Month: January 2023

New Mathematical Model for Potassium Homeostasis

Blood samples
Photo by National Cancer Institute on Unsplash

Potassium is essential to normal cellular function, helping the cardiac muscle work correctly and aids in the transmission of electrical signals within cells. A new mathematical model published in PLOS Computational Biology sheds light on the often mysterious process of potassium homeostasis.

Using existing biological data, researchers at the University of Waterloo built a mathematical model that simulates how an average person’s body regulates potassium, both in times of potassium depletion and during potassium intake. Because so many foods contain abundant potassium, the body is continually storing, deploying, and disposing of potassium to keep it in a healthy range, ie the process of potassium homeostasis. Understanding potassium homeostasis is essential in helping diagnose the source of the problem when something goes wrong, for example, when kidney disease or medication leads to dysregulation.

“Too much potassium in the body, or hyperkalaemia, can be just as dangerous as hypokalaemia, or too little,” said study lead author Melissa M. Stadt, a PhD student in applied mathematics. “Dysregulation of potassium can lead to dangerous and potentially fatal consequences.”

The model could be used for a virtual patient trial, allowing researchers to generate dozens of patients and then predict which ones would have hyper- or hypokalaemia based on different controls.

“A lot of our models are pieces of a bigger picture,” said Anita Layton, professor of applied mathematics and Canada 150 Research Chair in mathematical biology and medicine. “This model is one new and exciting piece in helping us understand how our incredibly complex internal systems work.”

The model is especially exciting because it allows scientists to test the muscle-kidney cross-talk signal hypothesis. Scientists have hypothesised that skeletal muscles, which store most of the body’s potassium, can directly signal to the kidneys to dump potassium when there’s too much stores, and vice versa. When the mathematical researchers tested the hypothesis in their model, it more accurately reflected existing biological data regarding potassium homeostasis, suggesting that muscle-kidney cross talk might be an essential piece in the puzzle of potassium regulation.

Source: University of Waterloo

Updated Bivalent Boosters Offer Better Protection against Omicron

Image by Ivan Diaz on Unsplash

A real-world effectiveness study of updated bivalent mRNA vaccines has shown that bivalent boosters are more effective than original monovalent boosters at preventing hospitalisation and death from the Omicron variant. The study was published today in The New England Journal of Medicine.

“While original COVID vaccines had been demonstrated to be safe and effective prior to the FDA’s authorisation, the Pfizer and Moderna bivalent vaccines that have been deployed in the United States since last fall were approved by the FDA for emergency use on the basis of non-clinical data for those two new vaccines,” explains Dr Danyu Lin, lead author on the study. “We were able to evaluate not only the effectiveness of the two bivalent boosters but also compare their effectiveness to that of monovalent boosters.”

Researchers at the at the University of North Carolina’s Gillings School of Global Public Health compared the incidence of severe Omicron infection resulting in hospitalisation or death for individuals aged 12 and up who received a monovalent or bivalent booster dose to those who did not. The study analysed vaccination and infection data of more than six million North Carolina residents from May to December of 2022, during which the Omicron variant’s BA.4.6/BA.5 and BQ.1/BQ.1.1 strains were predominant in the United States. Both the Pfizer and Moderna bivalent vaccines were included in the study, which also considered different age groups, previous infection status, and the number of booster doses already received.

The effectiveness of the booster was highest at roughly four weeks after administration and decreased afterward. Average effectiveness against severe infection resulting in hospitalisation or death over a three-month period was 25% for one monovalent booster dose and 62% for one bivalent booster dose.

“The increased effectiveness found in this study demonstrates why it’s important for people to protect themselves with the updated booster even if they had already gotten the original booster dose,” says Dr Zack Moore, State Epidemiologist with the North Carolina Department of Health and Human Services.

Source: University of North Carolina at Chapel Hill

Gum Infection may be a Risk Factor for Arrhythmia

Dentist checking teeth
Image by Caroline LM on Unsplash

Periodontitis can lead to a litany of dental issues from bad breath to bleeding and tooth loss, and has long been suspected to be connected to other negative health outcomes in the body. Researchers at Hiroshima University have now found evidence that periodontitis could be connected to atrial fibrosis and arrythmias.

In a study published in JACC: Clinical Electrophysiology, the team found a significant correlation between periodontitis and fibrosis (which is scarring to an appendage of the heart’s left atrium that can lead to an irregular heartbeat called atrial fibrillation) in a sample of 76 patients with cardiac disease.

