Tag: 3/5/23

Categories : AntibioticsTags :

Common Antibiotics Could Fight Resistant Bacteria

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Photo by Myriam Zilles on Unsplash

A new test revealed that commonly available antibiotics can effectively treat antibiotic-resistant bacteria. They are not prescribed, however, because the gold-standard test predicts they will not work. The new test may improve the way antibiotics are developed, tested and prescribed – and it is openly available to all.

Published in Cell Reports Medicine, the research has significant implications in the fight against bacterial resistance by optimising the prescription and use of currently available antibiotics and enhancing the efforts to discover new ones.

Performed by UC Santa Barbara scientists, the research addressed a fundamental flaw in the healthcare paradigm for determining antibiotic resistance. It does not account for environmental conditions in the body that impact drug potency.

By simulating conditions in the body, the new test identified several effective antibiotics rejected by standard testing. Further, when the new and standard tests agreed — a nearly perfect prediction of treatment success or failure was observed.

The study required a tour de force screening of more than 500 antibiotic-bacteria combinations. The findings suggest that the standard test is incorrect ~15% of the time. And since physicians rely on this test for treatment decisions – it may lead to prescription of the wrong antibiotic.

‘People are not Petri plates’

The project was led by professor Michael Mahan and his UC Santa Barbara research team of Douglas Heithoff, Lucien Barnes and Scott Mahan, along with Santa Barbara Cottage Hospital physicians Lynn Fitzgibbons, M.D. and Jeffrey Fried, M.D., and professor John House of University of Sydney, Australia.

“People are not Petri plates – that is why antibiotics fail,” said Mahan. “Testing under conditions that mimic the body improves the accuracy by which lab tests predict drug potency.”

Physicians are aware of the flaws in the gold-standard test. When recommended antibiotics do not work, they must rely on their experience to decide on the appropriate antibiotic(s) for their patients.

This study provides a potential solution to address the disparity between antibiotics indicated by standard testing and actual patient outcomes.

“Reevaluation of FDA-approved antibiotics may be of far greater benefit than the time and cost of developing new drugs to combat antimicrobial resistance,” explained Santa Barbara Cottage Hospital physician Lynn Fitzgibbons, MD, an infectious disease physician, “potentially leading to significant life-savings and cost-savings.”

“Sepsis treatments are expensive and require long hospital stays,” explained Heithoff, “and testing and re-testing is not only time- and labour-intensive, but also leads to antibiotic resistance.”

The new test will lead to reduced costs for the healthcare industry in their efforts to identify new drugs to fight antimicrobial resistant infections.

“More accurate testing reduces the costs of drug discovery by streamlining detection of lead candidates long before expensive human clinical trials,” said professor John House of University of Sydney, a clinical veterinarian.

Jeffrey Fried, MD, a critical care physician, added: “Human clinical safety and efficacy studies will need to be conducted to assure these findings are applicable to patients with various infections and sepsis.”

Source: University of California – Santa Barbara

Categories : Gender Neurodegenerative DiseasesTags :

Sex Differences in Alzheimer’s Rates may be Caused by Stress Responses

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Photo by Ravi Patel on Unsplash

Women are about twice as likely as men to be diagnosed with Alzheimer’s disease. Some of that is age: women outlive men in most countries, and advanced age is the strongest risk factor for Alzheimer’s. But not all of it explains the excess risk.

One such factor may be stress may be one such reason. A study published in Brain shows that the effect stress has on the brain differs by sex, at least in mice. In stressful situations, levels of the Alzheimer’s protein amyloid beta rises sharply in the brains of females but not males. In addition, the researchers identified a molecular pathway that is active in brain cells from female mice but not male mice, and showed that it accounts for the divergent responses to stress.

The findings, from researchers at Washington University School of Medicine in St. Louis, add to a growing collection of evidence that sex matters in health and disease. From cancer to heart disease to arthritis, scientists have found differences between males and females that could potentially affect how men and women respond to efforts to prevent or treat chronic diseases.

“How women respond to stress versus how men respond to stress is an important area of research that has implications for not just Alzheimer’s disease but other conditions, too,” said co-corresponding author Carla M. Yuede, PhD, an associate professor of psychiatry. “In recent years, the National Institutes of Health (NIH) has prioritized understanding sex differences in medicine. Stress is one area in which you can clearly see a difference between males and females. This study shows that reducing stress may be more beneficial for women than men, in terms of lowering the risk of Alzheimer’s disease.”

Stress falls into the category of socioeconomic risk factors, along with factors such as depression and social isolation, that together account for an estimated 8% of the risk of developing Alzheimer’s. That risk calculation, however, doesn’t take sex into account. Women consistently report higher levels of stress than men, and it affects them differently.

Corresponding author John Cirrito, PhD, an associate professor of neurology; Yuede; and first author Hannah Edwards, a graduate student in Cirrito’s lab, reasoned that stress also may affect women’s brains differently than men’s, and these differences may help explain the sex imbalance in Alzheimer’s disease.

