By measuring the proportions of certain immune cells in the cerebrospinal fluid when diagnosing amyotrophic lateral sclerosis (ALS), it is possible to predict the disease’s speed of progression, according to a study from Karolinska Institutet published in Nature Communications.
ALS is a rare, but fatal disease that affects the nerve cells and leads to paralysis of voluntary muscles and death. This new research offers a way to predict the course of the disease in ALS patients.
Between March 2016 and March 2020, researchers collected fresh blood and cerebrospinal fluid from 89 patients in Stockholm who had recently been diagnosed with ALS, and followed-up until October 2020.
The study shows that a high proportion of so-called effector T cells are associated with a low survival rate. At the same time, a high proportion of activated regulatory T cells indicate a protective role against the rapid disease progression. The findings provide new evidence for the involvement of T cells in the course of the disease and show that certain types of effector T cells accumulate in the cerebrospinal fluid of ALS patients.
“The study could contribute to the development of new treatments that target immune cells to slow down the course of the disease,” says study first author Solmaz Yazdani, a doctoral student at the Institute of Environmental Medicine at Karolinska Institutet.
The next step in her research is to study how T cells contribute to the course of the disease.
“We have plans to collect samples from these individuals to study changes in the immune cells over time. In addition, we want to study effector T cells in more detail to understand their role in ALS.”
Researchers have developed a vaccine that blocks fentanyl’s to enter the brain, thus eliminating the dangerous synthetic opioid’s “high”. The breakthrough discovery, reported in the journal Pharmaceutics, could have major implications for the rampant problem of opioid addiction by becoming a relapse prevention agent for people trying to quit using opioids.
While Opioid Use Disorder (OUD) is treatable, studies estimate that 80% of those dependent on the drug suffer a relapse. Fentanyl is 50 times stronger than heroin and 100 times stronger than morphine. Consumption of about 2mg of fentanyl (the size of two grains of rice) is likely to be fatal depending on bodyweight. Current treatments for OUD are methadone, buprenorphine and naltrexone. Naloxone is given in opioid overdose situations and can temporarily reverse the effects of the opioids.
“We believe these findings could have a significant impact on a very serious problem plaguing society for years – opioid misuse. Our vaccine is able to generate anti-fentanyl antibodies that bind to the consumed fentanyl and prevent it from entering the brain, allowing it to be eliminated out of the body via the kidneys. Thus, the individual will not feel the euphoric effects and can ‘get back on the wagon’ to sobriety,” said lead author Colin Haile, a research associate professor of psychology at University of Houston.
No any adverse side effects from the vaccine were observed in trial animals. The team plans to start manufacturing clinical-grade vaccine in the coming months with clinical trials in humans planned soon.
Fentanyl is an especially dangerous threat because it is often added to street drugs like cocaine, methamphetamine and other opioids, such as oxycodone and hydrocodone/acetaminophen pills, and even to counterfeit benzodiazepines like Xanax. These counterfeit drugs laced with fentanyl add to the amount of fentanyl overdoses in individuals who do not ordinarily consume opioids.
“The anti-fentanyl antibodies were specific to fentanyl and a fentanyl derivative and did not cross-react with other opioids, such as morphine. That means a vaccinated person would still be able to be treated for pain relief with other opioids,” said Haile.
The vaccine tested contains an adjuvant derived from E. coli named dmLT. An adjuvant molecule boosts the immune system’s response to vaccines, a critical component for the effectiveness of anti-addiction vaccines.
Therese Kosten, professor of psychology and director of the Developmental, Cognitive & Behavioral Neuroscience program at UH, calls the new vaccine a potential “game changer.”
“Fentanyl use and overdose is a particular treatment challenge that is not adequately addressed with current medications because of its pharmacodynamics and managing acute overdose with the short-acting naloxone is not appropriately effective as multiple doses of naloxone are often needed to reverse fentanyl’s fatal effects,” said Kosten, senior author of the study.
A major UK-wide trial has found that the the oral anticoagulant apixaban does not help patients recovering from moderate and severe COVID compared to standard care – despite this approach being offered to patients.
To date, more than a thousand NHS patients hospitalised with COVID have taken part in HEAL-COVID, a platform trial that is aiming to find treatments to reduce the number who die or are readmitted following their time in hospital.
The trial’s preliminary results have shown that prescribing the oral anticoagulant Apixaban does not affect subsequent mortality or rehospitalisation of COVID over the following year (apixaban 29.1%, versus standard care 30.8%).
As well as being ineffective, anticoagulant therapy has known serious side effects, and these were experienced by participants in the trial with a small number of the 402 participants receiving apixaban discontinuing due to bleeding events.
There was also no benefit from Apixaban in terms of the number of days alive and out of hospital at day 60 after randomisation (apixaban 59 days, versus standard care 59 days).
Following these results, the trial will continue to test atorvastatin, which acts on other mechanisms of disease that are thought to be important in COVID.
Chief Investigator for the trial Professor Charlotte Summers is an intensive care specialist at Addenbrooke’s Hospital and the University of Cambridge. She said: “These first findings from HEAL-COVID show us that a blood thinning drug, commonly thought to be a useful intervention in the post-hospital phase is actually ineffective at stopping people dying or being readmitted to hospital. This finding is important because it will prevent unnecessary harm occurring to people for no benefit. It also means we must continue our search for therapies that improve longer term recovery for this devastating disease.”
