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TMS for memory: link to article

  1. Philippe Albouy, Aurélien Weiss, Sylvain Baillet, Robert J. Zatorre. Selective Entrainment of Theta Oscillations in the Dorsal Stream Causally Enhances Auditory Working Memory Performance. Neuron, 2017; DOI: 10.1016/j.neuron.2017.03.015

The ability to remember sounds, and manipulate them in our minds, is incredibly important to our daily lives — without it we would not be able to understand a sentence, or do simple arithmetic. New research is shedding light on how sound memory works in the brain, and is even demonstrating a means to improve it.

Scientists previously knew that a neural network of the brain called the dorsal stream was responsible for aspects of auditory memory. Inside the dorsal stream were rhythmic electrical pulses called theta waves, yet the role of these waves in auditory memory were until recently a complete mystery.

To learn precisely the relationship between theta waves and auditory memory, and to see how memory could be boosted, researchers at the Montreal Neurological Institute of McGill University gave seventeen individuals auditory memory tasks that required them to recognize a pattern of tones when it was reversed. Listeners performed this task while being recorded with a combination of magnetoencephalography (MEG) and electroencephalography (EEG). The MEG/EEG revealed the amplitude and frequency signatures of theta waves in the dorsal stream while the subjects worked on the memory tasks. It also revealed where the theta waves were coming from in the brain.

Using that data, researchers then applied transcranial magnetic stimulation (TMS) at the same theta frequency to the subjects while they performed the same tasks, to enhance the theta waves and measure the effect on the subjects’ memory performance.

They found that when they applied TMS, subjects performed better at auditory memory tasks. This was only the case when the TMS matched the rhythm of natural theta waves in the brain. When the TMS was arrhythmic, there was no effect on performance, suggesting it is the manipulation of theta waves, not simply the application of TMS, which alters performance.

“For a long time the role of theta waves has been unclear,” says Sylvain Baillet, one of the study’s co-senior authors. “We now know much more about the nature of the mechanisms involved and their causal role in brain functions. For this study, we have built on our strengths at The Neuro, using MEG, EEG and TMS as complementary techniques.”

The most exciting aspect of the study is that the results are very specific and have a broad range of applications, according to Philippe Albouy, the study’s first author.

“Now we know human behavior can be specifically boosted using stimulation that matched ongoing, self-generated brain oscillations,” he says. “Even more exciting is that while this study investigated auditory memory, the same approach can be used for multiple cognitive processes such as vision, perception, and learning.”

The successful demonstration that TMS can be used to improve brain performance also has clinical implications. One day this stimulation could compensate for the loss of memory caused by neurodegenerative diseases such as Alzheimer’s.

“The results are very promising, and offer a pathway for future treatments,” says Robert Zatorre, one of the study’s co-senior authors. “We plan to do more research to see if we can make the performance boost last longer, and if it works for other kinds of stimuli and tasks. This will help researchers develop clinical applications.”

This study was published in the journal Neuron on March 23, and was a result of collaboration between the Neuroimaging/Neuroinformatics and Cognition research groups of the MNI.  < Sciencedaily

http://neurosciencenews.com/auditory-memory-magnets-6294/

The ability to remember sounds, and manipulate them in our minds, is incredibly important to our daily lives — without it we would not be able to understand a sentence, or do simple arithmetic. New research is shedding light on how sound memory works in the brain, and is even demonstrating a means to improve it.

Scientists previously knew that a neural network of the brain called the dorsal stream was responsible for aspects of auditory memory. Inside the dorsal stream were rhythmic electrical pulses called theta waves, yet the role of these waves in auditory memory were until recently a complete mystery.

To learn precisely the relationship between theta waves and auditory memory, and to see how memory could be boosted, researchers at the Montreal Neurological Institute of McGill University gave seventeen individuals auditory memory tasks that required them to recognize a pattern of tones when it was reversed. Listeners performed this task while being recorded with a combination of magnetoencephalography (MEG) and electroencephalography (EEG). The MEG/EEG revealed the amplitude and frequency signatures of theta waves in the dorsal stream while the subjects worked on the memory tasks. It also revealed where the theta waves were coming from in the brain.

Using that data, researchers then applied transcranial magnetic stimulation (TMS) at the same theta frequency to the subjects while they performed the same tasks, to enhance the theta waves and measure the effect on the subjects’ memory performance.

They found that when they applied TMS, subjects performed better at auditory memory tasks. This was only the case when the TMS matched the rhythm of natural theta waves in the brain. When the TMS was arrhythmic, there was no effect on performance, suggesting it is the manipulation of theta waves, not simply the application of TMS, which alters performance.

Image shows a brain.

Researchers gave 17 individuals auditory memory tasks that required them to recognize a pattern of tones when it was reversed, while being recorded on MEG and EEG. NeuroscienceNews.com image is credited to McGill University. Philippe Albouy.

“For a long time the role of theta waves has been unclear,” says Sylvain Baillet, one of the study’s co-senior authors. “We now know much more about the nature of the mechanisms involved and their causal role in brain functions. For this study, we have built on our strengths at The Neuro, using MEG, EEG and TMS as complementary techniques.”

The most exciting aspect of the study is that the results are very specific and have a broad range of applications, according to Philippe Albouy, the study’s first author.

“Now we know human behavior can be specifically boosted using stimulation that matched ongoing, self-generated brain oscillations,” he says. “Even more exciting is that while this study investigated auditory memory, the same approach can be used for multiple cognitive processes such as vision, perception, and learning.”

The successful demonstration that TMS can be used to improve brain performance also has clinical implications. One day this stimulation could compensate for the loss of memory caused by neurodegenerative diseases such as Alzheimer’s.

“The results are very promising, and offer a pathway for future treatments,” says Robert Zatorre, one of the study’s co-senior authors. “We plan to do more research to see if we can make the performance boost last longer, and if it works for other kinds of stimuli and tasks. This will help researchers develop clinical applications.”

Aging and NAD

A conserved NAD+ binding pocket interactions during aging

 

Story from Sciencedaily copied and pasted:

DNA repair is essential for cell vitality, cell survival and cancer prevention, yet cells’ ability to patch up damaged DNA declines with age for reasons not fully understood.

Now, research led by scientists at Harvard Medical School reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

The findings, published March 24 in Science, offer a critical insight into how and why the body’s ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. NAD, identified a century ago, is already known for its role as a controller of cell-damaging oxidation.

Additionally, experiments conducted in mice show that treatment with the NAD precursor NMN mitigates age-related DNA damage and wards off DNA damage from radiation exposure.

The scientists caution that the effects of many therapeutic substances are often profoundly different in mice and humans owing to critical differences in biology. However, if affirmed in further animal studies and in humans, the findings can help pave the way to therapies that prevent DNA damage associated with aging and with cancer treatments that involve radiation exposure and some types of chemotherapy, which along with killing tumors can cause considerable DNA damage in healthy cells. Human trials with NMN are expected to begin within six months, the researchers said.

“Our results unveil a key mechanism in cellular degeneration and aging but beyond that they point to a therapeutic avenue to halt and reverse age-related and radiation-induced DNA damage,” said senior author David Sinclair, professor in the Department of Genetics at HMS and professor at the University of New South Wales School of Medicine in Sydney, Australia.

A previous study led by Sinclair showed that NMN reversed muscle aging in mice.

A plot with many characters

The investigators started by looking at a cast of proteins and molecules suspected to play a part in the cellular aging process. Some of them were well-known characters, others more enigmatic figures.

The researchers already knew that NAD, which declines steadily with age, boosts the activity of the SIRT1 protein, which delays aging and extends life in yeast, flies and mice. Both SIRT1 and PARP1, a protein known to control DNA repair, consume NAD in their work.

Another protein DBC1, one of the most abundant proteins in humans and found across life forms from bacteria to plants and animals, was a far murkier presence. Because DBC1 was previously shown to inhibit vitality-boosting SIRT1, the researchers suspected DBC1 may also somehow interact with PARP1, given the similar roles PARP1 and SIRT1 play.

“We thought if there is a connection between SIRT1 and DBC1, on one hand, and between SIRT1 and PARP1 on the other, then maybe PARP1 and DBC1 were also engaged in some sort of intracellular game,” said Jun Li, first author on the study and a research fellow in the Department of Genetics at HMS.

They were.

To get a better sense of the chemical relationship among the three proteins, the scientists measured the molecular markers of protein-to-protein interaction inside human kidney cells. DBC1 and PARP1 bound powerfully to each other. However, when NAD levels increased, that bond was disrupted. The more NAD present inside cells, the fewer molecular bonds PARP1 and DBC1 could form. When researchers inhibited NAD, the number of PARP1-DBC1 bonds went up. In other words, when NAD is plentiful, it prevents DBC1 from binding to PARP1 and meddling with its ability to mend damaged DNA.

