Two-hit model of non-alcoholic fatty liver disease (credit: ILSI Europe)
In an open-access paper in the British Journal of Nutrition, a coalition of 17 experts explain how elevated unresolved chronic inflammation is involved a range of chronic diseases, and how nutrition influences inflammatory processes and helps reduce chronic risk of diseases.
According to the authors, “the nutrition status of the individual with for example a deficiency or excess of certain micronutrients (e.g. folate, vitamin B12, vitamin B6, vitamin 1, vitamin E, zinc) may lead to an ineffective or excessive inflammatory response.
“Studies have showed that high consumption of fat and glucose may induce post-prandial inflammation (manifesting itself after the consumption of a meal), which may have consequences for the development of diabetes and cardiovascular diseases. The Western-style diet, rich in fat and simple sugars but often poor in specific micronutrients, is linked to the increased prevalence of diseases with strong immunogical and autoimmune components, including allergies, food allergies, atopic dermatitis and obesity.”
“Inflammation acts as both a friend and foe, being essential in metabolic regulation, with unresolved low-grade chronic inflammation being a pathological feature of a wide range of chronic conditions including the metabolic syndrome and cardiovascular diseases,” commented a co-author, Prof. Anne Marie Minihane, University of East Anglia (UK).
Abstract of Low-grade inflammation, diet composition and health: current research evidence and its translation
The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute’s European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled ‘Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies’. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation–health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation–health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.
Researchers at the University of Massachusetts Medical School have found that Google Glass — presumably the Enterprise Edition — could effectively extend bedside toxicology consults to distant health care facilities such as community and rural hospitals to diagnose and manage poisoned patients, according to a paper in the Journal of Medical Toxicology.
“In the present era of value-based care, a toxicology service using hands-free devices, such as Google Glass, could conceivably expand its coverage area and enhance patient care, while potentially decreasing overall treatment costs,” said Peter R. Chai, MD, toxicology fellow at UMass Medical School. “Our work shows that the data transmitted by Google Glass can be used to supplement traditional telephone consults, validate bedside physical exams, and diagnose and manage patients.”
Traditional telemedicine devices usually consist of large desktop or laptop computers affixed to a big cart that has to be rolled from exam room to exam room. “Glass is positioned perfectly as an emergency medicine telemedical device. Its small, hands free and portable, so you can bring it right to the bedside and have a real-time specialist with you when you need one,” he said.
In the study, emergency medicine residents at UMass Memorial Medical Center performed 18 toxicology consults with Google Glass. ER physicians wearing Google Glass evaluated the patients at bedside while a secure video feed was sent to the toxicology supervising consultant. The supervising consultant then guided the resident through text messages displayed on the Glass. Consultants also obtained static photos of medication bottles, electrocardiograms (EKG) and other pertinent information at the discretion of the supervisor.
As a result of using Google Glass, consulting toxicologists reported being more confident in diagnosing specific toxidromes. Additional data collected showed that the use of Google Glass also changed management of patient care in more than half of the cases seen. Specifically, six of those patients received antidotes they otherwise would not have. Overall, 89 percent of the cases seen with Glass were considered successful by the consulting toxicologist.
Google currently lists several companies involved in the medical field as Glass At Work partners, such as Advanced Medical Applications, which specializes in “solutions in telemedicine, live-surgery demonstrations, and remote medical training.”
According to 9to5Google sources, the Google Glass Enterprise Edition will feature “a robust hinge mechanism that allows the computer and battery modules to fold down like a regular pair of glasses, and a hinge for folding down the left side of the band as well.” It also “includes a larger prism display for a better viewing experience, an Intel Atom processor that brings better performance, moderately improved battery life, and better heat management.”
Abstract of The Feasibility and Acceptability of Google Glass for Teletoxicology Consults
Teletoxicology offers the potential for toxicologists to assist in providing medical care at remote locations, via remote, interactive augmented audiovisual technology. This study examined the feasibility of using Google Glass, a head-mounted device that incorporates a webcam, viewing prism, and wireless connectivity, to assess the poisoned patient by a medical toxicology consult staff. Emergency medicine residents (resident toxicology consultants) rotating on the toxicology service wore Glass during bedside evaluation of poisoned patients; Glass transmitted real-time video of patients’ physical examination findings to toxicology fellows and attendings (supervisory consultants), who reviewed these findings. We evaluated the usability (e.g., quality of connectivity and video feeds) of Glass by supervisory consultants, as well as attitudes towards use of Glass. Resident toxicology consultants and supervisory consultants completed 18 consults through Glass. Toxicologists viewing the video stream found the quality of audio and visual transmission usable in 89 % of cases. Toxicologists reported their management of the patient changed after viewing the patient through Glass in 56 % of cases. Based on findings obtained through Glass, toxicologists recommended specific antidotes in six cases. Head-mounted devices like Google Glass may be effective tools for real-time teletoxicology consultation.
