New test method can offer safer dosages of hydroxychloroquine

News   •   Jun 01, 2020 01:00 BST

Researchers at Uppsala University and Uppsala University Hospital have developed a new method to measure levels of the medication hydroxychloroquine in patients with the rheumatic disease systemic lupus erythematosus (SLE). The analysis method may also be useful in other areas, such as in the treatment of COVID-19. The study is being published in Arthritis Research and Therapy.

Hydroxychloroquine was originally used to treat malaria but has also proven effective with SLE and rheumatoid arthritis (RA). Today it is recommended to all SLE patients since it protects against flares of the disease. Tests are now being conducted to see if it can also be used to treat COVID-19.

A disadvantage of hydroxychloroquine is its side effects which can be avoided, however, if the dosage is adjusted for each patient.

To achieve the protective effect against flares in SLE while also minimising the risk of side effects, Uppsala researchers have now developed a method that can be used in the medical care system to measure hydroxychloroquine levels in the blood of SLE patients. The method is based on high-resolution mass spectrometry and has been used at Uppsala University Hospital since December 2019.

First, the researchers went through available data on hydroxychloroquine measurements. They saw that results from measurements on whole blood, plasma and serum were not comparable with each other.

“It was shown that there were major differences between different reports, and there seemed to be very large individual differences,” says Kim Kultima, Associate Professor at the Department of Medical Sciences at Uppsala University and also active at Clinical Chemistry and Pharmacology at Uppsala University Hospital.

For this reason, his research team conducted a study together with the research team in rheumatology that compared the levels of hydroxychloroquine in plasma, serum and whole blood in SLE patients. They concluded that the levels in whole blood were about twice as high as in serum and plasma. Whole blood analyses were also the most dependable.

“One striking result, and a very important insight, was that levels in whole blood for patients prescribed the same dosage could differ by up to 15 times between individuals. This indicates a large individual variation in how the medication is metabolised.”

One problem pointed out by the study is that the services for electronic information on medicinal products in Sweden (FASS) provides concentrations of hydroxychloroquine in plasma. The researchers judge that these values provide an inaccurate and inappropriate picture for monitoring medication levels in patients.

“We also have to be very careful about drawing hasty conclusions about whether hydroxychloroquine is effective with COVID-19. What we know today is that the analysis method will hopefully lead to better data for providing the right dosages to SLE patients who are prescribed the medication.”

In collaboration with doctors at the Infectious Disease Clinic and within intensive care at Uppsala University Hospital, there are plans and preparations in place to be able to measure the levels of the medication in the blood of COVID-19 patients if the substance proves effective.

Carlsson. H. et al. Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS – Evaluation of whole blood, plasma and serum as sample matrices. Arthritis Research & Therapy. DOI: 10.1186/s13075-020-02211-1

For further information, please contact:
Kim Kultima, researcher at Department of Medical Sciences, Clinical Chemistry, Uppsala University
Telephone: +46 73 396 18 44
Email: kim.kultima@medsci.uu.se

Researchers at Uppsala University and Uppsala University Hospital have developed a new method to measure levels of the medication hydroxychloroquine in patients with the rheumatic disease systemic lupus erythematosus (SLE). The analysis method may also be useful in other areas, such as in the treatment of COVID-19. The study is being published in Arthritis Research and Therapy.

Read more »

New test method can offer safer dosages of hydroxychloroquine

Press releases   •   Jun 01, 2020 01:00 BST

Researchers at Uppsala University and Uppsala University Hospital have developed a new method to measure levels of the medication hydroxychloroquine in patients with the rheumatic disease systemic lupus erythematosus (SLE). The analysis method may also be useful in other areas, such as in the treatment of COVID-19. The study is being published in Arthritis Research and Therapy.

Hydroxychloroquine was originally used to treat malaria but has also proven effective with SLE and rheumatoid arthritis (RA). Today it is recommended to all SLE patients since it protects against flares of the disease. Tests are now being conducted to see if it can also be used to treat COVID-19.

A disadvantage of hydroxychloroquine is its side effects which can be avoided, however, if the dosage is adjusted for each patient.

To achieve the protective effect against flares in SLE while also minimising the risk of side effects, Uppsala researchers have now developed a method that can be used in the medical care system to measure hydroxychloroquine levels in the blood of SLE patients. The method is based on high-resolution mass spectrometry and has been used at Uppsala University Hospital since December 2019.

