Rare hormone producing cells in the gut secrete hormones in response to incoming food and play key roles in managing digestion and appetite. Researchers have now developed new tools to identify potential ‘nutrient sensors’ on these hormone producing cells and study their function. This could result in new strategies to interfere with the release of these hormones and provide avenues for the treatment of a variety of metabolic or gut motility disorders.
The intestine acts as a vital barrier. It protects the body from harmful bacteria and highly dynamic pH levels, while allowing nutrients and vitamins to enter the bloodstream. The gut is also home to endocrine cells, which secrete many hormones that regulate bodily functions. These enteroendocrine cells (endocrine cells of the gut) are very rare cells that release hormones in response to various triggers, such as stretching of the stomach, energy levels and nutrients from food. These hormones in turn regulate key aspects of physiology in response to the incoming food, such as digestion and appetite. Thus, enteroendocrine cells are the body’s first responders to incoming food, and instruct and prepare the rest of the body for what is coming.
Understanding hormone release
Medications that mimic gut hormones, most famously GLP-1, are promising for the treatment of multiple metabolic diseases. The ability to directly manipulate endocrine cells to adjust hormone secretion could open up new therapeutic options. However, it has been challenging to understand how gut hormone release can be influenced effectively. Researchers have had trouble identifying the sensors on cells.
Enteroendocrine cells represent less than 1% of cells in the intestinal epithelium. In addition, the sensors on these cells are expressed in low amounts. Current studies mainly rely on mouse models, but the signals to which mouse cells respond are likely different from those to which human cells respond. Therefore, new models and approaches were required to study these signals.
Enteroendocrine cells in organoids
The Hubrecht team has previously developed methods to derive large quantities of enteroendocrine cells in human organoids. Organoids contain the same cell types of the organ they are derived from. Therefore, they are useful to explore the development and function of cells. Using a special protein, Neurogenin-3, the researchers could generate high numbers of endocrine cells in organoids of the intestine.
Enteroendocrine cells have different sensors and hormone profiles in different regions of the gut. In order to study these rare cells, the researchers needed to make organoids of all these different regions.
Stomach organoids
In the current study, the team managed to enrich enteroendocrine cells in organoids of other parts of the digestive system, including the stomach. Like the real stomach, stomach organoids respond to known inducers of hormone release and secrete large amounts of the hormone Ghrelin. Ghrelin is also called the ‘hunger hormone’ because it plays a key role in signaling hunger to the brain. The Ghrelin production of the stomach organoids confirms that these organoids can be used to study hormone secretion in enteroendocrine cells.
Enteroendocrine cell sensors
Since enteroendocrine cells are rare, researchers have struggled to profile many of these cells. In the current study, the team identified a so-called surface marker, called CD200, on human cells. The researchers used this surface marker to isolate a large number of human enteroendocrine cells from organoids and study their sensors. This revealed numerous receptor proteins that had not yet been identified in enteroendocrine cells.
The team stimulated the organoids with molecules that would activate these receptors and identified multiple new sensory receptors that control hormone release. When the researchers inactivated these receptors using CRISPR-based gene editing, hormone secretion was often blocked.
Therapeutic applications
With these data, the researchers can now predict how human enteroendocrine cells respond when certain sensory receptors are activated. Their findings thus pave the way for additional studies to explore the effects of these receptor activations. The enteroendocrine cell-enriched organoids will allow the team to perform larger, unbiased studies to identify new regulators of hormone secretion. These studies may eventually lead to therapies for metabolic diseases and gut motility disorders.
Family physicians undergo an extra four years of training, with an emphasis on clinical governance and knowledge of social factors influencing people’s health. Photo by cottonbro studio
By Chris Bateman
Around twenty years ago, family physicians seemed set to take up roles as critical cogs across South Africa’s public healthcare system, but in the years since, doctors trained in this speciality have largely been underutilised. That is now finally set to change, according to the Department of Health, Chris Bateman reports.
