New research indicates that for patients with breast cancer, the cancer’s stage and receptor status can help clinicians predict whether and when cancer might recur after initial treatment. The findings are published in the journal cancer CANCER.
For the study, Heather Neuman, MD, MS, of the University of Wisconsin, and her colleagues analysed data on 8007 patients with stage I–III breast cancer who participated in nine clinical trials from 1997–2013 and received standard of care therapy.
Time to first cancer recurrence varied significantly between cancers with different receptors – including oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Within each receptor type, cancer stage influenced time to recurrence.
Risk of recurrence was highest and occurred earliest for ER−/PR−/HER2− (triple negative) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 45.5%. Risk of recurrence was lowest for ER+/PR+/HER2+ (triple positive) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 15.3%.
Based on their findings, the investigators developed follow-up recommendations by cancer stage and receptor type. For example, patients with the lowest risk should be seen by their oncology team once annually over five years, whereas those with the highest risk should be seen once every three months over five years.
“Our developed follow-up guidelines present an opportunity to personalize how we deliver breast cancer follow-up care,” said Dr Neuman. “By tailoring follow-up based on risk, we have the potential to have a strong, positive impact on both survivors and their oncology providers by improving the quality and efficiency of care.”
A phase II trial with the novel antihypertensive baxdrostat did not replicate the impressive results in a similar trial for the drug in treatment-resistant hypertension, failing to improve on placebo effect.
Deepak Bhatt, MD, MPH, of Mount Sinai Heart in New York City, presented the disappointing findings at the American College of Cardiology (ACC) annual meeting, but noted that the findings were not a complete write-off for the drug, hampered as the trial was by poor patient adherence and the confounding effect of other antihypertensives.
For baxdrostat, seated systolic blood pressure was lowered by 16.0–19.8mmHg across the doses tested, compared to 16.6mmHg for placebo, a nonsignificant difference. Diastolic blood pressure drops showed a similar pattern, even slightly favouring placebo.
HALO included 249 participants with a mean seated systolic blood pressure of 140–180 mmHg at baseline despite treatment with a stable regimen of an ACE inhibitor or one of those drugs plus a thiazide diuretic or a calcium channel blocker. They were randomised to placebo or a 0.5-, 1.0-, or 2.0-mg dose of baxdrostat for 8 weeks.
In the prior phase II BrighHTN trial, baxdrostat reduced systolic blood pressure by 11 and 8.1 mm Hg more than placebo in the two higher dose groups.
The drug, which is in a new class of highly selective aldosterone synthase inhibitors, did decrease serum aldosterone and increase plasma renin activity as expected compared with placebo in HALO.
A post hoc analysis to understand why the trial failed despite high pill-count based adherence showed that 36% of the baxdrostat patients in the highest, 2-mg dose group (20 of 54) were actually not adherent, based on plasma levels < 1% of expected.
ACC session moderator Kim Eagle, MD, of the University of Michigan in Ann Arbor wondered if the patients were flushing their pills, and Bhatt replied that these were clustered at a few sites, highlighting issues of site selection and providing patient support.
The adherence problem does not explain away the placebo effect, Eagle told MedPage Today. “The placebo effect may well be that by enrolling in a trial, the patient is also taking their other meds for hypertension. Recall that the patients were already supposed to be taking several antihypertensives.”
Nevertheless, he called it compelling that, in “patients who were taking the larger dose and who had evidence of adherence by blood levels, the drug clearly seems to work.”
Far more children and adolescents could be using drugs than admitted to in surveys, according to a new US survey using hair analysis to test for actual drug intake. Published in the peer-reviewed journal American Journal of Drug and Alcohol Abuse, the study of nearly 1300 children aged 9–13 found that, in addition to the 10% self-reporting drug use, an additional 9% had used drugs as determined by hair analysis.
The paper suggests hair analysis far outweighs the accuracy of assessing drug use compared to survey alone, and experts recommend that future research should combine both methods.
