The South African Health Products Regulatory Authority (SAHPRA) is aware of the product Lubri-A (Sterile Lubricating Jelly) manufactured by Electro-Spyres, classified as Class B medical device and currently being distributed across the country.
SAHPRA has been informed of multiple complaints received from health institutions, both public and private across the country. The complaints are as a result of a number of patients who became ill due to developing a fungal infection, caused by exposure to the fungal species, Wickerhamomyces anomalus (previously Candida pelliculosa) associated with use of Lubri-A (Sterile Lubricating Jelly).
Lubri-A is available in two presentations, the 2.5 g sachets and 50 g tubes.
Considering the wide usage of the product for lubricating purposes in medical and surgical procedures, the Regulator has taken a decision to urgently recall this product from the market as there are multiple contaminated batches, with the potential to cause serious and widespread nosocomial infections. SAHPRA is alerting healthcare professionals and the public to discontinue the use of the product, remove it from their inventory and return it through their normal distribution channel(s) with immediate effect.
As the source of the contamination of the product is still under investigation and not confirmed, all batches of Lubri-A are being recalled. Future manufacture and distribution of the product will be subject to review and authorisation by SAHPRA.
Classification of the recalls
The recall is being classified as a Class 1, Type A recall, which is associated with a serious product quality concern that may have severe consequences. This is a countrywide recall. The product is being recalled from hospitals, retail outlets, health care professionals, authorised prescribers and individual customers or patients.
What the public should know
Healthcare professionals that have used this product should contact their patients to determine any symptoms of infection after use of product.
The recall is limited to the product called LUBRI-A (2.5g and 50g sachets) and does not affect other lubricating gel products authorised for sale in South Africa.
The contact telephone numbers for Electro-Spyres are:
Landline: 011-608-3998 or 011-402-7208
“As a national regulatory authority, the recalling of medical products is a crucial measure to address safety concerns or quality issues so that we protect the health of the public. SAHPRA is recalling this product from the market as there are multiple suspected contaminated batches with the potential to cause serious and widespread nosocomial infections, ” indicates SAHPRA CEO, Dr Boitumelo Semete-Makokotlela.
An immune system protein that normally guards against fungal infections is also responsible for exacerbating certain autoimmune diseases such as irritable bowel disease (IBS), type 1 diabetes, eczema and other chronic disorders, new research from The Australian National University (ANU) has found.
The discovery, published in Science Advances, could pave the way for new and more effective drugs, without the nasty side effects of existing treatments.
In addition to helping to manage severe autoimmune conditions, the breakthrough could also help treat all types of cancer.
The scientists have discovered a previously unknown function of the protein, known as DECTIN-1, which in its mutated state limits the production of T regulatory cells.
These ‘guardian’ Treg cells are crucial to preventing autoimmune disease because they suppress the effects of a hyperactive immune system.
“Although the DECTIN-1 protein helps to fight fungal infections, in its mutated state it’s also responsible for exacerbating severe autoimmune disease,” lead author Dr Cynthia Turnbull, from ANU, said.
“Understanding how and why the mutated version of this protein causes autoimmunity in patients brings us a step closer to developing more effective drugs and offers new hope to more than one million Australians who suffer from some form of autoimmune disease.”
The scientists believe they can control the immune system by turning the DECTIN-1 protein on and off, like a light switch.
“Turning on the protein would lower the intensity of the immune system’s defensive response which would help to treat conditions such as autoimmune disease,” Professor Carola Vinuesa, from the Francis Crick Institute, said.
“On the other hand, turning off the protein could give the immune system a boost, sending its defensive mechanisms into overdrive and allowing the body to treat an entirely different set of diseases.
“The findings are exciting because there haven’t been many discoveries of so-called modifier proteins such as DECTIN-1, which can change the way the immune system behaves to the extent it can either cause a disease or prevent it.”
According to Dr Turnbull, this means DECTIN-1 could play a key role in treating cancer.
“Cancer cells can disguise themselves by releasing certain proteins and chemicals into the body that essentially render them invisible from the immune system’s natural defences,” she said.
“We think that by using drugs to turn off the DECTIN-1 protein, in combination with existing therapies, we can activate the immune system and help it identify and attack the cancerous cells.”
Current treatments for autoimmune?disease aren’t very effective and have a lot of damaging side effects.
This is because the majority of existing treatments suppress the entire immune system rather than targeting a specific area.