“Periodontitis is associated with a long-standing inflammation, and inflammation plays a key role in atrial fibrosis progression and atrial fibrillation pathogenesis,” said first author Shunsuke Miyauchi, assistant professor with the Hiroshima University’s Health Service Center. He is also affiliated with the university’s Graduate School of Biomedical and Health Sciences. “We hypothesised that periodontitis exacerbates atrial fibrosis. This histological study of left atrial appendages aimed to clarify the relationship between clinical periodontitis status and degree of atrial fibrosis.”

The left atrial appendages were surgically removed from the patients, and the researchers analysed the tissue to establish the correlation between severity of the atrial fibrosis and severity of the gum disease. They found that the worse the periodontitis, the worse the fibrosis, suggesting that the inflammation of gums may intensify inflammation and disease in the heart.

“This study provides basic evidence that periodontitis can aggravate atrial fibrosis and can be a novel modifiable risk factor for atrial fibrillation,” said corresponding author Yukiko Nakano, professor of cardiovascular medicine in Hiroshima University’s Graduate School of Biomedical and Health Sciences.

According to Nakano, in addition to improving other risk factors such as weight, activity levels, tobacco and alcohol use, periodontal care could aid in comprehensive atrial fibrillation management. However, she cautioned that this study did not establish a causal relationship, meaning that while gum disease and atrial fibrosis degrees of severity appear connected, researchers have not found that one definitively leads to the other.

“Further evidence is required for establishing that periodontitis contributes to the atrial fibrosis in a causal manner and that periodontal care can alter fibrosis,” Nakano said. “One of our goals is to confirm that periodontitis is a modifiable risk factor for atrial fibrillation and to promote dental specialists’ participation in comprehensive atrial fibrillation management. Periodontitis is an easy modifiable target with lower cost among known atrial fibrillation risk factors. Thus, the achievement of this study series may bring benefits for many people worldwide.”

Next, the researchers said they hope to conduct future clinical trials to clarify if periodontal intervention reduces atrial fibrillation occurrence and improves patient outcomes.

Source: Hiroshima University

First Guideline for Heart Complications in Childhood Cancer Treatment

Photo by National Cancer Institute on Unsplash

Experts led by researchers from the Murdoch Children’s Research Institute have created the world’s first international clinical guidelines to help prevent and treat heart complications in children undergoing cancer treatment.

Published in JACC:Advances, the guidelines cover cardiovascular disease assessment, screening and follow-up, for paediatric patients receiving cancer treatment with new molecular therapies, immunotherapy, chemotherapy and radiotherapy.

The expert consensus has defined the high-risk group of cancer patients who should undergo a heart check-up, standardised an approach to screening and surveillance during treatment and provided recommendations to protect vulnerable young hearts.

Murdoch Children’s Associate Professor Rachel Conyers said while international guidelines to monitor poor heart side effects during therapy exist for adult patients, none were specific to children.

Associate Professor Conyers said the success of new cancer drugs had increased the chances of cardiac side effects that occur early on during therapy, sometimes within days, which warranted closer heart health surveillance and earlier monitoring.

“Recent advances in treating childhood cancer have resulted in survival rates of more than 80 percent. However, improving serious health outcomes in survivors remains an important and essential focus and prevention is key,” she said.

“Heart complications are a leading cause of death for childhood cancer survivors, second only to cancer relapse. Modern treatments including precision medicine have broadened the agents that can cause heart problems.”

Childhood cancer survivors are 15 times more likely to have heart failure and eight times more likely to have heart disease than the general population.

Associate Professor Conyers said the guidelines would be an indispensable tool for clinicians to significantly reduce the harmful impact of cancer drugs on children’s hearts.

“The guidelines are a major advance for the cardio-oncology field as before this there was no defined approach for surveillance or follow up of pediatric patients during treatment despite new therapeutics having early heart complications such as high blood pressure, abnormal heart beats and heart failure,” she said.

The Australian and New Zealand expert group consisted of pediatric and adult cardiologists and pediatric oncologists who undertook a Delphi consensus approach across 11 areas of cardio-oncology care. The Australian New Zealand Children’s Oncology Group endorsed the study with the guidelines useful for any tertiary institutes treating pediatric oncology patients or initiating cardio-oncology clinics.

Source: Murdoch Children’s Research Institute

Antibiotic Regimen may be Ineffective in TB Meningitis

Tuberculosis bacteria
Tuberculosis bacteria. Credit: CDC

Research in animal models published in Nature Communications shows that an approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Limited human studies also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.

