Researchers from Massachusetts Eye and Ear and Schepens Eye Research Institute have shown an association between a defective myogenic response — the regulatory increase or decrease in blood pressure to keep blood flow within the vessels of the retina constant — and early, accelerated development of retinopathy in patients with type 1 diabetes. These findings identify one mechanism to explain why some patients develop diabetic retinopathy sooner than others. Furthermore, the findings provide a target for future study, which may lead to therapies to delay or prevent the development of accelerated onset diabetic retinopathy.
“In patients with a normal myogenic response, the retinal vessels constrict when increased pressure arrives, to maintain constant blood flow and avoid damage to the smaller vessels in the retina,” said Mara Lorenzi, M.D., senior scientist at Massachusetts Eye and Ear/Schepens Eye Research Institute and a professor of ophthalmology, part-time at Harvard Medical School. “But we saw that, in about half of the diabetic patients in our study, the vessels did not constrict. In fact, paradoxically, some patients’ vessels dilated, and the blood flow to the retina was increased. This becomes a mechanism of damage for the small vessels, because these tiny, delicate capillaries are exposed to a big flow of pressure that can lead to the little haemorrhages and fluid leakage that are characteristic of diabetic retinopathy.”
The study included a small prospective study, in which the researchers closely followed 17 patients with type 1 diabetes whose myogenic responses had been measured four years prior. In approximately half of those patients, the researchers had observed defective myogenic responses. Five out of seven patients with defective myogenic responses developed accelerated diabetic retinopathy. The study also included a different group of patients with type 1 diabetes who had just developed retinopathy. Among these patients, the defective myogenic response was found only in those in whom retinopathy had appeared after a short duration of diabetes (fewer than 15 years of diabetes).
The most common diabetic eye disease and a leading cause of blindness in American adults, diabetic retinopathy occurs when blood vessels in the retina become damaged and leak fluid. Accumulation of fluid into the retina can lead to macular oedema . As the damage due to diabetes progresses, the vessels become occluded and can no longer carry blood. New blood vessels grow on the surface of the retina (proliferative retinopathy); but the new vessels are immature and may rupture impairing vision. Loss of visual acuity as a result of diabetic retinopathy is often the first warning sign for patients yet to be diagnosed with type 2 diabetes.
Currently, there are no treatments for diabetic retinopathy beyond controlling blood sugar and blood pressure levels. The new vessels of proliferative retinopathy can be treated with laser techniques, often at the expense of a portion of the retina. With the knowledge gained from the new studies, the researchers hope to target the defective myogenic response and develop therapies to prevent the development of accelerated diabetic retinopathy in this population. A larger study is needed to test the predictive capability of this abnormality.
Massachusetts Eye and Ear
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The genomes of two distinct strains of the virus that causes the common lip cold sore, herpes simplex virus type 1 (HSV-1), have been identified within an individual person — an achievement that could be useful to forensic scientists for tracing a person’s travel history. The research also opens the door to understanding how a patient’s viruses influence the course of disease. The research by an international team was led by Moriah L. Szpara, assistant professor of biochemistry and molecular biology at Penn State University.
Most people harbour HSV-1, frequently as a strain acquired from their mothers shortly after birth and carried for the rest of their lives. The new discovery was made with the help of a volunteer from the United States. The research revealed that one strain of the HSV-1 virus harboured by this individual is of a European/North American variety and the other is an Asian variety — likely acquired during the volunteer’s military service in the Korean War in the 1950s.
“It’s possible that more people have their life history documented at the molecular level in the HSV-1 strains they carry,“ said Derek Gatherer, a lecturer in the Division of Biomedical and Life Sciences at Lancaster University in the United Kingdom and a member of the research team, which also includes scientists at Georgia State University, the University of Pittsburgh, and Princeton University.
Earlier research by the same team has demonstrated that the geographical origin of HSV-1 can be predicted, as well. Since Asian, African, and European/North American varieties of the virus exist, and the virus is often acquired early in life, the research implies that a personal strain of HSV-1 can reflect a person’s origin. Another implication is that two individuals who have identical strains of HSV-1 are more likely to be related than those who have different strains.
“Using similar genetic fingerprinting of HSV-1 could help flesh out a person’s life story, adding an extra layer of genetic information not provided by our genomes alone. Forensic virology could be on the way in the same way in which we use genetic fingerprinting of our human DNA to locate perpetrators at the scene of a crime and to help trace the relatives of unidentified bodies,’ Gatherer said.
“We’re working on better ways to sequence viral genomes from ever-smaller amounts of starting material, to allow identification and comparison of samples from diverse sources,” said Szpara, who also is affiliated with Penn State’s Huck Institutes of the Life Sciences. “Deep sequencing of viruses like HSV-1 will provide a better view of the viral genetic diversity that individuals harbor, and will provide valuable information about how that influences the course of disease.”
Penn State
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People with high levels of good cholesterol, or high-density lipoprotein, are not as safe from heart disease when high levels of a newly identified biomarker of inflammation in the arteries are also found in their bloodstream, according to a new study.
In the study of nearly 3,000 patients, researchers from the Intermountain Medical Center Heart Institute in Salt Lake City discovered that the presence of high levels of the biomarker glycoprotein acetylation, or GlycA, was associated with an increased risk of heart attack or stroke.
Inflammation of the artery walls is a contributing factor to heart attack and stroke because it increases the likelihood that plaque on the arterial walls will rupture, induce clot formation and block blood flow.
“We already know that HDL provides an anti-inflammatory effect on the arteries,” said Brent Muhlestein, MD, co-director of cardiovascular research at the Intermountain Medical Center Heart Institute. “But our research suggests there’s an interaction between GlycA and small HDL particles that reduces the anti-inflammatory capabilities of HDL and increases a person’s chances of having a heart attack or stroke.”
Using a test developed by LipoScience known as NMR spectroscopy, researchers measured lipoprotein particles and GlycA in 2,848 patients whose average age was 63 years old. Sixty-six percent of the patients were male and 65 percent had coronary artery disease.