“That means it might not fix the exact problem behind the patient’s disease and could inadvertently make them vulnerable to infections. Many people on these kinds of treatments also get bacterial, fungal and viral infections which can make their autoimmunity worse,” Professor Vinuesa said.
Mutation found in family
By examining the DNA of a Spanish family, the researchers discovered the DECTIN-1 mutation was responsible for exacerbating the severity of a chronic autoimmune disease suffered by the family’s only child.
“We found the family was also carrying a mutated version of another immune system protein known as CTLA-4. The CTLA-4 mutation prevents guardian cells from working properly and is known to cause severe autoimmune disease in about 60 to 70 per cent of people who carry it in their DNA,” Dr Pablo Canete, from the University of Queensland, said.
“Strangely, the remaining 30 to 40 per cent of the population who carry this mutated protein don’t develop disease.
“We discovered the family’s only child had both the DECTIN-1 mutation and the CTLA4 mutation, while his parents had only one of each. This helped us identify why the child, who is now in his twenties, was the only person in the family to develop severe autoimmunity, ending a 20-year-long mystery behind the cause of his disease.
“By discovering the existence of mutated versions of modifier proteins such as DECTIN-1, we finally have an explanation for why some people develop severe autoimmune diseases while others don’t, even if they inherit gene mutations passed down from family members.”
Immunotherapy in combination with chemotherapy has become an important therapeutic treatment option in some patients with metastatic breast cancer. Which patients will benefit the most, however, remains unclear; current biomarkers such as PD-L1 that are used to predict response are mediocre at best. Vanderbilt researchers led a clinical trial combining atezolizumab, an immunotherapy, in combination with chemotherapy in patients with metastatic triple-negative breast cancer to both evaluate the efficacy of the treatment combination and to understand biomarkers of response to immunotherapy.
Atezolizumab became the first approved immunotherapy for breast cancer when the Food and Drug Administration granted it accelerated approval in 2019, but two years later, its maker voluntarily withdrew the indication after additional data from a follow-up clinical trial failed to corroborate its efficacy. Atezolizumab had been approved for metastatic PD-L1-positive triple-negative breast cancer in combination with the chemotherapy nab-paclitaxel. Results from Vanderbilt’s clinical trial, published in JAMA Oncology, indicate that this immunotherapy does have a clinically meaningful benefit with a different chemotherapy partner and the correlative analyses provide insight to which patients will respond.
The clinical trial combined atezolizumab with carboplatin – a chemotherapy that works differently than nab-paclitaxel. The new combination significantly improved progression-free and overall survival of patients with metastatic triple-negative breast cancer. Atezolizumab with carboplatin lengthened progression-free survival from a median of 2.2 months to 4.1 months. Overall survival increased from a median of 8.6 months for the control group, who received carboplatin alone, to 12.6 months for those who received the combination therapy.
The phase 2 randomized clinical trial was conducted at six cancer centers through the Translational Breast Cancer Research Consortium and involved 106 patients of diverse ethnicities.
“Triple-negative breast cancer is difficult to treat because we don’t have a clear target, and understanding the underlying factors that affect response to a treatment is key. This study is so important because we were able to collect biopsies in all of the participants and really understand factors that affect response,” said Vandana Abramson, MD, the Donna S. Hall Professor in Cancer Research and co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center.
The researchers hypothesised that atezolizumab would have superior efficacy to carboplatin because the chemotherapy is a platinum agent, which causes structural DNA changes and generates neoantigens that may stimulate an immune response. Nab-paclitaxel chemotherapy works differently: it is a microtubule-stabilising agent that stops cancer cell division.
“The tremendous knowledge gained from our multidisciplinary analyses of the patients and their tumours will continue to be important for clinical decision-making. After our first description of the triple-negative breast cancer subtypes over 10 years ago, more recently, we refined the subtypes further into four, which were analysed in this study: two basal-like subtypes, a mesenchymal subtype and a lumen androgen receptor-expressing subtype. When we refined the triple-negative breast cancer subtypes, we revealed an immune-modulatory descriptor or correlation.
