Although males and females are equally affected by stroke Since oestrogen and progesterone have known neuroprotective effects, it is important to compare the size, severity and biochemical composition of the brain tissue following stroke in female and male animal models. In a paper published in IBRO Neuroscience Reports, researchers have discovered that certain biomarkers were different in the brains of male and female mice.
Stroke neurosurgeon and research coordinator Prof Nicole Sylvain and her colleagues are looking at treatments for post-stroke recovery that help supplement these energy losses. Using the Canadian Light Source (CLS) at the University of Saskatchewan (USask), the team was able to identify energy biomarkers in the brain, which could eventually inform clinicians about the effects of potential stroke treatments on brain recovery after a stroke.
The group’s recent study examined post-stroke differences between male and female mice, and found that female mice have higher amounts of glycogen in their brains. Glycogen is a sugar-like substance that circulates in our blood and nourishes our cells. When the supply of glycogen is disrupted by stroke, the brain is severely impacted.
Most pre-clinical stroke research has been performed using male lab animals, with results usually generalised to both sexes. In clinical stoke cases, females have a higher incidence of ischaemic stroke and poorer outcomes, compared to males.
“We found that, for the most part, male data can be generalised for females, however, some of the metabolic markers we measured were actually different,” Sylvain said. “It’s really important to do the research on both sexes.”
It would be impossible for the team to detect the biomarkers without to the Mid-IR beamline.
“The only way to detect them in such an accurate way across the brain is with infrared imaging, so the CLS has been absolutely vital to our research.”
Neurons that sense pain protect the gut from inflammation and associated tissue damage by regulating the microbial community living in the intestines, according to a study from Weill Cornell Medicine researchers.
The study, published inCell, found in a preclinical model that pain-sensing neurons in the gut secrete a molecule called substance P, which appears to protect against gut inflammation and related tissue damage by boosting the population of beneficial microbes in the gut. The researchers also found that these pain-sensing nerves are diminished in number, with significant disruptions to their pain-signaling genes, in people who have inflammatory bowel disease (IBD).
“These findings reshape our thinking about chronic inflammatory disease, and open up a whole new approach to therapeutic intervention,” said study senior author Dr David Artis at Weill Cornell Medicine.
The study’s first author, DrWen Zhang, added: “Defining a previously unknown sensory function for these specific neurons in influencing the microbiota adds a new level of understanding to host-microbiota interactions.”
IBD covers two distinct disorders, Crohn’s disease and ulcerative colitis. It is typically treated with drugs that directly target elements of the immune system. Scientists now appreciate that gut-dwelling bacteria and other microbes also help regulate gut inflammation.
As Dr Artis’s laboratory and others have shown in recent years, the nervous system, which is ‘wired’ into most organs, appears to be yet another powerful regulator of the immune system at the body’s barrier surfaces. In the new study, Dr Artis and his team specifically examined pain neurons that innervate the gut.
These gut-innervating pain neurons, whose cell bodies sit in the lower spine, express a surface protein called TRPV1, which serves as a receptor for pain-related signals. TRPV1 can be activated by high heat, acid, and the chili-pepper compound capsaicin, for example – and the brain translates this activation into a sense of burning pain. The researchers found that silencing these TRPV1 receptors in gut nerves, or deleting TRPV1-expressing neurons, led to much worse inflammation and tissue damage in IBD mouse models, whereas activating the receptors had a protective effect.
The investigators observed that the worsened inflammation and tissue damage in TRPV1-blocked mice were associated with changes in the relative populations of different species of gut bacteria. When this altered bacterial population was transplanted into normal mice, it caused the same worsened susceptibility to inflammation and damage. By contrast, broad-spectrum antibiotic treatment could reverse this susceptibility even in TRPV1-blocked mice. This result demonstrated that TRPV1-expressing nerves protect the gut mainly by helping to maintain a healthy gut microbe population.
The scientists found strong evidence that a large part of this microbe-influencing effect of TRPV1-expressing nerves comes from a molecule the nerves secrete called substance P – which they observed could reverse, on its own, most of the harmful effects of blocking TRPV1. Experiments also suggested that the signaling between neurons and microbes was two-way – some bacterial species could activate TRPV1-expressing nerves to get them to produce more substance P.
