The adverse side effects of certain hepatitis C medications can now be replicated and observed in Petri dishes and test tubes, thanks to a research team led by Craig Cameron, the Paul Berg Professor of Biochemistry and Molecular Biology at Penn State University. ‘The new method not only will help us to understand the recent failures of hepatitis C antiviral drugs in some patients in clinical trials,’ said Cameron. ‘It also could help to identify medications that eliminate all adverse effects.’ The team’s findings may help pave the way toward the development of safer and more-effective treatments for hepatitis C, as well as other pathogens such as SARS and West Nile virus.
First author Jamie Arnold, a research associate in Cameron’s lab at Penn State, explained that the hepatitis C virus (HCV), which affects over 170,000,000 people worldwide, is the leading cause of liver disease and, although antiviral treatments are effective in many patients, they cause serious side effects in others. ‘Many antiviral medications for treating HCV are chemical analogs for the building blocks of RNA that are used to assemble new copies of the virus’s genome, enabling it to replicate,’ he said. ‘These medications are close enough to the virus’s natural building blocks that they get incorporated into the virus’s genome. But they also are different in ways that lead to the virus’s incomplete replication. The problem, however, is that the medication not only mimics the virus’s genetic material, but also the genetic material of the patient. So, while the drug causes damage to the virus, it also may affect the patient’s own healthy tissues.’
A method to reveal these adverse side effects in the safety of a laboratory setting, rather than in clinical trials where patients may be placed at risk, has been developed by the research team, which includes Cameron; Arnold; Suresh Sharma, a research associate in Cameron’s lab; other scientists at Penn State; and researchers from other academic, government, and corporate labs. ‘We have taken anti-HCV medications and, in Petri dishes and test tubes, we have shown that these drugs affect functions within a cell’s mitochondria,’ Cameron explained. ‘The cellular mitochondria — a tiny structure known as ‘the powerhouse of the cell’ that is responsible for making energy known as ATP — is affected by these compounds and is likely a major reason why we see adverse effects.’ Cameron noted that scientists have known for some time that certain individuals have ‘sick’ mitochondria. Such individuals are likely more sensitive to the mitochondrial side effects of antiviral drugs.
‘We know that antiviral drugs, including the ones used to treat HCV, affect even normal, healthy mitochondria by slowing ATP output,’ Arnold added. ‘While a person with normal mitochondria will experience some ATP and mitochondrial effects, a person who is already predisposed to mitochondrial dysfunction will be pushed over the ‘not enough cellular energy’ threshold by the antiviral drug. The person’s mitochondria simply won’t be able to keep up.’
One of the problems with clinical trials, Arnold explained, is that a drug may be shown to be quite effective but, if even a miniscule percentage of patients have side effects, the U.S. Food and Drug Administration is obligated to put the trial on hold or stop the trial altogether. This possibility makes drug companies reluctant to invest money in drug trials after an adverse event has been observed, even when the drugs could still help millions of people. The researchers hope that their methods eventually will become a part of the pre-clinical development process for this class of antiviral drugs. ‘If we can show, in the lab, that a drug will cause side effects, then these compounds will not enter lengthy, expensive clinical trials and cause harm to patients ‘ he said. ‘What’s more, a drug company can invest its money more wisely and carefully in drug research that will produce safe and effective products. Better and more-willing investments by drug companies ultimately will help patients, because resources will be spent developing drugs that not only work, but that are safe for all patients.’
Penn State Univeristy
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Nearly 23 percent of American women of childbearing age met or exceeded the median blood levels for all three environmental chemical pollutants — lead, mercury, and PCBs — tracked in an analysis of data on thousands of women by Brown University researchers. All but 17.3 percent of the women aged 16 to 49 were at or above the median blood level for one or more of these chemicals, which are passed to foetuses through the placenta and to babies through breast milk.
The study identified several risk factors associated with a higher likelihood of a median-or-higher ‘body burden’ for two or more of these chemicals.
The three pollutants are of greatest interest because they are pervasive and persistent in the environment and can harm foetal and infant brain development, albeit in different ways, said study lead author Dr. Marcella Thompson. But scientists don’t yet know much about whether co-exposure to these three chemicals is more harmful than exposure to each chemical alone. Most researchers study the health effects of exposure to an individual chemical, not two or three together.
‘Our research documents the prevalence of women who are exposed to all three of these chemicals,’ said Thompson, who began the analysis as a doctoral student at the University of Rhode Island College of Nursing and has continued the research as a postdoctoral research associate for Brown University’s Superfund Research Program with co-author Kim Boekelheide, professor of pathology and laboratory medicine. ‘It points out clearly the need to look at health outcomes for multiple environmental chemical co-exposures.’
Most of the childbearing-age women — 55.8 percent — exceeded the median for two or more of the three pollutants.
Data were collected between 1999 and 2004 from 3,173 women aged 16 to 49 who participated in the Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES). The survey was designed to represent the national population of 134.5 million women of childbearing age. Because the original study also elicited a wide variety of information on health behaviours, socio-economic and demographic characteristics, Thompson and Boekelheide were able to identify specific risk factors associated with increased odds of having higher blood levels of lead, mercury, and PCBs.
They found several statistically significant risk factors. The most prominent among them was age. As women grew older, their risk of exceeding the median blood level in two or more of these pollutants grew exponentially to the point where women aged 30 to 39 had 12 times greater risk and women aged 40 to 49 had a risk 30 times greater than those women aged 16 to 19.
Thompson said women aged 40 to 49 would be at greatest risk not only because these chemicals accumulate in the body over time, but also because these women were born in the 1950s and 1960s before most environmental protection laws were enacted.
Fish and heavy alcohol consumption also raised the risk of having higher blood levels. Women who ate fish more than once a week during the prior 30 days had 4.5 times the risk of exceeding the median in two or more of these pollutants. Women who drank heavily had a milder but still substantially elevated risk.
Fish, especially top predators like swordfish and albacore tuna, are known to accumulate high levels of mercury and PCBs, Thompson said. However, there is no known reason why they found a statistically higher association between heavy drinking and a higher body burden of pollutants.
One risk factor significantly reduced a woman’s risk of having elevated blood levels of the pollutants, but it was not good news: breastfeeding. Women who had breastfed at least one child for at least a month sometime in their lives had about half the risk of exceeding the median blood level for two or more pollutants. In other words, Thompson said, women pass the pollutants that have accumulated in their bodies to their nursing infants.
Although the study did not measure whether women with higher levels of co-exposure or their children suffered ill health effects, Thompson said, the data still suggest that women should learn about their risks of co-exposure to these chemicals well before they become pregnant. A woman who plans to become pregnant in her 30s or 40s, for example, will have a high relative risk of having higher blood levels of lead, PCBs, and mercury.
‘We carry a history of our environmental exposures throughout our lives,’ Thompson said.