HEAL-COVID enrols patients when they are discharged from hospital, following their first admission for COVID. They are randomised to a treatment and their progress tracked.
The common chemotherapy drug ifosfamide could leave a lasting toxic legacy for children and grandchildren of adolescent cancer survivors, suggests a study published online in iScience.
Researchers from Washington State University found that male rats given ifosfamide during adolescence had offspring and grand-offspring with increased incidence of disease. Other studies have shown that cancer treatments can increase patients’ chance of developing disease later in life, this is one of the first-known studies showing that susceptibility can be passed down to a third generation of unexposed offspring.
“The findings suggest that if a patient receives chemotherapy, and then later has children, that their grandchildren, and even great-grandchildren, may have an increased disease susceptibility due to their ancestors’ chemotherapy exposure,” said corresponding author Michael Skinner, a WSU biologist and corresponding author on the study.
Skinner emphasised that the findings should not dissuade cancer patients from undertaking chemotherapy since it can be a very effective treatment. Chemotherapy drugs kill cancerous cells and stop multiplication, but have many side effects, including on reproductive systems.
The researchers therefore recommend that cancer patients who plan to have children later take precautions, such as using cryopreservation to freeze sperm or ova before having chemotherapy.
In the study, researchers exposed a set of young male rats to ifosfamide over three days, mimicking a course of treatment an adolescent human cancer patient might receive. Those rats were later bred with unexposed female rats. The resulting offspring were bred again with another set of unexposed rats.
The first-generation offspring had some exposure to the chemotherapy drug since their fathers’ sperm was exposed, but researchers found greater incidence of disease in not only the first- but also the second-generation, who had no direct exposure to the drug. While there were some differences by generation and sex, the associated problems included greater incidence of kidney and testis diseases as well as delayed onset of puberty and abnormally low anxiety, indicating a lowered ability to assess risk.
The researchers also looked for epigenetic changes. Previous research has shown that exposure to toxicants, particularly during development, can create epigenetic changes that can be passed down through sperm and ova.
The results of the researchers’ analysis showed epigenetic changes in two generations linked to the chemotherapy exposure of the originally exposed rats. The fact that these changes could be seen in the grand-offspring, who had no direct exposure to the chemotherapy drug, indicates that the negative effects were passed down through epigenetic inheritance.
Skinner and colleagues at Seattle Children’s Research Institute are currently working on a human study with former adolescent cancer patients to learn more about the effects chemotherapy exposure has on fertility and disease susceptibility later in life.
A better knowledge of chemotherapy’s epigenetic shifts could also help inform patients of their likelihood of developing certain diseases, creating the possibility of earlier prevention and treatment strategies, Skinner said.
“We could potentially determine if a person’s exposure had these epigenetic shifts that could direct what diseases they’re going to develop, and what they’re going to potentially pass on to their grandchildren,” he said. “We could use epigenetics to help diagnose whether they’re going to have a susceptibility to disease.”
In many trials testing cannabis for pain relief, there is no significant difference between placebo and the active cannabinoid substance. Still, these studies receive significant media coverage regardless of the clinical outcome, according to a study published in JAMA Network Open.
“We see that cannabis studies are often described in positive terms in the media regardless of their results,” says the study’s first author Filip Gedin, postdoc researcher at Karolinska Institutet. “This is problematic and can influence expectations when it comes to the effects of cannabis therapy on pain. The greater the benefit a treatment is assumed to have, the more potential harms can be tolerated.”
The study is based on an analysis of published clinical studies in which cannabis has been compared with placebo for the treatment of clinical pain. The change in pain intensity before and after treatment were the study’s primary outcome measurement.
The analysis drew on 20 studies published up to September 2021 involving almost 1500 individuals.
No difference between cannabis and placebo
The results of the study show that pain is rated as being significantly less intense after treatment with placebo, with a moderate to large effect. The researchers also observed no difference in pain reduction between cannabis and placebo, which corroborates results from another recently published meta-analysis.
“There is a distinct and clinically relevant placebo response in studies of cannabis for pain,” says Dr Gedin.
The researchers also examined a possible connection between the magnitude of the therapeutic effect shown by the cannabis studies and the coverage they receive in the media and in academic journals. Media presence was measured through Altmetric, which is a method of evaluating mentions in the media, in blogs and on social media. Academic impact was measured in terms of citations by other researchers.
The analysis of media presence included a total of 136 news items in traditional media and in blogs and was categorised as positive, negative or neutral, depending on how the results were presented concerning the effectiveness of cannabis as a treatment for pain.
Lots of media attention
The researchers found that the cannabis studies received much greater media attention than other published studies. The coverage was substantial regardless of the magnitude of the placebo response and regardless of the therapeutic effect of cannabis. They also observed no link between the proportion of positively described news about a study and the effect it reported.
The researchers add the caveat that their study combined trials of varying designs and quality and therefore the results should be interpreted with caution.
This research was financed by Riksbankens Jubileumsfond (Karin Jensen). The researchers report no potential conflicts of interest.