In the study from Johns Hopkins Children’s Center, the investigators showed that the Food and Drug Administration (FDA)-approved regimen of three antibiotics – bedaquiline, pretomanid and linezolid (BPaL) – used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid struggle to cross the blood-brain barrier.

Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation.

“Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis,” explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.

In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier.

In an effort to learn more, the research team synthesised a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were many times lower than in the brains of mice.

“When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what’s happening in the brain,” says Elizabeth Tucker, MD, a study first author and an assistant professor of anaesthesiology and critical care medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”

Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment for drug-susceptible strains, a combination of the antibiotics rifampin, isoniazid and pyrazinamide. Results showed that the antibacterial effect in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the “regimen that we think works really well for MDR-TB in the lung does not work in the brain.”

In another experiment involving healthy participants, three male and three female aged 20–53 years, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers.

Similar to the work with mice, this study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. “Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis,” says study author Xueyi Chen, MD, a paediatric infectious diseases fellow, who is now studying combinations of such therapies.

Limitations included the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution.

Source: Johns Hopkins Medicine

Outdoor Play can Mitigate the Worst Effects of Kids’ Screen Time

Photo by Emily Wade on Unsplash

Children around the world are spending more and more time with screens, which is a great concern for parents and physicians alike. New research from Japan indicates that more screen time at age 2 is associated with poorer communication and daily living skills at age 4 – but playing outdoor seems to reduce some of the negative effects.

For their study, published in JAMA Pediatrics, the researchers followed 885 children from 18 months to 4 years of age. They looked at the relationship between three key features: average amount of screen time per day at age 2, amount of outdoor play at age 2 years 8 months, and neurodevelopmental outcomes at age 4: communication, daily living skills, and socialization scores according to a standardised assessment tool called Vineland Adaptive Behavior Scale-II.

“Although both communication and daily living skills were worse in 4-year-old children who had had more screen time at aged 2, outdoor play time had very different effects on these two neurodevelopmental outcomes,” explains Kenji J. Tsuchiya, Professor at Osaka University and lead author of the study. “We were surprised to find that outdoor play didn’t really alter the negative effects of screen time on communication – but it did have an effect on daily living skills.”

Specifically, almost one-fifth of the effects of screen time on daily living skills were mediated by outdoor play, meaning that increasing outdoor play time could reduce the negative effects of screen time on daily living skills by almost 20%. The researchers also found that, although it was not linked to screen time, socialisation was better in 4-year-olds who had spent more time playing outside at 2 years 8 months of age.

“Taken together, our findings indicate that optimizing screen time in young children is really important for appropriate neurodevelopment,” says Tomoko Nishimura, senior author of the study. “We also found that screen time is not related to social outcomes, and that even if screen time is relatively high, encouraging more outdoor play time might help to keep kids healthy and developing appropriately.”

These results are particularly important given the recent COVID-related lockdowns around the world, which have generally led to more screen time and less outdoor time for children. Because the use of digital devices is difficult to avoid even in very young children, further research looking at how to balance the risks and benefits of screen time in young children is eagerly awaited.

Source: Osaka University

High-fat Diets Overload the Ability to Moderate Calorie Intake

Regularly eating a high fat/calorie diet could reduce the brain’s ability to regulate calorie intake, according to a study published in The Journal of Physiology. Rat studies revealed a signalling pathway which causes a quick response to high fat/high calorie intake, reducing food and calorie intake. But continuously eating a high fat/calorie diet seems to disrupt this signalling pathway, sabotaging this short-term protection.

Senior author Dr Kirsteen Browning said, “Calorie intake seems to be regulated in the short-term by astrocytes. We found that a brief exposure (three to five days) of high fat/calorie diet has the greatest effect on astrocytes, triggering the normal signalling pathway to control the stomach. Over time, astrocytes seem to desensitise to the high fat food. Around 10–14 days of eating high fat/calorie diet, astrocytes seem to fail to react and the brain’s ability to regulate calorie intake seems to be lost. This disrupts the signalling to the stomach and delays how it empties.”

Astrocytes initially react when high fat/calorie food is ingested, triggering the release of gliotransmitters, chemicals (including glutamate and ATP) that excite nerve cells and enable normal signalling pathways to stimulate neurons that control stomach function. This ensures the stomach contracts correctly to fill and empty in response to food passing through the digestive system. When astrocytes are inhibited, the cascade is disrupted. The decrease in signalling chemicals leads to a delay in digestion because the stomach doesn’t fill and empty appropriately.

