The Technion Researchers Find to NanoParticles may Threaten Heart

Nanoparticles, extremely tiny particles measured in billionths of a meter, are increasingly everywhere, and especially in biomedical products. Their toxicity has been researched in general terms, but now a team of Israeli scientists has for the first time found that exposure nanoparticles (NPs) of silicon dioxide (SiO2) can play a major role in the development of cardiovascular diseases when the NP cross tissue and cellular barriers and also find their way into the circulatory system. Their study is published in the December 2014 issue of Environmental Toxicology.

Prof. Michael Aviram
The research team was comprised of scientists from the Technion Rappaport Faculty of Medicine, Rambam Medical Center, and the Center of Excellence in Exposure Science and Environmental Health (TCEEH).

“Environmental exposure to nanoparticles is becoming unavoidable due to the rapid expansion of nanotechnology,” says the study’s lead author, Prof. Michael Aviram, of the Technion Faculty of Medicine, “This exposure may be especially chronic for those employed in research laboratories and in high tech industry where workers handle, manufacture, use and dispose of nanoparticles. Products that use silica-based nanoparticles for biomedical uses, such as various chips, drug or gene delivery and tracking, imaging, ultrasound therapy, and diagnostics, may also pose an increased cardiovascular risk for consumers as well.”

In this study, researchers exposed cultured laboratory mouse cells resembling the arterial wall cells to NPs of silicon dioxide and investigated the effects. SiO2 NPs are toxic to and have significant adverse effects on macrophages. a type of white blood cell that take up lipids, leading to atherosclerotic lesion development and its consequent cardiovascular events, such as heart attack or stroke. Macrophages accumulation in the arterial wall under atherogenic conditions such as high cholesterol, triglycerides, oxidative stress – are converted into lipids, or laden “foam cells” which, in turn, accelerate atherosclerosis development.

“Macrophage foam cells accumulation in the arterial wall are a key cell type in the development of atherosclerosis, which is an inflammatory disease” says co-author Dr. Lauren Petrick. “The aims of our study were to gain additional insight into the cardiovascular risk associated with silicon dioxide nanoparticle exposure and discover the mechanisms behind Si02’s induced atherogenic effects on macrophages. We also wanted to use nanoparticles as a model for ultrafine particle (UFP) exposure as cardiovascular disease risk factors.”

Both NPs and UFPs can be inhaled and induce negative biological effects. However, until this study, their effect on the development of atherosclerosis has been largely unknown. Here, researchers have discovered for the first time that the toxicity of silicon dioxide nanoparticles has a “significant and substantial effect on the accumulation of triglycerides in the macrophages,” at all exposure concentrations analyzed, and that they also “increase oxidative stress and toxicity.”

A recent update from the American Heart Association also suggested that “fine particles” in air pollution leads to elevated risk for cardiovascular diseases. However, more research was needed to examine the role of “ultrafine particles” (which are much smaller than “fine particles”) on atherosclerosis development and cardiovascular risk.

“The number of nano-based consumer products has risen a thousand fold in recent years, with an estimated world market of $3 trillion by the year 2020,” conclude the researchers. “This reality leads to increased human exposure and interaction of silica-based nanoparticles with biological systems. Because our research demonstrates a clear cardiovascular health risk associated with this trend, steps need to be taken to help ensure that potential health and environmental hazards are being addressed at the same time as the nanotechnology is being developed.

The Technion-Israel Institute of Technology is a major source of the innovation and brainpower that drives the Israeli economy, and a key to Israel’s renown as the world’s “Start-Up Nation.” Its three Nobel Prize winners exemplify academic excellence. Technion people, ideas and inventions make immeasurable contributions to the world including life-saving medicine, sustainable energy, computer science, water conservation and nanotechnology. The Joan and Irwin Jacobs Technion-Cornell Institute is a vital component of Cornell NYC Tech, and a model for graduate applied science education that is expected to transform New York City’s economy.

American Technion Society (ATS) donors provide critical support for the Technion—more than $1.95 billion since its inception in 1940. Based in New York City, the ATS and its network of chapters across the U.S. provide funds for scholarships, fellowships, faculty recruitment and chairs, research, buildings, laboratories, classrooms and dormitories, and more.

Source: ATS

HIV virus in disguise tricks immune system, Marie Larsson is Professor of Molecular Virology

Name: Marie LarssonTitle: Professor of Molecular Virology
Department: IKE

CONTACT

Phone: +46 (0)10-103 10 55
E-mail: marie.larsson@liu.se

Address:
Linköping University
Department of Clinical and Experimental Medicine
Virology
SE-581 85 Linköping
Sweden

Marie Larsson is Professor of Molecular Virology. Her research is in the area of immunovirology, specifically HIV research with focus on the immunomodulatory effect this virus has on dendritic cells and T cells. She has also ongoing projects exploring new adjuvants and vaccine constellations for cancer and virus. Furthermore, she is investigating the induction and sustainment of cancer associated inflammation and the deleterious effect this has on host immune defense.

Immunomodulatory effects of HIV-1’s interactions with DCs and T cells from

blood and mucosa
So far over 30 million people have died from HIV-1 infection (figure 1), the majority of them in the developing countries, and this epidemic is still cause for major concern. The existing antiretroviral therapy dampens the infection and the destruction of the immune system, i.e. AIDS, but does not cure the disease. Sadly, this therapy is not available to all HIV infected and is a very expensive lifelong commitment with severe side effects.

