Brain circuitry for positive vs. negative memories discovered in mice — ScienceDaily

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Neuroscientists have discovered brain circuitry for encoding positive and negative learned associations in mice. After finding that two circuits showed opposite activity following fear and reward learning, the researchers proved that this divergent activity causes either avoidance or reward-driven behaviors. They used cutting-edge optical-genetic tools to pinpoint these mechanisms critical to survival, which are also implicated in mental illness.

Source: Brain circuitry for positive vs. negative memories discovered in mice — ScienceDaily

Date:
April 29, 2015

Source:
NIH/National Institute of Mental Health

Summary:
Neuroscientists have discovered brain circuitry for encoding positive and negative learned associations in mice. After finding that two circuits showed opposite activity following fear and reward learning, the researchers proved that this divergent activity causes either avoidance or reward-driven behaviors. They used cutting-edge optical-genetic tools to pinpoint these mechanisms critical to survival, which are also implicated in mental illness.

 

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Neuronal projections encoding negative (red) and positive (green) associations were often intertwined, perhaps hinting at mechanisms by which positive and negative emotional associations may influence each other.
Credit: Praneeth Namburi, Anna Beyeler, Ph.D., Kay M. Tye, Ph.D., Massachusetts Institute of Technology

 

 

Neuroscientists have discovered brain circuitry for encoding positive and negative learned associations in mice. After finding that two circuits showed opposite activity following fear and reward learning, the researchers proved that this divergent activity causes either avoidance or reward-driven behaviors. Funded by the National Institutes of Health, they used cutting-edge optical-genetic tools to pinpoint these mechanisms critical to survival, which are also implicated in mental illness.

“This study exemplifies the power of new molecular tools that can push and pull on the same circuit to see what drives behavior,” explained Thomas R. Insel, M.D., director of NIH’s National Institute of Mental Health (NIMH). “Improved understanding of how such emotional memory works holds promise for solving mysteries of brain circuit disorders in which these mechanisms are disrupted.”

NIMH grantee Kay Tye, Ph.D., Praneeth Namburi and Anna Beyeler, Ph.D., of the Massachusetts Institute of Technology (MIT), Cambridge MA, and colleagues, report their findings April 29, 2015 in the journal Nature.

Prior to the new study, scientists suspected involvement of the circuits ultimately implicated, but were stumped by a seeming paradox. A crossroads of convergent circuits in an emotion hub deep in the brain, the basolateral amygdala, seem to be involved in both fear and reward learning, but how one brain region could orchestrate such opposing behaviors — approach and avoidance — remained an enigma. How might signals find the appropriate path to follow at this fork in the road?

To find out, Tye and colleagues explored whether two suspect circuit projections from the crossroads might hold clues. One projects to a reward center, the nucleus accumbens, and the other to a nearby fear center, the centromedial amygdala, the output station of the emotion hub.

Each circuit projection is composed of separate populations of intertwined neurons. The researchers first used telltale fluorescent bead tracers to sort out which neurons belonged to each circuit. They then measured an indicator of connectivity — the strength of neural connections — in the projections, after mice underwent fear or reward learning. Animals were trained to either fear a tone paired with a shock or to associate the tone with a sugar reward.

Strikingly, crossroads connectivity to reward center projections decreased after fear learning and increased with reward learning. By contrast, connectivity to fear center projections increased with fear learning and decreased after reward learning.

These converging mechanisms in anatomically intertwined circuits could hold clues to teasing apart how positive and negative emotional associations may influence each other, Tye suggested.

To prove a causal link between the projection-identified circuits and behavior, Tye’s team turned to optogenetics, which enables light pulses to control brain circuitry in animals genetically engineered to be light-responsive. Optically stimulating the reward center projection enhanced positive reinforcement, while stimulating the fear center projection promoted negative reinforcement. Similarly, blocking the fear center projection impaired fear learning and enhanced reward learning.

Finally, the researchers pinpointed defining electrophysiological, anatomic and genetic features of the two circuits that help to explain the opposite connectivity responses.

“Given that many mental health problems, including anxiety, addiction, and depression, may arise from perturbations in emotional processing, these findings could help to pave the way to a circuit-based approach to treating mental illness,” said Tye.


Story Source:

The above story is based on materials provided by NIH/National Institute of Mental Health. Note: Materials may be edited for content and length.


