Investigators at the Stanford University School of Medicine have learned the signal that tumour cells display on their surfaces to protect themselves from being devoured by the immune system also plays a role in enabling atherosclerosis, the process underlying heart attacks and strokes. A biological drug capable of blocking this so-called "don’t eat me" signal is now being tested in clinical trials in cancer patients. The same agent, the investigators found, was able to prevent the build-up of atherosclerotic plaque in several mouse models of cardiovascular disease. If this success is borne out in human studies, the drug could be used to combat cardiovascular disease – the world’s No. 1 killer – and do so by targeting not mere risk factors such as high cholesterol or high blood pressure, but the actual lesions bearing direct responsibility for cardiovascular disease: atherosclerotic plaques.
"It seems that heart disease may be driven by our immune system’s inability to take out the trash,’" said Nicholas Leeper, MD, associate professor of vascular surgery and of cardiovascular medicine.
Atherosclerosis is caused by the deposition of fatty substances along arterial walls. Over the years, these substances form plaques. It’s now known that numerous dead and dying cells accumulate in atherosclerotic plaques, which inflammation renders brittle and vulnerable to rupture, the ultimate cause of heart attack and stroke.
Contributing to the pathology is malfeasance on the part of a class of immune cells that first arrive at the site with presumably benign intentions, said Leeper.
"Even a perfectly healthy body turns over more than 100 billion cells a day, every day," he said. "One of the several jobs performed by immune cells called macrophages is to come and gobble up those dead and dying cells, which might otherwise begin releasing substances that can foster inflammation."
Many cells in the human body feature a "don’t eat me" signal on their surface: a protein called CD47. The protein tells the immune system that a cell is alive, still going strong and part of a person’s healthy tissue.
Normally, as a cell approaches death, its CD47 surface proteins start disappearing, exposing the cell to macrophages’ garbage-disposal service. But atherosclerotic plaques are filled with dead and dying cells that should have been cleared by macrophages, yet weren’t. In fact, many of the cells piling up in these lesions are dead macrophages and other vascular cells that should have been cleared long ago.
In the new study, Leeper, Kojima and their colleagues performed genetic analyses of hundreds of human coronary and carotid artery tissue samples collected at Stanford and at Sweden’s Karolinska Institute. They found that CD47 is extremely abundant in atherosclerotic tissue compared with normal vascular tissue, and correlated with risk for adverse clinical outcomes such as stroke.
Alerted to the Leeper lab’s discovery, Weissman, a co-author of the new study, provided anti-CD47 antibodies so Leeper’s group could test their efficacy in battling atherosclerosis.
In a laboratory dish, anti-CD47 antibodies induced the clearance of diseased, dying and dead smooth muscle cells and macrophages incubated in conditions designed to simulate the atherosclerotic environment. And in several different mouse models of atherosclerosis, blocking CD47 with anti-CD47 antibodies dramatically countered the build-up of arterial plaque and made it less vulnerable to rupture. Many mice even experienced regression of their plaques – a phenomenon rarely observed in mouse models of cardiovascular disease.
Looking at data from other genetic research, the scientists learned that surplus CD47 in atherosclerotic plaques strongly correlates with elevated levels, in these plaques, of a well-known infl ammationpromoting substance called TNF-alpha. Further experiments showed that TNFalpha activity prevents what would otherwise be a progressive decrease of CD47 on dying cells. Hence, those cells are less susceptible to being eaten by macrophages, especially in an atherosclerosis-promoting environment.
"The problem could be an endless loop," said Leeper, "in which TNF-alpha-driven CD47 overexpression prevents macrophages from clearing dying cells in the lesion. Those cells release substances that promote the production of even more TNF-alpha in nearby cells."
Leeper and Weissman said they hope to find out, in clinical trials of human patients, whether CD47-blocking antibodies will prove effective in breaking that vicious circle.

Stanford Medicine http://tinyurl.com/zts8ws4

Scientists have created a material that could make reading biological signals, from heartbeats to brainwaves, much more sensitive.

Organic electrochemical transistors (OECTs) are designed to measure signals created by electrical impulses in the body, such as heartbeats or brainwaves. However, they are currently only able to measure certain signals.

Now researchers led by a team from Imperial College London have created a material that measures signals in a different way to traditional OECTs that they believe could be used in complementary circuits, paving the way for new biological sensor technologies.

Semiconducting materials can conduct electronic signals, carried by either electrons or their positively charged counterparts, called holes. Holes in this sense are the absence of electrons – the spaces within atoms that can be filled by them.

Electrons can be passed between atoms but so can holes. Materials that use primarily hole-driven transport are called p-type’ materials, and those that use primarily electron-driven transport are called, and n-type’ materials.

An ambipolar’ material is the combination of both types, allowing the transport of holes and electrons within the same material, leading to potentially more sensitive devices. However, it has not previously been possible to create ambipolar materials that work in the body.

The current most sensitive OECTs use a material where only holes are transported. Electron transport in these devices however has not been possible, since n-type materials readily break down in water-based environments like the human body.

But in new research the team have demonstrated the first ambipolar OECT that can conduct electrons as well as holes with high stability in water-based solutions.

The team overcame the seemingly inherent instability of n-type materials in water by designing new structures that prevent electrons from engaging in side-reactions, which would otherwise degrade the device.

These new devices can detect positively charged sodium and potassium ions, important for neuron activities in the body, particularly in the brain. In the future, the team hope to be able to create materials tuned to detect particular ions, allowing ion-specific signals to be detected.

Lead author Alexander Giovannitti, a PhD student under the supervision of Professor Iain McCulloch, from the Department of Chemistry and Centre for Plastic Electronics at Imperial said: ‘Proving that an n-type organic electrochemical transistor can operate in water paves the way for new sensor electronics with improved sensitivity.

