Holmes – Up, Out, In, & Onward

April 28, 2018

Spleen Size Signals Swimming Skill

The Bajau people, or “Sea Nomads”, of the Southeastern Asian Islands are renowned as the best divers in the world. The Bajau have been occupying houseboats for generations, living an entirely marine existence as deep-water hunter-gatherers. They spend hours each day underwater, reaching depths of over 200 feet, equipped with no more than weights and wooden goggles. Numerous studies from Tibet looking at physiology and genetics of high altitude societies have raised the question, how are the best divers in the world adapted to their niche?

A recent study compared the Bajau to the neighboring land-dwelling Salaun people, by analyzing DNA, and spleen size. The human body is well adapted to diving; upon breath holding and the sensation of cold water on the face, the body will change its behavior to limit oxygen consumption and contract the spleen to release oxygenated red blood cells into the circulatory system. The Bajau people’s seemingly superhuman diving skills may be explained by physiological differences, like larger spleens.

Researchers took measurements of non–related Bajau (to avoid familial similarities) using ultrasounds and saliva samples to analyze spleen size and DNA, respectively. As a means of comparison, the scientists took similar measurements from the Salaun people of the same area, who have been identified through DNA to be amongst the most genetically similar to the Bajau, but live a grounded existence with little interaction to the marine environment.

The results show that the Bajau people did have significantly larger spleens than the Salaun people and DNA analysis confidently informed a specific gene related to spleen size and thyroid hormones that was expressed at significantly greater levels in Bajau than Salaun people. This is the physiological and genetic difference the researchers were looking for.

So does that mean professional divers have larger spleens than people who can’t swim? Not necessarily. These differences are the result of natural selection. For thousands of years the Bajau have occupied houseboats, traversing the seas of Southeast Asia, living off of materials and food gathered from deep sea floors, using only simple tools. Over so many years, generations, and deep-water dives, these people have evolved. The environment changed their bodies and their genetics to make them better divers. Imagine how your ancestor’s lives adapted you.

Source:

Ilardo MA, Moltke I, Korneliussen TS, Cheng J, Stern AJ, et al., (2018) Physiological and Genetic Adaptations to Diving in Sea Nomads. DOI: 10.1016/j.cell.2018.03.054

April 19, 2018April 19, 2018

Is It Cancer? Check Your Ink

Mouse tattoos — Calcium detecting tattoos in mice

In recent years increased research has been done on the medical applications of tattoos, they have proven effective in delivering drugs, administering vaccines, and working as blood sugar level sensors in conjunction with skin based electronics. New research out of Switzerland, published in Science, has essentially invented a tattoo that can detect cancer. The tattoo “ink” is injected under the skin, and only becomes visible when it detects elevated calcium levels in the blood, an indicator of breast cancer, colon cancer, lung cancer, and more.

The procedure was developed and demonstrated in mice using reprogrammed calcium detecting cells to produce melanin, a black pigment which color moles and freckles. Thus the tattoo would be invisible when administered, but would appear as a large black dot if blood calcium levels became consistently elevated, as in many types of cancer. Perhaps the greatest difficulty in cancer treatment is diagnosis; by the time a patient notices symptoms and seeks medical attention, the disease may have already begun to grow aggressively. By administering these dormant monitors in people, particularly those at a high risk, cancer can be detected as soon as physiological changes begin.

The tattoo ink is actually made from calcium detecting cells that humans use to regulate calcium in the blood. Calcium is an essential compound for maintaining functions like cell growth, cell death, cell movement and more. But its concentration is precisely regulated, if there is too little the bone marrow will produce more, if there is too much, the bones will stop producing it. So when calcium does become elevated it is usually corrected in a few minutes. But certain cancers can inhibit the hormone that acts to regulate calcium production, and so calcium levels remain consistently elevated.