“The results of our study reinforce the importance of the recommendations we offer to our patients working to reduce inflammation in their arteries by exercising regularly and eating heart-healthy foods,” said Dr. Muhlestein. “Some ways of increasing the HDL levels that will provide the anti-inflammatory protection include eating foods higher in Omega 3s and following the Mediterranean diet, which revolves around plant-based foods, healthy fats, and limited amounts of salt and red meat.”
Historically, C-reactive protein has been used as an indicator of inflammation in the body, and is predictive of future heart-related adverse events. Now, GlycA, a marker of inflammation identified through NMR, appears to show the same predictive ability.
However, researchers are currently seeking to determine if C-reactive protein and GlycA are completely independent of each other in terms of their impact on inflammation and heart disease.
“GlycA is a new particle we didn’t know much about, but now that we know there are epidemiologic associations, we need to look at additional ways to evaluate and understand the way it functions and interacts in the bloodstream,” said Dr. Muhlestein.
Intermountain Medical Center Heart Institute
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Skin cancer is the most common of all cancers, and melanoma, which accounts for 2% of skin cancer cases, is responsible for nearly all skin cancer deaths. Melanoma rates in the U.S. have been rising rapidly over the last 30 years, and although scientists have managed to identify key risk factors, melanoma’s modus operandi has eluded the world of medical research.
A new Tel Aviv University study sheds light on the trigger that causes melanoma cancer cells to transform from non-invasive cells to invasive killer agents, pinpointing the precise place in the process where “traveling” cancer turns lethal. The research was led by Dr. Carmit Levy of the Department of Human Genetics and Biochemistry at TAU’s Sackler School of Medicine and conducted by a team of researchers from TAU, the Technion Institute of Technology, the Sheba Medical Center, the Institut Gustave Roussy and The Hebrew University of Jerusalem.
If melanoma is caught in time, it can be removed and the patient’s life can be saved. But once melanoma invades the bloodstream, turning metastatic, an aggressive treatment must be applied. When and how the transformation into aggressive invasion takes place was a mystery until now.
‘To understand melanoma, I had to obtain a deep understanding about the structure and function of normal skin,’ said Dr. Levy, ‘Melanoma is a cancer that originates in the epidermis, and in its aggressive form it will invade the dermis, a lower layer, where it eventually invades the bloodstream or lymph vessels, causing metastasis in other organs of the body. But before invading the dermis, melanoma cells surprisingly extend upward, then switch directions to invade.
‘It occurred to me that there had to be a trigger in the microenvironment of the skin that made the melanoma cells ‘invasive,” Dr. Levy continued. ‘Using the evolutionary logic of the tumour, why spend the energy going up when you can just use your energy to go down and become malignant?’
After collecting samples of normal skin cells and melanoma cells from patients at hospitals around Israel, the researchers mixed normal and cancerous cells and performed gene analysis expression to study the traveling cancer’s behaviour. They found that, completely independent of any mutation acquisition, the microenvironment alone drove melanoma metastasis.
‘Normal skin cells are not supposed to ‘travel,” said Dr. Levy. ‘We found that when melanoma is situated at the top layer, a trigger sends it down to the dermis and then further down to invade blood vessels. If we could stop it at the top layer, block it from invading the bloodstream, we could stop the progression of the cancer.’
The researchers found that the direct contact of melanoma cells with the remote epidermal layer triggered an invasion via the activation of ‘Notch signalling,’ which turns on a set of genes that promotes changes in melanoma cells, rendering them invasive. According to the study, when a molecule expressed on a cell membrane — a spike on the surface of a cell, called a ligand — comes into contact with a melanoma cell, it triggers the transformation of melanoma into an invasive, lethal agent.
‘When I saw the results, I jumped out of the room and shouted, ‘We got it!” Dr. Levy said. ‘Now that we know the triggers of melanoma transformation and the kind of signalling that leads to that transformation, we know what to block. The trick was to solve the mystery, and we did. There are many drugs in existence that can block the Notch signalling responsible for that transformation. Maybe, in the future, people will be able to rub some substance on their skin as a prevention measure.’
Tel Aviv University
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Researchers have identified a new set of genes that may be responsible for the two most common and disabling neurological conditions, stroke and dementia.
The study may help researchers better understand, treat and prevent ischemic and haemorrhagic stroke, and perhaps Alzheimer’s disease and other dementias.
Stroke is the leading neurological cause of death and disability worldwide. Previous studies have looked mainly at genes causing atherosclerosis and genes affecting the function of platelets and clotting processes as risk factors for ischemic stroke (clot obstructing blood flow to the brain). A different set of genes has been associated with haemorrhagic stroke (bleeding into the brain).
Researchers from Boston University School of Medicine looked for new stroke genes using genome wide association as well as meta-analysis. They identified a new gene called FOXF2 which increased the risk of having a stroke due to small vessel disease in the brain. No previous study has identified a gene for the common type of small vessel disease stroke although some genes associated with familial small vessel diseases such as CADASIL are known.
Sudha-Seshadri“Our research has identified a gene affecting another type of ischemic stroke, due to small vessel disease, and also suggests some genes may be associated with both ischemic and haemorrhagic stroke and may act through a novel pathway affecting pericytes, a type of cell in the wall of small arteries and capillaries. Unravelling the mechanisms of small vessel disease is essential for the development of therapeutic and preventive strategies for this major cause of stroke,” explained corresponding author Sudha Seshadri, MD, professor of neurology at BUSM.
According to the researchers small vessel disease not only causes stroke but is also a major contributor to dementia risk, and is associated with gait problems and depression. “Hence, it is exciting that we are beginning to better understand the cause of this very important and poorly understood type of stroke,” she added.
Boston School of Medicine
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The human heart is a remarkable muscle, beating more than 2 billion times over the average life span.