What this suggests, the researchers said, is that as NAD declines with age, fewer and fewer NAD molecules are around to stop the harmful interaction between DBC1 and PARP1. The result: DNA breaks go unrepaired and, as these breaks accumulate over time, precipitate cell damage, cell mutations, cell death and loss of organ function.

Averting mischief

Next, to understand how exactly NAD prevents DBC1 from binding to PARP1, the team homed in on a region of DBC1 known as NHD, a pocket-like structure found in some 80,000 proteins across life forms and species whose function has eluded scientists. The team’s experiments showed that NHD is an NAD binding site and that in DBC1, NAD blocks this specific region to prevent DBC1 from locking in with PARP1 and interfering with DNA repair.

And, Sinclair added, since NHD is so common across species, the finding suggests that by binding to it, NAD may play a similar role averting harmful protein interactions across many species to control DNA repair and other cell survival processes.

To determine how the proteins interacted beyond the lab dish and in living organisms, the researchers treated young and old mice with the NAD precursor NMN, which makes up half of an NAD molecule. NAD is too large to cross the cell membrane, but NMN can easily slip across it. Once inside the cell, NMN binds to another NMN molecule to form NAD.

As expected, old mice had lower levels of NAD in their livers, lower levels of PARP1 and a greater number of PARP1 with DBC1 stuck to their backs.

However, after receiving NMN with their drinking water for a week, old mice showed marked differences both in NAD levels and PARP1 activity. NAD levels in the livers of old mice shot up to levels similar to those seen in younger mice. The cells of mice treated with NMN also showed increased PARP1 activity and fewer PARP1 and DBC1 molecules binding together. The animals also showed a decline in molecular markers that signal DNA damage.

In a final step, scientists exposed mice to DNA-damaging radiation. Cells of animals pre-treated with NMN showed lower levels of DNA damage. Such mice also didn’t exhibit the typical radiation-induced aberrations in blood counts, such as altered white cell counts and changes in lymphocyte and hemoglobin levels. The protective effect was seen even in mice treated with NMN after radiation exposure.

Taken together, the results shed light on the mechanism behind cellular demise induced by DNA damage. They also suggest that restoring NAD levels by NMN treatment should be explored further as a possible therapy to avert the unwanted side effects of environmental radiation, as well as radiation exposure from cancer treatments.

In December 2016, a collaborative project between the Sinclair Lab and Liberty Biosecurity became a national winner in NASA’s iTech competition for their concept of using NAD-boosting molecules as a potential treatment in cosmic radiation exposure during space missions.

Co-authors on the research included Michael Bonkowski, Basil Hubbard, Alvin Ling, Luis Rajman, Sebastian Moniot, Clemens Steegborn, Dapeng Zhang, L. Aravind, Bo Qin, Zhenkun Lou, and Vera Gorbunova.

The work was funded by the Glenn Foundation for Medical Research, the American Federation for Aging Research, Edward Schulak, grants from the National Institute on Aging and the National Institutes of Health, by the National Library of Medicine/NIH intramural program, the National Cancer Institute, and by Deutsche Forschungsgemeinschaft.

Aging increases cell-to-cell transcriptional variability upon immune stimulation

Scientists have resolved a key question in aging research by showing how mouse immune cells of different ages respond to stimulation. Study demonstrates weaker response of older cells is due to their coordination breaking down, making their response to immune stimulation more variable. Single-cell sequencing technology allows scientists to profile individual cells independently to view cellular activity in high resolution.

Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4+ T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong upregulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.

Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown how aging cripples the production of new immune cells, decreasing the immune system’s response to vaccines and putting the elderly at risk of infection. The study goes on to show that antioxidants in the diet slow this damaging process.

The research, published August 6 in the journal Cell Reports, focused on an organ called the thymus, which produces T lymphocytes, critical immune cells that must be continuously replenished to respond to new infections.

“The thymus begins to atrophy rapidly in very early adulthood, simultaneously losing its function,” said TSRI Professor Howard Petrie. “This new study shows for the first time a mechanism for the long-suspected connection between normal immune function and antioxidants.”

Scientists have been hampered in their efforts to develop specific immune therapies for the elderly by a lack of knowledge of the underlying mechanisms of this process.

To explore these mechanisms, Dr. Petrie and his team developed a computational approach for analyzing the activity of genes in two major thymic cell types — stromal cells and lymphoid cells — in mouse tissues, which are similar to human tissues in terms of function and age-related atrophy. The team found that stromal cells were specifically deficient in an antioxidant enzyme called catalase, which resulted in elevated levels of the reactive oxygen by-products of metabolism and, subsequently, accelerated metabolic damage.

To confirm the central role of catalase, the scientists increased levels of this enzyme in genetically altered animal models, resulting in preservation of thymus size for a much longer period. In addition, animals that were given two common dietary antioxidants, including vitamin C, were also protected from the effects of aging on the thymus.

Taken together, the findings provide support for the “free-radical theory” of aging, which proposes that reactive oxygen species such as hydrogen peroxide, produced during normal metabolism, cause cellular damage that contributes to aging and age-related diseases.

While other studies have suggested that sex hormones, particularly androgens such as testosterone, play a major role in the aging process, it fails to answer the key question — why does the thymus atrophy so much more rapidly than other body tissues?

“There’s no question that the thymus is remarkably responsive to androgens,” Dr. Petrie noted, “but our study shows that the fundamental mechanism of aging in the thymus, namely accumulated metabolic damage, is the same as in other body tissues. However, the process is accelerated in the thymus by a deficiency in the essential protective effects of catalase, which is found at higher levels in almost all other body tissues.”

Unrelated but neat:

  1. Meghan E. McGee-Lawrence Karl H. Wenger Sudipta Misra Catherine L. Davis Norman K. Pollock Mohammed Elsalanty Kehong Ding Carlos M. Isales Mark W. Hamrick Joanna R. Erion Marlena Wosiski-Kuhn Phonepasong Arounleut Mark P. Mattson Roy G. Cutler Jack C. Yu Alexis M. Stranahan. Whole-body Vibration Mimics the Metabolic Effects of Exercise in Male Leptin Receptor Deficient Mice. Endocrinology, 2017 DOI: 10.1210/en.2016-1250

    Abstract

    Whole-body vibration has gained attention as a potential exercise mimetic, but direct comparisons with the metabolic effects of exercise are scarce. To determine whether whole-body vibration recapitulates the metabolic and osteogenic effects of physical activity, we exposed male wildtype (Wt) and leptin receptor deficient (db/db) mice to daily treadmill exercise or whole-body vibration for three months. Body weights were analyzed and compared with Wt and db/db mice that remained sedentary. Glucose and insulin tolerance testing revealed comparable attenuation of hyperglycemia and insulin resistance in db/db mice following treadmill exercise or whole-body vibration. Both interventions reduced body weight in db/db mice and normalized muscle fiber diameter. Treadmill exercise and whole-body vibration also attenuated adipocyte hypertrophy in visceral adipose tissue and reduced hepatic lipid content in db/db mice. Although the effects of leptin receptor deficiency on cortical bone structure were not eliminated by either intervention, exercise and whole-body vibration increased circulating levels of osteocalcin in db/db mice. In the context of increased serum osteocalcin, the modest effects of TE and WBV on bone geometry, mineralization, and biomechanics may reflect subtle increases in osteoblast activity in multiple areas of the skeleton. Taken together, these observations indicate that whole-body vibration recapitulates the effects of exercise on metabolism in type 2 diabetes.

A less strenuous form of exercise known as whole-body vibration (WBV) can mimic the muscle and bone health benefits of regular exercise in mice, according to a new study. WBV consists of a person sitting, standing or lying on a machine with a vibrating platform. When the machine vibrates, it transmits energy to the body, and muscles contract and relax multiple times during each second.

A less strenuous form of exercise known as whole-body vibration (WBV) can mimic the muscle and bone health benefits of regular exercise in mice, according to a new study published in the Endocrine Society’s journal Endocrinology.

WBV consists of a person sitting, standing or lying on a machine with a vibrating platform. When the machine vibrates, it transmits energy to the body, and muscles contract and relax multiple times during each second.

Many people find it challenging to exercise regularly and that is contributing to the obesity and diabetes epidemics. These disorders can increase the risk of bone fractures. Physical activity can help to decrease this risk and reduce the negative metabolic effects of each condition.

