[ed note: Michael Jorrin is longtime medical writer who has been sharing his thoughts with our readers as “Doc Gumshoe” for several years (he’s not a doctor, I gave him the name). He generally covers medical and health news and sometimes health promotions and hype, but he rarely opines about investments or specific stocks. All of his past commentaries can be seen here]
Zika virus continues to be in the news and a matter of some concern. Gumshoe Nation likely remembers the recent piece about Cerus and the INTERCEPT system for treating plasma and blood platelets, which was being hyped as a brilliant innovation that would eradicate Zika. In a comment to that piece, I pointed out that Zika, in the overwhelming majority of cases, is transmitted by mosquitoes and not by blood transfusions; also that there are already efficient methods of cleansing plasma and platelets, such as the solvent-detergent system, so I didn’t see Cerus zooming to the stratosphere on the strength of that claim.
But now there is more news on that matter. For the first time, there have been documented cases of Zika transmission in the continental United States – 36 as I’m writing this. The first of these cases turned up in a one-square mile area called Wynwood close to downtown Miami, and they are thought to have been transmitted by those infected Aedes aegypti mosquitoes. Ten cases were really close together, within an area not wider than about 200 yards. Now, five more cases have been detected in Miami Beach, in an area between 8th and 28th streets. Two counties in the Miami area – Miami-Dade and Broward counties – have been asked to suspend blood donations until donated blood can be screened for the Zika virus. Health workers are currently going door-to-door in that neighborhood to collect urine samples to test for Zika. Meanwhile, in New York City, the health department is spraying to kill another mosquito variety, Aedes albopictus, which at this point is not a carrier of Zika. But I guess they’re figuring that a mutation in the virus could make this other mosquito a vector, and trouble would ensue, so better to take the precautionary step.
The FDA had already advised blood centers to refuse donations from persons who had traveled to regions where there had been Zika outbreaks. This would include not only Brazil and neighboring countries in South America, but also Puerto Rico, where about 5,500 cases of Zika infection have been documented, and there are likely many more undocumented, since, as we have observed, in at least 80% of cases the infected individual develops no symptoms and therefore has no reason to be tested.
The number of persons in the US with documented infections has been increasing. It’s at 2,260 as of the 17th of August and includes a very small number of cases of sexual transmission. One case, in New York, seems to have been female-to-male sexual transmission. So far, no cases of Zika transmission by donated blood have been identified in the United States. Such cases have been reported in Brazil, and when there was an outbreak of Zika in the French Polynesian islands in 2013, 2.8% of blood donors tested positive for Zika.
The FDA has stated that plasma and platelets treated with the solvent-detergent system is safe, and will not transmit Zika or other viruses such as HIV and hepatitis C. The Cerus-INTERCEPT system may also be employed in treating plasma and platelets, but it will not have much effect on controlling the Zika outbreak here or anywhere else. Other means are needed, especially mosquito control.
And now for something completely different…
Some tattoo ink may actually be toxic!
If you read my recent piece about viruses and hepatitis C, you probably already know that your faithful Doc Gumshoe doesn’t much care for tattoos. I cited evidence in that piece that tattooing significantly increased the risk of becoming infected with hep C, but not because the ink was toxic. The risk of infection was due to the possibility that the tattoo needles had not been properly disinfected. But now comes a report from the European Chemicals Agency (ECHA) that finds that the dyes in the tattoo inks can lead in some cases to cancer and systemic toxicity. A more likely consequence, already noted by the FDA and a number of other organizations, is painful itching, that can persist for years after the tattoo was inscribed upon the subject.
The FDA has also reported that tattoo inks regularly contain heavy metals, including lead. These are definitely not good for you, even in small quantities, and even if they are trapped between layers of skin. The red ink is supposedly the riskiest, but green, black, and blue inks are also considered harmful. What other colors are left, I wonder?
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A spokesman for the Tattoo and Piercing Industry Union in England put the blame for toxic inks on cheap inks imported from China and other nations, that were not subject to the supposedly high standards that tattoo parlors adhere to – voluntarily, of course, since tattoo parlors are not regulated in the UK either.
What’s happening on the Alzheimer’s disease front?
There’s no comparing Zika with Alzheimer’s as a matter of general concern. Because Zika infections confer a degree of immunity, Zika outbreaks tend to be self-limiting – the 2013 French Polynesian outbreak has not recurred. Alzheimer’s is another matter altogether. The official figure for the prevalence of AD in the United States is 5.4 million, but picking an exact number would require being able to draw the exact line of demarcation for the start of AD. It’s estimated that one in nine persons in the US will develop AD. Currently, the cost of treating AD is stated as being $236 billion. And, of course, “treatment” of AD is “treatment” in name only. Patients mostly do not get better; at best, treatment slows down the decline.