But the heart’s efficiency can decrease over time. One major contributor to this decreased function is cardiac hypertrophy – a thickening of the heart muscle, resulting in a decrease in the size of the left and right ventricles. This makes the heart work harder and pump less blood per cycle than a healthy heart.
Cornell researchers, working in collaboration with scientists in Switzerland, have identified a strong connection between a protein, SIRT5, and healthy heart function. SIRT5 has the ability to remove a harmful protein modification known as lysine succinylation, which robs the heart of its ability to burn fatty acids efficiently to generate the energy needed for pumping.
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“Our research suggests that perhaps one way to improve heart function is to find a way to improve SIRT5 activity,” said Hening Lin, professor of chemistry and chemical biology.
SIRT5 is one of a class of seven proteins called sirtuins that have been shown to influence a range of cellular processes. According to Sushabhan Sadhukhan, a postdoctoral fellow in Lin’s lab and lead author of the paper, most research on laboratory mice into sirtuin activity has focused on the liver, as opposed to the heart, due to the size of the liver and ease of obtaining tissue.
Lin’s lab tested mouse tissue from five locations (heart, liver, kidney, brain, muscle) and found that protein lysine succinylation occurs to the greatest extent in the heart. The testing involved mice that had SIRT5 deleted.
The removal of SIRT5 resulted in reduced activity of ECHA, a protein involved in fatty acid oxidation, and decreased levels of adenosine triphosphate (ATP), which stores and transfers chemical energy within cells. The effect of SIRT5 removal on heart function was even more pronounced as the mice aged. The researchers performed echocardiography on 8-week-old mice, with some reduced cardiac function observed. The mice were tested again at 39 weeks, and they showed hallmarks of cardiac hypertrophy – increased heart weight and left ventricular mass, along with reductions in both the shortening and ejection fractions of the heart.
The group’s findings could spawn new methods for the preservation of heart health and extension of healthy life, which could have significant implications for human health. According to the Centers for Disease Control and Prevention, heart disease is the leading cause death among both men and women, with more than 600,000 people in the U.S. dying from it annually.
Cornell University
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The occurrence of chemotherapy resistance is one of the major reasons for failure in cancer treatment. A study led by Óscar Fernández-Capetillo, Head of the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO), has identified a new determinant of chemotherapy resistance. In this regard, they employed ATR kinase inhibitors, which were previously described by the group as a cancer treatment strategy, and that could be tested on humans as early as 2017, according to the researcher. The determining factor is a protein that often appears increased in cancer cells, CDC25A. This discovery opens up new avenues for novel and more effective treatments as well as a way to predict which patients will particularly benefit from a therapy with ATR inhibitors.
Most chemotherapy agents are drugs that destroy the DNA of cancer cells. In this case, the CNIO’s strategy is targeting ATR kinase; a protein that is responsible for repairing the genome. This protein, ‘is present in all cells, both in healthy and cancerous cells; however, its function in tumour cells is even more vital because their genome is highly fragmented and needs to be repaired frequently so as not to become unstable and die,’ says Fernández-Capetillo. Disabling this genome guardian element in tumour cells is catastrophic for them, he adds, ‘it is like killing the fireman in the middle of a forest fire.’ This explains why this treatment is more toxic to tumour cells and not so toxic in the healthy tissues surrounding them.
In this project, the researchers have tried to anticipate the potential for the emergence of resistance during therapy in the clinic. In order to identify possible mutations that may confer resistance to ATR inhibitors in cells, the researchers made use of a new ally: the CRISPR genome editing technology. By implementing this technology, they generated a collection of cells, in which each cell contained a different mutated gene. ‘Taking into account that a mouse has around 20,000 different genes, it would have taken much longer to generate a collection of mutants like these using any other modification technique,’ explain Sergio Ruiz and Cristina Mayor-Ruiz, first authors of the study.
By subjecting the cells to treatment with ATR inhibitors, they were able to isolate some that were resistant to the treatment and subsequently identify the mutation they were carrying. It was demonstrated that cells with mutations in the CDC25A gene survived.
‘CDC25A is a protein that is normally highly expressed in tumours,’ explains Fernández-Capetillo. ‘This paper suggests that a way of identifying patients who will respond more successfully to treatment is by determining those whose tumours have higher levels of CDC25A.’ In addition to finding a mutation that allows cells to become resistant to treatment, the researchers also identified a treatment capable of eliminating resistant cells.
EurekAlert
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Coeliac disease is a chronic, immunological disease that is manifested as intolerance to gluten proteins present in wheat, rye and barley. This intolerance leads to an inflammatory reaction in the small intestine that hampers the absorption of nutrients. The only treatment is a strict, life-long, gluten-free diet.
It has been known for some time that coeliac disease develops in people who have a genetic susceptibility, but despite the fact that 40% of the population carry the most decisive risk factor (the HLA-DQ2 and DQ8 polymorphisms), only 1% go on to develop the disease. ‘What we have here is a complex genetic disease in which many polymorphisms play a role, each making a very small contribution to its development,’ explained the UPV/EHU researcher Ainara Castellanos, who has led the work published in Science.
One of the added risk factors is to be found, according to this research, in the so-called ‘junk’ DNA, in other words, in 95% of the DNA. It is the least-known part because, unlike the remaining 5%, it is not involved in synthesising proteins. Nevertheless, light is gradually being shed on its role in the control of the overall functioning of the genome, in other words, it regulates important processes in our organism such as immune response and that is where it might be possible to find the causes of auto-immune diseases such as coeliac disease.
A key gene in the regulating of the inflammatory response observed in coeliac patients has been found in one of the regions of the junk genome: it is the 1nc13. The ribonucleic acid produced by this gene belongs to the family of long, non-coding RNAs or lncRNA and is responsible for maintaining the normal levels of expression of pro-inflammatory genes. In coeliacs, this non-coding RNA is hardly produced at all so the levels of these inflammatory genes are not properly regulated and their expression is increased. But besides being produced in low quantities, the 1nc13 produced by coeliac patients has a variant that alters the way it functions. ‘That way an inflammatory environment is created and the development of the disease is encouraged,’ said Ainara Castellanos.
