Researchers at Stellenbosch University had discovered that an overload of inflammatory molecules, literally ‘trapped’ inside insoluble microscopic blood clots, might be behind some Long COVID symptoms.
From almost the beginning of the pandemic, blood clots have been reported in COVID patients in various organs besides the lungs.
Prof Resia Pretorius, a researcher at Stellenbosch University (SU), made this finding when she began examining micro clots and their molecular content in blood samples from individuals with Long COVID. The findings were reported in Cardiovascular Diabetology.
“We found high levels of various inflammatory molecules trapped in micro clots present in the blood of individuals with Long COVID. Some of the trapped molecules contain clotting proteins such as fibrinogen, as well as alpha(2)-antiplasmin,” Prof Pretorius explains.
Alpha(2)-antiplasmin prevents blood clot breakdown, while fibrinogen is the main clotting protein. Normally, the body’s plasmin-antiplasmin system maintains a fine balance between blood clotting and fibrinolysis.
With high levels of alpha(2)-antiplasmin in the blood of COVID patients and individuals suffering from Long COVID, the body’s ability to break down blood clots is inhibited.
Dr Maré Vlok, a senior analyst in the Mass Spectrometry Unit, noticed that the blood plasma samples from individuals with acute COVID and Long COVID continued to deposit insoluble pellets at the bottom of the tubes after dilution (a process called trypsinisation).
He alerted Prof Pretorius to this, which she then investigated further, using fluorescence microscopy and proteomics analysis. This marks the first reported detection micro clots in blood samples from those with Long COVID. “Of particular interest is the simultaneous presence of persistent anomalous micro clots and a pathological fibrinolytic system,” they wrote. This implies that the plasmin and antiplasmin balance may be central to pathologies in Long COVID, and provides further evidence that COVID, and now Long COVID, have significant cardiovascular and clotting pathologies.
Further research is recommended into a regime of therapies to support clotting and fibrinolytic system function in individuals with lingering Long COVID symptoms.
Working with vascular internist and article co-author, Dr Jaco Laubscher from Mediclinic Stellenbosch, they now plan to perform the same analysis on a larger sample of patients.
Researchers have found that human cells and tissues cells tolerate many more mutations than previously thought, without impacting their function or showing the features associated with ageing.
To understand the impact of defective DNA replication on cancer risk and features associated with ageing, researchers compared DNA taken from individuals with inherited mutations in genes involved in DNA replication with DNA from individuals with normal versions of these genes. The results, published in Nature Genetics, suggest that build-up of mutations in normal cells is unlikely to be the only factor in the development of age-related disease, adding to the ongoing debate about the causes of ageing.
One model of ageing suggests that accumulation of mutations in the DNA of healthy cells results in the changes that we see as the body grows older. This model is based on the observation that mutations accumulate in normal cells throughout life, theorising that the older people having more mutations compared to younger people results in impaired function of genes and disturbs cell function, ultimately leading to diseases of old age and the visible features typically associated with ageing.
However, this new research shows that human cells and tissues can function apparently normally with many more mutations than are usually present, suggesting that ageing may not solely be due to buildup of such mutations.
DNA replication is required to duplicate the DNA in a cell ready for cell division. It involves creating an entire error-free copy of the human genome from the existing strand, and is undertaken with very high accuracy in normal healthy cells by proteins called DNA polymerases. When the DNA polymerases have a mutation, causing them to be faulty, it leads to more DNA errors, or small mutations, accumulating with each and every cell replication.
In this study, researchers applied new techniques to sequence the DNA of normal cells and tissues from patients who have inherited mutated versions of the DNA polymerase genes, POLE and POLD1.
By comparing tissue samples with unaffected individuals, they found that normal tissues from those who had a faulty DNA polymerase had elevated mutation rates. These study participants did not, however, show features of early onset ageing or age-related diseases despite having accumulated numbers of mutations that would have made them hundreds of years old in terms of their ‘mutational age’. Therefore, other than an increased risk of certain cancers, the research shows that cells can accumulate many mutations and not show features associated with ageing, challenging the current model.
Further research is therefore needed to understand the biological processes underlying ageing.
New research has found that patients undergoing active chemotherapy had a lower immune response to two doses of the COVID vaccine, although a third dose increased response.
“We wanted to make sure we understand the level of protection the COVID vaccines are offering our cancer patients, especially as restrictions were being eased and more contagious variants were starting to spread,” said Rachna Shroff, MD, MS, University of Arizona Health Sciences.
To find out, Dr Shroff and colleagues looked at 53 Cancer Center patients on immunosuppressive active cancer therapy, such as chemotherapy. They compared the immune response following the first and second dose of the Pfizer-BioNTech COVID vaccine with that of 50 healthy adults.
After two vaccine doses, most of the cancer patients showed some immune response to the vaccine in that they had produced antibodies for SARS-CoV-2.
