Open Sweden: ME/CFS lactate, glucose and hypoxanthine

mango

mango

Senior Member (Voting Rights)
An ad is currently being circulated in Swedish ME groups on social media, a research study led by prof Jonas Bergquist at Uppsala University that is currently recruiting.

It's a study on altered energy metabolism in ME/CFS, focusing mainly on lactate, glucose and hypoxanthine.

(I couldn't find any info about this study on the ME/CFS Collaborative Research Center at Uppsala University's website, nor on the OMF website's page on Uppsala's research that it redirects to.)

They are inviting people mainly in Västa Götaland region, who have been diagnosed with ME/CFS according to the Canadian consensus criteria, and healthy controls too.

They are offering home visits for the tests (blood tests + light physical & mental exertion challenge).

Auto-translate said:
Participants for research study sought

Research study on changes in energy metabolism in ME/CFS seeks participants

Questions and answers about the study
The Research Centre for ME/CFS Research, Department of Chemistry - Biomedical Centre, Uppsala University is conducting a study to investigate whether changes in lactate (lactic acid), glucose and hypoxanthine (a molecule that reflects oxygenation) can be measured in ME/CFS patients and controls before and after light exertion (both mental and physical). The aim of the study is to explore whether there is any difference in energy metabolism that could explain some of the symptoms that affect ME/CFS patients. Ultimately, this could lead to better diagnosis and treatment for this patient group.

Information for research participants
If you are asked to participate in the study, you have been previously diagnosed with ME/CFS according to the Canada criteria. We are particularly looking for participants who live in the Västra Götaland region as we will offer home sampling. We are also looking for healthy volunteer controls among relatives and friends of ME/CFS patients.

The study involves venous blood sampling using a peripheral venous catheter in the arm (which involves only one needle stick). Total blood volume that will be collected is 30-40 mL in 1 mL portions throughout the trial. We also want to collect small drops of capillary blood during the experiment. You will be asked to perform three mildly strenuous mental and physical activities, over the course of one day. We will also want to collect information via some simple questionnaires some day before and some day after the study and possibly collect some information from the medical record to better understand your medical history.

Your participation is completely voluntary and you can choose to withdraw at any time. If you choose not to participate or wish to discontinue your participation, you do not need to tell us why, nor will it affect your future care or treatment.

Insurance and reimbursement
Patient injury insurance applies during participation in the study, just as it does for any other healthcare treatment. You will not be reimbursed for participating.

If you (and preferably a close relative or friend) are interested in participating in the study, please contact Professor Jonas Bergquist (jonas.bergquist@kemi.uu.se) and we will send a letter of interest with a stamped reply envelope to your postal address, which you can fill in and send by post to the following address:

Attn: Professor Jonas Bergquist, Research Centre for ME/CFS Research, Department of Chemistry - Biomedical Centre, Uppsala University, Box 599, 75124 Uppsala. Mark the envelope: ME/CFS lactate

With kind regards

Professor Jonas Bergquist, MD Dr Anders Tageson, MD
Research Director and Director of the ME/CFS Centre Sampling Officer
jonas.bergquist@kemi.uu.se

Translated with www.DeepL.com/Translator (free version)
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Attachments

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I have received copies of all the documents from the Ethical Review Authority now, too :) Too many, too large to upload them all here, but feel free to ask if you want more details on something.

Ethical approval was obtained on 21 July 2021.

Other people involved in this project are: professor emeritus Ola Saugstad, Oslo, Norway (advisor) and Anders Tageson, MD (responsible for collecting the samples).
 
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Some auto-translated bits:
Project title:
Changes in lactate, glucose and hypoxanthine levels in blood from patients with myalgic encephalomyelitis (ME) during mental and light physical exertion.
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Scientific question:
Using simple biomarkers in blood, we want to see if we can identify and possibly confirm a biochemical abnormality in lactate, glucose and hypoxanthine turnover and relate these to recovery and symptoms in patients with ME. PEM and other symptoms will be monitored using standardized questionnaires (SF-36, BANS and EQ-5D5L rating scales). As two control groups, age- and gender-matched healthy individuals will be studied. The first group consists of normally physically active individuals and the second group consists of individuals who train at an elite level.