“Our study is the first to show that whole-body vibration may be just as effective as exercise at combatting some of the negative consequences of obesity and diabetes,” said the study’s first author, Meghan E. McGee-Lawrence, Ph.D., of Augusta University in Augusta, Ga. “While WBV did not fully address the defects in bone mass of the obese mice in our study, it did increase global bone formation, suggesting longer-term treatments could hold promise for preventing bone loss as well.”

To conduct the study, researchers examined two groups of 5-week-old male mice. One group consisted of normal mice, while the other group was genetically unresponsive to the hormone leptin, which promotes feelings of fullness after eating. Mice from each group were assigned to sedentary, WBV or treadmill exercise conditions.

After a week-long period to grow used to the exercise equipment, the groups of mice began a 12-week exercise program. The mice in the WBV group underwent 20 minutes of WBV at a frequency of 32 Hz with 0.5g acceleration each day. Mice in the treadmill group walked for 45 minutes daily at a slight incline. For comparison, the third group did not exercise. Mice were weighed weekly during the study.

The genetically obese and diabetic mice showed similar metabolic benefits from both WBV and exercising on the treadmill. Obese mice gained less weight after exercise or WBV than obese mice in the sedentary group, although they remained heavier than normal mice. Exercise and WBV also enhanced muscle mass and insulin sensitivity in the genetically obese mice. Although there were no significant effects in the young healthy mice, the low-intensity exercise and WBV protocols were designed for successful completion by obese mice. These findings suggest that WBV may be a useful supplemental therapy to combat metabolic dysfunction in individuals with morbid obesity.

Nanoparticles and gut effects – generally recognized as safe?

Models for oral uptake of nanoparticles in consumer products

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

Zhongyuan Guo, Nicole J. Martucci, Fabiola Moreno-Olivas, Elad Tako, Gretchen J. Mahler. Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine. NanoImpact, 2017; 5: 70 DOI: 10.1016/j.impact.2017.01.002

In the study above, researchers took a meal’s worth of titanium oxide nanoparticles — 30 nanometers across — over four hours (acute exposure), or three meal’s worth over five days (chronic exposure) and determined the effect on the gut. Acute exposure caused no harm,  but chronic exposure diminished the absorptive projections on the surface of intestinal cells called microvilli. With fewer microvilli, the intestinal barrier was weakened, metabolism slowed and some nutrients — iron, zinc, and fatty acids, specifically — were more difficult to absorb. Enzyme functions were negatively affected, while inflammation signals increased. It turns out that nanoparticles are everywhere, especially in food, cosmetics, and pharmaceuticals. It can enter the digestive system through toothpastes, since Titanium dioxide is used to create abrasion needed for cleaning. The oxide is also used in some chocolate to give it a smooth texture; in donuts to provide color; and in skimmed milks for a brighter, more opaque appearance which makes the milk more palatable. Dunkin Donuts stopped using powdered sugar with titanium dioxide nanoparticles in 2015 in response to pressure from the advocacy group As You Sow.

http://www.binghamton.edu/us/story/417/food-additive-found-in-candy-chewing-gum-could-alter-digestive-cell-structu

There is emerging evidence that we have generated strategies to utilise nanoparticles for dietary and physiological benefit evolutionarily.  Thus, nanoparticulate structures are neither inherently toxic nor inherently safe: like all molecules these decisions will rest upon molecular structure, biological environment, degree of exposure and host susceptibility.

Nanoparticues act in a number of wasy internally, especially in the gut lumen, where they are exposed to mucin, proteins, pH changes, and other existing charged particles. There has been described a protein coating of nanoparticle surfaces, referred to as a ‘corona’, this phenomenon has been known for decades and will inevitably happen in the particle’s native environment. In the gastrointestinal tract it is likely that the acidic pH of the stomach, which mainly is maintained even postprandially, and the presence of gastrointestinal enzymes, will serve to denude ingested particles of their surface-adsorbed molecules but then re-adsorption of novel entities will occur in the less acidic small bowel lumen.

There are many exogenous inorganic particles are man-made particles comprising titanium dioxide or silicates/aluminosilicates. Titanium dioxide (designated E171 in Europe) is used for whitening and brightening foods, especially for confectionary, white sauces and dressings, and certain powdered foods.

Titanium dioxide (designated E171 in Europe) is used for whitening and brightening foods, especially for confectionary, white sauces and dressings, and certain powdered foods. It is also used in the pharmaceutical industry as an opacity agent. Titanium dioxide is typically found in gut tissue in the anatase polymorphic form and is a 100-200 nm diameter spherical particle that is resistant to gastrointestinal degradation. Particulate silicates and aluminosilicates (E554, E556 and E559 in Europe) are used in the food industry as anti-caking agents and to allow the flow of powders, and some are present in cheeses, sugars and powdered milks. In the UK, the major five food sources of particulate silicates are salt, drinking powders, chewing gum, instant pot savory snacks and icing sugar.Overall, intake of dietary inorganic microparticles in the UK has been estimated to be about 40 mg/person/day (35 mg for the silicates and 5 mg for titanium dioxide) which equates to a staggering daily exposure of 101214 particles/person.

How are  the partciles taken up in the gut? M-cell-uptake (transcytosis) at the surface of intestinal lymphoid aggregates is the quintessential pathway for gut particle uptake and is very well described, especially for large nanoparticles (20-100 nm) and small microparticles (100-500 nm). Hydrophobic particles appear to be much better taken up than hydrophilic particles,  and  generally, small particles are better taken up than large ones with, perhaps, an optimal size of around 50 nm diameter.

Other sources of nanoparticles (NM) relevant for oral exposure comprise mainly cosmetics (sunscreen, lipsticks, skin creams, toothpaste) and food (packaging, storage life sensors, food additives, juice clarifiers). Whereas NMs in food are intended to be ingested, nanoparticles for instance in cosmetics and ingredients in food packaging may accidently get into the gastrointestinal tract. Major materials used in these products are: silver, and metal oxides of zinc, silica, and titanium. Nanosilver (Ag) is used in food packaging. According to the Woodrow Wilson Nanotechnology Consumer Products Inventory 2011, Ag nanoparticles are the most commonly used new NM in consumer products followed by TiO2, ZnO, platinum (Pt) and silicium oxide NMs (http://www.nanotechproject.org/inventories/consumer/). Although gold NMs are also used in cosmetics, food packaging, beverage and toothpaste their main applications are in the medical field.

Decrease of particle size in the nanoscale has been identified as a main parameter for the increased toxicity of different materials. Polystyrene, for instance, is a very biocompatible polymer used in cell culture. Nanoparticles, however, made from this material are cytotoxic.

Compared to other metal and metal oxide nanoparticles intake of TiO2 by food is relatively high at 5 mg TiO2/person/d .Metal and metal oxide nanoparticles can accumulate in plants  and in animals of the food chain. That is worrisome.

A number of factors effect uptake of particles by the gut. Even in healthy individuals gastrointestinal transit is by far not constant and shows considerable variation through the large intestine . These effects are known to influence oral bioavailability of conventional drugs but are even more important for the effects of NMs because NMs readily adsorb proteins. Mucus represents an efficient acellular barrier. Mucus consists of mucin proteins (highly glycosylated extracellular proteins with characteristic gel-forming properties), antiseptic proteins (lysozyme) and other proteins (lactoferrin), inorganic salts and water. The major functions are the protection and the lubrication of the underlying tissue. The saliva, which is produced by the salivary glands, mainly consists of water (up to 99.5%), inorganic salts, proteins, and mucins. The high molecular weight mucin MG1 can bind to the surface of the epithelium and build the so-called mucus layer, displaying the acellular barrier of the oral cavity The mucus of the following parts, stomach and small and large intestine, is mainly produced by intraepithelial cells, and hickness increases from proximal to distal parts of the small and large intestine . Depending on the method used for the determination, the thickness of the mucus layer shows marked variation..The characteristics facilitating the passage through human mucus are relatively well known: electrostatic repulsion from negatively charged sugar moieties favors the penetration of positively charged hydrophilic molecules; the passage of lipophilic compounds is slow. Viruses, like the Norwalk virus with a size of 38 nm and human papilloma virus with a size of 55 nm diffused in human mucus as rapidly as they do in water These findings suggest that the surface charge plays a crucial role in the transport rates of nanoparticles through a mucus layer

In addition to particle size, dose and duration of the exposure are important for the interpretation of the data. In addition to particle size, dose and duration of the exposure are important. There is  a size-dependent decrease of the uptake from 34% for 50 nm particles to 26% for 100 nm particles , and dose and duration of the exposure are also important for absorption and uptake of NM.

Changes in mucus composition induced by Ag nanoparticles (Jeong et al., 2010), polystyrene particles and diesel exhaust increased mucus permeability and permeation of small molecules by a factor of 5. Thus NM enter more quickly through disease barriers.

