Category: 8. Health
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Tryptase Ratio May Improve Anaphylaxis Diagnosis in Children
TOPLINE:
In a decade-long study, a ratio of serum acute tryptase to serum baseline tryptase above 1.74 showed superior diagnostic performance compared with the current consensus formula, which requires serum acute tryptase to be greater than a personalized cutoff value. The ratio correctly identified more than two thirds of true cases while ruling out the majority of false cases in children with suspected anaphylaxis.
METHODOLOGY:
- Researchers reviewed medical records of 315 children (median age, 7.8 years; 56.2% boys) admitted to the emergency department with suspected anaphylaxis from January 2011 to December 2020 to assess the diagnostic performance of serum tryptase measurements.
- The diagnosis of anaphylaxis was confirmed when children showed at least one extracutaneous systemic symptom and had evidence of systemic mast cell activation or allergic sensitization to a trigger allergen.
- Those with a confirmed diagnosis constituted the anaphylaxis group (n = 175), while the remaining served as the control group (n = 142).
- Researchers compared the diagnostic performance of the consensus formula with that of five alternative tryptase interpretation algorithms.
TAKEAWAY:
- Food allergens triggered 82% of anaphylaxis reactions, with legumes, seeds, and nuts being the triggers in 36% of cases, followed by cow’s milk proteins in 28% of cases.
- Epinephrine was administered in 96 children with suspected anaphylaxis (30.3%), including 14 children who were initially misdiagnosed as having anaphylaxis due to cardiovascular involvement and a credible history of allergen exposure.
- The ratio of serum acute tryptase to serum baseline tryptase showed optimal diagnostic performance, with an area under the curve of 0.84, sensitivity of 66.7%, and specificity of 90% at a threshold of 1.74 — outperforming the current consensus formula, which has a sensitivity of 62.2% and specificity of 80%.
IN PRACTICE:
“Our study underlines the need for better implementation of both sAT [serum acute tryptase] and sBT [serum baseline tryptase] measurements at adequate sampling times in pediatric EDs [emergency departments] and contributes to the ongoing debate on the optimal interpretation of pediatric dynamic tryptase,” the authors wrote.
SOURCE:
Moïse Michel, PhD, with the Nîmes University Hospital, Nîmes, France, was the corresponding author of the study, which was published online on June 24 in the Journal of Allergy and Clinical Immunology: Global.
LIMITATIONS:
This study was limited by its retrospective design and the absence of grade 4 anaphylaxis cases in the cohort, limiting the evaluation of tryptase measurement performance.
DISCLOSURES:
This study did not receive any specific funding. One author reported receiving speaker or consultancy fees from various pharmaceutical manufacturers.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
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Human health risk assessment for microbial pesticides in the EU: challenges and perspectives | Environmental Health
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Cracking cancer’s code through functional connections
Among cancer researchers, their computers, servers and databanks store thousands of terabytes of omics data, enabling novel discoveries about genetic and proteomic relationships. However, making meaningful connections can be computationally challenging. What if there were a way to harness the power of machine learning to help interpret this data and identify unrecognized patterns that advance therapeutic strategies?
A recent paper in Nature Cancer introduces a new tool for decoding and uncovering functional connections within cancer biology. FunMap, a machine-learning-driven platform, allows researchers to understand how genes and proteins work together in cancer, even when they aren’t directly connected. Bing Zhang, a professor of molecular and human genetics at Baylor College of Medicine, and his lab aim to bridge the gap between large-scale cancer omics data and functional interpretation using machine learning.
The team used large-scale proteogenomic data, or integrated information about genes, RNA and proteins, across 11 cancer types to chart a functional network of more than 10,000 genes. Unlike traditional protein–protein interaction networks, which focus on physical contacts between proteins, FunMap assesses “cofunctionality,” the concept that genes or proteins can participate in the same biological process even if they do not physically interact.
“Think of a complex research lab,” Zhiao Shi, lead programmer in the lab and first author of the paper, explained the computational tool. “A computational biologist and a wet lab scientist may never perform experiments together, but the computational analysis is crucial for guiding the wet lab experiments and interpreting results. Though they do not interact directly, their roles are tightly coordinated to achieve scientific breakthroughs — this is cofunction.”