“We were pleasantly surprised,” said Deepta Bhattacharya, PhD, professor of immunobiology in the College of Medicine – Tucson. “We looked at antibodies, B cells and T cells, which make up the body’s defense system, and found the vaccine is likely to be at least partially protective for most people on chemotherapy.”
However, this immune response was much lower than in healthy adults, and a few of the patients had no response to the COVID vaccine. This translates to less protection against SARS-CoV-2, especially the now-dominant Delta variant.
Twenty patients returned for a third shot, which boosted the immune response for most. The overall group immune response after the third shot reached levels similar to those of people who were not on chemotherapy after two doses.
New research with low doses of the anaesthetic ketamine, recently approved by the FDA for use as an antidepressant, shows the drug could provide longer-lasting relief.
Depression is often treated with selective serotonin reuptake inhibitors, or SSRIs, but they can take six weeks before symptom relief begins, and in up to 30% of people they are ineffective.
For the past two decades, however, psychiatrists have been using low doses of ketamine, normally a veterinary anaesthetic, to treat patients whose depression has not responded to other treatments. It also has hallucinogenic effects and is sometimes abused as a street drug. Its use in psychiatry was long considered “off label,” but in 2019 the U.S. Food and Drug Administration approved a nasal spray version for use as an antidepressant, followed in 2020 by expanding the approval to include patients with depression who are having suicidal thoughts or have recently tried to take their own lives or otherwise harm themselves.
The approval opened up new possibilities as well as new lines of research that may change the way psychiatrists think about depression. Dr Benjamin Brody, an assistant professor of clinical psychiatry at Cornell University is heading a programme exploring ketamine to treat the condition. “What’s so exciting about ketamine is not only that it works for people whose symptoms are not responding to traditional treatments, but it also works much more rapidly — in days or even hours,” says Dr. Brody, who developed the protocol before the spray was approved, and still prefers infusions because they allow him to tailor each dose to a patient’s weight (while the spray only comes in two pre-set doses). “For some people, ketamine really does provide almost immediate relief. That’s wonderful and very gratifying to see.”
One problem with ketamine, however, is that its positive effects wear off within weeks or months. “Another major issue,” says Dr. Brody, “is that we have so little information on the long-term effects, or what type of treatment patients will need to remain well.”
Dr Conor Liston, associate professor of neuroscience in the Feil Family Brain and Mind Research Institute, is exploring the question of how ketamine works in the long term to create more synapses in a region of the brain called the medial prefrontal cortex. The new connections seem temporary, but if they could be augmented with another treatment, a person might be permanently cured of depression.
For a study published last year in Science, Dr. Liston and his team worked with mice that exhibited depression-like behavior, as determined by their reaction to a stressful situation. A mouse that freezes more than it attempts to wriggle free, known as “motivated escape behaviour”, displays an important feature of depression. “Mice are not people, and many symptoms that we think of as core to depression — sadness, hopelessness — are hard or probably even impossible to imagine modelling in a mouse,” said Dr Liston. “But there are some things we can measure.”
Dr Liston examined the mice’s brains before administering ketamine. As predicted, lacking motivated escape behaviour was correlated with lost synapses in the medial prefrontal cortex. Just hours after one dose, the mice no longer exhibited that ‘depressed’ behaviour and their brains showed that synapses had regrown. But just like humans, depressive symptoms returned days later and the new synapses had disappeared.
Interestingly, the reduction in depressive behaviour occurred before the new synapses appeared, meaning they could not have caused the immediate relief. However, the new synapses were apparently necessary for maintaining the antidepressant effects long after the ketamine dose. If those synapses were eliminated, the mice quickly became depressed again. “We think that some kind of intervention aimed at boosting the restoration of those synapses or enhancing their survival over time could be useful for augmenting ketamine’s antidepressant effects,” said Dr. Liston, adding that it could be another drug or an intervention as simple as exercise or improved sleep, two known factors in synapse survival.
Dr Liston noted that his team’s work is just a first step and more basic science needs to be done before work involving human subjects.
Patients with psoriasis have often reported that glycerine, common in many skin lotions, is effective at combatting their psoriasis and there is now objective evidence to support their reports.
Researchers found that whether applied topically or ingested in drinking water, glycerine, or glycerol, helps calm the classic scaly, red, raised and itchy patches in their psoriasis model, Dr. Wendy Bollag, cell physiologist and skin researcher at the Medical College of Georgia and Charlie Norwood VA Medical Center and her colleagues report in the International Journal of Molecular Sciences.
The studies also provide more evidence of the different ways glycerine enables the healthy maturation of skin cells through four stages that result in a smooth, protective skin layer. Psoriasis is an immune-mediated problem that typically surfaces in young adults in which skin cells instead multiply rapidly, piling up into inflamed patches.
“We have experimental data now to show what these patients with psoriasis are reporting,” said Dr Bollag, who nearly 20 years ago first reported that glycerine, a natural alcohol and water attractor known to help the skin look better, also safely helped it function better by helping skin cells mature properly.
Dr Bollag’s early report led to many anecdotal reports from individuals and their reports ultimately led to the newly published study.