“This JAMA Oncology study and others continue to confirm that lymphocytes, as measured by the immune-modulatory correlation, have predictive value for better relapse-free survival for triple-negative patients. Further, this study provides evidence that the luminal androgen receptor subtype is more like oestrogen receptor-positive (or ER+) disease. Prior studies investigating immunotherapy in breast cancers have shown that patients with ER+ disease have less benefit from immunotherapy, and we found that to be the case with patients with luminal androgen-positive tumours in this trial,” said Jennifer Pietenpol, PhD, the study’s corresponding author.
Interestingly, patients with higher body mass indexes and uncontrolled blood glucose levels had greater benefit from atezolizumab with carboplatin. The researchers noted that these patients may have more immune cells upon which anti-PD1/PD-L1 therapies can act. A lower risk of disease progression was also associated with high mutation burden and increased tumour-infiltrating lymphocytes.
“In this study, we observed that patients received benefit with atezolizumab even if the tumours were PD-L1 negative. We also show that, like prior clinical trials in melanoma and renal and lung cancers, tumours with high mutation burdens and the presence of immune cells within or around the tumour receive greater benefit from immunotherapy. This makes sense because each mutation has the potential to be recognised as non-self by the immune system, increasing the probability of immune cells already positioned around the tumour to recognise and target the cancer,” said Brian Lehmann, PhD, Research Associate Professor of Medicine and lead correlative scientist on the study.
“One surprising finding was the trend toward greater benefit for patients with higher body mass indexes and patients with uncontrolled blood glucose at prediabetic and diabetic levels while on the study. Both obesity and diabetes are linked to systemic inflammation, and the increased benefit may be attributed to higher adipose tissue composition in the breast and augmented by metabolic syndrome conditions such as Type 2 diabetes. Further studies are necessary to validate these findings and delineate the effects of blood glucose and obesity on immunotherapy,”
The combination therapy was generally well-tolerated, and toxic effects were consistent with previous reports for atezolizumab. The most common drug complications on the combination arm of the clinical trial were low blood platelet counts, anaemia, lymphocytopenia, nausea, fatigue and increased liver enzymes. The participants identified as 69% white, 19% African American, 10% unknown and 1% Asian.
The holiday season is a time for joy and celebration but many Americans admit the endless flurry of activities make it difficult to eat healthy, exercise and get adequate rest, according to a new survey from The Ohio State University Wexner Medical Center.
Two-thirds of those surveyed said they overindulge in food, nearly 45% said they take a break from exercise and more than half report feeling tired and have less time for themselves. Plus, a third admit they drink more alcohol during the holidays.
“Holiday travel, activities with friends and family, and trying to get a bunch of things done can cause people to lose track of their healthy habits,” said Barbara Bawer, MD, family medicine physician at Ohio State Wexner Medical Center and clinical assistant professor of family and community medicine at The Ohio State University College of Medicine.
“If one healthy habit drops off, it can affect other areas very quickly.”
To make it through the holiday season with healthy habits intact, Bawer suggests trying to stick to a normal routine as much as possible while giving yourself some grace.
“Once you’re out of a routine, which typically happens around the holidays, it’s really hard to get back on track partly because the motivation is no longer there,” said Bawer.
When the invitations start to pile up and decadent menus feels tempting, Bawer offers this advice, “Remember that it’s OK to say no.”
To keep healthy habits in check, try the following:
Diet: When it comes to sustaining healthy eating habits, it’s important to plan ahead. If you have an evening event, don’t starve yourself all day. Eat a high protein, low carb meal earlier in the day so you don’t overeat.
You can indulge with a favorite dish or dessert but it’s OK to say no to sampling every entrée or treat so you’re not eating excess calories at each event.
Exercise: Try to keep the same exercise schedule. If an obligation prevents you from going to a fitness centre or going for a run, be flexible. It’s OK to say no to the gym and consider doing an activity with family and friends that keeps you moving like going for a walk or playing a game of basketball.
Sleep: Go to sleep and wake up at your normal times, even when travelling. Limit the use of supplements like melatonin, as long-term use can disrupt healthy sleep-wake cycles. It’s OK to say no to some invitations if you feel like you’re going to overextend yourself.
Alcohol: People may drink more during the holidays but binge drinking is never a healthy choice. Binge drinking is when a man consumes five drinks or a woman consume four drinks in one setting. It’s OK to say no to excessive drinking. If you do drink, try to stick to the recommended two drinks for men or one drink for women. Avoid drinking on an empty stomach and drink plenty of water.
“Small, consistent changes and slowly adding to them can help you reach your health goals,” Bawer said.