With the ability to incorporate graph-neural-network-based deep learning, a type of model that learns from data structured as networks of connected elements, FunMap can identify cancer driver mutations with low frequencies. This expands the understanding of cancer pathogenesis beyond high-frequency mutations and may potentiate new discoveries in cancer diagnostics and treatment.
FunMap also advances functional genomics by shedding light on understudied cancer genes, such as RBM34 and MAB21L4, also known as dark genes. These understudied genes and their protein counterparts have not been studied in the context of cancer but are significantly over or under expressed in tumors. Shi explained that their approach “enables a more systematic and data-driven assignment of functions to poorly characterized cancer-associated genes, aiding in the discovery of novel cancer biology.”
The platform is available to the public at funmap.linkedomics.org, where scientists can explore the network and apply it to their own studies. The Zhang lab plans to expand its tool with additional data types, such as epigenomics and protein modification.
“By identifying key cancer-associated proteins and functional pathways, our findings can help prioritize therapeutic targets, ultimately contributing to the development of more effective treatments,” Shi said. “In the long run, this research could lead to improved cancer diagnostics and therapies, benefiting patients by making precision medicine more actionable and impactful.”
Bing Zhang, Baylor College of Medicine
Overview of FunMap, a machine learning and network-based framework that integrates pan-cancer proteogenomic data to identify functional modules, predict understudied protein functions, and discover low-frequency cancer drivers.
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Accurate Diagnosis And Enrollment Criteria Improve Intracerebral Hemorrhage Research
By Marc Dechamps, CEO, Bioxodes
Intracerebral hemorrhage (ICH) is responsible for half of all stroke-related deaths but attracts only a fraction of the attention its better-known relative ischemic stroke gets. At Bioxodes, a clinical-phase biotech company, we faced a poignant consequence of this paradox when we struggled to recruit sufficient ICH patients into a clinical trial. Trial protocols are based largely on experiences with ischemic stroke patients, investigators noticed, which are very different from those with ICH. This real-life example underscores that not only is ICH a disease that needs better research funding, it also needs more public awareness.
When you hear of somebody hit by a stroke, chances are ischemic stroke was the culprit. Triggered by a blood clot in the brain, the condition accounts for the vast majority of strokes. It is a dangerous disease, which kills 10% of patients within the first 30 days, after an often dramatically sudden onset. Such facts may explain why ischemic stroke tends to overshadow ICH, caused by a rupture of a blood vessel in the brain, in public perception and even in medical practice. Yet despite its severity, patients with ICH are faced with limited therapeutic options and fragmented systems of care, leaving them without a clear path to recovery.
But ICH’s life in the shadows stands in stark contrast to its deadly reality. While non-traumatic ICH accounts for only approximately 10%-15% of all strokes, it is responsible for nearly half of stroke-related deaths. Mortality approaches 50% at 30 days1,2 and approximatively half of all ICH-related deaths happen within the first 24 hours3. Survivors often face severe long-term disability, with fewer than 20% achieving functional independence after six months. The burden on public health systems is large: ICH contributes to 49% of global stroke-related disability-adjusted life years (DALYs), showing the long-term impact of this devastating condition4.
The lack of an approved treatment for ICH is making this situation even more acute. Thrombolytic agents such as Alteplase, the standard of care for ischemic stroke, are not fit for purpose in ICH because of the risk of increased bleeding. ICH treatment consists largely of monitoring and stabilizing patients and, in some cases, surgery. The fact that doctors will readily describe this practice as “watch and pray” underscores the need to raise awareness, catalyze innovation, and prioritize investment in academic and clinical research.
Late Diagnoses, Restrictive I/E Criteria Present Challenges
Just how great the need for more awareness is became clear during a clinical trial in ICH we ran at Bioxodes for our drug candidate BIOX-101. This recombinant version of a small protein found in the saliva of the tick (Ixodes ricinus) displays a dual mode of action. It targets neuroinflammation and, at the same time, prevents blood clot formation, but without increasing the risk of bleeding, an essential consideration for patients with ICH.