Brown University
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A new study reveals that primitive human stem cells are resistant to human cytomegalovirus (HCMV), one of the leading prenatal causes of intellectual disability, deafness and deformities worldwide. Researchers from the University of Pittsburgh School of Medicine found that as stem cells and other primitive cells mature into neurons, they become more susceptible to HCMV, which could allow them to find effective treatments for the virus and to prevent its potentially devastating consequences.
‘Previous studies have focused on other species and other cell types, but those studies did not evaluate what the cytomegalovirus does to human brain cells,’ said Vishwajit Nimgaonkar, M.D., Ph.D., professor of psychiatry at the University of Pittsburgh School of Medicine, and senior author of the report. ‘This study is the first of its kind, and the first to discover that primitive stem cells are actually resistant to HCMV.’
Access to cultured human neurons, necessary to understand the pathogenic effects of HCMV, has been limited by difficulties in growing the brain cells in the laboratory. Yet through human-induced pluripotent stem (iPS) cells, researchers were able to overcome this hurdle.
The study authors derived live iPS cells by reprogramming cells called fibroblasts obtained from human skin biopsies. The iPS cells were then induced to mature through several stages into neurons, the primary cells in the brain. The researchers were able to evaluate the patterns of damage caused by HCMV on all these cells.
The research findings suggest:
• Human iPS cells do not permit a full viral replication cycle, suggesting for the first time that these cells can resist CMV infection
• CMV infection distorts iPS cell differentiation into neurons, and that may be a mechanism by which infected babies develop impairments of brain maturation and intellectual ability
• iPS-derived mature neurons are more susceptible to CMV infection and once infected show effects including defective function that have been shown in other animal studies and in other human tissues, and the neurons die a few days after infection lab studies, possibly reflecting the impact of CMV on the human brain
‘The findings were quite surprising, but this is only the first in a series of studies on HCMV,’ added Nimgaonkar. ‘There is a lot of interest in what we can do to treat the infection, and current work is already underway to screen for new drugs that could be used to fight these viruses.’
Between 50 and 80 percent of people in the U.S. have been infected by HCMV by the time they reach 40. Infections are rarely serious, but the virus does not leave the body. CMV is also the most common congenital infection in the U.S., and occurs when a mother contracts CMV during pregnancy and passes the virus to her unborn child. According to the U.S. Centers for Disease Control and Prevention, one of every 150 children are born with CMV infection and one in five of them develop permanent problems, such as intellectual disability, vision and hearing loss, and seizures.
Pitt researchers are collaborating with the Drug Discovery Institute to further understand the cellular system and determine which agents are most effective against HCMV and similar viruses, and which treatments would be safe for human use.
University of Pittsburgh
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As part of their ongoing research on the role of genes in the development of type 1 diabetes, Joslin Diabetes Center scientists, in collaboration with scientists at the University of Würzburg, have demonstrated how a genetic variant associated with type 1 diabetes and other autoimmune diseases influences susceptibility to autoimmunity.
Recent studies of the human genome have identified genetic regions associated with autoimmune diseases such as type 1 diabetes. Joslin scientists in the Section of Immunobiology seek to understand how genes that are most widely associated with various autoimmune diseases contribute to disease risk.
One of these genes is PTPN22, which plays a role in lymphocyte (immune cell) function. A PTPN22 variant (or mutation) has been implicated as a risk factor for type 1 diabetes and several other autoimmune disorders. PTPN22 is involved in the formation of a key protein known as lymphoid tyrosine phosphatase (LYP), which helps control the activity of T and B cells in the immune system. The PTPN22 mutation generates a variation of LYP with a different molecular structure.
Most studies of the PTPN22 disease variant have suggested that this variant is a gain-of-function genetic mutation that enhances LYP activity and lessens the activity of T and B cells, which increases susceptibility to autoimmunity. ‘When immune cells are less reactive during the maturation phase of their development, the cells can evade mechanisms that help protect against autoimmunity,’ says study lead author Stephan Kissler, PhD, of the Section of Immunobiology. However, one study which analysed data from humans and genetically modified mice suggested that the LYP variant associated with type 1 diabetes is a loss-of-function mutation that reduces LYP activity.
To help resolve the conflicting data, Joslin scientists conducted studies with a unique mouse model developed by Dr. Kissler’s graduate student and co-author, Peilin Zheng. Using a technology that combines RNA interference, a method to silence gene expresson, with lentiviral transgenesis, a method to genetically modify animals, the scientists can manipulate gene activity in the most widely used mouse model for type 1 diabetes, the non-obese diabetic mouse (NOD). In this study, the researchers were able to easily turn off and on the PTPN22 gene in the NOD mouse. ‘We are the first to use this approach in the NOD mouse model,’ says Dr. Kissler. ‘It provides a very powerful way to study the contribution of PTPN22 to disease.’
When PTPN22 was turned off in mice, mimicking a loss-of-function mutation, the researchers observed an increase in regulatory T cells and a decreased risk of autoimmune diabetes. ‘This is the first study conducted on the diabetic mouse model that supports the LYP gain-of-function hypothesis,’ says Dr. Kissler. ‘Our work should help to resolve the controversy.’
By providing additional data that suggests the potential therapeutic value of PTPN22 manipulation, the study may further the development of new therapeutic options that inhibit LYP to reduce or prevent autoimmunity. ‘Our goal is to treat autoimmunity. Inhibiting LYP in patients may increase regulatory immune cells and could confer protection against autoimmunity, but it remains to be tested if our promising findings in this mouse model are reflected in humans,’ says Dr. Kissler.
Joslin Diabetes Research Center
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Reduced production of myelin, a type of protective nerve fibre that is lost in diseases like multiple sclerosis, may also play a role in the development of mental illness, according to researchers at the Graduate School of Biomedical Sciences at Mount Sinai School of Medicine.
Myelin is an insulating material that wraps around the axon, the threadlike part of a nerve cell through which the cell sends impulses to other nerve cells. New myelin is produced by nerve cells called oligodendrocytes both during development and in adulthood to repair damage in the brain of people with diseases such as multiple sclerosis (MS).
A new study led by Patrizia Casaccia, MD, PhD, Professor of Neuroscience, Genetics and Genomics; and Neurology at Mount Sinai, determined that depriving mice of social contact reduced myelin production, demonstrating that the formation of new oligodendrocytes is affected by environmental changes. This research provides further support to earlier evidence of abnormal myelin in a wide range of psychiatric disorders, including autism, anxiety, schizophrenia and depression.
‘We knew that a lack of social interaction early in life impacted myelination in young animals but were unsure if these changes would persist in adulthood,’ said Dr. Casaccia, who is also Chief of the Center of Excellence for Myelin Repair at the Friedman Brain Institute at Mount Sinai School of Medicine. ‘Social isolation of adult mice causes behavioural and structural changes in neurons, but this is the first study to show that it causes myelin dysfunction as well.’
Dr. Casaccia’s team isolated adult mice to determine whether new myelin formation was compromised. After eight weeks, they found that the isolated mice showed signs of social withdrawal. Subsequent brain tissue analyses indicated that the socially isolated mice had lower-than-normal levels of myelin-forming oligodendrocytes in the prefrontal cortex, but not in other areas of the brain. The prefrontal cortex controls complex emotional and cognitive behaviour.
