Cedars-Sinai researchers have linked Kawasaki Disease, a serious childhood illness that causes inflammation of blood vessels throughout the body, with early-onset and accelerated atherosclerosis, a leading cause of heart disease in adults.
In a study, an American Heart Association peer-reviewed medical journal, a team of researchers showed how Kawasaki Disease in young mice predisposed them to develop accelerated atherosclerosis, often called hardening of the arteries, in young adulthood. The study also suggests that aggressive early treatment of the blood vessel inflammation caused by Kawasaki Disease may reduce the future risk of developing accelerated atherosclerosis. Up to 25 percent of children with Kawasaki Disease will develop inflammation of the coronary arteries, making it the leading cause of acquired heart disease among children in developed countries.
‘Heart disease is the leading cause of death in this country and this study suggests that adult cardiovascular diseases likely start during childhood and that Kawasaki Disease may play a role in the childhood origin of adult heart disease,’ said Moshe Arditi, MD, executive vice chair of research in Cedars-Sinai’s Department of Pediatrics in the Maxine Dunitz Children’s Health Center and director of the Division of Pediatric Infectious Diseases and Immunology. ‘By recognising the connection between this vascular inflammatory disease and hardening of the arteries in young adults, physicians will be better prepared to provide preventive care to these vulnerable patients.’
Arditi said the study’s findings also may have implications for children with Kawasaki Disease in that they may need to be closely monitored for future development of early-onset atherosclerosis. Also, doctors treating children who have had Kawasaki Disease should closely monitor other known cardiovascular disease risk factors such as obesity, high blood pressure, high cholesterol and smoking, Arditi said.
Kawasaki Disease is diagnosed in approximately 5,000 U.S. children every year, predominantly affecting children younger than five. Boys are more likely than girls to acquire Kawasaki Disease, which starts with a sudden, persistent fever and causes swollen hands and feet, red eyes and body rash. Scientists suspect Kawasaki Disease is the body’s immune reaction to a virus that has yet to be identified.
Atherosclerosis occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. Over the course of years, plaque buildup makes it harder for blood to flow because the plaque narrows arteries and makes them stiffer. When pieces of plaque break off and move to smaller vessels, they can cause stroke, heart attack or pulmonary embolism.
In the study, which was funded with a grant from the National Institute of Allergy and Infectious Diseases, mice with Kawasaki Disease were fed a high-fat diet and then compared to mice that did not have Kawasaki Disease but did eat the same high-fat diet. The Kawasaki mice developed significantly more atherosclerotic plaque at a younger age.
‘This study suggests that timely diagnosis and aggressive initial treatment of the vascular inflammation may be important in preventing this potentially serious future complication,’ said co-author Prediman K. Shah, MD, director of cardiology, director of the and the Shapell and Webb Family Chair in Clinical Cardiology at the Cedars-Sinai Heart Institute. EurekAlert

When chromosomes replicate, sometimes there is an exchange of genetic material within a chromosome or between two or more chromosomes without a significant loss of genetic material. This exchange, known as a balanced chromosomal abnormality (BCA), can cause rearrangements in the genetic code.
Researchers from 15 institutions in three countries including Brigham and Women’s Hospital (BWH), Massachusetts General Hospital, Harvard Medical School, and the Broad Institute found that due to these rearrangements, BCAs harbour a reservoir of disruptions in the code that could lead to autism and other neurodevelopmental disorders. The researchers also uncovered 22 new genes that may contribute to or increase the risk of autism or abnormal neurodevelopment.
The researchers used a strategy that involved directly sequencing BCAs to reveal genes at the breakpoints and show that these genes are related to autism and other neurodevelopmental disorders.
This study is part of a larger, ongoing collaborative endeavour, the Developmental Genome Anatomy Project (DGAP), to identify genes critical in human development.
The researchers discovered that the genetic code can be disrupted at various distinct sites and still result in autism. The disruptions occur in several different groups of genes, including those already individually suspected to be associated with abnormal neurodevelopment; those which illuminate a single gene as important in large regions previously defined as genomic disorders; as well as those associated with psychiatric disorders that can have much later onset than neurodevelopmental disorders.
