How antibiotics interact

It is usually difficult to predict how well drugs will work when they are combined. Sometimes, two antibiotics increase their effect and inhibit the growth of bacteria more efficiently than expected. In other cases, the combined effect is weaker. Since there are many different ways of combining drugs — such as antibiotics — it is important to be able to predict the effect of these drug combinations. A new study has found out that it is often possible to predict the outcomes of combining certain antibiotics by quantitatively characterizing how individual antibiotics work. That is the result of a joint study by Professor Tobias Bollenbach at the University of Cologne with Professor Gasper Tkacik and the doctoral researcher Bor Kavcic at the Institute of Science and Technology Austria. The paper ‘Mechanisms of drug interactions between translation-inhibiting antibiotics’ has been published in Nature Communications.

‘We wanted to find out how antibiotics that inhibit protein synthesis in bacteria work when combined with each other, and predict these effects as far as possible, using mathematical models,’ Bollenbach explained. As head of the research group ‘Biological Physics and Systems Biology’ at the University of Cologne, he explores how cells respond to drug combinations and other signals.

Bacterial ribosomes can gradually translate the DNA sequence of genes into the amino acid sequence of proteins (translation). Many antibiotics target this process and inhibit translation. Different antibiotics specifically block different steps of the translation cycle. The scientists found out that the interactions between the antibiotics are often caused by bottlenecks in the translation cycle. For example, antibiotics that inhibit the beginning and middle of the translation cycle have much weaker effects when combined.

In order to clarify the underlying mechanisms of drug interactions, the scientists created artificial translation bottlenecks that genetically mimic the effect of specific antibiotics. If such a bottleneck is located in the middle of the translation cycle, a traffic jam of ribosomes forms, which dissolves upon introducing another bottleneck at the beginning of the translation cycle. Using a combination of theoretical models from statistical physics and experiments, the scientists showed that this effect explains the drug interaction between antibiotics that block these translation steps.

Tobias Bollenbach concluded: ‘A quantitative understanding of the effect of individual antibiotics allows us to predict the effect of antibiotic combinations without having to test all possible combinations by trial and error. This finding is important because the same approach can be applied to other drugs, enabling the development of new, particularly effective drug combinations in the long term.’

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Materials provided by University of Cologne. Note: Content may be edited for style and length.

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Research shows how a diet change might help US veterans with Gulf War illness

A new study from American University shows the results from a dietary intervention in U.S. veterans suffering from Gulf War Illness, a neurological disorder in veterans who served in the Persian Gulf War from 1990 to 1991.

The veterans’ overall number of symptoms were reduced and they experienced less pain and fatigue after one month on a diet low in glutamate, which is a flavor enhancer commonly added to foods, and that also functions as an important neurotransmitter in the nervous system.

Because the symptoms of GWI are similar to those of fibromyalgia, the U.S. Department of Defense provides funding for previously tested treatments in fibromyalgia that could also help veterans suffering from GWI. The low glutamate diet was previously shown to reduce symptoms in fibromyalgia, and thus, was a candidate for this funding. There are no cures for either illness, and treatments are being sought for both to manage chronic pain. GWI is thought to be connected to nervous system dysfunction in veterans. In the Gulf War, soldiers were exposed to various neurotoxins such as chemical warfare agents, pyridostigmine bromide (PB) pills, pesticides, burning oil fields, and depleted uranium.

“Gulf War Illness is a debilitating disorder which includes widespread pain, fatigue, headaches, cognitive dysfunction, and gastrointestinal symptoms. Veterans with GWI have a reduced quality of life as compared to veterans who do not have the illness,” said AU Associate Professor of Health Studies Kathleen Holton, who explores how food additives contribute to neurological symptoms and is a member of AU’s Center for Behavioral Neuroscience. “In this study testing the low glutamate diet, the majority of veterans reported feeling better. We saw significant reductions in their overall number of symptoms and significant improvements in pain and fatigue.”

The study, published in the journal Nutrients, details the experiments in a clinical trial of 40 veterans with GWI. The study participants were randomized to either immediately start the low glutamate diet for one month, or to a control group. After completion of the one-month diet, participants were challenged with monosodium glutamate and placebo to see if symptoms returned.

The challenge with MSG versus placebo resulted in significant variability in response among participants, with some subjects worsening, while others actually improved. This suggests that while a diet low in glutamate can effectively reduce overall symptoms, pain, and fatigue in GWI, more research is needed to understand how the diet may be altering how glutamate is handled in the body, and the specific role that nutrients may play in these improvements.

The role of glutamate

Glutamate is most easily identified when it is in the form of the food additive MSG; however, it appears most commonly in American diets hidden under many other food additive names in processed foods. Americans also consume glutamate through some foods where it occurs naturally, such as soy sauce, fish sauce, aged cheeses like parmesan, seaweed, and mushrooms.

