Secrets of Aging

What does a normally aging brain look like? Are diseases of aging such as Alzheimer’s inevitable?

By Carol Barnes | 

CORBIS, OWAKI/KULLA

Only 40 years ago it was widely believed that if you lived long enough, you would eventually experience serious cognitive decline, particularly with respect to memory. The implication was that achieving an advanced age was effectively equivalent to becoming senile—a word that implies mental defects or illness. As a graduate student back then, I was curious why such conclusions were being drawn about the elderly. I had only to look as far as my own great-grandmother and great-aunt to begin questioning the generalization. They lived to 102 and 93, respectively, and were exceptionally active and quick-witted enough to keep us twentysomethings on our toes. A closer look at the literature didn’t give me any confidence that either the biological basis of memory or how it might change with age was well understood. Many discoveries made in the years since have given us better tools to study memory storage, resulting in a major shift away from the view of “aging as a disease” and towards the view of “aging as a risk factor” for neurological diseases. So why do some people age gracefully, exhibiting relatively minor—and at worst annoying—cognitive changes, while others manifest significant and disabling memory decline? Answers to these questions are fundamental for understanding both how to prevent disease and how to promote quality of life.

A test for normal aging

Cognitive decline at older ages is marked by gradual loss in the ability to retain new information or to recall the past. Although many other changes occur during the aging process—impairment in range of motion, speed of gait, acuity of vision and hearing—none of these factors are as central to one’s personal identity as are one’s cumulative experiences. For me, it seemed that understanding memory, and how it changes with age or disease, was the key to understanding the aging brain.

Infographic: Molecular Learning
View full size JPG | PDFTAMI TOLPA

When I was in graduate school, in 1973, two papers came out that would change the shape of neuroscience and memory research. Terje Lømo, Tim Bliss, and Tony Gardner-Medwin devised a method that could experimentally alter synaptic strength. Earlier theoretical ideas had implied that strengthening the connection between neurons might explain how memories were formed: the stronger the connection, the better a message could be relayed or recalled. As electrophysiologists, Lømo and colleagues tested this idea by sending electrical currents through a group of neurons in the rabbit hippocampus in patterns that mimicked normal electrical activity, and measuring how the connections between the neurons changed. By stimulating neurons, they could create a durable increase in synaptic strength, which was later dubbed long-term potentiation, or LTP. But more than just an intriguing physiological observation, the research presented a fully controllable experimental proxy for learning that made it possible to study memory across the lifespan of an animal for the first time.

Thus, with the discovery of LTP, and the idea that animal models of human memory could be developed, I sought to finish my dissertation research in a lab that was routinely conducting LTP experiments. At the time, there were only three labs in the world that were doing these types of experiments: Graham Goddard’s laboratory at Dalhousie University, Tim Bliss’s at University College London, and Gary Lynch’s at UC, Irvine. As it turned out, my thesis advisor Peter Fried, at Carleton University in Ottawa, had been one of Goddard’s students, and introduced me to him by saying, “I don’t really want you to steal my student, but she has this idea that she thinks you might be interested in.” I explained to Goddard that I wanted to track an animal’s ability to make and keep spatial memories as it aged. Since the hippocampus—the area of the brain where LTP was first discovered—was also involved in spatial memory, I wanted to use Goddard’s setup and surgically implant electrodes that could measure LTP in awake, freely behaving rats. In an act of faith and generosity, Goddard soon purchased animals for me and began to “age” them in anticipation of my arrival the following year.

The behavioral tests used to study spatial memory at this time all used somewhat severe methods to motivate animals: either with shock—a significant stress—or by restricting eating or drinking, both of which were potentially detrimental to survival. Because the precious aged animals could not be replaced without waiting two years to grow another “old” batch, I developed a novel, milder task that is now often referred to as the Barnes maze. With rodents’ natural aversion to open, well-lit areas in mind, I designed a circular platform with many openings around its circumference, only one of which would allow the animal to escape into a dark box beneath the platform’s surface.

Aging is not equivalent to the aberrant process of Alzheimer’s disease; it is in fact a distinctly different neurological process.

