Latest evidence on using hormone replacement therapy for treating menopausal symptoms

Hormone replacement therapy (HRT) is the most effective treatment for menopausal symptoms, in particular for younger women at the onset of the menopause, suggests a new review published today (19 December) in The Obstetrician & Gynaecologist (TOG).

The review highlights that menopausal symptoms, including hot flushes and night sweats are common, affecting around 70% of women for an average of 5 years but may continue for many years in about 10% of women.
Every woman experiences the menopause differently; some experience one or two symptoms mildly while others have more severe symptoms. Menopausal symptoms can be debilitating and can adversely affect a woman's quality of life.
HRT is a medical treatment for the menopause. It provides low doses of the hormone estrogen, with or without progestogen, which a woman no longer produces.
The review notes that the risk-benefit ratio of HRT has always been debated and discusses previous studies examining the effects of HRT.
The Women's Health Initiative Study in 2003 examined the effect of HRT on healthy postmenopausal women with a particular interest in cardiovascular outcomes. The study reported an increase in breast cancer, stroke and venous thromboembolism. Consequently, an 80% reduction in HRT use was reported. However, the re-analysis in 2007 demonstrated that giving HRT to women within 10 years of the menopause was associated with fewer risks and a reduction in cardiovascular problems.
The Million Women Study in 2001 suggested that HRT use increased the risk of breast cancer significantly and the Cochrane Collaboration systematic review identified an increased risk of similar conditions.
However, the authors of the TOG review highlight that such studies failed to address the effect of HRT in symptomatic younger postmenopausal women and have not addressed the benefits of HRT given at the window of opportunity, for example, administrating HRT for symptom relief during the early phase of the menopausal transition.
Additionally, the review advises that any woman with relative contraindications should be offered the option of discussing this further with a menopause specialist. Women with premature ovarian sufficiency should be strongly advised to consider taking HRT until the average menopausal age of 51.4 years, state the authors.
The authors conclude that doctors should not be concerned about discussing the risks and benefits of HRT with women who have menopausal symptoms, or be hesitant to offer a trial of appropriate treatment. They also emphasise that HRT is a patient choice.
Shagaf Bakour, Honorary Senior Lecturer and Consultant Obstetrician and Gynaecologist at City Hospital, Birmingham, and co-author of the review said:
"Women are sometimes concerned about the increased risk of breast cancer related to HRT. However, this risk is much lower than that associated with other factors such as obesity, alcohol consumption and later maternal age.
"HRT is the most effective treatment for symptoms of the menopause and when HRT is individually tailored, women gain maximum advantages and the risks are minimised.
"There are various types and regimens of HRT and healthcare professionals will be able to advise on the suitability of HRT to any woman."
Jason Waugh, TOG Editor-in-chief added: "The use of HRT is an individual decision, which a woman can only make once she has been given correct information and advice from healthcare professionals.
"If women have any concerns about menopausal symptoms or HRT, they should talk to their doctor who will be happy to discuss treatment options further."
 

Journal Reference:

1. Shagaf H Bakour, Jennifer Williamson. Latest evidence on using hormone replacement therapy in the menopause. The Obstetrician & Gynaecologist, 2014; DOI: 10.1111/tog.12155 

Courtesy: ScienceDaily
 

The dementia that is not Alzheimer's disease

Lewy body dementia (LBD) -- a complex, challenging and surprisingly common brain disease -- is often misdiagnosed as its "cousin," Alzheimer's disease. And that could lead to devastating results.

According to the Lewy Body Dementia Association (LBDA), accurate and early diagnosis is critical because people with LBD typically have sensitivities to medication, and many drugs prescribed for Alzheimer's can be very harmful to those with LBD.
Although, LBD is the second most common cause of progressive dementia it is not well recognized by physicians, especially primary care and general health care providers.
"While the symptoms of LBD may be similar to Alzheimer's and Parkinson's disease, the treatment strategy is more challenging because fewer medications can be used safely," warns Howard I. Hurtig, M.D., Chair, Department of Neurology, Pennsylvania Hospital, and member of the LBDA Scientific Advisory Council. "I cannot overemphasize the need to avoid medications that can worsen the symptoms of LBD. Every patient with this disease and their caregivers should be familiar with the list of acceptable and forbidden drugs."
Is it Alzheimer's or LBD?
These two diseases share some clinical and biological similarities that can make them difficult for many physicians to distinguish. Dementia experts are more experienced at differentiating between dementia types. Alzheimer's disease affects cognitive function, including making new experiences into memories. The disorder in LBD affects different aspects of cognition, such as problem solving and complex reasoning and movement.
LBDA has just issued a new brochure -- Lewy Who? Recognizing when it's not Parkinson's or Alzheimer's Disease -- that offers a symptom comparison chart that can help clarify the confusion. It can be downloaded from the LBDA.org website.
A Different Diagnosis
Lewy body dementia, which affects 1.4 million Americans, refers to two related diagnoses: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Both DLB and PDD are considered Lewy body dementias. With DLB, cognitive (thinking) symptoms appear before Parkinson-like movement problems. With PDD, disabling cognitive symptoms do not develop until more than a year after movement problems begin.
LBD is characterized by an abnormal build up of Lewy bodies (alpha-synuclein protein deposits) in the areas of the brain that regulate behavior, memory, movement and personality. The most prominent symptoms of Parkinson's disease affect motor abilities. Alzheimer's disease primarily affects areas of the brain involving learning and memory. A specialist like a neurologist, geriatric psychiatrist or a neuropsychologist may be needed to distinguish the symptoms and provide an accurate diagnosis.
 

Story Source:
The above story is based on materials provided by Lewy Body Dementia Association. Note: Materials may be edited for content and length.
 

Courtesy: ScienceDaily

 

Atom-thick CCD could capture images

An atomically thin material developed at Rice University may lead to the thinnest-ever imaging platform.

