Excess weight or obesity raises mortality risk by between 22% to 91%, a significantly higher rate than previously believed, while the mortality risk of being slightly underweight has likely been overestimated, according to new research published in the journal Population Studies.
The analysis of nearly 18 000 participants counters prevailing wisdom that excess weight boosts mortality risk only in extreme cases, and it also challenges the use of body mass index (BMI) to investigate health outcomes due to its inherent biases. After accounting for those biases, it estimates that about 1 in 6 deaths in the US are related to excess weight or obesity.
“Existing studies have likely underestimated the mortality consequences of living in a country where cheap, unhealthy food has grown increasingly accessible, and sedentary lifestyles have become the norm,” said author Ryan Masters, associate professor of sociology at CU Boulder. “This study and others are beginning to expose the true toll of this public health crisis.”
Challenging the obesity paradox
While numerous studies show that heart disease, high blood pressure and diabetes (which are often associated with being overweight) elevate mortality risk, very few have shown that groups with higher BMIs have higher mortality rates.
Instead, in what some call the “obesity paradox,” most studies show a U-shaped curve: Those in the “overweight” category (BMI 25–30) surprisingly have the lowest mortality risk. Those in the “obese” category (30–35) have little or no increased risk over the so-called “healthy” category (18.5–25). And both the “underweight” (< 18.5) and extremely obese (> 35) are at increased risk of death.
“The conventional wisdom is that elevated BMI generally does not raise mortality risk until you get to very high levels, and that there are actually some survival benefits to being overweight,” said Masters, a social demographer who has spent his career studying mortality trends. “I have been suspicious of these claims.”
He noted that BMI, which doctors and scientists often use as a health measure, is based on weight and height only and doesn’t account for differences in body composition or how long a person has been overweight.
“It’s a reflection of stature at a point in time. That’s it,” said Masters, noting that Tom Cruise (at 170cm and an extremely muscular 91kg at one point), had a BMI of 31.5, famously putting him in the category of “obese.” “It isn’t fully capturing all of the nuances and different sizes and shapes the body comes in.”
Taking these nuances, Masters accessed data from the National Health and Nutrition Examination Survey (NHANES) the from 1988 to 2015, analysing 17 784 people, including 4468 deaths.
He discovered that a full 20% of the sample characterised as “healthy” weight had been in the overweight or obese category in the decade prior. When set apart, this group had a substantially worse health profile than those in the category whose weight had been stable.
Masters pointed out that a lifetime carrying excess weight can lead to illnesses that, paradoxically, lead to rapid weight loss. If BMI data is captured during this time, it can skew study results.
“I would argue that we have been artificially inflating the mortality risk in the low-BMI category by including those who had been high BMI and had just lost weight recently,” he said.
Meanwhile, 37% of those characterised as overweight and 60% of those with obese BMI had been at lower BMIs in the decade prior. Notably, those who had only recently gained weight had better health profiles.
“The health and mortality consequences of high BMI are not like a light switch,” said Masters. “There’s an expanding body of work suggesting that the consequences are duration-dependent.”
By including people who had spent most of their life at low-BMI weight in the high-BMI categories, previous studies have inadvertently made high BMI look less risky than it is, he said.
When he looked at differences in fat distribution within BMI categories, he also found that variations made a huge difference in reported health outcomes.
Exposing a public health problem
Collectively, the findings confirm that studies have been “significantly affected” by BMI-related bias.
When re-crunching the numbers without these biases, he found not a U-shape but a straight upward line, with those with low BMI (18.5–22.5) having the lowest mortality risk.
Contrary to previous research, the study found no significant mortality risk increases for the “underweight” category.
Previous studies attributed 2 to 3% of UA adult deaths to high BMI, but his study estimates an eight times higher rate.
Masters said he hopes the research will alert scientists to be “extremely cautious” when making conclusions based on BMI. But he also hopes the work will draw attention to what he sees not as a problem for individuals alone to solve but rather a public health crisis fuelled by an unhealthy or “obesogenic” environment in the US.
“For groups born in the 1970s or 1980s who have lived their whole lives in this obesogenic environment, the prospects of healthy aging into older adulthood does not look good right now,” he said. “I hope this work can influence higher-level discussions about what we as a society can do about it.”
Serotonin can impact the mitral valve of the heart and potentially accelerate a cardiac condition known as degenerative mitral regurgitation, according to a new study published in Science Translational Medicine.
Degenerative mitral regurgitation
Degenerative mitral regurgitation (DMR) is one of the most common heart valve diseases. The mitral valve is located between the left atrium and left ventricle of the heart, and normally it closes tightly when the heart contracts to prevent blood from leaking back into the left atrium.
In DMR, the mitral valve shape is distorted, preventing complete closure. This allows blood to leak back toward the lungs (regurgitation), limiting the amount of oxygen-rich blood moving through the heart to the rest of the body.