To confirm the relevance to humans, the researchers examined gut tissue from IBD patients, and found abnormal TRPV1 and substance P gene activity as well as fewer signs of TRPV1 nerves overall.
“These patients had disrupted pain-sensing nerves, which may have contributed to their chronic inflammation,” Dr Zhang said.
Precisely how substance P exerts its effects on the gut microbe population, and how these microbes “talk back,” are questions that the researchers are now trying to answer in ongoing studies. But the results so far suggest that the next generation of anti-inflammatory drugs for IBD and other disorders could be compounds that target the nervous system.
“A lot of current anti-inflammatory drugs work in only some patients, and pharma companies really haven’t known why,” Dr Artis said. “Maybe it’s because, when it comes to chronic inflammation, we’ve been seeing only some of the picture – and now the rest, including the role of the nervous system, is starting to come into focus.”
A new ultrasonic technique developed for emergency kidney stone treatments on Mars may offer an option to move kidney stones out of the ureter with minimal pain and no anaesthesia, according to a new feasibility study published in The Journal of Urology.
In the procedure, the physician uses a handheld transducer placed on the skin to direct ultrasound waves towards the stone. Using ultrasound propulsion, the stones can then moved and repositioned to promote their passage, while burst wave lithotripsy (BWL) can break up the stone.
Unlike with the standard technique of shock wave lithotripsy, there is minimal pain according to lead author Dr M. Kennedy Hall, a UW Medicine emergency medicine doctor. “It’s nearly painless, and you can do it while the patient is awake, and without sedation, which is critical.”
The researchers hope that one day the procedure of moving or breaking up the stones could eventually be performed in a clinic or emergency room setting with this technology, Dr Hall added.
Ureteral stones can cause severe pain and are a common reason for emergency department visits. Most patients with ureteral stones are advised to wait to see if the stone will pass on its own. However, this observation period can last for weeks, with nearly one-fourth of patients eventually requiring surgery, Dr Hall noted.
Dr Hall and colleagues evaluated the new technique to meet the need for a way to treat stones without surgery.
The study was designed to test the feasibility of using the ultrasonic propulsion or using BWL to break up stones in awake, unanaesthetised patients, Dr Hall said.
The study recruited 29 patients; 16 received propulsion and 13 received propulsion and BWL. In 19 patients, the stones moved. In two cases, the stones moved out of the ureter and into the bladder.
Burst wave lithotripsy fragmented the stones in seven of the cases. At a two-week follow up, 18 of 21 patients (86%) whose stones were located lower in the ureter, closer to the bladder, had passed their stones. In this group, the average time to stone passage was about four days, the study noted.
One of these patients felt “immediate relief” when the stone was dislodged from the ureter, the study stated.
The next step would a clinical trial with a control group, which would not receive either BWL bursts or ultrasound propulsion, to evaluate the degree to which this new technology potentially aids stone passage, Dr Hall said.
Development of this technology first started five years ago, when NASA funded a study to see if kidney stones could be moved or broken up, without anaesthesia, on long space flights, such as the Mars missions. The technology has worked so well that NASA has downgraded kidney stones as a key concern.
“We now have a potential solution for that problem,” Dr Hall said.
Metabolites are the substances made and used during the body’s metabolic processes – or, as a new discovery out of Scripps Research and its drug development arm, Calibr, indicates, they could also be potent molecules for treating severe diseases.
In a study published in the journal Metabolites, the researchers used novel drug discovery technologies to uncover a metabolite that converts white adipocytes (‘bad’ fat cells) to brown adipocytes (‘good’ fat cells). This discovery suggests a pathway to treating metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease. This creative drug discovery method could also identify countless other potential therapeutics.