Survey results and methodology This survey was conducted on behalf of The Ohio State University Wexner Medical Center by SSRS on its Opinion Panel Omnibus platform. The SSRS Opinion Panel Omnibus is a national, twice-per-month, probability-based survey. Data collection was conducted from Oct. 20-23 among a sample of 1 007 respondents. The survey was conducted via web (n = 977) and telephone (n = 30) and administered in English. The margin of error for total respondents is +/-3.6 percentage points at the 95% confidence level. All SSRS Opinion Panel Omnibus data are weighted to represent the target population of U.S. adults ages 18 or older.
HFA outlines presidential petition to prevent decimation of the SA healthcare system
The NHI Bill presented to President Cyril Ramaphosa cannot be permitted, as in its current form, it will infringe the rights of all South Africans by destroying the South African healthcare system. The Health Funders Association (HFA) has petitioned the President to withhold assent of the Bill on constitutional and procedural grounds and intends to take the matter as far as necessary and to the Constitutional Court if need be.
“We have taken a strong stand by respectfully urging the President to withhold assent of the Bill, citing constitutional and procedural concerns that pose a significant threat to the integrity of the country’s healthcare system,” remarks HFA Chairperson Craig Comrie.
“Should the need arise, the HFA is prepared to escalate the matter to the courts. Our goal is to meticulously align the legislation with the authentic objectives of Universal Health Coverage and the principles enshrined in the South African Constitution.
“Our action in opposing the NHI Bill being signed into law protects the interests of ALL South Africans who will require healthcare in future, including the people we are duty-bound to safeguard through the medical schemes and healthcare administrators we represent,” Comrie says.
While expressing unwavering support for achieving Universal Health Coverage (UHC) in South Africa, the HFA questions Parliament’s endorsement of a bill that raises significant constitutional and procedural concerns and fundamentally cannot achieve a sustainable system of UHC.
Some of the primary concerns outlined in the letter include:
Constitutional concerns: The NHI Bill’s clear infringement on constitutional rights, particularly the right to access healthcare and freedom of choice for South Africans, and by implication, the right to life. The Bill is seriously flawed in that regard, undermining the rule of law.
Procedural concerns: Questioning the extent and effectiveness of public consultation during the drafting and review of the NHI Bill, where thousands of submissions resulted in no meaningful changes to the Bill, the HFA advocates for a more inclusive and consultative approach.
The letter implores President Ramaphosa to exercise the powers granted by the Constitution to refer the NHI Bill back to Parliament for review.
“In addition to petitioning the President directly as guardian of the Constitution, the HFA will oppose the NHI Bill in its current form through every possible avenue, including approaching the courts to set aside the Bill on constitutional and procedural grounds.
“The HFA will also seek a High Court interdict against implementation of the NHI Act until the merits of our case have been heard and ruled upon by the High Court.
Craig Comrie concludes, “It is with a heavy heart that we make this plea, urging the President to secure the rights and wellbeing of our people. We will persist to ensure that what is right triumphs in our nation. South Africa deserves leadership that prioritises the welfare of all of its citizens, above all.”
A study published in Nature Communications has revealed that the time at which we eat could influence our risk of developing cardiovascular disease. This study, suggests that eating a late first or last meal is associated with a higher risk of cardiovascular disease. It also appears that a longer night-time fasting duration is associated with a reduced risk of cerebrovascular disease such as stroke. The findings, suggest the importance of daily meal timing and rhythm in reducing cardiovascular disease risk.
The study was led by scientists from INRAE, the Barcelona Institute for Global Health, Inserm, and the Université Sorbonne Paris Nord.
Diet plays a major role in the development and progression of cardiovascular diseases. The modern lifestyle of Western societies has led to specific eating habits such as eating dinner late or skipping breakfast. In addition to light, the daily cycle of food intake (meals, snacks, etc) alternating with periods of fasting synchronizes the peripheral clocks, or circadian rhythms, of the body’s various organs, thus influencing cardiometabolic functions such as blood pressure regulation. Chrononutrition is emerging as an important new field for understanding the relationship between the timing of food intake, circadian rhythms and health.
Scientists used data from 103,389 participants in the NutriNet-Santé cohort (79% of whom were women, with an average age of 42) to study the associations between food intake patterns and cardiovascular disease. To reduce the risk of possible bias, the researchers accounted for a large number of confounding factors, especially sociodemographic factors (age, sex, family situation, etc.), diet nutritional quality, lifestyle and sleep cycle.