Leukocyte (white blood cell) telomere length in study participants up to 115 years of age. Statistical regression lines belonging to these groups are indicated by the same color as the data. (credit: Yasumichi Arai et al./EBioMedicine)
Scientists say they have cracked the secret of why some people live a healthy and physically independent life over the age of 100: keeping inflammation down and telomeres long.
The study was published online in an open-access paper in EBioMedicine, a new open-access journal jointly supported by the journals Cell and Lancet.
“Centenarians and supercentenarians are different,” said Professor Thomas von Zglinicki, from Newcastle University’s Institute for Ageing, and lead author. “Put simply, they age slower. They can ward off diseases for much longer than the general population.”
Keeping telomeres long
The researchers studied groups of people aged 105 and over (semi-supercentenarians), those 100 to 104 (centenarians), and those nearly 100 and their offspring. They measured a number of health markers they believe contribute towards successful aging, including blood cell numbers, metabolism, liver and kidney function, inflammation, and telomere length.
Scientists expected to see a continuous shortening of telomeres with age. But what they found was that the children of centenarians, who have a good chance of becoming centenarians themselves, maintained their telomeres at a “youthful” level corresponding to about 60 years of age — even when they became 80 or older.
“Our data reveals that once you’re really old [meaning centenarians and those older than 100], telomere length does not predict further successful aging, said von Zglinicki. “However, it does show that [they] maintain their telomeres better than the general population, which suggests that keeping telomeres long may be necessary or at least helpful to reach extreme old age.”
Lower inflammation levels
Centenarian offspring maintained lower levels of markers for chronic inflammation. These levels increased in the subjects studied with age including centenarians and older, but those who were successful in keeping previously keeping them low had the best chance to maintain good cognition, independence, and longevity.
“It has long been known that chronic inflammation is associated with the aging process in younger, more ‘normal’ populations, but it’s only very recently we could mechanistically prove that inflammation actually causes accelerated aging in mice,” von Zglinicki said.
“This study, showing for the first time that inflammation levels predict successful aging even in the extreme old, makes a strong case to assume that chronic inflammation drives human aging too. … Designing novel, safe anti-inflammatory or immune-modulating medication has major potential to improve healthy lifespan.”
Data from three studies combined
Data was collated by combining three community-based group studies: Tokyo Oldest Old Survey on Total Health, Tokyo Centenarians Study, and Japanese Semi-Supercentenarians Study.
The research comprised 1,554 individuals, including 684 centenarians and (semi-) supercentenarians, 167 pairs of offspring and unrelated family of centenarians, and 536 very old people. The total group covered ages from around 50 up to the world’s oldest man at 115 years.
However, “presently available potent anti-inflammatories are not suited for long-term treatment of chronic inflammation because of their strong side-effects,” said Yasumichi Arai, Head of the Tokyo Oldest Old Survey on Total Health cohort and first author of the study.
Abstract of Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians
To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8.6% variance explained) in (semi-) supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = − 0.795 (− 1.436 to − 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.
Eating a group of specific foods — known as the MIND diet — may slow cognitive decline among aging adults, even when the person is not at risk of developing Alzheimer’s disease, according to researchers at Rush University Medical Center.
This finding supplements a previous study by the research team, reported by KurzweiliAI in March, that found that the MIND diet may reduce a person’s risk in developing Alzheimer’s disease.
The researchers’ new study shows that older adults who followed the MIND diet more rigorously showed an equivalent of being 7.5 years younger cognitively than those who followed the diet least. Results of the study were recently published online in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
So what is the MIND diet?
The MIND diet, which is short for “Mediterranean-DASH Diet Intervention for Neurodegenerative Delay,” was developed by Martha Clare Morris, ScD, a nutritional epidemiologist, and her colleagues. As the name suggests, the MIND diet is a hybrid of the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets. Both have been found to reduce the risk of cardiovascular conditions, like hypertension, heart attack and stroke.
“Everyone experiences decline with aging; and Alzheimer’s disease is now the sixth leading cause of death in the U.S., which accounts for 60 to 80 percent of dementia cases. Therefore, prevention of cognitive decline, the defining feature of dementia, is now more important than ever,” Morris says. “Delaying dementia’s onset by just five years can reduce the cost and prevalence by nearly half.”
