A recent analysis of Swedish military conscripts found that increased body mass index (BMI) in adolescent men is strongly linked developing early atrial fibrillation (AF) as well as with subsequent worse clinical outcomes after being diagnosed with AF.
The study, published in the Journal of the American Heart Association, included 1 704 467 young men (average age of 18.3 years) enrolled in compulsory military service in Sweden from 1969 through 2005. During a median follow-up of 32 years, 36 693 cases of atrial fibrillation were recorded, at an average age of 52.4 years at diagnosis. Compared with men with a baseline BMI of 18.5–<20.0 kg/m2, men with a BMI of 20.0–<22.5 kg/m2 had a 1.06-times higher risk of developing atrial fibrillation and those with a BMI of 40.0–50.0 kg/ m2 had a 3.72-times higher risk.
In men diagnosed with atrial fibrillation who were followed for a median of approximately 6 years, investigators identified 3767 deaths, 3251 cases of heart failure, and 921 cases of ischaemic stroke. Compared with those with a baseline BMI of <20 kg/m2, those with a baseline BMI of >30 kg/m2 had 2.86-times, 3.42-times, and 2.34-times higher risks of these outcomes, respectively.
“Whether screening for atrial fibrillation in early adulthood among individuals with long-standing obesity and more robust follow-up and initiation of anticoagulants in people with long-standing obesity and atrial fibrillation may improve survival needs to be addressed in future randomised trials” said corresponding author Demir Djekic, MD, PhD, of Sahlgrenska University Hospital/Östra, in Sweden.
Researchers at Karolinska Institutet in Sweden have found that the perception of one’s own body is largely based on the brain making guesses that are based on probability theory, instead of direct sensory input. The researchers detailed their findings in a study recently published in the journal eLife.
The researchers posit that the way humans perceive their bodies is largely governed by probability assessments based on past experiences, combined with sensory information such as sight and touch, for example.
“The experience of one’s own body is a statistical estimate of reality based on sensory information, sensory uncertainty, and previous experiences that can be summarised in a mathematical model”, explains Henrik Ehrsson, professor at the Department of Neuroscience, Karolinska Institutet.
Why are these results important?
“The results clarify the computational functions that govern the perception of one’s own body. This perception thus arises, not only as a result of a “direct” interpretation of signals from sight, touch sense, and proprioception as the textbooks say, but rather is based on active “guesses” that the brain constantly makes based on probability theory and the information that can be extracted from the patterns of sensory signals”, says Henrik Ehrsson.
“When we varied the degree of time delay between the visual and tactile impressions in small steps, or blurred the image in the augmented reality glasses to increase uncertainty, the illusion changed in a way that can be described by equations and curves: increased delay gave a weaker feeling of the rubber hand as its own, while increased uncertainty (blurriness) made the illusion stronger”, says Marie Chancel, corresponding author of the study.
Based on the experiments, the researchers came up with a statistical explanatory model for the brain’s perceptual awareness of its own body.
Changes in body ownership
The next step is to try to understand how the statistical model that determines own-bodily awareness is implemented by neural networks in the brain. In a preliminary study, the researchers have shown that neural activity in posterior parietal cortex follows the Bayesian model well in experiments where they measure brain activity with functional magnetic resonance imaging. The researchers also want to investigate how their model can explain changes in bodily awareness in various psychiatric and neurological conditions, such as Schizophrenia and Anorexia.
A global study of over 28 000 people has provided the strongest evidence to date that lowering blood pressure in later life can cut the risk of dementia. The study, which included five randomised controlled trials, was published in the European Heart Journal, and constitutes the highest grade of evidence for this preventative association.
Dr Ruth Peters, Program Lead for Dementia in The George Institute’s Global Brain Health Initiative, said that with no significant dementia treatment breakthroughs being made, reducing the risk of developing the disease would be a welcome step forward.
“Given population ageing and the substantial costs of caring for people with dementia, even a small reduction could have considerable global impact,” she said.
“Our study suggests that using readily available treatments to lower blood pressure is currently one of our ‘best bets’ to tackle this insidious disease.”
Dementia is fast becoming a global epidemic, currently affecting an estimated 50 million people worldwide. This number is projected to triple by 2050 mainly from ageing populations.
Current estimates put the cost at US$20–$40 000 per person with the condition each year.
Dr Peters explained that while many trials have looked at the health benefits of lowering blood pressure, few included dementia outcomes and even fewer were placebo-controlled.
“Most trials were stopped early because of the significant impact of blood pressure lowering on cardiovascular events, which tend to occur earlier than signs of dementia,” she said.
To examine the relationship between blood pressure and dementia more closely, researchers analysed five double-blind placebo-controlled randomised trials that used different blood pressure lowering treatments and followed patients until the development of dementia. A total of 28 008 individuals with an average age of 69 and a history of hypertension from 20 countries were included. Across these studies, the mid-range of follow up was just over four years.
“We found there was a significant effect of treatment in lowering the odds of dementia associated with a sustained reduction in blood pressure in this older population,” said Dr Peters.
“Our results imply a broadly linear relationship between blood pressure reduction and lower risk of dementia, regardless of which type of treatment was used.”
Researchers hope the results will help in designing public health measures to slow the advance of dementia as well as informing treatment, where there may be hesitancy in how far to lower blood pressure in older age.
“Our study provides the highest grade of available evidence to show that blood pressure lowering treatment over several years reduces the risk of dementia, and we did not see any evidence of harm,” said Dr Peters.