Journal Reference:

  1. Praneeth Namburi, Anna Beyeler, Suzuko Yorozu, Gwendolyn G. Calhoon, Sarah A. Halbert, Romy Wichmann, Stephanie S. Holden, Kim L. Mertens, Melodi Anahtar, Ada C. Felix-Ortiz, Ian R. Wickersham, Jesse M. Gray, Kay M. Tye. A circuit mechanism for differentiating positive and negative associations. Nature, 2015; 520 (7549): 675 DOI:10.1038/nature14366

 

Source: NIH/National Institute of Mental Health. “Brain circuitry for positive vs. negative memories discovered in mice.” ScienceDaily. ScienceDaily, 29 April 2015. <www.sciencedaily.com/releases/2015/04/150429132918.htm>.

Date:
April 27, 2015

Source:
McGill University

Summary:
An international team of scientists has discovered what amounts to a molecular reset button for our internal body clock. Their findings reveal a potential target to treat a range of disorders, from sleep disturbances to other behavioral, cognitive, and metabolic abnormalities.

 

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Investigators report that the body’s clock is reset when a phosphate combines with a key protein in the brain. This process, known as phosphorylation, is triggered by light.
Credit: © Focus Pocus LTD / Fotolia

 

 

An international team of scientists has discovered what amounts to a molecular reset button for our internal body clock. Their findings reveal a potential target to treat a range of disorders, from sleep disturbances to other behavioral, cognitive, and metabolic abnormalities, commonly associated with jet lag, shift work and exposure to light at night, as well as with neuropsychiatric conditions such as depression and autism.

In a study published online April 27 in Nature Neuroscience, the authors, led by researchers at McGill and Concordia universities in Montreal, report that the body’s clock is reset when a phosphate combines with a key protein in the brain. This process, known as phosphorylation, is triggered by light. In effect, light stimulates the synthesis of specific proteins called Period proteins that play a pivotal role in clock resetting, thereby synchronizing the clock’s rhythm with daily environmental cycles.

Shedding light on circadian rhythms

“This study is the first to reveal a mechanism that explains how light regulates protein synthesis in the brain, and how this affects the function of the circadian clock,” says senior author Nahum Sonenberg, a professor in McGill’s Department of Biochemistry.

In order to study the brain clock’s mechanism, the researchers mutated the protein known as eIF4E in the brain of a lab mouse so that it could not be phosphorylated. Since all mammals have similar brain clocks, experiments with the mice give an idea of what would happen if the function of this protein were blocked in humans.

Running against the clock

The mice were housed in cages equipped with running wheels. By recording and analyzing the animals’ running activity, the scientists were able to study the rhythms of the circadian clock in the mutant mice.

The upshot: the clock of mutant mice responded less efficiently than normal mice to the resetting effect of light. The mutants were unable to synchronize their body clocks to a series of challenging light/dark cycles — for example, 10.5 hours of light followed by 10.5 hours of dark, instead of the 12-hour cycles to which laboratory mice are usually exposed.

“While we can’t predict a timeline for these findings to be translated into clinical use, our study opens a new window to manipulate the functions of the circadian clock,” says Ruifeng Cao, a postdoctoral fellow in Dr. Sonenberg’s research group and lead author of the study.

For co-author Shimon Amir, professor in Concordia’s Department of Psychology, the research could open a path to target the problem at its very source. “Disruption of the circadian rhythm is sometimes unavoidable but it can lead to serious consequences. This research is really about the importance of the circadian rhythm to our general well-being. We’ve taken an important step towards being able to reset our internal clocks — and improve the health of thousands as a result.”


Story Source:

The above story is based on materials provided by McGill University. Note: Materials may be edited for content and length.


Journal Reference:

  1. Ruifeng Cao et al. Light-regulated translational control of circadian behavior by eIF4E phosphorylation. Nature Neuroscience, April 2015 DOI: 10.1038/nn.4010

 

Source: McGill University. “Finding the body clock’s molecular reset button.” ScienceDaily. ScienceDaily, 27 April 2015. <www.sciencedaily.com/releases/2015/04/150427152300.htm>.

