Sometimes in the health-care universe, the not-so-good news turns out to have beneficial consequences. It was certainly not good news that excessive sugar in our diets contributed to diabetes, a disease with dire consequences. However, that understanding led to effective options for the treatment of that disease. Diabetes affects many millions of people around the globe, but the current treatments permit people to live long lives in good health. Similarly, it was not good news that ingesting large amounts of animal fats could lead to deposits of plaque in our arteries, leading to heart disease, also not a cheerful outcome. Again, that discovery contributed to the development of ways to control cholesterol effectively so that people didn’t have to abjure all foodstuffs that came from any terrestrial animals. To put it succinctly, sometimes the bad news opens ways to live fairly normally in good health.

Here’s an item:

Contrary to expectations, low-fat milk may increase the risk of pre-diabetes

However, while low-fat milk seems to increase that risk, high-fat yogurt may lower it. This finding is highly counter-intuitive and may not apply to populations other than the population specifically described in the study, nor yet to the development of diabetes itself rather than pre-diabetes. Nonetheless, the study that gave rise to these finding was large, lengthy, and robust. (Slurink I. The American Journal of Clinical Nutrition, 118 (2023), 1077–1090

The LifeLines Cohort Study is a large population-based cohort study in the Netherlands that was established as a resource for research on complex interactions between environmental, phenotypic and genomic factors in the development of chronic diseases and healthy aging. The study included 74,132 Lifelines study participants. The researchers evaluated dairy consumption based on validated food-frequency questionnaires. At follow-up, prediabetes was defined based on the World Health Organization guidelines: specifically, fasting blood glucose ranging from 110 to 125 mg/dL and glycated hemoglobin (HbA1c) levels ranging from 6.0% to 6.5%.

I should insert a confusing note here. The range between 125 mg/dL and 140 mg/dL is also considered pre-diabetes by some authorities, as is the range between 6.5% and 7.0% HbA1c. It is above those ranges that the definition of diabetes itself applies. The limited range used in the Dutch study omits a sizable sector of individuals who could be considered to have pre-diabetes, which in turn could affect the outcome.

The study conducted baseline evaluations of the 74,132 Dutch participants from 2006 to 2013 and then subsequent assessments from 2014 to 2018, with follow-ups scheduled every five years. Of these participants, 3.7% developed prediabetes. The study focused on dairy products including fermented dairy, yogurt, milk, cream, ice cream, and cheese.

Here’s where the data gets confusing. Although most dairy products had no associations with prediabetes, one way or the other, low-fat and plain milk consumption tended to increase the risk. And, contrary to what we might assume, consumption of high-fat yogurt was associated with a lower risk of prediabetes.

The study subgroup that consumed low-fat milk and dairy products tended to report higher consumption levels of foods like meat, cheese, and bread. No such association was reported in the cohort that consumed high-fat yogurt. That cohort was about 25% of the total study population.

Particularly among individuals over 60 years old, high-fat dairy consumption was linked to a lower prediabetes risk. In other age groups, associations were non-significant. High-fat yogurt was related to lower prediabetes risk in particularly in highly educated individuals, while low-fat cheese was related to higher risk.

The authors of the study did not speculate as to possible reasons for this association, so it is left to Doc Gumshoe to do the speculating. My attention shifts immediately to the question: what else are those individuals who consumed low-fat dairy products including in their diets? And what are diets of those high-fat yogurt eaters?

My guess is that the high-fat yogurt folks are not much worried about their weight and are in reasonably good overall health, while the low-fat contingent are looking to cut out some calories here and there – and having saved those calories, they feel entitled to splurging on deserts and sweets. But that’s only a guess. However, it does point to a factor in the evaluation of a great many studies that have puzzling outcomes, namely that something else is going on, outside the scope of the study, that significantly affects those outcomes.