The results show that having a first meal later in the day (such as when skipping breakfast), is associated with a higher risk of cardiovascular disease, with a 6% increase in risk per hour delay. For example, a person who eats for the first time at 9 am is 6% more likely to develop cardiovascular disease than someone who eats at 8 am When it comes to the last meal of the day, eating late (after 9 pm) is associated with a 28% increase in the risk of cerebrovascular disease such as stroke compared with eating before 8 pm, particularly in women. Finally, a longer duration of night-time fasting – the time between the last meal of the day and the first meal of the following day – is associated with a reduced risk of cerebrovascular disease, supporting the idea of eating one’s first and last meals earlier in the day.
These findings, which need to be replicated in other cohorts and through additional scientific studies with different designs, highlight a potential role for meal timing in preventing cardiovascular disease. They suggest that adopting the habit of eating earlier first and last meals with a longer period of night-time fasting could help to prevent the risk of cardiovascular disease.
2023 was a busy year for healthcare in South Africa. There were several policy developments, landmark court cases, important pieces of legislation, and some changes in leadership. Yet, take a step back and not much seems to have changed. Shortages of healthcare workers persist, corruption is still rife, budgets tight, and our health governance crisis remains as acute as ever.
That ability to implement was dealt another blow this year with continued budget cuts in the public healthcare sector and the freezing of posts in some areas. As shown in several of the community healthcare monitoring group Ritshidze’s excellent provincial reports this year, staff shortages remain acute across much of the country – something that is unlikely to change given budget constraints. Though South Africa has a good healthcare worker strategy on paper, another year has passed with no clear indication that the state is committed to implementing it.
Instead, much of the political oxygen in 2023 was again consumed by National Health Insurance (NHI). As the year draws to an end, the NHI Bill has cleared parliament and chances are the President will sign it ahead of next year’s national and provincial elections – though actual implementation will take years.
Reforms to South Africa’s procurement legislation are also making its way through parliament, although critics have slammed the bill for not doing enough to clamp down on corruption. The State Liability Bill was delayed again because a report from the South African Law Reform Commission on medico-legal claims has still not been finalised.
As for leadership changes, this year South Africa got a new health ombud (we interviewed the outgoing ombud here) and a new registrar of the Health Professions Council – the latter institution remains in urgent need of reform. Maybe the most important leadership change this year, however, was the controversial removal in September of Dr Rolene Wagner as head of the Eastern Cape Health Department. Wagner’s removal seems symptomatic of ongoing and excessive political interference in the running of provincial health departments.
Several of these departments again made the headlines for the wrong reasons. Current and former Officials in both the North West and Northern Cape Department of Health are facing serious charges, but maybe most dispiriting was the ongoing dysfunction in the Gauteng Department of Health. From botched food and security contracts to the lacklustre response to alleged corruption at Tembisa Hospital, those who hoped for a turnaround in the department were disappointed. The end of the inquest into the Life Esidimeni tragedy this year served as reminder that the department’s problems are entrenched and long-standing.
South Africa’s TB response was given a boost this year with the adoption of an ambitious new test-and-treat strategy, whereby people who test positive for TB are treated and at-risk people who test negative are offered preventive therapy. Some new TB treatment regimens have been rolled out, but we are unfortunately still waiting for others. A reduced price for the DR-TB drug bedaquline was secured, largely due to the work of South African and international TB activists, and two philanthropies put up the money for a critically important phase 3 TB vaccine trial.
Pilot programmes testing HIV prevention injections and HIV prevention rings in South Africa were set to start at the beginning of the year, but the injection part of those pilots ended up being delayed. It is still not clear when the many young women in South Africa who could benefit from the prevention injection will be able to get it. A recently announced price for the injection is calculated to be far too high for our healthcare system.
There was some good news this year in that more people in South Africa are finally able to access breakthrough hepatitis C cures developed over the last decade. The picture looks less promising with new weight loss medicines – high prices, supply constraints, and monopolies are likely to keep these exciting medicines out of reach for most people in South Africa, despite the rising number of people with obesity who could benefit from them.
