Brain Trauma Raises Risk of Later PTSD in Active-Duty Marines
Deployment-related injuries are biggest predictor, but not the only factor
In a novel study of U.S. Marines investigating the association between traumatic brain injury (TBI) and the risk of post-traumatic stress disorder (PTSD) over time, a team of scientists led by researchers from the Veterans Affairs San Diego Healthcare System and University of California, San Diego School of Medicine report that TBIs suffered during active-duty deployment to Iraq and Afghanistan were the greatest predictor for subsequent PTSD, but found pre-deployment PTSD symptoms and high combat intensity were also significant factors.
The findings are published in the December 11 online issue of JAMA Psychiatry.
The team, headed by principal investigator Dewleen G. Baker, MD, research director at the VA Center of Excellence for Stress and Mental Health, professor in the Department of Psychiatry at UC San Diego and a practicing psychiatrist in the VA San Diego Healthcare System, analyzed 1,648 active-duty Marines and Navy servicemen from four infantry battalions of the First Marine Division based at Camp Pendleton in north San Diego County. The servicemen were evaluated approximately one month before a scheduled 7-month deployment to Iraq or Afghanistan, one week after deployment had concluded, and again three and six months later.
PTSD is a psychiatric condition in which stress reactions become abnormal, chronic and may worsen over time. The condition is linked to depression, suicidal tendencies, substance abuse, memory and cognition dysfunction and other health problems.
The servicemen were assessed at each evaluation using the Clinician-Administered PTSD Scale or CAPS, a structured interview widely employed to diagnose PTSD and severity. Researchers asked about any head injuries sustained prior to joining the service and any head injuries sustained during deployment from a blast or explosion, vehicle accident, fall or head wound from a bullet or fragment.
Traumatic brain injuries are common. At least 1.7 million Americans annually sustain a TBI, with an estimated 5 million Americans living with TBI-related disabilities. More than half (56.8 percent) of the servicemen reported a TBI prior to deployment; almost a fifth (19.8 percent) reported a TBI during deployment. The vast majority of deployment-related TBIs (87.2 percent) were deemed mild, with less than 24 hours of post-traumatic amnesia. Of the 117 Marines whose TBI resulted in lost consciousness, 111 said it was less than 30 minutes.
Skeletal muscle attaches to joints and long bones and is under the control of the conscious brain. As you read this blog, occasionally typing on your keyboard, it’s skeletal muscle directing your fingers through their finely-tuned tap dance.
(FYI: Aside from skeletal, there are two other major muscle types in your body: smooth and cardiac. Smooth is involuntary and non-striated. Generally, it’s either fully contracted or fully relaxed. Your urinary bladder, lungs and the irises of your eyes are controlled by smooth muscle. Cardiac muscle is also involuntary – doing its job automatically – but striated, meaning parts of it are able to contract while other parts do not. Your heart is composed of cardiac muscle.)
In this confocal fluorescent light micrograph by Thomas Deerinck at the National Center for Microscopy and Imaging Research at UC San Diego, you’re looking at a cross-section of parallel skeletal muscle fibers (stained red due to the presence of the proteins actin and myosin) sheathed in a sugar-protein complex (green). Cell nuclei are stained blue.
There are roughly 700 muscles in the body, in all shapes and sizes. The biggest single muscle is the Gluteus maximus, one of three muscles that comprise each buttock. Our big butts help make it possible for us to stand, move upright and run. Indeed, a 2006 paper by Harvard and University of Utah researchers suggested giant glutes make humans the undisputed best long-distance runners in the history of life on Earth.
The widest skeletal muscle in the human body is the Lastissimus dorsi, which is Latin for “wide back.” It’s the muscle that begins at the spine, fans out and attaches at the other end to the upper arms.
The longest muscle is the Sartorius, which begins at the outside of the hip, runs down the upper leg and terminates inside the knee. The name Sartorius means “tailor,” so-called because this muscle allows one to cross one’s legs, purportedly a common position assumed by working tailors. The Sartorius also assists in flexing the knees and hips.