As a result, DMR can bring about symptoms like fatigue and shortness of breath. Because of the reduced efficiency in circulation, the heart has to work harder, which over time causes permanent damage. This can lead to a number of serious and life-threatening cardiac issues, including atrial fibrillation and heart failure.
Currently, there is no treatment for mitral valve degeneration. “Certain medications can ease the symptoms and prevent complications, but they do not treat the mitral valve,” says co-lead researcher, Columbia University’s Giovanni Ferrari, PhD. “If the degeneration of the mitral valve becomes severe, surgery to repair or replace the valve is needed.”
The role of serotonin
Serotonin plays a part in a wide range of body functions, including emotional state, digestion, sleep, memory, and blood-clotting. Serotonin’s role as a neurotransmitter aids mood regulation; lower levels of serotonin are associated with anxiety and depression.
Serotonin binds to specific receptors on the surface of a cell, sending a signal to the cell to act accordingly. A protein known as the serotonin transporter (SERT or 5-HTT) moves serotonin into the cell to be reabsorbed and recycled, a process known as serotonin reuptake.
Medications called selective serotonin reuptake inhibitors (SSRIs) bind to the SERT to reduce serotonin reuptake, allowing serotonin to remain available for longer periods. This increased serotonin availability can help improve symptoms of mood disorders. SSRIs are some of the most widely prescribed types of antidepressants and include well-known medications like fluoxetine (Prozac) and sertraline (Zoloft).
Study design
The study examined clinical data from more than 9000 patients who had undergone valve repair or replacement surgery for DMR and evaluated 100 mitral valve biopsies. “Studying the data of these patients, we found that taking SSRIs was associated with severe mitral regurgitation that needed to be treated with surgery at a younger age than for patients not taking SSRIs,” says Ferrari.
The researchers also studied in vivo mouse models using transgenic mice lacking the SERT gene and normal mice. They discovered that mice without a SERT gene developed thicker mitral valves and that normal mice treated with high doses of SSRIs also developed thickened mitral valves.
Using genetic analysis, the researchers identified genetic variants in the SERT gene region 5-HTTLPR that affect SERT activity. They found that a “long” variant of 5-HTTLPR makes SERT less active in the mitral valve cells, especially when there are two copies (one maternal and one paternal). DMR patients with the “long-long” variant needed mitral valve surgery more often than those with other variants.
Mitral valve cells from DMR patients with the “long-long” variant were more prone to react to serotonin by producing more collagen, changing the shape of the mitral valve. Additionally, mitral valve cells with the “long-long” variant of 5-HTTLPR were more sensitive to fluoxetine than those with other variants.
Implications for MVD patients
The study indicates that for DMR patients with the “long-long” variant, taking SSRIs lowers SERT activity in the mitral valve. The researchers suggest testing DMR patients for potential low SERT activity by genotyping them for 5-HTTLPR, which can be determined easily from a DNA sample obtained from the blood or a mouth swab. “Assessing patients with DMR for low SERT activity may help identify patients who may need mitral valve surgery earlier,” says Ferrari. “Promptly fixing a mitral valve that is very leaky would protect the heart and could prevent congestive heart failure.”
The researchers did not find a negative effect with normal doses of SSRIs or the “long-long” variant in cells from healthy human mitral valves. “A healthy mitral valve can probably stand low SERT activity without deforming,” says Ferrari. “It is unlikely that low SERT can cause degeneration of the mitral valve by itself. SSRIs are generally safe for most patients. Once the mitral valve has started to degenerate, it may be more susceptible to serotonin and low SERT.”
Additional research may help determine if DMR patients who respond well to SSRIs should be regularly seen to assess progression of mitral degeneration, and whether DMR patients who are not responding well to SSRIs should consider switching to a non-SSRI antidepressant rather than raising the dose of the SSRI.
Analysing an infant’s genome has allowed scientists to find a new way genetics influences the body’s antiviral response by studying a life-threatening disease caused by a common virus: herpes simplex virus 1 (HSV-1). The findings, published in Science Immunology, hold potential as a genetic marker doctors could use to gauge a child’s risk of herpes encephalitis, although such mutations are generally very rare in the population.
The researchers analysed genetic data from a patient with immunodeficiency and hospitalised at nine months old with herpes encephalitis, a rare but life-threatening brain inflammation after HSV-1 infection. They identified novel mutations in the gene GTF3A, and found that these mutations impair the innate immune response.
Many people are infected in childhood with the HSV-1 virus but the vast majority don’t suffer from encephalitis. The most common symptom of HSV-1 is oral cold sores, but many people show no signs at all. HSV-1 is more threatening to children and adults who are immunodeficient, whose immune system cannot control the virus well.
“Genetic and mechanistic analyses of uncommon viral diseases like herpes encephalitis are quite rare. In fact, the causes underlying severe herpes encephalitis are often unknown,” says Michaela Gack, PhD, FRIC’s scientific director. “This information provides us with invaluable insight into the fundamental molecular processes that govern our immune response and opens up opportunities for future research on severe disease outcomes.”