At 2–3 years old (an age equivalent to about 70-80 human years), the rats were old enough to begin the behavior and electrophysiological experiments in the latter part of 1975. The animals were permanently implanted with electrodes that could both stimulate the neurons and record their activity. The electrodes allowed us to measure baseline synaptic transmission with single stimuli, then to induce LTP, and finally to monitor its decay over several weeks. We found that LTP decayed about twice as fast in the old rats as it did in the young, with the “synaptic memory” lasting 20 days rather than 40. Most importantly, the durability of LTP was correlated with the memory of the correct hole on the circular platform task. In fact, by combining behavior and electrophysiology techniques, we produced the first demonstration that instead of acting as a mere proxy for learning, LTP might actually represent the cellular mechanism by which all memories are created.¹

Just one year before I published my work on aging rats, Bruce McNaughton, then at Dalhousie University, demonstrated that for synaptic strengthening to occur, synapses from several neurons needed to converge and be coactive on the target neuron. The finding made perfect sense, since learning often comes from the association of two or more pieces of information, each of which could be carried by an individual neuron. Later experiments also demonstrated that under some conditions, LTP can be more difficult to induce in aged rats, and conversely, that a reduction in synaptic strength—called long-term depression or LTD—is easier to induce in the hippocampus of old rats.² This may mean that LTD participates in “erasing” LTP, or reducing its longevity, and thus possibly increases forgetting.

By the mid-1980s it was clear that even in normal aging there are subtle changes in the biological processes that underlie memory, and in the relationship between the strength of memory and the strength of the synapses. But the real message of these experiments was that old animals can and do learn. None of the older animals exhibited what could be considered behaviorally to be “dementia,” nor were their biological mechanisms that allow memory traces to be laid down completely dysfunctional.

Aging networks

While there is much to be learned about the physiology of neural systems by direct artificial stimulation, even the mildest currents do not exactly mimic the selective and distributed activity of cells in normal behavioral states. To more realistically understand the aging brain, it is necessary to monitor cell circuits driven by natural behaviors. Around the time that LTP was discovered, John O’Keefe at University College London discovered “place cells” in the hippocampus—a major breakthrough for the field. By simply placing small microwires very close to hippocampal cells, without stimulating them, John and his student Jonathan Dostrovski noted that individual hippocampal cells discharge action potentials only when a rat is at select physical locations as it traverses a given environment.³ The unique property of these place cells is that their “receptive fields,” or the features that make each of these cells fire, are related to specific regions of space.

Infographic: Lost in Space
View full size JPG | PDFTAMI TOLPA (MAZE); CAROL BARNES (COGNITIVE MAPS, SOURCE: NATURE 388/ 17 JULY 1997)

By recording from many individual place cells at once, using a multipronged electrode (the tetrode) developed by McNaughton, and determining which physical locations activated different cells in the brain, it was possible to visualize how the hippocampus constructs a “cognitive map” of the surroundings. If young rats were given one maze-running session in the morning, and another session in the afternoon, the same hippocampal map was retrieved at both time points—suggesting that the pattern of neuronal firing represented the memory of their walking through the rectangular, figure-eight maze. What surprised us was that about 30 percent of the time, when old rats went back for their second run of the day, a different place-cell distribution would appear—as if the older animals were retrieving the wrong hippocampal map.⁴ Certainly a rat navigating a familiar space with the wrong map is likely to appear lost, or as though it had forgotten its way. But why was the rat retrieving the wrong map?

The possible answer to this question was published in 1998 by Cliff Kentros, now at the University of Oregon. In young rats, Cliff pharmacologically blocked the NMDA receptor, a critical gateway regulating LTP and synaptic strengthening. When he and colleagues used a dose large enough to block the formation of LTP, the cognitive maps of the young rats began to degrade over time in much the same way as observed in aged rats, suggesting that faulty LTP mechanisms may be responsible for map instability in aging.⁵

Connecting the hippocampal dots

Even though the new multiple tetrode recording method was a large advance over the limitations of recording one or two neurons at a time, these methods were still constrained to sample sizes of ~100 to 200 cells.

One recent advance has allowed us to monitor cell activity on a broader scale, not with electrodes, but by tracking the expression of genes that are rapidly expressed during behavior. Monitoring the expression of one such gene, Arc, during behavioral tests, for example, John Guzowski in my lab developed a method that could report on activity over hundreds of thousands of cells across the brain (the ‘catFISH’ method).⁶ This large-scale imaging of single cells has been critical for identifying which cells, within which memory circuits, are altered during normal aging.