“It’s vital that we understand the factors that lead to drug use in teenagers, so that we can design targeted health initiatives to prevent children from being exposed to drugs at a young age,” says study leader Natasha Wade, an assistant professor of psychology at the University of California, San Diego.
Adolescent substance use is a serious public health issue, with 5% of US 8th graders (ages 13–14) reporting cannabis use in the last year. The numbers are even higher for alcohol and nicotine use, with 26% of 8th graders admitting to drinking and 23% to smoking nicotine in the past year. These numbers are worrying, as substance use in adolescence is linked to negative life outcomes, but they may be even higher.
To find out a multidisciplinary team of experts, led by Dr Wade, asked 1390 children whether they had taken drugs in the last year. Hair samples were then also taken so that independent tests could confirm whether recent drug-taking had taken place.
Of the children who were asked if they had taken drugs, 10% agreed that they had. Hair analyses also showed that 10% of adolescents overall tested positive for at least one drug, with 6.1% testing positive for cannabinoids, 1.9% alcohol, 1.9% amphetamines, and 1.7% cocaine.
However, the children that self-reported drug-taking were not the same as those who tested positive through hair samples. In fact, of the 136 cases that self-reported any substance use and 145 whose hair samples were positive for any drug, matches were found for only 23 cases.
Most importantly, hair drug analysis revealed an additional 9% of substance use cases over and above self-report alone, nearly doubling the number of identified substance users to 19%.
“A long-standing issue in substance use research, particularly that relating to children and adolescents, is a reliance on self-reporting despite the known limitations to the methodology. When asked, children may mis-report (unintentionally or intentionally) and say they take drugs when they don’t, or conversely deny taking drugs when they actually do,” Dr Wade adds.
“But rather than scrapping self-reporting of drug use altogether, a more accurate picture of teenage substance use can be gained by measuring both.
“Self-reporting has its own strengths, for instance young people may be more willing to disclose substance use at a low level, but are less likely to when frequent drug-taking patterns emerge.
“Conversely, hair assays are not sensitive enough to detect only one standard drink of alcohol or smoking one cannabis joint. Instead, the method is better at detecting frequent and moderate to heavy drug use.
“Combining both methodologies is therefore vital to accurately determine the levels of substance use in the teenage population.”
Commenting on the findings of their paper, the authors also add however, that it is important to note that there is a chance that some, perhaps even many, of these youth are unaware that they even used a substance, as it could have been given to them by a parent or peer or they may have simply forgotten they had used it.
Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash
When it comes to chronic infections and cancer, cytotoxic T cells play a central role in our defences. Research published in the journal Immunity has revealed that these cells can specialise into “sprinters” to fight a strong, short-term infection or into “marathon runners” for the long battle against chronic infections and cancer.
Professor Daniel Pinschewer at the Department of Biomedicine of the University of Basel led a study into understanding how cytotoxic T cells adapt to infection and cancer.
“These T cells can become specialised in two different ways: either as a kind of sprinter or as marathon runners,” explains Pinschewer. “However, the latter can also convert into sprinters at any time, in order to stamp out an infection.”
Chronic infections are a special case: the T cells are activated and a strong inflammatory response occurs at the same time. “This tends to ‘shock’ the T cells into developing into sprinters, which can only intervene effectively in the short term to remove infected cells,” says the virologist. “If all T cells behaved like that, our immune defences would break down pretty soon.”
Biological messenger counteracts the “shock”
The researchers examined how, in spite of this, the immune system is still able to provide enough T cells for the endurance race against chronic infections. According to their results, a biological messenger called interleukin-33 (IL-33) plays a key role. It allows the T cells to remain in their “marathon runner” state. “IL-33 takes away the shock of the inflammation, so to speak,” explains Dr Anna-Friederike Marx, lead author of the study.
In addition, the biological messenger causes the marathon T cells to proliferate, so that more endurance runners are available to combat the infection. “Thanks to IL-33, there are enough cytotoxic T cells around for the long haul that can still pull off a final sprint after their marathon,” says Marx.
