Discussing and documenting resuscitation status

DNR discussions are challenging. Through the years I've noticed several common mistakes which form barriers to meaningful decision making:

Use of medical jargon. Patients and their families watch TV and read newspapers, and think they understand this terminology, but they often don't.

Misunderstanding of clinical issues. A lack of understanding of the patient's disease processes on the part of the person leading the discussion may lead to over or under estimation of the prognosis.

Cursory or hurried discussions. Pressure to adhere to a regulatory or institutional policy may drive such discussions, which are not informative to patients and families.

Discussions postponed until the moment of crisis.

Vague and overly subjective discussions. Early in the conference the patient may say something like “Do whatever you have to if you think it will help” and there ends the discussion. Individual modalities of resuscitation and their anticipated benefits are often not addressed specifically.

Shared assumptions that DNR status means giving up. DNR patients may still warrant aggressive care, including ICU care. At Mayo Clinic, for example, (see below link) DNR status does not preclude the option of intubation and mechanical ventilation for patients who develop respiratory failure.

Issues concerning DNR discussions are reviewed in a recent issue of the Green Journal.

DSM: The Everlasting Gobstopper of Psychiatry

The DSM is the Everlasting Gobstopper of psychiatry, providing a seemingly endless store of material for bloggers, journalists, academics, and other commentators.

I looked through the comments on my last post and was impressed by how articulate they were. I'll spend the next few posts commenting on some of the comments. How's that for narcissistic exploitation of one's own blog?

S pointed out that “a reasonable, experienced, compassionate doctor will not be bound up by DSM diagnoses,” and accurately followed that up with “but I suspect all of us here know that there are plenty of doctors who can't see past rigid categorization or have a two-dimensional view of their patients.”

I agree. Michael First, who was the editor of DSM-IV, once told me, “We used to joke that DSM should come with a combination lock and you can only open the book if you agree to really explore what is going on in the patient’s minds.” I think of DSM is a map into the mental world. It allows us to locate a patient in a general region, but not much more than that. To truly make the diagnosis, we have to do the messy work of talking with the patient and exploring what’s going on. In fact, the term “diagnosis” is a misnomer and should probably never have been borrowed from the rest of medicine, since it implies a precision utterly lacking in psychiatry circa 2010.

Dr. Peter Huang likes the new dimensional aspects of the DSM-V, but is concerned that the new disorders being proposed "will serve as an even bigger seed that Big Pharma + the APA + the FDA will use to increase further the insanely vast quantities of psych meds that are prescribed.” This is also Dr. Allen Frances' main critique in his essay, Opening Pandora’s Box: The 19 Worst Suggestions For DSM5. I agree that this is an inevitable consequence of elaborating the DSM, but only if we psychiatrists acquiesce. Some of these "changes" represent little more than a shuffling around of criteria from one label to another. The two risk syndromes (for psychosis and dementia) are potentially more insidious and might be exploited by drug companies for commercial gain. For this reason, I find it rather unlikely that both will make it into the final version--I predict that mild dementia (in the new vocab, "mild neurocognitive disorder") will make it through the gauntlet, but not "risk syndrome for psychosis."

Dr. Joseph Arpaia points out that DSM is mute when it comes to how the environment produces psychiatric symptoms: “The minimizing of the environmental effects means that the brain's attempts to adapt to the environment are seen as inherent brain pathology. This is as absurd as stating that an immune response to a bacterial invasion is an inherent immune pathology.”

However, the reason DSM does not mention environment is that it attempts to be “agnostic” when it comes to statements of causation. Yes, depression can be caused by many things but DSM simply runs down the list of symptoms. This speaks to the issue of how the document is used. If someone invented a DSM robot (perhaps in Freud's likeness), such a machine would, indeed, simply go through the lists and makes a bunch of diagnoses divorced from context. But thoughtful clinicians, whether psychiatrists or psychologists or social workers, don’t use the manual this way. Don't expect DSM to be more than it is, which is bare-bones descriptive psychiatry. At this point, we know too little about causation to do anything more than describe symptoms.

That's all for now--stay tuned for our next installment of "Commenting on the Commenters."

New study possibly links cognitive and motor delays with 'flat head syndrome' in young babies

February 16, 2010

Researchers caution not to be alarmed; more study needed to determine if delays are persistent and significant

In a new study, infants averaging six months of age who exhibited positional plagiocephaly (flat head syndrome) had lower scores than typical infants in observational tests used to evaluate cognitive and motor development. Positional or deformational plagiocephaly may occur when external forces shape an infant's skull while it is still soft and malleable, such as extended time spent lying on a hard surface or in one position. This is the first controlled study to suggest that babies who have flattened areas on the back of their heads during the first year of life may be at risk for developmental delay. Led by clinical psychologist Matthew L. Speltz, PhD, from Seattle Children's Research Institute, these findings suggest that babies with plagiocephaly should be screened early in life for possible motor and cognitive delays. "Case-Control Study of Neurodevelopment in Deformational Plagiocephaly" published online on February 15 in Pediatrics.

"Developmental plagiocephaly seems to be associated with early neurodevelopmental disadvantage, which was most evident when testing motor skills," said Matthew L. Speltz, PhD, chief of outpatient psychiatric services at Seattle Children's Hospital and professor of psychiatry and behavioral sciences at the University of Washington School of Medicine. "This suggests that babies with flat head syndrome should be screened and monitored for possible cognitive and motor delays. However, it's also important to note that our study examined babies at one particular point in time, so we cannot say with certainty whether these observations continue to hold true as these infants grow older. Our future studies will re-visit this population at 18 and 36 months of age, to see whether this association persists as these infants mature."

"Statistically, there has been a dramatic rise in the diagnosis of positional plagiocephaly since the 1990's. This may be a result of multiple factors, including increased awareness and babies spending more time on their backs in strollers, car seats, infant seats, cribs and sleeping on their backs. This time period also coincides with the national Back-to-Sleep campaign designed to help protect babies against Sudden Infant Death Syndrome (SIDS), although it should be noted that a direct correlation with flat head syndrome hasn't been scientifically established," added Speltz. "For every ten babies, one or two may have at least mild plagiocephaly. Many parents and physicians have dismissed it as a cosmetic issue or one that babies will grow out of as they develop, but our study indicates that we should look deeper."

In the study, 472 babies with ages ranging from four to 12 months (average age six months) were screened for cognitive and motor development using the Bayley Scales of Infant Development III (BSID-III), a series of industry standard observational tests. These common tests observe babies for basic cognitive, language and motor skill development. During the BSID-III, trained examiners present a series of standardized test materials to the child and observe their responses to simple tasks that require problem-solving and memory, such as searching for a hidden toy, as well as the ability to imitate, vocalize, observe and respond to their environment. Infant motor skills like crawling, rolling from side to side, and being able to lift up from a tummy position are also observed and measured. Half of the babies in the study had exhibited and been diagnosed at the Seattle Children's Hospital Craniofacial Center with some level of flat head syndrome, while half were a "normal" control group.

For the study, cranial images and measurements of each baby's head shape and size were also obtained using a 12-camera, 3-D system that allows for 360o imaging of the head. The study found that those babies who exhibited some degree of flatness at the back of the head were more likely to perform worse on the BSID-III, by an average of 10 points for the motor test scale. The most significant lower scores showed in large muscle motor functions, such as rolling from back to side.

Though the findings indicated an association between flat head syndrome and developmental delay, they do not indicate a direct causal link, the researchers say. There may be a reverse correlation, if, for example, babies with pre-existing motor delays are more likely to end up with flatter heads because they may move less or remain in one stationary position for longer periods of time.