The MIND diet has 15 dietary components, including 10 “brain-healthy food groups” and five “unhealthy groups” to avoid — red meat, butter and stick margarine, cheese, pastries and sweets, and fried or fast food.
To adhere to and benefit from the MIND diet, a person would need to eat at least three servings of whole grains, a green leafy vegetable and one other vegetable every day — along with a glass of wine (or red-grape juice) — snack most days on nuts, have beans every other day or so, eat poultry and berries at least twice a week and fish at least once a week.
In addition, the study found that to have a real shot at avoiding the devastating effects of cognitive decline, he or she must limit intake of the designated unhealthy foods, especially butter (less than 1 tablespoon a day), sweets and pastries, whole fat cheese, and fried or fast food (less than a serving a week for any of the three).
Berries are the only fruit specifically to be included in the MIND diet. “Blueberries are one of the more potent foods in terms of protecting the brain,” Morris says, and strawberries also have performed well in past studies of the effect of food on cognitive function.
The National Institute of Aging-funded study evaluated cognitive change over a period of 4.7 years among 960 older adults who were free of dementia on enrollment. Averaging 81.4 years in age, the study participants also were part of the Rush Memory and Aging Project, a study of residents of more than 40 retirement communities and senior public housing units in the Chicago area.
During the course of the study, they received annual, standardized testing for cognitive ability in five areas — episodic memory, working memory, semantic memory, visuospatial ability and perceptual speed. The study group also completed annual food frequency questionnaires, allowing the researchers to compare participants’ reported adherence to the MIND diet with changes in their cognitive abilities as measured by the tests.
Abstract of MIND diet slows cognitive decline with aging
Background: The Mediterranean and dash diets have been shown to slow cognitive decline; however, neither diet is specific to the nutrition literature on dementia prevention.
Methods: We devised the Mediterranean-Dietary Approach to Systolic Hypertension (DASH) diet intervention for neurodegenerative delay (MIND) diet score that specifically captures dietary components shown to be neuroprotective and related it to change in cognition over an average 4.7 years among 960 participants of the Memory and Aging Project.
Results: In adjusted mixed models, the MIND score was positively associated with slower decline in global cognitive score (β = 0.0092; P < .0001) and with each of five cognitive domains. The difference in decline rates for being in the top tertile of MIND diet scores versus the lowest was equivalent to being 7.5 years younger in age.
Conclusions: The study findings suggest that the MIND diet substantially slows cognitive decline with age. Replication of these findings in a dietary intervention trial would be required to verify its relevance to brain health.
Range of voluntary movement prior to receiving stimulation compared to movement after receiving stimulation, physical conditioning, and the drug buspirone. The subject’s legs are supported so that they can move without resistance from gravity. The electrodes on the legs are used for recording muscle activity. (credit: Edgerton Lab/UCLA)
In a study conducted at UCLA, five men who had been completely paralyzed were able to move their legs in a rhythmic motion thanks to a new, noninvasive neuromodulation and pharmacological procedure that stimulates the spinal cord.
The researchers believe this to be the first time voluntary leg movements have ever been relearned in completely paralyzed patients without surgery. The results are reported in an open-access paper in the Journal of Neurotrauma.
“These findings tell us we have to look at spinal cord injury in a new way,” said V. Reggie Edgerton, senior author of the research and a UCLA distinguished professor of integrative biology and physiology, neurobiology and neurosurgery.
Edgerton said although it likely will be years before the new approaches are widely available, he now believes that it is possible to significantly improve quality of life for patients with severe spinal cord injuries, and to help them recover multiple body functions.
Earlier this year, a the researchers demonstrated that they could induce involuntary stepping movements in healthy, uninjured people using noninvasive stimulation. The finding led Edgerton to believe the same approach could be effective for people with complete paralysis.
Reawakening neural connections with electrical charges and a drug
In the new research, five men were given one 45-minute training session per week for 18 weeks. For four weeks, the men were also given twice daily doses of buspirone, a drug often used to treat anxiety disorders, as part of the treatment.
Researchers placed electrodes at strategic points on the skin, at the lower back and near the tailbone and then administered a unique pattern of noninvasive, painless transcutaneous (through the skin) electrical currents*. The electrical charges caused no discomfort to the patients, who were lying down.
