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Commentary: Osteoporosis Treatment and Fracture Outcomes

In a related commentary, Robert Lindsay, M.B., Ch.B., Ph.D., of Helen Hayes Hospital, West Haverstraw, N.Y., writes: "In this issue of JAMA Internal Medicine, Greenspan and colleague present intriguing data on zoledronic acid, one of the most potent drugs in the bisphosphonate family - if not the most potent - approved for treatment of osteoporosis."

"First, this study includes 181 participants rather than the thousands usually involved in fracture studies. ... As the authors point out, the study was not designed as a fracture study," the author continues.

"So what lessons can we derive from this study? ... It would be premature to use this study to immediately modify our clinical use of potent bone-active agents in the nursing home population with documented osteoporosis (i.e. those who have a low BMD as a major risk factor for fracture). ... Finally, this study draws attention to the need for large controlled clinical trials to determine if a combination of fall prevention strategies and treatment with bone-active drugs might produce additive benefits on fractures, especially in high-risk populations such as those living in nursing homes. These studies will be difficult, and Greenspan and her colleagues are to be congratulated on beginning to fill this void," the commentary concludes.

(JAMA Intern Med. Published online April 13, 2015. doi:10.1001/jamainternmed.2015.0757. Available pre-embargo to the media at http://media.jamanetwork.com.)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

http://www.eurekalert.org/pub_releases/2015-04/uol-foc041315.php

Fragment of continental crust found under south east Iceland

An international team, including researchers at the University of Liverpool, have shown that south east Iceland is underlain by continental crust.

The team found that the accepted theory, that Iceland consists only of very thick oceanic crust, is incorrect. Maps of crustal thickness produced from satellite gravity data, together with geochemical, plate tectonic reconstruction and mantle plume track analysis (an upwelling of abnormally hot rock), were used to show that south east Iceland is underlain by continental crust which extends offshore to the east.

Professor Nick Kusznir, from the University's School of Environmental Sciences, who produced the satellite data, said: "The established theory is that geological features such as Iceland, known as oceanic plateaux, are generated by the interaction of ocean-ridge sea-floor spreading with a hot mantle upwelling.

"Our results suggest that there is another critical ingredient which is the presence of fragments of continental crust. This discovery has important implications for how mantle plumes interact with plate tectonics."



Satellite mapping

Crustal thickness mapping shows thick crust under south east Iceland of up to 30 km, which is more 'typical' of continental crust in comparison to much thinner crust in the surrounding ocean basins and under the rest of Iceland.

The thick crust of south east Iceland extends eastwards offshore and is interpreted as being a sliver of continental crust originally part of, but now separated from, the Jan Mayan micro-continent to the north from which it has rifted during the formation of the north east Atlantic in the last 55 million years.

Professor Kusznir added: "Global crustal thickness mapping, using gravity inversion, suggests that tectonic features, such as Iceland, formed by the interaction of mantle plumes, sea-floor spreading and micro-continent fragments, are quite common.

"Other examples include Mauritius in the Indian Ocean; the Rio Grande High in the south Atlantic; and the Canary Islands in the Central Atlantic.

"Not only is this discovery important for the science of geo-dynamics, our findings also has important implications for natural resources in these regions. Continental crust has a very different composition and history to oceanic crust and is much richer in natural resources."



Oil and gas exploration

Crustal thickness mapping using the satellite gravity inversion methodology was developed by Professor Kusznir and has been used for locating the transition between continental and oceanic crust and micro-continents for the United Nations Convention on the Law of the Sea (UNCLOS) territorial claims and is used extensively by the hydrocarbon industry in deep water oil and gas exploration.



The research, published in Proceedings of the National Academy of Sciences (PNAS), is in collaboration with the University of Oslo and can be found here: http://www.pnas.org/content/early/2015/03/27/1423099112.full.pdf

http://www.eurekalert.org/pub_releases/2015-04/uoi-wwh041315.php

Why we have chins

University of Iowa researchers contend chin comes from evolution, not mechanical forces

Look at a primate or a Neanderthal skull and compare it with a modern human's. Notice anything missing?

We have one feature that primates, Neanderthals, archaic humans - any species, for that matter - don't possess: a chin.

"In some way, it seems trivial, but a reason why chins are so interesting is we're the only ones who have them," says Nathan Holton, who studies craniofacial features and mechanics at the University of Iowa. "It's unique to us."