The researchers also found changes in chromatin, the packing material for DNA. As a result, the DNA from the new oligodendrocytes was unavailable for gene expression.
After observing the reduction in myelin production in socially-isolated mice, Dr. Casaccia’s team then re-introduced these mice into a social group. After four weeks, the social withdrawal symptoms and the gene expression changes were reversed.
‘Our study demonstrates that oligodendrocytes generate new myelin as a way to respond to environmental stimuli, and that myelin production is significantly reduced in social isolation,’ said Dr. Casaccia. ‘Abnormalities occur in people with psychiatric conditions characterised by social withdrawal. Other disorders characterised by myelin loss, such as MS, often are associated with depression. Our research emphasises the importance of maintaining a socially stimulating environment in these instances.’
At Mount Sinai, Dr. Casaccia’s laboratory is studying oligodendrocyte formation to identify therapeutic targets for myelin repair. They are screening newly-developed pharmacological compounds in brain cells from rodents and humans for their ability to form new myelin.
EurekAlert
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Lung cancer researchers at St. Joseph’s Hospital and Medical Center in Phoenix, Ariz., in collaboration with researchers at the Translational Genomics Research Institute and other institutions, have identified a gene that plays a role in the growth and spread of non-small cell lung cancer tumours, opening the door for potential new treatment options.
Landon J. Inge, PhD, is the lead scientist in the thoracic oncology laboratory at St. Joseph’s Center for Thoracic Disease and Transplantation and was a member of the study’s research team.
Lung cancer is the leading cause of cancer deaths worldwide, and approximately 85 percent of these cancers are non-small cell lung cancers (NSCLC). Patients with NSCLC frequently have tumours with mutations in the epidermal growth factor receptor (EGFR) gene. When activated, this mutated gene leads to tumour development and growth. By studying lung cancer samples from patients who had undergone tumour resection, the researchers discovered that many patients with EGFR mutations also exhibited higher than normal levels of the gene fibroblast growth factor-inducible 14 (Fn14). The researchers believe that activation of EGFR can lead to increased expression and activity of the Fn14 gene.
The research team also discovered that while over-expression of Fn14 enhances lung tumour formation and metastasis, suppression of Fn14 reduces metastasis in NSCLC.
‘Our data suggest that Fn14 levels can contribute to NSCLC cell migration and invasion,’ says Dr. Inge. ‘Thus, tumour suppression through the targeting of Fn14 may prove to be a therapeutic intervention in NSCLC and other tumour types.’
The Fn14 gene has been found to be elevated in other types of tumours, as well, including glioblastoma and certain types of breast cancer, suggesting that Fn14 may be a therapeutic target for multiple cancer therapies.
EurekAlert
Scientists say they have developed a breath-test that can accurately tell if a person has bowel cancer. The test, which looks for exhaled chemicals linked to tumour activity, was able to identify a majority of patients with the disease.
The British Journal of Surgery reported an overall accuracy of 76%.
However, another scientist said it was unlikely a fully functioning and reliable breath-test would be available soon for the general public. Scientists are working on breath-tests for a host of other diseases, including several types of cancer, TB and diabetes.
If diagnosed and treated early, the chances of stopping cancer can be good, but there is often little or no outward sign of the disease until it has progressed significantly.
The current screening test for bowel cancer looks for signs of blood in the faeces, but only a small proportion of those who test positive actually have colorectal cancer, which means unnecessary and invasive further testing for many people.
The breath-test technology relies on the idea that the biology of tumours can lead to the production of specific ‘volatile organic compounds’, combinations of chemicals unlikely in a healthy person.
These can be found in small amounts in the breath of the patient, and early studies found dogs could be trained to identify them – although the latest study relies an electronic device to analyse breath gases.
The team from a hospital in Bari, southern Italy, compared the breath of 37 patients known to have bowel cancer with that of 41 ‘controls’ who were thought to be healthy.
The initial test identified the cancer patients with 85% accuracy, and although, when combined with a follow-up test, the overall result fell to 76%, the researchers were upbeat about its potential.
‘The present findings further support the value of breath-testing as a screening tool,’ they say.
It might be possible that the technique could help identify patients whose cancer was returning after treatment.
Bigger studies with a greater number of patients were now needed to fine-tune the test and confirm it worked, said Dr Donato Altomare and colleagues.
BBC
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The study, led by King’s College London’s Institute of Psychiatry (IoP) provides the most detailed understanding yet of the brain processes involved in teenage alcohol abuse.
Alcohol and other addictive drugs activate the dopamine system in the brain which is responsible for feelings of pleasure and reward. Recent studies from King’s IoP found that the RASGRF2 gene is a risk gene for alcohol abuse, however, the exact mechanism involved in this process has, until now, remained unknown.
Professor Gunter Schumann, from the Department of Social, Genetic and Developmental Psychiatry (SGDP) at King’s Institute of Psychiatry and lead author of the study says: ‘People seek out situations which fulfill their sense of reward and make them happy, so if your brain is wired to find alcohol rewarding, you will seek it out. We now understand the chain of action: how our genes shape this function in our brains and how that, in turn, leads to human behaviour. We found that the RASGRF-2 gene plays a crucial role in controlling how alcohol stimulates the brain to release dopamine, and hence trigger the feeling of reward. So, if people have a genetic variation of the RASGRF-2 gene, alcohol gives them a stronger sense of reward, making them more likely to be heavy drinkers.’
Approximately 6 out of 10 young people aged 11-15 in England report drinking, a figure which has remained relatively stable over the past 20 years. However, binge drinking has become more common, with teenagers reportedly drinking an average of 6 units per week in 1994 and 13 units per week in 2007. In the UK, around 5,000 teenagers are admitted to hospital every year for alcohol-related reasons. Teenage alcohol abuse is also linked to poor brain development, health problems in later life, risk taking behaviour (drunk driving, unsafe sex) and antisocial behaviour.
The study initially looked at mouse models without the RASGRF2 gene to see how they reacted to alcohol. They found that the absence of the RASGRF-2 gene was linked to a significant reduction in alcohol-seeking activity. Upon intake of alcohol, the absence of the RASGRF-2 impaired the activity of dopamine-releasing neurons in a region of the brain called the ventral tegmental area (VTA) and prevented the brain from releasing dopamine, and hence any sense of reward.
The research team then analysed the brain scans of 663 14 year old boys – who at that age had not been exposed to significant amounts of alcohol. They found that individuals with genetic variations to the RASGRF2 gene had higher activation of the ventral striatum area of the brain (closely linked to the VTA and involved in dopamine release) when anticipating reward in a cognitive task. This suggests that individuals with a genetic variation on the RASGRF-2 gene release more dopamine when anticipating a reward, and hence derive more pleasure from the experience.