Rice University researchers fabricated a three-pixel, CIS-based optoelectronic sensor array to test the two-dimensional compound’s ability to capture image information. They started with few-layer exfoliated CIS on a silicon substrate, fabricated three pairs of titanium/gold electrodes on top of the CIS and cut the CIS into three sections with a focused ion beam.

Synthetic two-dimensional materials based on metal chalcogenide compounds could be the basis for superthin devices, according to Rice researchers. One such material, molybdenum disulfide, is being widely studied for its light-detecting properties, but copper indium selenide (CIS) also shows extraordinary promise.
Sidong Lei, a graduate student in the Rice lab of materials scientist Pulickel Ajayan, synthesized CIS, a single-layer matrix of copper, indium and selenium atoms. Lei also built a prototype -- a three-pixel, charge-coupled device (CCD) -- to prove the material's ability to capture an image.
The details appear this month in the American Chemical Society journal Nano Letters.
Lei said the optoelectronic memory material could be an important component in two-dimensional electronics that capture images. "Traditional CCDs are thick and rigid, and it would not make sense to combine them with 2-D elements," he said. "CIS-based CCDs would be ultrathin, transparent and flexible, and are the missing piece for things like 2-D imaging devices."
The device traps electrons formed when light hits the material and holds them until released for storage, Lei said.
CIS pixels are highly sensitive to light because the trapped electrons dissipate so slowly, said Robert Vajtai, a senior faculty fellow in Rice's Department of Materials Science and NanoEngineering. "There are many two-dimensional materials that can sense light, but none are as efficient as this material," he said. "This material is 10 times more efficient than the best we've seen before."
Because the material is transparent, a CIS-based scanner might use light from one side to illuminate the image on the other for capture. For medical applications, Lei envisions CIS being combined with other 2-D electronics in tiny bio-imaging devices that monitor real-time conditions.
In the experiments for the newly reported study, Lei and colleagues grew synthetic CIS crystals, pulled single-layer sheets from the crystals and then tested the ability of the layers to capture light. He said the layer is about two nanometers thick and consists of a nine-atom-thick lattice. The material may also be grown via chemical vapor deposition to a size limited only by the size of the furnace, Lei said.
Because it's flexible, CIS could also be curved to match the focal surface of an imaging lens system. He said this would allow for the real-time correction of aberrations and significantly simplify the entire optical system.
Co-authors of the paper are Rice graduate students Fangfang Wen and Yongji Gong; postdoctoral researchers Bo Li, Pei Dong, Anthony George and Liehui Ge; undergraduates Qizhong Wang, James Bellah and Yihan Huang; complementary appointee Yongmin He of Lanzhou University, China; Jun Lou, an associate professor of materials science and nanoengineering, and Naomi Halas, the Stanley C. Moore Professor of Electrical and Computer Engineering and a professor of chemistry, biomedical engineering, physics and astronomy and of materials science and nanoengineering. Ajayan is Rice's Benjamin M. and Mary Greenwood Anderson Professor in Engineering, professor of materials science and nanoengineering and of chemistry and chair of the Department of Materials Science and NanoEngineering.
The research was supported by the Army Research Office Multidisciplinary University Research Initiative, the Function Accelerated nanoMaterial Engineering Division of the Semiconductor Technology Advanced Research Network, the Microelectronics Advanced Research Association, the Defense Advanced Research Projects Agency, the Netherlands Organization for Scientific Research, the Robert A. Welch Foundation, the National Security Science and Engineering Faculty Fellowship and the Office of Naval Research.

Journal Reference:

1. Sidong Lei, Fangfang Wen, Bo Li, Qizhong Wang, Yihan Huang, Yongji Gong, Yongmin He, Pei Dong, James Bellah, Antony George, Liehui Ge, Jun Lou, Naomi J. Halas, Robert Vajtai, Pulickel M. Ajayan. Optoelectronic Memory Using Two-Dimensional Materials. Nano Letters, 2014; 141217153644008 DOI: 10.1021/nl503505f 

Courtesy: ScienceDaily

Genes tell story of birdsong and human speech

His office is filled with all sorts of bird books, but Duke neuroscientist Erich Jarvis didn't become an expert on the avian family tree because of any particular interest in our feathered friends. Rather, it was his fascination with how the human brain understands and reproduces speech that brought him to the birds.