First, the researchers went through available data on hydroxychloroquine measurements. They saw that results from measurements on whole blood, plasma and serum were not comparable with each other.

“It was shown that there were major differences between different reports, and there seemed to be very large individual differences,” says Kim Kultima, Associate Professor at the Department of Medical Sciences at Uppsala University and also active at Clinical Chemistry and Pharmacology at Uppsala University Hospital.

For this reason, his research team conducted a study together with the research team in rheumatology that compared the levels of hydroxychloroquine in plasma, serum and whole blood in SLE patients. They concluded that the levels in whole blood were about twice as high as in serum and plasma. Whole blood analyses were also the most dependable.

“One striking result, and a very important insight, was that levels in whole blood for patients prescribed the same dosage could differ by up to 15 times between individuals. This indicates a large individual variation in how the medication is metabolised.”

One problem pointed out by the study is that the services for electronic information on medicinal products in Sweden (FASS) provides concentrations of hydroxychloroquine in plasma. The researchers judge that these values provide an inaccurate and inappropriate picture for monitoring medication levels in patients.

“We also have to be very careful about drawing hasty conclusions about whether hydroxychloroquine is effective with COVID-19. What we know today is that the analysis method will hopefully lead to better data for providing the right dosages to SLE patients who are prescribed the medication.”

In collaboration with doctors at the Infectious Disease Clinic and within intensive care at Uppsala University Hospital, there are plans and preparations in place to be able to measure the levels of the medication in the blood of COVID-19 patients if the substance proves effective.

Carlsson. H. et al. Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS – Evaluation of whole blood, plasma and serum as sample matrices. Arthritis Research & Therapy. DOI: 10.1186/s13075-020-02211-1

For further information, please contact:
Kim Kultima, researcher at Department of Medical Sciences, Clinical Chemistry, Uppsala University
Telephone: +46 73 396 18 44
Email: kim.kultima@medsci.uu.se

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

Researchers at Uppsala University and Uppsala University Hospital have developed a new method to measure levels of the medication hydroxychloroquine in patients with the rheumatic disease systemic lupus erythematosus (SLE). The analysis method may also be useful in other areas, such as in the treatment of COVID-19. The study is being published in Arthritis Research and Therapy.

Read more »

Cold-adapted enzymes can transform at room temperature

Press releases   •   May 26, 2020 10:00 BST

Enzymes from cold-loving organisms that live at low temperatures, close to the freezing point of water, display highly distinctive properties. In a new study published in Nature Communications, scientists at Uppsala University have used large-scale computations to explain why many cold-adapted enzymes stop functioning at around room temperature.

Enzymes are the “machines” that maintain metabolism in all living cells, but unfortunately all biochemical reactions normally stop at low temperatures. Evolution has solved this problem by developing cold-adapted enzymes in species whose internal cell temperature is the same as in the cold external environment. This applies to countless organisms, from bacteria to certain plants and cold-blooded vertebrates, such as fish that live in very cold water. These cold-adapted enzymes have special thermodynamic properties that enable them to function in freezing conditions. Evidently, they also melt at lower temperatures than ordinary enzymes; but it makes no difference if they melt at approximately 40° C, since they never need to work in such a warm environment.

However, one major unsolved enigma has been why many cold-adapted enzymes stop functioning even at around room temperature, long before they start melting. Researchers Jaka Socan, Miha Purg and Johan Åqvist have now, for the first time, succeeded in explaining this by means of extensive computer simulations.

The scientists simulated the chemical reaction in a starch-degrading enzyme from an Antarctic bacterium at various temperatures, and compared this with calculations relating to the same enzyme from an ordinary, warm-blooded pig. The Antarctic enzyme then proved to start breaking up locally even at room temperature, and this defect makes the starch molecules adhere much less well to the enzyme. This phenomenon gives rise to a maximum reaction speed at 25° C and takes place at some 15° C below the melting point. In the pig enzyme, on the other hand, the reaction speed just keeps increasing until the enzyme finally melts at roughly 60° C.

With computer calculations, it is thus possible to identify which parts of the cold-adapted enzymes give rise to their special properties.

“Both our new results and earlier ones from computer simulations of various cold-adapted enzymes, and their mutants, show that we’ve now reached a stage where one can rationally redesign enzymes to change their properties in a predictable way. This approach has long been an aim, but to date it hasn’t been able to compete with random laboratory evolution of enzymes, for which Frances Arnold was awarded the Nobel Prize in 2018,” says Johan Åqvist, Professor of Theoretical Chemistry at the Department for Cell and Molecular Biology, Uppsala University.