“The fact that they regained voluntary control so quickly must mean that they had neural connections that were dormant, which we reawakened,” said Edgerton, who for nearly 40 years has conducted research on how the neural networks in the spinal cord regain control of standing, stepping and voluntary control of movements after paralysis. “It was remarkable.”
* The researchers used monopolar rectangular pulsed stimuli (30 Hz at T11 and 5 Hz at Co1 with 1 ms duration for each pulse) filled with a carrier frequency of 10 kHz and at an intensity ranging from 80 to 180 mA .
Edgerton Lab/UCLA | Non-invasive Neuromodulation to regain voluntary movements after paralysis
Edgerton said most experts, including himself, had assumed that people who were completely paralyzed would no longer have had neural connections across the area of the spinal cord injury.
The researchers do not know yet whether patients who are completely paralyzed can be trained to fully bear their weight and walk. But he and colleagues have now published data on nine people who have regained voluntary control of their legs —four with epidural implants and five in the latest study.
“Many people thought just a few years ago we might be able to achieve these results in perhaps one out of 100 subjects, but now we have nine of nine,” Edgerton said. “I think it’s a big deal, and when the subjects see their legs moving for the first time after paralysis, they say it’s a big deal.”
The men in the newest study ranged in age from 19 to 56; their injuries were suffered during athletic activities or, in one case, in an auto accident. All have been completely paralyzed for at least two years. Their identities are not being released.
The research was funded by the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering (grants U01EB15521 and R01EB007615), the Christopher and Dana Reeve Foundation, the Walkabout Foundation and the Russian Scientific Fund.
“These encouraging results provide continued evidence that spinal cord injury may no longer mean a life-long sentence of paralysis and support the need for more research,” said Dr. Roderic Pettigrew, director of the National Institute of Biomedical Imaging and Bioengineering. “The potential to offer a life-changing therapy to patients without requiring surgery would be a major advance; it could greatly expand the number of individuals who might benefit from spinal stimulation. It’s a wonderful example of the power that comes from combining advances in basic biological research with technological innovation.”
Edgerton estimates that cost to patients of the new approach could be one-tenth the cost of treatment using the surgical epidural stimulator (which is also still experimental) — and, because no surgery is required, it would likely be more easily available to more patients.
The study’s co-authors were Gerasimenko, who conceived the new approach and is director of the laboratory of movement physiology at Russia’s Pavlov Institute and a researcher in the UCLA department of integrative biology and physiology, as well as Daniel Lu, associate professor of neurosurgery, researchers Morteza Modaber, Roland Roy and Dimitry Sayenko, research technician Sharon Zdunowski, research scientist Parag Gad, laboratory coordinator Erika Morikawa and research assistant Piia Haakana, all of UCLA; and Adam Ferguson, assistant professor of neurological surgery at UC San Francisco.
Edgerton and his research team also plan to study people who have severe, but not complete, paralysis. “They’re likely to improve even more,” he said.
The scientists can only work with a small number of patients, due to limited resources, but Edgerton is optimistic that the research can benefit many others. Almost 6 million Americans live with paralysis, including nearly 1.3 million with spinal cord injuries.
“A person can have hope, based on these results,” Edgerton said. “In my opinion, they should have hope.”
Abstract of Noninvasive Reactivation of Motor Descending Control after Paralysis
The present prognosis for the recovery of voluntary control of movement in patients diagnosed as motor complete is generally poor. Herein we introduce a novel and noninvasive stimulation strategy of painless transcutaneous electrical enabling motor control and a pharmacological enabling motor control strategy to neuromodulate the physiological state of the spinal cord. This neuromodulation enabled the spinal locomotor networks of individuals with motor complete paralysis for 2-6 years (AIS B) to be reengaged and trained. We showed that locomotor-like stepping could be induced without voluntary effort within a single test session using electrical stimulation and training. We also observed significant facilitation of voluntary influence on the stepping movements in the presence of stimulation over a four-week period in each subject. Using these strategies we transformed brain-spinal neuronal networks from a dormant to a functional state sufficiently to enable recovery of voluntary movement in 5/5 subjects. Pharmacological intervention combined with stimulation and training resulted in further improvement in voluntary motor control of stepping-like movements in all subjects. We also observed on-command selective activation of the gastrocnemius and soleus muscles when attempting to plantarflex. At the end of 18 weeks of weekly interventions the mean changes in the amplitude of voluntarily controlled movement without stimulation was as high as occurred when combined with electrical stimulation. Additionally, spinally evoked motor potentials were readily modulated in the presence of voluntary effort, providing electrophysiological evidence of the re-establishment of functional connectivity among neural networks between the brain and the spinal cord.