A vaccine blocking HIV infection is theDendritic cell sought-after solution but there is no hope that we will have such a vaccine in the near future. Instead we can hope for a therapy that induces a potent long lasting immune response consisting of CD4+ and CD8+ T cells, two types of control cells involved in the immune defense, that have proven to be important to control the infection. There exists a unique cell in all tissues in our bodies, the dendritic cell (DC) (Figure 2) with unique ability to activate T cells so they can perform their job in the body. DCs in the vaginal and rectal tissues are one of the first cells to encounter HIV during intercourse with an infected individual (Figure 3 and 4). Unfortunately, HIV hijacks the DCs, which makes this cell responsible for spreading the virus to interacting T cells in the body which provokes HIV-infection of T cells and cell death when it should be initiating immune responses to fight the infection.DC HIV

My research aspires to elucidate the mechanisms behind the immunomodulatory effects HIV exerts on DCs and on their ability to activate T cells. Focus will be on; Elucidation of the mechanisms involved in HIV’s binding to and uptake by DCs and the subsequent degradation that leads to DC antigen presentation of HIV peptides for activation of HIV specific T cells. Elucidation of the mechanisms responsible for the negative effects HIV exerts on DCs and if presence of HIV virions during DC T cell priming impairs the T cell function. Elucidate the effect opsonized HIV-1 exerts on immune cells such as DCs, NK cells and T cells. Identification of receptors and cells involved in the initial HIV infection of cervical mucosa and colorectal mucosa,  and potential microbiocides that can block the initial infection, and elucidation of why HIV affects the T cells in the gut to a higher extent than the T cells in blood.

HIV will continue to kill people and have a great impact on mankind until we have a drug that can stop this infection. My ambition is that the planed research will answer some basic questions regarding the role of DCs in HIV pathogenesis and induction of potent immune response against this virus. This knowledge will guide how a vaccine/therapy needs to be constructed in order to have high efficacy.

                                                             Mucosal transmission

                                                                Cervix

Cancer research

Elucidation the role of IL-1α and the microenvironment in development of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a common gastrointestinal malignancy with an exceptional poor prognosis and a mortality rate that nearly matches the rate of incidence. The cross-talk between PDAC and stroma cells, e.g. cancer associated fibroblasts (CAF), and immune cells, may create an environment with chronic inflammation augmenting tumor transformation and maintenance.

In PDAC, more than 70% of the total tumor mass can consist of fibrotic stroma, which makes CAFs the major component in this cancer. PDAC inflammatory environment consists of many mediators, e.g. IL-1, COX-2, IL-6, and CXCL8, and some of these factors correlate to tumor development and poor prognosis. Of note, elevated expression of IL-1 in tumors has been associated with more aggressive disease. Several studies, including ours have reported that dendritic cells (DCs), one of the immune cells found in the tumor microenvironment, show phenotypic and functional abnormalities when isolated from tumor bearing animals and individuals with PDAC. Recent findings provided some evidence that the COX-2 metabolite PGE2 is involved in the upregulation of immunomodulatory factors in DCs impairing their T cell stimulatory ability. The aims are to examine the receptor-ligands and signaling pathways involved in the cross talk between stroma cells, i.e. CAFs, and PDAC cells giving rise to the inflammatory environment and creating an environment sustaining the PDAC. To examine the role IL-1 cytokine family and effects these cytokines cell signaling have on creating the inflammatory environment and in tumor development and survival. To examine whether neutralization of IL1 signaling pathway enhances the survival and quality of life for individuals with pancreatic cancer.

The information gained from the proposed research will help us understand the mechanisms underlying the development of PDAC and the effect this solid tumor exert on the body and may help designing therapies for PDAC.

Source: Linköping University

Scheduling tool a big help in healthcare

The HIV virus avoids the body’s immune cells by disguising itself using proteins that normally take part in the defence against infections. These are the findings of research conducted at the Division of Molecular Virology.

Professor Marie LarssonThese “complement proteins” are soluble molecules that attach themselves to foreign particles and those of the body in different patterns. These patterns help the immune system to identify and attack dangerous intruders such as viruses and bacteria.

Phd student Rada EllegårdInstead, HIV exploits the complement proteins present in all body fluids in order to make its way into the body tissues without being attacked. It was known previously that infections are much more effective if the virus is surrounded by the bodily fluids normally present in blood or sexual contagion than if it is isolated in a laboratory environment. In an article in the Journal of Immunology Marie Larsson, professor of molecular virology (left) and PhD student Rada Ellegård (right) provide an explanation of this phenomenon.

“The ability to use our complement proteins in this way is probably key to the success of HIV in being transmitted. We are currently carrying out further work to investigate these mechanisms in the male genital mucous membrane – the tissue where the virus infection takes place in sexual transmission,” says Ms Larsson.

The first thing HIV particles come into contact with is dendritic cells, immune cells that function as sentry posts. Their job is to identify viruses as dangerous and hostile to the body, and to respond by producing the substances that combat infections and moving to a lymph node to set a specific immune defence in motion.

In the case of HIV, this process does not seem to work very well. The disguise stops the dendritic cells recognising the virus, which instead establishes an infection in the mucous membrane and uses the movement to the lymph nodes as a way to spread around the whole body.

As more and more cells are infected and killed, the virus slowly breaks down our immune system. Without treatment this sequence of events leads to AIDS, a condition where the victim becomes extremely vulnerable to infection and where normally harmless viruses and bacteria become life-threatening.