The National Department of Health has signalled that they want to see more family physicians appointed as clinical managers tasked with leading multi-disciplinary district hospital teams. This follows years of lobbying by the South African Academy of Family Physicians (SAAFP) advocating for the greater utilisation of family physicians in the country’s public healthcare system.
The SAAFP has long argued the cost and clinical effectiveness of these “super generalists”, who undergo an extra four years of training, with an emphasis on clinical governance and knowledge of social factors influencing people’s health. And it seems their patience has been rewarded with a five-year district health blueprint from government.
This was confirmed to Spotlight by Dr Luvuyo Bayeni, Chief Director of Human Resources for Health at the National Department of Health.
Advocates for the speciality argue that family physicians have been neglected, with posts thin on the ground and their potential contribution under-estimated. The discipline was registered with the HPCSA in 2007.
Professor Bob Mash, Distinguished Professor at Stellenbosch University where he heads the Division of Family Medicine and Primary Care, describes the specialty as “one of the most underutilised solutions to many of the problems facing district health service delivery”. Mash is the immediate past president of the SAAFP.
Bayeni, a former clinician/administrator in the Eastern Cape, was appointed to lead the health department’s human resource operations in July last year. Since then, he attended the last two annual SAAFP conferences and has been meeting regularly with the academy’s leadership.
With austerity measures being the catch-all rebuttal by provincial heads of department whenever the wisdom of freezing posts is questioned, Bayeni is trying to persuade his provincial counterparts to adopt a policy of appointing family physicians to clinical manager posts as a highly cost-efficient move, citing successes in the Western Cape. The idea is that family physicians are able to quickly diagnose and treat patients while mentoring junior colleagues. They also help design or tweak hospital and referral clinic systems for efficiency and identify preventative health interventions at community level.
Blueprint approved
In a wide-ranging interview with Spotlight, Bayeni said his family medicine oriented blueprint had been approved by the Presidency’s Department of Policy Planning, Monitoring and Evaluation for inclusion in all future health indicators. His plan is to initially get family physicians as clinical managers into all medium to large district hospitals (150 beds and above), before ensuring they are placed in every health district, including at lower level hospitals and community health centres, at all times leading a multi-disciplinary team.
“Instead of waiting for HR plans and organograms, this is going into the mid-term framework for monitoring. It’s a strategic opportunity, where we ask ourselves, ‘how do we define a multi-disciplinary team for a district hospital?’ and then work through and with them. We’ll define and map where our priority district hospitals are, starting with the medium to large district hospitals,” he said.
Bayeni said he met with his provincial counterparts and military health service chiefs last week, (14-18 October), where he said he was going to, “make sure they all know about this. Organograms are all fine and well and necessary, but I want this top of mind when they consider them.”
“Personally, by April next year, (the new financial year), I want to see more family physicians being appointed, either in the district or in the position of clinical managers wherever there are vacancies. I’ll ask the provinces to help me with monitoring and evaluation,” he said.
He said his ambition is to change the mindset of provincial healthcare leaders “wherever necessary” about family physicians being regarded as “just another specialty” when creating and enumerating posts.
Positive responses
Several top family medicine academics and clinicians around the country who have been at the forefront of providing data and lobbying for a more pragmatic healthcare delivery approach, welcomed the renewed focus on family physicians.
Professor Steve Reid, a veteran rural family physician and head of Primary Health Care at the University of Cape Town (UCT), told Spotlight the main problem was what he called a framing issue.
“The way we think about medicine is to just go to the doctor and get it sorted, rather than how a huge number of diseases can be managed and prevented early on – it’s been a major shift over the last fifty years. I mean we now have studies that link pre-natal health to later chronic diseases. The whole idea of social medicine went out of vogue, and the idea that health has far more to do with the social determinants of health than it has to do with the health system had too little purchase,” he said.