Though there are other pathologies that can cause elevated calcium levels, the tattoo worked well in mice to detect certain cancers before they became symptomatic. It has also been shown to be resilient to short term fluctuations in blood calcium levels and would be especially useful for patients who display risk factors for these cancers such as those with a diagnosed parent, a history of smoking, or work in hazardous environments.

But even if it is best used in niche applications, this represents a dramatic shift towards an entirely new field of diagnostic tests. Human beings can already have their DNA analyzed and identified for specific disease risk factors, if similar tattoos can be created for Celiac Disease, Parkinsons, Alzheimers, and the rest, then medical attention can be sought and treatment strategies implemented when the disease has only just taken hold, when it is at its most treatable.

Tastanova A, Folcher M, Müller M, Camenisch G, Ponti A, et al., (2018) Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer. DOI: 10.1126/scitranslmed.aap8562

April 3, 2018

Dietary Fiber Decreases Diabetic Difficulties

Every human digestive system is home to trillions of bacterial cells, known as a microbiota. In fact, there are more bacteria in a person’s digestive tract than there are human cells in their entire body. These bacteria play an essential role in digestion, breaking down otherwise indigestible nutrients, into compounds that humans can use. This study finds that increased consumption of fiber can lead to a dramatic reduction in symptoms for patients with Type 2 Diabetes.

Although dietary fiber is indigestible to humans, it is fermentable by the gut microbiota. The gut bacteria ferment the dietary fiber and break it down into short fatty acids, which are essential for moderating glucose, or sugar, concentration, and maintaining proper human health. It is when these fatty acid molecules are lacking that the effects of Type 2 Diabetes are most severe.

Type 2 Diabetes is characterized by an imbalance in glucose concentration in the blood. By increasing short chain fatty acids, excess glucose can be metabolized (broken down and utilized) and the effects of Type 2 Diabetes are greatly diminished. It should come as no surprise that a dietary solution can be offered for a disorder that is largely the result of dietary imbalances, but this study restates the critical importance of the gut microbiota in digestion, and diabetes research. Because though many essential nutrients are indigestible to by humans, there is a lot more at play in digestion than the human physiology.

This study was published in Science Magazine, and serves as a reminder that the gut microbiota is a complex ecosystem that differs greatly from person to person depending on a variety of factors. The relationship between gut bacteria and humans is a mutually beneficial one, as the human consumes fiber, which the bacteria breaks down into usable compounds, which both bacteria and human can utilize. This research may serve to shift the focus in diabetes treatment from dietary glucose, to a more comprehensive understanding of digestive processes.

Zhao L, Zhang F, Ding X, Wu G, Lam YY, et al., (2018) Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 359 (6380), 1151-1156

March 20, 2018

Tumors, No Longer a Guessing Game

What makes one tumor different from another? The word ‘cancer’ can be used to describe hundreds of maladies, from a misshapen mole, to sickle shaped blood cells, to massive tumors in the heart, lungs, or anywhere else. But what makes a heart tumor different from a lung tumor? And why are there four different types of lung cancer? The answer lies in the DNA of each cancer cell.

Currently, doctors diagnose different types of cancer based primarily on where they are, what they look like in scans, and what molecules they are made of when samples are taken in biopsies. A new study introduces a novel method, looking at the methylation of cancer DNA, a process that inhibits or expresses specific functions in a cell that can characterize different disorders. By identifying the specific DNA methylations in each tumor, they can be attributed to a specific diagnosis; this is done simply by removing a small piece of the tumor, and analyzing it in the lab.

This study looked specifically at tumors on the central nervous system (CNS) and performed the methylated cancer DNA diagnostic test for 1104 patients, each diagnosed with one of 64 distinct cancers resulting in CNS tumors. In 76% of cancers, the test matched the existing diagnosis. In 12% of cases, the original diagnosis was revised as a result of this test. In the remaining instances, the test could not match to a known methylation class.

These results are extremely encouraging, and point to the end of subjective cancer diagnoses, where doctors must act as detectives, gathering clues to point to the most likely diagnosis. But this new test is a fingerprint; every cancer has a different one, and once they can be told apart, they need only consult a database stocked with thousands of cancer prints.