‘This study confirms the importance of the regions of the genome previously regarded as ‘junk’ in the development of common complaints such as coeliac disease and opens up the door to a new possibility for diagnosis. Right now, we are interested in finding out whether the low levels of this RNA are an early feature of coeliac disease (and of other immune diseases), which could be used as a diagnostic tool before its onset,’ explained the UPV/EHU’s lecturer in Genetics José Ramón Bilbao, another of the authors of the work.
University of the Basque Country
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Newcastle scientists and medics have developed a new type of genetic blood test that diagnoses scarring in the liver – even before someone may feel ill. It is the first time an epigenetic signature in blood has been discovered which is diagnostic of the severity of fibrosis for people with Non-alcoholic Fatty Liver Disease (NAFLD).
NAFLD, caused by being overweight or having diabetes, affects one in three people in the UK and may progress to cirrhosis and liver failure, requiring a transplant.
The Newcastle team describe the proof of principle research in which they measure specific epigenetic markers to stratify NAFLD patients into mild or severe liver scarring, known as fibrosis.
Dr Quentin Anstee, Clinical Senior Lecturer at Newcastle University, Consultant Hepatologist within the Newcastle Hospitals and joint senior author explained what it could mean for patients: “This scientific breakthrough has great promise because the majority of patients show no symptoms.
“Routine blood tests can’t detect scarring of the liver and even more advanced non-invasive tests can really only detect scarring at a late stage when it is nearing cirrhosis. We currently have to rely on liver biopsy to measure fibrosis at its early stages – by examining a piece of the liver under the microscope.
“We know that the presence of even mild fibrosis of the liver predicts a worse long-term outcome for patients with NAFLD and so it’s important to be able to detect liver scarring at an early stage.”
In this first stage of research the team developed the blood analysis in 26 patients with NAFLD. The test detects chemical changes on tiny amounts of “cell-free” DNA that are released into the blood when liver cells are injured. Changes in DNA methylation at genes like PPARγthat controls scar formation are then used to stratify patients by fibrosis severity.
Senior author Dr Jelena Mann of Newcastle University’s Institute for Cellular Medicine added: “This is the first time that a DNA methylation ‘signature’ from the blood has been shown to match the severity of a liver disease.
“It opens up the possibility of an improved blood test for liver fibrosis in the future.”
Newcastle University
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The babies of obese women who develop gestational diabetes are five times as likely to be excessively large by six months of pregnancy, according to new research led by the University of Cambridge. The study, which shows that excessive foetal growth begins weeks before at-risk women are screened for gestational diabetes, suggests that current screening programmes may take place too late during pregnancy to prevent lasting health impacts on the offspring.
Gestational diabetes is a condition that can affect women during pregnancy, with those who are obese at greater risk. As well as affecting the mother’s health, the condition also causes the unborn child to grow larger, putting the mother at risk during childbirth and increasing the likelihood that her offspring will develop obesity and diabetes during later life. The condition can usually be controlled through a combination of diet and exercise, and medication if these measures fail.
Women are screened for the condition through a blood glucose test at around 8-12 weeks into pregnancy. Current guidelines in the UK and the USA recommend that mothers found to be at greatest risk should then be offered a full test at between 24 and 28 weeks into pregnancy; however, in practice the majority of women are screened at the 28 week mark.
Researchers at the Department of Obstetrics & Gynaecology at the University of Cambridge analysed data from the Pregnancy Outcome Prediction study, which followed more than 4,000 first time mothers using ultrasound scans to assess the growth of their babies in the womb. They measured the abdominal and head circumference of the foetuses and compared the growth in women who developed gestational diabetes with those who did not.
Of the 4,069 women studied, 171 (4.2%) were diagnosed with gestational diabetes at or beyond 28 weeks. The researchers found no association between the size of the child at 20 weeks and the mother subsequently developing gestational diabetes. However, they found that the foetuses of women subsequently diagnosed with gestational diabetes grew excessively prior to diagnosis, between 20 and 28 weeks. Hence, the babies were already large at the time of diagnosis, and their findings suggest that the onset of foetal growth disorder in gestational diabetes predates the usual time of screening.
The researchers also studied women who were obese, as it is well recognised that maternal obesity is a risk factor for childhood obesity. Even in the absence of diabetes, the babies of obese women were also twice as likely to be big at 28 weeks. The combination of obesity and gestational diabetes was associated with an almost 5-fold risk of excessive foetal growth by the 28 week scan.
“Our study suggests that the babies of women subsequently diagnosed with gestational diabetes are already abnormally large by the time their mothers are tested for the disease,” says Dr Ulla Sovio from the Department of Obstetrics and Gynaecology at the University of Cambridge, the study’s first author. “Given the risk of complications for both mother and child from gestational diabetes, our findings suggest that screening women earlier on in pregnancy may help improve the short and long term outcomes for these women.
“Early screening may be particularly beneficial for obese women, as fetal growth is already abnormal by 20 weeks among these women. Any intervention aimed at reducing the risk of abnormal birthweight in the infants of obese women may need to be implemented even earlier.”
Senior author Professor Gordon Smith, also from the University of Cambridge, adds: “We know that the offspring of women with gestational diabetes are at increased risk of childhood obesity, but so far no clinical trials have successfully demonstrated that screening and intervention in pregnancy reduces this risk. Our study suggests a possible explanation: screening and intervention is taking place when the effects of gestational diabetes are already manifested in the foetus.
Cambridge University
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Candidate biomarker of accelerated onset diabetic retinopathy
, /in E-News /by 3wmediaResearchers from Massachusetts Eye and Ear and Schepens Eye Research Institute have shown an association between a defective myogenic response — the regulatory increase or decrease in blood pressure to keep blood flow within the vessels of the retina constant — and early, accelerated development of retinopathy in patients with type 1 diabetes. These findings identify one mechanism to explain why some patients develop diabetic retinopathy sooner than others. Furthermore, the findings provide a target for future study, which may lead to therapies to delay or prevent the development of accelerated onset diabetic retinopathy.