To confirm these findings, the researchers analysed drinking behaviour from the same group of boys at 16 years old, when many had already begun drinking frequently. They found that individuals with the variation on the RASGRF-2 gene drank more frequently at the age of 16 than those with no variation on the gene.
Professor Schumann concludes: ‘Identifying risk factors for early alcohol abuse is important in designing prevention and treatment interventions for alcohol addiction.’
King’s College London
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Children with HIV have a 2.5 fold increased risk of atherosclerosis, according to research presented at EUROECHO and other Imaging Modalities 2012. Antiretroviral treatment, lipid lowering drugs and prevention with healthy lifestyles are needed to prevent early death from cardiovascular disease.
EUROECHO and other Imaging Modalities 2012 is the annual meeting of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the European Society of Cardiology (ESC).
Antiretroviral treatment is prolonging the lives of HIV patients, who no longer die prematurely from the infection. But the treatment is not a cure, and the virus remains in the body.
‘The infection makes the body fight for its life, so the immune system is always activated and there is chronic inflammation,’ said Dr Talia Sainz Costa, principal investigator of the study and a paediatrician from Madrid, Spain.
In addition, many antiretroviral drugs increase bad (LDL) cholesterol and lower good (HDL) cholesterol. Dr Sainz Costa said:
‘Children with HIV will have high cholesterol for a long period and on top of that the virus causes chronic inflammation – both are bad for the arteries.’
Patients with HIV die 10 years prematurely from non-AIDS disease which includes cardiovascular diseases, cancer, liver and renal diseases.
‘This is especially important for children because they have been living with HIV since birth or even before,’ said Dr Sainz Costa. ‘By the time they are 50 years old they will have accumulated more toxicity from the treatment and more secondary effects from the infection and will be at an even greater risk of heart attacks and other complications.’
The present study aimed to discover whether children and adolescents already have early atherosclerosis damage. Carotid intima-media thickness (IMT), a marker of atherosclerosis, was measured using echocardiography in 150 children and adolescents with HIV and 150 age and sex matched healthy controls.
The researchers found that 17% of the HIV group were smokers compared to 11% of the control group. Dr Sainz Costa said:
‘Smoking levels in adolescents in Spain are known to be high. The even higher levels in the HIV group are probably related to low socio-economic status and very complex social/family backgrounds.’
After adjustment for age, sex, BMI and smoking status, HIV was independently associated with thicker IMT (p=0.005). Children and adolescents had a 2.5 fold increased risk of higher IMT due to HIV. Dr Sainz Costa said:
‘Our study shows that children and adolescents with HIV have arteries that are more rigid and less elastic, which means that the process of atherosclerosis has begun and they have increased risk of an infarct in the future.’
The researchers also found that frequencies of activated T CD4+ cells were higher among HIV-infected children and young adults (p=0.002). ‘This shows that the immune system is more active,’ said Dr Sainz Costa.
They concluded that clinicians need to take cardiovascular prevention more seriously in children and adolescents with HIV, while continuing to treat the HIV infection. Dr Sainz Costa said: ‘Cardiovascular disease has already put down roots in children and adolescents with HIV and we need to take preventive measures at this early stage. We should be more aggressive in treating their high cholesterol with medication – this practice is common in adults but rare in children.’ She added:
‘We also need to be stricter about healthy lifestyle advice. Many children and adolescents with HIV come from families with low socio-economic status and are more prone to smoking, poor diet and inactivity. This age group also struggles with adherence to medication which is another worry, but we should not let this decrease our efforts to prevent future complications.’
Dr Sainz Costa concluded: ‘HIV research is investigating ways to control the inflammation and immune activation with agents such as probiotics, aspirin and corticoids. In the meantime clinicians need to focus on ensuring their young patients with HIV take the antiretroviral treatment, take lipid lowering drugs when necessary, and adopt healthier lifestyles.’
European Society of Cardiology
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An international team of researchers from 23 institutions across three continents has identified two genetic factors that are strongly associated with the most common form of non-syndromic craniosynostosis — premature closure of the bony plates of the skull. The team of geneticists, paediatricians, surgeons and epidemiologists includes Joan Richtsmeier, professor of anthropology at Penn State, and Yann Heuzé, a post-doc in the Richtsmeier lab.
During foetal and early childhood development, the skull is made of separate bony plates that allow for growth of the head. The borders between the plates do not normally fuse completely until a child is about two years old, leaving temporary ‘soft spots’ at the intersection of the seams.
If the bones fuse too early — the condition called craniosynostosis — a child will develop an abnormally shaped head. Left untreated the disorder can cause learning disabilities and other complications due to brain compression, such as neurologic and visual problems. Typically, craniosynostosis requires extensive neurosurgical correction.
About 20 percent of craniosynostosis cases previously have been linked to a number of different genetic syndromes, the researchers note, but the vast majority of cases (not associated with a syndrome involving other birth defects) arise without any known family history or cause. The most common form of non-syndromic craniosynostosis — affecting about 1 in 5,000 newborns — involves the sagittal suture, the main seam that runs down the centre of the top of the skull. These cases were the subject of the investigation.
Although the condition has long been thought to be partially determined by genes, since it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than non-identical twins, the exact basis was unclear.
To help determine the cause, the researchers conducted the first genome-wide association study for the disorder, which involves scanning the entire genome of a group of people with craniosynostosis and comparing it to a control group of people without it. The study searched for single nucleotide polymorphisms (SNPs) that are associated with craniosynostosis. SNPs are DNA sequence variations in which a single nucleotide differs from the usual one at that position. There are some 3 billion nucleotides, the basic building blocks of DNA, in the human genome.
The study first evaluated the DNA, which was extracted from whole blood or oral samples, of 201 cases and both of their parents, who did not have the condition. After reviewing the morphological and ethnic details of each case, the researchers restricted their final analysis to a group of 130 non-Hispanic white case-parent trios. This approach reduced the genetic variability inherent to individuals from different ethnicities and the potential of mixing of patients with other diseases. Their results identified very strong associations to SNPs in two areas of the genome, coding for bone morphogenetic protein 2 (BMP2) and Bardet-Biedl syndrome 9 protein (BBS9). Both proteins are known to play a role in skeletal development.
Richtsmeier studies the processes of growth and development that translate genetic information into tissues of specific shapes and sizes, using computed tomography scans of patients with craniofacial diseases and animal models for those same conditions. Heuzé analysed the computed tomography data of cases in this genetic analysis, both qualitatively to establish the degree of suture closure and quantitatively to estimate the magnitude of dysmorphology, to guarantee that the individuals whose genes were analysed in the study showed physical traits of the disease and were not mixing the sample with outlier cases.
The findings were replicated in another population of 172 cases of children with the condition and 548 unrelated controls. The extensive international collaboration came about because of the desire to include as many cases as possible worldwide to strengthen the findings.
‘Our results provide strong evidence that non-syndromic sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate,’ said Simeon Boyadjiev, a researcher affiliated with the University of California Davis MIND Institute. ‘The genetic changes we discovered could provide important clues for explaining how craniosynostosis occurs. This will be a critical first step in determining how it might be prevented.’