"Physicians, psychologists and parents all need to know that it remains very important for babies to continue sleeping on their backs," added Speltz. "Regardless of any suggestion of plagiocephaly or developmental delay, the safest way for babies to sleep still aligns with the Back-to-Sleep campaign's recommendations to help prevent SIDS."

Seattle Children's Research Institute

A Doctor’s Problem With Electronic Records

By James A. White

laptopPaper medical records can easily go missing, contain bad or missing information and undermine patient care. But consider the alternative, says Alexander Friedman, a fellow in maternal-fetal medicine at the University of Pennsylvania.

As a resident fresh out of medical school, Friedman was working an an ememrgency room switching over to electronic medical records, he writes in a guest column on WSJ.com. Checking boxes and inserting codes required by the new system became the focus rather than tending to the patient, he says. As a result, he adds:

I often stood turned away, typing on the computer mounted against the wall, occasionally turning my head over my shoulder to make eye contact. I used a pre-emptive apology — “I’m sorry. I apologize for having my back to you” — but knew the excuses didn’t make up for the rudeness. A patient in pain or worried about her pregnancy deserves attention.

Friedman says EMRs are designed to communicate with insurers, not for care providers to communicate with each other. At the same time, he notes the success of the Veterans Administration’s electronic system in producing dramatic care improvements, as cited in a 2003 NEJM study.

But he sees the VA’s broad effort to apply electronics for improving accountability, integrating services and improving patient safety as an exception to how most systems are designed. “If electronic records are only used to optimize billing and improve chart audits, patients will see little benefit,” he says.

Image: iStockphoto

Ostomy Covers and Bags (Ileostomy, Colostomy): I Bet You Didn't Think Of This

________________________________

Ostomy covers are just one in a long series of supplies necessary in the care of colostomy and ileostomy patients. The words ileostomy and colostomy refer to the procedure ending up with a bag coming out of the abdomen that fills with stool. They are usually placed in folks who have lost the distal portion of their colon (colostomy) or when the entire colon has been removed or when the small bowel must be diverted (ileostomy). They can sometimes be reversed (called a take down) when the underlying reasons for placing them are fixed (such as massive decubiti ulcers).

All ostomy sites, whether they are ileostomy or colostomy sites, must be protected to ensure their survival. Ostomies require care to prevent ulcers at the exit site. They can get ischemic and and swollen and obstructed. Sometimes they need to be surgically revised. They need to be kept clean at the surface to prevent infections. They should be kept dry while in the shower or bath.

And that stuff costs money. You can find ostomy covers and ostomy bags in all assorted sizes and colors at online stores or at your local medical supply company. In fact you can even find designer ostomy covers and bags. Maybe this represents a growth opportunity for the higher end designer bag makers Coach, Kate Spade and Loui Vitton.

Designer ostomy covers and bags could take future growth projections for these higher end bag makers to a whole new level. The growth opportunities are enormous for an aging and wealthy population who cares less about the bag on their shoulder and more about the bag on their belly.

But don't forget about the little ones out there. Perhaps even Disney could market Minnie ostomy covers and bags for the little kids out there stricken with illness. You could have the best first grade show and tell ever with your Goofy ostomy cover. Most kids bring a trinket . Your kid shows his Goofy ostomy cover.

Think of the other possibilities. Hospitals could throw designer ostomy cover and bag parties as a new way to fund their daily operations as the Medicare National Bank goes belly up. Or perhaps, in addition to pet therapy dogs, an ala carte menu of optional services for patients could include offering them special ostomy covers for their ostomy bags.

Look at the spirit of cooperation between hospitals and hospitalists and you can understand the power of market economics in medicine. Many doctors are troubled by today's EMRs. They don't know it yet, but someday EMRs will be their saving grace. And it has nothing to do with making medical care better or more efficient. In fact, as insurance cheapens the value of medical education, EMRs will become nothing more than a tool for direct marketing.

Medical doctors could go the way of chiropractic marketing and show up at trade shows and State Fairs peddling a whole array of ostomy covers and ostomy bags to a public willing to spend their money on everything but actual health care. Or better yet primary care doctors, internists and gastroenterologists could give the knock off jewelery and purse parties a run for their money. These doctors have a focused clientele right at their finger tips. If they have a patient panel and an EMR, they have a whole new and exciting business opportunity just waiting for them.

They just have to run an EMR comparison for those patients with an ostomy and send them an invitation to their private party selling designer or knockoff designer ostomy covers and bags. You think Pampered Chef parties are out of control. Wait until you have a million doctors inviting you to their ostomy cover parties. Just you wait. It's going to happen.

I don't think anyone in Washington thought of the unintended consequences of a declining Medicare payment model coupled with the explosion of EMR technology. Doctors are business owners with an entrepreneurial spirit. They will always search for alternative sources of income as insurance decimates their bottom line. Third party insurance companies just don't want to pay for health care anymore. I witnessed that first hand with my physician review experience. And selling ostomy covers is just one way for doctors to survive. But it won't stop with colostomy covers and ileostomy bags.

Someday you'll have pulmonologists using their EMR for direct marketing of their designer tracheostomy parties. You'll have vascular surgeons using their EMR for direct marketing of their designer stump parties. You'll have opthalmologists taking up designer eyeball tattoos with the help of their EMR. And you'll have primary care doctors doing botox. Oh wait, they are already doing that.

That's the future of the EMR. It has nothing to do with medical care. In fact, the future driving revenue for doctors won't be medical care at all. Insurance killed that idea. It will be medical supplies. Instead of using the EMR to streamline health care, doctors will use it to data mine their patients for the direct to consumer advertising and marketing of goods and services. You heard it here first. You thought the drug companies were bad. Just wait until doctors figure out the power of the EMR.

The whole idea of doctors using their office and patient panel as a direct marketing force de jour lies on the premise that patients are more willing to pay for things than for service. And that's true for most of them. You see them pulling up in their full sized SUVs with the shiny 26 inch rims, their smart phones, their $200 jeans and their cigarettes sticking out of their designer purse. You know they're willing to pay for image. But they won't pay a $10 copay to evaluate their diabetes, heart failure, COPD, atrial fibrillation, high cholesterol, leg pains, dizziness, shakes, dry skin, diarrhea, gas, rash and sore throat all in one visit. You want to survive the future of health care? I suggest you get yourself an EMR and start selling something tangible.

And for the patients who don't want anything to do with designer ostomy covers? What do we do about them? How do we make money on them in the future? We don't. But we take great pleasure in discovering the lengths people go to save a buck. And we enjoy the creative nature of the human mind. Like this awesome guy who made his own designer ostomy cover (actually for a urostomy) by cutting out the back side of a bottle of liquid laundry detergent. I suppose you could say his ostomy will never get dirty. Perhaps this guy should start his own business selling ostomy covers to poor people, so he can then buy one from you at your exclusive invitation only ostomy covers party.

Now there's a thought...

When Evidence Collides With Anecdote, Politics and Emotion: Breast Cancer Screening

By Gary Schwitzer on February 16, 2010 11:35 AM | No Comments | No TrackBacks

That's the title of an editorial in this week's Annals of Internal Medicine (subscription required - even though the article is marked as "free" on the Annals home page.)

It's a reflection on the US Preventive Service Task Force's recommendations on breast cancer screening from last fall. The Annals editors remind readers:

"Although some subspecialty organizations advocate more aggressive routine breast cancer screening, the update actually aligned the USPSTF recommendations more closely with guidelines from the American College of Physicians, the World Health Organization, and the United Kingdom's National Health Service."

Other excerpts:

"Annals posted a survey on our Web site to solicit readers' impressions. The responses suggest that clinicians are more inclined to change what they do in light of the new recommendations than are members of the general public. ...

