Cracks, unevenness, leakages, or speed and direction of liquid flows in vessels or pipes, hearts or pumps, are challenges faced by people in healthcare, oil & gas and the maritime sector. At the Centre for Innovative Ultrasound Solutions (CIUS), we work on improving ultrasound technology and usage to address these and other issues. Continue reading
Category Archives: Blood
A prerequisite for successful chemotherapy is that the drugs reach its target, and that damage to healthy tissue is limited. However, when drugs are injected into the blood, less than 1% of the drugs accumulate in tumours. Microbubbles combined with focused ultrasound shows great promise in enhancing delivery of nanoparticles and drugs thereby improving cancer therapy. Focused ultrasound and nanoparticles can also be used to temporarily open the blood-brain barrier thereby allowing nanoparticles and drugs to enter into brain tissue, which enables treatment of brain disorders. At the Department of Physics, NTNU, we are using two types of new microbubbles to improve the delivery of nanoparticles and drugs in combination with focused ultrasound. Continue reading
White blood cells are essential components of the immune system. Without these cells we would not stay healthy for long on a planet where infections thrive. But what are these cells up to when we’re not sick? They are present. And they are active, at all times.
Lean back and breathe in. Hold your breath. It can’t get much easier; what could there possibly here for a scientist to study? Well, there is something.
Evolution has shaped us for the environment we live in, and our environment is never completely static. The immune system is involved in rapid biological adjustments that protect us from harm caused by environmental perturbations. Some perturbations are of a cyclic nature, like those that are linked to the earth’s rotation around the sun and its own axis. In an elegant study published in the journal Nature in 2015, English and German scientists identified variations in the immune system that are perfectly aligned with the seasons. Actually, our bodies appear to lie slightly ahead of the seasonal changes: we appear to have a biological memory that fine-tunes the immune system just before the seasons change. Since many common infectious diseases appear in a seasonal pattern, this is an amazing adaptation for life on planet earth. If we speed the cycle up a bit, related effects have been observed over the 24 hrs cycle.
So the immune system shows cyclic variation.
What happens if we speed it up to the cycle of our breath?
Most of the time, we breathe without thinking about it. Our cells need oxygen for energy production, and once we have filled our lungs with air, it is the circulatory system – i.e. the heart, blood vessels and blood – that distributes oxygen to the cells in all parts of our body. We can all voluntarily hold our breath for a while, but some people do this better than the rest. Freedivers dive while holding their breath; the best of them can hold their breath for over 10 minutes.
In order to understand how white blood cells respond to an altered breathing pattern, we studied some of the world’s best free-diving athletes. We used a simple design: blood samples were drawn from contestants at an international free-diving competition before start, and then again one and three hours after completion of a series of dives where the athletes either lay face down in water or swam close to the surface for as long as they could.
Then the samples were transported to the NTNU Genomic Core Facility where total gene expression in the athletes’ white blood cells was measured by a method called full genome microarray analysis. The analysis results were striking: the activity of more than 5000 genes changed in response to the simple effort of breath-holding. This is almost ¼ of all genes found in human cells. With this amount of data we could dig deeper into cellular biology and calculate which specific types of white blood cells that reacted to breath-holding, and also see finer details in the biological processes going on within the cells.
The most striking finding we did was a marked increase of the white blood cell type neutrophil granulocytes. These blood cells are programmed for rapid response when the body perceives attacks from intruders; the neutrophils are capable of killing invading cells simply by eating them. But they also have another interesting trait that emerges when oxygen levels drop: neutrophil granulocytes are evolutionary old-timers that stem from an era when the atmosphere contained less oxygen than now, and their modern offspring still prefer environments where the oxygen levels are low. White blood cell types that use more oxygen – like lymphocytes – were less active in blood drawn after the athletes held their breath. What we observed are likely to be traces of evolutionary history still embedded in our immune system, visible when oxygen levels change. The study was published in November 2016 in the journal Physiological Genomics.
This study was done on healthy athletes.
Can it be relevant for understanding of human diseases?