A key observation from the trial performed in stroke units across Belgium was the unexpectedly low recruitment rate, with investigators noting a stark contrast in the hospital presentation patterns of ICH patients compared to those with ischemic stroke.
The reason was clear: ICH is often diagnosed late. Unlike ischemic stroke, which presents itself with the clear FAST symptoms (Facial drooping, Arm weakness, Speech difficulties, Time to call emergency services), symptoms for ICH are both more variable and less well known. As a result, many patients arrive at hospitals 12 to 24 hours after symptom onset — often too late to take part in clinical trials. Compounding the problem is that stroke care systems tend to be optimized for ischemic stroke, leaving ICH patients to navigate a fragmented and inconsistent care pathway. When we raised the maximum intake slot in our trial to 24 hours, which is still in line with the biology of the disease, we were able to complete recruitment rapidly.
These challenges revealed gaps in our healthcare system that need to be addressed. At the same time, the hope is that the change we made to our protocol will help investigators make future trials a success.
Accurate Diagnosis And Specialized Care Play Major Roles
Delays in treating patients are often compounded in hospitals that are insufficiently prepared to deal with stroke and where access to rapid neuroimaging, specialized care teams, and standardized protocols may be limited. In such settings, even the initial diagnosis of ICH can be delayed, narrowing the already brief window for possible trial inclusion.
While ischemic stroke benefits from well-established systems of care such as stroke codes, telestroke networks, and clearly defined pathways for thrombolysis or thrombectomy, ICH lacks those options. The absence of a universally accepted acute treatment strategy for ICH has led to inconsistent management across institutions, reducing the sense of urgency and coordination that are critical for both clinical outcomes and research participation.
Stroke units play a pivotal role in addressing these gaps. By centralizing expertise, ensuring rapid access to imaging and neurological assessment, and streamlining care processes, stroke units can significantly improve the early recognition and management of ICH. Importantly, they also enhance the infrastructure for enrolling patients in clinical trials, particularly when supported by research-trained personnel who can facilitate timely consent.
In Europe, as of 2019, there were 2,165 acute stroke units across 44 countries, a figure that represents a significant effort to centralize care and improve outcomes for stroke patients5. Yet, studies have shown that only about 30% of stroke patients are admitted to these specialized units6. In the United States, the system is similarly structured, with 2,563 certified stroke centers across the country. A study from 2019 revealed that 46% of emergency departments in the U.S. are located in hospitals with certified stroke centers, highlighting the widespread recognition of the need for specialized care in stroke management7.
An Underfunded Field Reveals Promise
Beyond patient awareness and education, a more fundamental problem remains: Treatment options for ICH are limited. This has led to a vicious circle where the absence of robust data demonstrating effective outcomes has led to a lack of interest from investors, which in turn has limited research options.
Recent developments are beginning to shift this downward spiral, with emerging clinical trials and novel therapies generating at least some promising data. One example comes from the ENRICH trial, which demonstrated good results with early minimally invasive parafascicular surgery. This approach significantly improved functional outcomes, reduced mortality, and shortened ICU and hospital stays, suggesting superior outcomes compared to medical management alone. However, the trial also highlighted an important nuance: while early clot removal can benefit some patients, it is not universally effective. These findings underscore that evacuation of the hematoma, while crucial, may not be enough to fully address neurological recovery, as secondary injury processes, such as neuroinflammation and ischemia, continue to play a role in poor outcomes. This is why therapeutics targeting thromboinflammation — such as those in development at Bioxodes — could become game-changers for ICH.
These are early signs that science may show us a way out for ICH patients. What is most needed is a joint effort to raise awareness and put ICH on the map among medical staff, investors, authorities, and the public. It is time to offer hope where, until recently, there was little.
References:
- Broderick, J.P., et al., Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke, 1993. 24(7): p. 987-93.
- Fogelholm, R., et al., Long term survival after primary intracerebral haemorrhage: a retrospective population based study. J Neurol Neurosurg Psychiatry, 2005. 76(11): p. 1534-8.
- Hemphill, J.C., 3rd, et al., The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke, 2001. 32(4): p. 891-7.