This technique also allowed us to tease apart which cells might be more susceptible to decline with age. Unlike electrodes that record LTP, which cannot differentiate between different types of neurons, the catFISH method allows us to distinguish between the three primary cell groups within the hippocampus—the granule cells of the dentate gyrus and the pyramidal cells of regions CA1 and CA3. We were able to show that cell-specific gene expression (and therefore cell activity) did not change with age in CA1 and CA3 cell regions, but that the number of granule cells engaged during behavior showed a continuous decline in aging rats, suggesting these cells are a weak link in the aging rat hippocampus.⁷ Could this also be true in primates?

Scott Small at Columbia University Medical Center helped me answer this question in young and old monkeys. Although MRI methods do not have single-cell resolution, they can provide an indirect gauge of activity over large segments of the brain. Using a variation of standard MRI that measures regional cerebral blood volume (CBV), we monitored the resting brain activity of monkeys ranging in age from 9 to 27 years (equivalent to 27 to 87 human years), and could then relate this brain activation to an individual animal’s performance in memory tests. There were no differences in resting metabolic measures in the areas of the brain that send most of the signals into or out of the hippocampus, nor were there differences in brain activity within CA1 or CA3. But the old monkeys did show reduced activity in the dentate gyrus, similar to what we had found in aging rats. Critically, we observed that the lower the activity in the dentate gyrus, the poorer the memory.⁷

Scott had observed a similar pattern in an earlier human aging study. However, with human studies there is always a concern that some of the people we assume are aging normally in fact have the undiagnosed beginnings of human-specific neurological disease, such as Alzheimer’s. Confirming the observation in aging animals, which do not spontaneously get this disease, provides strong evidence that the dentate gyrus is a major player in the changes that occur in normally aging mammals.

Furthermore, these data refute the contention that aging is effectively equivalent to an aberrant process like Alzheimer’s disease, revealing that it is in fact a distinctly different neurological process. In contrast to the results showing that aging primarily affects the dentate gyrus, the granule cells of this brain region in Alzheimer’s patients do not show changes (with respect to age-matched controls) until very late in the illness. Instead, it is the cells in CA1 and in the entorhinal cortex that are dramatically affected. Thus, while aging and Alzheimer’s may in some cases be “superimposed,” there is not a simple linear trajectory that leads us all to end up with the disease.

Memory genes

Infographic: The Seat of Memory
View full size JPG | PDFTAMI TOLPA

Presently, the omics revolution is leading us closer to an understanding of individual differences in aging and cognition. One example with respect to memory is a study that used a genome-wide association approach in 351 young adults to identify the single nucleotide polymorphisms (SNPs) most strongly related to memory. The most significant SNP identified was a simple nucleotide base change in the normal cytosine-thymine sequence at a specific location in the KIBRA gene, which encodes a neural protein that had been suspected of playing a role in memory. Those who had the thymine-thymine SNP had the best memories.⁸ This was further confirmed in an independent elderly population,⁹supporting the view that this particular SNP in the KIBRA gene predisposed people of any age to have “better memory.” This could be another clue to help guide our understanding of the molecular cascades that support good memory, as the activity of the KIBRA protein may influence mechanisms related to LTP. Could there be a link between KIBRA and age-related memory decline? One way to test this hypothesis was to find a way to manipulate part of the molecular circuit in which KIBRA is involved. Performing just such an experiment in collaboration with my lab, Matt Huentelman at the Translational Genomics Research Institute in Arizona identified a promising compound, hydroxyfasudil, a metabolite of a drug already approved for use in treatment of chest pain, or angina. As predicted, hydroxyfasudil improved spatial learning and working memory in aged rats.¹⁰The clinical applications of the drug’s effects on learning and memory are currently being explored.

David Sweatt at the University of Alabama at Birmingham also recently documented DNA methylation changes in response to learning, and was very interested in collaborating with us to determine whether changes in this epigenetic process during aging might explain our data on Arc expression, which is related to LTP formation and learning. Methylation of DNA typically downregulates transcription. After young and old rats performed exploratory behaviors that engaged the hippocampus, the methylation state of the Arc gene in hippocampal cells was, in fact, reduced in both age groups (which allowed more of the Arc mRNA to be transcribed). The difference between young and old animals was that certain cells of older animals, such as hippocampal granule cells, had higher overall methylation levels in the resting state, which resulted in production of less Arc protein during behavior, and the diminished ability to alter synapses via a mechanism such as LTP.¹¹ There are many complex facets of these data, but the results have led us and others to hypothesize that there may well be a number of epigenetic marks that accumulate during aging, and that epigenetic dysregulation may be a fundamental contributor to normal age-related cognitive decline. While the details of exactly how aging affects epigenetic modifications remain to be elucidated, it is at least a reasonable guess that understanding these mechanisms will be critical for future experimental designs aimed at optimizing cognition across the life span. Luckily, these processes are also amenable to pharmacological manipulation.