The most recent Doc Gumshoe screed on Alzheimer’s was December 21, 2015, and in it I discussed a considerable number of drugs that were in development for AD. Many of these were BACE inhibitors, directed against amyloid beta (Aβ); some were vaccines, and some targeted Tau protein. Of those, the one I thought was most promising, based on early clinical trial results, was TRx 0237, which was renamed LMTX. This agent came from a small biotech in Scotland, TauRX Pharma, and the latest trial results with LMTX failed to show either cognitive improvement or improvement in the ability to cope with daily functioning. A specific advantage of LMTX is that it is a small molecule, only about 40 atomic units, which gives it superior ability to pass the blood-brain barrier. BACE inhibitors, in contrast, are many orders of magnitude larger, and to get sufficient concentrations in the brain, the dosages have to be much, much higher, increasing the likelihood of adverse effects. LMTX is a derivative of a fairly common compound, methylene blue, which has been used for the treatment of malaria and an uncommon blood disease. Their version is methylonimium chloride, and researchers are working on variations of the compound to improve absorption and distribution. Early studies demonstrated significantly improved cerebral blood flow in early AD patients. My guess is that the recent set-back is certainly bad news, but possibly not the kiss of death for this mechanism.
The focus of a lot of AD research is on identifying patients at much earlier stages of the disease than is now usual. The hope is that whatever the disease process that results in the characteristic cognitive decline, whether it is the aggregation of Aβ or the Tau neurofibrillary tangles or some other as yet unsuspected mechanism, can be significantly slowed down, so patients are able to live on in comparative mental as well as physical health.
Understanding the risk factors that increase a person’s chances of developing AD is not the same thing, by any means, as predicting who will and who will not develop AD. The risk factors have been known for more than 25 years. Individuals with less education are more likely to progress to AD, regardless of economic status or ethnicity. If one sibling went to college and the other one didn’t graduate from high school, guessing which one will develop AD is easy. Hispanics are about one-and-a-half times more likely to develop AD than non-Hispanic whites, and African-Americans are about twice as likely. These differences are not thought to be due to ethnicity, but to increasing prevalence of the usual cardiovascular risk factors which increase the likelihood of developing AD: smoking, obesity, diabetes, elevated cholesterol, and high blood pressure.
But there are also some observed characteristics that appear to predict Alzheimer’s disease, or perhaps we should say that these characteristics are more like early signs of AD. It has been observed that nearly 90% of AD patients demonstrate a number of changes in behavior. The most frequent behavioral disturbances were apathy, which was seen in 72% of patients, followed by agitation (60%), anxiety (48%), irritability (42%), dysphoria and aberrant motor behavior (both 38%), disinhibition (36%), and delusions (22%).
Research at the University of Calgary’s Hotchkiss Brain Institute suggests that observable, sustained changes in behavior can be the first sign of a malfunction in the brain. When older adults have abandoned their social graces and have lost empathy for others, that could be an early clue. Another clue could be problems with impulse control, manifesting as agitation, obsessiveness, or the emergence of new compulsions such as gambling. In older persons with mild cognitive impairment, about 13% progress to dementia within a year. However, if this is accompanied by some of the behavior changes noted above, the rate of progression to dementia increases to about 25% per year.
Another surprising change that appears to predict dementia was discussed at the 2016 Alzheimer’s Association International Conference (AAIC 2016) on July 26th. A small study in persons who had mild cognitive impairment compared the predictive value of the presence of Aβ with another possible sign: performance on a test of the sense of smell. The test used was the University of Pennsylvania Smell Identification Test (UPSIT), which employs a “scratch and sniff” booklet in which subjects try to identify 40 different odors.
As expected, subjects in whom Aβ was detected experienced cognitive decline at the end of six-months of follow-up. A surprise was that subjects who identified fewer than 35 of the 40 odors were more likely to demonstrate cognitive decline than those who could identify 35 or more of the test odors.
From my perspective, both of those correlations make abundant sense. Behavior and the sense of smell are both governed by the brain. When brain function is impeded by the progressive changes which culminate in dementia, it’s the whole organ that is affected. In a previous Doc Gumshoe about AD, the deterioration in brain function was described in more detail, including the eventual decline of vital functions such as digestion of food and respiration.