Reid observed that no family physician can work in isolation – they made the most difference when they had a multi-disciplinary team around them.
Labelling family physicians “boundary-spanners par excellence”, he said “they join the dots rather than work in silos like other specialties who tend to guard their turf jealously.”
“Brazil is a middle-income country just like South Africa and their simple model of one doctor, a nurse and four to six community health workers per 4 000 population has got 80% of their population covered, including vast urban areas like Sao Paulo and Rio de Janeiro,” he said. In South Africa’s case, having a family physician as the leader will further enhance this model.
‘Around 400 needed’
Mash said South Africa’s previous health policies saw family physicians as a sub-specialty of internal medicine or as specialists who should work at tertiary hospitals and within primary care teams. Currently, chiefly due to the lack of posts, only a third of family medicine graduates were retained in the public sector, with ten percent emigrating and eleven percent giving up medicine altogether. Most were employed in the Western Cape, where the health system had committed to appointing family medicine practitioners at district hospitals and primary care facilities, Mash added.
The SAAFP recommends a mid-term goal of one family physician at every district hospital, community health centre or sub-district.
To achieve this, said Mash, another 400 family physicians are needed, but at current training rates this could take up to two decades, (not accounting for the current shortage of posts).
He agreed with Public Health Medicine Specialist Tracey Naledi, that only when there’s wider and stronger investment in primary healthcare across provinces will better deployment of Family Medicine practitioners begin to make a real difference to district level health and wellness. Naledi is Associate Professor in Public Health Medicine and Deputy Dean of Social Accountability and Health Systems at UCT’s Faculty of Health Sciences.
Naledi said that while there are many highly skilled veteran ‘utility’ Medical Officers in the district health system, the greater utility of family medicine is in clinical governance, health systems strengthening initiatives and capacity development. Besides teaching, monitoring, and evaluating healthcare delivery, she said family physicians also more appropriately and timeously refer patients to secondary and tertiary care.
Specialist support
“The family physicians should not just be seeing sixty patients at their door daily. They are specialist support – the Medical Officers should be calling them for advice. If family physicians were optimized, we’d see far less referral to tertiary level services,” she said.
The problem is structural, she believes.
“There are not enough human resources for health in general, so at district level people get pulled into doing what’s needed on the shop floor. There’s not enough time to do the strategic work,” she said.
“You can’t just talk about family medicine without talking about full staff requirements. When a family physician goes on outreach, it should not just be about dealing with difficult cases but building the capacity of the outlying areas. They need to ask themselves what they’re leaving behind. Otherwise, you’re cleaning the floor but not closing the tap,” she added.
Mash agreed that family medicine practitioners are “not the magic bullet – but introducing them into district health services can go quite a way towards strengthening the system”.
“We’ve trained them to work independently, to be the senior clinician with the full spectrum of needed skills, on top of which they provide the confidence for the doctors who are there to practice the skills they have. It’s very reassuring having a senior person to help if things go wrong, so it’s a combination of increased confidence and bringing in additional skills,” he said.
“A primary health nurse and community health worker can provide coverage and connection to the community, but a [family medicine] FM practitioner brings in a level of expertise so the team has both coverage and quality,” he added.
History and training
As Mash tells it, from the nineties into the first decade of the 2000s, no medical schools exposed undergraduates to Family Medicine. However, nearly thirty years on, curricula have completely turned around.
Mash says some twenty to thirty family medicine practitioners graduate from the ten South African campuses every year, among the chief disincentives to the specialisation being the paucity of available posts. He said it’s critical to create more family medicine posts “if we are to attract people into that career path. If managers believe a family physician’s contribution is worthwhile, they can outmanoeuvre these restrictive budgets.”
He said public health was being “hugely damaged” by an austerity mindset.