“In patients with a normal myogenic response, the retinal vessels constrict when increased pressure arrives, to maintain constant blood flow and avoid damage to the smaller vessels in the retina,” said Mara Lorenzi, M.D., senior scientist at Massachusetts Eye and Ear/Schepens Eye Research Institute and a professor of ophthalmology, part-time at Harvard Medical School. “But we saw that, in about half of the diabetic patients in our study, the vessels did not constrict. In fact, paradoxically, some patients’ vessels dilated, and the blood flow to the retina was increased. This becomes a mechanism of damage for the small vessels, because these tiny, delicate capillaries are exposed to a big flow of pressure that can lead to the little haemorrhages and fluid leakage that are characteristic of diabetic retinopathy.”
The study included a small prospective study, in which the researchers closely followed 17 patients with type 1 diabetes whose myogenic responses had been measured four years prior. In approximately half of those patients, the researchers had observed defective myogenic responses. Five out of seven patients with defective myogenic responses developed accelerated diabetic retinopathy. The study also included a different group of patients with type 1 diabetes who had just developed retinopathy. Among these patients, the defective myogenic response was found only in those in whom retinopathy had appeared after a short duration of diabetes (fewer than 15 years of diabetes).
The most common diabetic eye disease and a leading cause of blindness in American adults, diabetic retinopathy occurs when blood vessels in the retina become damaged and leak fluid. Accumulation of fluid into the retina can lead to macular oedema . As the damage due to diabetes progresses, the vessels become occluded and can no longer carry blood. New blood vessels grow on the surface of the retina (proliferative retinopathy); but the new vessels are immature and may rupture impairing vision. Loss of visual acuity as a result of diabetic retinopathy is often the first warning sign for patients yet to be diagnosed with type 2 diabetes.
Currently, there are no treatments for diabetic retinopathy beyond controlling blood sugar and blood pressure levels. The new vessels of proliferative retinopathy can be treated with laser techniques, often at the expense of a portion of the retina. With the knowledge gained from the new studies, the researchers hope to target the defective myogenic response and develop therapies to prevent the development of accelerated diabetic retinopathy in this population. A larger study is needed to test the predictive capability of this abnormality. Massachusetts Eye and Ear
Your viruses could reveal your travel history, and more
, /in E-News /by 3wmediaThe genomes of two distinct strains of the virus that causes the common lip cold sore, herpes simplex virus type 1 (HSV-1), have been identified within an individual person — an achievement that could be useful to forensic scientists for tracing a person’s travel history. The research also opens the door to understanding how a patient’s viruses influence the course of disease. The research by an international team was led by Moriah L. Szpara, assistant professor of biochemistry and molecular biology at Penn State University.
Most people harbour HSV-1, frequently as a strain acquired from their mothers shortly after birth and carried for the rest of their lives. The new discovery was made with the help of a volunteer from the United States. The research revealed that one strain of the HSV-1 virus harboured by this individual is of a European/North American variety and the other is an Asian variety — likely acquired during the volunteer’s military service in the Korean War in the 1950s.
“It’s possible that more people have their life history documented at the molecular level in the HSV-1 strains they carry,“ said Derek Gatherer, a lecturer in the Division of Biomedical and Life Sciences at Lancaster University in the United Kingdom and a member of the research team, which also includes scientists at Georgia State University, the University of Pittsburgh, and Princeton University.
Earlier research by the same team has demonstrated that the geographical origin of HSV-1 can be predicted, as well. Since Asian, African, and European/North American varieties of the virus exist, and the virus is often acquired early in life, the research implies that a personal strain of HSV-1 can reflect a person’s origin. Another implication is that two individuals who have identical strains of HSV-1 are more likely to be related than those who have different strains.
“Using similar genetic fingerprinting of HSV-1 could help flesh out a person’s life story, adding an extra layer of genetic information not provided by our genomes alone. Forensic virology could be on the way in the same way in which we use genetic fingerprinting of our human DNA to locate perpetrators at the scene of a crime and to help trace the relatives of unidentified bodies,’ Gatherer said.
“We’re working on better ways to sequence viral genomes from ever-smaller amounts of starting material, to allow identification and comparison of samples from diverse sources,” said Szpara, who also is affiliated with Penn State’s Huck Institutes of the Life Sciences. “Deep sequencing of viruses like HSV-1 will provide a better view of the viral genetic diversity that individuals harbor, and will provide valuable information about how that influences the course of disease.” Penn State
Elevated levels of inflammation biomarker offsets benefits of good cholesterol
, /in E-News /by 3wmediaPeople with high levels of good cholesterol, or high-density lipoprotein, are not as safe from heart disease when high levels of a newly identified biomarker of inflammation in the arteries are also found in their bloodstream, according to a new study.
In the study of nearly 3,000 patients, researchers from the Intermountain Medical Center Heart Institute in Salt Lake City discovered that the presence of high levels of the biomarker glycoprotein acetylation, or GlycA, was associated with an increased risk of heart attack or stroke.
Inflammation of the artery walls is a contributing factor to heart attack and stroke because it increases the likelihood that plaque on the arterial walls will rupture, induce clot formation and block blood flow.
“We already know that HDL provides an anti-inflammatory effect on the arteries,” said Brent Muhlestein, MD, co-director of cardiovascular research at the Intermountain Medical Center Heart Institute. “But our research suggests there’s an interaction between GlycA and small HDL particles that reduces the anti-inflammatory capabilities of HDL and increases a person’s chances of having a heart attack or stroke.”
Using a test developed by LipoScience known as NMR spectroscopy, researchers measured lipoprotein particles and GlycA in 2,848 patients whose average age was 63 years old. Sixty-six percent of the patients were male and 65 percent had coronary artery disease.