The vigorous investigation used behavioural observation to monitor food intake in rats which were fed a control or high fat/calorie diet for one, three, five or 14 days. This was combined with pharmacological and specialist genetic approaches (both in vivo and in vitro) to target distinct neural circuits, which enabled the researchers to specifically inhibit astrocytes in a particular region of the brainstem. In this way, they assessed the response of individual neurons.

Human studies will need to be carried out to confirm if the same mechanism occurs in humans. If this is the case, further testing will be required to assess if the mechanism could be safely targeted without disrupting other neural pathways.

The researchers have plans to further explore the mechanism. Dr Browning said, “We have yet to find out whether the loss of astrocyte activity and the signalling mechanism is the cause of overeating or that it occurs in response to the overeating. We are eager to find out whether it is possible to reactivate the brain’s apparent lost ability to regulate calorie intake. If this is the case, it could lead to interventions to help restore calorie regulation in humans.”

Source: The Physiological Society

Actin Filaments Act as Pipelines for Metastatic Factors

Lung cancer cells in the process of metastasising. Source: National Cancer Institute on Unsplash

When cancer cells metastasise, they have to break connections with neighbouring cells and migrate to other tissues. Both processes are promoted by signalling molecules released by the cancer cells, which thereby increase the malignancy of tumours. Researchers found that the release of these ‘prometastatic’ factors is influenced by the cellular skeleton – specifically, actin filaments. The study was published in Advanced Science.

Actin’s multiple role functions in cancer propagation

Actin filaments are part of the cell skeleton and essential for stability and motility. They form a network that dynamically builds up and gets broken down by the addition or detachment of building blocks at the filaments’ ends. These processes are precisely regulated by other molecules, such as formins. The dynamics of the actin network enable the movement of cells, for example during development or wound closure, but also that of spreading cancer cells. Actin also plays a role in the transport of substances within the cell. However, this is less well understood than that of other intracellular transport mechanisms.

The research team led by Prof Dr Robert Grosse and Dr Carsten Schwan from the University of Freiburg, now found that the actin network also enables the release of prometastatic factors, such as ANGPTL4 which is an important prometastatic factor that promotes the formation of metastases in various types of cancer. For their study, they used high-resolution microscopy to track the movement of individual transport vesicles within living cancer cells.

“We observed that ANGPTL4-loaded vesicles are conveyed to the periphery of the cell by means of dynamic and localised polymerisation of actin filaments,” says Grosse, who is a member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies at the University of Freiburg.

Transportation along actin filaments

Based on microscopic observations and genetic analyses, the scientists conclude that the vesicles’ movement is controlled by the formin-like molecule FMNL2 by initiating polymerisation (ie elongation) of actin filaments directly at the vesicle. “We already knew that increased FMNL2 activity has prometastatic effects in many types of tumours,” says Grosse. “In our current work we could now demonstrate an important underlying process and a connection to the TGFbeta signalling pathway.” According to the scientist, this knowledge could be used for tumour diagnostics or therapy. for example, by developing an antibody that indicates the presence of active FMNL2 or pharmacologically targets active, phosphorylated FMNL2.

Source: University of Freiburg

Momelotinib Trumps Standard Care in Treating Myelofibrosis

Photo by Louise Reed on Unsplash

A Phase III trial testing the targeted therapy momelotinib showed that patients with myelofibrosis had clinically significant improvement in disease-related symptoms, including anaemia and spleen enlargement.

The findings, published in The Lancet, support the use of momelotinib over the standard therapy (danazol) in treating myelofibrosis patients that were resistant, refractory or intolerant to firstline therapy, especially symptomatic patients and those with anemia.

“Current options for managing anaemia in our myelofibrosis patients provide only modest and temporary benefits, so we are excited about these findings,” said study lead Srdan Verstovsek, MD, PhD, professor of Leukemia at University of Texas. “The trial results suggest that momelotinib is safe, well-tolerated and can improve one of the most common and debilitating clinical problems for this patient population.”

Myelofibrosis is an uncommon bone marrow cancer that is part of a group of diseases known as myeloproliferative neoplasms. A hallmark of the disease is dysregulated JAK signalling, which disrupts blood cell production and leads to symptoms including an enlarged spleen and anaemia. Chronic anaemia in these patients is associated with poor prognoses.