Related content

Marie Larsson - research presentation >>

                                       HIV-illustration

When a virus is captured by a dendritic cell, it is recognised by a virus sensor that normally sets in motion infection reduction factors which inhibit the production of new virus particles (picture, left). HIV has the ability to clothe itself in complements, a type of protein present in our bodily fluids. In this way it can dampen the signals from the virus sensors and produce many new particles (picture, right).


Source: Linköping University

New Molecular Target Identified for Treating Cerebral Malaria

                                                             Mosquito Anopheles

A drug already approved for treating other diseases may be useful as a treatment for cerebral malaria, according to researchers at Harvard T. H. Chan School of Public Health. They discovered a novel link between food intake during the early stages of infection and the outcome of the disease, identifying two molecular pathways that could serve as new targets for treatment.

“We have known for a long time that nutrition can affect the course of infectious disease, but we were surprised at how rapidly a mild reduction in food intake could improve outcome in a mouse malaria model,” said senior author James Mitchell, associate professor of genetics and complex diseases. “However, the real importance of this work is the identification of unexpected molecular pathways underlying cerebral malaria that we can now target with existing drugs.”

The study appears online January 30, 2015 in Nature Communications.

Cerebral malaria — a severe form of the disease — is the most serious consequence of infection by the parasite Plasmodium falciparum, resulting in seizures, coma, and death. Currently there is a lack of safe treatment options for cerebral malaria, particularly for use in children, who represent the majority of cases. Even patients who receive early treatment with standard antimalarial chemotherapeutic agents run a high risk of dying, despite clearance of the parasite. Moreover, around 25% of survivors develop neurological complications and cognitive impairment.

Lead authors Pedro Mejia and J. Humberto Treviño-Villarreal, both researchers at Harvard T.H. Chan School of Public Health, found that leptin—a hormone secreted from fat tissue with roles in suppressing appetite, but also in activating adaptive immune and inflammatory responses—is increased upon infection in a mouse model of cerebral malaria, and turns out to be a major bad actor in promoting neurological symptoms and death. Remarkably, Mejia, Treviño-Villarreal and colleagues showed that reducing leptin using a variety of means, either genetically, pharmacologically, or nutritionally by reducing food intake during the first two days of infection, protected against cerebral malaria.

The researchers also found that leptin acted primarily on cytotoxic T cells by turning on the well-studied mTOR protein, for which pharmacologic inhibitors are readily available. In their animal model, treating mice with the mTOR inhibitor rapamycin protected them against the neurological complications of cerebral malaria. Protection was due in part to a preservation of the blood brain barrier, which prevented the entry of blood cells carrying the parasites into the brain. As rapamycin is already FDA-approved for use in humans, trials in humans for cerebral malaria treatment with this drug may be possible, according to the researchers.

This study was the result of an ongoing collaboration between the Mitchell lab in the Department of Genetics and Complex Diseases and the labs of Manoj Duraisingh and Dyann Wirth in the Department of Immunology and Infectious Diseases. Other Harvard T.H. Chan School of Public Health authors included  Christopher Hine, Eylul Harputlugil, Samantha Lang, Ediz Calay and Rick Rogers.

This study was supported in part by grants from NIH (DK090629 and AG036712) and the Glenn Foundation for Medical Research to J.R.M.; a Harvard T.H. Chan School of Public Health Yerby postdoctoral fellowship to Mejia, and financial support from the Universidad Auto´noma de Nuevo Leo´n to Treviño-Villarreal.

Source: Harvard

Adults Sought for Study on Aging and Mobility

                                                               Walking stickman
The Biomechanics Laboratory in the kinesiology department is recruiting volunteers for a study about the effects of age and exercise on walking and muscle function. The researchers hope to learn about how changes in muscle function with age are related to the onset of disability.

The lab is looking for individuals who meet the following criteria: ages 55-70 with healthy body weight who participate in fewer than five 30-minute bouts of exercise per week (or less than a total of 150 minutes of planned exercise per week), no history of reconstructive surgery of the legs, no major health issues (heart disease, diabetes, neurological disease), able to walk for 30 minutes and no contraindications to MRI (metal implant, claustrophobia).

The study consists of two visits: a 1-hour visit to an MRI facility in Amherst and one 3-hour visit to the Biomechanics Lab on campus. During the lab visit researchers will collect data on how participants’ joints move as they walk over the ground and on a treadmill. The study will also collect data on the strength of the muscles in participants’ thighs. All procedures are non-invasive.

Source: UMass

Use Social Media in Study of E-Cigarettes

Five-year grant from the National Institutes of Health will support project that is as much about data-gathering methods as it is about public health. Credit: UA

When Facebook announced in September that it would use all that personal data it collects to roll out a new ad platform to rival Google, privacy advocates groaned and marketers grinned.

But what if all that intelligence could be used to crack open one of today’s most pressing — yet least understood — public health issues?

That’s precisely the vision of the University of Arizona’s Daniel Zeng, MIS professor at the Eller College of Management, and Scott Leischow, adjunct faculty in the UA College of Medicine and professor of health services research at Arizona’s Mayo Clinic.

Fusing cutting-edge informatics and public health, their plan to scrape social media to create the world’s best data on e-cigarette usage and marketing recently won a five-year, $2.7 million grant from the National Institutes of Health.

The project will tackle four distinct goals. It will:

Create a massive, real-time and continuously growing data set of what consumers and marketers say about e-cigarettes on sites such as Facebook and Twitter, as well as social media forums focused on e-cigarettes and "vaping."

Mine that content for insights into why people use e-cigarettes, how they believe they affect their health and whether they help them quit smoking.