Aging in the future

Looking back on the rather grim expectations concerning memory and the elderly that were held only a few decades ago, the vision today is very different and much more positive. There are many who live to very old ages with minimal cognitive decline—and certainly no dementia. One particularly interesting study in this regard followed individuals who were 100 years of age (centenarians) at the beginning of the study until the time of their death, monitoring cognitive function and other factors in the “oldest old.” Interestingly, 73 percent of these centenarians were dementia free at the end of their lives (the oldest reaching an age of 111 years).¹² Watching the remarkable discoveries in biology over the past half century, one cannot help but look with excitement towards the next groundbreaking findings that are surely in the making. The future holds great promise for the once remote dream of understanding the core biological processes required for optimal cognitive health during aging—and progress in this regard should also provide the needed backdrop for understanding and preventing the complex neurological diseases that can be superimposed on the aging brain.

Carol Barnes is Director of the Evelyn F. McKnight Brain Institute and a Regents’ Professor of Psychology and Neurology at the University of Arizona.

This article is adapted from an upcoming review in F1000 Biology Reports. It will be available for citation at f1000.com/reports (open access).

References

1. C. A. Barnes, “Memory deficits associated with senescence: A neuro-physiological and behavioral study in the rat,” J Comp Physiol Psychol, 93:74-104, 1979. ↩
2. C. Norris et al., “Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging,” J Neurosci, 16:5382-92, 1996. ↩
3. J. O’Keefe, J. Dostrovsky, “The hippocampus as a spatial map: Preliminary evidence from unit activity in the freely-moving rat,” Brain Res, 34:171-75, 1971. ↩
4. C. Barnes et al., “Multistability of cognitive maps in the hippocampus of old rats,” Nature,388:272-75, 1997. ↩
5. C. Kentros et al., “Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade,” Science, 280:2121-26, 1998. ↩
6. J.F. Guzowski et al., “Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles,” Nat Neurosci, 2:1120-24, 1999. ↩
7. S.A. Small et al., “Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging,” PNAS, 101:7181-86, 2004. ↩
8. A. Papassotiropoulos et al., “Common Kibra alleles are associated with human memory performance,” Science, 314:475-78, 2006. ↩
9. K. Schaper et al., “KIBRA gene variants are associated with episodic memory in healthy elderly,”Neurobiol Aging, 29:1123-25, 2008. ↩
10. M.J. Huentelman et al., “Peripheral delivery of a ROCK inhibitor improves learning and working memory,” Behav Neurosci, 123:218-23, 2009. ↩
11. M.R. Penner et al., “Age-related changes in Arc transcription and DNA methylation within the hippocampus,” Neurobiol Aging, doi: 10.1016/j.neurobiolaging.2010.01.009 ↩
12. B. Hagberg, G. Samuelsson, “Survival after 100 years of age: a multivariate model of exceptional survival in Swedish centenarians,” J Gerontol A Biol Sci Med Sci, 63:1219-26, 2008. ↩

The Happiness of English

There are more positive words than negative ones in the written English language.

By Jef Akst |

Wikimedia Commons, Christoph Michels

Across books, songs, even news publications and social media sites, positives words are used more commonly than negative ones, according to a new study published Monday (August 29) on arXiv, an online prepublication site widely used in the physical sciences.

Hypotheses regarding the reasons language evolved as it did are varied, including purely practical explanations such as coordinating social behaviors, like hunting, and more cultural explanations, like the support of altruism and cooperation. The answer, some anthropologists believe, may be found in the language itself.

In one of the most comprehensive analyses of the English language to date, mathematicians from Cornell University and the University of Vermont collated more than 10,000 words from four sources of text—Google Books, Twitter, The New York Times, and song lyrics. The words were scored on a scale of 1 to 9, with 1 being the most negative and 9 being the most positive. (The highest score was awarded to “laughter,” which received an 8.5, while “terrorist” received the lowest, coming it at 1.3, according to Wired Science.)

Overall, the researchers found that positive words outnumbered negative ones, suggesting “a positivity bias” in the language, the authors wrote. “In our stories and writings we tend toward pro-social communication.” They added that future work is needed to determine the “positivity” of other languages and dialects, as well as the trends towards other emotions. Comparing the results could reveal interesting correlations between language characteristics and aspects of societal organization in different cultures around the world.