As for the numbers, the WHO this year estimated that in 2022 280 000 people fell ill with TB in South Africa and 54 000 people died of TB. According to the latest estimates from the Thembisa model, in 2022 around 13% of the population were living with HIV, 164 000 people were newly infected with HIV, and 48 000 died of HIV-related causes (there is substantial overlap since many people with HIV die of TB). The Human Sciences Research Council (HSRC) raised some eyebrows when it estimated that 91% of people diagnosed with HIV were on treatment in 2022, UNAIDS and the Thembisa model have this number at well under 80%. New UNAIDS and Thembisa estimates due in 2024 will be closely watched to see how they are impacted by the HSRC findings.
Glioblastoma is one of the most treatment-resistant cancers, with those diagnosed surviving for less than two years. In a new study in NPJ Genomic Medicine, researchers at the University of Notre Dame have found that a largely understudied cell could offer new insight into how the aggressive, primary brain cancer is able to resist immunotherapy.
“A decade ago, we didn’t even know perivascular fibroblasts existed within the brain, and not just in the lining of the skull,” said senior author Meenal Datta, assistant professor of aerospace and mechanical engineering at Notre Dame.
“My lab’s expertise is examining tumours from an engineering and systems-based approach and looking at the novel mechanical features in rare cancers that may have been understudied or overlooked.”
Using standard bioinformatics and newer AI-based approaches, Datta’s TIME Lab began analysing different genes expressed in the tumour microenvironment related to the extracellular matrix – or the scaffolding cells create to support future cell adhesion, migration, proliferation and differentiation – and other various cell types.
What they found was a surprising, fairly new cell type: perivascular fibroblasts.
These fibroblasts are typically found in the blood vessels of a healthy brain and deposit collagen to maintain the structural integrity and functionality of brain vessels.
“It was a serendipitous discovery,” said first author Maksym Zarodniuk, graduate student in the TIME Lab and the bioengineering doctorate programme.
“We started in a completely different direction and stumbled upon this population of cells by using a combination of both bulk and single-cell RNA sequencing analyses of patient tumours.”
In their data, researchers were able to identify two groups of patients: those with a higher proportion of perivascular fibroblasts and those with significantly less.
They found that brain cancer patients with more perivascular fibroblasts in their tumours were more likely to respond poorly to immunotherapies and have poor survival outcomes.
Further study revealed that perivascular fibroblasts support the creation of an immunosuppressive tumour microenvironment, allowing the cancer to better evade the immune system.
The fibroblasts may also help the cancer resist therapies such as chemotherapy that targets cell division by promoting stem-like cancer cells that rarely divide, which are believed to be a major source of tumour relapse and metastasis.
“Moving forward, we want to do new experiments to confirm what we found in this paper and provide some good ground to start thinking about how to improve response to immunotherapy,” Zarodniuk said.
Because perivascular fibroblasts are a part of a healthy brain’s vasculature, Datta believes that these cells are breaking off and getting close to or infiltrating the glioblastoma tumour.
However, instead of supporting healthy brain function, these fibroblasts are getting reprogrammed and helping the tumour instead.
“Most people think about the brain as being very soft, with soft cells and a soft matrix. But by putting down these fibroblasts and making these very fibrous proteins, it gives us an entirely different perspective on the structure of the brain and how it can be taken advantage of by cancer cells originating in the same organ,” Datta said.
A Cambridge-led study has shown why many women experience nausea and vomiting during pregnancy – and why some women, including the Duchess of Cambridge, become so sick they need to be admitted to hospital.
The culprit is a hormone produced by the foetus – a protein known as GDF15. But how sick the mother feels depends on a combination of how much of the hormone is produced by the foetus
The discovery, published today in Nature, points to a potential way to prevent pregnancy sickness by exposing mothers to GDF15 ahead of pregnancy to build up their resilience.
As many as seven in ten pregnancies are affected by nausea and vomiting. In some women – thought to be between one and three in 100 pregnancies – it can be severe, even threatening the life of the foetus and the mother and requiring intravenous fluid replacement to prevent dangerous levels of dehydration. So-called hyperemesis gravidarum is the commonest cause of admission to hospital of women in the first three months of pregnancy.
Although some therapies exist to treat pregnancy sickness and are at least partially effective, widespread ignorance of the disorder compounded by fear of using medication in pregnancy mean that many women with this condition are inadequately treated.
Until recently, the cause of pregnancy sickness was entirely unknown. Recently, some evidence, from biochemical and genetic studies has suggested that it might relate to the production by the placenta of the hormone GDF15, which acts on the mother’s brain to cause her to feel nauseous and vomit.