Document the marketing landscape — all the ways brands and vendors use these channels to promote their products and how consumers respond.

Integrate all of that information in the world’s first one-stop resource for wide-ranging data on e-cigarettes as revealed through social media as a tool for other researchers, health care professionals and more.

While e-cigarettes are relatively new in the U.S. — they were introduced in 2007 — sales are doubling annually and were expected to reach $1 billion last year. Even so, any time public dollars fund research, two questions naturally arise: Why study this? And why study it this way?

"There’s so much we don’t know about e-cigarettes," Leischow says. "The scientific community has found mixed data on whether they’re helpful for smoking cessation. We have questions about how different flavorings impact use, particularly among minors. And many health professionals worry that e-cigarettes may ultimately lead to more young people taking up smoking. All of these blind spots around a product that is still totally unregulated make this a top-priority area for the FDA."

As for why it makes sense to study e-cigarettes in this way, Zeng’s MIS expertise holds the key.  By mining social media in real time, as Zeng and Leischow have proposed, there are a number of strategic advantages:

Data comes from people interacting naturally in their day-to-day lives, thus removing “presentation bias” problems intrinsic in surveys.

The data collection is automated, which means sample size is not constrained by how much money or how many eyeball hours researchers can muster.

The lack of constraint also makes anecdotal information scientifically relevant: One personal story is just that, but 10,000 or 100,000 personal stories over time equal robust statistical data.

Because content is processed by algorithms, not people, data is available in near real time, not months or even years after countless hours of labor-intensive review.

The world of e-cigarettes, like that of any niche product or interest, has its own specialized vocabulary of acronyms and slang, so the research team will first need to construct a base lexical dataset for “training” the computers that will collect and process content.

It’s also one thing to scrape words but a much more complex challenge to automate the process of extracting meaning, so that a computer can spot when someone cites a reason for using e-cigarettes or mentions how the products affect his or her health (both of which first require a computer to detect who is or isn’t a user) or correctly catalog the marketing strategy used in an advertisement.

"We basically will be creating a suite of novel technologies for this study using both established building blocks of informatics and methods that have yet to be developed," Zeng says, "including analysis and visualization tools that were developed here at the U of A. 
Beyond that, we’re relying on proven tools for pattern mining, group behavior prediction, social network analysis and a lot more, but in ways that have never been combined for this level of research and in this topic area."

For Leischow, the knowledge those tools will produce is invaluable.

"There are all kinds of messages out there, from how effective e-cigarettes can be to help smokers quit tobacco to how they’re totally harmless or taste like candy," he says. "It may be that e-cigarettes prove beneficial to public health, or they may be shown to do more harm than good. In either case, it often takes many years for experts to fully recognize how products are being used and how they impact well-being, and even longer for regulation to catch up.

"This time, it’s going to be different. This time, we’re getting out ahead."

Source: UA

Drug combo supresses growth of late-stage prostate cancer turmors

By Natalie van Hoose

Low doses of metformin, a widely used diabetes medication, and a gene inhibitor known as BI2536 can successfully halt the growth of late-stage prostate cancer tumors, a Purdue University study finds.

Prostate cancer causes the second-highest number of cancer-related deaths in men in the U.S., and methods of treating advanced prostate cancer are limited.

Xiaoqi Liu (pronounced zhow-CHEE' LEE'-oo), associate professor of biochemistry and cancer research, and fellow researchers found that the drugs metformin and BI2536 can work together to suppress the spread of prostate cancer that resists all other available treatments, potentially prolonging patients' lives.

"We've found a promising way to treat late-stage prostate cancer," Liu said. "By combining low levels of two well-tolerated drugs, the progression of this disease could be significantly delayed. Completely curing the cancer at the advanced stage is pretty much impossible, but this treatment might manage it for a while - that's exciting."

A number of treatments exist for the earlier stages of prostate cancer, which grows slowly compared with many other cancers. Because prostate cancer cells need the male sex hormone androgen to develop, one way to treat the disease is to suppress androgen - a process known as castration. If the cancer continues to spread, the patient often undergoes chemotherapy. As a last resort, drugs that block the synthesis of androgen by prostate cancer cells can be used, but these medications only extend a patient's lifespan for several months.

New approaches to treating the most persistent forms of prostate cancer are "urgently needed," Liu said.

Adding to the challenge is the fact that castration treatment can inadvertently encourage the cancer to get tougher. It can heighten oxidative stress on the prostate gland, which increases the expression of Plk1, a gene that has been linked to many cancers. Over-expression of Plk1 can also trigger the synthesis of androgen.

"The goal of castration is to block androgen synthesis," Liu said. "But cancer cells eventually become 'smart' enough to make androgen anyhow, which is why the cancer continues to grow."

Additionally, castration can disrupt the body's metabolism and lead to insulin resistance, which also can stimulate the production of androgen. The cancer will spread until both of these side effects are stopped, Liu said.

Previous studies showed that metformin - an inexpensive, antidiabetic drug that has been commonly used for more than 40 years - is particularly potent to prostate cancer tumors.

Working with fellow researchers from Purdue, the University of Wisconsin-Madison and the Indiana University School of Medicine, Liu found that a combination of low levels of metformin and BI2536, a drug that stifles the activity of Plk1, could work in tandem to slow the growth of prostate tumors too advanced for current treatments by promoting the self-destruction of cancer cells and preventing androgen synthesis.

The drugs did not impact healthy prostate cells, a "key finding," Liu said. "Ideally, cancer therapy will have minimal effects on normal cells."