"We've known for many years that the singing behavior of birds is similar to speech in humans -- not identical, but similar -- and that the brain circuitry is similar, too," said Jarvis, an associate professor of neurobiology at the Duke University Medical School and an investigator at the Howard Hughes Medical Institute. "But we didn't know whether or not those features were the same because the genes were also the same."
Now scientists do know, and the answer is yes -- birds and humans use essentially the same genes to speak.
After a massive international effort to sequence and compare the entire genomes of 48 species of birds representing every major order of the bird family tree, Jarvis and his colleagues found that vocal learning evolved twice or maybe three times among songbirds, parrots and hummingbirds.
Even more striking is that the set of genes involved in each of those song innovations is remarkably similar to the genes involved in human speaking ability.
The findings are part of a package of eight scientific papers in a Dec. 12 special issue of Science and 21 additional papers appearing nearly simultaneously in Genome Biology, GigaScience and other journals. Jarvis' name appears on 20 papers and he is a corresponding author for 8 of them.
Jarvis co-led the Avian Phylogenomics Consortium with Guojie Zhang of the National Genebank at BGI in China and the University of Copenhagen and M. Thomas P. Gilbert of the Natural History Museum of Denmark. His Duke lab contributed to preparing samples, sequencing and annotating the genomes, performing the analyses and coordinating the overall project.
The Jarvis lab in the Bryan Research Building prepared DNA of many of the species, pulling it from little chunks of frozen, pink bird flesh collected over the past 30 years by museums and other institutions around the world. To ensure the DNA being sequenced really belonged to the Golden-collared manakin and not an undergraduate lab assistant, the lab has been kept spotlessly clean and many of its tools are used only once, to avoid the possibility of subsequent contamination.
"We change gloves a lot," said Carole Parent, the lab research analyst who set up a DNA isolation pipeline for the next stage of the project to sequence still more birds and supervised sample prep with a team of Duke undergrads and a student from East Chapel Hill High School.
All of this meticulous and somewhat tedious work has given Jarvis and hundreds of colleagues around the world a crack at an unprecedented amount of genomic data generated by BGI in China. The whole-genome comparison of the 48 bird species required new algorithms written at the University of Illinois and University of Texas that ran for 400 years of CPU time on three supercomputers in the U.S.
Of the 29 papers covering everything from penguin evolution to color vision, eight are devoted to bird song.
One of the Dec. 12 papers in Science found there is a consistent set of just over 50 genes that show higher or lower activity in the brains of vocal learning birds and humans. These changes were not found in the brains of birds that do not have vocal learning and of non-human primates that do not speak, according to this Duke team, which was led by Jarvis; Andreas Pfenning, a graduate of the Ph.D. program in computational biology and bioinformatics (CBB); and Alexander Hartemink, professor of computer science, statistical science and biology.
"This means that vocal learning birds and humans are more similar to each other for these genes in song and speech brain areas than other birds and primates are to them," Jarvis said.
These genes are involved in forming new connections between neurons of the motor cortex and neurons that control the muscles that produce sound.
A companion study by another CBB doctorate, Rui Wang, looked at the specialized activity of a pair of genes involved in the regions of the brain that control song and speech. This study, appearing in the Journal of Comparative Neurology, found that these genes are down- and up-regulated in one brain region of song-learning birds during the juvenile period of their vocal learning , changes that last into adulthood. This study, and that of Pfenning, hypothesize that changes in these genes could be critical for the evolution of song in birds and speech in humans.
"You can find those same genes in the genomes of all species, but they're active at much higher or lower levels in the specialized song or speech brain regions of vocal learning birds and humans," Jarvis said. "What this suggests to me is that when vocal learning evolves, there may be a limited way in which the brain circuits can evolve."
Another paper in Science from Duke, led by post-doc Osceola Whitney, Pfenning, Hartemink and Anne West, an associate professor of neurobiology, looked at gene activation in different areas of the brain during singing. This team found activation of 10 percent of the expressed genome during singing, with diverse activation patterns in different song-learning regions of the brain. The diverse gene patterns are best explained by epigenetic differences in the genomes of the different brain regions, meaning that individual cells in different brain regions can regulate genes at a moment's notice when the birds sing.
Among the three main groups of vocal learning birds, parrots are clearly different in their ability to mimic human speech. Mukta Chakraborty, a postdoc in the Jarvis lab, led a project that used the activity of some of the specialized genes to discover that the parrot's speech center is organized somewhat differently. It has what the researchers call a "song-system-within-a-song-system" in which the area of the brain with different gene activity for producing song has an outer ring of still more differences in gene expression.
Parrots are very social animals, Chakraborty said, and having the ability to quickly pick up "dialects" of parrot speech may account for their super-charged speech center. The "shell" or outer regions were found to be proportionally larger in the parrot species, which are believed to have the highest vocal, cognitive and social abilities. These species include Amazon parrots, the African Grey and the Blue and Gold Macaw.
Jarvis was also part of a team with Claudio Mello and his Ph.D. student Morgan Wirthlin at Oregon Health & Science University that found ten more genes that are unique to song-control regions of songbirds. This paper appears in BMC Genomics.
A paper in Science led by Zhang, Gilbert and Jarvis found the genomes of vocal learners are more rapidly evolving and have more chromosomal rearrangements compared to other bird species. This genomic comparison also found similar changes occurred independently in in the song-learning area of different birds' brains.
Jarvis said knowing more of this history of how speech evolved in birds makes vocal learning birds even more valuable model organisms for helping to answer the questions he and other researchers are addressing about human speech.
"Speech is difficult to study in human brains," he said. "Whales and elephants learn speech and songs, but they're too big to house in the lab. Now that we have a deeper understanding of how similar birdsong brain regions are to human speech regions at the genetic level, I think they'll be a better model than ever."
Jarvis' general exploration of the bird brain over his 16 years at Duke has also led to several unexpected discoveries unrelated to song.
In 2005, he and colleagues found a center of the brain in migratory birds that apparently enables sensing of magnetic fields through "night vision." That year he also led a revision of the understanding of bird brain organization and vertebrate brain evolution. Last year, he led a re-drawing of the geography of the bird brain based on analysis of 52 genes that are active in 23 areas of the brains of eight species of birds. This new map shows neuron groupings in the birds' brains to be organized in columns like the brains of humans and other mammals.
He also branched out a bit and learned about the brain structures that enable mice to "sing" in ultrasonic ranges beyond human hearing.
Jarvis said this first wave of findings from the Avian Phylogenomics Consortium is just the beginning of an exciting new era of genomic analysis. The international group is already sequencing more birds at the whole-genome level.
"This is an exciting moment," said Jarvis, who is also a member of the Duke Institute for Brain Sciences. "Lots of fundamental questions now can be resolved with more genomic data from a broader sampling. I got into this project because of my interest in birds as a model for vocal learning and speech production in humans, and it has opened up some amazing new vistas on brain evolution."
 

Journal References:

1. G. Zhang, E. D. Jarvis, M. T. P. Gilbert. A flock of genomes. Science, 2014; 346 (6215): 1308 DOI: 10.1126/science.346.6215.1308
2. A. R. Pfenning, E. Hara, O. Whitney, M. V. Rivas, R. Wang, P. L. Roulhac, J. T. Howard, M. Wirthlin, P. V. Lovell, G. Ganapathy, J. Mouncastle, M. A. Moseley, J. W. Thompson, E. J. Soderblom, A. Iriki, M. Kato, M. T. P. Gilbert, G. Zhang, T. Bakken, A. Bongaarts, A. Bernard, E. Lein, C. V. Mello, A. J. Hartemink, E. D. Jarvis. Convergent transcriptional specializations in the brains of humans and song-learning birds. Science, 2014; 346 (6215): 1256846 DOI: 10.1126/science.1256846 

Courtesy: ScienceDaily
 

Signaling mechanism could be target for survival, growth of tumor cells in brain cancer

UT Southwestern Medical Center neurology researchers have identified an important cell signaling mechanism that plays an important role in brain cancer and may provide a new therapeutic target.