I’m reminded of a study which had a similarly counter-intuitive conclusion. It was done several years ago in a single New York City hospital that served a patient population that was mostly persons of color and Hispanics. The study looked at overall health outcomes in their own patients and compared those who (self-reported) drank diet soda versus the ones who drank sugary soft drinks.

The surprising finding was that patients who regularly drank diet soda had higher rates of heart disease, diabetes, and several other chronic conditions than the contingent that drank the sugary soft drinks. That study was discussed in the media, and the speculation was all over the map. Of course, one possibility raised was that the artificial sweeteners used in diet soda were the culprits. There doesn’t seem to be much basis for this notion. Many kinds of artificial sweeteners have been investigated, and there is no substantial evidence that these substances specifically cause harm.

An explanation that strikes me as likely is that the diet soda drinkers – like the low-fat dairy products consumers – figured that having avoided the sugary soft drink menace, they had earned permission to indulge in whatever other kinds of food and drink they craved. Once again, the likely reason for this unexpected link was outside the scope of the study. But it reinforces the principle that in many studies with unexpected findings, we need to ask what other factors are at work.

Cardiovascular health in middle-aged Americans may be declining

This was the conclusion of a study published in December in the Annals of Internal Medicine (Liu M, Ann Intern Med 2023 Dec;176(12):1595-1605). The study was based on information from the National Health and Nutrition Examination Survey (NHANES) which had data on 20,761 middle-aged adults between 1999 and March 2020.

The prevalence of hypertension and diabetes was consistently higher among low-income adults aged 40 to 64 during the study period. Low-income adults had an increase in the prevalence of hypertension over the study period, from 37.2% to 44.7%, but no changes in diabetes or obesity. In contrast, higher-income adults did not have a change in hypertension but did have increases in diabetes, from 7.8% to 14.9%, and also increases in obesity, from 33.0% to 44.0%.

Cigarette use was significantly higher among low-income adults but showed almost no change during the study period, going from 33.2% at the start of the study period to 33.9% at the conclusion. Higher-income adults had much lower rates of cigarette use at the start of the study period, 18.6%, and that rate decreased considerably during the study period, going to 11.5% at the conclusion.

Treatment and control rates for hypertension exceeded 80% in both groups and were essentially unchanged at the conclusion of the study period. In contrast, diabetes treatment rates improved only among the higher-income group, going from 58.4% to 77.4%.

The study authors noted that income-based disparities in hypertension, diabetes, and cigarette use persisted in more recent years even after adjustment for insurance coverage, health care access, and food insecurity.

The lead author of the study, Dr Michael Liu of the Harvard Medical School commented, “Concerningly, we observed that poor cardiovascular health remains concentrated in low-income middle-aged adults. These disparities by income level persisted even after we accounted for insurance coverage, healthcare access, and food insecurity. These results emphasize the importance of addressing these and other social determinants of health that may contribute to the relationship between income and cardiovascular health, such as stable housing, green space for regular physical activity, medication affordability, environmental burdens, and adequate social support.”

What Dr Liu did not mention was that low-income cohort in the study was likely to have considerably different life habits than the higher-income group, and that these habits did not necessarily result from economic differences. To be blunt, lower-income persons are more likely by a wide margin to be cigarette smokers than their better-off counterparts. Also, food-consumption habits tend to differ considerably between socio-economic classes, and these differences are not simply based on the costs of groceries, but on practices based on education and life-style.

If there is a good-news aspect to the findings in this study, it may be that improvements in the prevalence of these health conditions do not depend on medical breakthroughs. They can be attained through simple and low-cost life-style changes.

The BMI takes a hit as an indicator of health status

I was happy to learn that at long last the American Medical Association has taken a position criticizing the commonly-employed body-mass index (BMI) as the determinant factor on whether an individual’s weight was healthy or not. In June of 2023, the AMA finally acknowledged the BMI’s obvious limitations. Here’s part of their statement, based on a report from the AMA Council on Science and Public Health:

“Under the newly adopted policy, the AMA recognizes issues with using BMI as a measurement due to its historical harm, its use for racist exclusion, and because BMI is based primarily on data collected from previous generations of non-Hispanic white populations. Due to significant limitations associated with the widespread use of BMI in clinical settings, the AMA suggests that it be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference and genetic/metabolic factors. The policy noted that BMI is significantly correlated with the amount of fat mass in the general population but loses predictability when applied on the individual level.”

