response: The efficacy and safety of leuprolide acetate (Lupron Depot®) in the treatment of
Alzheimer’s disease (AD) was conducted in a 48 week, double-blind, placebo-controlled,
dose-ranging study in women aged 65 years or older with mild to moderate AD. Post-
menopausal women were chosen for this study because they no longer produce sex steroids
and the treatment would only affect GnRH and LH; whereas in men there would also be a
loss of the testosterone they are still producing. A total of 109 women with mild to
moderate Alzheimer disease and a Mini-Mental State Exam score between 12 and 24
inclusive were randomized to low dose (LD) Lupron Depot® (11.25 mg leuprolide acetate),
high dose (HD) Lupron Depot® (22.5 mg leuprolide acetate) or placebo (P) injections every 12
weeks. There were no statistically significant differences in primary efficacy parameters
(ADAS-Cog and ADCS-CGIC). However, in a subgroup analysis of patients taking an
acetylcholine esterase inhibitor (AChEI) there was a statistically significant benefit in the high
dose group compared to both the low dose and placebo groups as determined by the ADAS-
Cog, a memory test (mean decline: HD: 0.18, LD: 4.21 and P: 3.30), ADCS-CGIC, a caregiver
index of decline (% subjects experiencing decline: HD: 38, LD: 82 and P: 63), and ADCS-ADL, a
measure of activities of daily living (mean decline: HD: -0.54, LD: -8.00 and P: -6.85),
respectively, after one year.

Craig S. Atwood
• Response: These data indicate that cognitive function is preserved in women treated with
high dose Lupron who were already using AChEI’s. Lupron is a drug with a good safety record
that has been used for decades in this age group. Another clinical study of this combination
therapy (i.e. Lupron and Aricept) is required to replicate the efficacy of this treatment for
Alzheimer’s disease in women.
• What recommendations do you have for future research as a result of this study?
• Response: This promising combination therapy (AChEI and Lupron Depot) warrants testing as
a treatment and for prevention of those at risk of Alzheimer’s disease. Clinical trials of this
combination therapy together with add-back testosterone in men are also warranted.
Unfortunately, there is no intellectual property protection for this treatment making it
unlikely that a pharmaceutical company will take the lead. One possibility is crowd funding
through an organization such as Give to the Cure. The authors have submitted an application
to Give to the Cure in the hope that it will promote this effort.
• Citation:
• A Clinical Study of Lupron Depot in the Treatment of Women with Alzheimer’s Disease:
Preservation of Cognitive Function in Patients Taking an Acetylcholinesterase Inhibitor and
Treated with High Dose Lupron Over 48 Weeks
• Bowen RL1, Perry G2, Xiong C3, Smith MA4, Atwood CS5.
J Alzheimers Dis. 2015 Jan 1;44(2):549-60. doi: 10.3233/JAD-141626.

Lab Finds Way To Lengthen Short Telomeres
Dr. John Ramunas PhD
Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative
Medicine, Clinical Sciences Research Center, Stanford University School of Medicine, Stanford, California
Dr. Ramunas: Telomeres comprise repetitive DNA sequences at the ends of chromosomes. Telomeres protect the ends of
chromosomes, but become shorter with each cell division and due to oxidative damage. Critically short telomeres are
implicated in diseases of aging and devastating genetic disorders of insufficient telomere maintenance .
Dr. Ramunas: Our main finding is that telomeres in human cells can be lengthened by a new method with therapeutic
potential. We delivered modified mRNA encoding TERT, the protein component of telomerase, the enzyme that increases
the length of telomeres by adding DNA repeats. The protein TERT is usually the rate limiting component of the enzyme. In
this study, we used four groups of cells. The first group received modified mRNA encoding TERT, and the other three groups
were controls that received either mRNA encoding an inactive form of TERT, the solution in which TERT is delivered, or no
treatment. The telomeres of the first group (telomere extending treatment group) were extended rapidly over a period of a
few days, whereas the telomeres of the three control groups were not extended. The first group was also able to undergo
more cell divisions, whereas the controls were not. Importantly for the potential safety of our approach, the telomeres of
the first group resumed shortening after they were extended. This is important because it shows that due to the short,
transient treatment, the cells were not immortalized, ie. not tumorigenic. Further, all of the cell populations treated to date
eventually stopped dividing, further indicating that they were not immortalized. We have tested the approach on cell types
including fibroblasts and myoblasts and are now testing it on stem cells. A surprising and exciting finding was that we could
treat the cells several times with enhanced effects on the capacity of cells to divide. For instance, after a first treatment, we
saw an increase of 50,000-fold in cell numbers before cells stopped dividing, compared to untreated cells. If we waited a
few weeks and repeated this treatment, we saw a similar gain in cell division and number. Since the increase in numbers is
compounded with each treatment, a small sample of cells, for example from a small biopsy, can be amplified to very large
numbers.

• Dr. Ramunas: Our finding has potential clinical significance because short telomeres are one
of the mechanisms implicated in conditions and diseases of aging, including heart disease,
cancer, and diabetes, as well as genetic diseases including dyskeratosis congenita and aplastic
anemia. Additionally, the Blau lab showed recently that Duchenne muscular dystrophy is due
to shortened telomeres in addition to genetic absence of dystrophin. Thus, our approach
may prove useful in delaying, prevent, or treating conditions and diseases of aging as well as
certain devastating and lethal genetic diseases. Our approach is also applicable to tissue
engineering, cellular reprogramming, disease modeling, drug screening, and regenerative
medicine by increasing the ability of cells to divide by a finite but useful amount without
immortalizing them

this study?
• Dr. Ramunas: Safety is our primary concern for use in patients, and much work remains to be
done to test and improve safety. The doses and time course of delivery of the telomere
extending treatment need to be studied in a range of different cell types. We envision a
major application of this treatment will be to increase the capacity of stem cells to divide for
regenerative medicine purposes. Extensive characterization will be necessary.
• Citation:
• Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells
• Ramunas J, Yakubov E, Brady JJ, Corbel SY, Holbrook C, Brandt M, Stein J, Santiago JG, Cooke
JP, Blau HM.
• FASEB J. 2015 Jan 22. pii: fj.14-259531. [Epub ahead of print]
•

MedicalResearch.com: Medical Research Exclusive Interviews January 28 2015

MedicalResearch.com: Medical Research Exclusive Interviews January 28 2015

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