New research led by Holton and colleagues at the UI posits that our chins don't come from mechanical forces such as chewing, but instead results from an evolutionary adaptation involving face size and shape - possibly linked to changes in hormone levels as we became more societally domesticated.

The finding, if true, may help settle a debate that's gone on intermittently for more than a century why modern humans have chins and how they came to be.

Using advanced facial and cranial biomechanical analyses with nearly 40 people whose measurements were plotted from toddlers to adults, the UI team concludes mechanical forces, including chewing, appear incapable of producing the resistance needed for new bone to be created in the lower mandible, or jaw area. Rather, they write in a paper published online in the Journal of Anatomy, it appears the chin's emergence in modern humans arose from simple geometry: As our faces became smaller in our evolution from archaic humans to today - in fact, our faces are roughly 15 percent shorter than Neanderthals' - the chin became a bony prominence, the adapted, pointy emblem at the bottom of our face.

"In short, we do not find any evidence that chins are tied to mechanical function and in some cases we find that chins are worse at resisting mechanical forces as we grow," says Holton, assistant professor and anthropologist in the Department of Orthodontics at the UI College of Dentistry. "Overall, this suggests that chins are unlikely related to the need to dissipate stresses and strains and that other explanations are more likely to be correct."

More intriguing, UI anthropologists led by Robert Franciscus think the human chin is a secondary consequence of our lifestyle change, starting about 80,000 years ago and picking up great steam with modern humans' migration from Africa about 20,000 years later. What happened was this: Modern humans evolved from hunter-gatherer groups that were rather isolated from each other to increasingly cooperative groups that formed social networks across the landscape. These more connected groups appear to have enhanced the degree to which they expressed themselves in art and other symbolic mediums.

Males in particular became more tranquil during this period, less likely to fight over territory and belongings, and more willing to make alliances, evidenced by exchanging goods and ideas, that benefited each and all.

The change in attitude was tied to reduced hormone levels, namely testosterone, resulting in noticeable changes to the male craniofacial region: One big shift was the face became smaller - retrenching in effect - a physiological departure that created a natural opportunity for the human chin to emerge.

"What we're arguing is that modern humans had an advantage at some point to have a well-connected social network, they can exchange information, and mates, more readily, there's innovation," says Franciscus, who was on the team that first laid out the theory in a paper published last August in the journal Current Anthropology and is a contributing author on the current paper, "and for that to happen, males have to tolerate each other. There had to be more curiosity and inquisitiveness than aggression, and the evidence of that lies in facial architecture."

The new study buttresses that argument, in that it seems to rule out the chin arose from mechanical exertion, such as chewing.

The researchers examined how the jaw region generally reacted to two forces - vertical bending and wishboning. In wishboning, one side of the jaw is pulled outward, resulting in compression in the outer part of the chin. In vertical bending, the ramus - the posterior more or less vertical part on each side of the lower jaw - splays outward, tensing the chin area. In both instances, the thinking went, the chin area is being mechanically stressed; on a microscopic level, new bone is being created, much like lifting weights creates little tears that allows new muscle to be created. Thus, arose the theory that mechanical forces, such as chewing, led to our chins.

But in examinations from periodic measurements of participants' heads from 3 years of age to more than 20 years old, the UI researchers found no evidence that these imperceptible mechanical forces led to new bone in the chin region. Instead, they found nearly the opposite: Individuals with the most mechanical resistance had chins most similar to a 3 -or 4-year-old - meaning they didn't have much of a chin at all.

What the researchers did notice is chin "growth" has more to do with how each feature in our face adapts as our head size increases, much like you'd fit individual pieces together in an expanding, shape-shifting, three-dimensional puzzle.

Children, for example, have flat, nearly imperceptible chins, much like what's seen in Neanderthals. That bony prominence only becomes visible as our heads and faces grow into adulthood.

"Our study suggests that chin prominence is unrelated to function," Holton says, "and probably has more to do with spatial dynamics during development."



Contributing authors, all from the UI, include: Laura Bonner, Jill Scott, Steven Marshall and Thomas Southard. The study was funded by the Department of Orthodontics, in the UI College of Dentistry.

http://www.eurekalert.org/pub_releases/2015-04/b-nbt040915.php

New breath technology picks up high risk changes heralding stomach cancer

Nanoarray analysis identifies key volatile organic compounds; could be used for screening, say researchers

A new type of technology that senses minute changes in the levels of particular compounds in exhaled breath, accurately identifies high risk changes which herald the development of stomach cancer, reveals research published online in the journal Gut.