The Ghent research team led by Filomeen Haerynck, MD, PhD, reached out to Dr Gack’s team after finding the mutations in the gene. Dr Gack’s lab studies interactions between the human immune system and viruses on a molecular level.
The GTF3A mutations shape how cells respond to viral activity through the genetic makeup of a protein called TFIIIA. TFIIIA plays a role in helping a human enzyme produce certain types of RNA that can determine specific functions inside cells. Some RNAs can elicit an anti-herpes viral immune response.
Dr Gack’s team tested cells that have the mutations, and found that because of defects in certain immunostimulatory RNAs, the cells were more susceptible to HSV-1 infection and lost the ability to control the HSV-1 virus.
The affected gene is part of the body’s defence system that produces interferons to combat viruses. Interferons are crucial to the human immune response and for suppressing virus infection and spread.
This new genetic pathway could be helpful in understanding the immune response to other viruses, like Epstein-Barr virus, a common virus linked to mononucleosis and associated with certain types of cancer and multiple sclerosis.
“Understanding the molecular processes underlying antiviral responses is key to treating or possibly preventing severe viral infections that change patients’ and families’ lives,” Dr Gack said. “Our findings on critical immune defence proteins may translate into new therapies in the future.”
The immune systems of preterm babies are especially weak, making them more vulnerable to infection. A new study published in JCI Insight suggests that this vulnerability instead stems from an immune signalling pathway being suppressed, perhaps due to a requirement for it for successful foetal development in utero.
The earlier babies are born, the higher the risk of life-threatening complications. Infections can lead to sepsis and are among the most frequent causes of death.
“In the case of very prematurely born infants, a bacterial infection can lead to death within hours,” says LMU physician Prof Markus Sperandio. The physiologist and former paediatrician and neonatologist researches the causes of this high susceptibility to infection together with his team at LMU’s Biomedical Center Munich. Now the researchers have demonstrated that an immunostimulatory signalling pathway is suppressed in the developing immune system.
In preterm infants, neutrophils ‘turned off‘
Sperandio had already shown in earlier studies that, in the foetus and in newborns, neutrophils do not work as in adults. Unlike in adults, foetal and neonatal neutrophils do not manage to sufficiently attach to the walls of blood vessels and extravasate into inflamed tissue. This is necessary, however, to trigger an inflammatory response and thus initiate immune defence.
Now the LMU researchers, working in collaboration with the Children and Women’s Clinic at University of Munich Hospital, have investigated which mechanisms are behind this immaturity. By means of a so-called transcriptomic analysis, they compared the gene activity of neutrophils in umbilical cord blood of premature and full-term babies with adult neutrophils. Compared to adults, there is a lot of gene activity in premature and full-term infants that counteracts immune defence. “In this case, these neutrophils act as if they were switched off,” says Sperandio.
Balance shift of immunoregulatory signalling pathways
This particularly affects signals transmitted via the NF-κB signalling pathway, which plays a decisive role in immune and inflammatory responses. It consists of two possible pathways for signals: one that promotes inflammation and one that can suppress it. Therefore, the activity of these two pathways must be finely balanced for proper regulation of the immune response.
“Our experiments have shown that this balance is shifted towards the anti-inflammatory pathway in foetal and neonatal neutrophils,” says Sperandio. “Whereas this regulation of neutrophil function is clearly a requirement for normal foetal growth in utero, it leads to immune defence problems in prematurely born infants who have to adapt ‘too soon’ to the world outside the uterus.” To what extent these findings will be a springboard for new therapeutic approaches in the future remains to be seen. “Due to the complex processes in the growing foetal and neonatal organism, maturation-adapted therapies are conceivable but remain a long way off at this stage,” says Sperandio.
In a study of 5589 US adults aged 65 years and older, persistent pain was common and was linked to meaningful declines in physical function and well-being over 7 years. Reporting in the Journal of the American Geriatrics Society, investigators found that 38.7% of participants reported persistent pain, and 27.8% reported intermittent pain. (“Persistent pain” was defined as being bothered by pain in the last month in two consecutive annual interviews and “intermittent” pain was defined as bothersome pain in one interview only.)
More than one-third of participants described pain in five or more sites. Over the subsequent 7 years, participants with persistent pain were more likely to experience declines in physical function (64% persistent pain, 59% intermittent pain, 57% no bothersome pain) and well-being (48% persistent pain, 45% intermittent pain, 44% no bothersome pain), but were not more likely to experience cognitive decline (25% persistent pain, 24% intermittent pain, 23% no bothersome pain).
“The findings from this study point to the importance of access to effective treatment for persistent pain in older adults and the need for additional research in chronic pain to optimise quality of life,” said lead author Christine Ritchie, MD, MSPH, of Massachusetts General Hospital.
Despite being one of the most common non-communicable diseases globally and there being highly effective treatments for it, asthma is often not well controlled in many low-resource settings, according to a cross-sectional study recently published in the Lancet medical journal.
