Day: March 23, 2022

Categories : Immune System Injury & TraumaTags :

Researchers Identify a Key Regulatory Mechanism in Inflammation

On By ModernMedia
Firefighter
Source: Pixabay CC0

A newly published study has identified a key regulatory mechanism in inflammation that may lead to new targets for resolving that inflammation –and the inflammation of patients with sepsis, cancer and COVID.

In the journal PNAS, scientists reported their discovery of a regulatory pathway for immune response after infection or injury, such as burns. Dysregulation of this pathway could differentiate those who are at risk of fatal sepsis or help identify targets to resolve this unregulated inflammation.

“We are very excited about the findings in this paper and the far-reaching impacts it could have on understanding a key regulatory step in the immune response,” said co-lead author Cindy McReynolds, who holds a doctorate in pharmacology and toxicology.

In a rodent model, the research team found that the metabolites of linoleic acid formed by the enzyme, soluble epoxide hydrolase (sEH), drive damaging inflammation after injury. These metabolites, known as lipid mediators, regulate inflammation, blood pressure and pain. Drugs that inhibit the sEH enzyme and reduce inflammation could lead to better outcomes.

“Our previous work identified that these same lipid mediators were up-regulated in severe COVID infections, and we are now finding that these compounds play a role in modulating the immune response so that the body is unable to fight infection or respond properly to trauma without leading to a potentially fatal overreaction,” said Dr McReynolds.

“This dysregulation has fatal consequences in serious diseases such as COVID, cancer, sepsis, burn, where fatality rates can be as high as 40 percent in severe cases,” she said. “An understanding of these pathways can help identify patients at risk of developing serious disease or identify new therapeutic targets for treatment.”

“The immunological disbalance we see in many cases of severe burn injury, trauma and sepsis pose a huge clinical challenge as we lack the understanding of how to diagnose and treat it,” explained co-lead author Dr Christian Bergmann. “With this work, we reveal an important mechanism how immune cells are functionally disabled by sEH-derived metabolites of linoleic acid.”

“The natural compounds we are studying in this paper are metabolites of linoleic acid (LA), an essential fatty acid the body needs in very small amounts to survive and is only available through the diet,” Dr McReynolds elaborated. “At lower concentrations, these metabolites are necessary for regulating thermogenesis and heart health but promote inflammation at higher concentrations. LA is more stable and much cheaper than longer chain polyunsaturated fatty acids, so heavily processed foods have higher LA content to increase shelf-life. Additionally, agricultural practices, such as feeding animals corn-based diets, have increased LA in meats and dairy products.”

“As a result, we are consuming the highest amount of linoleic acid and have the highest recorded concentration of LA in our fatty tissue in human history,” McReynolds said. “As our bodies respond to stress or disease, we metabolise LA into the regulatory metabolites that were monitored in this paper. At higher concentrations, the immune system was unable to properly respond to infection, thereby promoting a sustained immune response. These observations are important in inflammatory-driven diseases, such as sepsis and COVID, but could also be important in understanding many of the increased chronic diseases we are seeing in our population.”

Source: UC Davis

Categories : Antibiotics UncategorizedTags :

It’s in the Mix: Certain Combinations of Pathogens Resist Antibiotics

On By ModernMedia
Pseudomonas
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr

A study has found that much higher doses of antibiotics are needed to eliminate a bacterial infection of the airways when certain other microbes are present. This helps explain why treatment often fails to treat respiratory infections in people with diseases such as cystic fibrosis.

The study’s researchers, whose findings are published in The ISME Journal, say that even a low level of one type of microbe in the airways can have a significant impact on the response of other microbes to antibiotics.

The results highlight the need to consider the interaction between different species of microbe when treating infections with antibiotics – and to adjust dosage accordingly.

“People with chronic infections often have co-infection with several pathogens, but the problem is we don’t take that into account in deciding how much of a particular antibiotic to treat them with. Our results might help explain why, in these people, the antibiotics just don’t work as well as they should,” said Thomas O’Brien, PhD candidate and co-first author.

Chronic bacterial infections such as those in the human airways are very difficult to cure using antibiotics. Although these types of infection are often associated with a single pathogenic species, the infection site is frequently co-colonised by a number of other microbes, most of which are not usually pathogenic in their own right.