“But what we still don’t know is whether additional blood pressure lowering in people who already have it well-controlled or starting treatment earlier in life would reduce the long-term risk of dementia,” she added.
Haemophilia A, the most common severe form of haemophilia, affects almost exclusively males and can usually be with factor VII injections, but not for all sufferers, as the immune system may treat the factor as an intruder. New research has uncovered an important immune mechanism that targets B cells, which is crucial in making the the therapy effective. The study is published online in the Journal of Clinical Investigation.
Haemophilia A patients have a defect in factor VIII, a protein key for clotting. Most patients therefore receive an intravenous injection of the functional clotting factor every few days as treatment. But frequently, and especially at the start of treatment, the immune system recognises the injected agent as foreign to the body and attacks it. This is the most serious complication of haemophilia treatment because factor VIII can then no longer work.
In these cases, immune tolerance therapy, which was also developed at the University Hospital Bonn (UKB) more than 40 years ago, often helps. This involves regularly injecting the haemophilia sufferers with a high dose of factor VIII over several months, letting the immune system learn to tolerate it. The underlying immune mechanisms are unknown. “However, this doesn’t always work,” explains Prof Dr Johannes Oldenburg at the UKB. “In about 30 percent of patients, tolerance induction does not lead to success. So your body’s own defences continue to attack and destroy the factor VIII protein, which means that factor VIII cannot be used for treatment. We wanted to know the reason for this.”
To this end, the team looked at two cell types in the immune system, B cells and regulatory T cells. B cells recognise foreign molecules in the body and produce antibodies against them, which switch off the function of the molecule. For factor VIII, this means that it is no longer effective in haemophilia treatment.
Brake in the immune system
Regulatory T cells moderate the strength and duration of the immune response. The researchers have now found a new type of Treg cell that can act specifically against certain B cells rather than the overall immune response. “We were able to show that immunotolerance therapy results in the generation of regulatory T cells that exclusively induce B cells against factor VIII to commit suicide,” says Dr Janine Becker-Gotot of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at UKB. “These T cells have a sensor that allows them to recognise and attach to the corresponding B cells. In addition, they have the ability to push the self-destruct button on the surface of B cells.”
This button is a molecule called PD-1 which, on activation, leads to apoptosis. Every active B cell has this button. “Our experiments enabled us for the first time to detect regulatory T cells that can activate this self-destruct button only in very specific B cells, in order to specifically prevent unwanted immune responses,” explains IMMEI Director Prof Dr Christian Kurts.
The more PD-1 buttons the B cells against factor VIII carry on their surface, the easier it is for them to be driven to suicide by immune tolerance therapy. “The amount of PD-1 varies from person to person,” Becker-Gotot explains. “If it’s very low to begin with, there’s a good chance that many inhibitor-producing B cells will survive and continue to neutralise the injected factor VIII.”
Test to show in whom immunotolerance therapy is useful
Interestingly, B cells also produce more PD-1 once they come into contact with regulatory T cells. “We can now test how strong this reaction is,” the researcher says. “If PD-1 levels go up shortly after starting immune tolerance therapy and then stay up, that’s a clear sign that the treatment is going to be successful.” The team is currently developing a blood test that can be used to detect whether or not immune tolerance therapy is working in patients during the prolonged treatment.
“Our findings have great basic scientific value,” explains Prof Kurts. “And not just for haemophilia, but also for other congenital disorders where missing proteins are replaced therapeutically. In the long term, they could also be used to develop new treatments.”
New research in the Annals of Internal Medicine provides strong evidence that vitamin D deficiency is associated with premature death, prompting calls for people to follow healthy vitamin D level guidelines.
The study by the University of South Australia found that premature mortality increased in line with the severity of Vitamin D deficiency.
First author and UniSA PhD candidate, Josh Sutherland, says that while vitamin D has been connected with mortality, it has been challenging to establish causal effects.
“While severe vitamin D deficiency is rarer in Australia than elsewhere in the world, it can still affect those who have health vulnerabilities, the elderly, and those who do not acquire enough vitamin D from healthy sun exposure and dietary sources,” Sutherland says.
“Our study provides strong evidence for the connection between low levels of vitamin D and mortality, and this is the first study of its kind to also include respiratory disease related mortality as an outcome.
“We used a new genetic method to explore and affirm the non-linear relationships that we’ve seen in observational settings, and through this we’ve been able give strong evidence for the connection between low vitamin D status and premature death.
“Vitamin D deficiency has been connected with mortality, but as clinical trials have often failed to recruit people with low vitamin D levels – or have been prohibited from including vitamin deficient participants – it’s been challenging to establish causal relationships.”
The Mendelian randomisation study (an alternative to the gold standard of a randomised controlled trial) evaluated 307 601 records from the UK Biobank. Low levels of vitamin D were noted as less than <25 nmol/L with the average concentration found to be 45.2 nmol/L. Over a 14-year follow up period, researchers found that the risk for death significantly decreased with increased vitamin D concentrations, with the strongest effects seen among those with severe deficiencies.
Senior investigator Professor Elina Hyppönen says more research is now needed to establish effective public health strategies that can help achieve national guidelines and reduce the risk of premature death associated with low vitamin D levels.
“The take-home message here is simple – the key is in the prevention. It is not good enough to think about vitamin D deficiency when already facing life-challenging situations, when early action could make all the difference,” Prof Hyppönen says.
“It is very important to continue public health efforts to ensure the vulnerable and elderly maintain sufficient vitamin D levels throughout the year.”