“The reason many types of molecules don’t go to market is because of toxicity,” said co-senior author Gary Siuzdak, PhD. “With our technology, we can pull out endogenous metabolites – meaning the ones that the body makes on its own – that can have the same impact as a drug with less side effects. The potential of this approach is even evidenced by the FDA’s recent approval of Relyvrio, the combination of two endogenous metabolites for the treatment of amyotrophic lateral sclerosis (ALS).”
Metabolic diseases are often caused by an imbalance in energy homeostasis. This is why certain therapeutic approaches have centred around converting white adipocytes into brown adipocytes. White adipocytes store excess energy and can eventually result in metabolic diseases like obesity, while brown adipocytes dissolve this stored energy into heat – ultimately increasing the body’s energy expenditure and helping bring balance.
To uncover a therapy that could stimulate the production of brown adipocytes, the researchers searched through Calibr’s ReFRAME drug-repurposing collection – a library of 14 000 known drug compounds that have been approved by the FDA for other diseases or have been extensively tested for human safety. Using high-throughput screening – an automated drug discovery method for searching through large pools of information –the scientists scanned ReFRAME for a drug with these specific capabilities.
This is how they uncovered zafirlukast, an FDA-approved drug used for treating asthma. Through a set of cell culture experiments, they found zafirlukast could turn adipocyte precursor cells (known as preadipocytes) into predominantly brown adipocytes, as well as convert white adipocytes into brown adipocytes.
Unfortunately, zafirlukast is toxic at higher doses, and it wasn’t entirely clear how zafirlukast was converting the adipocytes. This is when the researchers partnered with Dr Siuzdak and his team of metabolite experts.
“We needed to use additional tools to break down the chemicals in zafirlukast’s mechanism,” explained Kristen Johnson, PhD, co-senior author of the paper. “Framed another way, could we find a metabolite that was providing the same functional effect that zafirlukast was, but without the side effects?”
Dr Siuzdak and his team designed a novel set of experiments, known as drug-initiated activity metabolomics (DIAM) screening, to help answer Johnson’s question. DIAM uses technologies such as liquid chromatography (a tool that separates components in a mixture) and mass spectrometry (an analytical technique that separates particles by weight and charge) to pool through thousands of molecules and identify specific metabolites. In this case, the researchers were searching through adipose tissue for metabolites that could lead to brown adipocyte cell production.
After reducing 30 000 metabolic features to just 17 metabolites, they came upon myristoylglycine – an endogenous metabolite that prompted the creation of brown adipocytes, without harming the cell. Of the thousands of metabolic features measured in the analysis, only myristoylglycine had this special characteristic, even among nearly structurally identical metabolites.
“Identifying myristoylglycine among the thousands of other molecules speaks to the power of Siuzdak’s approach and these technologies,” added Dr Johnson. “Our findings illustrate what happens when an analytical chemistry team and a drug discovery group closely collaborate with each other.”
While most senescent cells may be harmful “zombies” spewing toxic compounds and should be targeted to reduce the risk of age-related disease, not all of them are like this. In fact, according to new research in Science, some of them embedded in young, healthy tissues seem to help repair damage.
Scientists have now seen these cells in action in lung tissue, as well as other organs that serve as barriers in the body, such as the small intestine, colon and skin. When they used drugs called senolytics to kill these cells, injuries to lung tissues healed more slowly.
“Senescent cells can occupy niches with privileged positions as ‘sentinels’ that monitor tissue for injury and respond by stimulating nearby stem cells to grow and initiate repair,” said Tien Peng, MD, associate professor of pulmonary, critical care, allergy and sleep medicine, and senior author of the study.
Ageing cells can both damage and heal
A/Prof Peng said it was understandable that scientists at first viewed senescent cells as purely detrimental. As people age, senescent cells – often termed “zombie cells” – accumulate that have characteristics of old, worn-out cells, including the inability to make new cells. Instead of dying like normal aged cells, they to live on, spewing a cocktail of inflammatory compounds that form the senescence associated secretory phenotype (SASP). These factors are linked to Alzheimer’s disease, arthritis, and other age-related maladies including cancer.