Healthy people normally don’t have to worry about oxygen, but for common diseases like chronic obstructive lung disease (COPD) and sleep apnea, the body’s oxygen supply is limited. These diseases are associated with persistent inflammatory conditions, and increased risk of infections; both indicative of an impaired immune system. If we can use data from healthy individuals to distinguish secondary effects of low oxygen levels from the primary pathology of the disease, this may in turn be helpful for prevention and treatment strategies.
– And breathe out.
Researchers are trying to find out why U-2 pilots operating in high altitude have central nervous system changes in a NATO-led project involving researchers from the Barophysiology group at NTNU, researchers from the U.S. Air Force in Texas and from the Institute of Aviation Medicine in Oslo.
You have probably been in a passenger jet, and as you get ready for take-off, you register the cabin attendants going through the safety instructions, mentioning something about loss of cabin pressure and oxygen masks, but you don’t worry about it. 15 minutes later the captain announces that the airplane has reached its cruising altitude of 38,000 feet. At this altitude the barometric pressure is only 1/5 of sea level pressure.
Inside the aircraft the pressurisation system ensures that the cabin altitude according to international regulations will never exceed 8000 feet = ¾ of sea level pressure. So while you are travelling, you are actually performing a little mountain-excursion to the same altitude as Norway’s highest mountain, Galdhøpiggen.
Now imagine that you are flying twice as high as your airliner. At an altitude of 70,000+ feet the barometric pressure is 1/25th of an atmosphere. You can see the curvature of the earth and the blackness of space above. This is where the U-2 pilots are working. If you lose the cabin pressure in this environment, an oxygen mask will be of no help. You need to wear a space suit that will instantly inflate to a pressure of 0.3 bar (corresponding to 30,000 feet) and supply you with a breathing gas of 100% oxygen.
The U-2 planes have been operating since the 50s and are still in active duty. In fact, U-2 pilots have actually been flying more the last 10 years as other high-altitude reconnaissance airplanes have retired. This has resulted in an increased number of neurologic decompression sickness episodes.
A US Air Force research team has published findings of what are called white matter hyperintensities in the brain on magnetic resonance imaging (MRI) of U-2 pilots (McGuire et al., 2013) . Recently they have discovered similar findings in U.S. Air Force altitude chamber instructors (McGuire et al., 2014). This group works inside hypobaric chambers, training aircrew including U-2 pilots, in the effect of loss of cabin pressure and lack of oxygen. The altitude exposure in hypobaric chamber training is usually much shorter and less severe than in U-2 operations. None of the other U.S. Air Force control groups they have tested so far, including Air Force doctors, have had similar changes.
The U.S. Air Force research team visited the Institute for Aviation Medicine, Oslo, Norway, and wanted to meet Norwegian research groups that might contribute to understanding the pathophysiology behind the findings. Members of the NTNU Barophysiology group were invited based on their merits for a long time commitment to research on man in extreme environments.
Most of the work of the NTNU Barophysiology group has been related to the activity of diving and the adverse effects of working under water. Presently, the research is funded by the Norwegian Research Council through the Petromaks programme.
One of the technologies we are using in assessing possible stress after a dive is ultrasound detection of gas bubbles found in blood veins. These bubbles will form in nearly all diving activity, and it is recognised that the risk of decompression sickness increases with increasing amounts of bubbles.
Our way of observing vascular gas bubbles after diving has become a recognised method for evaluating procedures. It has also been shown both in animals and humans that the bubbles themselves influence the endothelium lining all blood vessels. When going to high altitudes, the pressure changes are opposite of diving. But there are many similarities as well, and the formation of bubbles is thought to be involved in the formation of the white matter hyperintensities.
After the meeting in Oslo, the researchers from NTNU did some preliminary investigations, and were invited to Lackland Air Force Base in Texas where the main investigation is taking place. The results from the tests at NTNU have already been presented at a NATO high altitude exposure meeting this summer in Paris, and has gained a lot of attention within NATO. Together with the Institute of Aviation Medicine in Oslo, the researchers from the Department of circulation and medical imaging are eager to continue the investigations.
Crucial to our gas and oil industry, the offshore divers perform their work on the ocean floor of the Norwegian continental shelf. Not unlike the astronauts, these divers – the aquanauts – encounter environments that challenge the body’s capacity for adaptations. We look at how their bodies respond and what makes them fit and healthy.