He added that the genetic differences do not fully explain the development of the condition and that other genes and environmental factors are also likely important. Further research is planned.
Penn State
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Hepatitis C treatment’s side effects can now be studied in the lab
, /in E-News /by 3wmediaThe adverse side effects of certain hepatitis C medications can now be replicated and observed in Petri dishes and test tubes, thanks to a research team led by Craig Cameron, the Paul Berg Professor of Biochemistry and Molecular Biology at Penn State University. ‘The new method not only will help us to understand the recent failures of hepatitis C antiviral drugs in some patients in clinical trials,’ said Cameron. ‘It also could help to identify medications that eliminate all adverse effects.’ The team’s findings may help pave the way toward the development of safer and more-effective treatments for hepatitis C, as well as other pathogens such as SARS and West Nile virus.
First author Jamie Arnold, a research associate in Cameron’s lab at Penn State, explained that the hepatitis C virus (HCV), which affects over 170,000,000 people worldwide, is the leading cause of liver disease and, although antiviral treatments are effective in many patients, they cause serious side effects in others. ‘Many antiviral medications for treating HCV are chemical analogs for the building blocks of RNA that are used to assemble new copies of the virus’s genome, enabling it to replicate,’ he said. ‘These medications are close enough to the virus’s natural building blocks that they get incorporated into the virus’s genome. But they also are different in ways that lead to the virus’s incomplete replication. The problem, however, is that the medication not only mimics the virus’s genetic material, but also the genetic material of the patient. So, while the drug causes damage to the virus, it also may affect the patient’s own healthy tissues.’
A method to reveal these adverse side effects in the safety of a laboratory setting, rather than in clinical trials where patients may be placed at risk, has been developed by the research team, which includes Cameron; Arnold; Suresh Sharma, a research associate in Cameron’s lab; other scientists at Penn State; and researchers from other academic, government, and corporate labs. ‘We have taken anti-HCV medications and, in Petri dishes and test tubes, we have shown that these drugs affect functions within a cell’s mitochondria,’ Cameron explained. ‘The cellular mitochondria — a tiny structure known as ‘the powerhouse of the cell’ that is responsible for making energy known as ATP — is affected by these compounds and is likely a major reason why we see adverse effects.’ Cameron noted that scientists have known for some time that certain individuals have ‘sick’ mitochondria. Such individuals are likely more sensitive to the mitochondrial side effects of antiviral drugs.
‘We know that antiviral drugs, including the ones used to treat HCV, affect even normal, healthy mitochondria by slowing ATP output,’ Arnold added. ‘While a person with normal mitochondria will experience some ATP and mitochondrial effects, a person who is already predisposed to mitochondrial dysfunction will be pushed over the ‘not enough cellular energy’ threshold by the antiviral drug. The person’s mitochondria simply won’t be able to keep up.’
One of the problems with clinical trials, Arnold explained, is that a drug may be shown to be quite effective but, if even a miniscule percentage of patients have side effects, the U.S. Food and Drug Administration is obligated to put the trial on hold or stop the trial altogether. This possibility makes drug companies reluctant to invest money in drug trials after an adverse event has been observed, even when the drugs could still help millions of people. The researchers hope that their methods eventually will become a part of the pre-clinical development process for this class of antiviral drugs. ‘If we can show, in the lab, that a drug will cause side effects, then these compounds will not enter lengthy, expensive clinical trials and cause harm to patients ‘ he said. ‘What’s more, a drug company can invest its money more wisely and carefully in drug research that will produce safe and effective products. Better and more-willing investments by drug companies ultimately will help patients, because resources will be spent developing drugs that not only work, but that are safe for all patients.’ Penn State Univeristy
Women 16–49 at risk of multiple pollutants
, /in E-News /by 3wmediaNearly 23 percent of American women of childbearing age met or exceeded the median blood levels for all three environmental chemical pollutants — lead, mercury, and PCBs — tracked in an analysis of data on thousands of women by Brown University researchers. All but 17.3 percent of the women aged 16 to 49 were at or above the median blood level for one or more of these chemicals, which are passed to foetuses through the placenta and to babies through breast milk.
The study identified several risk factors associated with a higher likelihood of a median-or-higher ‘body burden’ for two or more of these chemicals.
The three pollutants are of greatest interest because they are pervasive and persistent in the environment and can harm foetal and infant brain development, albeit in different ways, said study lead author Dr. Marcella Thompson. But scientists don’t yet know much about whether co-exposure to these three chemicals is more harmful than exposure to each chemical alone. Most researchers study the health effects of exposure to an individual chemical, not two or three together.
‘Our research documents the prevalence of women who are exposed to all three of these chemicals,’ said Thompson, who began the analysis as a doctoral student at the University of Rhode Island College of Nursing and has continued the research as a postdoctoral research associate for Brown University’s Superfund Research Program with co-author Kim Boekelheide, professor of pathology and laboratory medicine. ‘It points out clearly the need to look at health outcomes for multiple environmental chemical co-exposures.’
Most of the childbearing-age women — 55.8 percent — exceeded the median for two or more of the three pollutants.
Data were collected between 1999 and 2004 from 3,173 women aged 16 to 49 who participated in the Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES). The survey was designed to represent the national population of 134.5 million women of childbearing age. Because the original study also elicited a wide variety of information on health behaviours, socio-economic and demographic characteristics, Thompson and Boekelheide were able to identify specific risk factors associated with increased odds of having higher blood levels of lead, mercury, and PCBs.
They found several statistically significant risk factors. The most prominent among them was age. As women grew older, their risk of exceeding the median blood level in two or more of these pollutants grew exponentially to the point where women aged 30 to 39 had 12 times greater risk and women aged 40 to 49 had a risk 30 times greater than those women aged 16 to 19.
Thompson said women aged 40 to 49 would be at greatest risk not only because these chemicals accumulate in the body over time, but also because these women were born in the 1950s and 1960s before most environmental protection laws were enacted.
Fish and heavy alcohol consumption also raised the risk of having higher blood levels. Women who ate fish more than once a week during the prior 30 days had 4.5 times the risk of exceeding the median in two or more of these pollutants. Women who drank heavily had a milder but still substantially elevated risk.
Fish, especially top predators like swordfish and albacore tuna, are known to accumulate high levels of mercury and PCBs, Thompson said. However, there is no known reason why they found a statistically higher association between heavy drinking and a higher body burden of pollutants.
One risk factor significantly reduced a woman’s risk of having elevated blood levels of the pollutants, but it was not good news: breastfeeding. Women who had breastfed at least one child for at least a month sometime in their lives had about half the risk of exceeding the median blood level for two or more pollutants. In other words, Thompson said, women pass the pollutants that have accumulated in their bodies to their nursing infants.
Although the study did not measure whether women with higher levels of co-exposure or their children suffered ill health effects, Thompson said, the data still suggest that women should learn about their risks of co-exposure to these chemicals well before they become pregnant. A woman who plans to become pregnant in her 30s or 40s, for example, will have a high relative risk of having higher blood levels of lead, PCBs, and mercury.