The Gluteus maximus often is dubbed the strongest muscle because it works to keep the entire body upright, but there are many ways to measure strength:
The muscles of the uterus, for example, must be strong enough to push a baby through the birth canal.
The heart beats continuously for as long as you live – more than 3 billion times in a person’s life, pumping approximately 2,500 gallons of blood every day.
Similarly, the muscles of the eyes are constantly repositioning them. In an hour of reading, the external muscles of the eyes will make nearly 10,000 coordinated movements.
And let’s say something for the tongue, which is a bundle of tireless muscles. While eating, it moves around mixing food to aid digestion. It binds and contorts to make speech. Even when you’re asleep, it’s constantly pushing saliva down the throat.
But arguably the strongest muscle, at least based upon its weight, is the masseter or primary jaw muscle. When all of the muscles of the jaw are working together, humans can apply a bite force up to 55 pounds on the incisors and more than 200 pounds on the molars.
That’s nothing compared to the maximum chomping power of Tyrannosaurus rex (12,800 pounds), of course, but it still would hurt.
Be Patient. Genome Sequencing Coming Soon
These days, a visit to the doctor often involves taking a few diagnostic tests – an eye exam, for example – or providing blood or urine samples, which are sent off to a lab for analysis. For some patients, another kind of test is becoming increasingly common: genome sequencing. At UC San Diego Moores Cancer Center, it’s the stated standard of care.
Simply put, genome sequencing creates a map of a patient’s entire hereditary information, both the DNA-carrying genes that direct development and life and the non-coding regions that regulate the genes.
We asked Steven L. Gonias, MD, PhD, professor and chair of the Department of Pathology in the UC San Diego School of Medicine, to talk about why genome sequencing is important and why it is increasingly likely to be a part of every patient’s medical record.
Question: What is the value of genomic sequencing?
Gonias: Almost every person has had blood drawn for some sort of hospital laboratory test. There are two important ways that a doctor uses the results. In many cases, test results are used to inform a physician as to whether a patient has a health problem or how a known health problem is progressing.
With knowledge of the laboratory test result, the physician can make an informed choice of therapy. Other laboratory tests are performed to help determine risk of disease. A classic example is the cholesterol level. In this case, the laboratory test result may help the doctor guide a patient with regard to lifestyle choices or support prescribing a drug to decrease the chance of future illness.
Genome sequencing results are really very similar. Most of the genome is identical in every human being. Diversity in the genome explains differences in characteristics between individuals, including some aspects of health.
Understanding genome data may allow a physician to select the best therapy or treatment plan for an illness you already have or predict risk of acquiring a disease. Of course, understanding risk makes most sense when we can take steps to avoid illness in a patient at risk.
Question: Doesn’t genome sequencing open up a can of worms? For example, it might indicate you’re predisposed to a disease for which there is no treatment or cure.
Gonias: There are times when analyzing genomic data is straightforward; however, this is not always the case. The questions you raise are important and need to be addressed not only by physicians, but also by experts in medical ethics and everyone in society.
I typically teach that you should not perform a hospital laboratory test unless the results can be used to help the patient. When we examine the entire genome, some results will “open a can of worms” with limited opportunity for intervention. In casual conversations, some people tell me they really want to know if they are at risk to develop an illness in the future even if nothing can be done to avoid that illness. Others are less sure. Personally, I totally respect both viewpoints.
A related issue is confidentiality. If you learn that you are predisposed to develop an illness at a certain age, you might want to keep that information confidential; however, others may argue that relatives who might be affected by the same genetic information have a right to know your results. The federal government and insurance companies are grappling with this issue. I encourage everyone to become informed and participate in the debate.
Question: Why is genomic screening particularly useful in cancer care?
Gonias: In cancer, any of a number of gene products may be mutated so that cell growth is not normally controlled. New drugs that are being used to fight cancer have been designed to attack these mutated gene products in cancer cells.