Dr Fatima Cody Stanford, an obesity physician at Mass General Hospital, noted that the BMI was originally meant to determine the normal weight status for Scottish soldiers in the 1800s, and not meant to be extrapolated to the population as a whole. Working with an individual patient, she says, “Let’s look at who you are, as it relates to this number. How does this number relate to your cholesterol values? How does this number relate to your blood sugar? How does this number relate to your liver function tests? How does this number relate to your ability to move and function? I want to get you to the happiest, healthiest weight for you. What is that number? I don’t know.”

Back in May last year, Doc Gumshoe posted a piece entitled “Weight and Waistline Worries” that included a longish discussion of the BMI, concluding that its utility was very limited and that there were good alternatives. Here’s a bit of that piece:

“The rationale for using BMI as an indicator of health status is that is it a quick means of assessing how much fat a person is carrying. That assumes that fat is, of course, always bad for us. There is plenty of evidence that extreme obesity (regardless of how we define extreme obesity) lowers life expectancy. But when we track life expectancy and attempt to correlate it with BMI, the results are a bit contrary to what one might expect. At either end of the scale, no surprises – severely overweight as well as severely underweight individuals have significantly shorter life spans. But when we work our way back towards the middle of the scale, the longest life expectancies are right around a BMI of 25, which is the dividing line between normal and overweight. A BMI of about 27.5, which is in the middle of the overweight category, is associated with the same life expectancy as a BMI of 22,5, which is close to the middle of the normal category. What is more surprising is that as BMI values go lower, while still in the normal range, life expectancy drops. And for underweight persons with a BMI of 18 or lower, life expectancy drops significantly.

Many health authorities prefer metabolic syndrome as a predictor of adverse medical events that affect life expectancy. Metabolic syndrome is characterized by elevated blood pressure, serum cholesterol, and insulin resistance, with elevated levels of blood sugar. An additional characteristic that often predicts metabolic syndrome is greater waist than hip circumference, pointing to significant amounts of excess fat around the middle. As a shorthand method of assessing a person’s overall likelihood of heart disease, waist-to-hip ratio may be a bit more accurate than BMI scores.”

I apologize for repeating myself, but the subject is important, and the message that I would like to put across is that, while the BMI is not a good way to assess a person’s health status, it’s nonetheless important to try to arrive at a reasonable assessment of our health status by other means, and other means are indeed available.

Regular workouts may help to reduce harmful levels of inflammation

Let’s start out with a caveat, namely that the study that this conclusion was based on was carried out in mice, and, as we know, mice are not humans, so we cannot be sure that the same beneficial effect would occur in the likes of us. Still, the data were persuasive.

For a start, we should briefly review what inflammation is and what it does. Our inflammatory reaction is sometimes beneficial and sometimes harmful. When we experience any kind of trauma, ranging from a bruise to a serious wound or an infection, our bodies react with an inflammatory response. Body fluids are dispatched to make a cushion around the bruise, and cells are mobilized to attack invading pathogens and also cancers, which can provoke inflammation. But the mere act of physical exertion also triggers some inflammation. This has been known since the early 20th century, when runners in the Boston Marathon were found to have a sharp spike in their white blood cell count. White blood cells, as you may remember, are produced in the blood mostly as a response to infection, and recruitment of white blood cells is part of the inflammatory response.

However, inflammation also contributes to a number of diseases that present serious challenges to our well-being, including diabetes and heart disease, so a simple way to reduce inflammation could definitely be a benefit.