Dr. Amyn A. Habib, Associate Professor of Neurology and Neurotherapeutics at UT Southwestern and member of the Harold C. Simmons Cancer Center.

Researchers found that this mechanism -- a type of signaling termed constitutive or non-canonical epidermal growth factor receptor (EGFR) signaling -- is highly active in glioblastomas, the most common type of adult brain cancer and a devastating disease with a poor prognosis.
When activated in cancer cells, it protects the tumor cells, making them more resistant to chemotherapy treatment. The pathway may also have implications for other types of lung and breast cancers where overexpression of EGFR is a factor.
"Abnormal EGFR signaling, a common and key feature of human cancer, is of considerable interest both for a role in the growth of malignant cells and as a target for treatment," said Dr. Amyn A. Habib, Associate Professor of Neurology and Neurotherapeutics at UT Southwestern and member of the Harold C. Simmons Cancer Center, the only National Cancer Institute-designated cancer center in North Texas and one of just 66 NCI-designated cancer centers in the nation.
Glioblastomas (GBM) arise from astrocytes, which are star-shaped cells that make up the "glue-like" or supportive tissue of the brain, according to the American Brain Tumor Association. They represent about 17 percent of brain tumors, and are more common in males and those over 50.
Fueled by a good blood supply, they grow rapidly, increasing pressure on the brain and causing symptoms such as headaches, vomiting and nausea, speech and memory difficulties, muscle weakness on one side, and vision problems, depending on where the tumor grows in the brain. Due to that fast growth, average survival is just 15 months after diagnosis.
In their study, Dr. Habib and his team shed new light on why this difficult-to-treat cancer can be resistant to treatment.
The epidermal growth factor receptor is frequently amplified and mutated in human cancer, including lung and breast cancer, and plays an important role in the growth of cancer cells and in resistance to chemotherapy.
EGFR becomes activated when the epidermal growth factor (EGF) -- its ligand or partner molecule -- binds to it and triggers biochemical signals within cells that lead to tumor growth or resistance to treatment. In human cancers, the EGFR may be expressed with or without its ligand or partner.
"We found that brain cancer cells expressing EGFR are more resistant to chemotherapy in the absence of ligand," said Dr. Habib, and a staff physician at the North Texas VA Medical Center.
Specifically, the presence of EGF acts as a switch to turn off non-canonical signaling and turn on ligand-activated signaling. Non-canonical EGFR signaling results in activation of a transcription factor called IRF3. IRF3 activity activates immune signals and normally protects cells from virus infection but when activated in cancer cells may protect tumor cells from chemotherapy. Therefore, the IRF3 signaling network may be a new target for treatment in cancer, Dr. Habib said. For example, blocking IRF3 activation using small molecule inhibitors may be a strategy for stopping growth of tumor cells.
"The non-canonical EGFR signaling network may be an important target for treatment in those cancers in which the level of EGFR ligand is low," he said.
The research, which appears in Nature Communications, was supported by the National Institutes of Health, Department of Veterans Affairs, the William and Sylvia Zale Foundation and the Ethel Silvergold Philanthropic Fund of the Dallas Jewish Community Foundation, and by donations from Barbara F. Glick.
 

Journal Reference:

1. Sharmistha Chakraborty, Li Li, Vineshkumar Thidil Puliyappadamba, Gao Guo, Kimmo J. Hatanpaa, Bruce Mickey, Rhonda F. Souza, Peggy Vo, Joachim Herz, Mei-Ru Chen, David A. Boothman, Tej K. Pandita, David H. Wang, Ganes C. Sen, Amyn A. Habib. Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks. Nature Communications, 2014; 5: 5811 DOI: 10.1038/ncomms6811 

Courtesy: ScienceDaily
 

Women's age at first menstrual cycle linked to heart disease risk

Women who had their first menstrual cycle at age 10 or younger, or age 17 or older, may be at higher risk of developing heart disease, stroke, and complications of high blood pressure, according to new research in the American Heart Association's journal Circulation.

Researchers analyzed data collected from 1.3 million women aged 50 to 64 years old, who were mostly white. After over a decade of observation, those women who had their first menstrual cycle at the age of 13 had the least risk of developing heart disease, stroke, and high blood pressure.
Compared to women who had their first menstrual cycle at age 13, women with their first menstrual cycle at age 10 or younger, or age 17 or older, had up to:

• 27 percent more hospitalizations or deaths due to heart disease;
• 16 percent more hospitalizations or deaths from stroke; and
• 20 percent more hospitalizations with high blood pressure, or deaths due to its complications.

"The size of our study, the wide range of ages considered, and the vascular diseases being examined made it unique and informative," said Dexter Canoy, M.D, Ph.D., study lead author and cardiovascular epidemiologist at the Cancer Epidemiology Unit, Nuffield Department of Population Health at the University of Oxford in the U.K. "Childhood obesity, widespread in many industrialized countries, is linked particularly to early age at which the first menstrual cycle occurs. Public health strategies to tackle childhood obesity may possibly prevent the lowering of the average age of first menstrual cycle, which may in turn reduce their risk of developing heart disease over the long term."
The effect of age of the first occurrence of menstruation on heart disease was consistently found among lean, over-weight, and obese women, among never, past or current smokers, and among women in lower, middle, or higher socioeconomic groups.
For the majority of these women, however, their additional risk of developing a vascular disease was small. Of the million women, only four percent of them had their first menstrual cycle occurring at age 10 or younger, and only one percent at age 17 or older.
 