Clinicians who offer advice compatible with the new USPSTF recommendations are likely to meet resistance. Most women who responded to the survey resolved to continue as routine the practices that the USPSTF advises against being routine. ...

The Task Force's charge is to provide evidence-based, population-level guidance. Only rarely does evidence unequivocally support a single, definite "one-size-fits-all" recommendation. As the breast cancer recommendations so vividly illustrate, clinicians must often invoke the art of medicine to apply available evidence to an individual patient. Before these most recent guidelines, many clinical encounters about breast cancer screening probably involved little more than the physician handing the patient a mammography referral. Going forward, these interactions will surely involve more discussion about risks, harms, benefits, and preference. The Task Force's intent was to motivate such rational discussion, not to ration care. ...

Because the USPSTF issued recommendations that were politically unpopular among some constituents, there have been calls to curtail this independent body's work. If the USPSTF sinks in turbulent waters whipped up by emotion, anecdotes, and politics, Americans should mourn its loss."

Finally, the Annals editors referred to "a media cacophony" - a phrase I've used in reference to coverage of this episode. They wrote that "the media and politicians presented the breast cancer screening recommendations as a major departure from existing guidelines that heralded an age of rationed care in the United States. Confusion, politics, conflicted experts, anecdote, and emotion ruled front pages, airwaves, the Internet, and dinner-table conversations."

This episode was - and still can be - a golden opportunity for informing people about evidence - and for shared decision-making. This won't be last collision between evidence and anedote/politics/emotion. Will we be any smarter next time?

Don’t fall into the dementia trap when treating a developmental disability

February 16, 2010
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by Lockup Doc

In addition to correctional psychiatry, I spend about half of my professional time treating patients with developmental and intellectual disabilities (mental retardation). The majority of my patients have severe or profound mental retardation and are completely nonverbal.

Over the years I have observed that when many of them are admitted to the hospital for acute medical or surgical problems, because they are severely cognitively and functionally impaired, they are treated as though they have terminal illnesses. The treatment approach is often akin to that for patients with end-stage Alzheimer’s Disease.

By definition, a developmental disability (DD) occurs before the age of 18 and is a static condition. Most of my DD patients have genetic syndromes or have suffered from perinatal brain injuries. They have been far behind the curve in meeting developmental milestones, and many never will be able to walk, talk, or have the motor or communication skills or level of independence that most of us enjoy.

However, despite these deficits, each of them has unique strengths. Even those who require significant assistance with their activities of daily living still seem to be able to enjoy various activities in their lives. It would be easy to judge them as having little quality of life, but the longer I work with this population, the more I believe it to be a mistake for the developmentally normal to judge the quality of life of the chronically disabled.

On the surface, these patients are obviously severely impaired, and in many ways some of them do not look much different from those with severe dementia. The key point, though, is that their developmental disabilities are not progressive or terminal illnesses.

In contrast to those with developmental disabilities, patients with end-stage Alzheimer’s Disease have a progressive and ultimately fatal disease. In advanced Alzheimer’s Disease, patients often become incontinent of bowel and bladder, become nonverbal or minimally communicative, have difficulty eating or stop eating altogether, and eventually require assistance with all activities of daily living.

Primary care physicians are familiar with this latter scenario since Alzheimer’s Disease is fairly common. Often their end-stage dementia patient previously will have been a person with normal intellectual functioning who was quite independent. Considering hospice and withholding treatment can be the right decisions in advanced dementia. We often think of such patients as having very little quality of life because of the dramatic losses that have been inflicted by their dementing illness. They clearly are not the same people they used to be.

However, since severe and profound mental retardation are much less common than dementia, and because those with severe developmental disabilities may, on the surface, resemble those with advanced dementia, I believe it is easy to mistakenly think of the two as being in the same end-of-life category even though they are not.

When this mistake occurs, DD patients may have necessary diagnostic and therapeutic interventions withheld even though their physicians may be very competent and believe that they are doing the right thing by not treating these “obviously declining” patients too aggressively.

The key to avoiding falling into the dementia trap when treating a patient with a severe developmental disability is to learn as much as possible about the patient’s baseline level of functioning. For example, if a particular patient has always been nonverbal, incontinent, and gastrostomy-tube fed but does not seem to be losing skills, then the diagnostic and treatment approach likely will be similar to that for any other non-terminal patient. However, if the patient is obviously declining relative to baseline, then a more conservative approach may make sense.

The author is a psychiatrist who blogs at Lockup Doc.

A 31-Year-Old Woman With a Low-grade Glioma

Tom Delbanco, MD

JAMA. 2010;303(7):(doi:10.1001/jama.2010.222).

	Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.

The patient described and interviewed below faces a crossroads in her medical care. Consider her medical history and perspective, expressed in her own words, and review the questions posed. How would you approach this crossroads? Using evidence from the literature as well as your own experience, respond by using the link to the right. Responses will be selected for posting online based on their timeliness and quality, including use of the available evidence, weighing the issues, and addressing the patient's concerns. The discussion of this Clinical Crossroads case, authored by Peter C. Warnke, MD, will be published in the March 10, 2010, issue of JAMA; responses must be received by March 7, 2010, to be considered for online posting.

CASE PRESENTATION

Ms Q is a 31-year-old health care professional who is married and has children. She is currently not working and has commercial health insurance.

. . . [Full Text of this Article]

Author Affiliations: Dr Delbanco is Richard and Florence Koplow–James Tullis Professor of General Medicine and Primary Care, Harvard Medical School, Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Behavioural signs of autism become evident between the ages of 6 and 12 months

By UC Davis MIND Institute, [RxPG] A study of the development of autism in infants, comparing the behavior of the siblings of children diagnosed with autism to that of babies developing normally, has found that the nascent symptoms of the condition — a lack of shared eye contact, smiling and communicative babbling — are not present at 6 months, but emerge gradually and only become apparent during the latter part of the first year of life.

Researchers conducted the study over five years by painstakingly counting each instance of smiling, babbling and eye contact during examinations until the children were 3. They found that by 12 months the two groups’ development had diverged significantly. Intentional social and communicative behavior among children developing normally increased while among infants later diagnosed with autism it decreased dramatically. The study is published online early and will appear in the March issue of the Journal of the American Academy of Child & Adolescent Psychiatry.

“This study provides an answer to when the first behavioral signs of autism become evident,” said Sally Ozonoff, the study’s lead author, a professor of psychiatry and behavioral sciences and a researcher with the UC Davis MIND Institute. “Contrary to what we used to think, the behavioral signs of autism appear later in the first year of life for most children with autism. Most babies are born looking relatively normal in terms of their social abilities but then, through a process of gradual decline in social responsiveness, the symptoms of autism begin to emerge between 6 and 12 months of age.”

Autism is a pervasive developmental disorder of deficits in social skills and communication, as well as in repetitive and restricted behaviors, with onset occurring prior to age 3. Abnormal brain development, probably beginning prenatally, is known to be fundamental to the behaviors that characterize autism. Current estimates place the condition’s incidence at between 1 in 100 and 1 in 110 children in the United States.

Children with a sibling already diagnosed with autism are known to be among those at greatest risk of developing the disorder. The current study included 25 high-risk children who met criteria for autism at 3 years of age, matched with 25 low-risk peers who were developing normally. It was conducted at the MIND Institute and the University of California, Los Angeles. The sole inclusion criterion for the high-risk group was having a sibling with autism; low-risk participants had to have been born after 36 weeks gestation and have no autistic family members.

