Novel way to block blood vessels could improve cancer treatment  

According the researchers at the University of Helsinki, Finland, a novel strategy of blocking the growth of blood vessels with antibodies should result in improved treatment of cancerous tumours.  

The growth of new blood vessels from pre-existing vasculature is called angiogenesis. In adults, angiogenesis occurs only during wound healing and menstrual cycling, but is abundant and harmful in cancerous tumours and the old-age eye disease frequently leading to blindness called age-related macular degeneration (AMD). Without the formation of new blood vessels, tumours cannot grow beyond a small size due to lack of oxygen and nutrients. Inhibition of angiogenesis is used in the treatment of cancer and AMD, but not all cancer patients respond, while others become refractory to therapy.  

Academy professor Kari Alitalo and coworkers at the University of Helsinki, Finland, have previously shown that antibodies directed towards vascular endothelial growth factor receptor (VEGFR)-3, found on the surface of endothelial cells lining vessels, can inhibit lymphatic metastasis by 50-70% in preclinical tumour models. Furthermore, antibodies that inhibited the growth factor VEGF-C from binding to the VEGFR-3 suppressed angiogenesis. However, the trouble with this type of inhibitors is that they work poorly in high growth factor concentrations, when the growth factor easily outcompetes the inhibitor. Also the delivery of drugs into tumours is hampered by erratic blood flow and high tumour pressure, which may prevent sufficient amounts of the inhibitor from reaching its target within the tumour.  

The novel type of VEGFR-3 blocking antibody has an unprecedented mechanism of action, which was effective even at very high concentrations of the VEGF-C growth factor. Importantly, the authors showed that combined use of antibodies blocking growth factor binding VEGFR-3 dimerization provided not only an additive, but rather a synergistic inhibition.  

“The new dimerization inhibitor unveils a biologically meaningful rationale for suppressing angiogenesis in tumours that could outperform traditional competitive inhibitors of angiogenesis in tumour therapy. These findings should translate into improved anti-angiogenic and antilymphangiogenic tumour therapies,” says Prof Alitalo.  

Baby brain more developed than previously thought  

Full-term babies are born with a key collection of networks already formed in their brains, according to new research that challenges some previous theories about the brain’s activity and how the brain develops. The study is published in the 1 November 2010 issue of Proceedings of the National Academy of Sciences.

Researchers led by a team from the MRC Clinical Sciences Centre at Imperial College London used functional MRI scanning to look at ‘resting state’ networks in the brains of 70 babies, born at between 29 and 43 weeks of development, who were receiving treatment at Imperial College Healthcare NHS Trust.  

Resting state networks are connected systems of neurons in the brain that are constantly active, even when a person is not focusing on a particular task, or during sleep. The researchers found that these networks were at an adult-equivalent level by the time the babies reached the normal time of birth.

One particular resting state network identified in the babies, called the default mode network, has been thought to be involved in introspection and daydreaming. MRI scans have shown that the default mode network is highly active if a person is not carrying out a defined task, but is much less active while consciously performing tasks.

Earlier research had suggested that the default mode network was not properly formed in babies and that it developed during early childhood. The fact that the default mode network has been found fully formed in newborns means it may provide the foundation for conscious introspection, but it cannot be only thing involved, say the researchers behind today’s study.  

Professor David Edwards, lead author of the study from the MRC Clinical Sciences Centre at Imperial College London, said: “Some researchers have said that the default mode network is responsible for introspection – retrieving autobiographical memories and envisioning the future, etc. The fact that we found it in newborn babies suggests that either being a foetus is a lot more fun than any of us can remember – lying there happily introspecting and thinking about the future – or that this theory is mistaken.

“Our study shows that babies’ brains are more fully formed than we thought. More generally, we sometimes expect to be able to explain the activity we can see on brain scans terms of someone thinking or doing some task. However, most of the brain is probably engaged in activities of which we are completely unaware, and it is this complex background activity that we are detecting.”