Journal Reference:

1. Dexter Canoy, Valerie Beral, Angela Balkwill, F. Lucy Wright, Mary E. Kroll, Gillian K. Reeves, Jane Green, and Benjamin J. Cairns. Age at Menarche and Risks of Coronary Heart and Other Vascular Diseases in a Large UK Cohort. Circulation, December 2014 DOI: 10.1161/CIRCULATIONAHA.114.010070 

Courtesy: ScienceDaily
 

Controlling obesity with potato extract

Take a look in your pantry: the miracle ingredient for fighting obesity may already be there. A simple potato extract may limit weight gain from a diet that is high in fat and refined carbohydrates, according to scientists at McGill University. The results of their recent study were so surprising that the investigators repeated the experiment just to be sure.

Investigators fed mice an obesity-inducing diet for 10 weeks. The results soon appeared on the scale: mice that started out weighing on average 25 grams put on about 16 grams. But mice that consumed the same diet but with a potato extract gained much less weight: only 7 more grams. The benefits of the extract are due to its high concentration of polyphenols, a beneficial chemical component from the fruits and vegetables we eat.
"We were astonished by the results," said Prof. Luis Agellon, one of the study's authors. "We thought this can't be right -- in fact, we ran the experiment again using a different batch of extract prepared from potatoes grown in another season, just to be certain."
The rate of obesity due to over-eating continues to rise in Canada, affecting 1 in every 4 adults. Obesity increases the risk of cardiovascular disease and cancer. According to this study, potato extracts could be a solution for preventing both obesity and type 2 diabetes.
Extract derived from 30 potatoes
"The daily dose of extract comes from 30 potatoes, but of course we don't advise anyone to eat 30 potatoes a day," says Stan Kubow, principal author of the study, "as that would be an enormous number of calories." What the investigators envisage instead is making the extract available as a dietary supplement or simply as a cooking ingredient to be added in the kitchen.
Popularly known for its carbohydrate content, the potato is also a source of polyphenols. "In the famous French diet, considered to be very healthy, potatoes -- not red wine -- are the primary source of polyphenols," says Kubow. "In North America, potatoes come third as a source of polyphenols -- before the popular blueberries."
A low-cost solution
"Potatoes have the advantage of being cheap to produce, and they're already part of the basic diet in many countries," Kubow explains. "We chose a cultivated variety that is consumed in Canada and especially rich in polyphenols."
En route to the airport one day to catch the same flight, Stan Kubow, Associate Professor in the School of Dietetics and Human Nutrition and an expert on polyphenols, and Danielle Donnelly, Associate Professor in the Department of Plant Science and an expert on potatoes, had the bright idea of crossing their research interests, and together with Prof. Agellon, they carried out this study.
Although humans and mice metabolize foods in similar ways, clinical trials are absolutely necessary to validate beneficial effects in humans. And the optimal dose for men and women needs to be determined, since their metabolisms differ.
The team hopes to patent the potato extract, and is currently seeking partners, mainly from the food industry, to contribute to funding clinical trials.

Journal Reference:

1. Stan Kubow, Luc Hobson, Michèle M. Iskandar, Kebba Sabally, Danielle J. Donnelly, Luis B. Agellon. Extract of Irish potatoes (Solanum tuberosumL.) decreases body weight gain and adiposity and improves glucose control in the mouse model of diet-induced obesity. Molecular Nutrition & Food Research, 2014; 58 (11): 2235 DOI: 10.1002/mnfr.201400013 

Courtesy: ScienceDaily

Promising compound rapidly eliminates malaria parasite

An international research collaborative has determined that a promising anti-malarial compound tricks the immune system to rapidly destroy red blood cells infected with the malaria parasite but leave healthy cells unharmed. St. Jude Children's Research Hospital scientists led the study, which appears in the current online early edition of the Proceedings of the National Academy of Sciences (PNAS).

A new report says that the rapid action of (+)-SJ733 will likely slow malaria drug resistance.

Credit: Peter Barta, St. Jude Children's Research Hospital

The compound, (+)-SJ733, was developed from a molecule identified in a previous St. Jude-led study that helped to jumpstart worldwide anti-malarial drug development efforts. Malaria is caused by a parasite spread through the bite of an infected mosquito. The disease remains a major health threat to more than half the world's population, particularly children. The World Health Organization estimates that in Africa a child dies of malaria every minute.

In this study, researchers determined that (+)-SJ733 uses a novel mechanism to kill the parasite by recruiting the immune system to eliminate malaria-infected red blood cells. In a mouse model of malaria, a single dose of (+)-SJ733 killed 80 percent of malaria parasites within 24 hours. After 48 hours the parasite was undetectable.

Planning has begun for safety trials of the compound in healthy adults.

Laboratory evidence suggests that the compound's speed and mode of action work together to slow and suppress development of drug-resistant parasites. Drug resistance has long undermined efforts to treat and block malaria transmission.

"Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose," said corresponding author R. Kiplin Guy, Ph.D., chair of the St. Jude Department of Chemical Biology and Therapeutics. "These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude."

Whole genome sequencing of the Plasmodium falciparum, the deadliest of the malaria parasites, revealed that (+)-SJ733 disrupted activity of the ATP4 protein in the parasites. The protein functions as a pump that the parasites depend on to maintain the proper sodium balance by removing excess sodium.

The sequencing effort was led by co-author Joseph DeRisi, Ph.D., a Howard Hughes Medical Institute investigator and chair of the University of California, San Francisco Department of Biochemistry and Biophysics. Investigators used the laboratory technique to determine the makeup of the DNA molecule in different strains of the malaria parasite.

Researchers showed that inhibiting ATP4 triggered a series of changes in malaria-infected red blood cells that marked them for destruction by the immune system. The infected cells changed shape and shrank in size. They also became more rigid and exhibited other alterations typical of aging red blood cells. The immune system responded using the same mechanism the body relies on to rid itself of aging red blood cells.

Another promising class of antimalarial compounds triggered the same changes in red blood cells infected with the malaria parasite, researchers reported. The drugs, called spiroindolones, also target the ATP4 protein. The drugs include NITD246, which is already in clinical trials for treatment of malaria. Those trials involve investigators at other institutions.