There could be important benefits in being able to detect early signals of the development of AD. We are all painfully aware of the abysmal failure rate of drugs that were meant to treat AD. It’s not that 99% of those drugs have failed, but that no drug to date has been shown to reverse established AD. The best any drug has been able to accomplish is slow the progression of the disease.
But if AD could be more accurately predicted, whether based on behavior changes or odor recognition or any combination of other factors, slowing the progression might be enough to grant additional years of satisfactory life to millions of people. So, the battle against AD can be carried out on two fronts – better drugs to address disease progression and earlier detection of the disease itself.
(A small aside: the news release that alerted me to the study about the association between smell identification and likelihood of developing dementia was headlined as follows:
“Both Door Identification, Amyloid Status Predict Memory Decline in Older Adults”
I read the news release all the way through twice, finding no mention of “door” identification. Then I twigged. The writer meant “odor identification,” of course, and, as usual on the internet, there was no copy editor. That’s why I always compel my wife to read my stuff before I spring it on you.)
However, there continue to be bright spots on the drug development front. Here’s one:
An HIV drug that might be effective against Alzheimer’s disease
The drug in question is efavirenz (Sustiva, developed by Merck), which is part of the three-drug highly active anti-retroviral therapy (HAART) for HIV in combination with tenofovir and emtricitabine, marketed as Truvada by Gilead. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), and it is this mechanism that makes it effective against HIV. But that is not the mechanism that might also make it effective against AD.
An entirely different mechanism of efavirenz is that it binds to an enzyme, CYP46A1 that breaks down as much as 80% of cholesterol in the brain, actually enhancing that enzyme’s cholesterol-clearing efficiency. To date, this mechanism has been demonstrated in the mouse brain, where the efavirenz-bound enzyme removed about 40% of the cholesterol. It’s expected to be even more effective in human brains, and researchers believe that the evidence strongly suggests that efavirenz might be effective in delaying or preventing AD. Research on this mechanism has been carried out by Case Western and by the Institute for Bioscience and Biotechnology Research at the University of Maryland.
And here’s another cheerful news item:
… and a drug for rheumatoid arthritis that might also be effective against AD
The link between Alzheimer’s and inflammation has been the subject of a great deal of speculation. Is inflammation a – or even the – root cause of AD? A new study that identified more than 40,000 persons in the US with rheumatoid arthritis (RA) found that AD was seven times more prevalent in persons with RA than in the general population – 0.79% vs. 0.11%. (Chou RC, CNS Drugs, July 28, 2016) This was likely due to the heightened activity of the proinflammatory agent tumor necrosis factor alpha (TNFα) in RA patients. These RA patients were also assessed for the relative risk of developing AD based on which of seven standard RA therapies they were receiving. There was a lowered risk for AD in patients who were taking one of the three TNFα inhibitors, but not in patients who were taking the other standard therapies. The TNFα inhibitor that was associated with a lowered risk of AD was etanercept (Enbrel, from Amgen), which lowered the AD risk by about 30%.
So both of those fall into the “glimmers of hope” category, don’t you think?
The incidence of dementia in the US has been declining!
And the decline has been substantial. We’re talking here about dementia from all causes, including AD, but also what is termed “vascular dementia,” which is linked to smoking, diabetes, cardiovascular disease, and other causes.
The data comes from the Framingham Heart Study, and goes back to 1975, when the original Framingham cohort of 5,209 were assessed for cognitive status. The Framingham offspring cohort of 5,214 has been similarly monitored since 1979. Participants have been tested every five or six years since the mid-1970s, and the incidence of dementia has declined by about 20% for every decade during a 30-year period.
For purposes of comparison, researchers looked at four time periods or “epochs”– 1977 to 1983, 1986 to 1991, 1992 to 1998, and 2004 to 2008. Compared to the first epoch, the incidence of dementia in the second epoch declined by 22%, in the third epoch by 38%, and in the fourth epoch by 44%.
Much of the decline took place in vascular dementia, perhaps due to a decrease in the incidence of stroke, related to better control of stroke risk factors such as hypertension and smoking. The decline in Alzheimer’s incidence did not attain statistical significance.
This favorable trend was not seen in persons in that cohort with less than a completed high-school education, mirroring the AD data, and reinforcing the intuitively obvious proposition that people who use their wits more keep them longer.
It should also be pointed out that this decline was observed in a particular limited population. A major factor in the increase in the prevalence of AD in the general population is that people are living longer – currently nearly 20% of the US population is over 65 years of age, and this cohort is growing faster as a proportion of the general population. A hundred years ago, few people lived long enough to develop Alzheimer’s, but not anymore.