Source: TheScientist
http://the-scientist.com/2011/08/31/the-happiness-of-english/

Posted by
Robert Karl Stonjek

Philippines: Small Towns Find Solutions In Their Backyards to Fight Pollution

The Material Recovery Facility (MRF) in Sta. Cruz, Laguna, is one of the most well-managed MRFs in the Philippines. Around 13 million Filipinos are affected by the pollution in the Laguna Lake, which they depend on for drinking, fishing, irrigation, hydropower and economic activities. LISCOP aims to help save the lake from further degradation by working with stakeholders to reduce pollution and improve the environmental quality of the lake and its watershed. Under LISCOP, communities plan and carry out solid and wastewater management projects to save the Laguna Lake by finding solutions in their own backyards. Laguna, Philippines, August 26, 2011—In a manner of speaking, Laguna Lake is the cradle of civilization in Luzon, the country’s most economically vibrant island. But pollution from industrial, commercial, agricultural and domestic sources have been poured into the lake and have made it a virtual septic tank for various types of effluents. Around 13 million people directly depend on the lake for drinking, fishing, irrigation, hydro-electric power and employment through eco-tourism and other economic activities. One of them is Pacita H. de Guzman, 41, who lives in Sta. Cruz Laguna. With the high cost of caring for a child with special medical needs, garbage meant cash to her. “When I first learned that they were going to build a dumpsite near our home, all I could think was it would be smelly. I hoped they would build it somewhere else, not in my backyard,” she said in Filipino. But the Sta. Cruz Material Recovery Facility (MRF) turned out to be one of the most well-managed MRFs in the country. It didn’t smell nor had it been swarmed with flies and it even became a source of additional income for Ms. de Guzman and some of her neighbors. She is now part of a group of 23 garbage-pickers; they reduce the amount of solid waste polluting the Laguna Lake. Jennie D. Corpuz, the MRF Supervisor, said Sta. Cruz had a growing plastic and biological waste problem forcing the community to take solid waste management seriously. The MRF, funded and monitored by the Laguna de Bay Institutional Strengthening and Community Participation Project (LISCOP), is a model of how a local government unit with a tiny budget can run a state-of-the-art facility. Models of Innovation LISCOP is a World Bank-funded project that aims to improve the environmental quality of the Laguna Lake and its watershed through a “solution-in-my-backyard” approach. The project is slowly changing the way small towns around Laguna Lake think about garbage management, sanitation, using natural resources in a sustainable manner, soil erosion control, flood prevention, and eco-tourism, among other things. Another Sta. Cruz initiative supported by LISCOP is the construction and operation of a wastewater treatment facility that treats wastewater from the town’s slaughterhouse prior to discharge into the river. A visit to the slaughterhouse showed young people swimming in a nearby river where water from the slaughterhouse is released. Biogas is also harvested from the treatment facility that is used by the workers in cooking their food and boiling water. “A lot of our visitors are surprised that a slaughterhouse can be this clean and can release water that is safe for bathing,” says Edwin M. Kalacas, Officer-in-Charge of the slaughterhouse. “Cleanliness is very important to us.” Recycling lifestyle Also in Laguna is the Kalayaan Sanitary Landfill, the only one in the country fully operated by a small town for its own use, benefiting 4,314 households in three barangays. Situated on the Sierra Madre mountain range 220 meters above sea level, the landfill is a scenic place with a vegetable garden where local residents come for picnics. “Garbage is a big headache for us. That is why we really have to involve the community and enforce political will. We are operating strictly on a no-segregation-no-collection policy,” says Reinelsa B. Corpuz, the town’s Municipal Environmental and Natural Resources Officer. “They hated me in the beginning, but we just had to take the heat until they got used to it.” Through such initiatives, LISCOP has built concrete steps towards a pollution-free Laguna Lake. In January 2011, the World Bank noted a 10 percent reduction in pollution in the lake from the firms that have been regulated by LLDA since 2004. Enterprises increased compliance with environmental regulations by 30 percent. LLDA OIC General Manager and concurrent Assistant General Manager Dolora Nepomuceno said LISCOP's support to LGUs led to the upgrading of 23 out of the 41 LGU-operated open dumps into well-managed, solid waste management facilities like MRFs, composting facilities, and sanitary landfills. “An assessment of 11 MRFs with composting has shown that these facilities have diverted about 500 metric tons of solid waste annually,” he said. Ms. Nepomuceno said the project has also strengthened LLDA's capacity, modernized its regulatory and planning instruments through the use and expansion of the environmental user fee system (EUFS), and improved its partnership with key stakeholders including the LGUs. (EUFS refer to the market-based policy instrument designed to encourage companies to invest in water treatment facilities, practice waste minimization as well as reusing, recycling and greener production techniques.) “A particularly noteworthy result of the expansion of the EUFS is the reduced average industrial biochemical oxygen demand (BOD) loading, from 24.34 to 1.29 metric tons per firm for those covered by the EUFS. Firms are shifting to more efficient and cleaner production technologies,” said Ms. Nepomuceno. (BOD refers to a standard method for determining the amount of organic pollution in water bodies.) World Bank Country Director Bert Hofman said the EUFS has led industries to invest in pollution abatement systems. "This innovation with EUFs could be replicated in Manila Bay and other parts of the Philippines consistent with the 2004 Clean Water Act," said Mr. Hofman. Those involved in LISCOP say solutions to pollution, big or small, could be found in communities’ own backyards especially with the adoption of best practices tested around the world, and a collaborative, can-do attitude.