Closer to home, the Global Asthma Report from 2022 showed that there has been an increase in severe asthma symptoms among adolescents in Cape Town over the last few years. There is little data available for the rest of the country, which makes comparisons with other South African cities very tricky.
‘Disproportionate number of children have severe asthma’
Dr Ahmed Ismail Manjra, a paediatrician and allergologist at the Allergy and Asthma Centre in Durban, tells Spotlight that globally more children than adults have asthma. The centre is in the Life Westville Hospital and provides specialist services to adults and children with asthma or allergic disorders.
“Asthma is quite common in children. It is estimated [globally] that one in ten children have asthma, and in adults, the prevalence is less than in children,” he says. “But the problem is that in South Africa we see a disproportionate number of children with severe asthma. And what has been shown is that over the years the prevalence of asthma is rising, and the severity is rising.” (For more on what asthma is and how it is treated in South Africa’s public sector, see this Spotlight article from December 2022.)
Impact of undiagnosed uncontrolled asthma
The impact of undiagnosed or uncontrolled asthma on children is huge. First, according to Professor Refiloe Masekela, Paediatric Pulmonologist and the Head of Department of Paediatrics and Child Health at the University of KwaZulu-Natal, the symptoms are very noticeable, which can affect children socially. Secondly, a child with undiagnosed asthma will miss school because of their symptoms and be unable to participate in school activities like sport. They will also become less active because exercise may trigger symptoms, which have further effects on their health.
Another implication of uncontrolled asthma, according to Manjra, is poor sleep quality, which can impact a child’s academic performance.
“And in severe asthma without proper treatment, it can lead to recurrent admissions to hospital. This places a burden on the healthcare system, which can be easily prevented by proper management of asthma. And of course, in a small percentage of cases where the asthma is not well controlled, it can also lead to fatality,” he says.
Manjra urges parents to take their children to be checked for asthma if they have recurrent respiratory symptoms.
“The asthma treatment is extremely effective, very safe as well, [and] they have very few side effects. Parents should not be afraid to use asthma treatments to control their children’s asthma,” he says. “Although we don’t have a cure for asthma, we do have medicines that can control it and give better quality of life.”
Asthma trends in children: what the data says
Masekela explains that the data published in the Global Asthma Report is published by the Global Asthma Network (GAN), which consists of a network of centres across the world – including three in South Africa – that contribute data on asthma in their regions every few years.
This data collection effort started with the ISAAC one and ISAAC three studies (International Studies of Asthma and Allergens in Children). The GAN centre in Cape Town contributed data to ISAAC I in 1995 and for ISAAC III data was collected in Cape Town in 2002 and Polokwane in 2004-2005 where adolescents were also included.
According to Masekela, the latest study collecting data on asthma was the Global Asthma Network (GAN) Phase one study, to which the Cape Town centre contributed. Masekela says the data from the ISAAC studies – ISAAC 1 and ISAAC 3 as well as GAN is available in South Africa only for Cape Town.
This means that it is possible to compare trends in childhood asthma in Cape Town over a longer time period, and data from ISAAC 3 can be used to compare Polokwane and Cape Town. But there isn’t current data collected by the GAN to give a clear picture of childhood asthma in the other cities and provinces.
In the 2022 Global Asthma report changes among the prevalence of asthma symptoms – measured as a 12-month prevalence rate of wheezing among adolescents aged 13 to14 – showed that in ISAAC 1, 16% of the around 5 000 adolescents surveyed in Cape Town had symptoms, which increased to 20.3% of just over 5 000 surveys in ISAAC 3 and finally 21.7% of the just under 4 000 adolescents surveyed for the 2022 study.
Masekela says in Cape Town if we look at the period between ISAAC Phase 1 and phase three, there was an increase in the prevalence [of asthma in children], but from the ISAAC 3 to the GAN Phase 1, there has been a stabilisation in the asthma prevalence [among children. “So, it’s very high, it’s over 20%, but it’s stable so it hasn’t been increasing, which it was doing before.”
When comparing data from Polokwane and Cape Town in ISAAC 3, at the time of the study, more children and adolescents in Cape Town had severe asthma than in Polokwane. The prevalence of asthma in children and adolescents was also higher in Cape Town.
Situation is ‘interesting and worrying’
Masekela explains that in many low-and-middle-income countries, those living with asthma don’t have access to the right asthma medications, namely inhalers. What also happens is that when those individuals have access to asthma medications, they are only able to get the reliever inhaler, not the controller inhaler.
People living with asthma need two types of inhalers, a reliever inhaler which brings relief and opens up the chest during an asthma attack and a control medication which is used every day to reduce inflammation in the long run. In order to control asthma adequately, both inhalers need to be used and used correctly.
In South Africa, both types of inhalers are on the Essential Medicines List.
“The story of South Africa is interesting and worrying. We have in our essential medicine list inhalers [both relievers and controllers],” she says. “It should be available. It’s on the essential medicine list for the primary care level. So any person who has asthma in South Africa should have access to that first step of treatments.”