Disruptive potential of environmental exposures to mixtures of chemicals (credit: William H.Goodson III et al./Carcinogenesis)
Common environmental chemicals assumed to be safe at low doses may act separately or together to disrupt human tissues in ways that eventually lead to cancer, according to a task force of almost 200 scientists from 28 countries.
In a nearly three-year investigation of the state of knowledge about environmentally influenced cancers, the scientists studied low-dose effects of 85 common chemicals not considered to be carcinogenic to humans.
Common chemicals
The researchers reviewed the actions of these chemicals against a long list of mechanisms that are important for cancer development. Drawing on hundreds of laboratory studies, large databases of cancer information, and models that predict cancer development, they compared the chemicals’ biological activity patterns to 11 known cancer “hallmarks” – distinctive patterns of cellular and genetic disruption associated with early development of tumors.
The chemicals included bisphenol A (BPA), used in plastic food and beverage containers; rotenone, a broad-spectrum insecticide; paraquat, an agricultural herbicide; and triclosan, an antibacterial agent used in soaps and cosmetics.
In their survey, the researchers learned that 50 of the 85 chemicals had been shown to disrupt functioning of cells in ways that correlated with known early patterns of cancer, even at the low, presumably benign levels at which most people are exposed.
For 13 of them, the researchers found evidence of a dose-response threshold — a level of exposure at which a chemical is considered toxic by regulators. For 22, there was no toxicity information at all.
Synergistic effects over time
“Our findings also suggest these molecules may be acting in synergy to increase cancer activity,” said William Bisson, an assistant professor and cancer researcher at Oregon State University and a team leader on the study. For example, EDTA, a metal-ion-binding compound used in manufacturing and medicine, interferes with the body’s repair of damaged genes.
“EDTA doesn’t cause genetic mutations itself,” said Bisson, “but if you’re exposed to it along with some substance that is mutagenic, it enhances the effect because it disrupts DNA repair, a key layer of cancer defense.”
Bisson said the main purpose of this study was to highlight gaps in knowledge of environmentally influenced cancers and to set forth a research agenda for the next few years. He added that more research is still necessary to assess early exposure and to understand early stages of cancer development.
The study is part of the Halifax Project, sponsored by the Canadian nonprofit organization Getting to Know Cancer. The organization’s mission is to advance scientific knowledge about cancer linked to environmental exposures. The team’s findings are published in an open-access paper in a special issue of the journal Carcinogenesis.
Traditional risk assessment has historically focused on a quest for single chemicals and single modes of action — approaches that may underestimate cancer risk, said Bisson, an expert on computational chemical genomics (the modeling of biochemical molecular interactions in cancer processes). This study takes a different tack, examining the interplay over time of independent molecular processes triggered by low-dose exposures to chemicals.
“Cancer is a disease of diseases,” said Bisson. “It follows multi-step development patterns, and in most cases it has a long latency period. It has to be tackled from an angle that considers the complexity of these patterns.
“A better understanding of what’s driving things to the point where they get uncontrollable will be key for the development of effective strategies for prevention and early detection.”
Abstract of Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
HKUST researchers cut mouse corticospinal tract axons (labeled red). A year later, they deleted the Pten gene in the experimental group (bottom) but not the control group. The Pten gene removal resulted in axon regrowth in seven months, unlike the control group (top). (credit: Kaimeng Du et al./The Journal of Neuroscience)
Chronic SCI prevents a large number of injured axons from crossing a lesion, particularly in the corticospinal tract (CST). Patients inflicted with SCI often suffer a temporary or permanent loss of mobility and paralysis.
As reported in the July 1st issue of The Journal of Neuroscience, the researchers found that deleting the PTEN gene in mice neurons results in stimulation of growth of axons across the lesion (wound) and past it —- even when treatment was delayed up to 1 year after the original injury.
The deletion also up-regulated (increased) the activity of another gene called MTOR (the mammalian target of rapamycin), which further promoted regeneration of the axons.
“As one of the long descending tracts controlling voluntary movement, the corticospinal tract (CST) plays an important role for functional recovery after spinal cord injury,” says Kai Liu, PhD, the study’s senior author and assistant professor in life sciences at HKUST.
“The regeneration of CST has been a major challenge in the field, especially after chronic injuries. Here we developed a strategy to modulate PTEN/mTOR signaling in adult corticospinal motor neurons in the post-injury paradigm.