“The results of our study reinforce the importance of the recommendations we offer to our patients working to reduce inflammation in their arteries by exercising regularly and eating heart-healthy foods,” said Dr. Muhlestein. “Some ways of increasing the HDL levels that will provide the anti-inflammatory protection include eating foods higher in Omega 3s and following the Mediterranean diet, which revolves around plant-based foods, healthy fats, and limited amounts of salt and red meat.”
Historically, C-reactive protein has been used as an indicator of inflammation in the body, and is predictive of future heart-related adverse events. Now, GlycA, a marker of inflammation identified through NMR, appears to show the same predictive ability.
However, researchers are currently seeking to determine if C-reactive protein and GlycA are completely independent of each other in terms of their impact on inflammation and heart disease.
“GlycA is a new particle we didn’t know much about, but now that we know there are epidemiologic associations, we need to look at additional ways to evaluate and understand the way it functions and interacts in the bloodstream,” said Dr. Muhlestein. Intermountain Medical Center Heart Institute
Trigger of deadly melanoma
, /in E-News /by 3wmediaSkin cancer is the most common of all cancers, and melanoma, which accounts for 2% of skin cancer cases, is responsible for nearly all skin cancer deaths. Melanoma rates in the U.S. have been rising rapidly over the last 30 years, and although scientists have managed to identify key risk factors, melanoma’s modus operandi has eluded the world of medical research.
A new Tel Aviv University study sheds light on the trigger that causes melanoma cancer cells to transform from non-invasive cells to invasive killer agents, pinpointing the precise place in the process where “traveling” cancer turns lethal. The research was led by Dr. Carmit Levy of the Department of Human Genetics and Biochemistry at TAU’s Sackler School of Medicine and conducted by a team of researchers from TAU, the Technion Institute of Technology, the Sheba Medical Center, the Institut Gustave Roussy and The Hebrew University of Jerusalem.
If melanoma is caught in time, it can be removed and the patient’s life can be saved. But once melanoma invades the bloodstream, turning metastatic, an aggressive treatment must be applied. When and how the transformation into aggressive invasion takes place was a mystery until now.
‘To understand melanoma, I had to obtain a deep understanding about the structure and function of normal skin,’ said Dr. Levy, ‘Melanoma is a cancer that originates in the epidermis, and in its aggressive form it will invade the dermis, a lower layer, where it eventually invades the bloodstream or lymph vessels, causing metastasis in other organs of the body. But before invading the dermis, melanoma cells surprisingly extend upward, then switch directions to invade.
‘It occurred to me that there had to be a trigger in the microenvironment of the skin that made the melanoma cells ‘invasive,” Dr. Levy continued. ‘Using the evolutionary logic of the tumour, why spend the energy going up when you can just use your energy to go down and become malignant?’
After collecting samples of normal skin cells and melanoma cells from patients at hospitals around Israel, the researchers mixed normal and cancerous cells and performed gene analysis expression to study the traveling cancer’s behaviour. They found that, completely independent of any mutation acquisition, the microenvironment alone drove melanoma metastasis.
‘Normal skin cells are not supposed to ‘travel,” said Dr. Levy. ‘We found that when melanoma is situated at the top layer, a trigger sends it down to the dermis and then further down to invade blood vessels. If we could stop it at the top layer, block it from invading the bloodstream, we could stop the progression of the cancer.’
The researchers found that the direct contact of melanoma cells with the remote epidermal layer triggered an invasion via the activation of ‘Notch signalling,’ which turns on a set of genes that promotes changes in melanoma cells, rendering them invasive. According to the study, when a molecule expressed on a cell membrane — a spike on the surface of a cell, called a ligand — comes into contact with a melanoma cell, it triggers the transformation of melanoma into an invasive, lethal agent.
‘When I saw the results, I jumped out of the room and shouted, ‘We got it!” Dr. Levy said. ‘Now that we know the triggers of melanoma transformation and the kind of signalling that leads to that transformation, we know what to block. The trick was to solve the mystery, and we did. There are many drugs in existence that can block the Notch signalling responsible for that transformation. Maybe, in the future, people will be able to rub some substance on their skin as a prevention measure.’ Tel Aviv University
New gene responsible for stroke discovered
, /in E-News /by 3wmediaResearchers have identified a new set of genes that may be responsible for the two most common and disabling neurological conditions, stroke and dementia.
The study may help researchers better understand, treat and prevent ischemic and haemorrhagic stroke, and perhaps Alzheimer’s disease and other dementias.
Stroke is the leading neurological cause of death and disability worldwide. Previous studies have looked mainly at genes causing atherosclerosis and genes affecting the function of platelets and clotting processes as risk factors for ischemic stroke (clot obstructing blood flow to the brain). A different set of genes has been associated with haemorrhagic stroke (bleeding into the brain).
Researchers from Boston University School of Medicine looked for new stroke genes using genome wide association as well as meta-analysis. They identified a new gene called FOXF2 which increased the risk of having a stroke due to small vessel disease in the brain. No previous study has identified a gene for the common type of small vessel disease stroke although some genes associated with familial small vessel diseases such as CADASIL are known.
Sudha-Seshadri“Our research has identified a gene affecting another type of ischemic stroke, due to small vessel disease, and also suggests some genes may be associated with both ischemic and haemorrhagic stroke and may act through a novel pathway affecting pericytes, a type of cell in the wall of small arteries and capillaries. Unravelling the mechanisms of small vessel disease is essential for the development of therapeutic and preventive strategies for this major cause of stroke,” explained corresponding author Sudha Seshadri, MD, professor of neurology at BUSM.
According to the researchers small vessel disease not only causes stroke but is also a major contributor to dementia risk, and is associated with gait problems and depression. “Hence, it is exciting that we are beginning to better understand the cause of this very important and poorly understood type of stroke,” she added. Boston School of Medicine
Protein with power to improve heart function
, /in E-News /by 3wmediaThe human heart is a remarkable muscle, beating more than 2 billion times over the average life span.