Saturation diving is a very challenging job and the divers have to be extremely fit and healthy. The divers live at an elevated atmospheric pressure inside a pressure chamber, which is equal to the pressure at the water depth they will work at. They breathe a mixture of helium and oxygen called Heliox, which makes their voices sound like Mickey Mouse!
When working at depths of 50-180 metres, it is dark and the seawater is very cold – around 4-8°C. The divers are therefore dressed in neoprene wet suits where heated seawater is pumped through to keep them warm. It is like floating in a heated spa pool. They wear a helmet, wellington boots and rubber gloves, which could be mistaken for dishwashing gloves.
Many research projects have been conducted with recreational divers and also offshore air divers, but there are not many research projects on offshore saturation diving – and even less research done with real-life saturation divers in their own working environment.
New science indicates that the high-pressure working environment makes the body initiate an inflammatory reaction, with possible release of stress biomarkers into the blood stream. This is of course closely linked to the function of the vascular system. This gave us the idea to not only study the effects of diving on the vascular system and how the body adapts to such conditions; but also how to improve the long-term health monitoring.
The main part of my PhD project is to see if the intake of antioxidants in the form of vitamin C and E will reduce the stress biomarkers found in the blood of saturation divers. The participating offshore divers will be given vitamins every day whilst living in the pressure chamber and blood samples will be taken before entering and upon leaving the chamber. The results will be compared with a control group not taking vitamins.
After obtaining the approval of my employer, Technip – which performs subsea construction work for the oil & gas industry; and after securing funding from the Norwegian Research Council and the necessary ethical authorisation to perform research on humans, I could start my PhD research at the Medical Faculty at NTNU doing data- and samples collection during the 2015 offshore season.
Before going offshore, one of my PhD supervisors, Andreas Møllerløkken, provided training on how to use an ultrasound machine to run a test called Flow Mediated Dilation (FMD). This test measurers how much a large artery of the arm can expand after the blood flow has been reduced for 5 minutes using an inflated blood pressure cuff. FMD is a much used indicator of vascular health. We used my office colleagues as guinea pigs in order to practice before going offshore.
We also obtained the centrifuges and cooling transportation boxes required for our mission, and on 2nd June, it was time for the fun part of the project to begin!
My main supervisor, Ingrid Eftedal, and I took all the equipment to the hospital on board the Skandi Arctic Dive Support Vessel. We received a warm welcome by all the crew, and by the end of the first day, we had already tested two divers.
The divers had joined the vessel by 6th June. They all went through the medical pre-dive check and some were also due to have their annual direct oxygen uptake (VO2max) test.
Initially, eight divers agreed to participate in the project, and we took their blood samples and ran FMD tests. It was a great relief to actually get started.
As the blood samples also will be used in two other research projects run by the barophysiology group at NTNU, we are taking four test tubes of blood from the divers and 3 from the non-divers to study different paramenters. This has earnt me the nichname ‘The Vampire’, although it is the nurse taking the actual samples!
We centrifuge the tubes with blood and anticoagulant to separate the plasma into tubes for freezing and later analysis at the NTNU laboratory.
We also measure percentage of red blood cells onboard, and record the results in our log sheet.
In addition to ‘normal’ health check such as taking the blood pressure, we ran FMD test using an ultrasound machine in combination with an electro cardiogram (ECG). This test shows how much the brachial artery in the arm can expand after 5 minutes of pressure in the forearm. It is a good indicator of artery elasticity reflecting vascular health.
The divers who were due to take their annual VO2max test, measuring the maximum oxygen uptake in the blood, were running on the onboard treadmill placed within the vessel’s hospital.
I have to say it is not easy to work when the ‘ground’ is moving in all directions all the time, but when the sea calmed down enough, it was safe for the divers to run on the treadmill. All our non-divers also passed the test with extremely good results – it is amasing how fit these guys are despite varying lifestyles and age groups!
In fact there is a bit of jovial competition around the VO2max tests. And the vessel has several provisions for staying active with half a basketball pitch, golf course simulator, boxing gym, table-tennis room and a darts board in addition to the two gyms.