For further information, contact Johan Åqvist, tel. 46 70 425 0404, email Johan.Aqvist@icm.uu.se.

Reference to scientific article:
Computer simulations explain the anomalous temperature optimum in a cold-adapted enzyme, Nature Communications, DOI: 10.1038/s41467-020-16341-2

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

Enzymes from cold-loving organisms that live at low temperatures, close to the freezing point of water, display highly distinctive properties. In a new study published in Nature Communications, scientists at Uppsala University have used large-scale computations to explain why many cold-adapted enzymes stop functioning at around room temperature.

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Advanced X-ray technology tells us more about Ménière's disease

Press releases   •   May 20, 2020 08:00 BST

The organ of balance in the inner ear is surrounded by the hardest bone in the body. Using synchrotron X-rays, researchers at Uppsala University have discovered a drainage system that may be assumed to play a major role in the onset of Ménière's disease, a common and troublesome disorder. These results are published in the journal Scientific Reports.

Carl Linnaeus’s household laid the foundation for his scientific work

Press releases   •   May 20, 2020 07:00 BST

Without a wife and a well-functioning household, Carl Linnaeus would have had difficulty becoming the prominent scientist that he was. Mastering social codes, like clothing and hosting guests for dinners, was crucial for having a career in the 18th century. These are the conclusions of a recently defended thesis at Uppsala University.

​Treatment no better in clinical trials

Press releases   •   May 11, 2020 10:51 BST

Patients taking part in clinical trials do not receive better treatment than other patients. This is the conclusion of a new study led from Uppsala University and published in peer-reviewed journal BMC Cancer, which confirms the results of an earlier study from 2004.

How gene flow between species influences the evolution of Darwin’s finches

Press releases   •   May 04, 2020 15:42 BST

Despite the traditional view that species do not exchange genes by hybridisation, recent studies show that gene flow between closely related species is more common than previously thought. A team of scientists from Uppsala University and Princeton University now reports how gene flow between two species of Darwin’s finches has affected their beak morphology.

AI - a New Tool for Cardiac Diagnostics

Press releases   •   May 04, 2020 13:24 BST

Artificial intelligence (AI) may be an aid to interpreting ECG results, helping healthcare staff to diagnose diseases that affect the heart. Researchers at Uppsala University and heart specialists in Brazil have developed an AI that automatically diagnoses atrial fibrillation and five other common ECG abnormalities just as well as a cardiologist. The study has been published in Nature Communications.

An electrocardiogram (ECG) is a simple test that can be used to check the heart's rhythm and electrical activity. The results are shown on a graph that can reveal various conditions that affect the heart. The tool is routinely used in healthcare and each ECG needs to be interpreted manually by a cardiologist.

The new study demonstrates that an AI is capable of automatically diagnosing the abnormalities indicated by an ECG. The AI was initially trained on a database comprising over two million ECGs that had already been diagnosed manually. In this way, it can learn to recognise typical patterns for the six most common ECG abnormalities and then make a diagnosis of another patient with one of these conditions – with the same precision as a cardiologist.

The method is currently not ready for use in clinics and hospitals; however, the researchers believe that it offers great potential for improved cardiovascular care in low and middle-income countries where large parts of the population lack the same level of access to specialists who are able to interpret ECG results as we enjoy here in Sweden.

“This is the first result of a collaboration that we have built up over the past two years. I have great confidence that in the future this type of deep collaboration between AI researchers and medical researchers will be able to create new knowledge that can help people enjoy a better quality of life,” says Thomas Schön, professor of automatic control, who works in machine learning and AI at Uppsala University and was responsible for the technical part of the study.

The mathematical model (known as a deep artificial neural network) on which the study is based is a good example of the basic concept behind machine learning, where computers build their own model and then use it to learn to solve tasks based on collected data. The method differs from the classic method of working with a computer where the computer is manually programmed to perform a very specific task. The results for many problems have proved to be better when machine learning is used and the computer itself is allowed to identify patterns from gathered figures, texts, diagrams and images.