- Diseases, G.B.D. and C. Injuries, Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet, 2024. 403(10440): p. 2133-2161.
- Aguiar de Sousa, D., et al., Delivery of acute ischaemic stroke treatments in the European region in 2019 and 2020. Eur Stroke J, 2023. 8(3): p. 618-628.
- Prendes, C.F., et al., Burden of Stroke in Europe: An Analysis of the Global Burden of Disease Study Findings From 2010 to 2019. Stroke, 2024. 55(2): p. 432-442.
- Zachrison, K.S., et al., Estimated Population Access to Acute Stroke and Telestroke Centers in the US, 2019. JAMA Netw Open, 2022. 5(2): p. e2145824.
About The Expert:
Marc Dechamps is a biologist with more than 35 years of experience in the pharmaceutical industry, including at GSK and ViiVHealthcare. His expertise in developing new products ranges from infectious diseases, immunological disorders, oncology, and CNS disorders to vaccines. In 2016, Marc founded XMF Consulting, a company that supports biotech and biopharma businesses with strategic advice and management leadership. He has served as managing director of Delphi Genetics, a CDMO, and interim CEO of eTheRNA Immunotherapies, an mRNA biotech firm. Next to his busy role as Bioxodes CEO, Marc serves as president of the board of Investsud Tech (group InvestSud) and as board member of HealthTech for Care (HT4C). He is a co-academic director for the advanced master’s in biotech & medtech ventures at the Solvay Brussels School of Economics & Management, and he recently joined Ose Immunotherapeutics as an independent board member.Continue Reading
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Can Blocking AMH Reverse PCOS? New Study Says Yes
Researchers from the French National Institute of Health & Medical Research (Inserm), University of Lille in Lille, France, and the university’s teaching hospital CHU de Lille have identified a promising new therapeutic strategy for polycystic ovary syndrome (PCOS). In preclinical models, the use of antibodies that block the activity of anti-Müllerian hormone (AMH) helped prevent the onset of PCOS-like symptoms — and even reversed them in adults who were already affected. Paolo Giacobini, PhD, neuroendocrinologist and group leader at Inserm’s Lille Neuroscience and Cognition Research Center (Centre de recherche Lille Neuroscience et Cognition), shared the findings with Medscape’s French edition.
Reduced Quality of Life
PCOS is one of the most common causes of infertility among women of reproductive age, affecting approximately 1 in 10 women — or more than two million individuals in France alone. Currently, treatment options are limited to symptom management.
“This condition has a significant impact on women’s quality of life,” said Giacobini. “It presents with a broad spectrum of symptoms that vary between patients, including polycystic ovaries, elevated androgen levels leading to menstrual irregularities, acne, hair loss, excessive body hair, high levels of AMH, and, in some cases, metabolic syndrome. At least half of women with PCOS have associated comorbidities such as overweight or obesity, elevated insulin levels that increase the risk of developing type 2 diabetes, or cardiovascular disease.”
A Multifactorial Condition
Diagnosis of PCOS is typically based on the presence of at least two of the following three criteria: irregular menstrual cycles, clinical or biochemical signs of hyperandrogenism, and polycystic ovarian morphology as observed via ultrasound.
The exact cause of PCOS remains unclear. “We’ve done extensive laboratory research using preclinical models to better understand the heritability of the syndrome,” Giacobini said. “Genetics are a factor, but they do not fully explain the high prevalence. We’ve also identified epigenetic changes and environmental influences, such as hormonal exposures during fetal development or after birth. It is highly likely that PCOS has a multifactorial origin.”
In a recent study, Giacobini’s team focused on the role of AMH. In PCOS, the ovaries produce excess AMH, which impairs the maturation of follicles and contributes to androgen overproduction. “In previous preclinical studies, we found that prenatal exposure to AMH could induce PCOS-like symptoms in offspring, and these symptoms were transmitted across generations,” Giacobini explained. “We then examined critical periods of vulnerability in humans and observed that children of women with PCOS — both daughters and sons — had elevated AMH levels, even before puberty. We also found that mice exhibited high AMH levels during ‘mini-puberty,’ a transient hormonal phase in early infancy.”