The children’s development was evaluated at 6, 12, 18, 24 and 36 months of age using a series of widely implemented diagnostic tools, including the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R). Examiners were not told which babies were at high- or low-risk when evaluating the participants’ development.

The researchers found that there were few discernable differences between the two groups at the outset but that after six months, 86 percent of the infants who developed autism showed declines in social communication that were outside the range for typical development. “After six months,” the study found, “the autism spectrum disorder group showed a rapid decline in eye contact, social smiling, and examiner-rated social responsiveness.” Group differences were significant by 12 months in eye contact and social smiling and all other measures by 18 months, the study found.

The study is notable because of the accuracy and precision of its prospective methodology, assiduously recording exact numbers of social and communicative behaviors during lab visits. Previously, researchers have constructed evidence of autism’s earliest manifestations by interviewing parents about when they believed their children’s symptoms first arose or by reviewing home movies for clues to when children begin exhibiting symptoms of autism.

"Until now, research has relied on asking parents when their child reached developmental milestones. But that can be really difficult to recall, and there is a phenomenon called the “telescoping effect” where people usually say that they remember something happening more recently than when it occurred,” Ozonoff said. In addition parents frequently will turn off the video camera when their children are behaving poorly — precisely when autistic symptoms may appear.

Ozonoff said that the study provides a deeper understanding for parents, caregivers and health-care providers and for future research of the developmental trajectory for very young children with autism.

“We need to be careful about how we screen, and we need to know what we’re looking for,” Ozonoff said. “This study tells us that screening for autism early in the first year of life probably is not going to be successful because there isn’t going to be anything to notice. It also tells us that we should be focusing on social behaviors in our screening, since that is what declines early in life.”

“This study also found that the loss of skills continues into the second and third year of life,” she said. “So it may not be adequate, as the American Academy of Pediatrics currently suggests, that providers screen for autism twice before the end of the second year. Autism has a slow, gradual onset of symptoms, rather than a very abrupt loss of skills.”

“Screening may need to continue into the third year of life, since symptom emergence takes place over a long time. If a child starts exhibiting a declining trajectory and a sustained reduction in social communication we want to refer them into therapy, especially if they are at risk,” Ozonoff said, “even before we might be able to make a definitive diagnosis.”

Ozonoff said that the study does not address the etiology of autism or causality. In this study, the infants who participated were at high risk due to having strong family histories of autism, suggesting that genetics plays a major role in the later autism diagnoses, despite the fact that their symptoms were not apparent at birth.

FDA Approves REMS for Drugs That Combat Anemia

WASHINGTON -- The FDA has announced a formal strategy to reduce the risks of erythropoiesis-stimulating agents (ESAs) for cancer patients who take the drugs to treat anemia caused by chemotherapy. Beginning in March, the ESAs darbepoetin (Aranesp) and epoetin alfa (Epogen and Procrit) -- all made by Amgen -- will operate under a Risk Evaluation and Mitigation Strategy (REMS) that will require healthcare providers who prescribe the drugs for cancer patients to register with Amgen and enroll in a training program on use of the agents. The agency is requiring the REMS because studies have shown that ESA use can result in tumor growth and shorten survival in cancer patients who use them to combat anemia. ESAs have also been shown to increase the risk of MI, heart failure, stroke, and blood clots. Physicians who fail to enroll in Amgen's APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) program within a year will be barred from prescribing the drugs. The REMS also will require physicians to provide their cancer patients with a medication guide on how to safely use the drugs and will require doctors to discuss risks, benefits, indications, and dosing guidelines when prescribing ESAs to cancer patients. Patients will be required to sign a document indicating that they understand the risks. "We are doing this to make absolutely certain that patients are fully informed about the risks of these drugs before they begin treatment," said Richard Pazdur, the director of oncology drug products at the FDA, on a Tuesday press call. Use of the ESAs has been controversial. In 2007, CMS announced it would put limits on dose and duration of ESA therapy in reaction to an FDA decision to require a black box warning on the drugs. "We understand that the requirements of the safe use program will create new responsibilities for busy healthcare providers," Pazdur said. "It will require additional time for training, record-keeping, and other tasks related to complying with the program." "However, we are not doing this to make things more difficult for healthcare providers," he said. "We are doing this to make absolutely certain that patients are fully informed of the risks related to the use of these drugs before they begin treatment and throughout their treatment regimen." Hospitals and physicians that dispense ESAs to cancer patients can enroll in the APPRISE program by contacting Centocor Ortho Biotech Products or an Amgen field representative, according to a release from Centocor Ortho Biotech Products. ESAs, which stimulate bone marrow to make red blood cells, are often prescribed to cancer patients for chemotherapy-related anemia. The REMS does not apply to the drugs when they're used to treat kidney disease. The FDA has said it will hold an advisory panel meeting later this year to discuss using ESAs in that setting.

Nephro Endo Hem/Onc Rheum ID Neuro Neuro Allergy Admission Commonly used diabetes drug metformin smells bad and this may explain why many patients st

According to a new study, the diabetes drug metformin smells like fish or dirty socks to some people and this could account for the well-known side effects of the drug, which can make people nauseated.

But the problem could be solved by coating the pills so they do not smell or release the odor into the stomach, where it can be burped up.

Metformin. Image source: Wikipedia, public domain.

References:
http://www.reuters.com/article/idUSTRE61E54H20100215

Should Coke Talk About Heart Health?

By TARA PARKER-POPE

Frazer Harrison/Getty Images for Heart Truth Heidi Klum

Soft drink makers increasingly are being blamed for contributing to the nation’s obesity epidemic. Now a consumer advocacy group is questioning whether Coca-Cola should be allowed to sponsor a national heart health campaign.

The Center for Science in the Public Interest has issued a letter to the National Heart, Lung and Blood Institute asking the agency to end its partnership with Coca-Cola in a program that raises awareness of heart disease among women. Diet Coke is the most prominent sponsor of The Heart Truth campaign, which includes heart graphics on Diet Coke cans and appearances by model Heidi Klum as the “Diet Coke heart health ambassador.”

In a statement, the center’s executive director, Michael Jacobson, compared Coke’s corporate sponsorship to allowing a cigarette maker to fund a government anti-smoking campaign. The fact that the campaign is sponsored by Diet Coke, rather than a sugar-laden soda brand, is irrelevant, he said.

“Coca-Cola promotes heart disease by marketing drinks that contribute to obesity,” Mr. Jacobson wrote. “Coke has long sought to affiliate with or co-opt health groups and associate its brand with athletes and models. I fervently hope that N.H.L.B.I. officials understand that letting Coke bask in their agency’s good reputation does American hearts far more harm than good.”

Coca-Cola defended its participation in The Heart Truth program, saying in a statement:

We’ve used our communications and marketing expertise to reach millions of people with this important heart health message. We’ve made free heart health screenings available to thousands of people across the country. As a result of The Heart Truth campaign, awareness that heart disease is the No. 1 cause of death among women has risen to nearly 70 percent compared to 34 percent in 2000 when the campaign was first introduced. And since Diet Coke has been involved, awareness of The Heart Truth and our support of it has nearly doubled. We are extraordinarily proud of the work we’ve done in partnership with N.H.L.B.I. and Heidi Klum to have a positive impact on the lives of our consumers.

Mr. Jacobson also questioned why other food marketers, such as snack food company Snyder’s of Hanover and Sara Lee Corp. are co-sponsors of the campaign.

What do you think? Should Diet Coke continue as a sponsor of the nation’s heart health awareness campaign? Join the discussion below.