Because metformin helps regulate metabolism, it may reverse some of the metabolic damage caused by castration, he said.

The researchers tested the drugs in a classical cell culture assay of prostate cancer cells and in advanced prostate tumors in mice. Low concentrations of the drugs significantly slowed the development of cancer in both trials. The mice tumors were grown from the tumor cells of a late-stage prostate cancer patient, suggesting that the treatment would prove effective in humans.

"Those results were amazing," Liu said. "These are the first data we've generated from a real patient, so I was almost jumping in the air when I saw that it worked."

Liu said that the next step in the research is to test the combination of drugs in clinical trials. Further research is also needed to understand the underlying mechanism of metformin and why it is effective at suppressing prostate cancer

Source: Purdue Univesity

Ebola: Reports from the front lines

Dr. Noah Rosenberg “Ebola was never the only killer here, and our ability to appropriately diagnose and treat these patients is woefully limited.”

Alpert Medical School professors Michael Smit and Noah Rosenberg are in Sierra Leone and Liberia respectively, treating Ebola patients. There are some signs of a slowdown in the epidemic, but the doctors emphasize that the virus must be fought “until the last case.”

PROVIDENCE, R.I. [Brown University] — In a limited sense, two Brown University medical professors who have been fighting Ebola in West Africa this winter have good news to report. They have seen some signs of slowing disease transmission. But the broader reality of what Ebola has done in Sierra Leone and Liberia is grim, according to Drs. Michael Smit and Noah Rosenberg.

Ebola shouldn’t just be contained, they note: It must be treated until all cases are resolved.

Smit, assistant professor of pediatrics and a physician at Hasbro Children’s Hospital, arrived in Sierra Leone Dec. 3, 2014, and will remain there through Jan. 18. Rosenberg, clinical assistant professor of emergency medicine and a Lifespan doctor, arrived in Liberia in mid-December and will stay until Jan. 27. They answered questions for medical science writer David Orenstein about what they are doing and seeing, and what people back in the States need to know.

Please describe a typical day.

NR: I arrive at 7 a.m. and meet with the overnight doctor and nurses to discuss our patients. My team pulls on full personal protective equipment and enters the high-risk area. We examine each patient, inquire about their current symptoms, give routine supportive medications and IV fluids if needed. We take blood to test for Ebola. We remove our equipment while being intermittently sprayed with chlorine. Rounds repeat in the afternoon and we often make an additional trip for a new admission. In the evening we meet with the night team and then rest to return in the morning.

Dr. Michael Smit “The effect of the epidemic goes far beyond those infected with Ebola virus. ... The economic impact on the country is devastating.

MS: I am the medical team leader of one of four medical teams at the Mateneh Ebola Treatment Center (ETC). Our days differ depending on which shift we are working. When working the early shift, we eat breakfast around 7 a.m. and drive to the ETC. We change into our work uniforms of scrubs and rubber boots at the ETC. At 7:30 we receive signout on the patients from the overnight team. We then assign personnel to conduct the nursing rounds, physician rounds, admissions, and discharges. During the heat of the day, we try to limit time in the high-risk area in personal protective equipment (PPE) to one hour. We deliver meals, administer medications, place intravenous catheters, and draw blood for laboratory tests. We triage admissions as they come through the ambulance bay. We also process discharges. These include survivors discharged home and deaths transferred to the morgue. At the end of the shift, we sign out the patients to the oncoming team, change back into our civilian clothes, and go back to the compound to eat. The late and overnight shifts are the same as the early shift for the most part.

What do you observe and hear about the status of the epidemic where you are?

NR: The exponential growth of the epidemic is clearly over in Liberia, but sporadic outbreaks are likely to continue until every case has been eliminated from West Africa, which may take months. Most of our new admissions now test negative for Ebola; they frequently die nonetheless. This may seem counterintuitive, but Ebola was never the only killer here, and our ability to appropriately diagnose and treat these patients is woefully limited.

MS: It is difficult to assess the status of the epidemic from here. We have limited access to the Internet, so our updates of what is happening are intermittent. As for what we observe, after a slow start from our opening in mid-December, we saw a steady increase in cases in our district in Bombali. Over the last week, admissions have decreased. The reason for this is not clear. We hope that it reflects a reduction in transmission, but we cannot assume this given the complexities of case identification and transport here.

What do people in the United States most need to know, based on what you are experiencing?

NR: Before the epidemic Liberia suffered from a large disease burden and severely limited health care system. Decades of civil war, sparked by inequality and tension between descendants of indigenous West Africans and freed slaves, wrecked the infrastructure and economy. Not only was the U.S.A. responsible for the founding of Liberia, but many of the struggles here today have their origins in the slave trade. Ebola will soon fade from the news but the epidemic has only worsened an already grave condition. We have a special responsibility to Liberia and it deserves our sustained attention.

MS: People in the United States need to know that the epidemic here is far from over. Even in a situation with diminished transmission, the United States needs to send personnel and resources here to combat Ebola until the last case. The effect of the epidemic goes far beyond those infected with Ebola virus. The schools here in Sierra Leone have been closed for months. Teen pregnancy is increasing as a result. The economic impact on the country is devastating, with some estimates setting the economy back 10 years. Also, people in the United States need to know about the dedication and resilience of the local and international healthcare workers who are fighting the epidemic, often under challenging physical and emotional conditions.