Switching to another topic …
What we should – and shouldn’t! – eat
In the check-out line at our local supermarket I was behind a woman with two small yowly children. She was pushing a shopping cart loaded to the gunwales with packaged food products. I detected nothing from the produce section, which is pretty ample in our market; also nothing from the meat or fish counters, unless there were small packages buried under all the other stuff. She began the checkout process by taking a bundle of coupons out of her handbag and carefully presenting them to the checkout clerk (or should I say “customer service representative?”), so I had time to try to scrutinize the labels on some of the stuff she was buying. I recognized very little. She seems to have loaded up on the products in the two long supposedly health-food aisles; notwithstanding, she had a great number of bottles of drinks with labels I did not recognize, except that the word “diet” appeared on several of them. I do occasionally cruise down those aisles, which have organic, gluten-free, non GMO, and other food products that people buy for the sake of health, but I don’t buy much from those aisles.
I freely admit that I am something of a health-food skeptic. To be sure, there are some foods that some people definitely should stay away from, e.g., persons with celiac disease need to avoid wheat and other foods that contain gluten. Some people have food allergies; some foods trigger migraines in some people; foods – and especially drinks – with added sugars pose a metabolic threat. I tend to buy food – fruit, vegetables, meat, fish – not food products. (I do the shopping and cooking in our household, by the way.)
One would think that most people would have a pretty good idea of which foods were good for them and which not, but that’s evidently not so. The Upshot (a New York Times feature specializing in statistical analysis) surveyed a group of nutritionists and a group of ordinary citizens with no special knowledge of nutrition and found wide and peculiar disagreements on what each group thought was a healthy food. The general public thought that food items like granola bars, coconut oil, frozen yogurt, and SlimFast shakes were healthful; the nutritionists disagreed by very wide margins. Foods (and drinks) that nutritionists favored more than the general public included quinoa, tofu, sushi, hummus, wine, and shrimp. There seems to have been general agreement on some vegetables, nuts, olive oil, and the like.
It seems to me that the woman in front of me in the checkout line was not in tune with the nutritionists. Like too many people, she was mostly buying food products, not food. And she was feeding those food products to her kids, probably to save time. And she adopted the strategy of buying food products from the “healthy” aisles, perhaps because she truly believed that it was healthier, but certainly also because it made her feel she was doing the right thing.
There appears to be a great deal of confusion between food labeled “organic” and “non-GMO.” Both labels, to some degree, are a form of “green-marketing.” But there’s a great deal of difference between them, which the general public largely overlooks. In order to qualify for the “organic” label, at a minimum, crops have to be grown without the use of pesticides or chemical weed-killers, and chemical fertilizers may not be used. Organic farmers often have to hire lots of people to pull weeds by hand, and they have to use “natural” fertilizers like chicken manure. Some organic farmers go a step further – the chickens whose manure they use to fertilize their fruits and vegetables can’t have been raised on antibiotics, as so many of the chickens in our supermarkets have been. They need chicken manure from organically –raised chickens. This gets expensive.
In contrast, “non-GMO” is a cinch. A GMO – genetically-modified organism – is one whose DNA includes genetic material from another organism introduced in a laboratory by means of gene-splicing. The GMO label excludes organisms where the genetic material has been introduced by cross-breeding, which has been going on accidentally for eons and deliberately for centuries. If those organisms were included, then everything we ate would be GMO. The fact is that most of our food is non-GMO. There’s no GMO wheat on the market, GMO rice is still being tested, GMO oats don’t exist. And so forth.
Some genetically-modified crops can more easily be raised organically. For example, if the modification makes them naturally pest-resistant; this is one of the goals that those evil plant biologists are aiming for.
A reservation that I have had about GMO crops is that their widespread introduction would be counter to biodiversity. Imagine a GMO wheat strain that would have huge heads, short stout stalks that wouldn’t tend to clump together, would be disease and pest resistant, would use water economically and be responsive to small amounts of a cheap fertilizer, such as ammonia in the irrigation water. Every wheat farmer in the world would plant it. And then, if a new blight were found to affect that particular GMO wheat, a global famine might ensue.
I admit that’s an unlikely scenario. But as for the safety of GMO food, so far there has been nary a glint of evidence that GMO food is related to any health risk.