Giant renal oncocytoma: a case report and review of the literature

Abstract (provisional)

Introduction

Renal oncocytomas are benign neoplasms derived from cells of the distal renal tubule, and comprise 5% to 7% of primary renal neoplasms. Oncocytomas are mostly asymptomatic, and the majority of tumors are discovered incidentally. In this case report, we present a case of a patient with a giant oncocytoma arising from her left kidney.
Case presentation

We describe a 25-year-old Turkish woman who was admitted to our hospital with abdominal pain and a 3-year palpable abdominal mass, which was found present since her second pregnancy. Examination revealed a 15x20-cm mass in her abdominal cavity. Computed tomography revealed a mass with regular outlines, measuring 18x11x12cm, associated with the left kidney, and causing marked hydroureteronephrosis. We excised the mass and performed a left nephrectomy on our patient. The immunohistopathology of the mass was consistent with renal oncocytoma. No local or distant metastasis was seen at 6 months postoperatively.
Conclusion

To the best of our knowledge, this is the second largest renal oncocytoma described in the English language literature. This is also the first reported giant oncocytoma that presented during pregnancy.

NT: Nurses urged to use checklists to reduce human error in practice

Last month Nursing Times included an item on checklists, highlighting work by the WHO in perioperative nursing and the Patient Safety First campaign. Following surgery's lead is the realisation that similar checklists have the potential to improve communication and team working in other areas such as nutrition, situational awareness and pressure ulcer care.

Checklists are ubiquitous in our day-to-day lives, the dividend for using them is fairly obvious. What is less obvious is the fact that checklists alone are dead bureaucratic adornments. Checklists are animated by situations and thinking, reflective individuals in those situations. As Lomas reports there is a need to stop at an agreed key point in the patient pathway and ask the critical - checklist - questions. In team work this co-ordinated acknowledgement to complexity is essential for comprehensive, consistent and safe care.

What is interesting here is the emphasis on human factors. While checklists undoubtedly have a demonstrated - proven - role to play in safety, situational awareness is not a product of checklists alone. There is a need for learning and for the cultivation of cognitive lists. While human memory is fallibility incarnate - hence the role for checklists - there is also the need for skilled, knowledgeable professionals with the required communication and observational skills. The need for nurses to further develop observational skills has also been highlighted over recent months.

So as checklists are checked and logged: prepare a space for the mental checklist that is Hodges' model. The model is situated, person-centered and one of the original purposes was to help bridge the theory - practice gap. Try doing that with a checklist: alone

Clare Lomas Safety checklists could cut 'human error' in clinical practice, Nursing Times, 106, 3, 26 January 2010, p.2.

Did Malaria, Bone Disease Kill King Tut?

Feb. 16, 2010 -- Malaria and bone disease may have contributed to the death of King Tut more than 3,300 years ago, a new DNA analysis and other scientific methods indicate.

Many theories have been raised about the death of Tutankhamun, or King Tut, one of Egypt's most famous pharaohs, since his mummy was discovered in 1922. The theories include suggestions that he was murdered or died from an infection after breaking a leg in a fall.

But scientists who used a number of modern methods, including DNA analysis and radiological scans of mummies of Tut and probable close relatives, now report a variety of possible causes of death of Tutankhamun and others, including his grandparents, father, and siblings.

The study, led by Zahi Hawass, PhD, head of Egypt's Supreme Council of Antiquities, includes these points:

• King Tut suffered from avascular bone necrosis, a condition in which poor blood supply to the bone leads to weakening or destruction of an area of bone. This may have been from a rare condition called Kohler's disease that affects the foot.
• He was also found to have a club foot.
• Along with three mummies identified as Tutankhamun's close relatives, Tutankhamun had suffered at some time from malaria, possibly before death, but also perhaps at the time of his demise.
• The researchers write that the bone condition alone would not cause death but in addition to a malaria infection would be a likely cause. "These results suggest avascular bone necrosis in conjunction with the malarial infection as the most likely cause of death of Tutankhamun."

The researchers write that the discovery of several canes and sticks in Tut's tomb, some appearing to have been worn down by use, supports the idea that he had walking problems.

Tutankhamun died in the ninth year of his reign, about 1324 BC, at the age of 19, the researchers say. His mummy was discovered in 1922, and artifacts in the tomb have provided many clues about his life and his family's.

DNA Analysis of Mummy Yields New Clues to Pharaoh's Death

Searching for the Cause of King Tut's Death

Hawass and colleagues studied 11 royal mummies to search for pathological features attributable to inherited disorders, infectious diseases, and blood relationships. They also looked for evidence about what caused King Tut's death. Their research appears in the Feb. 15 issue of The Journal of the American Medical Association.

Some researchers have speculated that he died from complications from an injury, blood poisoning, or an embolism caused by a leg fracture or blow to the head. Others have said the young king may have been murdered because previous research has suggested death from a blow to the back of the head or possibly a fall from a chariot.

Between September 2007 and October 2009, royal mummies underwent detailed genetic, radiological, and anthropological studies. DNA also was extracted from the mummies.

Childhood trauma and psychosis

Great academic article from 2008 that very credibly disputes the biomedical model of psychiatry. This is just a small excerpt:

From Journal of Post Graduate Medicine:

A recent review of the North American psychiatric literature over the past 40 years concluded that potential social causes of psychosis, including schizophrenia, have been neglected in favor of the advancement of genetic and biological etiologies. [30] However, Kraeplinian conceptualizations of psychotic experiences as merely the symptoms of a disordered brain have been challenged by prominent academicians such as Richard Bentall and others who question the validity and utility of schizophrenia as a conceptual and diagnostic entity, and argue that psychotic experiences lie on a continuum with “normal” functioning and suggest that contemporary conceptualizations of “schizophrenia,” “bipolar disorder,” and associated complaints should take into account the role of adverse environmental factors. [31] Furthermore, in the last ten years there has been renewed interest and a growing body of literature examining the role of social and environmental factors in the etiology of psychosis and schizophrenia. Much of this research has specifically focused on the relationship between childhood trauma, psychosis, and schizophrenia.

A number of significant reviews of the literature examining the relationship between childhood trauma, psychosis and schizophrenia have been published in the last few years. [18],[32],[33],[34] A review by Read et al . [6] summarized research studies and examined other review papers addressing the relationship between childhood trauma, psychosis and schizophrenia. This review examined studies of psychiatric inpatients and outpatients where at least 50% were diagnosed with a psychotic condition. Studies that were included were required to have used interview protocols or questionnaire measures that specified examples of abusive acts to determine abuse, therefore chart reviews were excluded. The review produced weighted averages from 51 studies and reported that the majority of female patients (69%) reported either childhood sexual abuse (CSA) (48%) or childhood physical abuse (CPA) (48%). The majority of male patients (59%) reported either CSA (28%) or CPA (50%). The authors of this review point out that these rates are likely to be underestimates as child abuse is generally under-reported [35] especially by people who are inpatients [36],[37] and men in particular. [38] The bulk of the evidence considered in this review, however, was from studies using cross-sectional designs or uncontrolled group comparisons, which the authors concede can give us useful estimates of the prevalence of childhood trauma in clinical populations, but tell us little about whether the relationship between childhood trauma and psychosis is causal. Consequently, Read and colleagues also examined data from four large-scale studies with more sophisticated methodologies which represent a more robust test of the hypothesis that childhood trauma plays a causal role in psychosis. (read much more here)

Definitely an article to keep handy for those who want academic studies that support an alternative view to the biomedical model.

Goodbye false balance over vaccines and autism! May you stay gone!