Date: April 27, 2015

Source: University of Missouri-Columbia

Summary: The most widely accepted theory of the inhabitation of North America is that humans migrated from Siberia to Alaska by means of a ‘land bridge’ that spanned the Bering Strait. However, in the 1990s, a small group of researchers proposed that North America was first settled by people from Europe, who moved from east to west via a glacial ‘ice bridge.’ Now, researchers have definitively disproven the ice bridge theory.

 

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Map of Bering Sea. The Bering Strait is a comparatively shallow area between Alaska and Siberia.
Credit: NOAA

 

 

There has long been a debate among scholars about the origins of the first inhabitants of North America. The most widely accepted theory is that sometime before 14,000 years ago, humans migrated from Siberia to Alaska by means of a “land bridge” that spanned the Bering Strait. However, in the 1990s, a small but vocal group of researchers proposed that North America was first settled by Upper Paleolithic people from Europe, who moved from east to west through Greenland via a glacial “ice bridge.” Now, researchers at the University of Missouri, working with colleagues the Cleveland Museum of Natural History and elsewhere,have definitively disproved the ice bridge theory.

One piece of evidence that advocates of the ice bridge theory rely on comes from the Chesapeake Bay. In the early 1970s, the crew of a scallop trawling vessel, Cinmar, was operating off the coast of Virginia when it hit a snag and pulled up an ancient stone blade, along with pieces of a mastodon skeleton. Since radiocarbon dating isn’t available on inanimate objects, scholars correlated the date of the blade with the mastodon, which they could date at more than 22,000 years old.

“For more than two decades, proponents of the ice bridge theory have pointed to similarities between North American stone blades such as the one allegedly dredged from the Chesapeake and blades left by Solutrean foragers in western Europe,” said Michael J. O’Brien, a professor of anthropology at MU and dean of the College of Arts and Science. “We know, however, that Solutrean culture began around 22,000 to 17,000 years ago, which is later than North American dates pointed to by ice bridge theorists as proof that Solutrean people populated North America. That includes the date from the Cinmar mastodon.”

Mizzou scholars, including O’Brien’s postdoctoral student, Metin Eren, and graduate student Matthew Boulanger, point to the lack of first-hand accounts from the crew of the Cinmar who recovered the blade and mastodon remains. All published accounts were first written by proponents of the Solutrean hypothesis. According to a telephone interview of the ship’s captain, he “took particular note of the water depth” and “plotted the area on his navigation charts.”

“While the interview indicates that the Cinmar captain took detailed notes, researchers never indicated that they actually observed the charts,” O’Brien said. “In fact, captains keep ‘hang logs’ in which they record readings when they hit obstructions on the ocean floor. We reviewed countless snag reports from the Bay and the time frame when the snag should’ve occurred and didn’t find anything to corroborate the story. One of the most famous snags of all time — when the crew pulled up a mastodon — and it’s just not reported.”

While researching the history of the stone tool, its recovery and whereabouts for more than 40 years, the team also found inconsistencies with the origins and the ownership of the ship itself. The research team found that discrepancies in photographs of the Cinmar, the size of the ship and where it was assembled all point to contradictions in key pieces of the ice bridge theory.

“Until inaccuracies are cleared up, there really is no reason to accept the find as evidence of anything connected with the early peopling of North America,” O’Brien said.


Story Source:

The above story is based on materials provided by University of Missouri-Columbia. Note: Materials may be edited for content and length.


Journal Reference:

  1. Metin I. Eren, Matthew T. Boulanger, Michael J. O’Brien. The Cinmar discovery and the proposed pre-Late Glacial Maximum occupation of North America. Journal of Archaeological Science: Reports, 2015; DOI: 10.1016/j.jasrep.2015.03.001

 

Source: University of Missouri-Columbia. “Alternate theory of inhabitation of North America disproven.” ScienceDaily. ScienceDaily, 27 April 2015. <www.sciencedaily.com/releases/2015/04/150427145121.htm>.

New Publication: eSource Records in Clinical Research: Keeping it Simple

 

On April 16, 2015, Applied Clinical Trials published an article, entitled: “eSource Records in Clinical Research: Keeping it Simple.“ What is very special about this paper are the esteemed co-authors, 4 of whom are industry experts in their own right:Jonathan Helfgott, formerly Associate Director for Risk Science, Intelligence, & Prioritization FDA and now Director of Regulatory Affairs at Stage 2 Innovations; Tom Haag, Data Integrity Process Expert; eClinical Quality Assurance at Novartis Pharmaceuticals Corporation; Silvana Cappi, Executive Director, Biometrics, at Ferring Pharmaceuticals and Imogene McCanless, Senior Vice President, Biometrics and Regulatory Affairs, at TransTech Pharma, LLC, and 4 from Target Health (Jules Mitchel, Joonhyuk Choi, Yong Joong Kim, Timothy Cho, and Dean Gittleman).