Treatment options usually revolve around targeting the pathogen, and take little account of the co-habiting species. However, these treatments often fail to resolve the infection. Until now scientists have had little insight into why this is.

To get their results the team developed a simplified model of the human airways, containing artificial sputum designed to chemically resemble the real thing, packed with bacteria.

The model allowed them to grow a mixture of different microbes, including pathogens, in a stable way for weeks at a time. This is a novel approach, as usually one pathogen will rapidly outgrow the others and spoil the experiment. It enabled the researchers to replicate and study poly-microbial infections in the laboratory.

The three microbes used in the experiment were the bacteria Pseudomonas aeruginosa and Staphylococcus aureus, and the fungus Candida albicans – a combination often found in the airways of cystic fibrosis patients.

The researchers treated this microbial mix with colistin, which kills P. aeruginosa effectively. But when the other pathogens were present alongside P. aeruginosa, the antibiotic didn’t work.

“We were surprised to find that an antibiotic that we know should clear an infection of Pseudomonas effectively just didn’t work in our lab model when other bugs were present,” said Wendy Figueroa-Chavez at the University of Cambridge, joint first author of the paper.

The same effect happened when the microbial mix was treated with fusidic acid – an antibiotic that specifically targets Staphylococcus aureus, and with fluconazole, which specifically targets C. albicans.

The researchers found that significantly higher doses of each antibiotic were needed to kill bacteria when it was part of poly-microbial infection, compared to when no other pathogens were present.

“All three species-specific antibiotics were less effective against their target when three pathogens were present together,” said Professor Martin Welch at the University of Cambridge, senior author of the paper.

Currently, antibiotics are usually only lab tested against the targeted pathogen, to determine the lowest effective dose. But when the same dose is used to treat infection in a person it is often ineffective, and this study helps to explain why. The new model system will enable the effectiveness of potential new antibiotics to be tested against a mixture of microbe species together.

Poly-microbial infections are common in the airways of people with cystic fibrosis. Despite treatment with strong doses of antibiotics, these infections often persist long-term. Chronic infections of the airways in people with asthma and chronic obstructive pulmonary disorder (COPD) are also often poly-microbial.

Genetically analysing the Pseudomonas in their lab-grown mix, the researchers were able to pinpoint specific mutations that give rise to this antibiotic resistance. The mutations were found to arise more frequently when other pathogens were also present.

Comparison with the genetic code of 800 samples of Pseudomonas from around the world revealed that these mutations have also occurred in human patients who had been infected with Pseudomonas and treated with colistin.

“The problem is that as soon as you use an antibiotic to treat a microbial infection, the microbe will start to evolve resistance to that antibiotic. That’s what has happened since colistin started to be used in the early 1990’s. This is another reminder of the vital need to find new antibiotics to treat human infections,” said Prof Welch.

Source: University of Cambridge

Categories : CancerTags :

Minimally Invasive Hysterectomy Worse in Early Cervical Cancer

On By ModernMedia
Doctors and nurses performing a surgery
Photo by Piron Guillaume on Unsplash

Minimally invasive hysterectomy for patients with early cervical cancer resulted in significantly worse outcomes compared with open surgery, according a clinical trial’s final analysis, a result which confirmed initial findings.

The Laparoscopic Approach to Cervical Cancer (LACC) trial compared disease-free survival (DFS) and overall survival (OS) at 4.5-year follow-up from the initial 631 patients who were randomised to open surgery or to MIS.

In the intention-to-treat population, DFS at 4.5 years – the study’s primary outcome – was 96.0% with the open surgery approach versus 85.0% with minimally invasive surgery (MIS), with similar DFS rates of 97.3% and 86.0% in the per-protocol analysis, reported Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“When we presented the data in 2018, the recurrence rate for MIS was four times higher than for open surgery,” Dr Ramirez said at the Society of Gynecologic Oncology annual meeting. “And after completion of 4.5 years follow-up on all of the patients, it still remains the same.”

Since the initial publication of his team’s findings in 2018, said Dr Ramirez, national and international guidelines have changed their recommendations and now consider open radical hysterectomy as the new standard approach for patients with early cervical cancer. This final analysis confirms that patients with early cervical cancer “should not undergo the minimally invasive approach outside of a clinical trial,” he said.

DFS events occurred in 43 patients in the MIS arm versus 11 patients in the open surgery arm/ Additionally, the MIS arm patients had worse disease-specific survival, cumulative local/regional recurrence and overall survival.