Analysis of specific lactate and glucose concentrations to monitor energy metabolism will be performed in whole blood directly in the context of the activity trials (via peripheral venous catheter PVK), while hypoxanthine as a measure of hypoxia will be analysed in venous blood plasma after being sent for analysis to the Biomedical Centre at Uppsala University
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Project description:
The aim is to recruit at least 20 well-characterized ME/CFS patients diagnosed with the CCC or ICC criteria. Women will make up two thirds of the cohort to reflect the disease population (between 60-70% of ME patients are women).

Comorbidities such as fibromyalgia and hypothyroidism may be included.

Exclusion criteria will be diseases involving endocrine (except treated hypothyroidism), cardiovascular system or respiratory problems.
In parallel, 20 age-matched healthy controls and 20 elite athletes will be recruited.

The study will be conducted at a clinic visit (patients and controls) or at the patient's home (if the patient is too ill for a clinic visit). All participants will give written informed consent.

Blood sampling of lactate, glucose and hypoxanthin will be performed before and after physical and cognitive activities, according to the following protocol:

1. Rest for 60 minutes
2. Reading exercise with standardized text.
3. Eating a simple meal
4. A 5-minute walk
5. Controls also perform a maximal heart rate exercise test

Blood sampling (1 mL venous blood via a peripheral venous catheter, PVC) will be performed before, during, immediately after and then every 5 minutes for a total of 30 minutes after exercise. Between activities the subject will rest for at least 15 minutes.

Blood samples for glucose and lactate measurement will be collected capillary and analysed directly at the time of sampling using a portable analyser.

Hypoxanthine samples will be analysed by advanced liquid chromatography - tandem mass spectrometry at the Biomedical Centre at Uppsala University. Three different symptom questionnaires (SF-36, BANS and EQ-5D5L rating scales) will be provided for each participant to complete the day before and two days after the study. The results of the bioassays and clinical data are stored in a pseudonymised database. Statistical analyses will be performed with the support of the Uppsala Clinical Research Centre.

Ethical considerations:
Ethical considerations include the burden that the physical and cognitive tests may place on patients and the possible worsening of symptoms that may follow, which could potentially last for several hours or days. In order to minimize the strain, but still enough to stress the metabolism, we choose to perform very mild exercises.

Ethical considerations include the strain that the physical and cognitive tests may place on patients and the possible worsening of symptoms that may follow, which could potentially last for several hours or days. In order to minimize the strain, but still enough to stress the metabolism, we choose to perform very mild exercises.

Significance:
The aim of this project is to gain knowledge about metabolism during exercise and its link to PEM. Results will hopefully provide important information in the search for a much-needed disease marker. In the future, such discoveries may contribute to a treatment for ME/CFS, which is currently lacking.

Study population:
The aim is to collect samples from at least 20 well-characterized (diagnosis according to CCC and ICC) ME patients, 20 matched healthy normally physically active controls and 20 elite athletes.

Demographic and clinical parameters
Individuals >18 years and <65 years, 2/3 women (to represent the patient group), comorbidities (fibromyalgia and treated hypothyroidism can be included (common), disease with other endocrine, cardiovascular or disease with pulmonary impact are exclusion criteria).
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Timetable for the different components of the project:
Bioassays from autumn 2021-2023
Statistical analysis and bioinformatics from 2021-2024
Phased publication 2021-2025

The project, including analyses and publication, is expected to be completed by 2025-12-31.
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Original project title: Förändringar av laktat, glukos och hypoxantinnivåer i blod från patienter med myalgisk encefalomyelit (ME) under mental och lätt fysisk ansträngning.
 