 

Excerpt: “In this paper, we have demonstrated ways to satisfy regulatory concerns about data integrity and investigator controls over their source records, when incorporating 21st Century tools and processes as standard elements of clinical development operations. These solutions include 1) data entered directly into EDC systems at the time of the clinic visit, as well as 2) seamless integration with the EDC study database with data residing in the EMR, and ePRO systems. Integrating eSource solutions with the EDC database will result in the ability 1) to review data in real time, 2) for monitors and clinical sites to rapidly issue and respond to data queries, and thus improve quality, and 3) to reduce time and materials spending associated with data acquisition and review.“

 

Triboro Bridge in the Fog

 

We were on our way to Boston and here is what the Big Apple looks like from the train on a foggy afternoon.

 

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Triboro Bridge in the Fog – ©Target Health Inc. 2015

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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More About Probiotics

 

Probiotics are under considerable research, as the concept holds promise for human health and well-being, and corresponding commercial opportunities.

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Most probiotic strains belong to the genus Lactobacillus, also called Lactic acid bacteria; Wikipedia

 

Editor’s Note: We’re adding more pieces on probiotics, to the ON TARGET, newsletter recently, because not only have we read a great deal about probiotics research (and prebiotics), but have been taking a brand of live bacteria, recommended by a friend at Harvard Medical School, over 5 years ago, called Ultimate Flora. I can’t prove that this product is the reason for unbelievably good health, but for those whom we have suggested this product, well, their health has improved also.

 

Warning: we are not medical doctors and if you are interested in trying a probiotic product, ask your own doctor first. However, most doctors (even the brilliant ones) don’t know much about probiotics, so are reluctant to recommend them. We have no ulterior motive like monetary compensation etc. for mentioning the brand, Ultimate Flora. This was the brand recommended and this is the only brand, that we know of, that must be kept in the refrigerator. The live bacteria can be sustained for the shipping period, but once received, refrigerate right away. We get our supply on Amazon, where various strengths are available.

 

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A consensus definition of the term “probiotics“, based on the available information and scientific evidence, was adopted after a joint Food and Agricultural Organization (FAO) of the United Nations and World Health Organization (WHO) expert consultation. In October 2001, this expert consultation defined probiotics as: “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host.“ Probiotics are healthy bacteria, not just in supplements and capsules but also in 1) ___. The Harvard Health Letter ran an informative article about them in the May 2005 issue, which states that “a growing body of evidence suggests that you can treat and even prevent some illnesses with foods and supplements containing certain kinds of live bacteria.“ They go on to say that “The strains most often found in probiotic supplements and foods like yogurt are lactic acid bacteria belonging to the genera, Lactobacillus and genera Bifidobacterium

 

The term probiotic is currently used to name ingested 2) ___associated with beneficial effects to humans and other animals. A significant expansion of the potential market for probiotics has led to higher requirements for scientific substantiation of putative beneficial effects conferred by the microorganisms. Commonly claimed benefits of probiotics include the decrease of potentially pathogenic gastro-intestinal microorganisms; the reduction of gastro-intestinal discomfort; the strengthening of the immune 3) ___system; the improvement of the skin’s function; the improvement of bowel regularity; the strengthening of the resistance to cedar pollen allergens; the decrease in body pathogens; the reduction of flatulence and bloating; the protection of DNA; the protection of proteins and lipids from oxidative damage; and the maintaining of individual intestinal microbiota in subjects receiving antibiotic treatment.