"The data suggest that compounds targeting ATP4 induce physical changes in the infected red blood cells that allow the immune system or erythrocyte quality control mechanisms to recognize and rapidly eliminate infected cells," DeRisi said. "This rapid clearance response depends on the presence of both the parasite and the investigational drug. That is important because it leaves uninfected red blood cells, also known as erythrocytes, unharmed."

Laboratory evidence also suggests that the mechanism will slow and suppress development of drug-resistant strains of the parasite, researchers said.

Planning has begun to move (+)-SJ733 from the laboratory into the clinic beginning with a safety study of the drug in healthy adults. The drug development effort is being led by a consortium that includes scientists at St. Jude, the Swiss-based non-profit Medicines for Malaria Venture and Eisai Co., a Japanese pharmaceutical company.

Journal Reference:

1. María Belén Jiménez-Díaz, Daniel Ebert, Yandira Salinas, Anupam Pradhan, Adele M. Lehane, Marie-Eve Myrand-Lapierre, Kathleen G. O’Loughlin, David M. Shackleford, Mariana Justino de Almeida, Angela K. Carrillo, Julie A. Clark, Adelaide S. M. Dennis, Jonathon Diep, Xiaoyan Deng, Sandra Duffy, Aaron N. Endsley, Greg Fedewa, W. Armand Guiguemde, María G. Gómez, Gloria Holbrook, Jeremy Horst, Charles C. Kim, Jian Liu, Marcus C. S. Lee, Amy Matheny, María Santos Martínez, Gregory Miller, Ane Rodríguez-Alejandre, Laura Sanz, Martina Sigal, Natalie J. Spillman, Philip D. Stein, Zheng Wang, Fangyi Zhu, David Waterson, Spencer Knapp, Anang Shelat, Vicky M. Avery, David A. Fidock, Francisco-Javier Gamo, Susan A. Charman, Jon C. Mirsalis, Hongshen Ma, Santiago Ferrer, Kiaran Kirk, Iñigo Angulo-Barturen, Dennis E. Kyle, Joseph L. DeRisi, David M. Floyd, R. Kiplin Guy. ( )-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance ofPlasmodium. Proceedings of the National Academy of Sciences, 2014; 201414221 DOI: 10.1073/pnas.1414221111

 Courtesy: ScienceDaily

Injectable 3-D vaccines could fight cancer, infectious diseases

One of the reasons cancer is so deadly is that it can evade attack from the body's immune system, which allows tumors to flourish and spread. Scientists can try to induce the immune system, known as immunotherapy, to go into attack mode to fight cancer and to build long lasting immune resistance to cancer cells. Now, researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard's School of Engineering and Applied Sciences (SEAS) show a non-surgical injection of programmable biomaterial that spontaneously assembles in vivo into a 3D structure could fight and even help prevent cancer and also infectious disease such as HIV. Their findings are reported in Nature Biotechnology.

"We can create 3D structures using minimally-invasive delivery to enrich and activate a host's immune cells to target and attack harmful cells in vivo," said the study's senior author David Mooney, Ph.D., who is a Wyss Institute Core Faculty member and the Robert P. Pinkas Professor of Bioengineering at Harvard SEAS.
Tiny biodegradable rod-like structures made from silica, known as mesoporous silica rods (MSRs), can be loaded with biological and chemical drug components and then delivered by needle just underneath the skin. The rods spontaneously assemble at the vaccination site to form a three-dimensional scaffold, like pouring a box of matchsticks into a pile on a table. The porous spaces in the stack of MSRs are large enough to recruit and fill up with dendritic cells, which are "surveillance" cells that monitor the body and trigger an immune response when a harmful presence is detected.
"Nano-sized mesoporous silica particles have already been established as useful for manipulating individual cells from the inside, but this is the first time that larger particles, in the micron-sized range, are used to create a 3D in vivo scaffold that can recruit and attract tens of millions of immune cells," said co-lead author Jaeyun Kim, Ph.D., an Assistant Professor of Chemical Engineering at Sungkyunkwan University and a former Wyss Institute Postdoctoral Fellow.
Synthesized in the lab, the MSRs are built with small holes, known as nanopores, inside. The nanopores can be filled with specific cytokines, oligonucleotides, large protein antigens, or any variety of drugs of interest to allow a vast number of possible combinations to treat a range of infections.
"Although right now we are focusing on developing a cancer vaccine, in the future we could be able to manipulate which type of dendritic cells or other types of immune cells are recruited to the 3D scaffold by using different kinds of cytokines released from the MSRs," said co-lead author Aileen Li, a graduate student pursuing her Ph.D. in bioengineering at Harvard SEAS. "By tuning the surface properties and pore size of the MSRs, and therefore controlling the introduction and release of various proteins and drugs, we can manipulate the immune system to treat multiple diseases."
Once the 3D scaffold has recruited dendritic cells from the body, the drugs contained in the MSRs are released, which trips their "surveillance" trigger and initiates an immune response. The activated dendritic cells leave the scaffold and travel to the lymph nodes, where they raise alarm and direct the body's immune system to attack specific cells, such as cancerous cells. At the site of the injection, the MSRs biodegrade and dissolve naturally within a few months.
So far, the researchers have only tested the 3D vaccine in mice, but have found that it is highly effective. An experiment showed that the injectable 3D scaffold recruited and attracted millions of dendritic cells in a host mouse, before dispersing the cells to the lymph nodes and triggering a powerful immune response.
The vaccines are easily and rapidly manufactured so that they could potentially be widely available very quickly in the face of an emerging infectious disease. "We anticipate 3D vaccines could be broadly useful for many settings, and their injectable nature would also make them easy to administer both inside and outside a clinic," said Mooney.
Since the vaccine works by triggering an immune response, the method could even be used preventatively by building the body's immune resistance prior to infection.
"Injectable immunotherapies that use programmable biomaterials as a powerful vehicle to deliver targeted treatment and preventative care could help fight a whole range of deadly infections, including common worldwide killers like HIV and Ebola, as well as cancer," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D. who is also Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at Harvard SEAS. "These injectable 3D vaccines offer a minimally invasive and scalable way to deliver therapies that work by mimicking the body's own powerful immune-response in diseases that have previously been able to skirt immune detection."
 