The findings could help improve the treatment of chronic infections such as hepatitis C. It is conceivable that IL-33 could be administered to support an effective immune response. Thinking along the same lines, IL-33 could be one key to improving cancer immunotherapy, to enable T cells to wage an efficient and long-lasting offensive against tumour cells.
A new thesis by Karolinska Institutet student Tessa Schillemans has found that exposure persistent environmental pollutants did not increase biomarkers of cardiovascular disease risk – rather, exposure reduced them, raising further questions on their complex interactions with the environment and within the human body.
What is the thesis about? The thesis is about a group of environmental pollutants called per- and polyfluoroalkyl substances (PFAS), also called “forever-chemicals”. Since we all are exposed and their chemical structure resembles that of fatty acids, we wanted to investigate whether exposure to PFAS associated with increased risk of cardiovascular disease. Additionally, we also explored if we could gain insight in potential underlying molecular pathways by linking PFAS exposure to biological molecules in the blood.
Can you tell us about some interesting results? We found no evidence that PFAS was linked to increased risk of cardiovascular disease in the general population. If anything, rather the opposite – which also deserves careful consideration. We did observe associations with higher cholesterol, lower triglycerides and with lipid metabolism intermediates, which all point towards potential perturbations in lipid metabolism.
What further research is needed in the area? It is essential to fully understand any adverse consequences that PFAS may have, since they are omnipresent and persistent. Thus, epidemiological studies involving other outcomes and vulnerable subgroups (such as pregnant women and children) should also be performed, as disturbances in lipid metabolism could impact other physiological processes. For a deeper mechanistic understanding, integration of data from different biological systems (genome, epigenome, transcriptome, proteome, metabolome) in human and experimental settings would be optimal. Additionally, since humans are exposed to many different chemicals simultaneously and these could interact with each other, there is a need for studies that investigate multiple exposures at the same time (exposome studies).
Bempedoic acid, a new cholesterol-lowering drug, has the potential to be an effective substitute for patients who can’t tolerate statins. Bempedoic acid is an ATP citrate lyase inhibitor that reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events. Its effects on cardiovascular outcomes were uncertain, so researchers used a double-blind, randomised, placebo-controlled trial to determine outcomes on a variety of cardiovascular measures in statins-intolerant patients.
The study, published in the New England Journal of Medicine, recruited patients aged 18–85 years at increased cardiovascular risk and unable or unwilling to take statins due to adverse effects. Patients were first tested with placebo over a 4-week run-in period, and were not randomised if they experience unacceptable adverse effects or if adherence was less than 80%. The 13 970 patients who successfully completed run-in were randomised to receive bempedoic acid 180mg orally per day or matching placebo.
The mean LDL cholesterol level at baseline was 139.0mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2mg/dL; the observed difference in the percent reductions was 21.1 percentage points in favour of bempedoic acid.
Compared to placebo, risk of fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause after significantly were lower by 13%, after a median of 40.6 months of follow-up. The risk of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction was 15% lower with bempedoic acid than with placebo, and the risks of fatal or nonfatal myocardial infarction and coronary revascularisation were 23% lower and 19% lower, respectively.
The researchers noted that the LDL-cholesterol lowering effects were similar in magnitude and predicted reduction in cardiovascular risks to that observed with statins. In addition, bempedoic acid did not increase glycated haemoglobin levels or the incidence of new-onset diabetes, unlike statins. Due to the demonstrated benefits, those taking placebo were offered the chance to transition to taking bempedoic acid.
A trial limitation was that it only included patients with statins intolerance, and who therefore had higher LDL cholesterol levels at baseline.
Being overweight in childhood and in early adulthood are discrete risk factors for blood clots (thrombi) later in life, according to a study using school health care and military service records, according to a study published in the Journal of Internal Medicine.
The association between obesity and blood clots is already established. However, to date it has been unclear how much influence a raised BMI in childhood and puberty exerts. Thrombi usually arise in the legs, often starting in a blood vessel in the calf. Swelling, pain and redness are common symptoms. Though easily treated if caught early, they can result pulmonary embolism may be life-threatening.