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Safer Roads in Bosnia and Herzegovina

There are a lot more cars in Bosnia and Herzegovina than before. And as half of the roads are in poor shape, that means slower traffic and more bottlenecks and also more accidents. Jasmina Hadzic, the Communications Assistant in the Bosnia and Herzegovina World Bank Office, offers this story.

But there are bright spots: getting in and out of the capital Sarajevo at rush hour isn't the headache it once was. A major bridge spanning the Bosna River that squeezed traffic coming in and out of the city was rebuilt and the road crossing it was too. That has shaved lots of time off idling in the car.

Dzemal Pandza

"I drive through this section on a daily basis. Before there were traffic jams. I used to be stuck in traffic for a whole hour. People were nervous. Since the reconstruction, it is much easier to get to your destination. No nervousness, no traffic jams. Basically, it is much better now," says Dzemal Pandza, a courier who delivers packages and zigzags over the bridge several times a day.

Fixing the worst roads and most dangerous bridges is part of a project supported by the World Bank. The Bank has been supporting the rehabilitation of magisterial and regional roads through the Road Infrastructure and Safety Project, under implementation since 2008. The project builds on the results of an earlier Bank road project, which closed in June 2007. The success of this earlier project led the European Investment Bank (EIB) and the European Bank for Reconstruction and Development (EBRD) to contribute additional US$195 million to a program to help clear the maintenance backlog on the road network, while the World Bank project provides US$25 million to this follow-up program.

Most bridges and tunnels in Bosnia and Herzegovina need a lot of repairs. Roads need work, too. Of the country's approximately 22,615 kilometres of roads, half are in good condition, with the remaining half in either fair or poor condition.

The poor condition of roads and bridges is due to an extended period of neglect after the hostilities, insufficient funds for routine maintenance, lack of enforcement of axle-load limits, and a significant increase in traffic volumes.

Since 1996, with the World Bank assistance about 2,500 kilometres of roads around the country have been rebuilt.

Alma Kezo

"I drive over Jošanica Bridge at least three to four times a week, and as a driver, I can say that the reconstruction of the bridge has significantly improved the traffic. It is much easier to pass this part of the road, as it has always had traffic jams in the past. Now driving through this section is much easier, also thanks to the roundabout just off the bridge," says Alma Kezo, a resident of Sarajevo.

Fixing roads is important: road traffic in and around major urban areas is growing by five per cent each year. There are enough roads but they are not in good enough shape to handle the extra wear and tear. They need upgrading and enhancing. And that is despite a decade of substantial expenditures—insufficient money on maintenance since the end of the conflict has led to the premature deterioration of many roads. Large investments are required to reconstruct roads and bridges, and more importantly to build new ones with more capacity and of better quality to meet the needs of the market economy. Significant investments have been made, and improvements are evident, but more is required.

Road safety also remains a serious social and public health issue. The state of the road network, driver behaviour and limited education, poor or nonexistent enforcement, and significant growth in vehicle ownership and use have increased traffic accidents—there were 436 fatalities and 8,470 injuries in 2004. The 2008 rates declined slightly to 5.3 fatalities per 10,000 vehicles, but the rate is still nearly 3 times higher than the EU-27 average. Hence, road safety is a significant and growing concern that requires a comprehensive response.