The findings prompt the researchers to suggest that the technology - known as nanoarray analysis - could be used not only to test for the presence of stomach cancer, but also to monitor those at high risk of subsequently developing the disease.

Gastric cancer develops in a series of well-defined steps, but there's currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Most people in the developed world are diagnosed when it's too late to save their lives.

Previous research has concluded that nanoarray analysis could be used to detect stomach cancer, but these studies have involved small numbers of people, and none has looked at the technology's ability to pick up pre-cancerous changes.

The researchers therefore collected two breath samples from 484 people, after a 12 hour fast and abstention from smoking for at least three hours.

Ninety nine of the participants had already been diagnosed with stomach cancer, but not yet treated with chemotherapy or radiotherapy.

Participants were asked about their smoking and drinking habits and tested for Helicobacter pylori infection, a known risk factor for stomach cancer.

The first breath sample was analysed using a technique (GCMS) that measures the various volatile organic compounds in exhaled breath. The second sample was subjected to nanoarray analysis combined with pattern recognition.

The GCMS results showed that both patients with cancer and those without the disease had distinctive 'breath prints.'

Out of a total of 130 volatile organic compounds identified by GCMS in exhaled breath, levels of eight differed significantly when samples from the gastric cancer group were compared with those from the groups with pre-cancerous changes.

Furthermore, the nanoarray sensing patterns were able to accurately distinguish between the different pre-cancerous stages, marking out those patients at low and high risk of developing gastric cancer.

The findings held true, irrespective of other influential factors, such as age, alcohol intake, and use of stomach acid suppressant drugs (proton pump inhibitors).

The researchers point out that GCMS technology cannot be used for screening purposes, because it is very expensive and requires lengthy processing times and considerable expertise to operate it.

Nanoarray analysis, on the other hand, is not only accurate and highly sensitive, but offers a much simpler and cheaper alternative, they say.

Being able to accurately differentiate between low and high risk changes would avoid unnecessary endoscopies, and would enable any progression to cancer or signs of disease recurrence to be monitored, they suggest.

A large trial involving thousands of patients, including those with stomach cancer or pre-cancerous changes, is currently under way in Europe to test the technology's suitability as a screening method, they add.

"The attraction of this test lies in its non-invasiveness, ease of use (therefore high compliance would be expected), rapid predictiveness, insensitivity to confounding factors, and potentially low cost," they conclude.



http://www.eurekalert.org/pub_releases/2015-04/ibri-rda041415.php

Researchers discover an inactive tumor suppressor gene in lung cancer

Inactivation of PARD3 gene promotes tumor cell invasion and metastasis

Researchers at Genes and Cancer group at Bellvitge Biomedical Research Institute (IDIBELL), led by Montse Sanchez-Cespedes, have identified the PARD3 gene as a tumor suppressor that is inactivated in lung cancer squamous type. The results of the study have been published in Cancer Research.

Correct polarization (orientation in space) of bronchial epithelial cells is essential for the maintenance and proper development of this tissue under normal conditions.

PARD3 gene encodes a protein that regulates cell polarization and cell junctions. When the gene is inactivated, errors occur in this cell orientation and in contact with neighboring cells. "Any change affecting this structure promotes tumor development," said the researcher Montse Sanchez-Cespedes.



Tumor invasion and metastasis

By restoring protein encoded by PARD3 levels, both, cell lines and animal models of mice, we observed that regulating de novo polarization of cells, significantly reduced the risk of metastasis.



Lung cancer

Lung cancer is one of the tumors having higher mortality rates worldwide. Only in Spain each year about 20,000 people die from this cause. The high mortality rate is mainly due to late diagnosis of the disease, when it is already in an advanced stage.

Late detection and lack of effective therapies make the probability of survival of patients with lung cancer is very low. Overall, only 10% and 15% of patients survive more than five years after detection. The origin of more than 80% of cases is the consumption of snuff. The squamous lung cancer and lung adenocarcinoma type are the two most common types of lung tumor.