To find out, they measured levels of amyloid beta in the brains of mice every hour for 22 hours, beginning eight hours before the mice experienced stress. The experience was equally stressful for male and female mice, as measured by the levels of stress hormones in their blood. But the responses in their brains were not the same.

In female mice, amyloid beta levels rose significantly within the first two hours and stayed elevated through the end of the monitoring period. In male mice, brain amyloid levels did not change overall, although about 20% of them did show a delayed and weak rise in amyloid levels.

Further experiments revealed that the difference comes down to a cellular stress response pathway in brain cells. Stress causes the release of a hormone known as corticotropin releasing factor. Neurons from female rodents take up the stress hormone, triggering a cascade of events that results in increasing levels of amyloid beta in the brain. In contrast, neurons from male rodents lack the ability to take up the stress hormone. It is not known whether there are similar sex differences in how human neurons take up stress hormones.

“There’s a fundamental biological difference between males and females in how they respond to stress at the cellular level, in both mice and people,” Cirrito said. “We don’t think that stress is the sole factor driving the sex difference in Alzheimer’s disease. There are many other differences between men and women – in hormones, lifestyle, other diseases they have – that undoubtedly contribute in some way. But that stress is driving one aspect of this sex difference I think is very likely.”

Source: Washington University School of Medicine

Categories : Neurodegenerative DiseasesTags :

Gene Silencing Treatment Lowers Tau Proteins in Alzheimer’s Patients

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Neurons in the brain of an Alzheimer’s patient, with amyloid plaques caused by tau proteins. Credit: NIH

In a preliminary trial, a new ‘gene silencing’ treatment has been able to safely and successfully lower levels of the harmful tau protein known to cause the disease. This success, published in Nature Medicine, demonstrates that a ‘gene silencing’ approach could work in dementia and Alzheimer’s disease.

The approach uses a drug called BIIB080 (/IONIS-MAPTRx), which is an antisense oligonucleaotide (used to stop RNA producing a protein), to ‘silence’ the gene coding for the tau protein – known as the microtubule-associated protein tau (MAPT) gene. This prevents the gene from being translated into the protein in a doseable and reversible way. It also reduces production of that protein, altering the course of disease.

Further trials will be needed in larger groups of patients to determine whether this leads to clinical benefit, but the phase 1 results are the first indication that this method has a biological effect.

There are currently no treatments targeting tau. The drugs aducanumab and lecanemab – recently approved for use in some situations by the FDA – target a separate disease mechanism in AD, the accumulation of amyloid plaques.

The phase 1 trial enrolled 46 patients with an average age of 66, and looked at the safety of BIIB080, what it does in the body, and how well it targets the MAPT gene. The trial compared three doses of the drug, given by intrathecal injection (an injection into the nervous system via the spinal canal), with the placebo.

Results show that the drug was well tolerated, with all patients completing the treatment period and over 90% completing the post-treatment period.

Patients in both the treatment and placebo groups experienced either mild or moderate side effects – the most common being a headache after injection of the drug. However, no serious adverse events were seen in patients given the drug.

The research team also looked at two forms of the tau protein in the central nervous system (CNS) – a reliable indicator of disease – over the duration of the study.

They found a greater than 50% reduction in levels of total tau and phosphor tau concentration in the CNS after 24 weeks in the two treatment groups that received the highest dose of the drug.

Consultant neurologist Dr Catherine Mummery, who led the study, said: “We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations.

“But the results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow – or possibly even reverse – Alzheimer’s disease, and other diseases caused by tau accumulation in the future.”

Source: Imperial College London

Categories : Cancer GastrointestinalTags :

Higher Risk of Lymphoma in Patients Suffering from IBD

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Source: CC0

Karolinska Institutet researchers have found that the risk of developing lymphoma is slightly elevated in inflammatory bowel disease (IBD) and, in recent years has been on the rise in patients with Crohn’s disease. Publishing in Clinical Gastroenterology and Hepatology, the researchers also observed a risk increase in patients taking modern IBD drugs, which was less strong for those not taking them. Thus, the lymphoma risk could be affected by both the medication and the disease activity itself.

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic intestinal inflammation that can increase the risk of developing lymph node cancer (lymphoma), a disease that affects the immune system.  

“Previous studies of the lymphoma risk of IBD have been too small to draw reliable conclusions,” says the study’s first author Ola Olén, consultant and docent at the Department of Medicine (Solna), Karolinska Institutet. “The studies have not taken into account of important systematic errors or been representative of today’s IBD patients.”  

The present study included almost 170 000 IBD patients identified in Swedish and Danish national registries between 1969 and 2019. Compared to patients with a matched population without IBD, patients with both Crohn’s disease and ulcerative colitis had a higher risk of lymphoma. The highest risk was in patients with Crohn’s disease, the increase being driven mainly by T-cell lymphoma and aggressive B-cell lymphoma.