The healthful effects of exercise are well known. Exercise has been shown to reduce the risk of heart disease, protect us from diabetes, and even help shield us from becoming demented. How exactly this happens on a cellular or molecular level is not well understood, and this question has perplexed researchers for quite a long time.

A new study offers an explanation. The study suggests that the beneficial effects of exercise may be driven, at least partly, by the immune system. It shows that muscle inflammation caused by exertion mobilizes inflammation-countering regulatory T cells (Tregs), which enhance the muscles’ ability to use energy as fuel and improve overall exercise endurance. (Langston PK, Sci Immunology 2023 Nov 3;8(89):eadi5377)

Exercise is known to cause temporary damage to the muscles, unleashing a cascade of inflammatory responses. In the mouse study, the team analyzed what happens in cells taken from the hind leg muscles of mice that ran on a treadmill just one time and also mice that ran regularly on the treadmill. Then, the researchers compared them with muscle cells obtained from mice that did no exercise.

The muscle cells of the mice that ran on treadmills, whether once or regularly, showed classic signs of inflammation — greater activity in genes that regulate various metabolic processes and higher levels of chemicals that promote inflammation, including interferon.

Both groups had elevated levels of those Treg cells in their muscles , which lowered levels of that exercise-induced inflammation. None of those changes were seen in the muscle cells of sedentary mice.

However, the metabolic and performance benefits of exercise were apparent only in the regular exercisers — the mice that had repeated bouts of running. In that group, Tregs not only subdued exertion-induced inflammation and muscle damage, but also altered muscle metabolism and muscle performance. This finding aligns with well-established observations in humans that a single bout of exercise does not lead to significant improvements in performance. Regular exercise over time is needed to yield benefits.

Further analyses confirmed that Tregs were, indeed, responsible for the broader benefits seen in regular exercisers. Mice in which the Tregs had been removed had unrestrained muscle inflammation, marked by the rapid accumulation of inflammation-promoting cells in their hind leg muscles. Their muscle cells also had strikingly swollen mitochondria, a sign of metabolic abnormality.

Also, the mice lacking Tregs did not adapt to increasing demands of exercise over time the way mice with intact Tregs did. They did not derive the same whole-body benefits from exercise and had diminished aerobic fitness.

The muscles of these mice also had excessive amounts of interferon, a known driver of inflammation. Further analyses revealed that interferon acts directly on muscle fibers to alter mitochondrial function and limit energy production. Blocking interferon prevented metabolic abnormalities and improved aerobic fitness in mice lacking Tregs.

The study’s first author, Kent Langston said, “The villain here is interferon. In the absence of guardian Tregs to counter it, interferon went on to cause uncontrolled damage.”

This study suggests that regular exercise may provide a natural way to boost our body’s immune system to reduce harmful inflammation.

How the exercise level achieved by mice having regular workouts on a treadmill would translate to what we humans have to do to achieve the same results is a matter of conjecture. Would a perky daily walk be enough, or do we need an hour a day at the gym? I would welcome an answer.

What makes us itch, and can we find a way to prevent it?

Everybody, and I mean everybody, has an itch from time to time, and those itches can definitely be bothersome. Sometimes the itch develops with conditions like eczema, which is the name for a group of inflammatory skin conditions that cause itchiness, dry skin, rashes, scaly patches, blisters and skin infections. Itchy skin is the most common symptom of eczema. But how inflammation results in the pesky itching sensation has by no means been clear.

A study published in November 2023 has pinpointed a cause. That cause is rooted in a very common skin bacterium, Staphylococcus aureus, which acts directly on nerve cells, leading to the itch sensation. (Deng L, “S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.” Cell. 2023 Nov 22;186(24):5375-5393)

Once again, the study was conducted in mice, which of course is standard practice for early-stage research of this kind. The study experiments showed that S. Aureus releases a chemical that activates a protein on the nerve fibers which transmit signals from the skin to the brain.