‘We carry a history of our environmental exposures throughout our lives,’ Thompson said. Brown University
New light on virus associated with developmental delays and deafness
, /in E-News /by 3wmediaA new study reveals that primitive human stem cells are resistant to human cytomegalovirus (HCMV), one of the leading prenatal causes of intellectual disability, deafness and deformities worldwide. Researchers from the University of Pittsburgh School of Medicine found that as stem cells and other primitive cells mature into neurons, they become more susceptible to HCMV, which could allow them to find effective treatments for the virus and to prevent its potentially devastating consequences.
‘Previous studies have focused on other species and other cell types, but those studies did not evaluate what the cytomegalovirus does to human brain cells,’ said Vishwajit Nimgaonkar, M.D., Ph.D., professor of psychiatry at the University of Pittsburgh School of Medicine, and senior author of the report. ‘This study is the first of its kind, and the first to discover that primitive stem cells are actually resistant to HCMV.’
Access to cultured human neurons, necessary to understand the pathogenic effects of HCMV, has been limited by difficulties in growing the brain cells in the laboratory. Yet through human-induced pluripotent stem (iPS) cells, researchers were able to overcome this hurdle.
The study authors derived live iPS cells by reprogramming cells called fibroblasts obtained from human skin biopsies. The iPS cells were then induced to mature through several stages into neurons, the primary cells in the brain. The researchers were able to evaluate the patterns of damage caused by HCMV on all these cells.
The research findings suggest:
• Human iPS cells do not permit a full viral replication cycle, suggesting for the first time that these cells can resist CMV infection
• CMV infection distorts iPS cell differentiation into neurons, and that may be a mechanism by which infected babies develop impairments of brain maturation and intellectual ability
• iPS-derived mature neurons are more susceptible to CMV infection and once infected show effects including defective function that have been shown in other animal studies and in other human tissues, and the neurons die a few days after infection lab studies, possibly reflecting the impact of CMV on the human brain
‘The findings were quite surprising, but this is only the first in a series of studies on HCMV,’ added Nimgaonkar. ‘There is a lot of interest in what we can do to treat the infection, and current work is already underway to screen for new drugs that could be used to fight these viruses.’
Between 50 and 80 percent of people in the U.S. have been infected by HCMV by the time they reach 40. Infections are rarely serious, but the virus does not leave the body. CMV is also the most common congenital infection in the U.S., and occurs when a mother contracts CMV during pregnancy and passes the virus to her unborn child. According to the U.S. Centers for Disease Control and Prevention, one of every 150 children are born with CMV infection and one in five of them develop permanent problems, such as intellectual disability, vision and hearing loss, and seizures.
Pitt researchers are collaborating with the Drug Discovery Institute to further understand the cellular system and determine which agents are most effective against HCMV and similar viruses, and which treatments would be safe for human use. University of Pittsburgh
Researchers increase understanding of genetic risk factor for Type 1 Diabetes
, /in E-News /by 3wmediaAs part of their ongoing research on the role of genes in the development of type 1 diabetes, Joslin Diabetes Center scientists, in collaboration with scientists at the University of Würzburg, have demonstrated how a genetic variant associated with type 1 diabetes and other autoimmune diseases influences susceptibility to autoimmunity.
Recent studies of the human genome have identified genetic regions associated with autoimmune diseases such as type 1 diabetes. Joslin scientists in the Section of Immunobiology seek to understand how genes that are most widely associated with various autoimmune diseases contribute to disease risk.
One of these genes is PTPN22, which plays a role in lymphocyte (immune cell) function. A PTPN22 variant (or mutation) has been implicated as a risk factor for type 1 diabetes and several other autoimmune disorders. PTPN22 is involved in the formation of a key protein known as lymphoid tyrosine phosphatase (LYP), which helps control the activity of T and B cells in the immune system. The PTPN22 mutation generates a variation of LYP with a different molecular structure.
Most studies of the PTPN22 disease variant have suggested that this variant is a gain-of-function genetic mutation that enhances LYP activity and lessens the activity of T and B cells, which increases susceptibility to autoimmunity. ‘When immune cells are less reactive during the maturation phase of their development, the cells can evade mechanisms that help protect against autoimmunity,’ says study lead author Stephan Kissler, PhD, of the Section of Immunobiology. However, one study which analysed data from humans and genetically modified mice suggested that the LYP variant associated with type 1 diabetes is a loss-of-function mutation that reduces LYP activity.
To help resolve the conflicting data, Joslin scientists conducted studies with a unique mouse model developed by Dr. Kissler’s graduate student and co-author, Peilin Zheng. Using a technology that combines RNA interference, a method to silence gene expresson, with lentiviral transgenesis, a method to genetically modify animals, the scientists can manipulate gene activity in the most widely used mouse model for type 1 diabetes, the non-obese diabetic mouse (NOD). In this study, the researchers were able to easily turn off and on the PTPN22 gene in the NOD mouse. ‘We are the first to use this approach in the NOD mouse model,’ says Dr. Kissler. ‘It provides a very powerful way to study the contribution of PTPN22 to disease.’
When PTPN22 was turned off in mice, mimicking a loss-of-function mutation, the researchers observed an increase in regulatory T cells and a decreased risk of autoimmune diabetes. ‘This is the first study conducted on the diabetic mouse model that supports the LYP gain-of-function hypothesis,’ says Dr. Kissler. ‘Our work should help to resolve the controversy.’
By providing additional data that suggests the potential therapeutic value of PTPN22 manipulation, the study may further the development of new therapeutic options that inhibit LYP to reduce or prevent autoimmunity. ‘Our goal is to treat autoimmunity. Inhibiting LYP in patients may increase regulatory immune cells and could confer protection against autoimmunity, but it remains to be tested if our promising findings in this mouse model are reflected in humans,’ says Dr. Kissler. Joslin Diabetes Research Center
Changes in nerve cells may contribute to the development of mental illness
, /in E-News /by 3wmediaReduced production of myelin, a type of protective nerve fibre that is lost in diseases like multiple sclerosis, may also play a role in the development of mental illness, according to researchers at the Graduate School of Biomedical Sciences at Mount Sinai School of Medicine.
Myelin is an insulating material that wraps around the axon, the threadlike part of a nerve cell through which the cell sends impulses to other nerve cells. New myelin is produced by nerve cells called oligodendrocytes both during development and in adulthood to repair damage in the brain of people with diseases such as multiple sclerosis (MS).
A new study led by Patrizia Casaccia, MD, PhD, Professor of Neuroscience, Genetics and Genomics; and Neurology at Mount Sinai, determined that depriving mice of social contact reduced myelin production, demonstrating that the formation of new oligodendrocytes is affected by environmental changes. This research provides further support to earlier evidence of abnormal myelin in a wide range of psychiatric disorders, including autism, anxiety, schizophrenia and depression.