“We found an elevated relative risk of different types of lymphoma in both Crohn’s disease and ulcerative colitis, but we need to point out that the absolute risk is very low,” says the study’s last author Jonas F Ludvigsson, consultant and professor at Karolinska Institutet.

“The increase in risk equates to only one extra case of lymphoma in 1000 people with IBD, who were followed for ten years.”

“Both inflammation and treatment play a part”

The risk of lymphoma has increased in patients with Crohn’s disease over the past two decades, which coincides with the increasing use of immunomodulating drugs for IBD. While the highest risk of developing the cancer was observed in patients who had received these drugs, the researchers found that patients who were not on such medication were also at a higher risk of lymphoma. 

“This finding indicates that both the inflammation in itself and its treatment play a part,” says Dr Olén. “Since there’s a lot of talk about the lymphoma risk associated with immunomodulating drugs, it’s important to make it clear that also the disease and the inflammation per se seem to drive the development of lymphoma. One has to take account of this and discuss it when prescribing modern treatments where there might be a concern that they will increase the risk of lymphoma.” 

Dr Olén says the teamaims to use more detailed data to determine whether the disease itself or its treatment is more important in terms of lymphoma risk.

Source: Karolinska Institutet

Categories : Metabolic DisordersTags :

Meal Skipping, Diet Prescription Pills Least Effective Weight Loss Habits

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Photo by Andres Ayrton on Pexels

A new study in the Journal of the American Heart Association links a healthier diet and increased exercise to weight loss that reduces heart disease risk – while associating skipping meals and taking prescription diet pills with minimal weight loss, weight maintenance or weight gain.

For many in the study sample of more than 20 000, losing a “clinically significant” 5% of their body weight did not eliminate their risk factors for cardiovascular disease, results showed. In fact, the average composite score on eight risk factors for heart disease was the same across the entirety of the study population – regardless of weight loss or gain.

The study is the first to compare weight-loss strategies and results in the context of the American Heart Association’s “Life’s Essential 8,” a checklist promoting heart disease risk reduction through the pursuit of recommended metrics for body weight, blood pressure, cholesterol, blood sugar, smoking, physical activity, diet and sleep.

The Ohio State University researchers found that overall, US adults had an average score of 60 out of 100 on the Essential 8 suggesting there is plenty of room for improvement even among those whose diet and exercise behaviours helped move the needle on some metrics.

“The Life’s Essential 8 is a valuable tool that provides the core components for cardiovascular health, many of which are modifiable through behaviour change,” said senior study author Colleen Spees, associate professor of medical dietetics in the School of Health and Rehabilitation Sciences at Ohio State.

“Based on the findings in this study, we have a lot of work to do as a country,” she said. “Even though there were significant differences on several parameters between the groups, the fact remains that as a whole, adults in this country are not adopting the Life’s Essential 8 behaviours that are directly correlated with heart health.”

Data for the analysis came from 20 305 U.S. adults aged 19 or older (average age of 47) who participated in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016. Participants reported their smoking status, physical activity, average hours of sleep per night, weight history and weight loss strategy, and what they had eaten in the previous 24 hours. Health exams and lab tests measured their body mass index, blood pressure, LDL (bad) cholesterol and blood glucose.

The Ohio State researchers used the data to determine individuals’ values for Life’s Essential 8 metrics and assessed their diet quality according to the Healthy Eating Index, which gauges adherence to US Dietary Guidelines for Americans.

Of the sample, 17 465 participants had lost less than 5% of their body weight, maintained their weight or gained weight in the past year. The remaining 2840 reported intentional loss of at least 5% of their body weight in the same time frame.

“Clinically significant weight loss results in improvements in some health indices,” Spees said. “People should feel hopeful in knowing that losing just 5% of their body weight is meaningful in terms of clinical improvements. This is not a huge weight loss. It’s achievable for most, and I would hope that incentives people instead of being paralysed with a fear of failure.”

In this study, adults with clinically significant weight loss reported higher diet quality, particularly with better scores on intakes of protein, refined grains and added sugar, as well as more moderate and vigorous physical activity and lower LDL cholesterol than the group without clinically significant weight loss. On the other hand, the weight-loss group also had a higher average BMI and HbA1c blood sugar measure and fewer hours of sleep – all metrics that would bring down their composite Life’s Essential 8 score.

A greater proportion of people who did not lose at least 5% of their weight reported skipping meals or using prescription diet pills as weight-loss strategies. Additional strategies reported by this group included low-carb and liquid diets, taking laxatives or vomiting, and smoking.

“We saw that people are still gravitating to non-evidence-based approaches for weight loss, which are not sustainable. What is sustainable is changing behaviours and eating patterns,” Spees said.

Source: Ohio State University