Yet the data from South Africa suggests there is a problem. When looking at the symptoms of asthma among schoolchildren from the GAN phase one study, Masekela says it is worrying because they found that many children in South Africa with asthma symptoms don’t have an asthma diagnosis and of those that do have the diagnosis most only have the reliever inhaler and very few are using both the reliever and the controller inhaler.
“We know that asthma is under-diagnosed and actually the data from Cape Town, as well as Durban, is very similar. You see that 50% of adolescents have severe symptoms, half of them have never got the label – they’ve never been diagnosed as having asthma,” she says.
Under-diagnosed
A possible reason for the under-diagnosis, according to Masekela, is that when a child presents to a clinic with wheezing, the child is treated for something else that might be causing the symptoms and sent home. Then when the child goes back a few weeks or months later with the same symptoms, they are seen by a different doctor or nurse and there isn’t continuity, so the fact that the symptoms are recurrent isn’t picked up on.
Manjra tells Spotlight that asthma can sometimes be difficult to diagnose in small children because its symptoms – wheezing, shortness of breath, tight chest, and coughing – can be caused by a number of other diseases. Wheezing, in particular, can be caused by a number of conditions that can affect children.
“The most common being viral upper respiratory tract infection, particularly with RSV [respiratory syncytial virus] and rhinovirus. And sometimes in young children, it can be extremely difficult to make a correct diagnosis of asthma because there’s overlap between viral-induced wheezing and asthma,” he says.
“However, if the child has an underlying – what we call atopic predisposition – that means if the child has eczema or has allergic rhinitis or food allergy or has [an] inhalant allergy, then the possibility of that child having asthma is very high,” he says.
Other childhood conditions that can cause wheezing in children are TB and inhaling foreign bodies into the lungs.
“So, the diagnosis of asthma in young children is basically made by an exclusion of other causes of wheezing,” he says. “Asthma diagnosis is made over a period of time because, as I’ve mentioned, it’s recurrent wheezing.”
Another problem, according to Masekela, is that those people who do receive a diagnosis of asthma are often not getting the right treatment.
“People who have a label at least should have access to the treatments, but we do see that even in those that have the diagnosis, a lot of them are not using their medicine because they’re getting repeated attacks, they have severe symptoms,” she says. “So, something is not right. Either they are not getting the label, we know that’s happening, or they’re not getting the right treatment.”
This is a bi-directional problem, Masekela says, in that either healthcare workers are not adequately teaching patients how to use both inhalers or patients are relying on the reliever medications despite being taught how to use both.
Manjra says that while inhalers are on the EML, this doesn’t necessarily translate to healthcare facilities having stock. Meaning that there can be stock-out of the medication, but also of the spacers that children need to use with the inhalers.
According to Manjra, children are unable to use inhalers properly with spacers, because the inhaler releases the plume of medication too quickly for the child to be able to breathe it into their lungs. The spacer allows the medication to go into a holding chamber where the child is able to breathe the medication into their lungs in a controlled way, through a special valve.
Better education needed
The solution to the problems of the under-diagnosis of asthma and incorrect inhaler use is better education on all fronts, says Masekela. There needs to be better training among healthcare workers on how to recognise asthma, how to manage it and how to teach patients how to manage it properly.
“We know that there is a system problem about them [children] getting the correct medication, using the correct medication and that all boils down to education of the patient, education of the health workers. And really, overall education in the community about how to handle asthma,” she says.
She adds that patients and the wider community also need to be educated on what asthma is and how to manage it properly and destigmatise it. A good starting place is in schools so that children who are living with asthma and their peers are able to better understand the condition and be more accepting of the use of inhalers.
“It’s important that we then find strategies to get people to understand the need for using these medicines, even when they’re feeling well,” she says.
Eyewitness News reports that doctors at Groote Schuur Hospital have successfully performed Africa’s first incompatible kidney transplant. Known as ABO-incompatible (ABOi) transplants, these procedures are done when the donor’s blood type does not match the recipient’s – once a major contraindication.
The patient, a 35 year old woman named Chervon Meyer, received a kidney donation from her brother. She had been on dialysis for 10 years,
Incompatible living kidney transplants have long been contraindicated because of the presence of isohaemagglutinins, natural antibodies reacting with non-self ABO antigens. Due to the growing demand for transplant organs, incompatible donations were investigated in order to expand the pool of possible donors. This has changed with the development of new desensitisation regimens over the past decades. These include immunoadsorption and plasmapheresis and the immunosuppressive protocol.
The improvements have been so great that, despite a lack of randomised trials, recent meta analysis found that there is no difference in terms of graft and patient’s survival between ABOi and ABO compatible kidney transplant, even in the long term.
As nephrologist Dr Zunaid Barday explains, this procedure made use of a Glycosorb filter which reduced many of the risks associated with desensitisation, such as plasma exchange weakening the immune system. It works by binding anti-A and anti-B antibodies, reducing their levels in blood plasma. While expensive, the filter is a much cheaper alternative in the long run compared to years of dialysis.