Source: Brown University

HIV testing yields diagnoses in Kenya but few seek care

A sweeping effort in a rural region of Kenya to test all adults for HIV discovered 1,300 new infections, but few of the newly diagnosed people pursued treatment, a study in the journal Lancet HIV reports.
PROVIDENCE, R.I. [Brown University] — Between December 2009 and February 2011, health workers with the AMPATH Consortium sought to test and counsel every adult resident in the Bunyala subcounty of Kenya for HIV. A study in the journal Lancet HIV reports that the campaign yielded more than 1,300 new positive diagnoses, but few of those new patients sought health care.

“Home-based counseling and testing (HBCT) provided a diagnosis to nearly 40 percent of people living with HIV in this subcounty who otherwise most likely would not have gone for HIV testing,” said study lead author Becky Genberg, assistant professor (research) of health services, policy and practice in the Brown University School of Public Health. “They therefore would not have known about their HIV infection and not had the opportunity to change their behavior to protect others.”

AMPATH’s HBCT program is part of a strategy to identify all individuals living with HIV in the catchment area, start them on antiretroviral medication as soon as possible, and help them stay on their medications. Antiretroviral medication not only suppresses HIV infections for most patients but also reduces their ability to transmit the virus.

Genberg with co-author Edwin Sang “We are working on a variety of studies, all designed to understand the barriers facing the newly diagnosed, and to implement and evaluate strategies to increase their engagement and retention in HIV care over time.”

In Bunyala, home to about 66,000 people, the HBCT program tested about 32,000 adults. Among them, 3,482 had HIV. Of those, 2,122 already knew they were infected, but 1,360 did not know it yet.

A major finding of the study is that three years later only 15 percent of the newly diagnosed people had engaged in care for their infection. A likely reason why, Genberg said, is that newly diagnosed people typically don’t yet feel sick.

“That so few linked to care following HBCT is a call for innovative and creative strategies to work alongside HBCT to support the mostly healthy, asymptomatic newly diagnosed to engage with care in a way that is meaningful for them,” Genberg said.

In an editorial in the journal, Rashida Ferrand of the London School of Hygiene and Tropical Medicine said the study sounds a warning that home-based testing must be paired with effective ways to convince newly diagnosed patients to seek help.

“Unless paired with interventions targeted at hard-to-reach populations, the diagnosing of undiagnosed individuals in many settings will not be cost-effective and will have little effect on individual and population viral suppression,” she and colleagues wrote.

Genberg, who has been in Kenya this winter, said she is working with Kenyan collaborators on developing the needed interventions: “Right now we are working on a variety of studies, all designed to understand the barriers facing the newly diagnosed, and to implement and evaluate strategies to increase their engagement and retention in HIV care over time.”

In addition to Genberg the study’s authors are Joseph Hogan and Corey Duefield of Brown; Violet Naanyu, Juddy Wachira, and Samson Ndege of Moi University in Kenya; Edwin Sang, Monicah Nyambura, and Michael Odawa of AMPATH; and corresponding author Paula Braitstein of the University of Toronto.

The President’s Emergency Plan for AIDS Relief funded the study though USAID (grant AID-623-A-12-0001). Additional support came from the National Institutes of Health (K01MH099966) and the Bill and Melinda Gates Foundation.

Source: Brown University

New Zealand leads research on natural quit smoking remedy

New Zealand researchers have found that a low cost, plant-based product marketed for smoking cessation in parts of Europe for the last 40 years, is better than nicotine replacement therapy at helping smokers quit. 

Trial results show that the compound cytisine is more effective than nicotine replacement therapy (NRT) at helping smokers quit.

The trial is the first of its kind in the world and was carried out by the National Institute for Health Innovation at the University of Auckland.  The study results were published recently in the top-rated international medical journal, the New England Medical Journal.

Cytisine is a natural, plant-based compound that has been used in smoking cessation for more than 40 years in Eastern Europe and is commercially produced in Bulgaria and Poland.  The trial followed 1310 adult daily smokers who called the national Quitline in New Zealand.

 Smokers were randomly assigned to receive either cytisine for 25 days or eight weeks of NRT. Participants in both groups also received telephone-based Quitline behavioural support.

Results indicated that after using cytisine for 25 days, a smoker was more likely to have quit smoking at six months, compared to using NRT. Compared to NRT, cytisine users experienced a slight increase in side effects; the most common of which were nausea, vomiting and sleep disturbances.

 “Placebo-controlled trials showed that cytisine almost doubles the chances of still being smoke-free at six months,” says study senior author, Dr Natalie Walker, who is the Heart Foundation Douglas Senior Research Fellow (Prevention) at the University of Auckland’s National Institute for Health Innovation. “We wanted to see how effective cytisine was compared to NRT at helping smokers quit.”

 In New Zealand and many other Western countries NRT is the most common medication used to support people to quit smoking.

 Cytisine is an alkaloid which naturally occurs in the Golden Rain (Laburnum anagyroides) and other members of the Fabaceae plant family.

“To the brain cytisine looks a little like nicotine and so it works to alleviate any urges to smoke and reduces the severity of nicotine withdrawal symptoms.  Plus, if you do smoke whilst using cytisine it will be less satisfying - making quitting easier”, says Dr Walker.

Cytisine is a similar type of drug to varenicline (the most effective smoking cessation treatment available, marketed by Pfizer), but is substantially cheaper (cytisine: US$20-$30 for 25-days, NRT: US$112-$685 for 8-10 weeks, varenicline: US$474-501 for 12 weeks).

“There is a big opportunity for low and middle income countries to access a low priced quit remedy,” says Dr Walker. “It’s great for countries that cannot afford more expensive smoking cessation medicines.”