Glutamate is known to play a role in pain transmission, where it functions as an excitatory neurotransmitter in the nervous system. When there’s too much of it, it can cause disrupted signaling or kill cells, in a process called excitotoxicity. Previous research has shown that glutamate is high in pain processing areas of the brain in individuals with fibromyalgia and migraine. High concentrations of glutamate have also been linked to epilepsy, multiple sclerosis, Parkinson’s disease, ALS, cognitive dysfunction (including Alzheimer’s), and psychiatric issues such as depression, anxiety and PTSD.

In her research, Holton limits people’s exposure to glutamate, while also increasing intake of nutrients known to protect against excitotoxicity. She analyzes how diet affects cognitive function, brain wave activity, brain glutamate levels, and brain function using MRI. In the study of veterans, the low glutamate diet was made up of whole foods low in additives and high in nutrients. Holton theorizes that the increased consumption of nutrients that are protective against excitotoxicity may have led to improved handling of glutamate in the nervous system. The study and diet tested in the veterans were similar to her previous studies, where she observed improvements in those with fibromyalgia, as well as in Kenyan villagers living with chronic pain.

It will take more research to determine if reducing exposure to glutamate can be used as a treatment for chronic widespread pain and other neurological symptoms in U.S. veterans with GWI. Holton is currently pursuing funding for her next grant, which will recruit 120 veterans for a Phase 3 clinical trial to confirm the study’s findings in a larger group, and further explore the mechanisms for these effects.

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Materials provided by American University. Original written by Rebecca Basu. Note: Content may be edited for style and length.

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What happens when babies with heart defects become adults?

More than 90% of babies born with heart defects survive into adulthood. As a result, there are now more adults living with congenital heart disease than children. These adults have a chronic, lifelong condition and the European Society of Cardiology (ESC) has produced advice to give the best chance of a normal life. The guidelines are published online today in European Heart Journal,1 and on the ESC website.2

Congenital heart disease refers to any structural defect of the heart and/or great vessels (those directly connected to the heart) present at birth. Congenital heart disease affects all aspects of life, including physical and mental health, socialising, and work. Most patients are unable to exercise at the same level as their peers which, along with the awareness of having a chronic condition, affects mental wellbeing.

“Having a congenital heart disease, with a need for long-term follow-up and treatment, can also have an impact on social life, limit employment options and make it difficult to get insurance,” said Professor Helmut Baumgartner, Chairperson of the guidelines Task Force and head of Adult Congenital and Valvular Heart Disease at the University Hospital of Münster, Germany. “Guiding and supporting patients in all of these processes is an inherent part of their care.”

All adults with congenital heart disease should have at least one appointment at a specialist centre to determine how often they need to be seen. Teams at these centres should include specialist nurses, psychologists and social workers given that anxiety and depression are common concerns.

Pregnancy is contraindicated in women with certain conditions such high blood pressure in the arteries of the lungs. “Pre-conception counselling is recommended for women and men to discuss the risk of the defect in offspring and the option of foetal screening,” said Professor Julie De Backer, Chairperson of the guidelines Task Force and cardiologist and clinical geneticist at Ghent University Hospital, Belgium.

Concerning sports, recommendations are provided for each condition. Professor De Backer said: “All adults with congenital heart disease should be encouraged to exercise, taking into account the nature of the underlying defect and their own abilities.”

The guidelines state when and how to diagnose complications. This includes proactively monitoring for arrhythmias, cardiac imaging and blood tests to detect problems with heart function.

Detailed recommendations are provided on how and when to treat complications. Arrhythmias are an important cause of sickness and death and the guidelines stress the importance of correct and timely referral to a specialised treatment centre. They also list when particular treatments should be considered such as ablation (a procedure to destroy heart tissue and stop faulty electrical signals) and device implantation.

For several defects, there are new recommendations for catheter-based treatment. “Catheter-based treatment should be performed by specialists in adult congenital heart disease working within a multidisciplinary team,” said Professor Baumgartner.

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Materials provided by European Society of Cardiology. Note: Content may be edited for style and length.

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Researchers 3D print lifelike heart valve models

Researchers from the University of Minnesota, with support from Medtronic, have developed a groundbreaking process for multi-material 3D printing of lifelike models of the heart’s aortic valve and the surrounding structures that mimic the exact look and feel of a real patient.

These patient-specific organ models, which include 3D-printed soft sensor arrays integrated into the structure, are fabricated using specialized inks and a customized 3D printing process. Such models can be used in preparation for minimally invasive procedures to improve outcomes in thousands of patients worldwide.

The research is published in Science Advances, a peer-reviewed scientific journal published by the American Association for the Advancement of Science (AAAS).

The researchers 3D printed what is called the aortic root, the section of the aorta closest to and attached to the heart. The aortic root consists of the aortic valve and the openings for the coronary arteries. The aortic valve has three flaps, called leaflets, surrounded by a fibrous ring. The model also included part of the left ventricle muscle and the ascending aorta.

“Our goal with these 3D-printed models is to reduce medical risks and complications by providing patient-specific tools to help doctors understand the exact anatomical structure and mechanical properties of the specific patient’s heart,” said Michael McAlpine, a University of Minnesota mechanical engineering professor and senior researcher on the study. “Physicians can test and try the valve implants before the actual procedure. The models can also help patients better understand their own anatomy and the procedure itself.”