Category: Alternative medicine • Antivaccination lunacy • Autism • Entertainment/culture • Medicine • Popular culture • Television
Posted on: February 17, 2010 12:00 AM, by Orac

I realize that Chris Mooney is a polarizing figure here on the ol' ScienceBlogs, but I have to give him props for doing a damned fine job handling questions about vaccines, autism, and Andrew Wakefield's utterly discredited 1998 Lancet study, which was retracted by the Lancet's editors last week:

Visit msnbc.com for breaking news, world news, and news about the economy

I wish I could say the same thing for Nancy Snyderman. Although she was mostly right, I cringed--big time--when she insisted that there are no studies that show a link between vaccines and autism. Wrong, wrong, wrong, wrong! What she should have said is that there exist studies that show a link between vaccines and autism, but that they are all crap and many of them are published in highly dubious journals. Heck, I've even blogged about such crappy studies myself on multiple occasions over the years. I suppose you could argue that it's all semantics and that, technically Snyderman is correct, but the way she says it makes it sound as though there are no studies out there on the other side, which is simply not true. The studies touted by the antivaccine propagandists as showing a link between vaccines and autism are all either preliminary studies refuted by later studies or bad science. Let's also not forget that none of Wakefield's followup studies to his 1998 Lancet article has been retracted. They're still out there in the medical literature, even though, as Stephen Bustin showed, they are in essence false positives because the lab that ran the PCR on Wakefield's samples was incompetently run. In any case, Snyderman's statement grated on me and is the sort of thing that plays right into anti-vaccinationists' hands.

It's also interesting to note that Joe Scarborough, who, as you may remember, appeared to buy into the whole refuted thimerosal-autism link back in 2005 when Robert F. Kennedy, Jr. was pushing the link far and wide thrugh the media, appears to have rejoined the reality-based world. He seems to have spit out the Kool Aid and no longer appears to buy into the pseudoscience that falsely links vaccines to autism. I wouldn't have thought it possible five years ago.

Finally, do you notice one more good thing about this video? That's right, there's no balance! There are no boosters of pseudoscience pushing the vaccine-autism link and pulling vaccine Gish gallop.

Even though Chris Mooney is right that the supporters of a vaccine-autism link won't give up (heck, I've already written about that a couple of times), I see reason for optimism. The lazy journalistic trope of false "balance" seems to be giving way to letting the science speak.

A guy can dream, can't he?

In any case, whatever you think of Chris Mooney, be aware that I'm giving him props here. He handled himself well in this case.

What patients dislike about IVF doctors

One of the commonest complaints patients have about their IVF treatment is how secretive most IVF clinics are about the treatment. Many doctors deliberately obfuscate and do not provide any clarity regarding the plan of action. Everything seems to be done on an ad-hoc day to day basis, so the patient is often completely clueless about what is going to happen next.

It's often hard to talk to the doctor ( who is very busy) , which means most decisions seem to be taken either by the nurses or the assistants. Even basic information ( how many follicles are growing on the ultrasound scan ? how many eggs were retrieved during the egg collection ?) is not provided - and the commonest answer the sonographer or assistant provides is - the doctor will explain to you ( but the doctor is never available ! )

Even after the treatment is over, patients are not given a printed treatment summary. No photos of embryos are provided, which means most patients are completely in the dark about the fate of their eggs and embryos - and what went right and what went wrong.

It's high time IVF patients started insisting on clear documentation ! It's best to do this before the cycle starts ( before you part with your money !)

U-M researchers find key interaction that controls telomeres

In the dominoes that make up human cells, researchers at the University of Michigan Comprehensive Cancer Center have traced another step of the process that stops cells from becoming cancerous. It starts with the enzyme telomerase, which affects the caps, or telomeres, at the end of a chromosome. Telomeres shorten over time. But telomerase prevents this from happening, making the cell immortal. If cancer is triggered in the cell, the presence of telomerase leads to the growth of the cancer.

Telomerase is kept in control by the protein TRF1, which keeps the telomeres operating correctly. But another protein, Fbx4, can bind to TRF1 and degrade it, causing the telomeres to lengthen.

Now, researchers have discovered, a third protein, TIN2, can step in and override Fbx4 by binding to TRF1 first and preventing Fbx4 from attaching to it.

This finding paves the way for developing a drug that acts like TIN2, keeping everything in check and stopping the first domino from falling.

Results of the study appear in the Feb. 16 issue of Developmental Cell.

"In 90 percent of cancers, no matter what caused the cancer to form, it needs telomerase activity to maintain the cell. Without telomerase, the cell will die. Our work is key to understanding a detailed mechanism for how these molecules interact and how to design a drug to block Fbx4," says senior author Ming Lei, Ph.D., assistant professor of biological chemistry at the University of Michigan Medical School.

The researchers found that the location in the molecule where Fbx4 binds to TRF1 overlaps with where TIN2 binds to TRF1. Where both Fbx4 and TIN2 are present, the TIN2 wins out and binds to the TRF1 first. This blocks Fbx4 from binding to the TRF1, thereby stabilizing TRF1 and keeping the telomere length in control.

The researchers are now looking at peptides that mimic TIN2's binding to TRF1, in order to block Fbx4. The work is still in preliminary stages and no new therapies are being tested in patients.

If a drug is discovered, it could impact all cancer types. Currently, molecularly targeted therapies address a pathway or gene that's involved in only specific types of cancer. But telomerase is involved in all types of cancer.

"If we find a drug that can inhibit telomerase activity in any fashion, that could be a universal cancer drug," says Lei, a Howard Hughes Medical Institute Early Career Scientist.

Source: University of Michigan Health System

The Misuse of Quetiapine

Dr Shock

A lot of medication gets misused, as is the right expression, meaning not used for the intention or indication it was developed for in the first place. This reminded me of one of my first publications on the abuse of anticholinergics.

From case reports it appears that quetiapine is sought after for recreational use and inappropriate use such as intranasal and intravenous administration. Quetiapine is also for sale on the street, symptom malingering to obtain the drug and higher dosage requests. It’s always important to recognize such misuse of medication because in the case of quetiapine it can induce weight gain, glucose intolerance, in rare cases movement disorders. Moreover, these drugs are very expensive and will cost society more money when misused.

In a recent publication a case report and a review of previous case reports is discussed. The patients mostly seek the “dreamy”, calming, or soporific state with quetiapine. Most patients had a prior drug or alcohol problem and the misuse was often connected to a forensic setting.

Moreover, the authors present possible mechanism as explanation for it’s misuse. First it has an anticholinergic activity which has been described previously with other drugs as cause for misuse. Anticholinergic agents usually cause an euphoric and stimulatory state in patients which doesn’t match with the accounts of patients misusing quetiapine. The authors suggest that the antihistaminic property of questiapine is responsible for it’s misuse.

The misuse potential of quetiapine is likely related to its histaminic blockade coupled with its comparatively mild action at dopamine receptors. Accordingly, quetiapine substitutes for sedating agents and individuals with a history of alcohol, benzodiazepine, or opiate abuse are particularly at risk.

Fischer, B., & Boggs, D. (2010). The role of antihistaminic effects in the misuse of quetiapine: A case report and review of the literature Neuroscience & Biobehavioral Reviews, 34 (4), 555-558 DOI: 10.1016/j.neubiorev.2009.11.003

Multitasking Silicone Elastomers Find Applications in Medical Textiles and Lingerie

February 16, 2010 – 11:45 pm

I don’t think I have ever seen lingerie and medical textiles mentioned in the same sentence (with the possible exception of a David Cronenberg movie), so Bluestar Silicones deserves kudos for breaking new ground. The company has launched a line of silicone elastomers for the fabrication of elastic bands that are equally at home in the boudoir and the OR.