The present study comprises 37 672 men in Sweden, born between 1945 and 1961. It is based on information about height, weight, and BMI from the men’s records, first from school health care services (at the age of 8 years) and, second, from medical examinations on enrolment in the Armed Services (at age 20), along with register data on any blood clots up to age 62 on average.
Distinctly elevated thrombus risk
The results showed that BMI at both ages 8 and 20, independently of each other, can be linked to venous blood clots. These may occur in, for example, the leg (deep vein thrombosis, DVT) or the lung (pulmonary embolism).
In adulthood, two groups were found to be at a significantly increased risk of venous thrombi. The first was individuals who had been overweight both as children and as young adults, while the second was composed of those whose weight in childhood was normal and who became overweight only in early adulthood.
Moreover, being overweight in both childhood and young adulthood was found to raise the risk of arterial thrombi – clots resulting from constricted blood vessels with fatty deposits and inflammation. Since there were few cases of arterial blood clots in the study, however, further studies are needed to confirm these findings. All comparisons in the study were made with the control group, whose weight was normal at both 8 and 20 years of age.
Overweight in puberty an important factor
The first and corresponding author of the study is Lina Lilja, a doctoral student at Sahlgrenska Academy, University of Gothenburg, and paediatrician. At the time of the study, she worked at the Kungshöjd paediatric clinic in Gothenburg. Today, she is a senior physician in child health care in Region Västra Götaland.
“Our study shows that both overweight in childhood and overweight in young adulthood increase the risk of venous blood clots later in life. The latter, overweight when the men were young adults, proved to be a more influential factor than overweight when they were children,” Lilja notes.
The study includes data from the BMI Epidemiology Study (BEST) in Gothenburg, a population study, and from Swedish national registers.
Regular physical activity can improve young adolescents’ mental health and help with behavioural difficulties, suggests research published in Mental Health and Physical Activity. Investigators found that engaging in regular moderate to vigorous physical activity at age 11 was associated with better mental health between the ages of 11 and 13.
Physical activity was also associated with reduced hyperactivity and behavioural problems, such as loss of temper, fighting with other children, lying, and stealing, in young people.
Researchers from the Universities of Edinburgh, Strathclyde, Bristol, and Georgia in the United States explored data from the Children of the 90s study (also known as the Avon Longitudinal Study of Parents and Children; ALSPAC). They looked at the levels of physical activity of 4755 11-year-olds which was measured using devices.
The devices recorded levels of moderate physical activity, typically defined as brisk walking or cycling, as well as vigorous activity which boosts heart rate and breathing, such as aerobic dancing, jogging or swimming.
The young people and their parents reported on their levels of depressive symptoms from age 11 and at age 13 years. Participants’ parents and teachers were also quizzed about the young people’s general behaviour and emotional difficulties.
In analysing the impact of moderate to vigorous exercise on the young people’s mental health and behaviour, the team also considered factors such as age, sex and socio-economic status.
They found that higher levels of moderate or intense physical activity had a small but detectable association with decreases in depressive symptoms and emotional difficulties.
Regular exercise had a small but detectable association with reduced behavioural problems, even after controlling for other possible influences, the study found.
The findings suggest regular moderate and intense physical activity may have a small protective influence on mental health in early adolescence, researchers say.
Dr Josie Booth, of the University of Edinburgh’s Moray House School of Education and Sport, said: “This study adds to the increasing evidence base about how important physical activity is for all aspects of young people’s development – it can help them feel better, and do better at school. Supporting young people to lead healthy active lives should be prioritised.”
Researchers say the study is the first to offer such a comprehensive approach to examining mental health and exercise in young people.
Professor John Reilly, at the University of Strathclyde, said: “While it might seem obvious that physical activity improves mental health the evidence for such a benefit in children and young people has been scarce, so the study findings are important. The findings are also important because levels of moderate-to-vigorous intensity activity globally are so low in pre-teens globally – less than a third achieve the 60 minutes per day recommended by the WHO and UK Health Departments.”