Significant progress has been made to work towards better drivers and safer roads. An institutional framework for road safety has been established, and road safety strategies, have been approved in Bosnia and Herzegovina.

New tests for ‘legal marijuana,’ ‘bath salts’ and other emerging designer drugs

Posted by Biomechanism 

Marijuana plant

Scientists have reported developing new tests to help cope with a wave of deaths, emergency room visits and other problems from a new genre of designer drugs sold legally in stores and online that mimic the effects of cocaine, ecstasy and marijuana. They spoke at the 242nd National Meeting & Exposition of the American Chemical Society (ACS), being held here this week.

The reports, among more than 7,500 on the ACS agenda, focus on drugs sold as “bath salts,” “plant food,” “incense” and other products with colorful names, such as “Ivory Wave,” “Red Dove” and “legal marijuana.” They provide users with a high, but many have not been made illegal and are undetectable with current drug tests. In one presentation on these “legal highs,” a United Kingdom researcher reported a new method to trace the source of the substances in “bath salts.” In the other, a U.S. researcher discussed the challenges facing law enforcement and policymakers in regulating synthetic versions of marijuana.

Oliver Sutcliffe, PhD, and his collaborators reported the successful use of a method called isotope ratio mass spectrometry (IRMS) to determine who is making bath salts — drugs that can cause euphoria, paranoia, anxiety and hallucinations when snorted, smoked or injected — and which chemical companies supplied the raw materials. He and his co-workers are based at the University of Strathclyde and the James Hutton Institute in the U.K.

“With the new method, we could work backwards and trace the substances back to the starting materials,” said Sutcliffe. IRMS measures the relative amounts of an element’s different forms, or isotopic ratio. “This method was successful because the isotopic ratio of the starting material is transferred like a fingerprint through the synthesis,” he explained.

“Bath salts” first garnered significant media attention in the U.K. in early 2010 and then became a problem in the U.S. These products are not in the supermarket soap aisle — they are sold on the Internet, on the street and in stores that sell drug paraphernalia. They are sold in small individual bags for as low as $20 each to provide a cheap, legal high.

The powders often contain mephedrone, which is a synthetic compound structurally related to methcathinone, which is found in Khat. This plant is illegal in many countries, including the U.K. and the U.S. Usually, that would mean that these compounds (and derivatives thereof) would be illegal in those countries too, but because the bath salts are labelled “not for human consumption,” they get around this restriction and other legislation governing the supply of medicines for human use. However, Florida and Louisiana — two hotspots of abuse of bath salts — specifically banned the substances. U.K. officials banned the import of bath salts, which may lead some in the drug trade to set up clandestine labs on U.K. soil, said Sutcliffe. The new method allows law enforcement to track down these bath salts manufacturers.

In previous work, Sutcliffe developed the first pure reference standard for mephedrone and the first reliable liquid chromatography test for the substance, which could be efficiently run in a typical law enforcement lab. The team is also developing a colour-change test kit for mephedrone, which he estimates may be available by the end of the year.

In another presentation, Robert Lantz, Ph.D., from the Rocky Mountain Instrumental Laboratories, described another high that is legal in most of the U.S. — synthetic cannabinoids marketed as incense, a spice product or “legal marijuana” that give a high similar to marijuana without showing up in conventional drug tests.

“We can detect synthetic cannabinoids with modern analytical chemistry techniques, such as liquid or gas chromatography coupled to mass spectrometry, but these assays are too expensive for the 5,000-10,000 urine samples that most drug testing labs receive daily,” said Lantz. Most labs screen for drugs with less expensive antibody assays, but because the structures of these substances are so dissimilar, different antibodies would likely be required for many of them, driving up the cost of a more comprehensive test.

Synthetic cannabinoid abuse rose sharply in 2010, according to U.S. poison control centres, up to 2,863 compared to only 14 in 2009. About 200 synthetic cannabinoids exist, but the U.S. Drug Enforcement Agency (DEA) banned only five. A handful of states, such as Washington, Georgia and Colorado, refused five, but they are not always the same five that the DEA banned. “The states banned several specific compounds without a particular basis for their choices,” Lantz pointed out.

Colorado recently passed a law banning any substance that binds to a cannabinoid receptor in the human body. “The bill was well-intentioned, but technically, the new law not only covers synthetic cannabinoids but also endocannabinoids, which are naturally occurring substances that the human body produces to regulate many normal processes,” said Lantz.