Blocking AMH Receptors
The research team next investigated whether blocking AMH could help prevent PCOS. To do this, they developed a novel antibody, Ha13, designed to block AMH receptors located both in the ovaries and on gonadotropin-releasing hormone (GnRH)-producing neurons, which regulate reproductive function.
“By administering this antibody to young mice during the mini-puberty phase, we were able to prevent the development of PCOS in adulthood,” said Giacobini. “And when we treated adult mice already exhibiting PCOS symptoms, we reversed all reproductive abnormalities — normalizing menstrual cycles, ovulation, and androgen levels.”
Giacobini views this study as “a gateway to further research on the pharmacokinetics of this antibody, which could eventually pave the way for human trials.” Although the molecule has been patented, several steps remain before it can be considered for clinical use. “The effects in animals are very promising, but we still need to evaluate long-term outcomes and establish optimal dosing,” he emphasized.
An Advanced Alternative
Another therapeutic avenue targeting the GnRH receptor is already further along in development. “We published our preclinical research on GnRH antagonists in 2018, and, thanks to European funding, we were able to initiate clinical trials. The pilot-phase results have been encouraging,” Giacobini said.
“One advantage is that this molecule is already approved by the US Food and Drug Administration and the European Medicines Agency for other indications. We’re already familiar with its pharmacological profile and side effects, which significantly accelerates development,” he concluded.
This story was translated from Medscape’s French edition.
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Attitudes to aging, depression, and death anxiety among community-dwelling older adults: a cross-sectional correlational study | BMC Geriatrics
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Experimental medication sensitizes glioblastoma to treatment and blocks tumor spread
A potential treatment for glioblastoma crafted by scientists at The Wertheim UF Scripps Institute renders the deadly brain cancer newly sensitive to both radiation and chemotherapy drugs, and blocks the cancer’s ability to invade other tissue, a new study shows.
The experimental medication, called MT-125, has received approval from the FDA to move to clinical trials as a possible first-line treatment for the most aggressive form of the brain cancer.
Each year, 14,000 people in the United States receive the devastating news that they have glioblastoma. It is a cancer with an average survival of just 14 to 16 months. Standard treatments include surgery, radiation and chemotherapy. But half of glioblastoma patients have a subtype that doesn’t respond to any approved cancer drugs, said Courtney Miller, Ph.D., a professor and academic affairs director at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.
New options are urgently needed for those patients, said Miller, a member of the University of Florida Health Cancer Center.
We know glioblastoma patients are awaiting a breakthrough, and we are moving as fast as humanly possible.”
Courtney Miller, Ph.D., professor and academic affairs director at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Miller and her colleagues have long focused on molecular “motors” in the cell, nanoscale proteins called myosin. They look and act like machines, converting the cell’s energy into activity. Myosin motors enable cells to move, connect to other cells or contract and expand, Miller said. They are found throughout the body, including in heart, muscle and brain tissue.
As a result, they have potential as therapeutic targets for a wide range of conditions, from cancer to substance use disorders, she said. However, there are no current medications that target them, or even selective drug-like tools that scientists can use to study them.
Miller teamed up with her Wertheim UF Scripps colleagues to design a spectrum of potential drug candidates to block myosin motors in different contexts. Their work was published Tuesday, July 1, in the scientific journal Cell.
Medicinal chemist Theodore Kamenecka, Ph.D., engineered the array of compounds, in consultation with structural biologist Patrick Griffin, Ph.D., The Wertheim UF Scripps Institute’s scientific director.
To test the oncology potential of the myosin motor drugs, the team joined forces with Steven Rosenfeld, M.D., Ph.D., a scientist and neuro-oncologist at the Mayo Clinic in Jacksonville. Their out-of-the-box strategy appears to have opened a new route to attacking the hardest-to-treat glioblastoma. It works in four ways, the scientists reported in a companion paper published in Cell on June 10.
“In animal studies, MT-125 makes malignant cells that were previously resistant to radiation responsive to it,” Miller said. “You also end up with multinucleated cells that cannot separate, and so they get marked for cell death.”