Using senolytics that selectively kill “zombie cells,” researchers made the exciting discovery that clearing senescent cells from animals thwarted or diminished age-related disease and extended the lifespan of the animals. Thereafter, a boom of activity ensued in research labs and pharmaceutical companies focused on discovering and refining more powerful versions of these drugs.
But killing off senescent cells has dangers, A/Prof Peng said. For one thing, this current study showed that senescent cells also possess the ability to promote normal healing through activation of stem cell repair. “Our study suggests that senolytics could adversely affect normal repair, but they also have the potential to target diseases where senescent cells drive pathologic stem cell behaviour,” said A/Prof Peng.
Lighting up senescent cells
One major challenge to studying senescent cells is that biomarkers of senescence (such as the gene p16) are often quite sparse, making it difficult to detect the cells. In early experiments, researchers extracted cells called fibroblasts into culture dishes, allowing them to grow and produce enough cells to experiment with, and then stressed the cells with chemicals that induced them to become senescent. But in living organisms, cells interact with tissues around them, strongly affecting the cells’ gene activity. This means that the characteristics of cells growing isolated in a glass dish could be quite different from that of cells in their natural environment.
To create a more powerful tool for their studies, the researchers improved on a common technique of fusing a relevant gene – in this case, the p16 gene, which is overly active in senescent cells –with green fluorescent protein (GFP) as a marker that can reveal the location of the cells under ultraviolet light. By enhancing the quantity and stability of green fluorescent protein in these senescent cells, the fluorescent signal was greatly amplified, finally enabling the researchers to see senescent cells in their natural habitat of living tissues.
“Zombies” stimulate stem cells shortly after birth
Using this highly sensitive tool, the researchers found that senescent cells exist in young and healthy tissues to a greater extent than previously thought, and actually begin appearing shortly after birth. The scientists also identified specific growth factors that senescent cells secrete to stimulate stem cells to grow and repair tissues. Relevant to aging and tissue injury is the discovery that cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation seen in aged or damaged tissue is a critical modifier of senescent cell activity and regeneration.
In their studies of lung tissue, A/Prof Peng’s team observed green glowing senescent cells lying next to stem cells on the basement membrane that serves as a barrier preventing foreign cells and harmful chemicals from entering the body and also allows oxygen to diffuse from air in the lungs into underlying tissues. Damage can occur at this dynamic interface. The team saw senescent cells in similar positions in other barrier organs such as small intestine, colon, and skin, and their experiments confirmed that if senescent cells were killed with senolytics, lung stem cells were not able to properly repair the barrier surface.
Diarrhoea remains one of the leading causes of death, ill health and disability among children under five years of age in developing countries,1 accounting for 19% of deaths of under-fives in South Africa and for 46% on the African continent.1 Globally, diarrhoea is the second leading infectious cause of death, accounting for 9.2% of deaths in under-fives.1
The high incidence of malnutrition in South Africa2 adds to this toll. The relationship between diarrhoea and malnutrition is bidirectional: diarrhoea may lead to malnutrition, while malnutrition may aggravate the course of diarrhoea.3 Diarrhoea is more common and more severe in children with malnutrition (ie, undernutrition), and malnourished children often have persistent or repeated diarrhoea.4 In addition, malnourished children are more likely to develop severe diarrhoea and die from it.4 Vulnerable groups such as pregnant women and children under five years of age are the most affected by malnutrition, especially in rural areas.5
Identifying children at risk
The Centres for Disease Control advises that caregivers should be trained to recognise signs of illness or treatment failure that necessitate medical intervention.6 Infants with acute diarrhoea are more prone to becoming dehydrated than older children,6 and healthcare workers or parents of infants with diarrhoea should promptly seek medical evaluation as soon as the child appears to be in distress. Reports of changing mental status in the child are of particular concern.6
When the child’s condition is in doubt, immediate evaluation by a healthcare professional is recommended.6 Clinical examination of the child provides an opportunity for physical assessment, including vital signs, degree of dehydration, and a more detailed history, and for providing better instructions to the caregivers.6
Treatment
The treatment emphasis for acute diarrhoea in children is the prevention and management of dehydration, electrolyte abnormalities and comorbid conditions.3 The objectives of diarrhoeal disease management are to prevent weight loss, encourage catch-up growth during recovery, shorten the duration and decrease the impact of the diarrhoea on the child’s health.3
A number of studies have shown that probiotics shorten the duration of diarrhoea and prevent recurrence of other episodes.7 Furthermore, probiotics can prevent diarrhoea from infection in infants with malnutrition.7
Momeena Omarjee, Consumer Healthcare Country Head: Scientific Affairs, at Sanofi South Africa says: “Good gut health is crucial for one’s wellbeing – and healthcare professionals should encourage parents to give children a daily, regular probiotic which could go a long way in preventing diarrhoea and illness.”