On 9th June there was a crew change, another four of the divers agreed to participate in the project. As one of my biggest concerns has been to get enough divers to participate and to be able to do the tests as planned, I was very pleased about this.
By the 14th June, the campaign was completed and we headed back to Stavanger. Here I did a full handover to the new nurse, who would perform the tests on the batch of divers coming out of decompression on the 15th. The day after, a new team of divers arrived, and most of them agreed to participate thanks to the efforts of our crewing office in Aberdeen.
In July I will sign on again, and if all goes well, I will be done with all the sampling and diver testing by mid-July, just in time to spend Ramadhan in Stavanger. In the autumn I will analyse the blood samples and test results, and hopefuly we will be able to share some early results with the Skandi Arctic crew presenting the results to those that partcipated or otherwise have shown an interest in our work.
Working offshore has its challenges including seasickness and a working environment in constant motion. Although phone signals were patchy I managed to get in touch with my family in Algeria and tell them their Saharan girl was having a blast in the middle of the North Sea!
Fatima Zohra Kiboub is a Lead QHSE Engineer at Technip and is doing an industrial PhD with the barophysiology group at the Deparment of circulation and medical imaging (ISB) at NTNU.
Want to know more about life onboard the Skandi Arctic? Check out this video.
A recent study published in Traffic journal contributes to new understandings of the mechanisms behind bacteria-induced inflammation and septic shock. CEMIR researchers have used molecular biology approaches together with advanced imaging techniques (Fluorescence Recovery After Photobleaching, Total Internal Reflection Fluorescence microscopy and conventional confocal microscopy) to reveal new details on how bacterial products assemble a functional TLR4 – signaling complex on the surface of immune cells. The study also delineates and visualizes the mobility and transport mechanisms of the signaling complex to compartments inside immune cells where production of signaling molecules occurs.
Can dead neurons grow again in stroke patients? And, how far are the research from brain transplantation of the whole or parts of the brain?
Answer from: Ioanna Sandvig,
Research scientist at Department of Neuroscience, NTNU and Visiting research scientist, John Van Geest Centre for Brain Repair, University of Cambridge, UK
Stroke is caused either when a clot blocks a blood vessel and interrupts blood supply to the brain, or when a blood vessel breaks and bleeds into the brain. Both causes result in massive loss of neurons and also other cells in the brain. In fact, about 2 million neurons are lost for every minute that passes after the onset of stroke. As a result, many neuronal connections in a number of different brain locations are permanently lost. This is the reason why stroke patients often have severe, long-term motor and cognitive deficits.
Blogger: Bendik Lund
During treatment of childhood blood cancer, great variations in side-effects are seen – both in terms of prevalence and seriousness. Some children get more serious side-effects than others. Potentially, the diversity in the toxicity burden for individual patients could reflect the normal genetic variation between patients.
In parallel with the biotechnological development over the last 10-15 years, we have gained extensive knowledge about the normal sequence variation in DNA, which differs from person to person. This sequence variation might explain some of the differences between people, for example height, hair colour, risk of diseases and the body’s reactions to medicines (pharmacogenetics).
There are many types of DNA-variations and one of the most common ones is single nucleotide polymorphism (SNP), where one letter in our genetic code has been replaced by another letter. DNA consists of long chains of base pairs (letters, totalling around 3 billion) and a SNP occurs approximately for every 300th base pair.
We wanted to study what role the natural genetic variation plays in the development of side effects in children treated for leukaemia (cancer of the blood). The most common form of blood cancer in children is acute lymphoblastic leukaemia, and 30-40 children are diagnosed in Norway every year with this type of leukaemia. The treatment consists of chemotherapy given over a period of 2.5 years, and the survival rate today is around 85%. The treatment causes many side effects including reduced immune function and infections. In some cases, the treatment can lead to so serious side effects that the patient dies from the toxicity.
Knowledge about pharmacogenetic variation is already used in the standard treatment for acute lymphoblastic leukaemia when using the chemotherapy 6-mercaptopurine. This drug is dosed based on the patient’s SNP variants for the enzyme that metabolises 6-mercaptopurine (TPMT-genetic variants).