‘We knew that a lack of social interaction early in life impacted myelination in young animals but were unsure if these changes would persist in adulthood,’ said Dr. Casaccia, who is also Chief of the Center of Excellence for Myelin Repair at the Friedman Brain Institute at Mount Sinai School of Medicine. ‘Social isolation of adult mice causes behavioural and structural changes in neurons, but this is the first study to show that it causes myelin dysfunction as well.’
Dr. Casaccia’s team isolated adult mice to determine whether new myelin formation was compromised. After eight weeks, they found that the isolated mice showed signs of social withdrawal. Subsequent brain tissue analyses indicated that the socially isolated mice had lower-than-normal levels of myelin-forming oligodendrocytes in the prefrontal cortex, but not in other areas of the brain. The prefrontal cortex controls complex emotional and cognitive behaviour.
The researchers also found changes in chromatin, the packing material for DNA. As a result, the DNA from the new oligodendrocytes was unavailable for gene expression.
After observing the reduction in myelin production in socially-isolated mice, Dr. Casaccia’s team then re-introduced these mice into a social group. After four weeks, the social withdrawal symptoms and the gene expression changes were reversed.
‘Our study demonstrates that oligodendrocytes generate new myelin as a way to respond to environmental stimuli, and that myelin production is significantly reduced in social isolation,’ said Dr. Casaccia. ‘Abnormalities occur in people with psychiatric conditions characterised by social withdrawal. Other disorders characterised by myelin loss, such as MS, often are associated with depression. Our research emphasises the importance of maintaining a socially stimulating environment in these instances.’
At Mount Sinai, Dr. Casaccia’s laboratory is studying oligodendrocyte formation to identify therapeutic targets for myelin repair. They are screening newly-developed pharmacological compounds in brain cells from rodents and humans for their ability to form new myelin. EurekAlert
St. Joseph’s researchers identify gene involved in lung tumor growth
, /in E-News /by 3wmediaLung cancer researchers at St. Joseph’s Hospital and Medical Center in Phoenix, Ariz., in collaboration with researchers at the Translational Genomics Research Institute and other institutions, have identified a gene that plays a role in the growth and spread of non-small cell lung cancer tumours, opening the door for potential new treatment options.
Landon J. Inge, PhD, is the lead scientist in the thoracic oncology laboratory at St. Joseph’s Center for Thoracic Disease and Transplantation and was a member of the study’s research team.
Lung cancer is the leading cause of cancer deaths worldwide, and approximately 85 percent of these cancers are non-small cell lung cancers (NSCLC). Patients with NSCLC frequently have tumours with mutations in the epidermal growth factor receptor (EGFR) gene. When activated, this mutated gene leads to tumour development and growth. By studying lung cancer samples from patients who had undergone tumour resection, the researchers discovered that many patients with EGFR mutations also exhibited higher than normal levels of the gene fibroblast growth factor-inducible 14 (Fn14). The researchers believe that activation of EGFR can lead to increased expression and activity of the Fn14 gene.
The research team also discovered that while over-expression of Fn14 enhances lung tumour formation and metastasis, suppression of Fn14 reduces metastasis in NSCLC.
‘Our data suggest that Fn14 levels can contribute to NSCLC cell migration and invasion,’ says Dr. Inge. ‘Thus, tumour suppression through the targeting of Fn14 may prove to be a therapeutic intervention in NSCLC and other tumour types.’
The Fn14 gene has been found to be elevated in other types of tumours, as well, including glioblastoma and certain types of breast cancer, suggesting that Fn14 may be a therapeutic target for multiple cancer therapies. EurekAlert
‘Promising results’ for bowel cancer breath-test
, /in E-News /by 3wmediaScientists say they have developed a breath-test that can accurately tell if a person has bowel cancer. The test, which looks for exhaled chemicals linked to tumour activity, was able to identify a majority of patients with the disease.
The British Journal of Surgery reported an overall accuracy of 76%.
However, another scientist said it was unlikely a fully functioning and reliable breath-test would be available soon for the general public. Scientists are working on breath-tests for a host of other diseases, including several types of cancer, TB and diabetes.
If diagnosed and treated early, the chances of stopping cancer can be good, but there is often little or no outward sign of the disease until it has progressed significantly.
The current screening test for bowel cancer looks for signs of blood in the faeces, but only a small proportion of those who test positive actually have colorectal cancer, which means unnecessary and invasive further testing for many people.
The breath-test technology relies on the idea that the biology of tumours can lead to the production of specific ‘volatile organic compounds’, combinations of chemicals unlikely in a healthy person.
These can be found in small amounts in the breath of the patient, and early studies found dogs could be trained to identify them – although the latest study relies an electronic device to analyse breath gases.
The team from a hospital in Bari, southern Italy, compared the breath of 37 patients known to have bowel cancer with that of 41 ‘controls’ who were thought to be healthy.
The initial test identified the cancer patients with 85% accuracy, and although, when combined with a follow-up test, the overall result fell to 76%, the researchers were upbeat about its potential.
‘The present findings further support the value of breath-testing as a screening tool,’ they say.
It might be possible that the technique could help identify patients whose cancer was returning after treatment.
Bigger studies with a greater number of patients were now needed to fine-tune the test and confirm it worked, said Dr Donato Altomare and colleagues. BBC
Research reveals why some teenagers more prone to binge drinking
, /in E-News /by 3wmediaThe study, led by King’s College London’s Institute of Psychiatry (IoP) provides the most detailed understanding yet of the brain processes involved in teenage alcohol abuse.
Alcohol and other addictive drugs activate the dopamine system in the brain which is responsible for feelings of pleasure and reward. Recent studies from King’s IoP found that the RASGRF2 gene is a risk gene for alcohol abuse, however, the exact mechanism involved in this process has, until now, remained unknown.
Professor Gunter Schumann, from the Department of Social, Genetic and Developmental Psychiatry (SGDP) at King’s Institute of Psychiatry and lead author of the study says: ‘People seek out situations which fulfill their sense of reward and make them happy, so if your brain is wired to find alcohol rewarding, you will seek it out. We now understand the chain of action: how our genes shape this function in our brains and how that, in turn, leads to human behaviour. We found that the RASGRF-2 gene plays a crucial role in controlling how alcohol stimulates the brain to release dopamine, and hence trigger the feeling of reward. So, if people have a genetic variation of the RASGRF-2 gene, alcohol gives them a stronger sense of reward, making them more likely to be heavy drinkers.’
Approximately 6 out of 10 young people aged 11-15 in England report drinking, a figure which has remained relatively stable over the past 20 years. However, binge drinking has become more common, with teenagers reportedly drinking an average of 6 units per week in 1994 and 13 units per week in 2007. In the UK, around 5,000 teenagers are admitted to hospital every year for alcohol-related reasons. Teenage alcohol abuse is also linked to poor brain development, health problems in later life, risk taking behaviour (drunk driving, unsafe sex) and antisocial behaviour.