“It not only promoted the sprouting of uninjured CST axons, but also enabled the regeneration of injured axons past the lesion in a mouse model of spinal cord injury, The results considerably extend the window of opportunity for regenerating CST axons severed in spinal cord injuries.
“It is interesting to find that chronically injured neurons retain the ability to reform tentative synaptic connections,” says Liu. “PTEN inhibition can be targeted on particular neurons, which means that we can apply the procedure specifically on the region of interest as we continue our research.”
Abstract of Pten Deletion Promotes Regrowth of Corticospinal Tract Axons 1 Year after Spinal Cord Injury
Chronic spinal cord injury (SCI) is a formidable hurdle that prevents a large number of injured axons from crossing the lesion, particularly the corticospinal tract (CST). This study shows that Pten deletion in the adult mouse cortex enhances compensatory sprouting of uninjured CST axons. Furthermore, forced upregulation of mammalian target of rapamycin (mTOR) initiated either 1 month or 1 year after injury promoted regeneration of CST axons. Our results indicate that both developmental and injury-induced mTOR downregulation in corticospinal motor neurons can be reversed in adults. Modulating neuronal mTOR activity is a potential strategy for axon regeneration after chronic SCI.
SIGNIFICANCE STATEMENT As one of the long descending tracts controlling voluntary movement, the corticospinal tract (CST) plays an important role for functional recovery after spinal cord injury. The regeneration of CST has been a major challenge in the field, especially after chronic injuries. Here we developed a strategy to modulate Pten/mammalian target of rapamycin signaling in adult corticospinal motor neurons in the postinjury paradigm. It not only promoted the sprouting of uninjured CST axons, but also enabled the regeneration of injured axons past the lesion in a mouse model of spinal cord injury, even when treatment was delayed up to 1 year after the original injury. The results considerably extend the window of opportunity for regenerating CST axons severed in spinal cord injuries.
Tiny, implantable devices are capable of delivering light or drugs to specific areas of the brain, potentially improving drug delivery to targeted regions of the brain and reducing side effects. Eventually, the devices may be used to treat pain, depression, epilepsy and other neurological disorders in people. (credit: Alex David Jerez Roman)
A team of researchers has developed a tiny “wireless optofluidic neural probe” the width of a human hair that can be implanted in the brain and triggered by remote control to deliver drugs and activate targeted populations of brain cells.
The technology, demonstrated for the first time in mice, may one day be used to treat pain, depression, epilepsy, and other neurological disorders in people by targeting therapies to specific brain circuits with fewer side effects, according to the researchers at Washington University School of Medicine in St. Louis and the University of Illinois at Urbana-Champaign.
Soft optofluidic neural probe during simultaneous drug delivery and photostimulation (from micro-ILED). Drugs would be delivered via the fluidic channel and activated with light as needed. (Insets) Comparison of such a device (top) and a conventional metal cannula (bottom). Scale bars, 1 mm. (credit: Jae-Woong Jeong et al./Cell)
The research builds on earlier work in optogenetics, a technology that makes individual brain cells sensitive to light and then activates those targeted populations of cells with flashes of light.
The study was published online today (July 16) in the journal Cell and will appear in the July 30 print issue.
Previous attempts to deliver drugs or other agents, such as enzymes or other compounds, to experimental animals have required the animals to be tethered to rigid pumps and tubes that restricted their movement and often caused them to experience stress.
Exploded-view schematic diagram that illustrates an array of inorganic light-emitting diodes mounted on top of a soft microfluidic system that includes four separate microfluidic channels, each connected to a set of fluid reservoirs that include copper membranes as hermetic seals, expandable composite materials as mechanical transducers, and microscale heating elements as actuators (credit: Jae-Woong Jeong et al./Cell)
The new wireless optofluidic neural probes were built with four chambers to carry drugs directly into the brain via microfluidic channels and microscale pumps, and the probes are soft like brain tissue.
New tool for mapping brain-circuit activity
A freely moving rat with head-mounted device for drug delivery and photostimulation via the optofluidic system. The device is remotely controlled via infrared technology, similar to that used in a TV remote. Scale bar, 1 cm. (credit: Jae-Woong Jeong et al./Cell)
By activating brain cells with drugs and with light, the scientists are getting an unprecedented look at the inner workings of the brain.
“This is the kind of revolutionary tool development that neuroscientists need to map out brain circuit activity,” said James Gnadt, PhD, program director at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH).
“It’s very much in line with the goals of the NIH’s BRAIN Initiative, a program designed to accelerate the development and application of new technologies to shed light on the complex links between brain function and behavior.”