The adherence of polystyrene nanoparticles to inflamed colonic mucosa was much higher than to normal mucosa. Inflammation appears to increase uptake and permeation of NMs in vitro and in vivo. Inflammation caused by Yersinia pseudotuberculosis increases the uptake of 100 nm carboxyl polystyrene particles in cell monolayers and in intestinal biopsies. Other factors of absorption include pH and thickness of the mucus layer, the gastrointestinal flora and in gastrointestinal passage time (motility)

Whereas plasma membranes restrict the cellular access for metal ions like silver cations, silver nanoparticles were readily internalized and intracellular silver concentrations were much higher than for silver ions. Studies for uptake and toxicity should, therefore, include AgNO3 for silver nanoparticles (Trojan horse effect) or bulk material.. Absorption may also be altered by a changed metabolization by enterocytes. Polystyrene and silver particles have been shown to inhibit the activity of cytochrome P450 enzymes, of note

To avoid foods rich in titanium oxide nanoparticles you should avoid processed foods, and especially candy. This information may make one question if these NM have any impact on the surge of colitis seen ion the general poplulation? How about autoimmune diseases? How about general inflammation, for if NM damage the intestinal barrier, inflammation results and it’s attendant consequences.

 

http://www.nanotechproject.org/cpi/

Intubation during resuscitation – studies decreasing it’s value

I attached more evidence of the harm caused by intubation of patients in cardiac arrest in-hospital or out of hospital. The JAMA article attached demonstrated the harm caused by the rush to intubate in-hospital patients during cardiac arrest. Early intubation resulted in poorer outcomes:

 

Association Between Tracheal Intubation During Adult In-Hospital Cardiac Arrest and Survival  Abstract and snippets below:

RESULTS

The propensity-matched cohort was selected from 108 079 adult patients at 668 hospitals. The median age was 69 years (interquartile range, 58-79 years), 45 073 patients (42%) were female, and 24 256 patients (22.4%) survived to hospital discharge. Of 71 615 patients (66.3%) who were intubated within the first 15 minutes, 43 314 (60.5%) were matched to a patient not intubated in the same minute. Survival was lower among patients who were intubated compared with those not intubated: 7052 of 43 314 (16.3%) vs 8407 of 43 314 (19.4%), respectively (risk ratio [RR] = 0.84; 95% CI, 0.81-0.87; P < .001). The proportion of patients with ROSC was lower among intubated patients than those not intubated: 25 022 of 43 311 (57.8%) vs 25 685 of 43 310 (59.3%), respectively (RR = 0.97; 95% CI, 0.96-0.99; P < .001). Good functional outcome was also lower among intubated patients than those not intubated: 4439 of 41 868 (10.6%) vs 5672 of 41 733 (13.6%), respectively (RR = 0.78; 95% CI, 0.75-0.81; P < .001). Although differences existed in prespecified subgroup analyses, intubation was not associated with improved outcomes in any subgroup.

CONCLUSIONS AND RELEVANCE

Among adult patients with in-hospital cardiac arrest, initiation of tracheal intubation within any given minute during the first 15 minutes of resuscitation, compared with no intubation during that minute, was associated with decreased survival to hospital discharge. Although the study design does not eliminate the potential for confounding by indication, these findings do not support early tracheal intubation for adult in-hospital cardiac arrest.

Since 2010, guidelines have deemphasized the importance of tracheal intubation during cardiac arrest in adults, and the most optimal approach to airway management during cardiac arrest remains unknown. The 2015 guidelines of both the American Heart Association and the European Resuscitation Council state that either a bag-valve-mask device or an advanced airwaymay be used for ventilation and oxygenation during cardiac arrest, and the guidelines make no distinction between the out-of-hospital and in-hospital setting. 

2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care

A large Japanese observational study of out-of-hospital cardiac arrest showed that advanced airway management was associated with a decreased chance of good outcome  Association of Prehospital Advanced Airway Management With Neurologic Outcome and Survival in Patients With Out-of-Hospital Cardiac Arrest

Data source: Get With The Guidelines Registry

In this large,multicenter, retrospective, observational,matched cohort study, tracheal intubation at anyminute within the first 15 minutes during in-hospital cardiac arrest, compared with no intubation during that minute, was associated with a 3% absolute reduction and 16% relative reduction in survival to hospital discharge. Intubation was also associated with a 2% absolute reduction and 3% relative reduction in ROSC and a 3% absolute reduction and 22% relative reduction in good functional outcome at hospital discharge. An observational study (n = 470) from 1990 of patients with in-hospital cardiac arrest found that tracheal intubation during the cardiac arrest was associated with increased mortality,20 similar to an observational study from 2001 (n = 445). A  large observational study (n = 649 359) from Japan found that tracheal intubation during out-of-hospital cardiac arrest was associated with decreased odds of neurologically favorable survival. In this study, there were important differences in several prespecified subgroup analyses. Tracheal intubation was associated much more strongly with decreased survival among patients with an initial shockable rhythm (32% relative decrease) compared with those with an initial nonshockable rhythm (9% relative decrease). Similar subgroup differences have been reported in the out-of-hospital setting. Association of Prehospital Advanced Airway Management With Neurologic Outcome and Survival in Patients With Out-of-Hospital Cardiac Arrest  

A prior meta analysis demonstrated worse survival with advanced airway interventions:

Airways in Out-of-hospital Cardiac Arrest Systematic Review and Meta-analysis   Results. This meta-analysis included 388,878 patients. The short-term survival for AAI compared to BAI were overall OR 0.84(95% CI 0.62 to 1.13), for endotracheal intubation (ETI) OR 0.79 (95% CI 0.54 to 1.16), and for supraglottic airways (SGA) OR 0.59 (95% CI 0.39 to 0.89). Long-term survival for AAI were overall OR 0.49 (95% CI 0.37 to 0.65), for ETI OR 0.48 (95% CI 0.36 to 0.64), and for SGA OR 0.35 (95% CI 0.28 to 0.44). Sensitivity analyses shows that limiting analyses to adults, non-trauma victims, and instances where AAI was both attempted and successful did not alter results meaningfully. A third of all studies did not adjust for any other confounding factors that could impact on survival. Conclusions. This meta-analysis shows decreased survival for AAIs used out-of-hospital in cardiac arrest, but are likely biased due to confounding, especially confounding by indication. A properly conducted prospective study or a controlled trial is urgently needed and are possible to do.

Further Information from the  study verbatim:

The current study also identified an important subgroup difference according to preexisting respiratory insufficiency: intubation was not significantly associated with outcomes in those with preexisting respiratory insufficiency. A proportion of patients with preexisting respiratory insufficiency might have had cardiac arrest as a consequence of respiratory failure, and early advanced airway management could be beneficial for these patients. Although the effect estimate varied according to subgroup, intubation was not associated with improved survival in any of the subgroups.

A few relatively small randomized trials have been conducted in the out-of-hospital setting comparing various airway devices vs usual care or tracheal intubation, finding no differences in clinical outcomes between groups.

Trial of Continuous or Interrupted Chest Compressions during CPR  In patients with out-of-hospital cardiac arrest, continuous chest compressions during CPR performed by EMS providers did not result in significantly higher rates of survival or favorable neurologic function than did interrupted chest compressions.

Esophageal Gastric Tube Airway vs Endotracheal Tube in Prehospital Cardiopulmonary Arrest   We evaluated the efficacy ofthe esophageal airway (EA) by prospectively randomizing 175 prehospital cardiopulmonary arrest patients to receive either an esophageal gastric tube airway (ECTA) or an endotracheal tube (ET~ If attempts with the initial airway failed, the alternate airway was attempted. The cost of training paramedics in EA use was considerably less than the ET($80 vs ‘l,OOO~ Survival to the emergency room, to hospitalization and to discharge in ET and EGTA groups were 64.4 percent, 1S.6 percent, ILl percent, and 54.1 percent, 27.1 percent, 12.9 percent, respectively-differences not statistically significant. The incidence ofneurologic residual (ET 50 percent, EGTA 36.4 percent) and congestive heartfailure (ET40 percent, ECTA 45.5 percent) in surviving ET and EGTA patients did not differ (NS~ An additional 125consecutive patients with only the opporbmity to receive an EA were also evaluated and did not differ in mortality, neurologic residual, or congestive heartfailure from ETpatients. We conclude that theEA is a s~tisfactory a1temative to the ETfor short-term prehospital use in cardiopulmonary arrest patients.