The study is a long-term health-research project that enrolled more than 14 000 pregnant women in 1991 and 1992.
Children of the 90s has been following the health and development of the parents and their children in detail and is currently recruiting the children and the siblings of the original children into the study. It receives core funding from the Medical Research Council, the Wellcome Trust and the University of Bristol.
Scientific evidence that supports vaping as an additional approach to tackle smoking-related morbidity and mortality is fast growing. The time is ripe for decisionmakers to embrace tobacco harm reduction and to steer away from precautionary principle-based tobacco control policies. This is according to Dr Riccardo Polosa, Founder of the Centre of Excellence for the Acceleration of Harm Reduction (CoEHAR) and Professor of Internal Medicine of the University of Catania, Italy.
Towards the end of 2022, the South African Tobacco Products and Electronic Delivery Systems Control Bill was officially introduced into parliament by the Minister of Health. Now, in the coming months, it will be discussed and possibly amended by a portfolio committee.
With this Bill lumping Electronic Nicotine Delivery Systems (ENDS, i.e. e-cigarettes and vapes) in the same category as smoking, Kurt Yeo, co-founder of consumer advocacy group Vaping Saved My Life (VSML), explains that it is essential for those involved in this process to consider the mounting scientific evidence demonstrating that vaping is far less harmful than tobacco smoking and is an effective way to support smokers seeking less risky alternatives and/or wanting to quit.
Dr Colin Mendelsohn is an Australian academic, researcher and clinician, who has helped smokers quit for over 30 years, says that vaping nicotine is a more effective quitting aid than nicotine replacement products such as patches and gums and is the most popular aid for quitting or reducing smoking globally. “It has the potential to save the lives of hundreds of thousands of South African smokers and prevent untold disease and suffering.”
He adds that vaping has been estimated to cause no more than 5% of the harm from smoking. “While the long-term effects have not yet been established, e-cigarettes are certain to be far less harmful than smoking. Vaping carries only a small fraction of the risk of tobacco smoking and is an effective quitting aid or long-term safer substitute for smoking. Vaping should be easily accessible to help adult smokers to quit deadly cigarettes.”
Dr Polosa highlights that decisionmakers and the public should also beware of many flawed articles scientific and fake news that are propagating ‘findings’ of potential harms, thus feeding the counter-narrative that e-cigarettes are ‘not as safe as promoted’. “Proliferation of poor-quality science and fake news need to be actively contrasted by good quality science and by correct information/education.”
The proof is in the numbers
“Countries which have supported vaping such as the United Kingdom and New Zealand have had accelerated declines in smoking rates,” explains Dr Mendelsohn. “For example, in New Zealand the national adult smoking rate fell by an unprecedented 33% in the two years between 2020 and 2022 after vaping was legalised.”
Illustrating this point further, Dr Polosa says that according to the same national surveys used for reporting smoking prevalence to the World Health Organization (WHO), these countries show faster declines in smoking prevalence compared with neighbouring countries with lower uptake of these alternatives. “In Sweden and Norway, eradication of smoking is now almost a reality with a daily smoking prevalence among Norwegian and Swedish youth close to zero (1% and 3%, respectively). Widespread diffusion of e-cigarettes in New Zealand and the United States is also contributing to the historical acceleration in the downward trend in daily prevalence of smoking among young people (1.3% and 1.9%, respectively).”
Regulation is essential, but the proposed Bill is deeply flawed
When it comes to regulation, Dr Polosa asserts that vaping and smoking are completely different animals. “Smoking kills. Vaping does not.”
Therefore, to regulate vaping in the same way as smoking does not make any sense, says Dr Polosa. “Doing so denies smokers access to much lower risk products. Rather, the South African government should table a risk-proportionate approach where the main regulatory levers are applied differentially.”