‘BCAs provide a unique opportunity to pinpoint a gene and validate it in a disorder,’ said Cynthia Morton, PhD, BWH director of cytogenetics, and principal investigator of DGAP. ‘These discoveries can illuminate biological pathways that may be a window to a new therapy. We are all grateful to the individuals and their families who make these fundamental findings possible through their participation as subjects in these studies.’ Brigham and Women’s Hospital

Big gaps in basic knowledge about the numbers and causes of apparently inexplicable heart attacks among young sportsmen and women are seriously hampering our ability to prevent them, says a sport and exercise medicine specialist in the British Journal of Sports Medicine.
At the very least, we need to start building reliable databases of all such events across sport, in a bid to start plugging these knowledge gaps, say Dr Richard Weiler and colleagues.
His comments come in the wake of the recent high profile case of premier league footballer, Fabrice Muamba, who collapsed on pitch, in front of a stadium packed with spectators, after sustaining a sudden heart attack.
Fortunately, Mr Muamba recovered, but cases like these, although rare, are still likely to occur despite screening programmes, and they are poorly understood, emphasises Dr Weiler.
These cases have prompted improvements in pitch-side and acute sports medicine, including emergency life support, defibrillation and the development of practical education courses and emergency care guidelines, says Dr Weiler.
None the less, he says: ‘We still lack many answers to basic questions about these afflictions. We do not know the exact numbers and trends in prevalence or incidence, and do not understand the [multiple causes] that trigger sudden cardiac death in previously healthy athletes.’
Issues that still need further investigation are the roles of gender and ethnicity, geography and genes, he says.
For example, Sub-Saharan Africa may be a ‘cardiac hotspot,’ with recent research linking sudden heart attacks to sickle cell trait.
Other research suggests that African Americans are three times more prone to sudden cardiac death/arrest than white athletes, although the rates vary considerably depending on the type of sport played.
And another study found that heart (ECG) tracing patterns differ between white and black athletes, although whether this is normal or indicates a higher risk for sudden cardiac death is not known, says Dr Weiler.
Screening programmes throw up a considerable number of false positive results, and it is still far from clear whether screening actually cuts the number of deaths, whether it is cost effective, and how to manage any abnormal findings, he says.
‘It is vital that we start to answer these questions based on reliable science and evidence,’ he insists. ‘To achieve this, we propose the collection and recording of reliable data across sport of every sudden cardiac death/arrest,’ he writes.
But for this to happen, co-operation and collaboration will be needed among sporting organisations, federations, and clubs, in addition to the establishment of sport specific and national registries for these incidents, he suggests.
Dr Weiler cites a FIFA (International Football Federation) initiative. This requires a medical assessment before a match for all FIFA competitions, and includes a recently established database for all its 208 member associations in a bid to build up an evidence base and better understand the condition.
‘This is one of many efforts needed to fill knowledge gaps and enable us to mitigate the risks of sudden cardiac arrest/death,’ concludes Dr Weiler, adding that minimum standards of pitch-side medical care across all sports are essential. EurekAlert

French researchers have found a way to identify quickly the 5-10% of patients in whom the commonly used painkiller, tramadol, does not work effectively. A simple blood test can produce a result within a few hours, enabling doctors to switch a non-responding patient on to another painkiller, such as morphine, which will be able to work in these patients.
Dr Laurent Varin, an anaesthesiologist at the Caen Teaching Hospital (Caen, France), presented the findings.
Tramadol is a synthetic opioid that is metabolised in the liver via an enzyme called cytochrome P450 2D6 (CYP2D6) to produce a small molecule (or ‘metabolite’) called O-demethyltramadol (ODT). ODT is between two and four times better at inducing analgesia than tramadol that is not metabolised successfully. This is because ODT has a 200-fold higher affinity to the opioid receptors in humans than un-metabolised tramadol, meaning that it binds to the receptors more successfully, blocking out the signals for pain.