The researchers found that the resting state networks mainly develop after 30 weeks – in the third trimester – and are largely complete by 40 weeks when most babies are born. They reached their conclusions after carrying out functional MRI scans on 70 babies, born at between 29 and 43 weeks of development, who were receiving treatment at Imperial College Healthcare NHS Trust and whose parents had given consent for them to be involved in the study. Some of the babies scanned were under sedation and others were not, but the researchers found no difference in results between sedated and non-sedated babies.

The researchers used a 4-dimensional brain atlas developed with scientists in the Department of Computing at Imperial College London to map the activity that they found in the babies’ brains against what is known about the location of different brain networks.

The next step for this research is to find out how these networks are affected by illnesses and to see if they can be used to diagnose problems.  

. Reference: Edward D. et al “Emergence of resting state networks in the preterm human brain,” Proceedings of the National Academy of Sciences, 1 November 2010

Trials set to test weight management using new tech & social media

To engage young adults in protecting their future heart health, the US National Institutes of Health's National Heart, Lung, and Blood Institute (NHLBI) has funded seven clinical trials that combine behavioural weight management programmes with technologies such as text messaging, online social networking, and Bluetooth-enabled scales.

“These studies have the potential to teach us about successfully engaging young adults in achieving a healthy weight at a critical time in their lives,” said Susan B. Shurin, MD, acting director of the NHLBI. “Learning effective strategies for weight management further empowers young adults to protect their future heart health. These studies are designed to provide evidence to help us guide young adults toward approaches that work and allow them to choose the options that work best for them.”  

The Early Adult Reduction of Weight through Lifestyle Intervention (EARLY) Trials seek to prevent weight gain and promote weight loss among young adults, defined as ages 18-35, through healthy eating and physical activity. The trials are receiving a total of US$36 million over the next five years.  

“We expect the use of technology will help us reach young adults at risk of weight gain and inspire them to stay at a healthy weight,” said trials steering committee chair Leslie Lytle, PhD, who is leading a trial that features Web-based social networking among community college students.  

Seven individual trials will be run. Although each trial is slightly different and will be conducted at a single institution, the teams are using a set of common measures and questionnaires so they can better compare their findings when the trials are complete with the aim of maximizing what the research community learns about developing strategies to address weight control among young adults.

The seven trials are:

1. Treating Adults at Risk for Weight Gain with Interactive Technology (TARGIT) at the University of Tennessee, Memphis, will use the iPod Touch, webinars, and podcasts to deliver a behavioral weight loss intervention to young adults who are trying to quit smoking.

2. Innovative Approaches for Diet, Exercise, and Activity (IDEA) at the University of Pittsburgh will test how a weight loss intervention enhanced with text message reminders and wearable exercise monitors improves weight loss as compared to a standard intervention.

3. eMoms Roc: Electronically Mediated Weight Interventions for Pregnant and Postpartum Women at Cornell University/University of Rochester, N.Y., will test Internet-based programs to promote the health of pregnant and postpartum women.

4. Choosing Healthy Options in College Environments and Settings (CHOICES) at the University of Minnesota, Minneapolis, will test a for- credit course that includes Web-based social networking to prevent unhealthy weight gain in student participants.

5. Cell Phone Intervention for You (CITY) at Duke University, Durham, N.C., will test two weight loss approaches against a control.

6. Social/Mobile Approaches to Reducing Weight (SMART) at the University of California, San Diego, will test a behavioral intervention that uses mobile phones, Facebook, and the Web.

7. Study of Novel Approaches for Prevention (SNAP) at Brown University/Miriam Hospital will test a Web-based weight management intervention against a control.

Viral counts necessary to gauge health of children with HIV For children being treated for HIV in less developed countries, monitoring to predict the occurrence of serious HIV- related illnesses is most accurate if it includes a measure of HIV levels in the blood, according to a US National Institutes of Health study conducted throughout Latin America.

Termed viral load, the quantity of human immunodeficiency virus (HIV) genetic material in the blood is a barometer of the effectiveness of HIV treatment. High viral loads indicate potential treatment failure, which can then lead to a weakened immune system and increased risk of infections.  

Monitoring children's viral load is standard in the United States. However, the technology to perform viral load testing is difficult and expensive to maintain and, for these reasons, is often unavailable in less developed settings. Instead, in these settings, clinical symptoms or immune cell number are used to monitor the effectiveness of therapy. The current study is the first to assess the value of adding viral load to monitoring of symptoms and tests of immune function in children receiving anti-HIV treatment in a less developed setting.  