This organ model was specifically designed to help doctors prepare for a procedure called a Transcatheter Aortic Valve Replacement (TAVR) in which a new valve is placed inside the patient’s native aortic valve. The procedure is used to treat a condition called aortic stenosis that occurs when the heart’s aortic valve narrows and prevents the valve from opening fully, which reduces or blocks blood flow from the heart into the main artery. Aortic stenosis is one of the most common cardiovascular conditions in the elderly and affects about 2.7 million adults over the age of 75 in North America. The TAVR procedure is less invasive than open heart surgery to repair the damaged valve.

The aortic root models are made by using CT scans of the patient to match the exact shape. They are then 3D printed using specialized silicone-based inks that mechanically match the feel of real heart tissue the researchers obtained from the University of Minnesota’s Visible Heart Laboratories. Commercial printers currently on the market can 3D print the shape, but use inks that are often too rigid to match the softness of real heart tissue.

On the flip side, the specialized 3D printers at the University of Minnesota were able to mimic both the soft tissue components of the model, as well as the hard calcification on the valve flaps by printing an ink similar to spackling paste used in construction to repair drywall and plaster.

Physicians can use the models to determine the size and placement of the valve device during the procedure. Integrated sensors that are 3D printed within the model give physicians the electronic pressure feedback that can be used to guide and optimize the selection and positioning of the valve within the patient’s anatomy.

But McAlpine doesn’t see this as the end of the road for these 3D-printed models.

“As our 3D-printing techniques continue to improve and we discover new ways to integrate electronics to mimic organ function, the models themselves may be used as artificial replacement organs,” said McAlpine, who holds the Kuhrmeyer Family Chair Professorship in the University of Minnesota Department of Mechanical Engineering. “Someday maybe these ‘bionic’ organs can be as good as or better than their biological counterparts.”

In addition to McAlpine, the team included University of Minnesota researchers Ghazaleh Haghiashtiani, co-first author and a recent mechanical engineering Ph.D. graduate who now works at Seagate; Kaiyan Qiu, another co-first author and a former mechanical engineering postdoctoral researcher who is now an assistant professor at Washington State University; Jorge D. Zhingre Sanchez, a former biomedical engineering Ph.D. student who worked in the University of Minnesota’s Visible Heart Laboratories who is now a senior R&D engineer at Medtronic; Zachary J. Fuenning, a mechanical engineering graduate student; Paul A. Iaizzo, a professor of surgery in the Medical School and founding director of the U of M Visible Heart Laboratories; Priya Nair, senior scientist at Medtronic; and Sarah E. Ahlberg, director of research & technology at Medtronic.

This research was funded by Medtronic, the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health, and the Minnesota Discovery, Research, and InnoVation Economy (MnDRIVE) Initiative through the State of Minnesota. Additional support was provided by University of Minnesota Interdisciplinary Doctoral Fellowship and Doctoral Dissertation Fellowship awarded to Ghazaleh Haghiashtiani.

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A coffee and catnap keep you sharp on the nightshift, study suggests

A simple coffee and a quick catnap could be the cure for staying alert on the nightshift as new research from the University of South Australia shows that this unlikely combination can improve attention and reduce sleep inertia.

In Australia, more than 1.4 million people are employed in shift work, with more than 200,000 regularly working night or evening shifts.

Lead researcher, Dr Stephanie Centofanti from UniSA Online and the Sleep and Chronobiology Laboratory at UniSA says the finding could help counteract the kind of sleep inertia that is experienced by many shiftworkers.

“Shift workers are often chronically sleep-deprived because they have disrupted and irregular sleep patterns,” Dr Centofanti says.

“As a result, they commonly use a range of strategies to try to boost their alertness while on the nightshift, and these can include taking power naps and drinking coffee — yet it’s important to understand that there are disadvantages for both.

“Many workers nap during a night shift because they get so tired. But the downside is that they can experience ‘sleep inertia’ — that grogginess you have just after you wake up — and this can impair their performance and mood for up to an hour after their nap.

“Caffeine is also used by many people to stay awake and alert. But again, if you have too much coffee it can harm your overall sleep and health. And, if you use it to perk you up after a nap, it can take a good 20-30 minutes to kick in, so there’s a significant time delay before you feel the desired effect.

“A ‘caffeine-nap’ (or ‘caff-nap’) could be a viable alternative — by drinking a coffee before taking a nap, shiftworkers can gain the benefits of a 20-30-minute nap then the perk of the caffeine when they wake. It’s a win-win.”

The small pilot study tested the impact of 200 mg of caffeine (equivalent to 1-2 regular cups of coffee) consumed by participants just before a 3.30am 30-minute nap, comparing results with a group that took a placebo.

Participants taking a ‘caffeine-nap’ showed marked improvements in both performance and alertness, indicating the potential of a ‘caffeine-nap’ to counteract sleep grogginess.

Dr Centofanti says this shows a promising fatigue countermeasure for shift workers. She says the next move is to test the new finding on more people.

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Materials provided by University of South Australia. Note: Content may be edited for style and length.

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