A new study published in the Journal of Experimental Medicine provides a strategy for finding treatments optimally tailored for women and men to prevent cognitive decline in aging as well as progression of neurodegenerative diseases by leveraging sex differences in the brain.
Ageing is associated with cognitive decline and brain atrophy, and is a major neurodegenerative disease risk. Studying sex differences in brain aging and neurodegenerative diseases can reveal new candidate treatment targets tailored for women and men.
One new approach to identifying neuroprotective treatments lies in understanding the role of sex chromosome gene expression in the brain as sex hormones wane during the ageing process.
UCLA researchers Dr Rhonda Voskuhl, Professor, and Dr Yuichiro Itoh, Associate Researcher, in the Department of Neurology, have created a roadmap to identify novel neuroprotective treatments tailored for women and men that leverage known sex differences in brain aging and neurodegenerative diseases.
Previously, research pursuing treatments for neurodegenerative diseases ignored sex differences in the brain and pooled data together from males and females, taking a “one size fits all” approach. This could dilute out robust effects that exist in one sex but not the other at the clinical research level and fail to capitalize on known disease modifiers in the discovery of new treatment targets at the basic research level.
In their study Voskuhl and Itoh write that known sex differences in the brain as well as the effect of higher expression of certain X chromosome genes in females (XX) compared to males (XY) can be assessed for their role in neurodegeneration during aging, a stage of life characterised by loss of potentially neuroprotective hormones in females (namely oestrogen in menopause) and males (testosterone in andropause). The study offers a roadmap for disentangling the contribution of these sex-specific factors, which can yield treatments optimized and targeted for each sex.
In the future, this roadmap can be used by researchers to discover targets on the X chromosome gene for development of modulatory treatments that prevent neurodegeneration and promote neural repair during brain aging.
“Given the aging population and lack of treatments to prevent cognitive decline during health and to reduce the risk for developing neurodegenerative diseases, it is now imperative to apply new strategies to identify neuroprotective treatments,” said Voskuhl. “Leveraging what is known about sex differences in multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease can reveal candidate treatment targets tailored for women and men affected by these conditions. Sex chromosome effects remain understudied and represent a promising frontier for discovery, particularly in the context of declining levels of sex hormones during menopause and andropause.”
In patients with Huntington’s disease, neurons in a part of the brain called the striatum are some of the worst affected. Degeneration of these neurons contributes to patients’ loss of motor control, which is one of the major hallmarks of the disease.
Neuroscientists at MIT have now shown that two distinct cell populations in the striatum are affected differently by Huntington’s disease. Reporting their results in Nature Communication, they believe that neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in structures called striosomes, may explain the mood disorders that are often see in the early stages of the disease.
“As many as 10 years ahead of the motor diagnosis, Huntington’s patients can experience mood disorders, and one possibility is that the striosomes might be involved in these,” says Ann Graybiel, an MIT Institute Professor and one of the senior authors of the study.
Using single-cell RNA sequencing to analyse the genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of the striosomes and another structure, the matrix, begin to lose their distinguishing features as the disease progresses. The researchers hope that their mapping of the striatum and how it is affected by Huntington’s could help lead to new treatments that target specific cells within the brain.
This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder, the researchers say.
Neuron vulnerability
Huntington’s disease leads to degeneration of brain structures called the basal ganglia, which are responsible for control of movement and also play roles in other behaviors, as well as emotions. For many years, Graybiel has been studying the striatum, a part of the basal ganglia that is involved in making decisions that require evaluating the outcomes of a particular action.
Many years ago, Graybiel discovered that the striatum is divided into striosomes, which are clusters of neurons, and the matrix, which surrounds the striosomes. She has also shown that striosomes are necessary for making decisions that require an anxiety-provoking cost-benefit analysis.
In a 2007 study, Richard Faull of the University of Auckland discovered that in postmortem brain tissue from Huntington’s patients, the striosomes showed a great deal of degeneration. Faull also found that while those patients were alive, many of them had shown signs of mood disorders such as depression before their motor symptoms developed.
To further explore the connections between the striatum and the mood and motor effects of Huntington’s, Graybiel teamed up with Kellis and Heiman to study the gene expression patterns of striosomal and matrix cells. To do that, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from two mouse models of Huntington’s disease.
Within the striatum, neurons can be classified as either D1 or D2 neurons. D1 neurons are involved in the “go” pathway, which initiates an action, and D2 neurons are part of the “no-go” pathway, which suppresses an action. D1 and D2 neurons can both be found within either the striosomes and the matrix.
The analysis of RNA expression in each of these types of cells revealed that striosomal neurons are harder hit by Huntington’s than matrix neurons. Furthermore, within the striosomes, D2 neurons are more vulnerable than D1.
The researchers also found that these four major cell types begin to lose their identifying molecular identities and become more difficult to distinguish from one another in Huntington’s disease. “Overall, the distinction between striosomes and matrix becomes really blurry,” Graybiel says.