 

The history of probiotics can be traced back to the first use of cheese and fermented products, that were well known to the Greeks and Romans who recommended their consumption. The fermentation of dairy foods represents one of the oldest techniques for food 4) ___. Bifidobacteria were first isolated from a breast-fed infant by Henry Tissier, in the early 20th century, who also worked at the Pasteur Institute. The isolated bacterium named Bacillus bifidus communis was later renamed to the genus Bifidobacterium. Tissier found that bifidobacteria are dominant in the gut flora of 5) ___-fed babies and he observed clinical benefits from treating diarrhea in infants with bifidobacteria. The claimed effect was bifidobacterial displacement of proteolytic bacteria causing the disease. In 1917, when there was an outbreak of shigellosis, a strain of Escherichia coli was isolated from the feces of a soldier who was not affected by the disease. Methods of treating infectious diseases were needed at that time when 6) ___ were not yet available. This Escherichia coli strain was used in cases of in acute gastrointestinal infectious, salmonellosis and shigellosis. In 1920, Rettger and Cheplin conducted experiments involving rats and humans volunteers, by feeding them with Lactobacilus acidophilus. They observed changes in composition of fecal microbiota, which they described as “transformation of the intestinal flora“. Rettger further explored the possibilities of Lactobacilus acidophilus and reasoned that bacteria originating from the gut were more likely to produce the desired effect in this environment. In 1935 certain strains of Lactobacillus acidophilus were found to be very active when implanted in the human digestive 7) ___. Trials were carried out using this organism, and encouraging results were obtained especially in the relief of chronic constipation.

 

The oldest known citation of the term “probiotics“ was first introduced in 1953 to describe organic and inorganic food supplements applied to restore health to patients suffering from malnutrition. Contrasting antibiotics,8) ___ were defined as microbially derived factors that stimulate the growth of other microorganisms. In 1989, Roy Fuller suggested a definition of probiotics that has been widely used: “A live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance“. Fuller’s definition emphasizes the requirement of viability for probiotics and introduces the aspect of a beneficial effect on the host.

 

The term “probiotic“ originally referred to microorganisms that have effects on other microorganisms, a usage credited to Lilly and Stilwell (1965). Their conception of probiotics involved the notion that substances secreted by one microorganism stimulated the growth of another microorganism. The term was used again in 1971 by Sperti to describe tissue extracts which stimulated microbial growth. The term probiotics was taken up by Parker in 1974 who defined the concept as, “organisms and substances that have a beneficial effect on the host animal by contributing to its intestinal microbial 9) ___“. Later, the definition was greatly improved by Fuller in 1989, whose explanation was very close to the definition used today. Fuller in 1989 described probiotics as a “live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance“. He stressed two important facts of probiotics: the viable nature of probiotics and the capacity to help with intestinal balance. In the following decades, intestinal lactic acid bacterial species with alleged health beneficial properties have been introduced as probiotics, including Lactobacillus rhamnosus, Lactobacillus casei, and Lactobacillus johnsonii.

 

The scientist who gets all the credit for his careful and prolific research revealing the existence and benefit of probiotics, is the “father of natural immunity“ the term bestowed on Dr. Elie Metchnikoff, who first suggested the possibility of colonizing the gut with beneficial 10) ___ in the early 20th century.

 

 

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Ilya Ilyich Mechnikov (Elie Metchnikoff) (1845-1916)

 

ANSWERS: 1) foods; 2) microorganisms; 3) system; 4) preservation; 5) breast; 6) antibiotics; 7) tract; 8) probiotics; 9) balance; 10) flora

 

Ilya Ilyich Metchnikoff (Elie Metchnikoff) (1845-1916)

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Elie Metchnikoff first suggested the possibility of colonizing the gut with beneficial flora in the early 20th century.

 

Ilya Ilyich Metchnikoff the great Russian biologist, changed his name to Elie Metchnikoff, after his permanent move from Russia to Paris, France. Metchnikoff was a biologist and zoologist, best known for his pioneering research into the immune system. In particular, he is credited with the discovery of phagocytes (macrophages) in 1882, and his discovery turned out to be the major defense mechanism in innate immunity. He and Paul Ehrlich were awarded the 1908 Nobel Prize in Physiology or Medicine “in recognition of their work on immunity.“ He is also credited by some sources with coining the term gerontology in 1903, for the emerging study of aging and longevity. He established the concept of cell-mediated immunity, while Ehrlich that of humoral immunity. Their works are regarded as the foundation of the science of immunology. In immunology he is given an epithet the “father of natural immunity“.