The best way to know who may benefit from a certain anticancer drug is to know which gene products are mutated. We understand that specific genes tend to be mutated more or less in different types of cancer. However, the time has come to stop guessing in cancer care. That is why, at UC San Diego, the goal is now to perform genome sequence analysis for every newly diagnosed cancer patient.
We do not examine the entire genome. Instead, we sequence a panel of 47 genes that are known to cause cancer or be involved in the progression of cancer. These gene products are called “actionable.” That means that knowledge of the mutation can guide therapy. When we perform genome sequencing, we look directly at the cancer tissue and at normal cells from the blood. Other specific genetic tests may be performed to complement genome sequencing and provide the best information to oncologists. This is a major breakthrough in cancer care and one that we hope will improve outcome for many people in the San Diego area.
Human brain specimen with glioblastoma multiforme.
Brain Cancer Cells Hide While Drugs Seek
Tumor cells temporarily lose mutation to evade drugs targeting mutation
A team of scientists, led by principal investigator Paul S. Mischel, MD, a member of the Ludwig Institute for Cancer Research and professor in the Department of Pathology at the University of California, San Diego School of Medicine, has found that brain cancer cells resist therapy by dialing down the gene mutation targeted by drugs, then re-amplify that growth-promoting mutation after therapy has stopped.
The findings are published in the December 5, 2013 online issue of Science.
“This discovery has considerable clinical implications because if cancer cells can evade therapy by a ‘hide-and-seek’ mechanism, then the current focus (of drug therapies) is unlikely to translate into better outcomes for patients,” said Mischel.
In recent years, new cancer therapies have emerged that target tell-tale gene mutations to identify specific cancer cells for destruction. Unfortunately, a variety of “resistance mechanisms” have also emerged, among them incomplete target suppression, second-site mutations and activation of alternative kinases or enzymes that maintain growth-promoting signals to the cancer itself.
“Most research is aimed at developing better drugs or better drug combinations to suppress these downstream signals,” Mischel said. “However, one thing that has not been carefully considered is whether cancer cells can modulate the levels of – and thus their dependence on – the target of the drug, evade therapy, and then re-acquire the oncogene to promote tumor growth when the drug is withdrawn.”
Anopheles gambiae mosquitoes, a key vector of malaria and carrier of the Plasmodium falciparum parasite.
By targeting enzyme in mosquito-borne parasite, researchers aim to eliminate malaria
Using advanced methodologies that pit drug compounds against specific types of malaria parasite cells, an international team of scientists, including researchers at the University of California, San Diego School of Medicine and the Genomics Institute of the Novartis Research Foundation, have identified a potential new weapon and approach for attacking the parasites that cause malaria.
Their findings are published in the November 27, 2013 advanced online publication of Nature.
Despite advances in prevention and treatment in recent years, malaria remains one of the world’s great infectious scourges. In 2010, according to the World Health Organization, there were an estimated 219 million cases globally and 660,000 deaths, mostly among African children.
The disease is caused by Plasmodium parasites, which are transmitted to humans by the infectious bite of an Anopheles mosquito. Plasmodium vivax and Plasmodium falciparum are the most problematic of the parasite species. The former is the most widespread globally; the latter most deadly.
Principal investigator Elizabeth A. Winzeler, PhD, professor in the Division of Pharmacology and Drug Discovery, Department of Pediatrics and director of translational research at the UC San Diego Health Sciences Center for Immunity, Infection & Inflammation, and colleagues found a key metabolic enzyme (phosphatidylinositol 4-kinase or PI4K) that is used for intracellular development by Plasmodium species at each stage of infection in the vertebrate host.
The discovery could have significant ramifications for eventually eradicating malaria as a global disease. “Elimination efforts are more effective with better tools and infrastructure,” said Winzeler. “Clearly we have better infrastructure and communication now than we had in the 1960s. To make more progress, though, we need more effective drugs.”