Professor Shabir Moosa, Family Physician in the Department of Family Medicine at Wits University, suggested offering a two-year distance learning diploma in family medicine to get family medicine practitioners into practice faster and then offering in-service further tuition to a full post-graduate degree. Moosa is a former President of the World Organization of Family Doctor’s Africa region.
“Right now, you have family physicians in community healthcare centres which see a thousand people a day. Their job is capacity building, but they’re stuck with menial tasks. Also, right now qualified Family Medicine practitioners, at Wits at least, have a thirty percent teaching commitment so they’re being pulled in many different directions.”
Like Mash, he said “turnstile leadership” in the provinces wrecked progress while leadership in primary healthcare at district and lower levels was mainly by nurses, who were uncomfortable sharing space with family physicians whom they saw as a “power threat”.
Moosa says most family medicine practitioners in rural South Africa (with the exception of the Western Cape), are foreign qualified doctors who found studying it an “easy entrance route”. He takes issue with the emphasis on training family physicians exclusively for use in rural areas, saying that with accelerating urbanisation, this is short-sighted.
Parallel with clinical associates
Associate Professor Tasleem Ras, President of the SAAFP and Postgraduate Programme Director of Family Medicine at UCT, drew a parallel with clinical associates which some provinces had adopted and others not, saying they had no career pathways which has become “a political hot potato”. (Spotlight previously reported under the under-utilisation of clinical associates here and here.)
Ras was alluding to the provincially disparate usage of both categories of healthcare professionals. In the case of family physicians at least, senior medical officer and registrar posts are being creatively used by some provinces to place them, with salary adjustments built in. Clinical associates have no such luxury.
Naledi says she suspects that healthcare delivery leaders in individual provinces have widely differing views on how to use family physicians, with commensurately differing patient care outcomes. She says the grading of healthcare facilities by the Office for Healthcare Standards Compliance eloquently illustrates an overemphasis on curative service-based funding, with lower-level primary healthcare facilities scoring worst, followed by secondary or district hospitals with tertiary hospitals scoring the highest. Unless this changes, she says “we will continue failing to get bang for buck”.
She adds: “If you look at the district health system, it doesn’t have the full cadre of staff. I mean palliative care, mental health, dental services – these are all structural and broader resource issues for me. You can’t look at family medicine in isolation.”
The argument is that building more capacity for prevention and health promotion would begin to dismantle a self-perpetuating cycle of predominantly curative services. Family medicine training, Naledi says, focuses a lot more on the social determinants of health, prevention, rehabilitation, and palliative care. “It’s not just about clinical abilities but about them being family and community doctors,” she adds.
For those of a certain age, Coneheads is an iconic 90s film. But for breakdancers, it seems, developing a cone-shaped head can be an occupational hazard.
According to a 2024 medical case report, a breakdancer who’d been performing for 19 years was treated for “headspin hole”, a condition also known as “breakdancer bulge” that’s unique to breakdancers. It entails a cone shaped mass developing on top of the scalp after repetitive head-spinning. Additional symptoms can include hair loss and sometimes pain around the lump.
Approximately 30% of breakdancers report hair loss and inflammation of their scalp from head-spinning. A headspin hole is caused by the body trying to protect itself. The repeated trauma from head-spinning causes the epicranial aponeurosis – a layer of connective tissue similar to a tendon, running from the back of your head to the front – to thicken along with the layer of fat under the skin on top of the head in an attempt to protect the bones of skull from injury.
The body causes a similar protective reaction to friction on the hands and feet, where callouses form to spread the pressure and protect the underlying tissues from damage. Everyday repetitive activities from holding smartphones or heavy weights through to poorly fitting shoes can result in callouses.
But a cone-shaped head isn’t the only injury to which breakdancers are prone, however. Common issues can include wrist, knee, hip, ankle, foot and elbow injuries, and moves such as the “windmill” and the “backspin” can cause bursitis – inflammation of the fluid filled sacs that protect the vertebrae of the spine. A headspin hole isn’t the worst injury you could sustain from breakdancing either. One dancer broke their neck but thankfully they were lucky enough not to have any major complications.
