Tuesday, November 14, 2017

BREAKING DEFENSE: Congress Should Drop Pentagon Experimental Drug FDA Waiver Clause


SOURCE:  Breaking Defense, November 13, 2017

https://breakingdefense.com/2017/11/congress-drop-sec-716-fda-exemption-from-ndaa/


ARCHIVED ARTICLE:


Congress: Drop Sec. 716 — FDA Exemption — From NDAA

The 2018 National Defense Authorization Act contains billions of dollars and much policy concerning medical research and, of course, matters relating to nuclear, biological and chemical warfare. We don’t cover most of those medical issues except when they relate to NBC issues or raise basic military policy considerations. This is one of those cases. In this commentary, the distinguished medical ethicist and professor at the University of Pennsylvania, Jonathan Moreno, calls on Congress to scrap a provision in the 2018 NDAA concerning emergency medical exemptions from FDA oversight. Read on! The Editor.
The final draft of the National Defense Authorization Act would give the Pentagon authority to decide when unapproved drugs and devices (called somewhat vaguely “agents of war” in the proposed legislation), could be used on military personnel in an emergency. Historical experience suggests that this is a very bad idea that would create both medical and morale problems for the military and obscure the difference between medical intervention and experimentation.
This proposal should be dropped from the legislation.
Those who support the new rules complain that they have to enter into continuing discussions with the Food and Drug Administration (FDA) while potentially useful drugs and other materials are given temporary approval. No doubt careful information gathering can be frustrating. But it is also the only way to know that something isn’t harmful and might actually help. The history of civilian and military medicine is full of examples of presumed therapies that turned out to be useless or caused harm.
The FDA is the only government agency authorized to approve drugs and devices for prevention and treatment. Under the proposed rule change the Defense Department would be the first federal agency that would have a separate regulatory system, a dangerous and needless precedent for all concerned. The FDA and the DoD have long worked together to make it possible for commanders to get unapproved drugs and devices to troops. This system both allows the FDA to weigh in with its expertise on potential risks and benefits – information that commanders would surely want to have in case after using the stuff things go south – and provides a degree of “cover” to the Pentagon in case there are complaints later on. As there surely would be.
Consider the experience with unapproved drugs in Desert Storm/Desert Shield (DS/DS).  As the Pentagon was preparing for the invasion of Kuwait in 1990, it received reports that Saddam Hussein had stores of several biological and chemical agents and the ability to deliver them. The available treatments and preventions for these agents were speculative to varying degrees. For instance, the botulism toxin (BT) vaccine was considered “investigational” by the FDA. DoD petitioned the FDA commissioner for a waiver of the usual informed consent requirement, noting the therapeutic potential of the treatments against threats to the force. The FDA then adopted a rule that allowed the commissioner to drop the consent requirement in combat situations when such consent was “not feasible.”
Even this arrangement mainly stated what has already long been understood. Military medical ethicists and regulators agree that although people in uniform cannot be ordered to be in an experiment – a view that only emerged after World War II – commanders may justifiably order the use of drugs or devices that do not have demonstrated safety and efficacy if they believe that their force is under imminent threat and that their use is the best option. In turn, people in uniform will accept pretty much anything that is in the line of duty, especially if it will help them protect their brothers and sisters in arms, but they understandably resent being used as “human guinea pigs” as much as anyone else.
Problems of data collection, so crucial to gaining knowledge of drug effects, are severe enough in a carefully planned peacetime context of clinical trials. During a shooting war these problems are far greater as the confusion of combat conditions affects the way drugs are given and taken. Record keeping for the drugs that were used in Desert Storm and Desert Shield was poor even though logisticians could have helped gather information useful in future deployments. Perhaps 8,000 troops received the BT vaccine in the weeks before the invasion of Kuwait. Another 150,000 or so were vaccinated for inhalational anthrax. Tens of thousands received blister packs of a theorized antidote to nerve gas called pyridostigmine bromide (PB), used to treat myasthania gravis, a disease that progressively weakens muscles. The use of PB was voluntary but many thought it was required. The Pentagon had in fact tested PB on a few dozen personnel, not including those who might be sensitive to the drug or women, but those people were not excluded when the drug was given out.
In the months and years after the first Gulf War, veterans complained that their medical problems, often grouped under the term Gulf War Illness, were due partly to the drugs they were given. The etiology of this set of symptoms has never been fully understood but the anger can’t be questioned. Among the earliest Internet list serves were those of Gulf War veterans expressing their resentment. Over the years, I have been approached by many vets complaining about their medical conditions and the fact that records aren’t available, a concern that was echoed by a VA lawyer in a conversation I had just a few weeks ago.
Ironically, the FDA gave the Pentagon an opportunity to avoid much of the later anger by issuing their waiver on the condition that military personnel receive information about what they were being ordered or asked to take. That didn’t happen. In 1994 some members of Congress expressed their annoyance at the civilian agency for granting the waiver in the first place (though the FDA noted that it’s not expert at fighting wars), and then for not complaining to the DoD that they failed to uphold their side of the deal. So, in the end, the civilian agency got it from both ends, which actually took some heat off the Pentagon. This is a story I told in my book, Undue Risk.
Going back to the 1950s the Department of Defense has a mixed record on human experiments, but the FDA’s evolved role in drug and device approval gives our military organization a substantive argument that it takes respect for the troops seriously. It’s too bad that the Pentagon can’t take yes for an answer.
Jonathan Moreno, an expert in medical and military ethics, is the David and Lyn Silfen University Professor at the University of Pennsylvania.  