Unfounded pesticide concerns adversely affect the health of low-income populations

Posted by Biomechanism

The increasingly prevalent notion that expensive organic fruits and vegetables are safer because pesticides — used to protect traditional crops from insects, thus ensuring high crop yields and making them less expensive — are a risk for causing cancer has no good scientific support, an authority on the disease said here today. Such unfounded fears could have the unanticipated consequence of keeping healthful fruits and vegetables from those with low incomes.

Bruce N. Ames, Ph.D., developer of a widely used test for potential carcinogens that bears his name, spoke at the 242nd National Meeting & Exposition of the American Chemical Society (ACS), being held here this week. With more than 7,500 reports on new advances in science and more than 12,000 scientists and others expected in attendance, it will be one of 2011′s largest scientific gatherings.

Ames described his “triage theory,” which explains how the lack of essential vitamins and minerals from fruit and vegetables in the diet of younger people can set the stage for cancer and other diseases later in life. A professor emeritus of biochemistry and molecular biology at the University of California at Berkeley, Ames also is a senior scientist at Children’s Hospital Oakland Research Institute, where he works on healthy aging. He developed the Ames test, which uses bacteria to test whether substances damage the genetic material DNA and, in doing so, have the potential to cause cancer. He has received the U.S. National Medal of Science among many other awards.

In the presentation, Ames said that today’s animal cancer studies unfairly label many substances, including pesticides and other synthetic chemicals, as dangerous to humans. Ames’ and Lois Swirsky Gold’s research indicates that almost all pesticides in the human diet are substances present naturally in plants to protect them from insects.

“Animal cancer tests, which are done at very high doses of synthetic chemicals such as pesticides — the “maximum tolerated dose” (MTD) — are being misinterpreted to mean that minuscule doses in the diet are relevant to human cancer. 99.99 percent of the pesticides we eat are naturally present in plants to protect them from insects and other predators. Over half of all chemicals tested, whether natural or synthetic, are carcinogenic in rodent tests,” Ames said. He thinks this is due to the high dose itself and is not relevant to low doses.

At very low doses, many of these substances are not of concern to humans, he said. For example, a single cup of coffee contains 15-20 of these natural pesticides and chemicals from roasting that test positive in animal cancer tests, but they are present in very low amounts. Human pesticide consumption from fresh food is even less of a concern, according to Ames — the amount of pesticide residues that an average person ingests throughout an entire year is even less than the amount of those “harmful” substances in one cup of coffee. In fact, evidence suggests coffee is protective against cancer in humans.

Unfounded fears about the dangers of pesticide residues on fruit and vegetables may stop many consumers from buying these fresh, healthful foods. In response, some stores sell “organic” foods grown without synthetic pesticides, but these foods are much more expensive and out of the reach of low-income populations. As a result, people — especially those who are poor — may consume fewer fruits and vegetables.

But how does a lack of fresh produce lead to cancer and other aging diseases? That’s where Ames’ triage theory comes in.

In wartime, battlefield doctors with limited supplies and time do a triage, making quick decisions about which injured soldiers to treat. In a similar way, the body makes decisions about how to ration vital nutrients while experiencing an immediate moderate deficiency, but this is often at a cost.

“The theory is that, as a result of recurrent shortages of vitamins and minerals during evolution, natural selection developed a metabolic rebalancing response to shortage,” he said. “Rebalancing favors vitamin- and mineral-dependent proteins needed for short-term survival and reproduction while starving those proteins only required for long-term health.” Ames noted that the theory is strongly supported by recent work (Am J Clin Nutr. DOI: 10.3945/ajcn.2009.27930; FASEB J DOI:10.1096/fj.11-180885; J Nucleic Acids DOI:10.4061/2010/725071).

For example, if a person’s diet is low in calcium — a nutrient essential for many ongoing cellular processes — the body takes it from wherever it can find it — usually the bones. The body doesn’t care about the risk of osteoporosis 30 or 40 years in the future (long-term health) when it is faced with an emergency right now (short-term survival). Thus, insidious or hidden damage happens to organs and DNA whenever a person is lacking vitamins or minerals, and this eventually leads to aging-related diseases, such as dementia, osteoporosis, heart trouble and cancer.

And with today’s obesity epidemic, resulting largely from bad diets that lack healthful foods containing vitamins, minerals and fiber, aging-related diseases are likely to be around for some time to come.