MT-125 also blocks the cells’ ability to squeeze and change shape, which means they cannot proliferate and invade other parts of the brain, she said. And if MT-125 is combined with existing chemotherapy drugs, including sunitinib, the drug appears to deliver a very powerful response, Rosenfeld said. Sunitinib belongs to a class of chemotherapy drugs called kinase inhibitors.
“We found in mice that combining MT-125 with a number of kinase inhibitors created long periods of a disease-free state that we haven’t seen in these mouse models before,” Rosenfeld said.
The scientists cautioned that many potential drugs that perform well in mice fail in human studies, due to differences in biology, so it will take time and study to learn if MT-125 is the hoped-for breakthrough, Rosenfeld said.
Toxicity is another worry. But because the cancer cells are much more sensitive to MT-125 than healthy cells, and because the drug doesn’t stay in the body long, pulsed administration of the medication over a brief period seems to address the issue, Rosenfeld said.
“I have been in the field for 35 years, and I always thought the solution to this problem would have to come from out-of-the-box thinking,” Rosenfeld said. “The tried-and-true methods don’t seem to work for this disease.”
The compound, MT-125, has been licensed to a Jupiter, Florida-based biotechnology company started by the scientists, Myosin Therapeutics. They are working hard to begin first-in-human clinical trials within the year in glioblastoma patients, Miller said. The U.S. Food and Drug Administration has given them the green light to proceed. They are awaiting release of a federal grant that has internal approval, she said. The National Institutes of Health has provided study funding, as well as the William Potter Glioblastoma Research Fund at The Wertheim UF Scripps Institute, which was established by William Potter’s wife, Ronnie Potter, in his memory.
Looking ahead, Miller says there is evidence that MT-125 could prove beneficial not only against the aggressive variant of glioblastoma, but for malignant gliomas and other cancers.
In parallel, Miller and her collaborators are working to prepare a clinical trial for a related compound, MT-110, which appears to block drug cravings for people with methamphetamine use disorder. This compound is described in more detail in the July 1 Cell study.
Source:
Journal reference:
Radnai, L., et al. (2025). Development of clinically viable non-muscle myosin II small molecule inhibitors. Cell. doi.org/10.1016/j.cell.2025.06.006.
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Association of pulmonary function with the risk of stroke based on the NHANES database | BMC Public Health
Our study adds to the growing body of literature by investigating the relationship between pulmonary function and stroke in a large NHANES cohort. We observed a consistent inverse association between pulmonary function, as measured by spirometry-derived metrics such as FEV1, FVC, and PEF, and the risk of stroke, suggesting that preserved lung function may confer protective effects against stroke risk.
These findings are consistent with previous studies that have reported associations between lung function and cardiovascular events, including stroke [14, 15, 16]. Logitudinal studies found that a higher pulmonary function was associated with lower risk of new-onset stroke using data from the UK Biobank [11]. However, a two-sample Mendelian randomisation study confirmed that there was weak evidence that reduced lung function increased risk of ischaemic stroke [12]. Greater longitudinal declines in these spirometric measures are further associated with cardiovascular morbidity and mortality. Previous conclusions were mostly based on the patients with chronic obstructive pulmonary disease. Our study extended the association in general adults, affirming the significance of respiratory health in cardiovascular outcomes [17, 18]. Interestingly, we observed that the association between reduced pulmonary function and stroke was significantly stronger among participants aged 60 years and older. This age-dependent interaction may reflect cumulative vascular injury, reduced physiologic reserve, and heightened susceptibility to systemic inflammation and hypoxia in older adults. These findings suggest that pulmonary health maintenance may be particularly critical in mitigating stroke risk among the aging population. The inverse association between physical activity and stroke risk observed in our study is consistent with prior research. Physical activity improves vascular health through mechanisms such as lowering blood pressure, enhancing insulin sensitivity, and reducing inflammation. It also helps control key risk factors like obesity and dyslipidemia. Epidemiological studies, including the ARIC and Nurses’ Health Study, have similarly reported reduced stroke incidence with higher activity levels.