 

 

 

A little smile may make you less depressed – Botox and depression treatment

treatment-of-depression-with-onabotulinumtoxina-a-randomized-trial-2013

Summary:

Converging lines of evidence suggest a role for facial expressions in the pathophysiology and treatment of mood disorders. To determine the antidepressant effect of onabotulinumtoxinA (OBA) treatment of corrugator and procerus muscles in people with major depressive disorder, we conducted a double blind, randomized, placebo-controlled trial. In an outpatient clinical research center, eighty-five subjects with DSM-IV major depression were randomized to receive either OBA (29 units for females and 40 units for males) or saline injections into corrugator and procerus frown muscles (74 subjects were entered into the analysis). Subjects were rated at screening, and 3 and 6 weeks after OBA treatment. The primary outcome measure was the response rate, as defined by ! 50% decrease in score on the MontgomeryeAsberg Depression Rating Scale (MADRS). Response rates at 6 weeks from the date of injection were 52% and 15% in the OBA and placebo groups, respectively (Chi-Square (1) ¼ 11.2, p < 0.001, Fisher p < 0.001). The secondary outcome measure of remission rate (MADRS score of 10 or less) was 27% with OBA and 7% with placebo (Chi-square (1) ¼ 5.1, p < 0.02, Fisher p < 0.03). Six weeks after a single treatment, MADRS scores of subjects were reduced on average by 47% in those given OBA, and by 21% in those given placebo (ManneWhitney U, p < 0.0005). In conclusion, a single treatment with OBA to the corrugator and procerus muscles appears to induce a significant and sustained antidepressant effect in patients with major depression.

emotional-proprioception-treatment-of-depression-with-afferent-facial-feedback

We develop the concept of emotional proprioception, whereby the muscles of facial expression play a central role in encoding and transmitting information to the brain’s emotional circuitry, and describe its underlying neuroanatomy. We explore the role of facial expression in both reflecting and influencing depressed mood. The circuitry involved in this latter effect is a logical target for treatment with botulinum toxin, and we review the evidence in support of this strategy. Clinical trial data suggest that botulinum toxin is effective in treating depression. We discuss the clinical and theoretical implications of these data. This novel treatment approach is just one example of the potential importance of the cranial nerves in the treatment of depression.

prospective-analysis-of-the-use-of-onabotulinumtoxina-botox-in-the-treatment-of-chronic-migraine

Background:

Chronic migraine affects 2% of the population. It results in substantial disability and reduced quality of life. Medications used for prophylaxis in episodic migraine may also work in chronic migraine. The efficacy and safety of OnabotulinumtoxinA (BOTOX) in adults with chronic migraine was confirmed in the PREEMPT programme. However, there are few real-life data of its use.

Method: 254 adults with chronic migraine were injected with OnabotulinumtoxinA BOTOX as per PREEMPT Protocol between July 2010 and May 2013, their headache data were collected using the Hull headache diary and analysed to look for headache, migraine days decrements, crystal clear days increment in the month post treatment, we looked at the 50% responder rate as well.

Results: Our prospective analysis shows that OnabotulinumtoxinA, significantly, reduced the number of headache and migraine days, and increased the number of headache free days. OnabotulinumtoxinA Botox also improved patients’ quality of life. We believe that these results represent the largest post-marketing cohort of patients treated with OnabotulinumtoxinA in the real-life clinical setting.

 Conclusion: OnabotulinumtoxinA is a valuable addition to current treatment options in patients with chronic migraine. Our results support findings of PREEMPT study in a large cohort of patients, we believe, is representative of the patients seen in an average tertiary headache centre. While it can be used as a first line prophylaxis its cost may restrict its use to more refractory patients who failed three oral preventive treatments

http://www.botoxfordepression.com/ < Website promoting botox use for depression

 

Adalimumab for Hidradenitis Suppurativa

I wrote about Hidradenitis Suppurativa in an earlier post. Of interest is a recent NEJM article on the use of Adalimumab for the treatment of this horrible disease.

 

In the phase three trial:

 

Treatment with adalimumab (40 mg weekly), as compared with placebo, resulted in significantly higher clinical response rates in both trials at 12 weeks; rates of serious adverse events were similar in the study groups. We enrolled 307 patients in PIONEER I and 326 in PIONEER II. Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P<0.001). 

 

Their protocol:

In period 1, patients were randomly assigned in a 1:1 ratio to 40 mg of adalimumab weekly or matching placebo for 12 weeks. In period 2, patients were reassigned to adalimumab at a weekly or every-other-week dose or to placebo for 24 weeks. The primary end point was a clinical response, defined as at least a 50% reduction from baseline in the abscess and inflammatory-nodule count, with no increase in abscess or draining-fistula counts, at week 12.

 

The use of this TNF-alpha inhibitor demonstrated efficacy, but not a cure for this scarring and painful disease. Significant improvement was noted in the rank ordered secondary outcomes of lesion count, pain score, and disease severity.

 

The wording goes:

In conclusion, these two randomized trials involving patients with moderate-to-severe hidradenitis suppurativa showed that adalimumab substantially increased the likelihood of a clinically significant response at week 12, as defined by at least a 50% reduction from baseline in the total abscess and inflammatory-nodule count and no increase in abscess or draining-fistula counts, with or without continued antibiotic treatment.

Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa

 

MIND diet and complex nutritional interactions

 

Hybrid ‘MIND’ Diet Keeps Aging Brain Sharp

MIND diet slows cognitive decline with aging.

Physical Activity Recommendations for the Aging Brain A Clinician-Patient Guide

Is the Mediterranean diet a feasible approach to preserving cognitive function and reducing risk of dementia

Detoxification reactions Relevance to aging

Dietary patterns, cognitive decline, and dementia a systematic review.

Are Anxiety Disorders Associated with Accelerated Aging A Focus on Neuroprogression.

Mediterranean Diet, Cognitive Function, and Dementia A Systematic Review

Highlights From the Institute for Functional Medicine’s 2014 Annual Conference Functional Perspectives on Food and NutritionThe Ultimate Upstream Medicine.

“MIND” is an acronym for Mediterranean-DASH Diet Intervention for Neurodegenerative Delay. Both the Mediterranean and DASH diets have been found to reduce the risk for hypertension, myocardial infarction, and stroke.

What Are the Components to the MIND Diet

MIND diet associated with reduced incidence of Alzheimer’s disease

The MIND diet has 15 dietary components, including 10 “brain-healthy” food groups and five unhealthy groups (ie, red meat, butter and stick margarine, cheese, pastries and sweets, and fried or fast food). To stick to the MIND diet, a person has to limit intake of the designated unhealthy foods, especially butter (<1 tablespoon/day), sweets and pastries, whole fat cheese, and fried or fast food (<1 serving a week for any of the three). As for the brain-healthy foods, a person would need to eat at least three servings of whole grains, a green leafy vegetable, and one other vegetable each day, along with having a glass of wine. They would also need to snack most days on nuts, have beans every other day or so, and eat poultry and berries at least two times a week (berries are the only fruits allowed in the MIND diet) and fish at least once a week. The overall rate of change in cognitive score was a decline of 0.8 standardized score units per year. In mixed models adjusted for a variety of relevant factors, including age, sex, education, total energy intake, APOE4 carrier status, and participation in cognitive activities, the MIND diet score was “positively and statistically significantly” associated with slower decline in global cognitive score (β = 0.0092; P < .0001) and with five cognitive domains, especially episodic memory, semantic memory, and perceptual speed, the researchers report. If a person is eating in a manner that is heart healthy, that’s probably also going to be brain healthy, because the brain does use so much of the nutrients and the oxygen that are carried in the vascular system, and as you age, if your brain isn’t getting enough nutrients and oxygen, it is going to be less likely to be able to deal with other factors that cause Alzheimer’s disease or other dementias. 