The new devices may ultimately also help people with neurological disorders and other problems, according to co-first author Jae-Woong Jeong, PhD, a former postdoctoral researcher at the University of Illinois and now assistant professor of electrical, computer and energy engineering at the University of Colorado, Boulder.
“The device can remain in the brain and function for a long time without causing inflammation or neural damage,” Jeong said.
The researchers also believe that similar, more flexible devices could have applications in areas of the body other than the brain, including peripheral organs.
Messing with mice minds
As part of the study, the researchers, who clearly are having way too much fun, showed that by delivering a drug to one side of an animal’s brain, they could stimulate neurons involved in movement, which caused the mouse to move in a circle.
In other mice, shining a light directly onto brain cells expressing a light-sensitive protein prompted the release of dopamine, a neurotransmitter that rewarded the mice by making them feel good. The mice then returned to the same location in a maze to seek another reward. But the researchers were able to interfere with that light-activated pursuit by remotely controlling the release of a drug that blocks the action of dopamine on its receptors.
The researchers hope to incorporate a design much like a printer’s ink cartridge so that drugs can continue to be delivered to specific cells in the brain, or elsewhere in the body, for as long as required and needed to replace the entire device.
Abstract of Wireless Optofluidic Systems for Programmable In Vivo Pharmacology and Optogenetics
In vivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (m-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens rewardrelated behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine.
Cancer tumors secrete enzymes are triggered by peptide coatings (blue) to slice the coatings open, safely delivering an anti-cancer drug (red) (credit: Cassandra E. Callmann et al./Advanced Materials)
Scientists have engineered a drug delivery system that uses specially designed nanoparticles that release drugs in the presence of a specific enzymes — the very ones that enable cancers to metastasize.
“We can start with a small molecule and build that into a nanoscale carrier that can seek out a tumor and deliver a payload of drug,” said Cassandra Callmann, a graduate student in chemistry and biochemistry at the University of California, San Diego, and first author of the report published in the journal Advanced Materials July 14.
Trojan-horse strategy
The system takes advantage of a class of enzymes called matrix metalloproteinases (MMPs) that many cancers make in abundance. MMPs normally chew through through the body’s membranes, allowing cancer cells to escape to metastasize (colonize other regions of the body), often with deadly consequences.
Trojan-horse strategy: an anti-cancer drug (Paclitaxel) and a peptide self-assemble into nanoparticles. Released at the cancer location, the peptide shell triggers cancer-cell enzymes (MMP) to rip apart the nanoparticle shell, releasing the drug (credit: Cassandra E. Callmann/Advanced Materials)
So Callmann created tiny spheres packed with the anti-cancer drug paclitaxel (also known by the trade names Taxol and Onxal) and coated with a peptide shell. When MMPs sense the peptide, they go pitbull on it, tearing up that shell, and releasing the drug. The shell fragments form a ragged mesh that holds the drug molecules near the tumor.
16 times higher anti-cancer dose safely administered
To package the drug into the spheres, Callmann had to add chemical handles. As it turns out, a group of atoms essential to the drug molecule’s effectiveness, and also toxicity, made for a good attachment point. That means the drug was safely inactivated as it flowed through the circulatory system until it reached the tumor.
The protection allowed the researchers to safely give a dose 16 times higher than they could with the formulation now used in cancer clinics, in a test in mice with grafted in fibrosarcoma tumors.
In additional preliminary tests, Callmann and colleagues were able to halt the growth of the tumors for a least two weeks, using a single lower dose of the drug. In mice treated with the nanoparticles that were coated with peptides that are instead impervious to MMPs or given saline, the tumors grew to lethal sizes within that time.
Gianneschi says they will broaden their approach to create delivery systems for other diagnostic and therapeutic molecules. “This kind of platform is not specific to paclitaxel. We’ll test this in other models — with other classes of drug and in mice with a cancer that mimics metastatic breast cancer, for example.”
They’ll also continue to modify the shell, to provide even greater protection and avoid uptake by organs such as liver, spleen and kidneys, he said. “We want to open up this therapeutic window.”
Abstract of Therapeutic Enzyme-Responsive Nanoparticles for Targeted Delivery and Accumulation in Tumors
An enzyme-responsive, paclitaxel-loaded nanoparticle is described and assessed in vivo in a human fibrosarcoma murine xenograft. This work represents a proof-of-concept study demonstrating the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes.