Cytisine is licensed for use as an ‘over the counter’ medication, on prescription or via the internet in a number of Central and Eastern European countries, but it is not yet available in New Zealand.  

“Internationally, very few researchers are undertaking research on the use of cytisine for smoking cessation,” says Associate Professor Chris Bullen, Director of the National Institute for Health Innovation.

“Researchers at the University of Auckland are leading the way.  For example, other researchers in the Department of Pharmacology and at the School of Pharmacy are looking at how cytisine is absorbed and metabolised by the body,” he says.

The trial is funded by the Health Research Council of New Zealand and is one of a number of studies the Institute have undertaken to find innovative options for smokers to stop smoking to achieve smoke-free New Zealand by 2025.  The last trial they completed was one involving e-cigarettes

The study, ‘Randomized comparison of cytisine versus nicotine for smoking cessation’, by Dr Natalie Walker (National Institute for Health Innovation, University of Auckland), Dr Colin Howe (NIHI), Dr Marewa Glover (Centre for Tobacco Control Research, UoA), Dr Hayden McRobbie (Queen Mary University London), Associate Professor Jo Barnes (School of Pharmacy, UoA), Dr Vili Nosa (UoA), Ms Varsha Parag (NIHI), Mr Bruce Bassett (Quit Group), Associate Professor Chris Bullen (Director, NIHI).

Source: Auckland University

Cheap malaria drug could treat colorectal cancer effectively too, say experts

Artemisinin is isolated from the plant Artemisia annua also known as sweet wormwood. Credit: Image courtesy of University of St George's London

Medical experts say a common malaria drug could have a significant impact on colorectal cancer providing a cheap adjunct to current expensive chemotherapy.

A pilot study by researchers at St George's, University of London, has found the drug artesunate, which is a widely used anti-malaria medicine, had a promising effect on reducing the multiplication of tumour cells in colorectal cancer patients who were already going to have their cancer surgically removed.

Colorectal cancer (CRC) makes up about 10 percent of the annual 746,000 global cancer cases in men and 614,000 cases in women.

In the UK, 110 new cases are diagnosed daily, with older patients particularly at risk of death. Prognosis even with the best available treatments does not increase disease free or overall survival beyond 60 percent, five years after diagnosis.

Professor Sanjeev Krishna, an infectious disease expert at St George's who jointly-led the study, said: "There is therefore a continuing and urgent need to develop new, cheap, orally effective and safe colorectal cancer treatments.

"Our approach in this study was to take a close look at an existing drug that already had some anticancer properties in experimental settings, and to assess its safety and efficacy in patients.

"The results have been more than encouraging and can offer hopes of finding effective treatment options that are cheaper in the future."

"Larger clinical studies with artesunate that aim to provide well tolerated and convenient anticancer regimens should be implemented with urgency, and may provide an intervention where none is currently available, as well as synergistic benefits with current treatment regimens," added Professor Devinder Kumar, a leading expert in colorectal cancer at St George's and joint-lead of this study.

For most patients globally, access to advanced treatments is difficult as they are too expensive to be widely available, or associated with significant morbidity thereby further compromising their survival.

"In the St George's study, patients were examined and then were given either the anti-malaria drug artesunate or a placebo. After 42 months following surgery, there were six recurrences of cancer in the placebo group (of 12 patients) and one recurrence in an artesunate recipient (of 10 patients).The survival beyond two years in the artesunate group was estimated at 91% whilst surviving the first recurrence of cancer in the placebo group was only 57%.

This is the first randomized, double blind study to test the anti-CRC properties of oral artesunate. The anticancer properties of artemisinins have been seen in the laboratory previously but this is the first time their effect has been seen in patients in a rigorously designed study.

Source: University of St George's London

Mushroom extract, AHCC, helpful in treating HPV

Judith A. Smith, Pharm.D. Credit: Image courtesy of University of Texas Health Science Center at Houston

A Japanese mushroom extract appears to be effective for the eradication of human papillomavirus (HPV), according to a pilot clinical trial at The University of Texas Health Science Center at Houston (UTHealth) Medical School.

The results were presented at the 11th International Conference of the Society for Integrative Oncology in Houston today by principal investigator Judith A. Smith, Pharm.D., associate professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at the UTHealth Medical School.

Ten HPV-positive women were treated orally with the extract, AHCC (active hexose correlated compound) once daily for up to six months. Five achieved a negative HPV test result -- three with confirmed eradication after stopping AHCC -- with the remaining two responders continuing on the study.

Currently, there is no effective medicine or supplement to treat HPV, which is associated with more than 99 percent of cervical cancer cases. According to the Centers for Disease Control and Prevention, several other cancers are related to HPV, including 95 percent of anal cancer, 60 percent of oropharyngeal, 65 percent of vaginal cancer, 50 percent of vulvar cancer and 35 percent of penile cancer.

AHCC is a readily available nutritional supplement that works to improve the innate immune system. Human and preclinical studies have shown that AHCC increases the number and/or activity of Natural Killer (NK) cells, dendritic cells and cytokines, which help the body fight off infections and block tumor growth.

"The results are very encouraging," Smith said. "We were able to determine that at least three months of treatment is necessary but some need to extend that to six months. Since AHCC is a nutritional supplement with no side effects and other immune modulating benefits, we will be planning on using six months of treatment in our phase II clinical study to have consistent study treatment plan. This confirms our earlier preclinical research."