Currently approved JAK inhibitors can improve spleen responses and other disease-related symptoms, but they also can worsen anaemia. In this trial, momelotinib improved anaemia and reduced transfusion dependency in myelofibrosis patients previously treated with a JAK inhibitor. Momelotinib, a potent ACVR1/ALK2 and JAK1/2 inhibitor, can be administered and maintained at full dose because it does not suppress bone marrow activity like other JAK inhibitors.  

The randomised Phase III MOMENTUM trial was designed to compare the clinical benefits of momelotinib to danazol, a synthetic androgen currently used to treat anaemia in symptomatic myelofibrosis patients.

The trial enrolled 195 adult patients (63% male, 37% female) from 107 research sites across 21 countries. Trial participants were randomised (2:1) to receive momelotinib plus placebo or danazol plus placebo. A significantly greater proportion of patients who received momelotinib saw benefits in their disease symptoms (25%) compared to those receiving danazol (9%).

Patients treated with momelotinib also experienced a significant reduction in their spleen size, with 25% responding after 24 weeks of therapy. Additionally, these patients required fewer blood transfusions compared to those receiving danazol.

The safety profile of momelotinib was comparable to previous clinical trials. The most common non-haematological side effects experienced by trial participants in the momelotinib group included diarrhoea, nausea, weakness and itching or irritated skin.

“If approved, momelotinib could offer an effective option for patients with myelofibrosis to improve anemia, splenomegaly and other disease-related symptoms over other approved medications so far,” Verstovsek said. “Momelotinib may also be an ideal partner for combinations with other investigational agents in development to further control myelofibrosis symptoms.”

Patient follow-up is ongoing and long-term survival continues to be monitored.

Source: University of Texas MD Anderson Cancer Center

Periods of Hypoglycaemia Worsen Progression of Diabetic Retinopathy

Credit: National Eye Institute

People with diabetes who experience periods of hypoglycaemia, a common event in those new to blood sugar management, are more likely to have worsening diabetic eye disease. Now, researchers say they have linked such low blood sugar levels with a molecular pathway that is activated in hypoxic cells in the eye.

The research, involving human and mouse eye cells and intact retinas grown in a low glucose environment in the laboratory, as well as mice with low glucose levels, was published in Cell Reports.

“Temporary episodes of low glucose happen once or twice a day in people with insulin-dependent diabetes and often among people newly diagnosed with the condition,” says Akrit Sodhi, MD, PhD, Johns Hopkins Medicine professor. Low glucose levels can also occur during sleep in people with non-insulin dependent diabetes. “Our results show that these periodic low glucose levels cause an increase in certain retinal cell proteins, resulting in an overgrowth of blood vessels and worsening diabetic eye disease,” adds Sodhi.

Up to a third of diabetic patients will develop diabetic retinopathy, which is characterised by the overgrowth of abnormal blood vessels in the retina.

Sodhi says the current study suggests that people with diabetic retinopathy may be particularly vulnerable to periods of low glucose, and keeping glucose levels stable should be an important part of glucose control.

For the study, the researchers analysed protein levels in human and mouse retinal cells and intact retinas grown in an environment of low glucose in the laboratory, as well as in mice that had occasional low blood sugar.

In human and mouse retinal cells, low glucose levels triggered a cascade of molecular changes that can lead to blood vessel overgrowth. First, the researchers saw that low glucose caused a decrease in retinal cells’ ability to break down glucose for energy.

When the researchers focused on Müller glial cells, which are supportive cells for neurons in the retina and rely primarily on glucose for energy production, they found that the cells increased the expression of the GLUT1 gene, which makes a protein that transports glucose into cells.

The researchers found that, in response to low glucose, the cells increased levels of a transcription factor, hypoxia-inducible factor (HIF)-1α. This turned on the cellular machinery, including GLUT1, needed to improve their ability to utilise available glucose, preserving the limited oxygen available for energy production by retinal neurons.

However, in hypoxic environments, as occurs in the retinas of patients with diabetic eye disease, this normal, physiologic response to low glucose triggered a flood of HIF-1α protein into the nucleus.

This resulted in an increase in the production of proteins such as VEGF and ANGPTL4, which cause the growth of abnormal, leaky blood vessels – the key culprit of vision loss in people with diabetic eye disease.

The researchers plan to study whether low glucose levels in people with diabetes may impact similar molecular pathways in other organs, such as the kidney and brain.

Sodhi says the HIF-1α pathway may serve as an effective target for developing new treatments for diabetic eye disease.

Source: Johns Hopkins Medicine