Dietary intakes of berries and flavonoids in relation to cognitive decline  Results: Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend ¼ 0.014 and mean difference ¼ 0.04, 95% confidence interval [CI] ¼ 0.01–0.07, comparing extreme categories of intake; for strawberries: p-trend ¼ 0.022 and mean difference ¼ 0.03, 95% CI ¼ 0.00–0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we found for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends ¼ 0.015 and 0.053, respectively, for the global score). Interpretation: Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults.

http://www.medscape.com/viewarticle/863839

Diet and Cognitive Decline Untangling the Evidence

When it comes to single or multiple nutrients, the evidence has also exploded. For example, omega-3 fatty acids or E vitamins, curcumin, vitamin D, and caffeinated foods: These are all different dietary components that may or may not play a role in development of Alzheimer disease. Dr Martha Clare Morris and her colleagues from Rush University presented a great paper that studied very specific brain-healthy eating patterns, which she calls the MIND diet, with the results suggesting a reduction in the likelihood of developing cognitive impairment significantly over several years.  omega-3 fatty acids: First of all, not all omega-3’s are created equal. DHA and EPA have the most evidence for reducing a person’s risk of developing cognitive decline. The key here is that certain people with different genes may respond preferentially; people with an ApoE4 gene may respond favorably while people without that gene may respond less. When it comes to Alzheimer’s treatment, those omega-3’s didn’t pan out in terms of randomized studies, but omega-3’s used for Alzheimer’s prevention or risk reduction are something we want to think about. Also, when it comes to personalized medicine based on genes, we can focus on Alzheimer disease in a new area called clinical precision medicine, where we look not only at genetics, but also at people’s individual biologies, nutritional patterns, and lifestyle patterns, and then give a clinically precise approach for treatment or prevention. For example, if a person has high homocysteine levels, then B complex vitamins—folic acid, B12, and B6—in randomized studies have been shown to slow overall brain atrophy as well as increase memory function. The key take-home point here is that B complex therapy only works in patients who have high homocysteine levels and those who have an adequate level of omega-3’s in the blood. When it comes to blueberries, you’ve heard about flavonols. Dark cocoa powder may be effective for boosting memory. You can’t just eat one blueberry and think you’re going to prevent or cure Alzheimer disease—it doesn’t work that way. But in the Nurses’ Health Study,[3] a half a cup of blueberries two to three times a week was shown to delay the onset of cognitive decline.

Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects the Cocoa, Cognition, and Aging (CoCoA) Study : This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age. Abstract—Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing 990 mg (high flavanols), 520 mg (intermediate flavanols), or 45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P0.05) lower in subjects assigned to high flavanols (38.1010.94 and 104.1028.73 seconds, respectively) and intermediate flavanols (40.2011.35 and 115.9728.35 seconds, respectively) in comparison with those assigned to low flavanols (52.6017.97 and 139.2343.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.506.75 versus 22.308.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained 40% of composite z score variability through the study period (partial r2 0.4013; P0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity. 

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment

9 Brain Boosting Benefits of Dark Chocolate

 

The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state

Results Significant increases in regional perfusion across the brain were observed following consumption of the high flavanol drink relative to the low flavanol drink, particularly in the anterior cingulate cortex and the central opercular cortex of the parietal lobe.

The prevention and treatment of cognitive decline and dementia_ An overview of recent research on experimental treatments

Diet and Alzheimer’s disease risk factors or prevention the current evidence

Polyphenol Stilbenes Molecular Mechanisms of Defence against Oxidative Stress and Aging-Related Diseases.

Phytochemical Compounds and Antioxidant Capacity of Tucum-Do-Cerrado (Bactris setosa Mart), Brazil’s Native Fruit.

Polyphenols multipotent therapeutic agents in neurodegenerative diseases.

Pinosylvin-mediated protection against oxidative stress in human retinal pigment epithelial cells.

Mechanisms of Neuroprotection by Quercetin Counteracting Oxidative Stress and More.

Antioxidants inhibit neuronal toxicity in Parkinson’s disease-linked LRRK2.

Cereve Sleep system for Insomnia – launches in 2017

Patients with insomnia, the frontal cortex stays active, preventing them from getting deeper, more restorative sleep. These patients often describe a “racing mind” that interferes with getting a sound sleep.

FDA Approves New Device for Insomnia

Gently cooling the forehead within a precise, clinically proven therapeutic range reduced this activity in the frontal cortex. The new software-controlled bedside device cools and pumps fluid to a forehead pad that is worn throughout the night. Three clinical studies that included more than 230 patients over 3800 research nights demonstrated the safety and efficacy of the device. In one of these — a randomized, placebo-controlled trial of people with primary insomnia at seven clinical sites across the United States — results from polysomnographic sleep measurements showed a statistically significant reduction in latency to stage 1 sleep, the time taken to get into the first stage of sleep, as well as latency to stage 2 sleep.

Cereve FDA product for sleep

This is the first and only insomnia device cleared to reduce sleep latency to stage 1, the first stage of sleep, as well as stage 2, a stage of sleep that typically represents over 50% of the sleep period.

New formulations for preventing Alzheimer’s – functional medical foods

A multi-ingredient dietary supplement abolishes large-scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice

Transgenic growth hormone mice (TGM) are a recognized model of accelerated aging with characteristics including chronic oxidative stress, reduced longevity, mitochondrial dysfunction, insulin resistance, muscle wasting, and elevated inflammatory processes. Growth hormone/IGF-1 activate the Target of Rapamycin known to promote aging. TGM particularly express severe cognitive decline. We previously reported that a multi-ingredient dietary supplement (MDS) designed to offset five mechanisms associated with aging extended longevity, ameliorated cognitive deterioration and significantly reduced age-related physical deterioration in both normal mice and TGM. Here we report that TGM lose more than 50% of cells in midbrain regions, including the cerebellum and olfactory bulb. This is comparable to severe Alzheimer’s disease and likely explains their striking agerelated cognitive impairment. We also demonstrate that the MDS completely abrogates this severe brain cell loss, reverses cognitive decline and augments sensory and motor function in aged mice. Additionally, histological examination of retinal structure revealed markers consistent with higher numbers of photoreceptor cells in aging and supplemented mice. We know of no other treatment with such efficacy, highlighting the potential for prevention or amelioration of human neuropathologies that are similarly associated with oxidative stress, inflammation and cellular dysfunction. Environ. Mol. Mutagen. 57:382–404, 2016.

A dietary supplement containing ingredients commonly found in health food stores appears to prevent the decline in brain structure and function typically seen in Alzheimer’s disease, the results of an animal study indicate.  Dietary Supplement May Prevent Cognitive Decline    In a mouse model of accelerated aging and severe cognitive decline, a combination of vitamins and minerals, as well as nutraceuticals, such as beta carotene, bioflavonoids, cod liver oil, flax seed, garlic, and green tea extract, not only maintained brain cell numbers and mass and cognitive function but also appeared to prevent deterioration of sight and smell. Mechanisms of degenration , which include oxidative stress, inflammation, and mitochondrial dysfunction, “happen in a multitude of species as they get older” and are not “something that is specifically a human phenomenon that has been attempted to be recreated in a mouse model.

http://onlinelibrary.wiley.com/doi/10.1002/em.22019/abstract

Effects of treatment with a multi-ingredient dietary supplement designed to ameliorate key mechanisms of aging showed treatment was associated with reduced anxiety-like behaviors, augmented discrimination of environmental context, improved motor balance, and improved visual and olfactory acuity. This was correlated with positive morphological changes and higher neuronal populations in the cerebellum and olfactory bulb, increased overall brain cell numbers and improved brain function. Intact olfaction is strongly indicative of suppression of neuronal degeneration. Retinal atrophy (associated with AMD) was also diminished in supplemented mice. Given that MDS treatment has been shown to signifi-cantly reduce oxidative damage, boost mitochondrial function [Lemon et al 2008a,b; Aksenov et al., 2010; Aksenov et al., 2013] and alleviate symptoms of inflammation [Lemon et al., 2005], suggests that neuronal protection and sensory function are likely attributed to diminishing oxidative/inflammatory stress and improved energy balance. The extent of functional benefits attained by our MDS here and in earlier studies [Lemon et al., 2003, 2005, 2008a,b; Aksenov et al., 2010, 2013; Long et al., 2012; Hutton et al., 2015’ strongly suggests that aging animals retain the capacity to support youthful phenotypes and that powerful impacts can be achieved through multi-ingredient dietary supplementation that addresses the multifactorial nature of aging organisms.

A Complex Dietary Supplement Extends Longevity of Mice

A Dietary Supplement Abolishes Age-Related Cognitive Decline in Transgenic Mice Expressing Elevated Free Radical Processes

Finding Ponce de Leon’s Pill Challenges in Screening for Anti-Aging Molecules

Lifespan and healthspan extension by resveratrol

Screening SIRT1 Activators from Medicinal Plants as Bioactive Compounds against Oxidative Damage in Mitochondrial Function.

