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.”
Digitally enhanced image of human heart. Wellcome Images.
Caf-fiends in a can
If your heart beats faster at the thought of quaffing a cold can of energy drink (think Red Bull, Monster, Rockstar and their ilk), there may be something wrong with you more worrisome than your sense of taste.
Almost nobody drinks these hugely popular concoctions for their sublime flavor. They are consumed almost entirely for the much touted neurological jolt derived from an overabundance of stimulating caffeine (as much as three times more than in a comparable serving of coffee or soda) and ingredients like B vitamins, the amino acid taurine, guarana, a South American plant with a higher caffeine concentration than coffee, ginseng and ginkgo biloba.
Judging from sales - $12.5 billion in 2012 in the U.S. alone – these commercial energy drinks deliver their promised punch – and worse.
A report presented this week at the Radiological Society of North America found that energy drinks appear to adversely alter heart function. Specifically, they can cause rapid heart rate, palpitations, a blood pressure spike and, possibly, seizures or death.
If that’s not enough of an eye-opener, consider this statistic from the Substance Abuse and Mental Health Services Administration: Each year almost 21,000 energy drink consumers find themselves in hospital emergency rooms being treated for unwanted side effects of the beverages.
So next time you need something to snap you awake, try water – eight icy cold ounces dashed to the face generally does the trick.
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.
All things anthropogeny
Established in 2008 by co-founders Ajit Varki, Margaret Schoeninger and Fred Gage, the Center for Academic Research and Training in Anthropogeny (CARTA) promotes transdisciplinary research in the study of human origins.
Anthropogeny is not a synonym for human evolution, but rather encompasses investigation of all factors involved in human origins, including climate, cultural, geographic, social and ecological. The word was popularized by the noted German zoologist Ernst Haeckel.
Not surprisingly, it’s a rich and diverse topic of conversation. Consider CARTA’s regular symposia, which have produced more than 150 scholarly presentations on subjects ranging from language and the biology of altruism to the evolution of nutrition and whether the human mind is unique. Future symposia will discuss child-rearing in human evolution and the role of male aggression and violence.
Recently, the number of online hits of CARTA videos topped 10 million in just four years – a big number in a blink of geologic time.