Dr Varin said: ‘In our hospital we frequently use tramadol after surgery – about 50-60% of patients are treated with it, while the rest are treated with nefopam, which is a non-opioid painkiller. However, in about 5-10% of Caucasian patients the CYP2D6 enzyme is inefficient and does not produce enough ODT to bind effectively to the opioid receptors; these patients are known as ‘poor metabolisers’ and will have poorly controlled pain unless the problem is identified quickly and they are switched to morphine or nefopam.’
In order to identify the ‘poor metabolisers’, Dr Varin and his colleagues decided to investigate the ratio between tramadol and ODT in patients’ blood to see if this would give an indication of how efficiently CYP2D6 was working. They recruited 294 Caucasian patients who were receiving tramadol after surgery for a number of digestive conditions such as stomach, bowel and liver cancer, or for surgery on the spleen, gall bladder or pancreas. They collected blood samples after 24 and 48 hours post-surgery, and tested them for concentrations of tramadol and ODT using ‘high performance liquid chromatography tandem mass spectrometry’, which separates out the different components in the blood.
The researchers also used genotyping to analyse and identify the DNA make-up of the patients to discover which of them had inefficient CYP2D6. This revealed that eight per cent (23) of the patients were ‘poor metabolisers’. Then the researchers assessed the ratio of tramadol to ODT in the blood samples of the ‘poor metabolisers’ and the other patients.
‘We found that, after 24 hours, an ODT/tramadol ratio of less than 0.1 indicated a deficient CYP2D6 activity with an accuracy of 87% sensitivity – the test’s ability to correctly identify positive results – and 85% specificity – the test’s ability to correctly identify negative results,’ said Dr Varin. ‘This means that this ratio is highly accurate at detecting ‘poor metabolisers’ who need to be switched to another painkiller.’
Dr Varin and his colleagues believe that the ODT/tramadol ratio gives doctors a new tool to identify ‘poor metabolisers’ in the clinic. ‘This test is simple and cheap, costing only about 30 Euros. It can be performed quickly in just a few hours, instead of many days when the genotyping method is used, and will enable clinicians to make the best treatment choices for their patients. If a patient is suffering unrelieved postoperative pain and the blood test reveals an ODT/tramadol ratio of less than 0.1, then the clinicians can switch quickly to morphine, rather than trying to increase the dose of tramadol and risk adverse drug effects by overdosing. EurekAlert

Widely used antibiotics may increase incidence and severity of allergic asthma in early life, according to a University of British Columbia study.
The study shows that certain antibiotics that affect intestinal bacteria also had a profound impact on allergic asthma.
‘It has long been suspected that kids exposed to more antibiotics – like those in developed countries – are more prone to allergic asthma,’ says the study’s author, UBC microbiologist Brett Finlay. ‘Our study is the first experimental proof that shows how.’
Finlay’s team at UBC’s Dept. of Microbiology and Immunology and Michael Smith Laboratories examined how two widely used antibiotics – streptomycin and vancomycin – affected the bacterial ‘ecosystem’ in the gut. They found that vancomycin profoundly alters the bacterial communities in the intestine and increases severity of asthma in mouse models.
The same antibiotics do not impact adult mice’s susceptibility to asthma, indicating that early life is a critical period of establishing a healthy immune system.
Allergic asthma affects more than 100 million people worldwide and its prevalence is increasing on average by 50 per cent every decade, particularly among children in industrialized countries. According to the Asthma Society of Canada, asthma affects at least 12 per cent of Canadian children.
The human gut is colonised by approximately 100 trillion bacteria, and contains upwards of 1,000 bacterial species. While not fully understood, these micro-organisms, known as ‘gut flora,’ perform a host of useful functions, says Finlay.
‘Modern societal practices, such as improved sanitation methods and widespread antibiotic use, are causing the disappearance of ancestral species of bacteria in our gut that may be critical to a healthy immune system,’ says Finlay.
‘Our study shows this is the case with certain antibiotics and allergic asthma, and the gut-lung connection is also consistent with observations that incidence of asthma has not increased significantly in developing countries where antibiotic use is less prevalent – and in turn, the gut flora is permitted to fully develop.’ University of British Columbia