Others, such as Ukrainian breakdancer Anna Ponomarenko, have experienced pinched nerves that have left them paralysed. Ponomarenko recovered to represent her country in the Paris 2024 Olympics.
As with other sports, it’s unsurprising to hear that the use of protective equipment results in the reduction of injuries in breakdancing too.
But breakdancers aren’t the only ones to develop cone shaped heads.
Newborns
Some babies are born with a conical head after their pliable skull has been squeezed and squashed during the journey through the vaginal canal and the muscular contractions of mother’s uterus.
A misshapen head can also be caused by caput secundum, where fluid collects under the skin, above the skull bones. Usually, this condition resolves itself within a few days. Babies who’ve been delivered using a vacuum assisted cup (known as a Ventouse) – where the cup is applied to the top of the baby’s head to pull them out – can develop a similar fluid lump called a chignon.
Vacuum assisted delivery can also result in a more significant lump and bruising called a cephalohematoma, where blood vessels in the bones of the skull rupture. This is twice as common in boys than in girls and resolves within two weeks to six months.
If you’ve ever seen newborns wearing tiny hats in the first few hours of their life, then one of these conditions may be the reason.
Newborn skulls are made up of lots of small bony plates that aren’t fused together, which enables babies’ brains to grow without restriction. Usually, once the brain reaches a slower growth pace that the bones can keep up with, the plates fuse together. In craniosynostosis, the plates fuse together too early creating differently shaped heads. Surgery can prevent brain growth restriction but is usually unnecessary if the child hasn’t been identified as having an shaped head by six months of age.
Colourised scanning electron micrograph of a breast cancer cell. Credit: NIH
Researchers from Tampere University, Finland, and Izmir Institute of Technology, Turkey, have developed an in vitro cancer model to investigate why breast cancer spreads to bone. Their findings, published in PLOS One, hold promise for advancing the development of preclinical tools to predict breast cancer bone metastasis.
Breast canceris a significant global public health challenge, with 2.3 million new cases and 700 000 deaths every year. Approximately 80% of patients with primary breast cancer can be cured, if they are diagnosed and treated promptly. However, in many cases, the cancer has already metastasised at the time of diagnosis.
Metastatic cancer is incurable and accounts for more than 90% of cancer-related deaths. Currently, there are no reliable in vitro models to study how breast cancer spreads to secondary organs such as bone, lung, liver or brain. Now, researchers from the Precision Nanomaterials Group at Tampere University in Finland, and the Cancer Molecular Biology Lab at Izmir Institute of Technology in Turkey, have used lab-on-a-chip platforms to create a physiologically relevant metastasis model to study the factors controlling breast cancer bone metastasis.
“Breast cancer most frequently spreads to bone, with an estimated rate of 53%, resulting in severe symptoms such as pain, pathological bone fractures, and spinal cord compressions. Our research provides a laboratory model that estimates the likelihood and mechanism of bone metastasis occurring within a living organism. This advances the understanding of molecular mechanisms in breast cancer bone metastasis and provides the groundwork for developing preclinical tools for predicting bone metastasis risk,” says Burcu Firatligil-Yildirir, postdoctoral researcher at Tampere University and the first author of the paper.
According to Nonappa, Associate Professor and leader of the Precision Nanomaterials Group at Tampere University, developing sustainable in vitro models that mimic the complexity of the native breast and bone microenvironment is a multidisciplinary challenge.
“Our work shows that physiologically relevant in vitro models can be generated by combining cancer biology, microfluidics and soft materials. The results open new possibilities for developing predictive disease, diagnostic and treatment models,” he says.