 

Metchnikoff was born in the village Panasovka (or Ivanovka) near Kharkov (now Kharkiv in Ukraine), Russian Empire. He was the youngest of five children of Ilya Ivanovich Metchnikoff, an officer of the Imperial Guard. His mother, Emilia Lvovna (Nevakhovich), the daughter of the Jewish writer Leo Nevakhovich, largely influenced him on his education, especially in science. His elder brother Lev became a prominent geographer and sociologist. He entered Kharkov Lycee in 1856 and developed his interest in biology. Convinced by his mother to study natural sciences instead of medicine, in 1862 he tried to study biology at the University of Wurzburg. But the German academic session would not start by the end of the year. So he enrolled at Kharkiv University for natural sciences, completing his four-year degree in two years. In 1864 he went to Germany to study marine fauna on the small North Sea island of Heligoland. He was advised by the botanist Ferdinand Cohn to work with Rudolf Leuckart at the University of Giessen. It was in Leuckart’s laboratory that he made his first scientific discovery of alternation of generations (sexual and asexual) in nematodes. In 1865, while at Giessen, he discovered intracellular digestion in flatworm, and this study influenced his later works. He was greatly influenced by Charles Darwin’s theory of evolution. He first read Fritz Muller’s Fur Darwin (For Darwin) in Giessen. From this he became a supporter of natural selection and Ernst Haeckel’s biogenetic law. His scientific works and theories were inspired by Darwinism. Moving to Naples the next year he worked on a doctoral thesis on the embryonic development of the cuttle-fish Sepiola and the crustacean Nelalia. A cholera epidemic in the autumn of 1865 made him move to the University of Gottingen, where we worked briefly with W. M. Keferstein and Jakob Henle. In 1867 he returned to Russia to get his doctorate with Alexander Kovalevsky from the University of St. Petersburg. Together they won the Karl Ernst von Baer prize for their theses on the development of germ layers in invertebrate embryos. Metchnikoff was appointed docent at the newly established Imperial Novorossiya University (now Odessa University in Ukraine). Only twenty-two years of age, he was younger than his students.

 

After becoming involved in a conflict with a senior colleague over attending scientific meetings, in 1868 he transferred to the University of St. Petersburg, where he experienced a worse professional environment. In 1870 he returned to Odessa to take up the appointment of Titular Professor of Zoology and Comparative Anatomy. In 1882 he resigned from Odessa University due to political turmoil after the assassination of Alexander II. He went to Messina to set up his private laboratory, but then, returned to Odessa as director of an institute set up to carry out Louis Pasteur’s vaccine against rabies. Due to more difficulties, he left Russia for the last time in 1888 and went to Paris to seek Pasteur’s advice. Pasteur gave him an appointment at the Pasteur Institute, where he remained for the rest of his life.

 

Mechnikov became interested in the study of microbes, and especially the immune system. At Messina, in Ukraine, he discovered phagocytosis after experimenting on the larvae of starfish. In 1882 he first demonstrated the process when he pinned small thorns into starfish larvae, and he found unusual cells surrounding the thorns. The thorns were from a tangerine tree made into Christmas tree. He realized that in animals which have blood, the white blood cells gather at the site of inflammation, and he hypothesized that this could be the process by which bacteria were attacked and killed by the white blood cells. He discussed his hypothesis with Carl Friedrich Wilhelm Claus, Professor of Zoology at the University of Vienna, who suggested the term “phagocyte“ for cells which can surround and kill pathogens. Metchnikoff delivered his findings at Odessa University in 1883. His theory, that certain white blood cells could engulf and destroy harmful bodies such as bacteria, met with skepticism from leading specialists including Louis Pasteur, Behring and others. At the time most bacteriologists believed that white blood cells ingested pathogens and then spread them further through the body. His major supporter was Rudolf Virchow who published his research in his Arechiv fur pathologische Anatomie und Physiologie und fur klinische Medizin (now called the Virchows Archiv). His discovery of these phagocytes ultimately won him the Nobel Prize in 1908. In Paris he worked with ?mile Roux on calomel, an ointment to prevent people from contracting syphilis.