But the heart’s efficiency can decrease over time. One major contributor to this decreased function is cardiac hypertrophy – a thickening of the heart muscle, resulting in a decrease in the size of the left and right ventricles. This makes the heart work harder and pump less blood per cycle than a healthy heart.
Cornell researchers, working in collaboration with scientists in Switzerland, have identified a strong connection between a protein, SIRT5, and healthy heart function. SIRT5 has the ability to remove a harmful protein modification known as lysine succinylation, which robs the heart of its ability to burn fatty acids efficiently to generate the energy needed for pumping.
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“Our research suggests that perhaps one way to improve heart function is to find a way to improve SIRT5 activity,” said Hening Lin, professor of chemistry and chemical biology.
SIRT5 is one of a class of seven proteins called sirtuins that have been shown to influence a range of cellular processes. According to Sushabhan Sadhukhan, a postdoctoral fellow in Lin’s lab and lead author of the paper, most research on laboratory mice into sirtuin activity has focused on the liver, as opposed to the heart, due to the size of the liver and ease of obtaining tissue.
Lin’s lab tested mouse tissue from five locations (heart, liver, kidney, brain, muscle) and found that protein lysine succinylation occurs to the greatest extent in the heart. The testing involved mice that had SIRT5 deleted.
The removal of SIRT5 resulted in reduced activity of ECHA, a protein involved in fatty acid oxidation, and decreased levels of adenosine triphosphate (ATP), which stores and transfers chemical energy within cells. The effect of SIRT5 removal on heart function was even more pronounced as the mice aged. The researchers performed echocardiography on 8-week-old mice, with some reduced cardiac function observed. The mice were tested again at 39 weeks, and they showed hallmarks of cardiac hypertrophy – increased heart weight and left ventricular mass, along with reductions in both the shortening and ejection fractions of the heart.
The group’s findings could spawn new methods for the preservation of heart health and extension of healthy life, which could have significant implications for human health. According to the Centers for Disease Control and Prevention, heart disease is the leading cause death among both men and women, with more than 600,000 people in the U.S. dying from it annually. Cornell University
New mechanism of resistance to chemotherapy
, /in E-News /by 3wmediaThe occurrence of chemotherapy resistance is one of the major reasons for failure in cancer treatment. A study led by Óscar Fernández-Capetillo, Head of the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO), has identified a new determinant of chemotherapy resistance. In this regard, they employed ATR kinase inhibitors, which were previously described by the group as a cancer treatment strategy, and that could be tested on humans as early as 2017, according to the researcher. The determining factor is a protein that often appears increased in cancer cells, CDC25A. This discovery opens up new avenues for novel and more effective treatments as well as a way to predict which patients will particularly benefit from a therapy with ATR inhibitors.
Most chemotherapy agents are drugs that destroy the DNA of cancer cells. In this case, the CNIO’s strategy is targeting ATR kinase; a protein that is responsible for repairing the genome. This protein, ‘is present in all cells, both in healthy and cancerous cells; however, its function in tumour cells is even more vital because their genome is highly fragmented and needs to be repaired frequently so as not to become unstable and die,’ says Fernández-Capetillo. Disabling this genome guardian element in tumour cells is catastrophic for them, he adds, ‘it is like killing the fireman in the middle of a forest fire.’ This explains why this treatment is more toxic to tumour cells and not so toxic in the healthy tissues surrounding them.
In this project, the researchers have tried to anticipate the potential for the emergence of resistance during therapy in the clinic. In order to identify possible mutations that may confer resistance to ATR inhibitors in cells, the researchers made use of a new ally: the CRISPR genome editing technology. By implementing this technology, they generated a collection of cells, in which each cell contained a different mutated gene. ‘Taking into account that a mouse has around 20,000 different genes, it would have taken much longer to generate a collection of mutants like these using any other modification technique,’ explain Sergio Ruiz and Cristina Mayor-Ruiz, first authors of the study.
By subjecting the cells to treatment with ATR inhibitors, they were able to isolate some that were resistant to the treatment and subsequently identify the mutation they were carrying. It was demonstrated that cells with mutations in the CDC25A gene survived.
‘CDC25A is a protein that is normally highly expressed in tumours,’ explains Fernández-Capetillo. ‘This paper suggests that a way of identifying patients who will respond more successfully to treatment is by determining those whose tumours have higher levels of CDC25A.’ In addition to finding a mutation that allows cells to become resistant to treatment, the researchers also identified a treatment capable of eliminating resistant cells. EurekAlert
A key gene in the development of coeliac disease has been found in ‘junk’ DNA
, /in E-News /by 3wmediaCoeliac disease is a chronic, immunological disease that is manifested as intolerance to gluten proteins present in wheat, rye and barley. This intolerance leads to an inflammatory reaction in the small intestine that hampers the absorption of nutrients. The only treatment is a strict, life-long, gluten-free diet.
It has been known for some time that coeliac disease develops in people who have a genetic susceptibility, but despite the fact that 40% of the population carry the most decisive risk factor (the HLA-DQ2 and DQ8 polymorphisms), only 1% go on to develop the disease. ‘What we have here is a complex genetic disease in which many polymorphisms play a role, each making a very small contribution to its development,’ explained the UPV/EHU researcher Ainara Castellanos, who has led the work published in Science.
One of the added risk factors is to be found, according to this research, in the so-called ‘junk’ DNA, in other words, in 95% of the DNA. It is the least-known part because, unlike the remaining 5%, it is not involved in synthesising proteins. Nevertheless, light is gradually being shed on its role in the control of the overall functioning of the genome, in other words, it regulates important processes in our organism such as immune response and that is where it might be possible to find the causes of auto-immune diseases such as coeliac disease.