And this database is already live and free the world over, the data for every cancer case tested in this manner will be available and shared. Doctors will be able to readily compare the DNA in the cancers they encounter with other cases, which will likely lead to the discovery of new, unique cancers, and dramatically improve the accuracy of diagnoses overall.

Source:

Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, et al., (2018) DNA methylation-based classification of central nervous system tumours. Nature. doi:10.1038/nature26000

March 6, 2018

Asthmatics Breathe a Sigh… of Exasperation

Glucocorticoids are a class of steroids patients with asthma use the world over by way of an inhaler. They are one of several drug classes that can reliably save a persons life in the event of an asthmatic exacerbation. But as many know all too well, severe asthmatic episodes can still persist despite the application of this drug. Conventional wisdom among parents and doctors has been to increase the dosage of administered glucocorticoids in patients with more serious symptoms.

But a new study on asthmatic children across the United States by the National Heart, Blood, and Lung institute finds that there is no significant differences in severity of asthma symptoms or frequency of episodes across average and quintuple doses of glucocorticoids. Further, the study even suggests high doses may stunt growth in children, revealing the possibility of more serious problems in childhood use. The article was published in The New England of Medicine.

The year long study consisted of over 250 asthma sufferers aged 5 to 11 years old, and divided them into 2 groups of continued low-level use, and quintupled use. The experiment was carried out such that neither the patients, their parents, nor the doctors knew which treatment they were receiving.

The results suggest no significant difference between the occurrence of asthmatic exacerbations or their intensity regardless of how much glucocorticoid is administered. The study also collected data on the childrens height and weight during the period and found that the patients taking the quintuple dose displayed slightly shorter stature when controlling for various differences. This may be an indicator of serious developmental problems caused by continuous high use of the drug, and should be a concern for anyone taking or prescribing it.

This study highlights a need for more effective medications in asthma sufferers, and a better understanding of how existing medications work. Glucocorticoids are self-administered in the form of an inhaler, often on an as needed basis. Add to this the fact that children are the most heavily afflicted by asthma, and it becomes extremely easy for a patient to take too much of their prescription. Granted, quintuple dose is a far cry from the average, but when double or triple dose does not lessen the symptoms, one can tend to take too much. In an age of ultra targeted and molecular approaches to medicine, a more precise asthma treatments should be available, given the low threshold of effectiveness on glucocorticoids, let alone its possible ill affects.

Jackson DJ, Bacharier LB, Mauger DT, Boehmer S, Beigelman A, et al., (2018) Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations. DOI: 10.1056/NEJMoa1710988

February 27, 2018February 27, 2018

Liquid Biopsy, Detecting Cancer DNA Before Tumors

A new blood test is capable of identifying genetic markers for eight major types of cancer. Though it only correctly identified cancer 70% of the time, this so-called “liquid biopsy” is a minimally invasive way to screen for cancer when no symptoms are present. It is at this stage cancer is at its most treatable, and at $500 costs no more than a colonoscopy, mammogram, or other cancer screenings.

The importance of such a test cannot be overstated in the fight against cancer. Insidious cancer cells can essentially lie dormant for 20-30 years before they grow into large, spread out masses that are difficult or impossible to eradicate. By identifying the cancer in its nascent stages, it can be usually be readily cured using radiation, surgery, or other common treatments. The difficulty lies in identifying the cancer DNA in patients blood, which is often present in miniscule amounts, and even when identified it can be difficult to trace the tissue of origin.

The eight major cancer types being screened here account for 60%, or 360,000, of all cancer deaths in the US last year, and there is nothing more critical to their effective treatment than an early diagnosis. Though as you can see from the accompanying chart, detectability varies; but this methodology is a work in process with large-scale human trials set to begin soon.