The study authors noted that, in resource poor settings, shipping blood samples to a central facility where viral load levels could be measured might provide a cost effective alternative to performing viral load measurements at each clinical care site.

The researchers found that a viral load of 5,000 copies per millilitre of blood predicts a higher risk of serious illness in children on HIV treatment, providing clinical evidence for new World Health Organisation recommendation on when to change HIV medications when it appears that a child’s HIV treatment is failing.

“Our study showed that adding viral load monitoring would significantly improve the monitoring regimen used to safeguard the health of children being treated for HIV,” said George K. Siberry, MD, MPH, senior author of the study.  

The authors noted that using dried blood spots for viral load testing might provide a cost effective alternative to routine viral load testing methods. Although they did not evaluate this alternative in their study, the authors cited earlier research, of blood spots collected on filter paper. The authors noted that blood spots could be readily used to detect viral load at the level that predicted clinical illness in the current study. Filter paper, such as that used for newborn screening programmes in the United States, could be used to collect blood samples in remote or poor areas, which could then be shipped to a central facility where they could be processed reliably and economically.

The study was led by Ricardo Oliveira, of the Federal University of Rio de Janeiro. The findings were published online in the journal Clinical Infectious Diseases.  

Groundbreaking lighting system decontaminates air, kills MRSA

A pioneering lighting system that can kill hospital superbugs – including MRSA and C.diff – has been developed by researchers at the University of Strathclyde in Glasgow, Scotland.

The technology decontaminates the air and exposed surfaces by bathing them in a narrow spectrum of visible-light wavelengths, known as HINS-light.

Clinical trials at Glasgow Royal Infirmary have shown that the HINS-light Environmental Decontamination System provides significantly greater reductions of bacterial pathogens in the hospital environment than can be achieved by cleaning and disinfection alone, providing a huge step forward in hospitals’ ability to prevent the spread of infection.  

This novel decontamination technology was discovered and developed by a multidisciplinary team of experts, Professor Scott MacGregor (Electrical Engineer), Professor John Anderson and Dr Michelle Maclean (Microbiologists) and Professor Gerry Woolsey (Optical Physicist).

Prof Anderson said: “The technology kills pathogens, but is harmless to patients and staff, which means for the first time, hospitals can continuously disinfect wards and isolation rooms.  

“The system works by using a narrow spectrum of visible-light wavelengths to excite molecules contained within bacteria. This in turn produces highly reactive chemical species that are lethal to bacteria such as meticillin-resistant Staphylococcus aureus, or MRSA, and Clostridium difficile, known as C.diff.”  

Dr Maclean added: “The clinical trials have shown that the technology can help prevent the environmental transmission of pathogens and thereby increase patient safety.”  

The technology uses HINS-light which has a violet hue, but the research team have used a combination of LED technologies to produce a warm white lighting system that can be used alongside normal hospital lighting.

Professor Scott MacGregor, Dean of the Faculty of Engineering, said: “New approaches to disinfection and sterilisation are urgently needed within the clinical environment, as traditional methods have significant limitations.

“Decontamination methods involving gas sterilants or UV-light can be hazardous to staff and patients, while cleaning, disinfection and hand washing, although essential routine procedures, have limited effectiveness and problems with compliance.

“HINS-light is a safe treatment that can be easily automated to provide continuous disinfection of wards and other areas of the clinical environment. The pervasive nature of light permits the treatment of air and all visible surfaces, regardless of accessibility, either through direct or reflected exposure to HINS-light within the treated environment.”

From touchpad to thoughtpad  

Move over, touchpad screens: New research funded in part by the US National Institutes of Health shows that it is possible to manipulate complex visual images on a computer screen using only the mind.

The study, published in Nature, found that when research subjects had their brains connected to a computer displaying two merged images, they could force the computer to display one of the images and discard the other. The signals transmitted from each subject’s brain to the computer were derived from just a handful of brain cells.