A key gene in the regulating of the inflammatory response observed in coeliac patients has been found in one of the regions of the junk genome: it is the 1nc13. The ribonucleic acid produced by this gene belongs to the family of long, non-coding RNAs or lncRNA and is responsible for maintaining the normal levels of expression of pro-inflammatory genes. In coeliacs, this non-coding RNA is hardly produced at all so the levels of these inflammatory genes are not properly regulated and their expression is increased. But besides being produced in low quantities, the 1nc13 produced by coeliac patients has a variant that alters the way it functions. ‘That way an inflammatory environment is created and the development of the disease is encouraged,’ said Ainara Castellanos.
‘This study confirms the importance of the regions of the genome previously regarded as ‘junk’ in the development of common complaints such as coeliac disease and opens up the door to a new possibility for diagnosis. Right now, we are interested in finding out whether the low levels of this RNA are an early feature of coeliac disease (and of other immune diseases), which could be used as a diagnostic tool before its onset,’ explained the UPV/EHU’s lecturer in Genetics José Ramón Bilbao, another of the authors of the work. University of the Basque Country
Promising new blood test is first of its kind to detect liver scarring
, /in E-News /by 3wmediaNewcastle scientists and medics have developed a new type of genetic blood test that diagnoses scarring in the liver – even before someone may feel ill. It is the first time an epigenetic signature in blood has been discovered which is diagnostic of the severity of fibrosis for people with Non-alcoholic Fatty Liver Disease (NAFLD).
NAFLD, caused by being overweight or having diabetes, affects one in three people in the UK and may progress to cirrhosis and liver failure, requiring a transplant.
The Newcastle team describe the proof of principle research in which they measure specific epigenetic markers to stratify NAFLD patients into mild or severe liver scarring, known as fibrosis.
Dr Quentin Anstee, Clinical Senior Lecturer at Newcastle University, Consultant Hepatologist within the Newcastle Hospitals and joint senior author explained what it could mean for patients: “This scientific breakthrough has great promise because the majority of patients show no symptoms.
“Routine blood tests can’t detect scarring of the liver and even more advanced non-invasive tests can really only detect scarring at a late stage when it is nearing cirrhosis. We currently have to rely on liver biopsy to measure fibrosis at its early stages – by examining a piece of the liver under the microscope.
“We know that the presence of even mild fibrosis of the liver predicts a worse long-term outcome for patients with NAFLD and so it’s important to be able to detect liver scarring at an early stage.”
In this first stage of research the team developed the blood analysis in 26 patients with NAFLD. The test detects chemical changes on tiny amounts of “cell-free” DNA that are released into the blood when liver cells are injured. Changes in DNA methylation at genes like PPARγthat controls scar formation are then used to stratify patients by fibrosis severity.
Senior author Dr Jelena Mann of Newcastle University’s Institute for Cellular Medicine added: “This is the first time that a DNA methylation ‘signature’ from the blood has been shown to match the severity of a liver disease.
“It opens up the possibility of an improved blood test for liver fibrosis in the future.” Newcastle University
Maternal obesity and diabetes in pregnancy result in early overgrowth of the baby in the womb
, /in E-News /by 3wmediaThe babies of obese women who develop gestational diabetes are five times as likely to be excessively large by six months of pregnancy, according to new research led by the University of Cambridge. The study, which shows that excessive foetal growth begins weeks before at-risk women are screened for gestational diabetes, suggests that current screening programmes may take place too late during pregnancy to prevent lasting health impacts on the offspring.
Gestational diabetes is a condition that can affect women during pregnancy, with those who are obese at greater risk. As well as affecting the mother’s health, the condition also causes the unborn child to grow larger, putting the mother at risk during childbirth and increasing the likelihood that her offspring will develop obesity and diabetes during later life. The condition can usually be controlled through a combination of diet and exercise, and medication if these measures fail.
Women are screened for the condition through a blood glucose test at around 8-12 weeks into pregnancy. Current guidelines in the UK and the USA recommend that mothers found to be at greatest risk should then be offered a full test at between 24 and 28 weeks into pregnancy; however, in practice the majority of women are screened at the 28 week mark.
Researchers at the Department of Obstetrics & Gynaecology at the University of Cambridge analysed data from the Pregnancy Outcome Prediction study, which followed more than 4,000 first time mothers using ultrasound scans to assess the growth of their babies in the womb. They measured the abdominal and head circumference of the foetuses and compared the growth in women who developed gestational diabetes with those who did not.
Of the 4,069 women studied, 171 (4.2%) were diagnosed with gestational diabetes at or beyond 28 weeks. The researchers found no association between the size of the child at 20 weeks and the mother subsequently developing gestational diabetes. However, they found that the foetuses of women subsequently diagnosed with gestational diabetes grew excessively prior to diagnosis, between 20 and 28 weeks. Hence, the babies were already large at the time of diagnosis, and their findings suggest that the onset of foetal growth disorder in gestational diabetes predates the usual time of screening.
The researchers also studied women who were obese, as it is well recognised that maternal obesity is a risk factor for childhood obesity. Even in the absence of diabetes, the babies of obese women were also twice as likely to be big at 28 weeks. The combination of obesity and gestational diabetes was associated with an almost 5-fold risk of excessive foetal growth by the 28 week scan.
“Our study suggests that the babies of women subsequently diagnosed with gestational diabetes are already abnormally large by the time their mothers are tested for the disease,” says Dr Ulla Sovio from the Department of Obstetrics and Gynaecology at the University of Cambridge, the study’s first author. “Given the risk of complications for both mother and child from gestational diabetes, our findings suggest that screening women earlier on in pregnancy may help improve the short and long term outcomes for these women.
“Early screening may be particularly beneficial for obese women, as fetal growth is already abnormal by 20 weeks among these women. Any intervention aimed at reducing the risk of abnormal birthweight in the infants of obese women may need to be implemented even earlier.”
Senior author Professor Gordon Smith, also from the University of Cambridge, adds: “We know that the offspring of women with gestational diabetes are at increased risk of childhood obesity, but so far no clinical trials have successfully demonstrated that screening and intervention in pregnancy reduces this risk. Our study suggests a possible explanation: screening and intervention is taking place when the effects of gestational diabetes are already manifested in the foetus. Cambridge University