Journal Reference:

1. Jaeyun Kim, Weiwei Aileen Li, Youngjin Choi, Sarah A Lewin, Catia S Verbeke, Glenn Dranoff, David J Mooney. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nature Biotechnology, 2014; DOI: 10.1038/nbt.3071

 Courtesy: ScienceDaily

Many animals steal defenses from bacteria: Microbe toxin genes have jumped to ticks, mites and other animals

It's a dog eat dog world, and bacteria have been living in it for a long time. It's of no surprise that bacteria have a sophisticated arsenal to compete with each other for valuable resources in the environment. In 2010, work led by University of Washington Department of Microbiology Associate Professor Joseph Mougous uncovered a weaponry system used in this warfare between bacteria. The combatants inject deadly toxins into rival cells.

This is a tick resting on a blade of grass. Some species of ticks are among the many animals that have incorporated bacterial toxin

Now, in a surprising twist, Mougous and colleagues have found that many animals have taken a page from the bacterial playbook. They steal these toxins to fight unwanted microbes growing in or on them. The researchers describe their findings in a report to be published online Nov. 24 in the journal Nature.
The animal toxins were serendipitously discovered when the Mougous group was working with evolutionary biologist Harmit Malik at Fred Hutchinson Cancer Research Center in Seattle to find more bacterial competition toxins.
"When we started digging into genome databases, we were surprised to find that toxin genes we thought were present only in bacteria were also in several animals," explained co-author Matt Daugherty, a postdoctoral fellow in the Malik lab. "We immediately started wondering why they were there."
Their analyses revealed that these genes had jumped from bacteria into animals. These genes had become permanently incorporated into the genomes of these animals through a process known as horizontal gene transfer. While such transfer events are common between microbes, very few genes have been reported to jump from bacteria to more complex organisms.
The organisms carrying the bacterial toxins were incredibly diverse and included several species of ticks and mites. The team of scientists immediately recognized the potential medical importance of the toxin in one organism in particular -- the deer tick, infamous for its ability to transmit Lyme disease.
"We were excited to see this in the deer tick, given the increasing prevalence of Lyme disease in North America. Lyme disease is caused by a bacterium, so we speculated that the transferred antibacterial toxin might affect how the tick interacts with the Lyme disease agent," said co-author Seemay Chou, a postdoctoral researcher in the Mougous group.
Ticks carry pathogens in their guts and transmit them through their saliva when they feed on animals. The toxin was abundant in both of these sites in the tick. The researchers observed that, when they used genetic strategies to reduce production of the toxin in ticks, levels of the Lyme disease pathogen rose significantly.
"We are now following up on these results by looking into how these toxins influence Lyme disease transmission," said Chou.
How the toxins function in organisms other than ticks remains to be explored. The researchers now are looking at the possibility that other bacterial toxins have been repurposed by animals for antibacterial defense.
"Given the rate by which we are discovering new toxins, it would not surprise me at all if we find more that have been horizontally transferred" noted Mougous.
The Nature paper is titled, "Transferred interbacterial antagonism genes augment eukaryotic innate immune function."

Journal Reference:

1. Seemay Chou, Matthew D. Daugherty, S. Brook Peterson, Jacob Biboy, Youyun Yang, Brandon L. Jutras, Lillian K. Fritz-Laylin, Michael A. Ferrin, Brittany N. Harding, Christine Jacobs-Wagner, X. Frank Yang, Waldemar Vollmer, Harmit S. Malik, Joseph D. Mougous. Transferred interbacterial antagonism genes augment eukaryotic innate immune function. Nature, 2014; DOI: 10.1038/nature13965

Courtesy: ScienceDaily

ScienceDaily: Your source for the latest research news Featured Research from universities, journals, and other organizations 'Off switch' for pain discovered: Activating the adenosine A3 receptor subtype is key to powerful pain relief

n research published in the medical journal Brain, Saint Louis University researcher Daniela Salvemini, Ph.D. and colleagues within SLU, the National Institutes of Health (NIH) and other academic institutions have discovered a way to block a pain pathway in animal models of chronic neuropathic pain including pain caused by chemotherapeutic agents and bone cancer pain suggesting a promising new approach to pain relief.

Pain is an enormous problem. As an unmet medical need, pain causes suffering and comes with a multi-billion dollar societal cost. Current treatments are problematic because they cause intolerable side effects, diminish quality of life and do not sufficiently quell pain.

The scientific efforts led by Salvemini, who is professor of pharmacological and physiological sciences at SLU, demonstrated that turning on a receptor in the brain and spinal cord counteracts chronic nerve pain in male and female rodents. Activating the A3 receptor -- either by its native chemical stimulator, the small molecule adenosine, or by powerful synthetic small molecule drugs invented at the NIH -- prevents or reverses pain that develops slowly from nerve damage without causing analgesic tolerance or intrinsic reward (unlike opioids).
An Unmet Medical Need
Pain is an enormous problem. As an unmet medical need, pain causes suffering and comes with a multi-billion dollar societal cost. Current treatments are problematic because they cause intolerable side effects, diminish quality of life and do not sufficiently quell pain.
The most successful pharmacological approaches for the treatment of chronic pain rely on certain "pathways": circuits involving opioid, adrenergic, and calcium channels.
For the past decade, scientists have tried to take advantage of these known pathways -- the series of interactions between molecular-level components that lead to pain. While adenosine had shown potential for pain-killing in humans, researchers had not yet successfully leveraged this particular pain pathway because the targeted receptors engaged many side effects.
A Key to Pain Relief
In this research, Salvemini and colleagues have demonstrated that activation of the A3 adenosine receptor subtype is key in mediating the pain relieving effects of adenosine.
"It has long been appreciated that harnessing the potent pain-killing effects of adenosine could provide a breakthrough step towards an effective treatment for chronic pain," Salvemini said. "Our findings suggest that this goal may be achieved by focusing future work on the A3AR pathway, in particular, as its activation provides robust pain reduction across several types of pain."
Researchers are excited to note that A3AR agonists are already in advanced clinical trials as anti-inflammatory and anticancer agents and show good safety profiles. "These studies suggest that A3AR activation by highly selective small molecular weight A3AR agonists such as MRS5698 activates a pain-reducing pathway supporting the idea that we could develop A3AR agonists as possible new therapeutics to treat chronic pain," Salvemini said.
 