The new platinum polyaddition bicomponent products feature improved anti-slip properties compared with existing technologies while being more comfortable to wear, according to Bluestar Silicones. Silbione TCS 7560 combines elasticity with less compression for the wearer, whilst Silbione TCS 7561 is even more flexible with very low compression, notes the firm. Reduced skin compression and friction afford the wearer greater comfort and confidence for new sensations and enhanced pleasure, adds the press release, although this may not be referencing the material’s medical virtues.

Bluestar Silicones was created in 2007, when China National BlueStar Corp. acquired Rhodia Silicones. It is a global supplier of silicones with manufacturing sites in all regions of the world.

What ailed King Tut?

I admit that I am a bit of an Egyptophile (is this a word?). It was great fun to read “Ancestry and Pathology in King Tutankhamun’s Family”, in JAMA’s February 17 issue. King Tut, made famous by the Steve Martin song of the same name, was portrayed in tomb art (statues/reliefs/sculptures) as androgynous and having a “bizarre form of gynecomastia.”

The authors of the article examined several mummies thought to be related to Tutankhamun via radiological and genetic studies. They developed a family tree, and surprise, surprise, the Tutankhamun family intermarried. Turns out the boy king was the product of a brother sister relationship, and he in turn, likely married his sister. Tut’s apparent grandpappy, Amenhotep had a club foot,which he passed on to Tut. In addition, Tut’s father, the beleaguered Akhenaten, had a cleft palate, which Tut had too. Scoliosus ran rampant as well.

In addition, King Tut had evidence of Plasmodium falciparuminfection, as well as juvenile aseptic bone necrosis, and had may have had to use a cane for much of his life. Images of Tutankhamun frequently show him sitting during activities in which one would usually stand, like hunting. When Tut’s tomb was opened over 130 canes were found, showing signs of wear.

As for the bizarre body type seen it statuary and artistic renderings of the period? The authors found no evidence of inherited syndromes that would cause androgynous features and “bizarre” gynecomastia. The authors conclude that the artistic representations of Akenaten and Tutankhamun were likely stylized and idealized according to the wishes of the king.

The great thing is, the boy king is not likely to sue if the authors are wrong!

Photo

Tags: diseases, King Tut

Predictive Testing of the Melanocortin 1 Receptor for Skin Cancer and Photoaging

Abstract and Introduction

Abstract

Genetic predisposition to melanoma and nonmelanoma skin cancer extends far beyond the Fitzpatrick phenotype classification scheme. Specific alleles of the gene that codes for the malnocortin 1 receptor are predictive of skin cancer risk independent of skin type and hair color. The ability to identify high risk patients independent of the red hair phenotype may help to modify routine sun and skin monitoring behaviors. In addition, as this increased skin cancer risk is likely due to impaired UVA and UVB defence mechanisms, consideration of genetic predisposition may also be appropriate for patients undergoing psoralen + UVA (PUVA) or UVB treatments for various cutaneous disorders, such as psoriasis, eczema, and vitiligo. Testing aimed at improving prognostication may serve to limit the influence of certain risk factors.

Introduction

It has long been known that cutaneous pigmentation is our principal photoprotective defence against the carcinogenic and aging effects of ultraviolet radiation (UVR). Recent evidence,1 however, indicates that much of the defence provided by eumelanin is independent of pigmentation. This photoprotective mechanism, therefore, is determined not only by the quantity of eumelanin in the skin, but also by the variants of eumelanin.

Melanocortin 1 Receptor (MC1R)

The melanocortin 1 receptor (MC1R or alpha melanocytestimulating hormone receptor) is a key protein regulating skin and hair pigmentation. Melanin synthesis is largely modulated by the agonistic binding of alpha-melanocortin (alpha-MSH) and adrenocorticotropic hormone (ACTH) to MC1R. This initiates the cAMP mediated pathway required for UV-induced tanning and ultimately yields the blackbrown pigment (eumelanin). Total melanin content (quantity and variety), as well as the relative amounts of eumelanin and phaeomelanin, are important determinants for skin color, hair color and photoprotection.

Melanin-containing granules (melanosomes) form supranuclear caps in keratinocytes, thus shielding the nuclear deoxyribonucleic acid (DNA) from UVR. In dark skin, melanosomes are found throughout the epidermis, but in fair skin they are absent from the suprabasal layer, allowing for increased UVR penetration and DNA damage.^[2,3] Eumelanin is also a scavenger for reactive oxygen species (ROS).^[3] On the other hand, phaeomelanin may contribute to UV-induced skin damage due to its potential to generate singlet oxygen and hydroxyl radicals in response to UVR.^[3,4] Furthermore, it is also known that the chromophore backbone of eumelanin is responsible for the absorption and scattering of UVR; however, there are several different chromophore monomer units and not all perform this function equally well. As such, it is clear that eumelanin does much more than pigment our skin and there are potential clinical outcomes associated with the eumelanin mix that we are genetically coded to produce.

More than 120 genes have been shown to regulate pigmentation,^[5] with a key gene being HomoloGene 1789 (locus: Chr.16:q24.3). This gene encodes the MC1R, a 7-transmembrane G protein-coupled receptor (GCR) expressed on the surface of melanocytes. The modulation of MC1R function regulates melanin synthesis both qualitatively and quantitatively.^[6] The human MC1R gene is highly polymorphic with over 70 identified alleles.^[7] Certain allelic variants are associated with the red hair phenotype (red hair, fair skin, lack of tanning ability, and propensity to freckle),^[5] melanoma, and nonmelanoma skin cancer.^[2,8–11] The MC1R gene is, of course, not the only gene that is associated with skin cancer risk, but it has been widely studied. As well, 7 identified risk alleles,^[5,9–11] independent of skin type and hair color, appear to confer a greater risk of nonmelanoma skin cancer, melanoma, and photoaging.

Exposing cultured human melanocytes to increasing doses of UVR has shown that total melanin and eumelanin content (MC and EC) correlate inversely with the extent of UVR-induced growth arrest, apoptosis, and induction of cyclobutane pyrimidine dimers (CPD). Melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. MC, mainly EC, and MC1R function are therefore independent determinants of UVR-induced DNA damage in melanocytes.^[3] This may help to explain why the predictive value for skin cancer and photoaging from alleles that code for the MC1R receptor are independent of skin type and hair color.

Furthermore, in helping to explain the independence of photoprotection and pigmentation, it has been demonstrated that melanocortins reduce the generation of hydrogen peroxide and enhance repair of DNA photoproducts independently of pigmentation. Natural expression of certain MC1R allelic variants sensitizes melanocytes to the cytotoxic effect of UVR and increases the burden of DNA damage and oxidative stress.^[1]

It is clear, therefore, that the Fitzpatrick classification of skin type and hair color is insufficient to predict susceptibility to the photo consequences of UVR. While there is no doubt that Fitzpatrick skin type I is more susceptible to burning, skin cancer, and photoaging, the large number of melanoma and nonmelanoma skin cancer patients seen in clinical practice presenting with Fitzpatrick skin types II, III, and IV suggest that additional diagnostic tools are required to identify the spectrum of at-risk patients.