A major obstacle has been the developmental nature of the P. vivax parasite. While some antimalarial drugs effectively kill P. vivax as it circulates in the host’s bloodstream, the parasite also produces an early-stage form called a hypnozoite that can lie dormant and undetected in the livers of infected persons for years before reinitiating development and triggering relapse.
“Most drugs selectively work on certain stages of the (parasite) lifecycle, but not all stages,” said Case McNamara, PhD, the study’s first author and a researcher at the Genomics Institute of the Novartis Research Foundation in San Diego. “Therefore, inhibitors of this drug target have the potential to not only cure individuals of a malaria infection, but to also prevent infections and even block transmission of the parasite back to the mosquito.”
Currently, the only licensed antimalarial drug capable of fully cleansing hidden hypnozoites and eliminating the possibility of relapse – known as the “radical cure” – is primaquine, a drug first tested in the 1940s and licensed by the Food and Drug Administration in 1952.
But primaquine has significant adverse side effects and shortcomings, according to Winzeler, most notably that it can cause life-threatening anemia in people with a specific inherited metabolic enzyme deficiency frequently found in malaria-endemic regions.
“In addition, it may not work all of the time and it requires a prolonged dosing schedule, up to 14 days, which means compliance is an issue. People often do not take the full dose,” Winzeler said. “Primaquine is an old drug and it’s not clear that it would ever be licensed in today’s regulatory environment.”
Primaquine was developed “by simply injecting a lot of compounds into monkeys and seeing which compound cured malaria infections,” said Winzeler. It was later tested in humans using prisoners.
The new approach is far more finely tuned, based on a series of detailed cellular assays that seek to model different parasite lifecycle stages in miniature test tubes. The researchers looked for the rare compound class that had activities in all parasite stages, but no activity against human cells and which was also drug-like. A new chemical class, called imidazopyrazines, possessed these properties. The researchers then identified the protein target of these compounds as PI4K.
“(Dr. Winzeler) had a very creative and powerful idea to help identify malaria drug targets,” said McNamara. “By patiently evolving drug-resistant parasites against the drug of interest, we can probe the genome for the changes responsible for conferring resistance.
“Fortunately, malaria parasites will often try to alter the drug target in subtle ways to prevent the drug from working effectively. So, by identifying these changes we, in turn, identify the drug target. This approach has worked so well that it has quickly become a standard technique in our field to help study and characterize all new antimalarials.”
Because PI4K is also found in humans, Winzeler said the next challenge is to develop a superior drug that continues to discriminate between the parasite and human versions of this enzyme. “Since we know the identity of this protein and will hopefully soon solve its structure, this task will be much easier,” she said.
Human goblet cell. Image courtesy of the University of Edinburgh, Wellcome Images
Raise a glass to the goblet cell
In a paper published last week in Virology Journal, Pascal Gagneux and colleagues at UC San Diego School of Medicine describe how influenza A viruses snip through the protective mucus net to both infect respiratory cells – and then later cut their way out infect other cells.
Mucus is usually deemed a disgusting annoyance, but really it’s not. (Sorry, couldn’t resist.) It is oil in the human engine, lubricating the passages of the mouth, nose, sinuses, throat, lungs and gastrointestinal tract, preventing underlying epithelial tissues from drying out. It’s also a sort of sticky flypaper, trapping unwanted substances like bacteria and dust before they can too deeply penetrate the fairly pristine and sterile inner body.
Each day, a healthy person churns out about 4 to 6 cups of mucus. Most of it trickles down your throat unnoticed. The little factories that make mucus are called goblet cells. It’s an apt moniker because goblet cells are little more than vessels filled to the brim with globules of mucin. That’s a globule cell in the image above; the mucin globules colored blue.
Mucins are glycosylated proteins, but you can think of them more simply as dehydrated bits of mucus packed inside a globule cell. Once released into the water-rich environment of your airways, however, they expand rapidly, absorbing water to reach full, gooey size within 20 milliseconds. That’s one-thousandth of a second. That’s fast. A single flap of a hummingbird’s wing takes 5 to 80 milliseconds.