The research comes out of Johns Hopkins University in Baltimore and has been published in the journal Science. As this research begins large-scale human trials it will be evaluated for its utility in hospitals and doctors offices. The hope is that the principles underlying this methodology can be expanded to identify more types of cancer, and with greater accuracy. We may never be able to cure late stage cancer, and the treatments are often ghastly; but if the disease can be identified before it even forms tumors, the cancer can very likely be cured.

Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, et. al. (2018) Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 359(6378): 926-930

February 20, 2018

Ketamine for Dopamine: Club Drug Cures Depression?

Recently ketamine has come under focus for its notable effects treating depression. A new study seeks to identify the pathway that allows its rapid anti-depressant effects. The horse tranquilizer turned party drug may have found another niche. The study was published in Nature, funded by the National Key R&D program of China.

As this research is in its introductory stages, researchers used a mouse model instead of human subjects. To simulate depression symptoms, rats were specifically bred as “Congenitally Learned Helpless” and mice as “Chronic Restraint Stress”. The animals were then injected with Ketamine and their behavior or electrophysiology was examined.

The findings revealed that the ketamine works by inhibiting the NMDAR pathway, nicknamed the “anti-reward center”. Burst evoking stimulation of this pathway has been show to lead to depressive behavior and anhedonia. By inhibiting the NMDAR, downstream reward centers have been shown to quickly elevate mood and produce rapid acting anti-depressant effects.

This research does not address the question of what the long-term effects of ketamine are, and its utility may lie in helping to understand the pathways that regulate depressive mood rather than paving the way for ketamine prescriptions as an antidepressant, being that it has a significant potential for abuse (not to mention a sorted reputation).

Anti-depressants tend to focus on boosting serotonin and dopamine expression to elevate mood, but by understanding and manipulating the pathway that inhibits their expression, a more targeted and effective treatment can be administered. The discovery of the NMDAR antagonist and its rapid anti-depressant effects has been called the most important advance in psychiatry in the last century. We live in an age where clinical depression has become relatively commonplace, and the recently discovered effects of Ketamine as this critical antagonist cannot be ignored.

Yang Y, Cui Y, Sang K, Dong Y, Ni Z et. al. (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554: 317-22

February 13, 2018

Weighing the Risks: Gastric Surgery May Lengthen Life

A recent study found that obese patients who received gastric surgery, rather than nonsurgical weight loss treatment, saw a significant decrease in mortality rates over a 4.5 year period. The researchers identified three specific surgeries, which effectively reduce the size of the stomach so that the patient will feel full with less food. The study consisted of over 8000 obese Israeli citizens and was conducted by the state health service.

The study lasted from 2005-2014, with each patient being followed up with for a minimum of one year after entering the study, an average of 4.5 years and a maximum of 11 years. Specifically, the findings reported a 1.3% mortality rate among obese patients who received gastric surgery and a 2.3% mortality rate among obese patients who opted for nonsurgical treatment. These findings are significant, because even with all the associated risks of surgery, there was still a higher survival rate with it than without.

There is a tendency to dismiss any treatment for obesity other than diet and exercise, as the presence or absence of these are the only treatment or cause of obesity. But in patients who have a history of struggling with this traditional prognosis, they would be better off having the surgery to force them into a lesser diet rather than face the health risks of continuing to remain obese under a less drastic treatment plan, based on these findings.

As a 10 year long study following the ongoing care of 8385 patients, the parameters are more than sufficient to inspire confidence in its results. And even though a 1.3-2.3% may sound small, it is a significant increase in the proportion of mortalities and an indicator of future health and longevity. So perhaps patients who struggle with obesity should consider gastric surgery as a new strategy.