The mechanisms linking pulmonary function to stroke risk are complex and likely involve multiple pathways. Reduced pulmonary function cause reduced oxygen exchange and contribute to systemic inflammation [19], endothelial dysfunction [20], and impaired vascular homeostasis [21], all of which are implicated in the pathogenesis of atherosclerosis and cerebrovascular disease. Additionally, impaired lung function may lead to hypoxemia and neurovascular dysfunction [22, 23], thereby predisposing individuals to ischemic stroke. Finally, reduced pulmonary function may alter coagulation and platelet aggregation, increasing the risk of thromboembolic events, including stroke.
Our study builds on previous research by using a nationally representative cohort, which includes a broad range of demographic, clinical, and pulmonary function variables. However, several limitations should be considered when interpreting our findings. First, the cross-sectional design of NHANES precludes determination of temporal or causal relationships between pulmonary function and stroke risk. Stroke survivors may experience reduced physical activity, neuromuscular dysfunction, and an increased risk of aspiration pneumonia, all of which can impair respiratory mechanics and lung capacity. Second, stroke history was based on self-report, which may be affected by recall bias or misclassification. However, previous studies suggest that self-reported stroke in NHANES has reasonable validity. Third, despite extensive adjustment for confounders, residual confounding cannot be entirely excluded, such as a history of cerebrovascular disease and prior use of medications like hypoglycemic agents and statins. Forth, spirometry-derived metrics may not fully capture the complexity of respiratory physiology, and other measures of lung function, such as diffusion capacity and airway resistance, were not assessed in our study. Finally, we acknowledge that group size imbalance may still introduce residual confounding. We did not apply propensity score matching in the current analysis. Therefore, future studies with larger event numbers consider incorporating PSM as a complementary strategy will strengthen causal inference and improve the robustness of results.
These findings suggest that pulmonary function testing could serve as a useful adjunct in stroke risk assessment, especially among older adults. Although our findings suggest that lower pulmonary function is associated with higher stroke prevalence, our study does not evaluate whether pulmonary function measures add incremental predictive value beyond traditional risk scores such as the Framingham Stroke Risk Profile. Therefore, the clinical utility of incorporating pulmonary function testing into routine stroke risk assessment remains uncertain. Future studies should investigate whether pulmonary function improves risk prediction models and whether interventions aimed at preserving or improving lung function can reduce the burden of stroke.
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Targeting a key enzyme could reverse early Parkinson’s effects
Putting the brakes on an enzyme might rescue neurons that are dying due to a type of Parkinson’s disease that’s caused by a single genetic mutation, according to a new Stanford Medicine-led study conducted in mice.
The genetic mutation causes an enzyme called leucine-rich repeat kinase 2, or LRRK2, to be overactive. Too much LRRK2 enzyme activity changes the structure of brain cells in a way that disrupts crucial communication between neurons that make the neurotransmitter dopamine and cells in the striatum, a region deep in the brain that is part of the dopamine system and is involved in movement, motivation and decision making.
Findings from this study suggest that inhibiting the LRRK2 enzyme could stabilize the progression of symptoms if patients can be identified early enough.”
Suzanne Pfeffer, PhD, the Emma Pfeiffer Merner Professor in Medical Sciences and professor of biochemistry
Researchers can mitigate overactive LRRK2 using MLi-2 LRRK2 kinase inhibitor, a molecule that attaches to the enzyme and decreases its activity.
Pfeffer added that because the genetic mutation is not the only way to end up with overactive LRRK2 enzyme, the inhibitor treatment might help with other types of Parkinson’s disease or even other neurodegenerative diseases.
Pfeffer is the senior author of the study to be published in Science Signaling on July 1. Ebsy Jaimon, PhD, a postdoctoral scholar in biochemistry, is the lead author. The work is part of a longstanding collaboration with Dario Alessi, PhD, at the University of Dundee in Scotland.
Cellular antennae
About 25% of Parkinson’s disease cases are caused by genetic mutations, and the single genetic mutation that makes the LRRK2 enzyme too active is one of the most common. An overactive LRRK2 enzyme causes cells to lose their primary cilia, a cellular appendage that acts like an antenna, sending and receiving chemical messages. A cell that has lost its primary cilia is like your mobile phone when the network is down – no messages come through or are sent.