Table 1. Formulation of a Dietary Supplement Designed to Reduce Oxidative Stress and Inflammation, Maintain Membrane and Mitochondrial Integrity, and Enhance Insulin Sensitivity Supplement Dosage Vitamin B1b 0.72 mg/day Vitamin B3b 0.72 mg/day Vitamin B6b 0.72 mg/day Vitamin B12b 0.72 mcg/day Vitamin Cb 3.6 mg/day Vitamin Db 2.5 IU/day Vitamin Eb 1.44 IU/day Acetyl L-carnitinec 14.4 mg/day Alpha-lipoic acide 0.72 mg/day ASAd 2.5 mg/day Beta caroteneb 50.0 IU/day Bioflavinoidsh 4.32 mg/day Chromium picolinatei 1.44 mcg/day Cod liver oilb 5.04 IU/day CoEnzyme Q10h 0.44 mg/day DHEAg 0.15 mg/day Flax seed oilh 21.6 mg/day Folic acidb 0.01 mg/day Garlicb 21.6 mcg/day Gingerh 7.2 mg/day Gingko bilobah 1.44 mg/day Ginseng (Canadian)h 8.64 mg/day Green tea extractsf 7.2 mg/day L-Glutathionea 0.36 mg/day Magnesiumb 0.72 mg/day Melatoning 0.01 mg/day N-Acetyl cysteinee 7.2 mg/day Potassiumb 0.36 mg/day Rutinh 0.72 mg/day Seleniumh 1.08 mcg/day Zinc (chelated)b 0.14 mg/day

Vitamin brands are as follows: a ¼ Cell Life; b ¼ Jamieson vitamins; c ¼ Jarrow Formulas; d ¼ Lifebrand; e ¼ Natural Factors; f ¼ Naka; g ¼ Promatrix; h ¼ Swiss vitamins; i ¼ Vitamin Power Inc

That is typically because our cells are working in such a complex way that we have many mechanisms that are occurring simultaneously, and when something’s going wrong, it’s usually knocking everything out of balance. When the level of one particular component is increased in the cells, “you tend to also knock everything out of whack.

Previous research by the team showed that the supplement extended longevity and reduced cognitive and age-related physical deterioration in both normal mice and transgenic growth hormone mice (TGM). TGM are characterized by accelerated aging accompanied by severe cognitive decline, as well long-term oxidative stress, insulin resistance, and other traits.
For the current study, the team mated heterozygous TGM and normal mice to create equal numbers of TGM and normal mice with a similar genetic background. The mice were then randomly assigned at weaning either to receive a liquid form of the supplement every day, with the doses of the ingredients adjusted to correspond to the amounts recommended for humans, or to be left untreated.

The mice then underwent a series of somatosensory tests to determine the severity of age-related losses in motor coordination and overall mobility. Their brains were examined for histologic changes, and the degree of apoptosis and changes in cell counts were assessed. Single-photon emission computed tomography and positron-emission tomography scanning was also performed.

The team found that compared with normal mice, untreated TGM displayed brain cell losses, deterioration of sensory function, and reductions in cerebral metabolic rate and blood perfusion that were equivalent to those seen in patients with Alzheimer’s disease.

Specifically, the mice had greater than a 50% loss at a cellular level, a 36% reduction in brain mass, and at least twofold reductions in brain metabolism and blood flow at 12 months. Furthermore, in the untreated TGM, motor and cognitive functions were severely compromised. 

Although the supplement did not have significant effects on brain cell numbers, brain weight, or brain metabolism or perfusion in normal mice, it had striking effects in TGM.

With the supplement, brain mass and brain cell density were maintained at levels seen in young mice. Brain metabolic activity was comparable to that in control mice, with no significant difference between the groups. Moreover, the supplement was associated with a twofold increase in brain perfusion in TGM.

 

The results also showed that the supplement restored cognitive function in TGM and led to significant improvements in motor coordination. It also appeared to reduce anxiety, allowing TGM to explore “unsafe/novel” environments.

The team found that the supplement appeared to offset deterioration of visual acuity in TGM. It was associated with increases in the thickness of the retinal outer nuclear layer and outer segment of 26% and 29%, respectively, in TGM compared with untreated mice.

TGM that received the supplement also showed improvements in olfactory sensitivity and greater numbers of mitral cells in the olfactory bulb in comparison with untreated mice. Inasmuch as olfactory loss is associated with an increased risk of developing severe neurodegenerative conditions, the researchers say these findings suggest that the supplement may be offsetting neurodegeneration throughout the brain.

Above from Medscape:

Vitamin B12 May Slow Brain Aging

total brain volume losses were lower in individuals with higher baseline vitamin B12 levels, whereas the opposite was true of those with increased homocysteine levels. Vitamin B12 and tHcy [total homocysteine] might be independent predictors of markers of brain aging in elderly individuals without dementia. Venous blood samples were collected at baseline, from which circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids were determined. These were correlated with changes in brain tissue volumes and total white matter hyperintensity (WMH) over 6 years

Between baseline and the 6-year follow-up, the mean total brain tissue (TBT) volume decreased from 74.3% to 71.6% of the total cranial volume (P < .001), whereas the mean WMH volume increased from 0.0004% to 0.0007% (P < .001).

Multiadjusted linear mixed model analysis revealed that increased baseline levels of vitamin B12 and holotranscobalamin (the biologically active fraction of B12) were associated with a decreased rate of TBT volume loss, at respective beta values of 0.048 (P < .001) and 0.040 (P = .002) for each standard deviation increase. Furthermore, the researchers found that each standard deviation increase in total homocysteine levels was linked to more rapid rates of TBT volume loss, at a beta value of -0.035 (P = .02). Increases in total homocysteine levels were also associated with increases in the progression of WMH in individuals with a systolic blood pressure >140 mmHg, at 0.000019 per standard deviation increase (P = .047).

Association of Vitamin B12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults

Results  In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, β (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (β [SE] per 1-SD increase, –0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (β [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids.

Conclusions and Relevance  This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults.

Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment A Randomized Controlled Trial

Methods and Findings

Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B6 and B12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.

Results

A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.

Conclusions and Significance

The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer’s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.

the single-center, randomized VITACOG study, in which 271 individuals older than 70 years who had mild cognitive impairment received supplementation with high-dose folic acid and vitamins B6 and B12. They lost less brain compared to people who had normal homocysteine and normal vitamin levels, meaning that those with high levels of homocysteine or with clinical or biochemical vitamin deficiency can benefit from supplementation.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012244

 

Medical Food Linked to Memory Improvement in Mild Alzheimer’s

Presented here at the Alzheimer’s Association International Conference (AAIC) 2012, results from an open-label extension (OLE) trial of a medical nutrition product (Souvenaid, Nutricia/Danone) showed that memory performance continued to improve in drug-naïve patients with mild AD for up to 48 weeks.

Efficacy of Souvenaid in Mild Alzheimer’s

Efficacy of Souvenaid in Mild Alzheimer’s Disease: Results from a Randomized, Controlled Trial
Abstract: Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer’s disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p=0.023; Cohen’s d=0.21; 95% confidence interval [-0.06]–[0.49]). A trend for an effect was observed on the NTB total composite z- score (p=0·053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]).  No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

Efficacy of a medical food in mild Alzheimer’s disease: A randomized, controlled trial     Below:

Abstract

Objective

To investigate the effect of a medical food on cognitive function in people with mild Alzheimer’s disease (AD).

Methods

A total of 225 drug-naïve AD patients participated in this randomized, double-blind controlled trial. Patients were randomized to active product, Souvenaid, or a control drink, taken once-daily for 12 weeks. Primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale–revised, and the 13-item modified Alzheimer’s Disease Assessment Scale–cognitive subscale at week 12.

Results

At 12 weeks, significant improvement in the delayed verbal recall task was noted in the active group compared with control (P = .021). Modified Alzheimer’s Disease Assessment Scale–cognitive subscale and other outcome scores (e.g., Clinician Interview Based Impression of Change plus Caregiver Input, 12-item Neuropsychiatric Inventory, Alzheimer’s disease Co-operative Study–Activities of Daily Living, Quality of Life in Alzheimer’s Disease) were unchanged. The control group neither deteriorated nor improved. Compliance was excellent (95%) and the product was well tolerated.

Conclusions

Supplementation with a medical food including phosphatide precursors and cofactors for 12 weeks improved memory (delayed verbal recall) in mild AD patients. This proof-of-concept study justifies further clinical trials.

http://hcp.souvenaid.com.au/ – ALZHEIMERS mixture Link

Synapse loss, he said, is an early event in the AD process. By providing the nutritional precursors and cofactors for synapse formation, researchers hope to support the formation and function of synapses.