Striosomal disorders
The findings suggest that damage to the striosomes, which are known to be involved in regulating mood, may be responsible for the mood disorders that strike Huntington’s patients in the early stages of the disease. Later on, degeneration of the matrix neurons likely contributes to the decline of motor function, the researchers say.
In future work, the researchers hope to explore how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders.
Previous research has shown that overactivity of striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive compulsive disorder, and Tourette’s syndrome. In this study, at least one of the genes that the researchers discovered was overexpressed in the striosomes of Huntington’s brains is also linked to autism.
Additionally, many striosome neurons project to the part of the brain that is most affected by Parkinson’s disease (the substantia nigra, which produces most of the brain’s dopamine).
“There are many, many disorders that probably involve the striatum, and now, partly through transcriptomics, we’re working to understand how all of this could fit together,” Graybiel says.
In October last year, Eastern Cape Health MEC Nomakhosazana Meth announced a three-phase plan to address key challenges with the province’s emergency medical services. PHOTO: Black Star/Spotlight
By Siyabonga Kamnqa for Spotlight
Gogo Nothembile Fanti (76) says she suffers from a heart condition and every time her grandchildren call an ambulance, they are told to wait, but it never arrives. She is one of about 40 patients – mostly older persons – sleeping on the floor and in chairs at All Saints Hospital in Ngcobo in the Eastern Cape during Spotlight’s visit on 30 January. They are all waiting for an ambulance to take them to referral hospitals such as Nelson Mandela Academic Hospital and Bedford Hospital about 60 kilometres away in Mthatha. They come from various villages around Ngcobo.
Fanti, like many other patients, says they are forced to sleep there overnight as the free transport provided by the hospital leaves at the crack of dawn.
“I had to call my neighbour to [bring] me here, otherwise I could have died waiting for the ambulance. They told me that I have to be taken to Mthatha to see a specialist, but having to sleep under these conditions at my age is a terrible experience,” she says.
An old problem
The challenges with patient transport, specifically emergency medical transport in the Eastern Cape, are not new. Spotlight has previously reported on the issue here, here, and here.
In October last year, Eastern Cape Health MEC Nomakosazana Meth in a response to a written question in the provincial legislature by DA MPL Jane Cowley said that there are 84 Emergency Medical Services (EMS) bases in the Eastern Cape – 16 of those are in the Chris Hani District where All Saints Hospital is situated.
Based on the numbers Meth provided, the district also has the highest vacancy rate – 65%. This means of the 796 posts available, there were 518 vacancies for EMS staff at the time of her response in October. Overall, for the whole province, the total posts were 3 269, but 1 202 were vacant at the time.
The province needs 671 ambulances based on its population but has 447 ambulances of which only 200 were rostered, meaning they were in service at the time. In Chris Hani District, they need at least 72 ambulances but only have 62 of which just 38 were rostered and on the road to provide a service.
Staff shortages and ambulances undergoing maintenance are among the reasons why there are not enough ambulances rostered in the province. Not one of the 84 EMS bases in the province complied with the national EMS regulations for personnel numbers.
According to the DA’s provincial health spokesperson, Jane Cowley, there are 150 ambulances at any given time in for repairs. “The average turnaround time for repairs is a shocking 100 days – this is because they use the Government Fleet Management Services, who are owed in excess of R300 million by the [provincial health department] so they really don’t prioritise ambulance repairs.” She says the DA has been calling for the decentralisation of ambulance repairs and the development of public-private partnerships, which the party believes would speed up repair turnaround times dramatically.
Shouldering the burden
Providing some perspective on the impact this has on services and patient lives, a doctor says there are some districts where, at times, there is only one paramedic on duty per shift (the doctor spoke to Spotlight on condition of anonymity given the risks of reprisals from the health department). “When there is a serious call from opposite ends of the district, then you have to wait for the paramedic to deal with the one case, then come to the second. Patients in hospitals are deemed ‘less serious’ than if they are on the roadside. So, patients can wait for hours in a district hospital before being referred to a tertiary hospital. We recently had an elderly man with wet gangrene on his foot who waited in a casualty for two days. Then he died,” the doctor says.
The doctor says they often have a full casualty unit on Saturday nights. At times there may be four patients waiting for a referral. They may have gunshot wounds, been stabbed in the neck, and assaulted with a head injury. The casualty fills up as time passes and the number of patients waiting for referrals now grew by three, while the other four are still waiting in casualty. The three may be all orthopaedic patients. The doctor will ask the nurse about the patients and is told EMS said “no ambulances available”. “Maybe you have the energy to paste this update on the EMS WhatsApp group. Maybe you try to phone someone yourself to escalate this issue. Maybe someone is able to contact the provincial office and request a private ambulance to assist. But by morning, there are still six patients waiting… then one dies. The oncoming team will now have to re-discuss these patients with the new team at the referral centre. The same thing happens day after day… patients miss appointments, have to be re-discussed, get a new date due to the perseverance of the doctors, then maybe miss another date due to EMS not being available… It is extremely exhausting for all concerned,” the doctor says.