Now, an international study, involving scientists at the University of Cambridge and researchers in Scotland, the USA and Sri Lanka, has made a major advance in understanding the role of GDF15 in pregnancy sickness, including hyperemesis gravidarum.
The team studied data from women recruited to a number of studies, including at the Rosie Maternity Hospital, part of Cambridge University Hospitals NHS Foundation Trust and Peterborough City Hospital, North West Anglia NHS Foundation Trust. They used a combination of approaches including human genetics, new ways of measuring hormones in pregnant women’s blood, and studies in cells and mice.
The researchers showed that the degree of nausea and vomiting that a woman experiences in pregnancy is directly related to both the amount of GDF15 made by the foetal part of placenta and sent into her bloodstream, and how sensitive she is to the nauseating effect of this hormone.
GDF15 is made at low levels in all tissues outside of pregnancy. How sensitive the mother is to the hormone during pregnancy is influenced by how much of it she was exposed to prior to pregnancy – women with normally low levels of GDF15 in blood have a higher risk of developing severe nausea and vomiting in pregnancy..
The team found that a rare genetic variant that puts women at a much greater risk of hyperemesis gravidarum was associated with lower levels of the hormone in the blood and tissues outside of pregnancy. Similarly, women with the inherited blood disorder beta thalassemia, which causes them to have naturally very high levels of GDF15 prior to pregnancy, experience little or no nausea or vomiting.
Professor Sir Stephen O’Rahilly, Co-Director of the Wellcome-Medical Research Council Institute of Metabolic Science at the University of Cambridge, who led the collaboration, said: “Most women who become pregnant will experience nausea and sickness at some point, and while this is not pleasant, for some women it can be much worse – they’ll become so sick they require treatment and even hospitalisation.
“We now know why: the baby growing in the womb is producing a hormone at levels the mother is not used to. The more sensitive she is to this hormone, the sicker she will become. Knowing this gives us a clue as to how we might prevent this from happening. It also makes us more confident that preventing GDF15 from accessing its highly specific receptor in the mother’s brain will ultimately form the basis for an effective and safe way of treating this disorder.”
Mice exposed to acute, high levels of GDF15 showed signs of loss of appetite, suggesting that they were experiencing nausea, but mice treated with a long-acting form of GDF15 did not show similar behaviour when exposed to acute levels of the hormone. The researchers believe that building up woman’s tolerance to the hormone prior to pregnancy could hold the key to preventing sickness.
Co-author Dr Marlena Fejzo from the Department of Population and Public Health Sciences at the University of Southern California whose team had previously identified the genetic association between GDF15 and hyperemesis gravidarum, has first-hand experience with the condition. “When I was pregnant, I became so ill that I could barely move without being sick. When I tried to find out why, I realised how little was known about my condition, despite pregnancy nausea being very common.
“Hopefully, now that we understand the cause of hyperemesis gravidarum, we’re a step closer to developing effective treatments to stop other mothers going through what I and many other women have experienced.”
The work involved collaboration between scientists at the University of Cambridge, University of Southern California, University of Edinburgh, University of Glasgow and Kelaniya University, Colombo, Sri Lanka. The principal UK funders of the study were the Medical Research Council and Wellcome, with support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre.
In one of every 10 people, and in one third of children with celiac disease, the enamel coating of the teeth appears defective, failing to protect the teeth properly. As a result, teeth become more sensitive to heat, cold and sour food, and they may decay faster. In most cases, the cause of the faulty enamel production is unknown.
Now, a study by Prof Jakub Abramson and his team at the Weizmann Institute of Science, published recently in Nature, may shed light on this problem by revealing a new children’s autoimmune disorder that hinders proper tooth enamel development. The disorder is common in people with a rare genetic syndrome and in children with celiac disease. These findings could help develop strategies for early detection and prevention of the disorder.