 

Metchnikoff also developed a theory that aging is caused by toxic bacteria in the gut and that lactic acid could prolong life. Based on this theory, he drank sour milk every day. He wrote The Prolongation of Life: Optimistic Studies, in which he espoused the potential life-lengthening properties of lactic acid bacteria (Lactobacillus delbrueckii subsp. bulgaricus). He attributed the longevity of Bulgarian peasants due to their yogurt consumption. This later inspired Japanese scientist Minoru Shirota to begin investigating a causal relationship between bacteria and good intestinal health, which eventually led to the worldwide marketing of Yakult, kefir and other fermented milk drinks, or probiotics. The original modern hypothesis of the positive role played by certain bacteria was first introduced by Metchnikoff, who in 1907 suggested that it would be possible to modify the gut flora and to replace harmful microbes with useful microbes. Metchnikoff, was at that time a professor at the Pasteur Institute in Paris. He proposed the hypothesis that putrefactive (proteolytic) microbes produced toxic substances in the large bowel. Proteolytic bacteria such as clostridia, which are part of the normal gut flora, do produce toxic substances, including phenols, indols and ammonia from the digestion of proteins. According to Metchnikoff these compounds were responsible for “intestinal auto-intoxication“ would “seed“ the intestine with harmless lactic-acid bacteria and decrease the intestinal pH and that this would suppress the growth of proteolytic bacteria. In 1907 he suggested that “the dependence of the intestinal microbes on food, makes it possible to adopt measures to modify the flora in our bodies and to replace the harmful microbes by useful microbes“. Metchnikoff himself introduced in his diet sour milk fermented with the bacteria he called “Bulgarian Bacillus“ and found his health benefited. Friends in Paris soon followed his example and physicians began prescribing the sour milk diet for their patients.

 

When his wife died, Metchnikoff tried to commit suicide, but his attempt failed. Metchnikoff died in 1916 in Paris from heart failure. And another beautiful person left the world better than when he entered.

 

Drugs That Activate Brain Stem Cells May Reverse Multiple Sclerosis

 

Specialized cells called oligodendrocytes lay down multiple layers of a fatty white substance known as myelin around axons, the long “wires“ that connect brain cells. Myelin acts as an insulator and enables fast communication between brain cells. In multiple sclerosis there is breakdown of myelin and this deterioration leads to muscle weakness, numbness and problems with vision, coordination and balance. It is unknown how myelin-producing cells are damaged, but research suggests they may be targeted by malfunctioning immune cells and that multiple sclerosis may start as an autoimmune disorder. Current therapies for multiple sclerosis include anti-inflammatory drugs, which help prevent the episodic relapses common in multiple sclerosis, but are less effective at preventing long-term disability. Experts believe that therapies that promote myelin repair might improve neurologic disability in people with multiple sclerosis.

 

Adult brains contain oligodendrocyte progenitor cells (OPCs), which are stem cells that generate myelin-producing cells. OPCs are found to multiply in the brains of multiple sclerosis patients as if to respond to myelin damage, but for unknown reasons they are not effective in restoring white matter. As a result, according to a study published online in Nature (20 April 2015), two drugs already on the market — miconazole (an antifungal) and clobetasol (a steroid), may potentially take on new roles to stimulate OPCs to increase myelination as treatments for multiple sclerosis. OPCs have been difficult to isolate and study, but the authors have developed a novel method to investigate these cells in a petri dish. Using this technique, they were able to quickly test the effects of hundreds of drugs on the stem cells. The compounds screened in this study were obtained from a drug library maintained by NIH’s National Center for Advancing Translational Sciences (NCATS). All are approved for use in humans. After screening, the authors examined whether the drugs, when injected into a mouse model of multiple sclerosis, could improve re-myelination. They found that both drugs were effective in activating OPCs to enhance myelination and reverse paralysis. As a result, almost all of the animals regained the use of their hind limbs. They also found that the drugs acted through two very different molecular mechanisms.

 

The authors caution that more research is needed before miconazole and clobetasol can be tested in multiple sclerosis clinical trials. They are currently approved for use as creams or powders on the surfaces of the body but their safety administered in other forms, such as injections, in humans is unknown. According to the authors, off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms and they are actively working to have a safe and effective drug for clinical use.

 

The online version of this release contains an illustration of remyelination.

 

The National Center for Advancing Translational Sciences is a distinctly different entity in the research ecosystem. Rather than targeting a particular disease or fundamental science, NCATS focuses on what is common across diseases and the translational process. The Center emphasizes innovation and deliverables, relying on the power of data and new technologies to develop, demonstrate and disseminate advancements in translational science that bring about tangible improvements in human health.