Article reference

Bonastre E, Verdura S, Zondervan I, Facchinetti F, Lantuejoul S, Chiara MD, Rodrigo JP, Carretero J, Condom E, Vidal A, Sidransky D8, Villanueva A, Roz L, Brambilla E, Savola S, Sanchez-Cespedes M. PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion. Cancer Res. 2015 Apr 1;75(7):1287-97. doi: 10.1158/0008-5472.CAN-14-2444.

http://www.eurekalert.org/pub_releases/2015-04/fi-fsd041415.php

Forsyth study details how gum disease treatment can prevent heart disease

Newly published research underscores the important connection between oral inflammation and heart health

CAMBRIDGE, Mass. - A new study from the Forsyth Institute is helping to shed more light on the important connection between the mouth and heart. According to research recently published online by the American Heart Association, scientists at Forsyth and Boston University have demonstrated that using an oral topical remedy to reduce inflammation associated with periodontitis, more commonly known as gum disease, also results in the prevention of vascular inflammation and can lower the risk of heart attack.

This study is the first time researchers anywhere have demonstrated the ability of an oral treatment for gum disease to also reduce inflammation in the artery wall. The active ingredient is an inflammation resolving molecule, known as Resolvin E1. This discovery further underscores the increasing body of evidence showcasing how problems in the mouth - and how they are treated - can have life changing influences on other key systems in the body, such as the heart in this case.

"Our research is helping to underscore the very real link between oral health and heart disease," said Lead Investigator Hatice Hasturk, DDS, PhD, an associate member of Forsyth's Department of Applied Oral Sciences and director of Forsyth's Center for Clinical and Translational Research. "The general public understands the connection between heart health and overall wellness, and often takes appropriate steps to prevent heart disease. More education is needed to elevate oral wellness into the same category in light of proven connections to major health conditions."

According to the CDC, heart disease accounts for one in four deaths in the United States, and the rate continues to rise. Forsyth's findings suggest a need to expand the public's understanding of risk factors beyond cholesterol, smoking, hypertension and diabetes to include a focus on oral health. With support from the scientific community, Forsyth aims to generate greater awareness of gum disease (affecting 64.7 million American adults according to the CDC) as a critical risk factor for heart disease, independent from diet and lifestyle.

The study, titled, "Resolvin E1 Prevents Atheromatous Plaque Formation," will be published in print in the May issue of Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB), a journal of the American Heart Association. It is the first paper to show a rabbit model of accelerated heart disease, demonstrating a range of atherosclerotic plaque stages that more closely resemble those in humans without genetic modification of the animal. This research is authored by Hatice Hasturk, Rima Abdallah, Alpdogan Kantarci, Daniel Nguyen, Nicholas Giordano, James Hamilton and Thomas E. Van Dyke.



http://www.eurekalert.org/pub_releases/2015-04/mali-ath041415.php

Antimalarial tea - from herbal remedy to licensed phytomedicine

Herbal medication derived from N'Dribala licensed and sold as an antimalarial phytomedicine

New Rochelle, NY - Malaria is a critical health problem in West Africa, where traditional medicine is commonly used alongside modern healthcare practices.

An herbal remedy derived from the roots of a weed, which was traditionally used to alleviate malarial symptoms, was combined with leaves and aerial portions from two other plants with antimalarial activity, formulated as a tea, and eventually licensed and sold as an antimalarial phytomedicine.

The fascinating story and challenges behind the development of this plant-based treatment are presented in The Journal of Alternative and Complementary Medicine, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. The article is available free on The Journal of Alternative and Complementary Medicine website until May 14, 2015.

Dr. Merlin Willcox (University of Oxford, U.K.), Dr. Z├ęphirin Dakuyo (Phytofla, Banfora, Burkina Faso), and coauthors discuss the antimalarial and pharmacological properties of the herbal medication derived from Cochlospermum planchonii (a shrubby weed known as N'Dribala), Phyllanthus amarus, and Cassia alata.normal.img-000.jpg

Cochlospermum planchonii. The shape of the leaves is characteristic. The related species, C. tinctorium, has similar flowers, but these appear on the ground before the development of any leaves. Photo ª Merlin Willcox.