Studies Yield Clues to Roots of Gulf War Illness

Studies Yield Clues to Roots of Gulf War Illness: Presentations at the Society for Neuroscience meeting point to changes in neurons and connectivity between brain regions as potential components of the enigmatic condition.





ARCHIVED ARTICLE:



http://www.the-scientist.com/?articles.view/articleNo/50930/title/Studies-Yield-Clues-to-Roots-of-Gulf-War-Illness/



Studies Yield Clues to Roots of Gulf War Illness

Presentations at the Society for Neuroscience meeting point to changes in neurons and connectivity between brain regions as potential components of the enigmatic condition.
By  | November 13, 2017
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burning oil fieldsISTOCK, KARENFOLEYPHOTOGRAPHYCombat in the Gulf War of 1990-91 lasted less than two months, but it’s estimated that hundreds of thousands of the troops who served in the Middle East during that time may still experience symptoms of Gulf War Illness (GWI). Thought to be caused by exposure to chemical and biological weapons or other hazardous chemicals, GWI’s symptoms include difficulties with memory and speech, mood swings, and chronic pain.
Two studies presented at the annual Society for Neuroscience Meeting on November 11 and 14 provide some clues to GWI’s biological basis. The first, described by Anika Patil of Drexel University College of Medicine, treated cultured rat neurons with a sarin gas analogue, and found it led to the deacetylation—and destabilization—of the cells’ microtubules, which are needed to transport mitochondria and other cellular components. Pretreating the cells with corticosterone to mimic the effects of stress exacerbated the effect. For deployed service members, “there is an ongoing stress from the moment you leave until the moment you return,” commented Col. Deborah Whitmer of Walter Reed Army Institute of Research, who moderated a press conference about the findings.
In another study discussed at the press conference, Kaundinya Gopinath of Emory University and colleagues compared the resting state fMRI scans of 22 Gulf War veterans with those of 30 controls, and found that the veterans had less neural communication in areas associated with visual and other sensory processing, mood regulation, language, and motor coordination, but more activity in pain perception networks. “The results from this study provide strong evidence of neuropathology in GWI patients from exposures to neurotoxic agents,” Gopinath says in a statement, adding that finding brain mechanisms to explain that pathology could lead to treatments.

Boston Study Shows Gulf War Chemicals Linked with Memory, Mood, and Cognitive Symptoms

(91outcomes.com) - Newly published research results show a clear link between higher chemical exposures during the 1991 Gulf War and increased cognitive and mood symptoms among veterans of that war.

The study included extensive interviews and examinations of "159 Gulf War-deployed preventative medicine personnel who had varying levels of pesticide exposures during their work as pesticide applicators or other preventative medicine roles".  

According to the study's publication, "Study results showed that the participants with both high pesticide and high [Nerve Agent Protective Pill (PB)] exposure performed worse on specific measures than the groups with high single exposures or low exposures to both toxicants."  

Study results showed that "high combined exposure was associated with significantly slower information processing reaction times, attentional errors, worse visual memory functioning, and increased mood complaints. In addition, ... analyses of individual pesticide exposures found that pest strip exposure was associated with slower reaction times and attentional errors, and that fly bait and delouser exposures predicted greater mood complaints."

The chemicals involved affect brain chemistry and, "are known to produce chronic health and cognitive symptoms at sufficient exposure levels," according to earlier research cited in the study.  The chemical warfare nerve agents Sarin and Cyclosarin -- acknowledged to have been released at the Khamisiyah munitions depot demolitions immediately following the war's ceasefire -- are in the same class of chemicals (Organophosphates, or OP's) as some of the pesticides analyzed in this study.  