A bit more about prostate cancer screening
If you’ve been reading these Doc Gumshoe pieces, you likely already know that I strongly disagree with the position of the U. S. Preventive Services Task Force (USPSTF) regarding prostate cancer screening using the blood test for prostate specific antigen (PSA). In 2008, the USPSTF recommended omitting PSA testing in men over the age of 74, and in 2012 this panel’s recommendation was that no men should have the PSA test, not even men at high risk, on the grounds that the harms resulting from unnecessary treatment outweighed the benefits from treatment in the relatively small percentage of men whose prostate cancers would likely advance to life-threatening stages.
I posted a blog on this subject on May 27, 2013, in which I observed, among other things, that one of the two studies on which the USPSTF based their recommendation was seriously flawed. It purported to compare two cohorts – men who had had PSA tests versus men who had not had PSA tests. But it turned out that the many of the men who had not had PSA tests at the initial screening went ahead and got PSA tests later on, so the study wound up comparing a group of men all of whom had had PSA tests with another group of men many of whom had had PSA tests. So it’s hardly surprising that the outcomes were pretty similar – i. e., little or no benefit in terms of reducing cancer deaths.
But now there’s new data, and no matter how the supporters of the USPSTF’s recommendations hedge and waffle, the picture isn’t pretty.
On the one hand, the number of cases of prostate cancer that have been detected has dropped by large margins. The key word in that sentence is “detected.” The number of early stage prostate cancers dropped from 540.8 cases per 100,000 men aged 50 and older in 2008 to 416.2 per 100,000 in 2012. The total reduction in diagnoses of prostate cancer was 33,519 cases. Is it possible that the actual incidence of prostate cancer – not the diagnosis but the incidence – declined by that much over a four year period? Not even remotely likely. Probably the large majority of those men whose cancers escaped diagnosis are living with their undetected cancer. However, in a small percentage, those cancers will prove fatal.
And now, there’s more evidence to support that view. A paper in Prostate Cancer Prostatic Disease (Weiner AB et al, July 19, 2016) reported a steep increase in the incidence of metastatic prostate cancer during the years from 2007 to 2013. Metastatic prostate cancer means that cancerous cells escape the prostate capsule and take up residence elsewhere in the body. A frequent site for metastatic prostate cancer is the bones. In the same period (2007 – 2013) during which the detected incidence of low-risk prostate cancer decreased by about 37%, the incidence of metastatic prostate cancer increased by 72%. In men aged 55 – 69 years, that increase was 92%, from 702 new cases in 2004 to 1,345 cases in 2013.
That study identified all men diagnosed with prostate cancer in the National Cancer Data Base at over a thousand health-care facilities in the US in the decade from 2004 to 2013. The study was not specifically designed to track prostate cancer incidence as a response to the USPSTF’s recommendations. The steepest increase in the incidence of metastatic prostate cancer actually began in 2007, a year before the USPSTF’s first set of recommendations was promulgated, so there is at least a possibility that some other factors may be at work here – possibly more accurate imaging that detects the spread of cancer to the lymph nodes. However, most of the increase occurred after the recommendations went into effect, greatly reducing the number of men who are having PSA tests.
So, in my view, what are the results of the USPSTF’s recommendations? One: tens of thousands of cases of prostate cancer are going undetected each year. Two: many hundreds of those cases of undetected early stage cancer are progressing to late stage, frequently fatal metastatic cancer.
As I’ve said before, it amounts to making more work for the undertaker.
Where do we go from there? The nearly universal response is that better, more accurate, more sensitive screening methods are needed. The USPSTF is hardly about to eat crow, and the medical community, including the most staunch advocates of PSA screening – i.e., the Prostate Cancer Foundation – is not about to brand the USPSTF as a congregation of dunces. Admittedly, current screening methods are not very good. But after PSA testing came into widespread use in the 1990s, there was a steep decline, about 50%, in the incidence of metastatic prostate cancer. And now, when PSA testing itself is in decline, the incidence of metastatic prostate cancer is increasing. What does that tell us? Yes, better screening methods would be terrific, but in the meantime, let’s not scrap the screening methods that we have.
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A small post-script: in a new comment on an old post, “A Defense Against the Evil Cardiac Killer,” a reader requested a list of supplements that I thought might be added to the daily intake of a person at high risk for heart disease. My answer to this is that I do not practice medicine, and I do not advocate for any particular forms of treatment, whether established or alternative medicine. I am not a physician, and I don’t think any responsible physician would suggest a treatment (and, yes, supplements are treatments!) for a patient without first assessing the patient carefully. In case this reader is not keeping up with the Doc Gumshoe output, I’ll respond directly. But to all, please keep the comments coming!