According to two paramedics (who also spoke on condition of anonymity), they struggle with inadequate equipment in EMS vehicles. This, coupled with poor road infrastructure, often puts them under enormous pressure, they say. “Cellphone network also disappears during loadshedding and this makes it impossible for patients to reach our services,” says one of the paramedics. “When we eventually arrive at the accident scene or at a sick patient, we are often met with insults from frustrated patients who said they’ve been trying to get hold of an ambulance for hours. Often, they forget about the challenges we face in trying to get to them on time,” he said.
Three-phased plan – yet to be financed
Meth in her parliamentary response last year said, “The[se] frequent transfers of patients put a heavy burden on the emergency medical services as there are no ambulances to do inter-facility transfers and therefore the emergency ambulances are used to transfer patients from hospitals to other hospitals over long distances with no ambulances left for emergency response at community level.” She said this is why there are often poor ambulance response times or no response at all.
In an attempt to address this, the provincial health department is working on a three-phased EMS plan targeting 28 hospitals across districts – among them All Saints.
This plan, however, will need funding to get off the ground.
Explaining the department’s three-phased plan, provincial health spokesperson Yonela Dekeda last week said the department plans to recruit additional personnel as funding becomes available and so did not provide timeframes. She says phase one is aimed at providing a dedicated inter-hospital transfer ambulance on a day-shift basis at the 28 priority hospitals. They aim to appoint 120 new staff members for this.
In phase two, the department wants to appoint an additional 120 personnel to make the day service a twenty-four-hour service and phase three is to extend this to other hospitals and provide them with the personnel needed.
But, says Dekeda, the department will need R27 million and they expect funding only to be made available in the 2023/24 financial year.
Working to address EMS challenges
Meanwhile, she says, the department has been working to address the many challenges facing EMS in the province and there are some improvements. “These include the response rate to priority 1 calls (life-threatening calls). Over the past three quarters – ending December 2022 – the department has been meeting its targets for priority 1 calls by responding within 30 minutes (urban areas) and 60 minutes (rural areas).” She didn’t however specify what percentage of calls met these targets.
According to her, the department has taken a developmental approach to achieve compliance with the national EMS regulations. She says over the next three years there will be continued investments in infrastructure, equipment, staffing, and vehicles to promote compliance with the ideal promulgated in the regulations.
“We have purchased an additional 50 ECG monitors at a cost of R19 million to supplement the equipment in our ambulances as required by the regulations. About R15 million has been allocated to improving the infrastructure at selected EMS stations around the province and an additional allocation is expected in the next financial year to support the strategy,” she says.
In the current financial year, she says, the Engcobo Local Service Area where All Saints Hospital is located was allocated two intermediate life support practitioners.
Dekeda says the department’s priority remains emergency patient care, so the majority of the current resources are still allocated to this.
“We are using our staff interchangeably between planned patient transport and the emergency transport service. One will understand that the planned patient transport works on weekdays (Monday to Friday) while emergency ambulance services are a 7-day operation, 24 hours a day. We are committed to increasing the number of staff on the emergency transport and then developing a separate staff complement for the planned patient transport service.”
Dekeda also says recruiting more staff is coupled with interventions to have the district hospitals offer the appropriate package of services, which will reduce the number of trips transferring patients. She says by employing dedicated teams to manage transfers of patients at the 28 priority hospitals as part of the three-phased plan, the hope is to improve the overall responsiveness of the ambulance fleet.
“We will continue with this recruitment in the next financial year and also focus on the operational staff to assist with the transfers of critical patients. All Saints is one of the district hospitals that will benefit,” she stresses.
“A total mess”
But some Eastern Cape residents remain sceptical.
Responding to the new plans, activist and community leader from Xhora Mouth, Phumzile Msaro says they are tired of empty promises. “This EMS problem is going to be with us for a long time as long as there are still unreliable people at the top. Every day we are faced with challenges as rural dwellers. Just yesterday (09 February), I called an ambulance for an elderly villager from Xhora Mouth who had fits. The assistants at the call centre lied and said the ambulance was on its way but we waited all day, only for the ambulance to arrive at 7 pm after a number of frantic calls throughout the day. The elderly person only managed to arrive and get assistance at Madwaleni Hospital at 9 pm. We keep hearing about all these so-called plans but nothing gets implemented on the ground. It’s a total mess,” he says.
Cowley echoes these sentiments. She says due to ambulance shortages and the severe shortage of EMS personnel, especially advanced life support paramedics, ambulance turnaround times are very slow, particularly in rural areas. “People can wait up to a day for an ambulance and sometimes that is too late. They have many plans but cannot seem to implement them as there is no political will to do so. It’s just a talk shop. In all my extensive oversight visits, the constant and main complaint is the lack of or slow ambulance service.”