This extensive, multi-year research project was funded by a Fiscal Year 2006 grant from the Gulf War Illness Research Program (GWIRP), part of the Congressionally Directed Medical Research Program (CDMRP) funded by Congress within the Defense health program.  

The study's principal investigator was Dr. Kimberly Sullivan of the Department of Environmental Health with the Boston University School of Public Health.  

Dr. Sullivan currently leads a major Gulf War Illness treatment development Consortium, which is also funded by the CDMRP.  This treatment development study is currently recruiting both healthy Gulf War veterans and those with Gulf War Illness at its study sites in Boston, Miami, and Houston.  

More information about the ongoing Gulf War Illness treatment development study is available at:  http://sites.bu.edu/gwic . 

-91outcomes

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Study Highlights

Gulf War Veterans (GWV) were exposed to pesticides and pyridostigmine bromide (PB) pills during the war.
We compared cognitive and mood functioning in GWV who were pesticide applicators or non-applicators during the war.
GWV with high pesticide/PB exposures had slower information processing, worse visual memory and increased mood complaints.
Specific pesticides also contributed independently to poorer cognitive and mood outcomes.

Abstract

1991 Gulf War (GW) veterans continue to experience debilitating cognitive and mood problems more than two decades following their return from deployment. Suspected causes for these cognitive complaints include additive and/or synergistic effects of the varying combinations of exposures to chemicals in theater, including pesticides and pyridostigmine bromide (PB) pills. This study was undertaken to address one of the key recommendations of the US Department of Defense Environmental Exposure Report on Pesticides, which was to conduct an epidemiological study to further evaluate the role of neurotoxicant exposures in the expression of central nervous system symptoms reported by GW veterans. This study evaluated the role of pesticides and/or PB in the development of chronic neuropsychological dysfunction in GW veterans. We examined the associations between self-reported measures of pesticide and PB exposures and performance on neuropsychological tests in a group of 159 GW-deployed preventative medicine personnel who had varying levels of pesticide exposures during their work as pesticide applicators or other preventative medicine roles. These veterans had a unique knowledge of pesticides and their usage during the war. It was hypothesized that pesticide applicator personnel with higher exposures would perform significantly worse on objective cognitive measures than lower-exposed personnel and that multiple chemical exposures (pesticide and PB) would further diminish cognitive functioning and increase mood complaints. Study results showed that the participants with both high pesticide and high PB exposure performed worse on specific measures than the groups with high single exposures or low exposures to both toxicants. High combined exposure was associated with significantly slower information processing reaction times, attentional errors, worse visual memory functioning, and increased mood complaints. In addition, stepwise regression analyses of individual pesticide exposures found that pest strip exposure was associated with slower reaction times and attentional errors, and that fly bait and delouser exposures predicted greater mood complaints.

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FULL JOURNAL ARTICLE:


Volume 65, January–February 2018, Pages 1–13
Full length article

Neuropsychological functioning in military pesticide applicators from the Gulf War: Effects on information processing speed, attention and visual memory

  • a Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, United States
  • b VA Boston Healthcare System, 150 South Huntington Avenue, Boston, MA 02130, United States
  • c Department of Neurology, Boston University School of Medicine, Boston, MA 02118, United States
  • d Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, United States
  • e Parsons Corporation, Syracuse, NY 13212, United States1
  • f Ibis Reproductive Health, Boston, MA 02130, United States
  • g Reliant Medical Group, Worcester, MA 01604, United States

Sunday, November 12, 2017

VA: White matter brain damage linked to chronic musculoskeletal pain in Gulf War Veterans

SOURCE:  U.S. Department of Veterans Affairs, VA Research Communications, October 26, 2017

https://www.research.va.gov/currents/1017-White-matter-damage-linked-to-chronic-musculoskeletal-pain.cfm


More information: Stephanie M. Van Riper et al. Cerebral white matter structure is disrupted in Gulf War Veterans with chronic musculoskeletal pain, PAIN (2017). DOI: 10.1097/j.pain.0000000000001038 

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White matter damage linked to chronic musculoskeletal pain in Gulf War Veterans