“The subjects were able to use their thoughts to override the images they saw on the computer screen,” said the study’s lead author, Itzhak Fried, MD, PhD, a professor of neurosurgery at the University of California, Los Angeles.  

The study reflects progress in the development of brain-computer interfaces (BCIs), devices that allow people to control computers or other devices with their thoughts. BCIs hold promise for helping paralysed individuals to communicate or control prosthetic limbs. But in this study, BCI technology was used mostly as a tool to understand how the brain processes information, and especially to understand how thoughts and decisions are shaped by the collective activity of single brain cells.  

“This is a novel and elegant use of a brain-computer interface to explore how the brain directs attention and makes choices,” said Debra Babcock, MD, PhD, a programme director at NINDS.

The study involved 12 people with epilepsy who had fine wires implanted in their brains to record seizure activity. Recordings like these are routinely used to locate areas of the brain that are responsible for seizures. In this study, the wires were inserted in the medial temporal lobe, a brain region important for memory and the ability to recognise complex images, including faces.  

While the recordings from their brains were transmitted to a computer, the research subjects viewed two pictures superimposed on a computer screen, each picture showing a familiar object, place, animal or person. They were told to select one image as a target and to focus their thoughts on it until that image was fully visible and the other image faded away. The monitor was updated every one-tenth of one second based on the input from the brain recordings.  

As a group, the subjects attempted this game nearly 900 times in total, and were able to force the monitor to display the target image in 70% of these attempts. Subjects tended to learn the task very quickly, and often were successful on the first try.  

The brain recordings and the input to the computer were based on the activity of just four cells in the temporal lobe. Prior research has shown that individual cells in this part of the brain respond preferentially – firing impulses at a higher rate – to specific images. For instance, one cell in the temporal lobe might respond to seeing a picture of Marilyn Monroe, while another might respond to Michael Jackson. Both were among the celebrity faces used in the study.

Dr Fried’s team first identified four brain cells with preferences for celebrities or familiar objects, animals or landmarks, and then targeted the recording electrodes to those cells. The team found that when subjects played the image-switching game, their success appeared to depend on their ability to power up cells that preferred the target image and suppress cells that preferred the non-target image.  

“The remarkable aspects of this study are that we can concentrate our attention to make a choice by modulating so few brain cells and that we can learn to control those cells very quickly,” said Dr Babcock.

Prior studies on BCIs have shown that it is possible to perform other tasks, such as controlling a computer cursor, with just a few brain cells. However, the task here was more complex and might have been expected to involve legions of cells in diverse brain areas needed for vision, attention, memory and decision-making.

. Reference: Cerf M et al. “On-line, voluntary control of human temporal lobe neurons,” Nature, 28 October 2010

Researchers produce powerful synchrotron x-rays from tabletop device

Researchers have developed a tabletop device that produces tightly focused beams of high energy x-rays that could dramatically increase the resolution of medical imaging systems and measure atomic and molecular interactions that occur on the femtosecond timescale. The development could make this type of x- ray simpler and cheaper.  

The study, published in Nature Physics, describes how researchers from Imperial College London, the University of Michigan and Instituto Superior Téchnico Lisbon use a tabletop instrument to produce synchrotron x-rays, whose energy and quality rivals that produced by some of the largest x-ray facilities in the world.  

Scientific and medical advances often depend on the development of better diagnostic and analytical tools, to enable more precise investigations at higher resolutions. The development and use of high energy light sources to probe the details of a wide range of materials for research and commercial purposes is a rapidly growing area of science and engineering. However, high power, high quality x-ray sources are typically very large and very expensive. For example, the Diamond Light Source synchrotron facility in Didcot, UK, is 0.5km in circumference and cost £263M to build.  

The researchers behind this study have demonstrated that they can replicate much of what these huge machines do, but on a tabletop. Their micro-scale system uses a tiny jet of helium gas and a high power laser to produce an ultrashort pencil-thin beam of high energy and spatially coherent x-rays.

“This is a very exciting development,” said Dr Stefan Kneip, lead author on the study from the Department of Physics at Imperial College London. “We have taken the first steps to making it much easier and cheaper to produce very high energy, high quality x-rays. Extraordinarily, the inherent properties of our relatively simple system generates, in a few millimetres, a high quality x-ray beam that rivals beams produced from synchrotron sources that are hundreds of metres long. Although our technique will not now directly compete with the few large x-ray sources around the world, for some applications it will enable important measurements which have not been possible until now.”