“This means that the most stringent and restrictive regulation would be applied to the most harmful products: tobacco cigarettes. Regulation of the smoke-free alternatives would focus on consumer protection (i.e., benefits to the consumer) and control of uptake by adolescents in a way that does not cause significant harm to adult smokers. This would meet the demands of people who cannot or do not wish to quit completely, but with much less cancer, cardiovascular and respiratory disease as a result,” Dr Polosa explains.
Dr Mendelsohn agrees and says that the preferred regulatory model is for nicotine liquids for vaping to be sold as adult consumer products from licensed premises, with strict age verification, like cigarettes and alcohol. “Regulation of e-cigarettes should be proportionate to risk and a light touch approach is more appropriate. A balanced regulatory model is needed which allows adult smokers easy access to regulated vaping products while restricting access to underage users. The current proposals will restrict adult smokers’ access to an effective quitting aid which can save lives and prevent smoking-related illness.”
“A precautionary approach to prevent the use of much less harmful smoke-free products is unjustified in the face of the massive burden of smoked tobacco products, which are widely available. This principle requires policymakers to compare the risks of introducing a product with the risks of delaying its introduction. In the case of vaping, the relatively small risks of harm will be outweighed by the far more substantial harms from delaying access to current smokers,” Dr Mendelsohn explains.
He points out that harsh restrictions on the sale and marketing of electronic cigarettes will have negative unintended consequences and will lead to black market sales of unregulated products to both adults and children. “The public health goal should be to encourage smokers who are unable to quit to switch to vaping, a far safer alternative.”
Yeo concludes by saying: “With the Bill aiming to reduce the incidence of tobacco-related illness, disability and death, regulations should be drawn up based on all available research and case studies to ensure South Africa’s smokers are truly helped.”
A new study details the step-by-step cascade that allows bacteria to break through the brain’s protective layers, the meninges, and cause meningitis, a highly fatal disease. Published inNature, the mouse-based research shows that bacteria exploit nerve cells in the meninges to suppress the immune response and allow the infection to spread into the brain.
“We’ve identified a neuroimmune axis at the protective borders of the brain that is hijacked by bacteria to cause infection – a clever manoeuvre that ensures bacterial survival and leads to widespread disease,” said study senior author Isaac Chiu, associate professor of immunology in the Blavatnik Institute at Harvard Medical School.
The study identifies two central players in this molecular chain of events that leads to infection – a chemical released by nerve cells and an immune cell receptor blocked by the chemical. The study experiments show that blocking either one can interrupt the cascade and thwart the bacterial invasion.
If replicated through further research, the new findings could lead to much-needed therapies for this hard-to-treat condition that often leaves those who survive with serious neurologic damage.
Such treatments would target the critical early steps of infection before bacteria can spread deep into the brain.
“The meninges are the final tissue barrier before pathogens enter the brain, so we have to focus our treatment efforts on what happens at this border tissue,” said study first author Felipe Pinho-Ribeiro, a former post-doctoral researcher in the Chiu lab, now an assistant professor at Washington University in St. Louis.
A recalcitrant disease in need of new treatments
More than 1.2 million cases of bacterial meningitis occur globally each year, according to the US Centers for Disease Control and Prevention. Untreated, it kills seven out of 10 people who contract it. Treatment can reduce mortality to three in 10. However, among those who survive, one in five experience serious consequences, including hearing or vision loss, seizures, chronic headache, and other neurological problems.
The meninges are three membranes that lie atop one another, wrapping the brain and spinal cord to shield the central nervous system from injury, damage, and infection. The dura mater, outermost of the three layers, contains pain neurons that detect signals. Such signals could come in the form of mechanical pressure: blunt force from impact or toxins that make their way into the central nervous system through the bloodstream. The researchers focused on the dura mater as the site of initial interaction between bacteria and protective border tissue.
Recent research has revealed that the dura mater also harbours a wealth of immune cells, and that immune cells and nerve cells reside right next to each other – a clue that captured Chiu’s and Pinho-Ribeiro’s attention.