October 26, 2017
By Tristan Horrom 
VA Research Communications
Dr. Dane Cook is a professor of kinesiology at the University of Wisconsin-Madison and a health scientist and research physiologist at the William S. Middleton Memorial Veterans Hospital. (Photo courtesy of UW)<em>
Dr. Dane Cook is a professor of kinesiology at the University of Wisconsin-Madison and a health scientist and research physiologist at the William S. Middleton Memorial Veterans Hospital. (Photo courtesy of UW) 
A study from the Madison VA Hospital in Wisconsin has shown that structural damage in the white matter of the brain may be linked to chronic musculoskeletal pain in Gulf War Veterans.
The results appeared online Aug. 8, 2017, in the journal Pain.
Using magnetic resonance imaging, the researchers found that participants with chronic pain had widespread disruptions in the structure of their white matter across several regions of the brain. White matter is deep tissue within the brain that contains axons, nerve fibers that conduct electrical signals and connect different areas of the brain. Many of the brain regions found to be affected in the study are involved in the interpretation of pain stimuli and the emotional aspects of pain perception.
The results showed that poorer white matter health was linked to higher pain levels. It was also connected with higher levels of fatigue and, to a lesser extent, depression. In the words of the researchers, “These data suggest that poor white matter health may contribute to the persistent widespread pain that is experienced by a significant number of Veterans who were deployed to the Persian Gulf.”
According to Dr. Dane E. Cook, corresponding author on the article, results such as these can provide objective evidence of a person’s subjective experience. He explains, “Changes in brain white matter show that there is something wrong in the central nervous system that may explain why the Veteran is experiencing widespread pain.”

Chronic pain common in Gulf War Vets

"Changes in brain white matter show that there is something wrong in the central nervous system that may explain why the Veteran is experiencing widespread pain." 
Chronic musculoskeletal pain affects around 25 percent of Veterans who were deployed during the Persian Gulf War. It is one of the cardinal symptoms of Gulf War illness, a chronic condition with a variety of symptoms that is largely medically unexplained. Veterans deployed to Iraq and Afghanistan more recently as part of operations Enduring Freedom and Iraqi Freedom have also shown similar rates of chronic musculoskeletal pain.
The patients in the Madison VA study with chronic pain also had lower quality of life and physical functioning than those without chronic pain, according to assessments given to each participant.
Evidence has suggested that Gulf War illness symptoms are related to structural changes in the brain. A 2008 report by the VA Research Advisory Committee on Gulf War Veterans’ Illnesses linked decreased white matter volume to Gulf War illness. In the new study, the researchers were looking for brain structural damage specifically linked to pain. To do so, they recruited 30 Veterans with chronic musculoskeletal pain from operations Desert Storm, Desert Shield, and Iraqi Freedom. They also tested 31 Veterans of these conflicts without chronic pain, for comparison.
The researchers took MRIs of each participant’s brain. They used a technique called diffusion tensor imaging to study the spread of water through the brain. Water tends to diffuse along the direction of the axons, the researchers explain, meaning that MRI can be used to map the structural integrity of white matter. One study by Georgetown University researchers was able to tell the difference between patients with Gulf War illness and those without by using diffusion mapping.
The disruptions in water diffusion found in the Madison VA study suggest that the myelin structure of axons is impaired in those with chronic pain, write the researchers. Myelin is a material that surrounds axons and nerve cells. It serves as an electrical insulator and allows the nervous system to function properly.

VA RESEARCH 
TOPIC PAGES

Central nervous system affected

Finding disruptions in white matter that are significantly related to the experience of pain is an important step towards determining the mechanisms of chronic pain in Gulf War Veterans, explains Cook. The findings “emphasize that chronic pain in Gulf War Vets and perhaps Gulf War illness affects the central nervous system.” Other chronic pain conditions and diseases are categorized as central nervous system diseases, but Gulf War illness is less well understood. Figuring out how Gulf War illness affects the central nervous system and causes pain can help doctors understand and treat the condition.
According to the researchers, the results could aid in testing and treatments designed to improve brain health. Understanding the connection between white matter damage and pain could lead to new testing and treatment techniques. However, they explain, “what is yet to be determined is whether these microstructural relationships are reversible with appropriate treatment, and whether changes in white matter structure will lead to improvements in symptoms.”
The next step, says Cook, is to test whether treatments aimed at relieving pain also change the white matter. The research team is in the final year of a clinical trial using exercise training as a treatment for Veterans with chronic pain. They are assessing both pain symptoms and white matter over time to test whether changes in white matter are related to changes in pain. Cook hopes that this ongoing study could lead to better treatments for chronic pain: “Our premise is that by targeting potential mechanisms of disease maintenance, we will be better able to target our treatments, a form of personalized medicine.”