How can the risk of diarrhoea be reduced?
Breastfeeding, a clean safe water supply, appropriate hand-washing and good sanitation will prevent most cases of diarrhoea.8
Research shows that diarrhoea is closely linked to socioeconomic status and has the most adverse effects in South Africa’s impoverished communities.9 South African children living in poverty are approximately 10 times more likely to die from diarrhoea than their more privileged counterparts.9
Says Omarjee: “Many of these under-privileged children in South Africa do not have adequate access to clean, potable water and quality early childcare and development, and they experience limited access to health and nutrition services. KwaZulu-Natal (KZN), for example, is experiencing outbreaks of diarrhoea and other water-borne diseases due to the recent floods.”
Although government and NGOs have been working tirelessly to distribute clean, potable water to affected areas in the province, many communities continue to face challenges and intervention is needed to not only provide clean water to the communities, but also to manage the high risk of diarrhoea and related water-borne diseases.
“Sanofi has therefore embarked on an ambitious campaign, in partnership with a non-profit organisation, Save the Children South Africa, from October 2022 to assist these areas in need, and to impact over 2,000,000 lives through hygiene education and access to water,” says Omarjee.
Sanofi, working together with Save the children South Africa, will donate water tanks to Early Childhood Care and Development (ECCD) centres in the communities identified, based on Save the Children’s baseline assessment, and will ensure access to clean, potable water.
The provision of information, counselling, education and support to children and their caregivers is also limited, which translates into low use of services and uptake of practices promoting good health. Education campaigns on healthy hygiene habits will be rolled out to children and their caregivers and will be run through the Child Health Awareness Days (CHAD) events, training of ECCD centres practitioners, and community health workers.
Sanofi is committed to ensuring that no child dies of a preventable disease, especially when there are effective treatments available. Says Omarjee: “Healthcare professionals need to encourage parents and caregivers to act promptly and seek assistance when instances of diarrhoea in children under age five do not abate swiftly.”
Awotione, O.F., et al. 2016. Systematic review: Diarrhoea in children under five years of age in South Africa (1997-2014). Tropical Medicine and International Health, 21(9), 1060-1070.
Cleary, K. 2020. In-depth: The long shadow of malnutrition in South Africa. Available from: https://www.spotlightnsp.co.za, accessed 29 September 2022.
Nel, E. 2010. Diarrhoea and malnutrition. South African Journal of Clinical Nutrition, 23, suppl 1, 15-18.
Child Healthcare. n.d. What is the relationship between diarrhoea and malnutrition? Available from: https://childhealthcare.co.za, accessed 29 September 2022.
Govender, L., et al. 2021. Assessment of the nutritional status of four selected rural communities in KwaZulu-Natal, South Africa. Nutrients, 13(9), 2920.
Centers for Disease Control. 2003. Managing acute gastro-enteritis among children. MMWR, 52(RR16), 1-16.
Solis, B. et al. 2002. Probiotics as a help in children suffering from malnutrition and diarrhoea. European Journal of Clinical Nutrition, 56, S57-59.
Child Healthcare. n.d. How can the risk of diarrhoea be reduced? Available from: https://childhealthcare.co.za, accessed 29 September 2022.
Chola, L., et al. 2015. Reducing diarrhoea deaths in South Africa: costs and effects of scaling up essential interventions to prevent and treat diarrhoea in under five children. BMC Public Health, 15, 394.