We have collaborated with a research group at the laboratory in Copenhagen (Bonkolab, Rigshospitalet) and, based on existing literature, around 2300 candidate genes that could be significant for children with acute lymphoblastic leukaemia have been identified. Furthermore, the group has made a cost-efficient analysis method where 34,000 genetic variants (SNPs) per patient within these genes (extended candidate gene model) are analysed. Samples from several patients can also be analysed in the same sample tube (multiplexing).
We used this method in a study where we included 69 Danish children with leukaemia and compared the gene variant pattern with clinical data for infections that occurred during the first 50 days of treatment. We identified a SNP profile which with great accuracy can predict the risk for infections in this early phase of the treatment, where many infections are life-threatening.
If these findings are confirmed in similar studies, we may in the future be able to quickly determine whether a patient has an increased risk for serious infections by taking a simple blood test. If the patient is at high risk for serious infections, the treatment could be adapted accordingly for example giving prophylactic antibiotics, or by reducing the intensity of the chemotherapy. Hopefully this will lead to less side effects and higher survival rates.
Blogger: Sjoerd Hak
The Research Council of Norway has recently awarded grants under the funding scheme Independent Basic Research Projects – Medicine, Health Sciences and Biology (FRIMEDBIO). There is tough competition for this funding nationally, and only the best projects get through. The Faculty of Medicine, NTNU, has been awarded funding for three talented young researchers, three research projects and two post docs. You can read about all these projects on the blog over the coming weeks. Sjoerd Hak received FRIMEDBIO-funding for his post doc project: “Multimodal in vivo study of nanoparticle decomposition and targeting dynamics”
In the field of nanomedicine, the use of drug loaded nanoparticles to deliver drugs to tumours is now well established (see Figure 1).
Tumour bloodvessels are very leaky as compared to healthy vasculature. When drug loaded nanoparticles are injected into the bloodstream, they can leak from the leaky tumour bloodvessels into the tumour tissue; whereas leakage from the blood vessels in healthy tissue is limited.
Exciting developments in nanotechnology have allowed for the production of a wide variety of advanced nanoparticles.
As compared to conventional therapy without nanoparticles, this results in a larger part of the injected drugs ending up in the tumour and a reduction in side effects (Figure 1B).
Although this has improved therapy for a group of cancer patients, the full potential of nanoparticles in cancer therapy remains to be explored. Exciting developments in nanotechnology have allowed for the production of a wide variety of advanced nanoparticles.
One highly interesting development is the synthesis of so-called targeted nanoparticles: Nanoparticles equipped with molecules on their surface making them specifically recognise and accumulate in tumour tissue (Figure 1C). This is a very promising approach to deliver drugs specifically to tumours and to spare healthy tissue (Figure 1 D-E).
For the development and successful application of such targeted nanoparticles, detailed studies to learn about and understand the in vivo behaviour of these novel targeted nanoparticles are essential.
For example, it is not well known how fast targeted nanoparticles accumulate in tumour tissue after injection. Moreover, it is now becoming clear that certain nanoparticles readily disintegrate upon injection into the blood, resulting in drug release in the blood. As such, the drug may be released before the tumour is reached. Hence, knowledge of nanoparticle degradation and tumour targeting rates and dynamics are crucial for successful development and application of targeted nanoparticles. However, these dynamics remain largely unstudied, which may be compounded by the fact that suitable experimental in vivo tools to do so are lacking
Ultimately, we anticipate to fine-tune our nanoparticle design and increase their value in the battle against cancer.
Over the last four years, during my recently completed PhD project, we have established the synthesis of innovative nanoparticles of which such dynamics can be quantitatively monitored. Furthermore, combining in vivo microscopy and magnetic resonance imaging, we have developed a unique experimental set-up which is highly suitable to study in vivo nanoparticle dynamics.
Over the next years, this novel experimental approach will be exploited to study degradation and targeting dynamics of our nanoparticles at an unprecedented level of detail. Importantly, this will provide general knowledge applicable to a variety of targeted therapies. Ultimately, we anticipate to fine-tune our nanoparticle design and increase their value in the battle against cancer.