In a healthy brain, many messages are sent back and forth between dopamine neurons in a region of the brain called the substantia nigra and the striatum. These cellular “conversations” are possible because dopamine neuron axons, which are tubular extensions coming off the cell body, reach all the way to the striatum to communicate with neurons and glia, cells that support neuronal function.
An important communication that is disrupted by too much LRRK2 enzyme activity occurs when dopamine neurons are stressed and release a signal in the striatum called sonic hedgehog (named after the cartoon character). In a healthy brain, it causes certain neurons and astrocytes, a type of glial support cell, in the striatum to produce proteins called neuroprotective factors. As their name suggests, these proteins help shield other cells from dying. When there is too much LRRK2 enzyme activity, many of the striatal cells lose their primary cilia – and their ability to receive the signal from dopamine neurons. This disruption in sonic hedgehog signaling means that needed neuroprotective factors are not produced.
“Many kinds of processes necessary for cells to survive are regulated through cilia sending and receiving signals. The cells in the striatum that secrete neuroprotective factors in response to hedgehog signals also need hedgehog to survive. We think that when cells have lost their cilia, they are also on the pathway to death because they need cilia to receive signals that keep them alive,” Pfeffer explained.
Restored cilia were unexpected
The goal of the study was to test if the MLi-2 LRRK2 kinase inhibitor reversed the effects of too much LRRK2 enzyme activity. Because the neurons and glia that were examined in this study were fully mature and no longer reproducing through cell division, the researchers were initially unsure whether cilia could regrow. Working with mice with the genetic mutation that causes overactive LRRK2 and symptoms consistent with early Parkinson’s disease, the scientists first tried feeding the mice the inhibitor for two weeks. There were no changes detected in brain structure, signaling or the viability of the dopamine neurons.
Recent findings on neurons involved in regulating circadian rhythms, or sleep-wake cycles, inspired the researchers to try again. The primary cilia on those cells – which were also no longer dividing – grew and shrank every 12 hours.
“The findings that other non-dividing cells grow cilia made us realize that it was theoretically possible for the inhibitor to work,” Pfeffer said.
The team decided to see what happened after mice with overactive LRRK2 enzyme consumed the inhibitor for a longer period of time; Pfeffer described the results as “astounding.”
After three months of eating the inhibitor, the percentage of striatal neurons and glia typically affected by the overactive LRRK2 enzyme that had primary cilia in mice with the genetic mutation was indistinguishable from that in mice without the genetic mutation. In the same way moving from an area with spotty cell service to one with good service restores our ability to send and receive text messages, the increase in primary cilia restored communication between dopamine neurons and the striatum.
The striatal neurons and glia were again secreting neuroprotective factors in response to hedgehog signaling from dopamine neurons in the same amounts as the brains of mice without the genetic mutation. The hedgehog signaling from dopamine neurons decreased, suggesting they were under less stress. And, indicators of the density of dopamine nerve endings within the striatum doubled, suggesting an initial recovery for neurons that had been in the process of dying.
“These findings suggest that it might be possible to improve, not just stabilize, the condition of patients with Parkinson’s disease,” Pfeffer said.
The earliest symptoms of Parkinson’s disease begin about 15 years before someone notices a tremor. Typically, these symptoms are a loss of smell, constipation and a sleep disorder in which people act out their dreams while still sleeping, according to Pfeffer. She said the hope is that people who have the LRRK2 genetic mutation can start a treatment that inhibits the enzyme as early as possible.
The next step for the research team is to test whether other forms of Parkinson’s disease that are not associated with the LRRK2 genetic mutation could benefit from this type of treatment.
“We are so excited about these findings. They suggest this approach has great promise to help patients in terms of restoring neuronal activity in this brain circuit,” Pfeffer said. “There are multiple LRRK2 inhibitor clinical trials underway, and our hope is that these findings in mice will hold true for patients in the future.”
The study was funded by The Michael J. Fox Foundation for Parkinson’s Research, the Aligning Science Across Parkinson’s initiative and the United Kingdom Medical Research Council.
Source:
Journal reference:
Jaimon, E., et al. (2025). Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson’s disease–linked LRRK2 -mutant mice. Science Signaling. doi.org/10.1126/scisignal.ads5761
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