Tooth enamel is made up primarily of mineral crystals that are gradually deposited on protein scaffolds during enamel development. Once the crystals are in place, the protein scaffold is dismantled, leaving behind a thin, exceptionally hard layer of enamel. A strange phenomenon was identified in people with a rare genetic disorder known as APS-1: although the enamel layer of their milk teeth forms perfectly normally, something causes its faulty development in their permanent teeth. Since people with APS-1 suffer from a variety of autoimmune diseases, Abramson and his team hypothesised that the observed enamel defects may also be of an autoimmune nature
In autoimmune disease, to prevent T cells from triggering the immune system to attack body tissues, T cells developing in the thymus gland must be educated’ to discriminate between the body’s own proteins and those of foreign origin. To this end, T cells are presented with short segments of self-proteins that make up various tissues and organs in the body. When a ‘poorly educated’ T cell erroneously identifies a self-protein in the thymus as a target for attack, that T cell is labelled as dangerous and destroyed, so that it could not cause any damage after being released from the thymus.
This critical education step is impaired in APS-1 patients as a result of a mutation in a gene known as the autoimmune regulator (Aire). This gene is essential for the T cell education process: It produces a protein that is responsible for the collection of self-proteins presented to the T cells in the thymus. In their new study, scientists from Abramson’s lab in Weizmann’s Immunology and Regenerative Biology Department, led by research student Yael Gruper, sought to work out how mutations in the Aire gene lead to deficient tooth enamel production. The researchers discovered that, in the absence of Aire, proteins that play a key role in the development of enamel are not presented to the T cells in the thymus gland. As a result, T cells that are liable to identify these proteins as targets are released from the thymus, and they encourage the production of antibodies to the enamel proteins. But why do these autoantibodies damage permanent teeth and not baby teeth?
The answer to this question lies in the fact that milk teeth develop in the embryonic stage, when the immune system is not yet fully formed and cannot create autoantibodies. In contrast, the development of enamel on permanent teeth starts at birth and continues until around the age of six, when the immune system is sufficiently mature to thwart enamel development. Furthermore, the researchers found a correlation between high levels of antibodies to enamel proteins and the severity of the harm to enamel development in children with APS-1. This strengthens the assumption that the presence of enamel-specific autoantibodies in childhood can potentially lead to dental problems.
When the researchers looked into deficiencies in enamel development in people with other autoimmune diseases, they found a very similar phenomenon in children with celiac disease, a relatively common autoimmune disorder that affects around 1% of people in the West. When people with this disease are exposed to gluten, their immune system attacks and destroys the cellular layer lining the small intestine, leading to attacks on other self-proteins in the intestine.
In an attempt to understand how celiac disease, known to cause intestinal damage, may also cause damage to tooth enamel, the researchers first examined whether people with this disease have autoantibodies against enamel. They found that a large proportion of celiac patients have these autoantibodies, just as do people with APS-1. But the ‘education’ in the thymus gland of these patients seems normal, so why do they develop these antibodies? The researchers hypothesised that some proteins are found in both the intestine and the dental tissue and that these proteins play an important role in the development of tooth enamel. In this case, the antibodies that identify proteins in the intestine might move through the bloodstream to the dental tissue, where they could start to disrupt the enamel production process.
Since many celiac patients had previously been found to develop sensitivity to cow’s milk, the researchers decided to focus on the k-casein protein, a major component of dairy products. Strikingly, they found that the human equivalent of k-casein is one of the main components of the scaffold necessary for enamel formation. This led them to hypothesise that antibodies produced in the intestines of celiac patients in response to certain food antigens, such k-casein, may subsequently cause collateral damage to the development of enamel in the teeth, similarly to the way in which antibodies against gluten can eventually trigger autoimmunity against the intestine.
Indeed, they discovered that most of the children diagnosed with celiac had high levels of antibodies against k-casein from cows’ milk, which in many cases can also react against k-casein’s human equivalent expressed in the enamel matrix. This means that in theory, the same antibodies that are produced in the intestine against the milk protein could act against the human k-casein in the teeth.
These findings could have implications for the food industry. “Similarly to the lessons learned from gluten, we can assume that the consumption of large quantities of dairy products could lead to the production of antibodies against k-casein,” Abramson explains. “This protein increases the amount of cheese that can be produced from milk, so the dairy industry deliberately raises its concentration in cow’s milk. Our study, however, found that the milk k-casein is a potent immunogen, which may potentially trigger an immune response that can harm the body itself.”
Tooth enamel flaws are common, not just among people with celiac disease or APS-1. “Many people suffer from impaired tooth enamel development for unknown reasons,” Abramson says. “It is possible that the new disorder we discovered, along with the possibility of diagnosing it in a blood or saliva test, will give their condition a name. Most important, early diagnosis in children may enable preventive treatment in the future.”