The rapid release allows goblet cells to respond almost instantly to many different stimuli, from inhaled microbes to a mouthful of eye-watering wasabi.
A colored scanning electron micrograph of a human T lymphocyte. Image courtesy of the National Institute of Allergy and Infectious Disease
Using microRNA Fit to a T (cell)
Researchers show B cells can deliver potentially therapeutic bits of modified RNA
Researchers at the University of California, San Diego School of Medicine have successfully targeted T lymphocytes – which play a central role in the body’s immune response – with another type of white blood cell engineered to synthesize and deliver bits of non-coding RNA or microRNA (miRNA).
The achievement in mice studies, published in this week’s online early edition of the Proceedings of the National Academy of Sciences, may be the first step toward using genetically modified miRNA for therapeutic purposes, perhaps most notably in vaccines and cancer treatments, said principal investigator Maurizio Zanetti, MD, professor in the Department of Medicine and director of the Laboratory of Immunology at UC San Diego Moores Cancer Center.
“From a practical standpoint, short non-coding RNA can be used for replacement therapy to introduce miRNA or miRNA mimetics into tissues to restore normal levels that have been reduced by a disease process or to inhibit other miRNA to increase levels of therapeutic proteins,” said Zanetti.
“However, the explosive rate at which science has discovered miRNAs to be involved in regulating biological processes has not been matched by progress in the translational arena,” Zanetti added. “Very few clinical trials have been launched to date. Part of the problem is that we have not yet identified practical and effective methods to deliver chemically synthesized short non-coding RNA in safe and economically feasible ways.”
Zanetti and colleagues transfected primary B lymphocytes, a notably abundant type of white blood cell (about 15 percent of circulating blood) with engineered plasmid DNA (a kind of replicating but non-viral DNA), then showed that the altered B cells targeted T cells in mice when activated by an antigen – a substance that provokes an immune system response.
“This is a level-one demonstration for this new system,” said Zanetti. “The next goal will be to address more complex questions, such as regulation of the class of T cells that can be induced during vaccination to maximize their protective value against pathogens or cancer.
Microscopic view of an influenza virus. Image courtesy of Sanofi Pasteur.
You, the flu, some Qs - answers too.
We are well into the official flu season, which typically begins in October and may run as long as May. For most healthy people, a bout of the flu is a discomfiting but passing annoyance, a few days of fever, aches, pains, coughing and a sore throat. We recover and get on with our lives.
For some, though, most notably the very young, old and immune suppressed, influenza can be life-threatening. Each year, depending upon prevailing strains and other factors, approximately 3,000 to 49,000 Americans die from complications caused by seasonal flu viruses.
Preventing infection is obviously the best option, which means (aside from good hygiene like washing your hands regularly and thoroughly, coughing into your sleeve and not going to work when you’re sick), getting vaccinated.
We asked Kim M. Delahanty, a registered nurse and administrative director of the Infection Prevention/Clinical Epidemiology and TB Controlat the UC San Diego Health System, to answer a few commonly asked questions about getting “the flu shot.”
Q: After getting a flu shot, some folks complain that they invariably come down with the flu – or at least do not feel well for a few days. What is the risk of becoming sick after being vaccinated?
A: Flu vaccines cause antibodies to develop in the body about two weeks after vaccination. These antibodies provide protection against infection by the viruses that are in the vaccine. So, if the influenza virus is circulating in the community before the person receives their flu vaccination, there is a potential risk in that two-week period that they could be exposed to influenza and come down with a much milder case.
The vaccine does not cause the flu. It is the lack of an immune response in your body and exposure to someone with influenza that causes flu within that two-week period after you received the vaccine. This is why it is recommended to get your flu shot earlier than later in the season.
Also, there are a lot of respiratory illnesses the influenza vaccine does not cover, such as the common cold. You may still get one of these during influenza season.
And remember nausea, vomiting and diarrhea are not traditionally signs and symptoms of influenza, but more indicative of “stomach flu,” which may be causes by a variety of things.