Researchers also found that progression-free survival (PFS) was worse for MIS compared with open surgery, with 48 patients in the MIS arm experiencing events compared with 12 in the open surgery arm, consistent with the 2018 findings.

Since the initial publication of his team’s findings in 2018, said Dr Ramirez, national and international guidelines have altered their recommendations and now consider open radical hysterectomy as the new standard approach for patients with early cervical cancer. This final analysis confirms that patients with early cervical cancer “should not undergo the minimally invasive approach outside of a clinical trial,” he said.

The researchers also assessed outcomes by tumour size, conisation status, and carcinomatosis rates.

They found that 21% of MIS patients with tumours ≥ 2 cm had DFS events compared with about 5% of patients who had open surgery (HR 4.25).

Dr Ramirez emphasised that while the trial was not designed to answer the question of the effect of tumour size on surgical outcomes, “this highlights the fact that for larger tumours, there is clearly a disadvantage to minimally invasive surgery in terms of the difference in recurrence events.”

As for tumours less than 2 cm, the investigators found that no DFS events occurred among 65 patients who underwent open surgery versus seven DFS events among 75 MIS patients.

“It is important to highlight this because comments have been made that if patients have tumours less than 2cm, then perhaps it is appropriate to proceed with minimally invasive surgery,” Dr Ramirez pointed out.

Among those patients who did not have previous conisation, there were worse outcomes for those who underwent MIS. Among patients who did have a previous cone, there was no difference between the two arms.

When there were recurrences in the open surgery arm, no patients manifested with carcinomatosis versus 24% of patients in the MIS arm.

Source: MedPage Today

Categories : Mental HealthTags :

‘Huge Deficit’ in Data for Psilocybin’s Interaction with Existing Medication

On By ModernMedia
Mushroom
Photo by Timothy Dykes on Unsplash

As the US state of Oregon becomes the first to permit psilocybin in clinical use, a new systematic evidence review reveals a lack of scientific research describing the interactions between widely used psychiatric medications and psychedelics like psilocybin and MDMA. The review was published in the journal Psychopharmacology.

The scarcity of data is problematic for people believed to benefit most from psychedelics: those with mental health conditions such as depression, anxiety and post-traumatic stress disorder.

“There’s a huge deficit in the scientific literature,” said lead author Aryan Sarparast, MD, assistant professor of psychiatry at the Oregon Health and Science University. “There’s a major incongruence between the public enthusiasm and exuberance with psychedelic substances for mental health issues – and what happens when they combine with the existing mental health treatments that we have now.”

The researchers decided to conduct the evidence review because they wanted to learn more about interactions between widely prescribed medications such as antidepressants and psychedelics, including MDMA and psilocybin.

They found a total of 40 studies dating back to 1958, including 26 from randomised controlled studies, 11 case reports and three epidemiologic studies.

Only one study was found that examined how psilocybin interacts with antidepressant medications. A/Prof Sarparast also noted that all of the clinical trials were conducted with healthy volunteers who were administered a psychiatric medication and a psychedelic at the same time – clearly showing a need for further research into combining pharmaceutical medications with psilocybin.

A/Prof Sarparast said he is concerned that the lack of evidence will lead many providers to direct patients to taper off existing medications before being offered clinical psilocybin therapy. In Oregon rules are being drawn up to permit the clinical use of psilocybin products and services from next year.

Patients with mental health conditions might well benefit from psilocybin therapy, but A/Prof Sarparast said he is concerned about the implications of stopping existing psychiatric treatment in order to receive psilocybin services. Vulnerable people may end up being forced into choosing between their existing medical treatment or psilocybin services.

“That’s a very, very tough place to be,” A/Prof Sarparast said.

A considerable amount of important data exists that is not captured in a literature review related to real-world use, noted co-author Christopher Stauffer, MD, assistant professor of psychiatry in the OHSU School of Medicine and a physician-scientist at the VA Portland Health Care System.

“Psilocybin has been around in Western society since the late 1950s, before many of our psychiatric medications have existed,” A/Prof Stauffer said. “Nonetheless, people attempting to navigate Oregon’s psilocybin services in the context of ongoing psychiatric treatment should work closely with knowledgeable professionals.”

Source: Oregon Health & Science University