Friday, November 10, 2017

A Consumer's Perspective: Always Faithful

GEORGETOWN: Brain chemistry study shows chronic fatigue syndrome, Gulf War illness as unique disorders

(91outcomes.com)  A new research study out of Georgetown University adds further evidence to a growing body of research that suggests that Gulf War Illness is a diagnosable health condition distinct from Chronic Fatigue Syndrome and other health disorders.  

This research was funded by the treatment-focused Gulf War Illness Research Program within the DoD Congressionally Directed Medical Research Program (cdmrp.army.mil/GWIRP), and the Sergeant Sullivan Center, Dr. Barbara Cottone, Dean Clarke Bridge Prize, and the National Institutes of Health National Institute of Neurological Diseases and Stroke.

The diagnostic technology has been patented by the researchers.  

-91outcomes


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SOURCE:  Press Release, Eureka Alert
https://www.eurekalert.org/pub_releases/2017-11/gumc-bcs110817.php


PUBLIC RELEASE: 

Brain chemistry study shows chronic fatigue syndrome, Gulf War illness as unique disorders

GEORGETOWN UNIVERSITY MEDICAL CENTER
WASHINGTON -- Researchers at Georgetown University Medical Center have found distinct molecular signatures in two brain disorders long thought to be psychological in origin -- chronic fatigue syndrome (CFS) and Gulf War Illness (GWI). 
In addition, the work supports a previous observation by GUMC investigators of two variants of GWI. The disorders share commonalities, such as pain, fatigue, cognitive dysfunction and exhaustion after exercise.
Their study, published in Scientific Reports, lays groundwork needed to understand these disorders in order to diagnosis and treat them effectively, says senior investigator, James N. Baraniuk, MD, professor of medicine at Georgetown University School of Medicine. Narayan Shivapurkar, PhD, assistant professor of oncology at the medical school worked with Baraniuk on the research.
The changes in brain chemistry -- observed in levels of miRNAs that turn protein production on or off -- were seen 24 hours after riding a stationary bike for 25 minutes. 
"We clearly see three different patterns in the brain's production of these molecules in the CFS group and the two GWI phenotypes," says Baraniuk. "This news will be well received by patients who suffer from these disorders who are misdiagnosed and instead may be treated for depression or other mental disorders."
Chronic fatigue syndrome affects between 836,000 and 2.5 million Americans, according to a National Academy of Medicine report. The disorder was thought to be psychosomatic until a 2015 review of 9,000 articles over 64 years of research pointed to unspecified biological causes. Still, no definitive diagnosis or treatment is available.
Gulf War Illness has developed in more than one-fourth of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War, Baraniuk and his colleagues have reported in earlier work. 
Gulf War veterans were exposed to combinations of nerve agents, pesticides and other toxic chemicals that may have triggered the chronic pain, cognitive, gastrointestinal and other problems, Baraniuk says. Although the mechanisms remain unknown, the study provides significant insights into brain chemistry that can now be investigated. 
This study focused on spinal fluid of CFS, GWI and control subjects who agreed to have a lumbar puncture. Spinal taps before exercise showed miRNA levels were the same in all participants. In contrast, miRNA levels in spinal fluid were significantly different after exercise. The CFS, control and two subtypes of GWI groups had distinct patterns of change. For example, CFS subjects who exercised had reduced levels of 12 different mRNAs, compared to those who did not exercise. 
The miRNA changes in the two GWI subtypes add to other differences caused by exercise. One subgroup developed jumps in heart rate of over 30 beats when standing up that lasted for two to three days after exercise. Magnetic resonance imaging showed they had smaller brainstems in regions that control heart rate, and did not activate their brains when doing a cognitive task. In contrast, the other subgroup did not have any heart rate or brainstem changes, but did recruit additional brain regions to complete a memory test. The two groups were as different from each other as they were from the control group.
Finding two distinct pathophysiological miRNA brain patterns in patients reporting Gulf War disease "adds another layer of evidence to support neuropathology in the two different manifestations of Gulf War disease," he says.
Baraniuk adds that miRNA levels in these disorders were different from the ones that are altered in depression, fibromyalgia, and Alzheimer's disease, further suggesting CFS and GWI are distinct diseases.
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The study was supported by funding from The Sergeant Sullivan Center, Dr. Barbara Cottone, Dean Clarke Bridge Prize, Department of Defense Congressionally Directed Medical Research Program (CDMRP) W81XWH-15-1-0679, and National Institute of Neurological Diseases and Stroke R21NS088138 and RO1NS085131.
Baraniuk and Shivapurkar are named as inventors on a patent application that has been filed by Georgetown University related to the technology described.
About Georgetown University Medical Center
Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health. Connect with GUMC on Facebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@gumedcenter).