Q: Are there any complications or concerns if you got your last flu shot late in the season and now, just a few months later, are getting vaccinated for the new flu season?
A: None that I’m aware of.
Q: A recent study confirmed that the seasonal flu vaccine is safe for pregnant women. Are there groups of people for whom the vaccine poses sufficient risk that they should not get the shot?
A: There are very few true contraindications and precautions for getting the influenza vaccine. Children under six months of age and people who have ever had a severe allergic reaction to influenza vaccine are contraindicated and should consult their physician.
There are other precautions. People with a history of Guillain-Barré Syndrome (a severe paralytic illness, also called GBS) that occurred after receiving influenza vaccine and who are not at risk for severe illness from influenza should generally not receive vaccine. Tell your doctor if you’ve had Guillain-Barré Syndrome. He or she will help you decide whether the vaccine is recommended for you.
People who are moderately or severely ill with or without fever should usually wait until they recover before getting flu vaccine. If you are ill, talk to your doctor about whether to reschedule the vaccination. People with a mild illness can usually get the vaccine.
Q: How do allergies complicate getting the flu vaccine?
A: There is now an egg-free version of the influenza vaccine called RIV Recombinant Influenza Vaccine. If you have an egg allergy, consult your physician before getting the flu vaccine. People who have had a severe allergic reaction to influenza vaccine in the past are contraindicated.
Q: Is there a difference between getting the vaccine as a shot or as a nasal spray? Is one better than the other?
A: The Centers for Disease Control and Prevention does not have a preference for which of the available flu vaccine options people should get this season. All are acceptable options, but some vaccines are intended for specific age groups. Talk to your doctor or nurse about the best options for you and your loved ones. The important thing is to get a flu vaccine every year.
There are three versions: Inactivated Influenza Vaccine (IIV) is not a live-virus vaccine. This is the flu vaccine most people receive. Recombinant Influenza Vaccine (RIV) Live does not use the influenza virus in its production and contains no egg proteins, antibiotics or preservatives. It is indicated for active immunization against disease caused by influenza virus subtypes A and type B and is approved for persons 18 through 49 years of age. People with egg allergies may take this. Live Attenuated Influenza Vaccine (LAIV) is administered intra-nasally (through the nose) for those that are adverse to needles.
All of these vaccines have different instructions for use.
In this cartoon, experimental magnetic beads are coated with human or pig mucins (grey mesh), which are proteins containing sialic acids (red or blue diamonds), part of a protective mucus net secreted by respiratory cells. Humans and pigs have different sialic acids on their mucins, as indicated by the bottom molecular structures. The flu virus (green stars) bind to and cleave off sialic acids, snipping through the host mucus net to infect cells.
Stuck on Flu
How a sugar-rich mucus barrier traps the virus – and it gets free to infect
Researchers at the University of California, San Diego School of Medicine have shown for the first time how influenza A viruses snip through a protective mucus net to both infect respiratory cells and later cut their way out to infect other cells.
The findings, published online today in Virology Journal by principal investigator Pascal Gagneux, PhD, associate professor in the Department of Cellular and Molecular Medicine, and colleagues, could point the way to new drugs or therapies that more effectively inhibit viral activity, and perhaps prevent some flu infections altogether.
Scientists have long known that common strains of influenza specifically seek and exploit sialic acids, a class of signaling sugar molecules that cover the surfaces of all animal cells. The ubiquitous H1N1 and H3N2 flu strains, for example, use the protein hemagglutinin (H) to bind to matching sialic acid receptors on the surface of a cell before penetrating it, and then use the enzyme neuraminidase (N) to cleave or split these sialic acids when viral particles are ready to exit and spread the infection.
Mucous membrane cells, such as those that line the internal airways of the lungs, nose and throat, defend themselves against such pathogens by secreting a mucus rich in sialic acids – a gooey trap intended to bog down viral particles before they can infect vulnerable cells.