What the researchers did was to expose the skin of laboratory mice to S. aureus. The mice developed intensifying itch over several days, and as they kept scratching, it caused worsening skin damage that spread beyond the original site of S. aureus exposure.

Moreover, those mice exposed to S. aureus became hypersensitive to stimuli that would not typically cause any itching. The exposed mice were more likely than unexposed mice to develop abnormal itching in response even to a light touch.

This hyperactive response, a condition called alloknesis, is also common in human patients with chronic conditions of the skin characterized by a persistent itch. But it can also happen in people without any underlying conditions, such as when we don a scratchy wool sweater right on our bare skin.

To determine how the S. aureus microbe triggered itch, the researchers tested multiple modified versions of S. aureus that were engineered to lack specific pieces of the microbe’s molecular makeup. The team focused on 10 enzymes known to be released by this microbe upon skin contact. One after another, the researchers eliminated nine of the suspects, eventually showing that a bacterial enzyme called protease V8 was single-handedly responsible for initiating itch in mice. Human skin samples from patients with atopic dermatitis also had more S. aureus and higher V8 levels than healthy skin samples.

The analyses showed that V8 triggers itch by activating a protein called PAR1, which is found on skin neurons that originate in the spinal cord and carry various signals – touch, heat, pain, itch – from the skin to the brain. Normally, PAR1 lies dormant but upon contact with certain enzymes, including V8, it gets activated. The research showed that V8 snips one end of the PAR1 protein and awakens it. Experiments in mice showed that once activated, PAR1 initiates a signal that the brain eventually perceives as itch. When researchers repeated the experiments in lab dishes containing human neurons, these neurons also responded to V8.

The experiments also demonstrated that, contrary to what might be assumed from previous investigations, various immune cells implicated in skin allergies and classically known to cause itch — mast cells and basophils — did not drive itch after bacterial exposure. Nor did inflammatory chemicals called interleukins, which are activated during allergic reactions and are also known to be elevated in skin diseases.

Because PAR1—the protein activated by S. aureus—is involved in blood-clotting, researchers wanted to see whether an already approved anticlotting drug that blocks PAR1 would stop itch. One such PAR1 inhibitor is vorapaxar, an FDA-approved drug used for reducing the risk of cardiovascular events caused by blood clots, including heart attacks and strokes. Tests in mice showed that the drug did indeed stop itching. The itchy mice whose skin was exposed to S. Aureus experienced rapid improvement when treated with the drug.

Not only did the mice’s impulse to scratch diminish dramatically, but also the skin damage caused by scratching. And once treated with PAR1 blockers, the mice no longer experienced abnormal itching in response to innocuous stimuli such as a gentle touch. Vorapaxar also significantly reduced V8 protease-induced alloknesis for about three hours after V8 injection, which had been identified as the enzyme that causes the itching response.

Vorapaxar is already used in humans to prevent blood clots and could be repurposed as anti-itch medication. For example, the researchers noted, the active ingredient in the medicine could become the basis for anti-itch topical creams.

The development of a really effective anti-itch cream would not rank as a major medical breakthrough, but for people who are severely affected by itching, it could be hugely helpful. In high school I had a shop teacher who was widely known as “Itchy Koch.” The poor chap could not stop scratching. He would have one hand on whatever tool he was demonstrating and the other hand scratching away at an itchy spot on the back of his neck, or wherever it was bothering him most. A vorapaxar ointment might have changed his life.

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This installment of Doc Gumshoe’s pronouncements doesn’t have any notably good news in it, nor yet any really bad news. What I hope it contains is interesting news that affects most of us, in one way or another.

It’s time to take another look at developments on the migraine front. Migraines affect a lot of people, and they have major effects on the daily lives of migraineurs (as the folks who are susceptible to migraines are called). But there have been developments that offer some relief to migraineurs, and I will attempt to bring Gumshoe Nation an update. As always, I welcome questions and comments of all kinds. Stay well!

Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]