Erin Yamamoto, MD, and Juan Piantino, MD, are among the co-authors of a new study from Oregon Health & Science University that used imaging of neurosurgery patients to definitively reveal the existence of waste-clearance pathways in the human brain known as the glymphatic system. (OHSU/Christine Torres Hicks)
Scientists have long theorised about a network of pathways in the brain that are believed to clear metabolic proteins that would otherwise build up and potentially lead to Alzheimer’s and other forms of dementia. But they had never definitively revealed this network in people – until now.
A new study involving five patients undergoing brain surgery at Oregon Health & Science University provides imaging of this network of perivascular spaces (fluid-filled structures along arteries and veins) within the brain for the first time.
“Nobody has shown it before now,” said senior author Juan Piantino, MD, associate professor of pediatrics (neurology) in the OHSU School of Medicine and a faculty member of the Neuroscience Section of the Papé Family Pediatric Research Institute at OHSU. “I was always skeptical about it myself, and there are still a lot of skeptics out there who still don’t believe it. That’s what makes this finding so remarkable.”
The study combined the injection of an inert contrasting agent with a special type of magnetic resonance imaging to discern cerebrospinal fluid flowing along distinct pathways in the brain 12, 24 and 48 hours following surgery. In definitively revealing the presence of an efficient waste-clearance system within the human brain, the new study supports the promotion of lifestyle measures and medications already being developed to maintain and enhance it.
“This shows that cerebrospinal fluid doesn’t just get into the brain randomly, as if you put a sponge in a bucket of water,” Piantino said. “It goes through these channels.”
More than a decade ago, scientists at the University of Rochester first proposed the existence of a network of waste-clearance pathways in the brain akin to the body’s lymphatic system, part of the immune system. Those researchers confirmed it with real-time imaging of the brains of living mice. Due to its dependence on glial cells in the brain, they coined the term “glymphatic system” to describe it.
However, scientists had yet to confirm the existence of the glymphatic system through imaging in people.
Pathways revealed in patients
The new study examined five OHSU patients who underwent neurosurgery to remove tumours in their brains between 2020 and 2023. In each case, the patients consented to having a gadolinium-based inert contrasting agent injected through a lumbar drain used as part of the normal surgical procedure for tumour removal. The tracer would be carried with cerebrospinal fluid into the brain.
Afterward, each patient underwent magnetic resonance imaging, or an MRI, at different time points to trace the spread of cerebrospinal fluid.
Rather than diffusing uniformly through brain tissue, the images revealed fluid moving along pathways — through perivascular spaces in clearly defined channels. Researchers documented the finding with a specific kind of MRI known as fluid attenuated inversion recovery, or FLAIR. This type of imaging is sometimes used following the removal of tumors in the brain. As it turns out, it also revealed the gadolinium tracer in the brain, whereas the standard MRI sequences did not.
“That was the key,” Piantino said.
“You can actually see dark perivascular spaces in the brain turn bright,” said co-lead author Erin Yamamoto, MD, a resident in neurological surgery in the OHSU School of Medicine. “It was quite similar to the imaging the Rochester group showed in mice.”
Clearing waste from the brain
Scientists believe this network of pathways effectively flushes the brain of metabolic wastes generated by its energy-intensive work. Wastes include proteins such as amyloid and tau, which have been shown to form clumps and tangles in brain images of patients with Alzheimer’s disease.
Emerging research suggests medications that may be useful, but much of the focus around the glymphatic system has revolved around lifestyle-based measures to improve the quality of sleep, such as maintaining a regular sleep schedule, establishing a relaxing routine, and avoiding screens in the bedroom before bed. Especially at night during deep sleep, researchers believe a well-functioning glymphatic system efficiently carries waste proteins toward veins exiting the brain.
“People thought these perivascular spaces were important, but it had never been proved,” Piantino said. “Now it has.”
The authors credited the late Justin Cetas, MD, PhD, who initiated the study as an OHSU neurosurgeon before leaving the university to become chair of neurological surgery at his alma mater, the University of Arizona Health Sciences Center in Tucson. He died in a motorcycle accident in 2022.