Journal Reference:

1. J. W. Little, A. Ford, A. M. Symons-Liguori, Z. Chen, K. Janes, T. Doyle, J. Xie, L. Luongo, D. K. Tosh, S. Maione, K. Bannister, A. H. Dickenson, T. W. Vanderah, F. Porreca, K. A. Jacobson, D. Salvemini. Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain, 2014; DOI: 10.1093/brain/awu330 

 Courtesy: ScienceDaily

Experimental Ebola vaccine appears safe, prompts immune response

An experimental vaccine to prevent Ebola virus disease was well-tolerated and produced immune system responses in all 20 healthy adults who received it in a Phase 1 clinical trial conducted by researchers from the National Institutes of Health. The candidate vaccine, which was co-developed by the NIH's National Institute of Allergy and Infectious Diseases (NIAID) and GlaxoSmithKline (GSK), was tested at the NIH Clinical Center in Bethesda, Maryland. The interim results are reported online in advance of print in the New England Journal of Medicine.

A 39-year-old woman, the first participant enrolled in VRC 207, receives a dose of the investigational NIAID/GSK Ebola vaccine at the NIH Clinical Center in Bethesda, Md. on September 2.

"The unprecedented scale of the current Ebola outbreak in West Africa has intensified efforts to develop safe and effective vaccines, which may play a role in bringing this epidemic to an end and undoubtedly will be critically important in preventing future large outbreaks," said NIAID Director Anthony S. Fauci, M.D. "Based on these positive results from the first human trial of this candidate vaccine, we are continuing our accelerated plan for larger trials to determine if the vaccine is efficacious in preventing Ebola infection."
The candidate NIAID/GSK Ebola vaccine was developed collaboratively by scientists at the NIAID Vaccine Research Center (VRC) and at Okairos, a biotechnology company acquired by GSK. It contains segments of Ebola virus genetic material from two virus species, Sudan and Zaire. The Ebola virus genetic material is delivered by a carrier virus (chimpanzee-derived adenovirus 3 or cAd 3) that causes a common cold in chimpanzees but causes no illness in humans. The candidate vaccine does not contain Ebola virus and cannot cause Ebola virus disease.
The trial enrolled volunteers between the ages of 18 and 50. Ten volunteers received an intramuscular injection of vaccine at a lower dose and 10 received the same vaccine at a higher dose. At two weeks and four weeks following vaccination, the researchers tested the volunteers' blood to determine if anti-Ebola antibodies were generated. All 20 volunteers developed such antibodies within four weeks of receiving the vaccine. Antibody levels were higher in those who received the higher dose vaccine.
The investigators also analyzed the research participants' blood to learn whether the vaccine prompted production of immune system cells called T cells. A recent study by VRC scientist Nancy J. Sullivan, Ph.D., and colleagues showed that non-human primates inoculated with the candidate NIAID/GSK vaccine developed both antibody and T-cell responses, and that these were sufficient to protect vaccinated animals from disease when they were later exposed to high levels of Ebola virus.
The experimental NIAID/GSK vaccine did induce a T-cell response in many of the volunteers, including production of CD8 T cells, which may be an important part of immune protection against Ebola viruses. Four weeks after vaccination, CD8 T cells were detected in two volunteers who had received the lower dose vaccine and in seven of those who had received the higher dose.
"We know from previous studies in non-human primates that CD8 T cells played a crucial role in protecting animals that had been vaccinated with this NIAID/GSK vaccine and then exposed to otherwise lethal amounts of Ebola virus," said Julie E. Ledgerwood, D.O., a VRC researcher and the trial's principal investigator. "The size and quality of the CD8 T cell response we saw in this trial are similar to that observed in non-human primates vaccinated with the candidate vaccine."
There were no serious adverse effects observed in any of the volunteers, although two people who received the higher dose vaccine did develop a briefly lasting fever within a day of vaccination.
 

Journal References:

1. Julie E. Ledgerwood, Adam D. DeZure, Daphne A. Stanley, Laura Novik, Mary E. Enama, Nina M. Berkowitz, Zonghui Hu, Gyan Joshi, Aurélie Ploquin, Sandra Sitar, Ingelise J. Gordon, Sarah A. Plummer, LaSonji A. Holman, Cynthia S. Hendel, Galina Yamshchikov, Francois Roman, Alfredo Nicosia, Stefano Colloca, Riccardo Cortese, Robert T. Bailer, Richard M. Schwartz, Mario Roederer, John R. Mascola, Richard A. Koup, Nancy J. Sullivan, Barney S. Graham. Chimpanzee Adenovirus Vector Ebola Vaccine — Preliminary Report. New England Journal of Medicine, 2014; 141126135947008 DOI: 10.1056/NEJMoa1410863
2. Daphne A Stanley, Anna N Honko, Clement Asiedu, John C Trefry, Annie W Lau-Kilby, Joshua C Johnson, Lisa Hensley, Virginia Ammendola, Adele Abbate, Fabiana Grazioli, Kathryn E Foulds, Cheng Cheng, Lingshu Wang, Mitzi M Donaldson, Stefano Colloca, Antonella Folgori, Mario Roederer, Gary J Nabel, John Mascola, Alfredo Nicosia, Riccardo Cortese, Richard A Koup, Nancy J Sullivan. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nature Medicine, 2014; DOI: 10.1038/nm.3702

 Courtesy: ScienceDaily