 

Malaria Vaccine May Be Working – Huge Event with a Global Impact

 

The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. The current report, published online in The Lancet (23 April 2015), reports the final results from the same trial, including the efficacy of a booster dose.

 

We are all in this together: The trial was sponsored by GlaxoSmithKline Biologicals SA (GSK), the vaccine developer and manufacturer, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative (MVI). GlaxoSmithKline Biologicals SA received a grant from MVI to run the trial and MVI received a grant from the Bill & Melinda Gates Foundation to run this trial.

 

Between March 2009 and January 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centers in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomization with minimization by center to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. Vaccine efficacy (VE) against clinical malaria was analyzed by negative binomial regression and against severe malaria by relative risk reduction.

 

8,922 children and 6,537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months and young infants for 38 months after dose 1. From month 0 until study end, compared with 9,585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6,616 episodes occurred in the R3R group (VE 36.3%) and 7,396 occurred in the R3C group (28.3%, 23?3-32?9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32.2%) and 169 in the R3C group (1?1%). In young infants, compared with 6,170 episodes of clinical malaria that met the primary case definition in the C3C group, 4,993 episodes occurred in the R3R group (VE 25.9%) and 5,444 occurred in the R3C group (18?3%); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17.3%) and 104 in the R3C group (10.3%). In children, 1,774 cases of clinical malaria were averted per 1,000 children in the R3R group and 1,363 per 1000 children in the R3C group. The numbers of cases averted per 1,000 young infants were 983 in the R3R group and 558 in the R3C group.

 

The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalized convulsive seizures within 7 days of RTS,S/AS01 booster was 2.2 per 1,000 doses in young infants and 2.5 per 1,000 doses in children.

 

According to the authors, RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.

 

First-of-its-Kind Corneal Implant Approved to Improve Near Vision

 

Presbyopia is the loss of the ability to change the focusing power of the eye. It occurs with normal aging and results in difficulty with near vision, generally in adults 40 to 50 years of age. The KAMRA inlay is an opaque, ring-shaped device intended for use in patients 45 to 60 years old who, in addition to not having had cataract surgery, are unable to focus clearly on near objects or small print and need reading glasses with +1.00 to +2.50 diopters of power – but do not need glasses or contacts for clear distance vision.

 

The FDA has approved the KAMRA inlay, a device implanted in the cornea of one eye (the clear, front surface) to improve near vision in certain patients with presbyopia. It is the first implantable device for correction of near vision in patients who have not had cataract surgery. The device works by blocking unfocused light rays entering the eye in order to improve near vision. It blocks peripheral light rays while allowing central light rays to pass through a small opening in the center of the device, making near objects and small print less blurry.

 

To insert the device, an eye surgeon uses a laser to create a pocket in the cornea of one eye of the patient and implants the device in that pocket. This is intended to allow the patient to have improved near vision in the eye containing the implant, while not affecting the distance vision of the two eyes working together. To evaluate the safety and efficacy of the KAMRA inlay, the FDA reviewed the results of three clinical studies. The results of the main study showed that 83.5% of the evaluable 478 participants achieved uncorrected near visual acuity of 20/40 or better at 12 months. This is the level of vision needed to read most text in magazines and newspapers.

 

The device is not intended for patients who have had cataract surgery or patients with severe dry eye; an active eye infection or inflammation; corneal abnormalities related to thinning and irregular shape of the surface of their eyes; insufficient corneal thickness to withstand the procedure; a recent or recurring herpes eye infection or problems resulting from past infection; uncontrolled glaucoma; uncontrolled diabetes; or active autoimmune or connective tissue disease. The labeling warns that the device’s safety and effectiveness in patients who have had LASIK or other refractive procedures is unknown. The KAMRA inlay may cause or worsen dry eye and various vision-related problems, such as glare, halos, night vision problems, and blurry vision. It also can cause corneal complications such as swelling, clouding, thinning and potential perforation, and challenges evaluating and managing eye problems. For patients experiencing vision problems after the surgery, removal of the device may improve vision in some cases. In other cases, decreased vision could become permanent. There is also a potential risk for the focusing power of the eye to change, causing blurry vision and requiring glasses.

 

The KAMRA inlay is manufactured by AcuFocus Inc., based in Irvine, California.

 

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