Lasagna? No, an open lattice of 3-D printed material, with materials having different characteristics of strength and flexibility indicated by different colors (credit: the researchers)
Researchers at three universities have developed a new way of making tough — but soft and wet — biocompatible hydrogel materials into complex and intricately patterned shapes. The process might lead to scaffolds for repair or replacement of load-bearing tissues, such as cartilage. It could also allow for tough but flexible actuators for future robots, the researchers say.
The new process is described in a paper in the journal Advanced Materials, co-authored by MIT associate professor of mechanical engineering Xuanhe Zhao and colleagues at MIT, Duke University, and Columbia University.
Zhao says the process can produce complex hydrogel structures that are “extremely tough and robust,” but still allow for encapsulating cells in the structures. That could make it possible to 3D-print complex biostructures.
Biocompatible structures
Hydrogels are defined by water molecules encased in rubbery polymer networks that provide shape and structure. They are similar to natural tissues such as cartilage, which is used by the body as a natural shock absorber.
While synthetic hydrogels are commonly weak or brittle, a number of them that are tough and stretchable have been developed over the last decade. However, making tough hydrogels has usually involved “harsh chemical environments” that would kill living cells encapsulated in them, Zhao says.
The new hydrogel materials are generated by combining polyethylene glycol (PEG) and sodium alginate, which synergize to form a hydrogel tougher than natural cartilage. The materials are benign enough to synthesize together with living cells — such as stem cells — which could then allow high viability of the cells, says Zhao, who holds a joint appointment in MIT’s Department of Civil and Environmental Engineering.
3-D printing strong, flexible biomaterials
3-D printed tough, biocompatible PEG–alginate–nanoclay hydrogels in ear and nose shapes (credit: Sungmin Hong et al./ Advanced Materials)
Previous work was not able to produce complex 3-D structures with tough hydrogels, Zhao says. The new biocompatible tough hydrogel can be printed into diverse 3-D structures such as a hollow cube, hemisphere, pyramid, twisted bundle, multilayer mesh, or physiologically relevant shapes, such as a human nose or ear.
The new method uses a commercially available 3D-printing mechanism, Zhao explains. “The innovation is really about the material — a new ink for 3-D printing of biocompatible tough hydrogel,” he says, specifically, a composite of two different biopolymers.
“Each [material] individually is very weak and brittle, but once you put them together, it becomes very tough and strong. It’s like steel-reinforced concrete.”
The PEG material provides elasticity to the printed material, while sodium alginate allows it to dissipate energy under deformation without breaking. A third ingredient, a biocompatible “nanoclay,” makes it possible to fine-tune the viscosity (how easily it flows) of the material, improving the ability to control its flow through the 3D-printing nozzle.
The material can be made so flexible that a printed shape, such as a pyramid, can be compressed by 99 percent, and then spring back to its original shape, Sungmin Hong, a lead author of the paper and a former postdoc in Zhao’s group, says; it can also be stretched to five times its original size. Such resilience is a key feature of natural bodily tissues that need to withstand a variety of forces and impacts.
Such materials might eventually be used to custom-print shapes for the replacement of cartilaginous tissues in ears, noses, or load-bearing body joints, Zhao says. Lab tests have already shown that the material is even tougher than natural cartilage.
Enhancing resolution
The next step in the research will be to improve the resolution of the printer, which is currently limited to details about 500 micrometers (0.5 millimeters) in size, and to test the printed hydrogel structures in animal models. “We are enhancing the resolution,” Zhao says, “to be able to print more accurate structures for applications.”
The technique could also be applied to printing a variety of soft but tough structural materials, he says, such as actuators for soft robotic systems.
“This is really beautiful work that demonstrates major advances in the utilization of tough hydrogels,” says David Mooney, a professor of bioengineering at Harvard University who was not involved in this work. “This builds off earlier work using other polymer systems, with some of this earlier work done by Dr. Zhao, but the demonstration that one can achieve similar mechanical performance with a common biomedical polymer is a substantial advance.
“It is also quite exciting that these new tough gels can be used for 3-D printing, as this is new for these gels, to my knowledge.”
The work was supported by the National Institutes of Health, the Office of Naval Research, AOSpine Foundation, and the National Science Foundation.
Abstract of 3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures
A 3D printable and highly stretchable tough hydrogel is developed by combining poly(ethylene glycol) and sodium alginate, which synergize to form a hydrogel tougher than natural cartilage. Encapsulated cells maintain high viability over a 7 d culture period and are highly deformed together with the hydrogel. By adding biocompatible nanoclay, the tough hydrogel is 3D printed in various shapes without requiring support material.