‘It will also allow new applications, particularly in the sensing of biologically important positive ions, which are not feasible with current devices. For example, these materials might be able to detect abnormalities in sodium and potassium ion concentrations in the brain, responsible for neuron diseases such as epilepsy.’

Imperial College London www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_7-10-2016-15-7-31

Siemens Healthineers recently announced the company is expanding its informatics capabilities for point-of-care testing with the acquisition of Conworx Technology GmbH, the Berlin-based developer of point-of-care device interfaces and data management solutions. The addition of the Conworx suite – including UniPOC and POCcelerator – complements the Siemens Healthineers award-winning RAPIDComm Data Management System and will elevate the informatics offerings for the point-of-care market by delivering open connectivity for more than 100 different instruments from all major manufacturers.
This acquisition is another proof point of the Siemens Healthineers strategic direction to enable healthcare providers around the world to meet their current and evolving challenges and to excel in their respective environments. Through products and solutions designed to increase efficiency and to reduce costs, Siemens Healthineers is setting new trends in healthcare together with its customers – working under the motto ‘Engineering Success. Pioneering Healthcare. Together.’
As the trend of consolidation and industrialization in healthcare continues and regulatory requirements for point-of-care testing intensify, the need for sophisticated informatics to communicate instrument and patient data at the point of care becomes increasingly important. Siemens Healthineers and Conworx will deliver open connectivity offerings that will enable seamless data integration from any manufacturer’s point-of-care analyser – managed by a single informatics solution to streamline operations and access to data, and improve risk management.
‘As hospitals consolidate and acquire physician offices, there is a huge need by emerging healthcare networks for seamless integration of hundreds of decentralized devices that are spread across dozens of sites.’ said Peter Koerte, President, Point of Care Diagnostics, Siemens Healthineers. ‘It is clear to us that to satisfy our customers’ needs, we must deliver solutions that ensure superb connectivity, no matter which analyser is being connected. We are determined to continue Conworx’s practice of working closely with every vendor to ensure that all connected analysers are working to the best of their ability.’
Now a wholly-owned subsidiary of Siemens Healthcare GmbH, Conworx’s team of 75 employees will merge with the Siemens Healthineers team to become Siemens Healthineers Point of Care Informatics. This new team of interface development, application development and data management specialists will be led by Roman Rosenkranz, the current CEO of Conworx Technology GmbH.
‘By joining with Siemens Healthineers, we will get access to a global organization to even better support our joint customer base’ said Roman Rosenkranz, CEO of Conworx Technology GmbH. ‘Together we will be able to develop leading informatics products that help our customers to manage their growing point-of-care networks now and in the future.’
Conworx Technology GmbH was established in 1999. The deal was closed by Siemens Healthcare GmbH in late October 2016.

www.conworx.com/en/ www.siemens.com/healthineers

A novel heart valve replacement method has been revealed that offers hope for the thousands of patients with rheumatic heart disease who need the procedure each year.

‘Over the past decade heart valve surgery has been revolutionised by transcatheter aortic valve implantation (TAVI),’ said lead author Dr Jacques Scherman, a cardiac surgeon in the Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, South Africa. ‘Heart valves are replaced or repaired via a catheter, obviating the need for open heart surgery or a heart-lung machine.’

He continued: ‘TAVI is only indicated in patients with calcific degenerative aortic valve disease, which is the most prevalent aortic valve pathology in developed countries. In developing countries, rheumatic heart disease still accounts for the majority of patients in need of a heart valve intervention.’
Rheumatic heart disease is caused by rheumatic fever, which results from a streptococcal infection. Patients develop fibrosis of the heart valves, leading to valvular heart disease, heart failure and death. In Africa alone there are around 15 million patients living with rheumatic heart disease of whom 100 000 per year might need a heart valve intervention at some stage of their life. The vast majority of these patients have no access to cardiac surgery or sophisticated cardiac imaging.

Dr Scherman said: ‘Inspired by the success of TAVI for calcific aortic valve disease, we developed a simplified TAVI device for transcatheter aortic valve replacement in patients with rheumatic heart disease.’
Currently available balloon expandable TAVI devices require the use of sophisticated cardiovascular imaging to correctly position the new valve. They also use a temporary pacemaker which allows the heart to beat so quickly that it stops blood circulating to the rest of the body (called rapid ventricular pacing).

Dr Scherman said: ‘Rapid ventricular pacing can only be tolerated for a short period and therefore limits the time available to do the implantation.’
The team in South Africa developed a novel TAVI device which is ‘non-occlusive’, meaning that there is no need to stop blood circulating to the body with rapid ventricular pacing. The device is also ‘self-locating’ and does not require sophisticated cardiac imaging for positioning.

The proof of concept study presented today tested the device in a sheep model. The investigators found that the device was easy to use and positioned the valve correctly, and the procedure could be performed without rapid ventricular pacing.

Dr Scherman said: ‘We showed that this new non-occlusive, self-locating TAVI delivery system made it easy to perform transcatheter aortic valve replacement. Using tactile feedback the device is stabilised in the correct position within the aortic root during the implantation. It also has a temporary backflow valve to prevent blood leaking backwards into the ventricle during the implantation of the new valve. All these factors together allowed for a slow, controlled implantation compared to the currently available balloon expandable devices.’

He added: ‘This simplified approach to transcatheter aortic valve replacement could be done in hospitals without cardiac surgery at a fraction of the cost of conventional TAVI. It has the potential to save the lives of the large numbers of rheumatic heart disease patients in need of valve replacement.’

European Society of Cardiology www.escardio.org/The-ESC/Press-Office/Press-releases/novel-heart-valve-replacement-offers-hope-for-thousands-with-rheumatic-heart-disease