“When it comes to meningitis, most of the research so far has focused on analysing brain responses, but responses in the meninges – the barrier tissue where infection begins – have remained understudied,” Ribeiro said.
What exactly happens in the meninges when bacteria invade? How do they interact with the immune cells residing there? These questions remain poorly understood, the researchers said.
How bacteria break through the brain’s protective layers
In this particular study, the researchers focused on two pathogens – Streptococcus pneumoniae and Streptococcus agalactiae, leading causes of bacterial meningitis in humans. In a series of experiments, the team found that when bacteria reach the meninges, the pathogens trigger a chain of events that culminates in disseminated infection.
First, researchers found that bacteria release a toxin that activates pain neurons in the meninges. The activation of pain neurons by bacterial toxins, the researchers noted, could explain the severe, intense headache that is a hallmark of meningitis. Next, the activated neurons release a signalling chemical called CGRP. CGRP attaches to an immune-cell receptor called RAMP1. RAMP1 is particularly abundant on the surface of immune cells called macrophages.
Once the chemical engages the receptor, the immune cell is effectively disabled. Under normal conditions, as soon as macrophages detect the presence of bacteria, they spring into action to attack, destroy, and engulf them. Macrophages also send distress signals to other immune cells to provide a second line of defence. The team’s experiments showed that when CGRP gets released and attaches to the RAMP1 receptor on macrophages, it prevented these immune cells from recruiting help from fellow immune cells. As a result, the bacteria proliferated and caused widespread infection.
To confirm that the bacterially induced activation of pain neurons was the critical first step in disabling the brain’s defences, the researchers checked what would happen to infected mice lacking pain neurons.
Mice without pain neurons developed less severe brain infections when infected with two types of bacteria known to cause meningitis. The meninges of these mice, the experiments showed, had high levels of immune cells to combat the bacteria. By contrast, the meninges of mice with intact pain neurons showed meagre immune responses and far fewer activated immune cells, demonstrating that neurons get hijacked by bacteria to subvert immune protection.
To confirm that CGRP was, indeed, the activating signal, researchers compared the levels of CGRP in meningeal tissue from infected mice with intact pain neurons and meningeal tissue from mice lacking pain neurons. The brain cells of mice lacking pain neurons had barely detectable levels of CGRP and few signs of bacterial presence. By contrast, meningeal cells of infected mice with intact pain neurons showed markedly elevated levels of both CGRP and more bacteria.
In another experiment, the researchers used a chemical to block the RAMP1 receptor, preventing it from communicating with CGRP, the chemical released by activated pain neurons. The RAMP1 blocker worked both as preventive treatment before infection and as a treatment once infection had occurred.
Mice pretreated with RAMP1 blockers showed reduced bacterial presence in the meninges. Likewise, mice that received RAMP1 blockers several hours after infection and regularly thereafter had milder symptoms and were more capable of clearing bacteria, compared with untreated animals.
A path to new treatments
The experiments suggest drugs that block either CGRP or RAMP1 could allow immune cells to do their job properly and increase the brain’s border defenses.
Compounds that block CGRP and RAMP1 are found in widely used drugs to treat migraine, a condition believed to originate in the top meningeal layer, the dura mater. Could these compounds become the basis for new medicines to treat meningitis? It’s a question the researchers say merits further investigation.
One line of future research could examine whether CGRP and RAMP1 blockers could be used in conjunction with antibiotics to treat meningitis and augment protection.
“Anything we find that could impact treatment of meningitis during the earliest stages of infection before the disease escalates and spreads could be helpful either to decrease mortality or minimize the subsequent damage,” Pinho-Ribeiro said.
More broadly, the direct physical contact between immune cells and nerve cells in the meninges offers tantalizing new avenues for research.
“There has to be an evolutionary reason why macrophages and pain neurons reside so closely together,” Chiu said. “With our study, we’ve gleaned what happens in the setting of bacterial infection, but beyond that, how do they interact during viral infection, in the presence of tumour cells, or the setting of brain injury? These are all important and fascinating future questions.”