The authors provide a unique historical perspective in describing the early evaluation, development, and production of this phytomedicine. They present the ongoing research and challenges in scaling up cultivation and harvesting of the plants and in production of the final product. The article also describes other traditional uses of the medication, such as to treat hepatitis.



http://www.eurekalert.org/pub_releases/2015-04/uocm-aht041315.php

Ancient herbal therapy can prevent - and reverse - cardiac hypertrophy in mice

A natural compound derived from the bark of the magnolia tree, can protect the heart from hypertrophy

A natural compound derived from the bark of the magnolia tree, can protect the heart from hypertrophy, a thickening of cardiac muscle often caused by chronic high blood pressure that can lead to heart failure, researchers report in the April 14 issue of the online journal Nature Communications.

When injected into mice, honokiol (hoh-NOH'-kee-ohl) reduced the excess growth of individual cardiac muscle cells, decreased ventricular wall thickness and prevented the accumulation of interstitial fibrosis, a stiffening of cardiac muscle cells that reduces their ability to contract. It also protected heart muscle cells from the damage caused by oxidative stress, which can damage DNA.

The researchers, based at the University of Chicago Medicine, also describe how this ancient remedy, widely used in Asia for centuries, protects the heart.

They found the compound activates SIRT3, a protective protein associated with delayed aging, stress resistance and metabolic regulation.

"Honokiol, by increasing SIRT3 levels, effectively blocked both the induction and progression of cardiac hypertrophy in mice," said study author Mahesh Gupta, PhD, director of the Cardiac Cell Biology Research Program at the University of Chicago. "It even mitigated pre-existing cardiac hypertrophy. This has the potential to play a significant role in the prevention and treatment of heart failure." "To the best of our knowledge, this is the first report to describe a pharmacologic activator of SIRT3" he added. "Until now, caloric restriction combined with endurance exercise has been the only way to boost SIRT3 levels. Very few people have been able to follow such a rigorous regimen."

One of a family of sirtuin proteins, SIRT3 is primarily active in the mitochondria, the cell's main source of energy. It plays a central role there in energy metabolism and in preventing acetylation, a process that can alter the function of proteins. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, which can impair function.

Human studies show that sedentary patients over 60 years old have nearly 40 percent less SIRT3. Mice that lack the gene for SIRT3 have 40 percent lower levels of ATP, a primary source of energy, than those with the gene.

The researchers tested multiple compounds in search of one that could activate SIRT3. They found that honokiol reduced mitochondrial protein acetylation. When they tested it in the heart muscle cells from mice, they found that a small amount of honokiol nearly doubled SIRT3 levels within 24 hours.

Additional studies showed that honokiol, acting through SIRT3, could reduce or prevent hypertrophic growth in cardiac muscle cells, prevent mice from developing full blown hypertrophy and even reduce existing damage from established hypertrophy. It also blocked the production of fibroblasts - cells that interfere with heart muscle performance - and reduced production of myofibroblasts, cells that speed wound healing but can impair heart function. The researchers did not detect any appreciable toxicity.

To confirm the mechanism, the researchers performed the same experiments on mice that lacked the SIRT3 gene. In those studies, honokiol had no effect. They also determined that honokiol binds directly to SIRT3. The combination appears to increase SIRT3's activity.

The results, the authors wrote, suggest pharmacological activation of SIRT3 by honokiol could be "a potential therapeutic strategy to prevent adverse cardiac remodeling and other diseases associated with abnormal cellular growth and organ fibrosis." "Although we feel this is extremely promising," Gupta said, "there is still much work to be done."

Honokiol is available as an herbal remedy but the purity of such preparations is undetermined. "We treated the mice with injections into the peritoneal cavity," Gupta emphasized, "rather than by mouth, which is how this compound has traditionally been administered. We are testing to see if oral use will have a similar effect." Despite those caveats, "we are tremendously excited," Gupta said. "We are working to design a clinical trial involving patients with cardiac hypertrophy and potentially other metabolic diseases, such as type 2 diabetes."

The National Institutes of Health, the Rabinowitch-Davis Foundation and the Margolis Foundation funded this study. Additional authors were Vinodkumar Pillai, Sadhana Samant, Nagalingam Sundaresan, Hariharasundaram Raghuraman and Gene Kim of the University of Chicago; Michael Bonner and Jack Arbiser of the Atlanta VA Medical Center; Douglas I. Walker and Dean Jones of the Emory University School of Medicine; and David Gius of Northwestern University.

http://www.eurekalert.org/pub_releases/2015-04/aiop-hef041015.php

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