Antônio H. Ribeiro, Manoel H. Ribeiro, Gabriela M.M. Paixão, Derick M. Oliveira, Paulo R. Gomes, Jéssica A. Canazart, Milton P. S. Ferreira, Carl R. Andersson, Peter W. Macfarlane, Wagner Meira Jr., Thomas B. Schön, Antonio Luiz P. Ribeiro. Automatic diagnosis of the 12-lead ECG using a deep neural network. Nature Communications, 11(1760), 2020. DOI: 10.1038/s41467-020-15432-4

For further information, please contact: Thomas Schön, professor at the Department of Information Technology, Division of Systems and Control, Uppsala University
Email: thomas.schon@it.uu.se
Telephone: +46 73 593 38 87

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

Artificial intelligence (AI) may be an aid to interpreting ECG results, helping healthcare staff to diagnose diseases that affect the heart. Researchers at Uppsala University and heart specialists in Brazil have developed an AI that automatically diagnoses atrial fibrillation and five other common ECG abnormalities just as well as a cardiologist.

Read more »

Lymphatic vessels in mice and humans: alike yet different

Press releases   •   May 04, 2020 12:23 BST

In an international collaboration, researchers from Uppsala University have mapped the lymph node lymphatic vessels in mice and humans down to the level of individual cells. The results may eventually help scientists to discover new methods for strengthening the immune system against viruses and cancer. Their work has been published in the journal Frontiers of Cardiovascular Research.

The unique microenvironment of the lymph nodes plays an important role in maintaining an efficient immune system. When we have an infection, the lymph nodes swell and release activated white blood cells into the body through the lymphatic vessels. It is important to understand how these vessels work if we are to develop new drugs to improve the immune system; for example, new vaccines.

Previous research has shown that the specialised cells that make the lymphatic vessels, known as lymphatic endothelial cells, both communicate with white blood cells and actively assist in regulating the immune system. Until now, however, researchers have only understood the importance of a few of the genes that control the versatility of these cells.

Our immune system is involved in a range of different diseases, including chronic inflammatory diseases such as psoriasis, atherosclerosis and cancer. In order to study the role of the immune system in disease mechanisms, many scientists use model systems, including mice.

“By using model systems, we researchers can test the function of various genes and evaluate treatment strategies, all of which provides us with valuable knowledge. However, in order to translate findings from mouse models to humans we need a better understanding of the similarities and differences between the signalling pathways and genes that control cell function in the different species,” explains Maria Ulvmar, a researcher who led the study at Uppsala University’s Department of Immunology, Genetics and Pathology.

The research teams that conducted the study analysed the activity of genes in individual cells in mice and humans. Based on the gene activity profiles, they were able to demonstrate that both species have five distinct and similar groups of lymphatic endothelial cells in the lymph nodes, two of which were previously unknown. This discovery, complements previous published analysis of the lymphatic vessels in the lymph nodes and will help the scientific understanding of how immune cells enter and leave the lymph nodes and how their activity is regulated.

The results support the proposition that basic vessel functionality is the same in mice and humans. At the same time, researchers noted crucial differences in gene activity between the two species. This discovery is important for future research.

“This new knowledge will make it possible for my team and other researchers to focus our research on the genes expressed in humans and eventually identify new ways to strengthen the immune system against viral diseases and cancer for example. My team is currently looking at how the lymph node endothelium changes in cancer and contributes to metastases in breast cancer. This an exciting new area of research and we are looking forward to new advances in our understanding of organ-specific and immune-regulating functions of the lymphatic endothelial cells over the next few years,” says Maria Ulvmar.

The study has been conducted in collaboration with researchers from Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre in Stockholm and research teams in Finland and the United States.

Xiang M., Adrián Grosso R, Takeda A., Pan J., Bekkhus T., Brulois K., Dermadi D., Nordling S., Vanlandewijck M., Jalkanen S., Maria H. Ulvmar* and Eugene C. Butcher* (2020) A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature. Frontiers in Cardiovascular Medicine 30 April 2020. DOI:10.3389/fcvm.2020.00052
*equal contribution

For further information, please contact:
Maria Ulvmar, Researcher Department of Immunology, Genetics and Pathology, Uppsala University. Tel: +46 737 83 42 97 Email: maria.ulvmar@igp.uu.se

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

In an international collaboration, researchers from Uppsala University have mapped the lymph node lymphatic vessels in mice and humans down to the level of individual cells. The results may eventually help scientists to discover new methods for strengthening the immune system against viruses and cancer. Their work has been published in the journal Frontiers of Cardiovascular Research.

Read more »

Large differences in personality traits between patients with social anxiety disorder

Press releases   •   Apr 29, 2020 19:00 BST

Individuals with social anxiety disorder have markedly different personality traits than others. Emotional instability and introversion are hallmarks, according to a new study from Uppsala University published in PLOS ONE.

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