The x-rays produced from the new system have an extremely short pulse length. They also originate from a small point in space, about 1 micron across, which results in a narrow x-ray beam that allows researchers to see fine details in their samples. These qualities are not readily available from other x-ray sources and so the researchers’ system could increase access to, or create new opportunities in, advanced x-ray imaging. For example, ultra short pulses allow researchers to measure atomic and molecular interactions that occur on the femtosecond timescale. A femtosecond is one quadrillionth of a second.

Dr Zulfikar Najmudin, the leader of the experimental team from the Department of Physics at Imperial College, added: “We think a system like ours could have many uses. For example, it could eventually increase dramatically the resolution of medical imaging systems using high energy x-rays, as well as enable microscopic cracks in aircraft engines to be observed more easily. It could also be developed for specific scientific applications where the ultrashort pulse of these x-rays could be used by researchers to “freeze” motion on unprecedentedly short timescales .”

. Reference: Najmudin C et al. “Bright spatially-coherent synchrotron x-rays from a tabletop source” Nature Physics, 24 October 2010

SHARP trial results show 25% of heart attacks in kidney patients preventable Around a quarter of all heart attacks, strokes, and operations to open blocked arteries could be avoided in people with chronic kidney disease by using the combination of ezetimibe and simvastatin to lower blood cholesterol levels. That’s the conclusion from the world’s largest ever randomised trial in kidney disease.

The key findings of the Study of Heart and Renal Protection (SHARP) trial were presented 20 November 2010 at the American Society of Nephrology.

Professor Colin Baigent, the trial’s principal investigator said: “This is excellent news for patients who have kidney disease.

It was already known that cholesterol- lowering could reduce the risk of heart attacks, strokes and the need for surgery to unblock arteries in people with normal kidney function. But, this trial now shows that cholesterol-lowering has similar effects in people with chronic kidney disease, irrespective of the severity of their illness.”  

The SHARP trail involved almost 9,500 volunteers aged 40 or over with chronic kidney disease recruited from 380 hospitals in 18 countries. Patients included in the trial had lost at least 50% of their normal kidney function, with a third of them requiring dialysis treatment. None had had a previous heart attack or needed bypass surgery or stents to unblock their heart arteries. Volunteers in this double-blind placebo-controlled trial were randomly allocated to take either cholesterol- lowering therapy with a tablet containing ezetimibe 10mg daily and simvastatin 20mg daily, or matching placebo tablets. Study treatment and follow-up continued for an average of five years.

SHARP was designed, conducted and analysed independently of all funding sources by the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) of Oxford University, with guidance by an independent Steering Committee that included many of the world’s leading kidney specialists. The study was supported by Merck & Co., (MSD outside the US and Canada) who also supplied the study treatments, with additional support from the Australian National Health and Medical Research Council (NHMRC), the British Heart Foundation (BHF) and the UK Medical Research Council (MRC).

Planning began in the mid-1990s, with two pilot studies followed by a main study that started in 2003 and ended in September of this year. Summary of major findings

. The patients allocated to take ezetimibe plus simvastatin had one-sixth fewer heart attacks, strokes or operations to unblock arteries (“major atherosclerotic events”), with similar reductions observed in all types of patient studied.

. During this long trial, the proportion of patients who stopped taking their allocated treatment was about one third, but this was not generally due to side-effects and was the same for both real and dummy treatments. If taken without interruption, however, ezetimibe plus simvastatin could have even larger effects than were seen in SHARP, potentially reducing risk by about one quarter.

. Adding 10mg daily of ezetimibe to 20mg daily of simvastatin produced a large reduction in LDL (“bad”) cholesterol safely. This combination treatment may be particularly good for kidney patients, as it avoids the possibility of side-effects with high statin doses.

. There was no support for previous concerns with ezetimibe about possible adverse effects on cancer, and no evidence of an increased risk of muscle or liver problems.  

SHARP
www.sharpinfo.org 

                                  
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