Reges O, Greenland P, Dicker D, Leibowitz M, Hoshen M, Gofer I, Rasmussen-Torvik LJ, Balicer RD. Association of Bariatric Surgery Using Laparoscopic Banding, Roux-en-Y Gastric Bypass, or Laparoscopic Sleeve Gastrectomy vs Usual Care Obesity Management With All-Cause Mortality. JAMA. 2018;319(3):279–290. doi:10.1001/jama.2017.20513

February 6, 2018March 20, 2018

Pepper Patch for Pain Relief

A double blind study out of the Netherlands, funded by Astellas Pharma, have found that skin patches containing capsaicin, the active component of chili peppers, has been show to significantly reduce pain in patients suffering from Painful Diabetic Peripheral Neuropathy (PDPN).

PDPN is characterized by nerve damage due to chronically high blood sugar and diabetes, causing numbness, and often pain in hands, feet, and legs. It is a common complication of diabetes and is most often treated broadly as chronic pain or nerve damage. This study takes a more targeted approach.

The completed study consisted of 352 PDPN patients, half of whom were giving a placebo patch, the other half given a 8% capsaicin patch for only 30 minutes. The patients with the capsaicin achieved at least a 30% reduction on average daily pain, shortened treatment response time, and increased sleep quality. These effects were sustained for up to 12 weeks.

Painful Diabetic Peripheral Neuropathy is a debilitating condition that affects approximately one quarter of type 2 diabetes patients. A lack of treatment consensus has led Doctors to prescribe opiods, antidepressants, and anti-seizure medications to combat the pain. However these medications act on the entire central nervous system, not just the site of the pain, and have the potential for addiction, abuse, withdrawal, and worse. The concentrated capsaicin acts by shocking hyperactive neuron receptors near the skin providing rapid and targeted pain relief after only one 30-minute treatment.

Though over 35% of the non-placebo group reported adverse reactions (compared to 13% in the placebo group), most were mild to moderate in intensity; though 3 non-placebo patients saw severe irritation at the application site.

Doubtlessly this will not replace traditional treatment regimens anytime soon, but as research progresses on the effectiveness of capsaicin for nerve pain relief, it will be helpful to doctors and patients to have a moderately effective and comparably benign treatment for such a complex problem.

To date this is the first known study using a capsaicin patch for pain relief in this population, but if the results are any indication it will not be the last.

Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study Simpson, David M. et al. The Journal of Pain , Volume 18 , Issue 1 , 42 – 53

February 1, 2018February 1, 2018

Throwing the Baby in With the Bathwater: Underwater Bubble CPAP

A new method of Continuous Positive Airway Pressure may be less invasive, more effective, and a far lower cost than traditional methods. A CPAP ventilator system is essential for ensuring the normal breathing of newborn, particularly pre-term infants. CPAP has been shown to increase the survival rates of infants and the Underwater Bubble technique would allow it to be used with fewer limitations.

The underwater bubble technique is named such because as air is pumped into the infants lungs, it exhales into a tube the end of which is submerged in a container of water, regulating the pressure of the entire system. Pressure can be adjusted simply by raising or lowering the depth of the tube.

This study did not conduct trials and experiments but rather evaluated the techniques and their effectiveness in a newborn intensive care unit at a Brazilian university hospital.

The underwater bubble method does not require the insertion of a breathing apparatus making it minimally invasive, and is much lower cost than present alternatives, making the technique more readily available to the developing world.

Really the goal of CPAP is to ensure that newborns are able to breathe without the need for mechanical ventilation or intubation, two invasive and high risk techniques that are fortunately becoming less needed as CPAP progresses.

Another study (Dunn 2011) found that CPAP allowed 48% and 54% of newborns to be managed without mechanical respiration or lung inflating fluid.

Sources:

Abelenda V.L.B., Valente T.C.O,. Marinho C.L., and Lopes A.J. 2018 Effects of underwater bubble CPAP on very-low-birthweight preterm newborns in the delivery room and after transport to the neonatal intensive care unit. Journal of Child Health Care: XX(X) 1-12

Dunn MS, Kaempf J, de Klerk A, et al. (2011) Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 128(5): 1069–1076.

http://journals.sagepub.com/doi/pdf/10.1177/1367493517752500