Smith is director of UTHealth's Women's Health Integrative Medicine Research Team, which focuses on the safe and effective use of nutritional and herbal supplements with pharmacologic modalities as it relates to women's health and cancer.

This research is proceeding to a randomized, double-blind, placebo-controlled Phase II clinical trial which has just begun at UTHealth, Smith said. For more information on enrolling in the trial, go to http://go.uth.edu/judithresearch.

Source: University of Texas Health Science Center at Houston

Platelets modulate clotting behavior by 'feeling' their surroundings

Researchers devised a way to separate the physical stiffness of the material where platelets spread out from its biochemical properties. Credit: Wilbur Lam

Platelets, the tiny cell fragments whose job it is to stop bleeding, are very simple. They don't have a cell nucleus. But they can "feel" the physical environment around them, researchers at Emory and Georgia Tech have discovered.

Platelets respond to surfaces with greater stiffness by increasing their stickiness, the degree to which they "turn on" other platelets and other components of the clotting system, the researchers found.

"Platelets are smarter than we give them credit for, in that they are able to sense the physical characteristics of their environment and respond in a graduated way," says Wilbur Lam, MD, PhD, assistant professor in the Department of Pediatrics at Emory University School of Medicine and in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The results are published in Proceedings of the National Academy of Sciences. The first author of the paper is research associate Yongzhi Qiu. Lam is also a physician in the Aflac 

Cancer and Blood Disorders Center, Children's Healthcare of Atlanta.

The researchers' findings could influence the design of medical devices, because when platelets grab onto the surfaces of catheters and medical implants, they tend to form clots, a major problem for patient care.

Modifying the stiffness of materials used in these devices could reduce clot formation, the authors suggest. The results could also guide the refinement of blood thinning drugs, which are prescribed to millions to reduce the risk of heart attack or stroke.

The team was able to separate physical and biochemical effects on platelet behavior by forming polymer gels with different degrees of stiffness, and then overlaying them each with the same coating of fibrinogen, a sticky protein critical for blood clotting. Fibrinogen is the precursor for fibrin, which forms a mesh of insoluble strands in a blood clot.

With stiffer gels, platelets spread out more and become more activated. This behavior is most pronounced when the concentration of fibrinogen is relatively low, the researchers found.

"This variability helps to explain platelet behavior in the 3D context of a clot in the body, which can be quite heterogenous in makeup," Lam says.

Qiu and colleagues were also able to dissect platelet biochemistry by allowing the platelets to adhere and then spread on the various gels under the influence of drugs that interfere with different biochemical steps.

Proteins called integrins, which engage the fibrinogen, and the protein Rac1 are involved in the initial mechanical sensing during adhesion, while myosin and actin, components of the cytoskeleton, are responsible for platelet spreading.

"We found that the initial adhesion and later spreading are separable, because different biochemical pathways are involved in each step," Lam says. "Our data show that mechanosensing can occur and plays important roles even when the cellular structural building blocks are fairly basic, even when the nucleus is absent."

Source: Emory Health Sciences

Patient's question triggers important study about blood thinners

Physicians around the world now have guidance that can help them determine the best oral blood thinners to use for their patients suffering from blood clots in their veins, thanks to a patient of The Ottawa Hospital who asked his physician a question he couldn't answer. This new guidance is found in a study published today by JAMA, the Journal of the American Medical Association.

"Right there in the clinic, he identified an important knowledge gap for clinicians. We decided to act on it and find the answer," says hematologist Dr. Marc Carrier, who also a scientist at The Ottawa Hospital and associate professor at the University of Ottawa.

Dr. Carrier was treating Jamie Dossett-Mercer for major blood clotting in his leg veins, called deep vein thrombosis, that reached from his ankle to his groin. If one of these clots were to break off, it could travel to the lung and cause a pulmonary embolism, which is often fatal. These two common medical conditions are known together as venous thromboembolism and form the third leading cause of cardiovascular death.

In recent years, a number of new oral anticoagulants have been approved for use. Faced with eight possible therapies, Dossett-Mercer asked, "How do all these different blood thinners compare head to head?"

Dr. Carrier went looking for the answer. Although he found dozens of trials that studied the effect of different agents separately, none had analyzed all the results together.

His team reviewed 45 randomized trials (involving nearly 45,000 patients) using a process called network meta-analysis, which allows them to set a baseline treatment and compare all the other treatments to that. All the clinical trials they found compared the newer treatments to the standard of care, which is low-molecular-weight heparin (LMWH) with vitamin K antagonists.

Using the LMWH-vitamin K antagonist combination as the central node of the network, they compared safety and effectiveness with seven other anticoagulant therapies for venous thromboembolism: unfractionated heparin (UFH) with vitamin K antagonists; fondaparinux with vitamin K antagonists; LMWH with dabigatran; LMWH with edoxaban; rivaroxaban; apixaban; and LMWH alone.

While they found no major differences in effectiveness and safety, there were some notable variations.

• Patients taking the UFH-vitamin K antagonist combination had a higher percentage who experienced a recurrent blood clot within three months.
• Patients taking rivaroxaban and apixaban had a lower percentage who experienced a major bleeding event within three month.

"This will help physicians tailor their care according to patient characteristics," says Dr. Carrier. "For example, if I am worried about recurrent clotting, but I'm not too worried about the risk of bleeding, then I can select the drug with the best safety profile."

"I was already impressed with Dr. Carrier's exceptional care," says Dossett-Mercer. "But that he would do this research based on a patient question is just astounding."

Source: Ottawa Hospital Research Institute