Topically, glycerine is known to have a soothing, emollient effect. But once glycerine enters skin cells through the aquaporin 3 channel, the enzyme phospholipase-D-2 converts it to the lipid phosphatidylglycerol. Phosphatidylglycerol ultimately regulates the function of keratinocytes and suppresses inflammation in the skin. Dr Bollag and team previously reported that topical application of phosphatidylglycerol reduced inflammation and raised skin patches in a mouse model of psoriasis.
For this study, they focused on its glycerin precursor, which was either applied topically or fed to mice with induced psoriasis. Either way, glycerine helped reduce development of the characteristic skin lesions, showing that glycerin works in more than one way to improve the skin condition.
Glycerine worked as an emollient even in mice lacking phospholipase-D-2. It also seems to block hydrogen peroxide in the aquaporin 3 channel. At low levels, hydrogen peroxide is a cell signaling molecule, but at high levels results in destructive oxidative stress, possibly leading to psoriasis. Topical glycerine reduced the levels of hydrogen peroxide entering skin cells. When they added glycerin and hydrogen peroxide at the same time directly to skin cells, they found that glycerin protected against the oxidative stress from hydrogen peroxide.
“Glycerol is basically outcompeting the hydrogen peroxide in getting in there and preventing it from being able to enter and increase oxidative stress,” Dr Bollag said. Glycerine could also help by maintaining the skin’s water permeability barrier.
On the other hand, when glycerin was ingested by the mice missing the phospholipase- D-2, it simply did not work, Dr Bollag said, which confirmed their earlier findings that internally anyway, glycerine pairs with the enzyme to produce the signal essential to skin cell maturation.
Some of their other most recent work is detailing more about how phosphatidylglycerol decreases inflammation.
Dr Bollag would like next steps to also include clinical trials with dermatologists and patients and is working to find a formulation scientist who can make what she thinks will be the optimal combination: glycerin and phosphatidylglycerol in the same topical cream.
The addition of phosphatidylglyerol itself, rather than just the glycerine that makes it, is essentially a backup since there is some evidence that in psoriasis the essential conversion of glycerin to phosphatidylglycerol is not optimal. Dr Bollag’s lab and others have shown reduced levels of aquaporin 3 in psoriasis, which likely means less phosphatidylgycerol, so making more glycerine available could somewhat help raise the availability of this key lipid.
She suspects that this sort of two-punch combination, could help keep early signs of psoriasis at bay and, with more advanced disease, use existing psoriasis treatments to get the skin condition under control then start applying glycerin to help keep it that way.
While its exact cause is unclear, psoriasis is an immune-mediated condition and patients have higher levels of inflammation, as well as too many skin cells being produced then maturing abnormally. The heightened inflammation also puts them at increased risk for problems like heart disease.
Biologics used to treat psoriasis work different ways to stem this overactive immune response but in addition to their high cost, can put the patient at risk for problems like serious infections and cancer. The only side effect she has seen in about 20 years of working with glycerine and the clinical and cosmetic use already out there, is sticky-feeling skin.
Individuals with a history of using cannabis have a much greater risk of developing mental health problems including anxiety and depression, as well as more severe mental illnesses, according to new research.
The findings indicate the need to emphasise the importance of general practitioners to continue enquiring about recreational drug use.
While there is extensive research linking cannabis use to severe mental illnesses such as schizophrenia and psychosis, associations are less clear between cannabis use as described in patient’s GP records and mental health problems such as anxiety.
In a new study, published in Psychological Medicine, researchers reported a strong link between general practice recorded cannabis use and mental ill health in one of the largest cohorts ever studied.
Senior author Dr Clara Humpston said: “Cannabis is often considered to be one of the ‘safer’ drugs and has also shown promise in medical therapies, leading to calls for it be legalised globally. Although we are unable to establish a direct causal relationship, our findings suggest we should continue to exercise caution since the notion of cannabis being a safe drug may well be mistaken.”
Dr Joht Singh Chandan said: “The research reaffirms the need to ensure a public health approach to recreational drug use continues to be adopted across the UK. We must continue to progress measures to improve the prevention and detection of drug use as well as implement the appropriate supportive measures in an equitable manner to prevent the secondary negative health consequences.”
Drawing on primary care data from the IQVIA Medical Research Database (IMRD-UK), analysis showed that following the first recorded use of cannabis, patients were three times more likely to develop common mental health problems such as depression and anxiety. In addition, they were almost 7 times more likely to develop severe mental illnesses such as psychosis or schizophrenia.
The dataset included records from 787 GP practices gathered between 1995 and 2018. The researchers were able to include data from 28 218 patients with a recorded exposure to cannabis. These were matched to 56 208 patients who had not been using cannabis and controlled for factors such as sex and age.
The cannabis users also had much higher rates of having a recorded history of using other drugs such as heroin, cocaine and amphetamines. The next steps will be to investigate levels of cannabis use or the potency of ingredients.