Early work performed in the UK identified a dosage effect of MC1R alleles on sensitivity to UVR (degree of tanning after repeated sun exposure).^[12] Given that red hair approximates an autosomal recessive trait and that there is a higher risk for sun sensitivity amongst heterozygotes of certain allelic variants of the MC1R, this gene is likely associated with diversification in the skin's response to UVR in a majority of the population without red hair. As heterozygotes for the MC1R gene are common, this suggests that the MC1R gene may be regarded with substantial importance as a susceptibility gene for sunburn, photoaging, and skin cancer.^[12]

Studies of MC1R Associated Skin Cancer Risk

In 2000, an Australian investigation across 859 subjects showed MC1R variants in 72% of individuals with cutaneous malignant melanoma (CMM), whereas only 56% of the control individuals carried at least 1 variant (P<>[13] doubled the risk for CMM for each additional allele carried (odds ratio [OR]=2.0; 95% confidence interval [CI] 1.6–2.6).^[8]

In 2001, a broader Dutch study across 961 subjects showed that numerous MC1R gene variants predisposed individuals to cutaneous melanoma. In stratified analyses, the genetic predisposition was shown to be largely independent of skin type and hair color. The ORs, after adjusting for skin type, were 3.6 (95% CI 1.7–7.2) for 2 variants and 2.7 (95% CI 1.5–5.1) for 1 variant. The Asp84Glu variant appeared to confer the highest risk.^[9]

As the tendency to sunburn and inability to tan after sun exposure are known risk factors for both melanoma and nonmelanoma skin cancer,^[14–18] the interest to further investigate the MC1R gene as a predictive indicator for nonmelanoma skin cancer was pursued.

A second Australian study investigated 220 individuals [111 high risk and 109 low risk for basal cell (BCC) and squamous cell carcinomas (SCC)]. Comparative allele frequencies for 9 MC1R variants were determined. An association was demonstrated between the prevalence of BCC, SCC, and solar keratosis (OR=3.15; 95% CI 1.7–5.82) and 3 alleles with a known association with skin UV sensitivity and melanoma. It was concluded that the presence of at least 1 variant allele was informative in predicting risk beyond that gained from observation of pigmentation phenotype.^[10]

A larger study involving 838 subjects (453 with nonmelanoma skin cancer and 385 with no skin cancer) found that the presence of 2 variant alleles indicated increased risk of developing cutaneous SCC (OR=3.77; 95% CI 2.11–6.78), nodular BCC (OR=2.26; 95% CI 1.45–3.52), and superficial multifocal BCC (OR=3.43; 95% CI 1.92–6.15) when compared with carriers of 2 wild type alleles. Furthermore, when stratified by skin type and hair color, the analysis demonstrated that these factors did not materially alter the relative risks.^[11]

It is important to note that all observed odds ratios are expressed as multiples of some baseline level of risk; in this report, it is defined as the level or risk seen with that of none of the studied MC1R risk alleles being present.

Epidemiology

With respect to melanoma, public awareness is increasing, but its incidence is rising at an annual rate of 4–5%. The melanoma incidence in Australia is the highest in the world, exceeding 50 per 100,000 individuals. The lifetime risk of developing melanoma in the US is 1 out of 52 in men and 1 out of 77 in women.19 In the US in 2005, 59,000 people were diagnosed with melanoma and 7700 died of the disease, which translates to about 1 melanoma death per hour.

Melanoma represents one of the most common types of cancer occurring in young adults; it is the leading cause of skin cancer death among this population. Recent data from Cancer Research United Kingdom has shown that skin malignancies have overtaken cervical cancer as the most prevalent cancer striking British women in their 20s.^[20] Although women in this age group represent only a small percentage of patients diagnosed with melanoma, nearly one-third of all cases occur in those younger than 50 years.^[20]

In the US, there has been a 15-fold increase in the incidence of melanoma over the last 40 years, which is a more rapid rate of growth than any other malignancy.^[21] As early metastasis is possible and late stage disease usually fatal, prevention and early detection are crucial. The potential cost savings to the health care system resulting from implementation of these measures in both melanoma and nonmelanoma skin cancer can be significant. It is well known that adopting sun awareness, safer "in sun" behaviors, and greater vigilance, as well as diagnostic advances, can save lives and reduce health care costs. Consequently, screening for specific MC1R allelic variants that could identify patients at higher risk for skin cancer and photoaging independent of their skin type or hair color has generated great interest.

Genomic Testing of MC1R

It is now possible to accurately assess the MC1R receptor using a noninvasive skin sample taken with an epithelial swab. A commercial test is presently available in Canada (and soon in other countries) that identifies the 7 high-risk genetic markers associated with MC1R for melanoma, nonmelanoma skin cancer, and photoaging that are independent of skin type and hair color. The gene assays are performed by a central laboratory and results are generally return to the doctor's office in 14 days.

Travellers Beware: UQ Research Shows Canecutter's Disease On The Rise

A team led by PhD researcher Dr Colleen Lau from the School of Population Health http://www.sph.uq.edu.au/, has discovered the disease, known medically as leptospirosis, was traditionally a concern for males working in the agricultural and livestock industries, as it is contracted from contact with the urine of host animals.

Ms Lau said recreational exposure and international travel have emerged as increasingly important sources of infection over the past decade.

"Many of the areas with a high incidence of leptospirosis are popular destinations for domestic and international travellers," Dr Lau said.

"With the increasing popularity of ecotourism and outdoor adventure activities, travellers are likely to become increasingly exposed through activities that involve contact with freshwater, soil and animals."

Leptospirosis causes influenza-like symptoms such as fever, chills, headache and jaundice but can lead to more serious illness including kidney failure, liver failure, lung haemorrhage, brain infections, and can occasionally be fatal.

Called canecutter's disease in Queensland due to the spread of the disease by canefield rats, the study, published in the journal Travel Medicine and Infectious Disease (click here for abstract), has opened up a new way of looking at the spread of the disease.

As an under-diagnosed cause of fever in adventure seekers and returned travellers, Dr Lau and her co-authors, Professor Phil Weinstein and Lee Smythe, urged clinicians to change their perceptions of the population at risk of contracting leptospirosis, even if they do not fit the mould of a male agricultural worker.

"Early recognition, diagnosis, and treatment will reduce the incidence of severe illness and deaths," she said.

Known high-risk areas for leptospirosis include tropical and subtropical regions such as Queensland, New Zealand, the Pacific Islands, parts of South East Asia and the Caribbean.

Dr Lau is working in one such island, American Samoa, to complete her PhD on an analysis of risk factors for contracting leptospirosis.

Source:
Jeann Wong
Research Australia

CRP is risk factor for heart disease

CRP (C-reactive protein) is a protein made by the liver which is known to be a ‘marker’ for a state of inflammation in the body. In recent years, there has been growing interest in the role CRP might play in heart disease. For instance, CRP is present in the atherosclerotic plaque that is the hallmark of heart disease. Raised CRP may indicate a state of inflammation in the coronary arteries that may set the scene for heart disease. So should doctors be measuring CRP as a risk factor, as they do cholesterol and blood pressure?

A report from the Emerging Risk Factors Collaboration, led by doctors at the University of Cambridge, UK, suggests that we should, indeed, take CRP seriously as a risk factor in heart disease. In this meta analysis, they looked at CRP and other risk factors in 54 long-term prospective studies covering over 160,000 people. CRP was found to be associated with various known heart disease risk factors, like high cholesterol, and with other inflammatory markers. Higher CRP was linked to increased risk of heart disease, stroke, death from these conditions, and overall mortality.

These findings do not, however, prove that CRP actually causes heart disease or stroke, although other studies have suggested it may play a part in blood clotting or rupture of plaque in the arteries, triggering heart attack and stroke. It has also been argued that measuring CRP might help to pinpoint patients at high risk of heart disease more accurately. Some studies have shown, for example, that patients with high CRP may have more to gain from treatment with cholesterol-lowering statins. Further studies are now needed to clarify the role of CRP in heart disease and stroke. Drugs that target CRP are currently in development; it will be interesting to see if these will be a new approach to the prevention and treatment of heart disease and stroke.

Source:

The Emerging Risk Factors Collaboration C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis The Lancet January 9 2010;375:132-140