Grigor said:
Interesting. Thank you for sharing! Had never heard of hypoxanthine. Had it ever been tested in relation to ME?
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I don't know if it has been researched in relation to ME before. Here's what the Background section in the ethics application says:
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In September 1973, Ola Saugstad joined the Perinatal Unit at Uppsala University Hospital as a PhD student. He had just finished his medical studies in Oslo and was offered an unpaid position to work with Prof Gösta Rooth, as supervisor.

The assignment was to test whether purine metabolites could be used as indicators of neonatal asphyxia. He quickly decided to focus on the metabolite hypoxanthine.

With the help of the above professor, he developed a simple method to measure hypoxanthine in plasma, based on its oxidation to uric acid in the presence of xanthine oxidase.

The next step was to show that hypoxanthine becomes elevated after asphyxia - which it does.

When he returned to Oslo in 1974, he consequently carried out a series of animal experiments, and showed that hypoxanthine is a sensitive indicator of hypoxia from various causes.

Around 1978, this research changed direction when he first suggested that it might be harmful to combine hypoxanthine and oxygen in a post-hypoxic state, due to a explosive formation of oxygen radicals.

From 1980 onwards, he focused mainly on the pathophysiological effects of free radicals formed by Hypoxanthine - Xanthine - Oxidase system on various organ systems such as lung and perinatal circulation.

At the same time he got the idea that oxygen should not be given during reoxygenation because it can increase any damage.

In clinical trials, it was shown that the survival of newborns is significantly higher if they resuscitated with air compared to pure oxygen gas.

The 2010 International Guidelines for Neonatal Resuscitation (ILCOR 2010) changed from oxygen to air - and it has been estimated that 2 - 500,000 newborns are saved globally each year because of this change in practice.The principle of using oxygen sparingly is now being used more and more in other areas of medicine, e.g. in reoxygenation after stroke or myocardial infarction.

In 2012, Professor Ola Saugstad was awarded the Nordic Medicine Prize for this research.

Translated with www.DeepL.com/Translator (free version)
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From the Overview section of the ethics application:
Auto-translate said:
This study aims to further investigate energy dysregulation in ME/CFS by focusing on the proposed dysfunction in PDH, hypothesized to result in abnormal levels of glucose and lactate that can be measured in blood after mild exertion.

The purine hypoxanthine is a marker of hypoxia and is a breakdown product of ATP (Saugstad OD, 1988). We assume and want to investigate whether hypoxanthine may increase abnormally in ME/CFS patients both at rest and after mild exertion due to ATP depletion caused by the blocked energy metabolism at the PDH level.

The study will also investigate whether there is a association between changes in these biomarkers and patient recovery or worsening of symptoms (PEM).
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Bacckground said:
The next step was to show that hypoxanthine becomes elevated after asphyxia - which it does.
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Overview said:
The purine hypoxanthine is a marker of hypoxia and is a breakdown product of ATP (Saugstad OD, 1988). We assume and want to investigate whether hypoxanthine may increase abnormally in ME/CFS patients both at rest and after mild exertion due to ATP depletion caused by the blocked energy metabolism at the PDH level.
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So, the hypothesis is that hypoxanthine is increased.

Andy said:
Lower Hypoxanthine, and altered glucose and lactate levels, were associated with self reported PEM in this study,
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The McGregor study associated lower hypoxanthine with PEM.

Andy said:
Also, this earlier study reported lower hypoxanthine in pwME, Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in CFS, 2017, Armstrong et al
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And Andy tells us this one found lower hypoxanthine in pwME.

It's interesting. Hopefully the study will tell us more. Possibly it will take some careful stratification of participants, including determining whether they are in PEM or not.
 
mango said:
Jonas Bergquist shared some preliminary findings from this study in a TV interview today (video, 13 minutes, in Swedish).
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The programme is geofenced outside the EU/EEC so haven't watched myself but based on the English summaries in Anil's twitter thread below they found some interesting mitochondrial markers during very light physical exertion. Finding markers without having to put pwME through the whole 2-day CPET thing would be great.

But where did the claim that ME is now sometimes labelled MS-CCD (Multisystem Complex Chronic Disease) come from? Haven't we enough names? Is MS-CCD a Swedish thing?
 
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