The once-a-day drink contains a patented nutrient combination with the following ingredients:

  • Eicospentaenoic acid, 300 mg
  • Docosahexaenoic acid, 1200 mg
  • Phospholipids 106 mg
  • Choline, 400 mg
  • Uridine monophosphate, 625 mg
  • Vitamin E (alpha-tocopherol equivalents), 40 mg
  • Selenium, 60 µg
  • Vitamin B12, 3 µg
  • Vitamin B6, 1 mg
  • Folic acid, 400 µg

The current findings also showed there was a statistically significant beneficial effect on memory in favor of Souvenaid at 6 months. Of the 238 patients who completed this trial, 198 participants entered the OLE study. Of these participants, 181 completed it. The results revealed that at 48 weeks, the product was well tolerated with no serious adverse events. In addition, the compliance rate was more than 90% The OLE results also revealed that memory performance as measured by the neuropsychological test battery (NTB) continued to improve significantly in study participants who received Souvenaid for the full 48 weeks (P = .025). In addition, in the group that received placebo for the first 24 weeks, there was a significant improvement in NTB memory scores during the OLE following conversion to the active treatment (P = .009).

http://www.neurogrow.com/

 

 

 

Gintonin, a Ginseng-Derived Lyophosphatidic acid recepto ligand attenuates alzheimers

Medical Error – everyone makes mistakes – patients and doctors

The trouble with the world
is that the stupid are cocksure
and the intelligent are full of doubt.
— Bertrand Russell

Health Affairs Website Link

Global Trigger Tool Shows That Adverse Events In Hospitals May Be Ten Times Greater Than Previously Measured

To Err is Human – IOM 1999

A comparison of hospital adverse events identified by three widely used detection methods

Medical Error and death

Medical error and death medscape article

Medical error—the third leading cause of death in the US

Patient Safety in American hospitals 2004

ADVERSE EVENTS IN HOSPITALS

Makary and Daniel noted that a “medical error” may or may not cause harm to the patient and defined an error as:

  • An unintended act (either of commission or omission);
  • An act that does not achieve its intended outcome;
  • The failure of a planned action to be completed (an error of execution);
  • The use of a wrong plan to achieve an aim (an error of planning); or
  • Deviation from the process of care.

 

Cognitive-proximity biases; the Kübler-Ross sequence of denial and anger; the psychological need to assign blame; the risks associated with procedural management of cancer or cardiovascular disease in an unstable, aging population; and retrospective cause-and-effect attributions are all driving factors in random catastrophic lethal events being attributed inappropriately to healthcare provider-caused errors.
Preventable systematic lethal or egregious human errors do occur, but overall they are relatively small in number compared with random, unpreventable events. Oversight efforts to prevent these errors (eg, electronic health records) can have the opposite unintended consequence of increased random events, because quality provider-patient clinical ‘face time’ is reduced.

Other clinicians from the “error happens” camp believe that systems, not humans, are largely to blame for errors. A registered nurse explained. “System errors, not people intent on making mistakes, are the main culprit. Tort reform is much needed because many family members who feel the pain of loss are eager to punish someone for a loved one’s death.”

Errors are not the fault of physicians but of systems. Human disease and top causes of death have changed from acute infections to chronic problems, but the mindset that drugs and interventions that worked so well in the past are also the solution in today’s world is wrong. It is a sign that medicine needs to change with the times. We should be putting more emphasis on preventive medicine, holistic approaches, and physiological nutrition, because the drugs and interventions are doing nothing to stop the top killers.

There may no doubt that many deaths are due to clinician, nursing, and pharmacy error. Yet nowhere is it accounted for that the population as a whole is horribly sick from their own devices

Death certificates depend on International Classification of Diseases (ICD) codes for cause of death, so causes such as human and system errors are not recorded on them.

Unskilled and unaware of it: How difficulties in recognizing one’s own incompetence lead to inflated self-assessments.

People tend to hold overly favorable views of their abilities in many social and intellectual domains. The authors suggest that this overestimation occurs, in part, because people who are unskilled in these domains suffer a dual burden: Not only do these people reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the metacognitive ability to realize it. Across 4 studies, the authors found that participants scoring in the bottom quartile on tests of humor, grammar, and logic grossly overestimated their test performance and ability. Although their test scores put them in the 12th percentile, they estimated themselves to be in the 62nd. Several analyses linked this miscalibration to deficits in metacognitive skill, or the capacity to distinguish accuracy from error. Paradoxically, improving the skills of the participants, and thus increasing their metacognitive competence, helped them recognize the limitations of their abilities.

Has it ever seemed to you that less competent people rate their competence higher than it actually is, while more competent people humbly rate theirs lower?

It’s not just your imagination. This is a genuine cognitive bias called the Dunning-Kruger Effect.

The Dunning-Kruger experiments behind the research focused on cognitive tasks (logic, grammar, and evaluating humor), but similar disparities exist in other areas. In self-assessment of IQ, below-average people overestimated their score and those above average underestimated.

Studies of healthy and unhealthy behaviors are handicapped when they rely on self-reporting because test subjects tend to improve their evaluation. In self-evaluations of driving ability, job performance, and even immunity to bias, we tend to polish our image.

This is called the Lake Wobegone Effect, named after the town where “all the children are above average.”

Notice that there are two different categories of error:

(1) the error where there is a preferred answer and most people are biased toward giving that answer (“How much snack food do you eat?” or “How popular would you say you are?” or “How good a driver are you?”), and

(2) the error where bias changes depending on actual competence, with the less and more competent groups rating themselves too high and too low, respectively.

Let’s look at the second category, where the two extremes make opposite errors. The Dunning-Kruger research hypothesizes that the competent overestimate others’ skill levels. But the error is more complicated for the incompetent—they overestimate their own skill level and they lack the metacognition to realize their error. In other words, they were too incompetent to recognize their own incompetence. Improving their metacognitive skills drove down their self-assessment scores as they became better evaluators of their own limitations.

Medical Errors Are No. 3 Cause Of U.S Deaths, Researchers Say

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease—the top three causes of death in the U.S. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease. Analyzing medical death rate data over an eight-year period, Johns Hopkins patient safety experts have calculated that more than 250,000 deaths per year are due to medical error in the U.S. Their figure, published May 3 in The BMJ, surpasses the U.S. Centers for Disease Control and Prevention’s third leading cause of death—respiratory disease, which kills close to 150,000 people per year.  Most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

The authors also suggest that hospitals carry out a rapid and efficient independent investigation into deaths to determine whether error played a role. A root cause analysis approach would help while offering the protection of anonymity. It’s public pressure that brings about change. Hospitals have no incentive to publicize errors; neither do doctors or any other provider. However, such a major step as adding error information to death certificates is unlikely if not accompanied by tort reform. Medical Error Is Third Leading Cause of Death in US

Medical Error in Public Eye at Geriatrics Meeting  Medical Error in Public Eye at Geriatrics Meeting

To Err Is Human, for a Pathologist to Apologize Is Uncommon

Better Handoffs Cut Medical Errors 30% in Multicenter Trial

Changes in Medical Errors after Implementation of a Handoff Program NEJM

Who Believes That Medical Error Is the Third Leading Cause of Hospital Deaths

 

Medical error in the US Excerpt See article below:

Analyzing medical death rate data over an eight-year period, Johns Hopkins patient safety experts have calculated that more than 250,000 deaths per year are due to medical error in the U.S. Their figure, published May 3 in The BMJ, surpasses the U.S. Centers for Disease Control and Prevention’s third leading cause of death—respiratory disease, which kills close to 150,000 people per year.

The Johns Hopkins team says the CDC’s way of collecting national health statistics fails to classify medical errors separately on the death certificate. The researchers are advocating for updated criteria for classifying deaths on death certificates.

“Incidence rates for deaths directly attributable to medical care gone awry haven’t been recognized in any standardized method for collecting national statistics,” says Martin Makary, professor of surgery at the Johns Hopkins University School of Medicine and an authority on health reform. “The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used.”

In 1949, Makary says, the U.S. adopted an international form that used International Classification of Diseases billing codes to tally causes of death.

“At that time, it was under-recognized that diagnostic errors, medical mistakes, and the absence of safety nets could result in someone’s death,” says Makary, “and because of that, medical errors were unintentionally excluded from national health statistics.”

In their study, the researchers examined four separate studies that analyzed medical death rate data from 2000 to 2008. Then, using hospital admission rates from 2013, they extrapolated that based on a total of 35,416,020 hospitalizations, 251,454 deaths stemmed from a medical error, which the researchers say now translates to 9.5 percent of all deaths each year in the U.S.

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease—the top three causes of death in the U.S. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease.

“Top-ranked causes of death as reported by the CDC inform our country’s research funding and public health priorities,” Makary says. “Right now, cancer and heart disease get a ton of attention, but since medical errors don’t appear on the list, the problem doesn’t get the funding and attention it deserves.”

The researchers caution that most medical errors aren’t due to inherently bad doctors, and that reporting these errors shouldn’t be addressed by punishment or legal action. Rather, they say, most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

“Unwarranted variation is endemic in health care,” Makary says. “Developing consensus protocols that streamline the delivery of medicine and reduce variability can improve quality and lower costs in health care. More research on preventing medical errors from occurring is needed to address the problem.”