The study initially looked at mouse models without the RASGRF2 gene to see how they reacted to alcohol. They found that the absence of the RASGRF-2 gene was linked to a significant reduction in alcohol-seeking activity. Upon intake of alcohol, the absence of the RASGRF-2 impaired the activity of dopamine-releasing neurons in a region of the brain called the ventral tegmental area (VTA) and prevented the brain from releasing dopamine, and hence any sense of reward.
The research team then analysed the brain scans of 663 14 year old boys – who at that age had not been exposed to significant amounts of alcohol. They found that individuals with genetic variations to the RASGRF2 gene had higher activation of the ventral striatum area of the brain (closely linked to the VTA and involved in dopamine release) when anticipating reward in a cognitive task. This suggests that individuals with a genetic variation on the RASGRF-2 gene release more dopamine when anticipating a reward, and hence derive more pleasure from the experience.
To confirm these findings, the researchers analysed drinking behaviour from the same group of boys at 16 years old, when many had already begun drinking frequently. They found that individuals with the variation on the RASGRF-2 gene drank more frequently at the age of 16 than those with no variation on the gene.
Professor Schumann concludes: ‘Identifying risk factors for early alcohol abuse is important in designing prevention and treatment interventions for alcohol addiction.’ King’s College London
Atherosclerosis found in HIV children
, /in E-News /by 3wmediaChildren with HIV have a 2.5 fold increased risk of atherosclerosis, according to research presented at EUROECHO and other Imaging Modalities 2012. Antiretroviral treatment, lipid lowering drugs and prevention with healthy lifestyles are needed to prevent early death from cardiovascular disease.
EUROECHO and other Imaging Modalities 2012 is the annual meeting of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the European Society of Cardiology (ESC).
Antiretroviral treatment is prolonging the lives of HIV patients, who no longer die prematurely from the infection. But the treatment is not a cure, and the virus remains in the body.
‘The infection makes the body fight for its life, so the immune system is always activated and there is chronic inflammation,’ said Dr Talia Sainz Costa, principal investigator of the study and a paediatrician from Madrid, Spain.
In addition, many antiretroviral drugs increase bad (LDL) cholesterol and lower good (HDL) cholesterol. Dr Sainz Costa said:
‘Children with HIV will have high cholesterol for a long period and on top of that the virus causes chronic inflammation – both are bad for the arteries.’
Patients with HIV die 10 years prematurely from non-AIDS disease which includes cardiovascular diseases, cancer, liver and renal diseases.
‘This is especially important for children because they have been living with HIV since birth or even before,’ said Dr Sainz Costa. ‘By the time they are 50 years old they will have accumulated more toxicity from the treatment and more secondary effects from the infection and will be at an even greater risk of heart attacks and other complications.’
The present study aimed to discover whether children and adolescents already have early atherosclerosis damage. Carotid intima-media thickness (IMT), a marker of atherosclerosis, was measured using echocardiography in 150 children and adolescents with HIV and 150 age and sex matched healthy controls.
The researchers found that 17% of the HIV group were smokers compared to 11% of the control group. Dr Sainz Costa said:
‘Smoking levels in adolescents in Spain are known to be high. The even higher levels in the HIV group are probably related to low socio-economic status and very complex social/family backgrounds.’
After adjustment for age, sex, BMI and smoking status, HIV was independently associated with thicker IMT (p=0.005). Children and adolescents had a 2.5 fold increased risk of higher IMT due to HIV. Dr Sainz Costa said:
‘Our study shows that children and adolescents with HIV have arteries that are more rigid and less elastic, which means that the process of atherosclerosis has begun and they have increased risk of an infarct in the future.’
The researchers also found that frequencies of activated T CD4+ cells were higher among HIV-infected children and young adults (p=0.002). ‘This shows that the immune system is more active,’ said Dr Sainz Costa.
They concluded that clinicians need to take cardiovascular prevention more seriously in children and adolescents with HIV, while continuing to treat the HIV infection. Dr Sainz Costa said: ‘Cardiovascular disease has already put down roots in children and adolescents with HIV and we need to take preventive measures at this early stage. We should be more aggressive in treating their high cholesterol with medication – this practice is common in adults but rare in children.’ She added:
‘We also need to be stricter about healthy lifestyle advice. Many children and adolescents with HIV come from families with low socio-economic status and are more prone to smoking, poor diet and inactivity. This age group also struggles with adherence to medication which is another worry, but we should not let this decrease our efforts to prevent future complications.’
Dr Sainz Costa concluded: ‘HIV research is investigating ways to control the inflammation and immune activation with agents such as probiotics, aspirin and corticoids. In the meantime clinicians need to focus on ensuring their young patients with HIV take the antiretroviral treatment, take lipid lowering drugs when necessary, and adopt healthier lifestyles.’ European Society of Cardiology
Genetic differences discovered in kids with premature skull closure
, /in E-News /by 3wmediaAn international team of researchers from 23 institutions across three continents has identified two genetic factors that are strongly associated with the most common form of non-syndromic craniosynostosis — premature closure of the bony plates of the skull. The team of geneticists, paediatricians, surgeons and epidemiologists includes Joan Richtsmeier, professor of anthropology at Penn State, and Yann Heuzé, a post-doc in the Richtsmeier lab.
During foetal and early childhood development, the skull is made of separate bony plates that allow for growth of the head. The borders between the plates do not normally fuse completely until a child is about two years old, leaving temporary ‘soft spots’ at the intersection of the seams.
If the bones fuse too early — the condition called craniosynostosis — a child will develop an abnormally shaped head. Left untreated the disorder can cause learning disabilities and other complications due to brain compression, such as neurologic and visual problems. Typically, craniosynostosis requires extensive neurosurgical correction.
About 20 percent of craniosynostosis cases previously have been linked to a number of different genetic syndromes, the researchers note, but the vast majority of cases (not associated with a syndrome involving other birth defects) arise without any known family history or cause. The most common form of non-syndromic craniosynostosis — affecting about 1 in 5,000 newborns — involves the sagittal suture, the main seam that runs down the centre of the top of the skull. These cases were the subject of the investigation.
Although the condition has long been thought to be partially determined by genes, since it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than non-identical twins, the exact basis was unclear.
To help determine the cause, the researchers conducted the first genome-wide association study for the disorder, which involves scanning the entire genome of a group of people with craniosynostosis and comparing it to a control group of people without it. The study searched for single nucleotide polymorphisms (SNPs) that are associated with craniosynostosis. SNPs are DNA sequence variations in which a single nucleotide differs from the usual one at that position. There are some 3 billion nucleotides, the basic building blocks of DNA, in the human genome.
The study first evaluated the DNA, which was extracted from whole blood or oral samples, of 201 cases and both of their parents, who did not have the condition. After reviewing the morphological and ethnic details of each case, the researchers restricted their final analysis to a group of 130 non-Hispanic white case-parent trios. This approach reduced the genetic variability inherent to individuals from different ethnicities and the potential of mixing of patients with other diseases. Their results identified very strong associations to SNPs in two areas of the genome, coding for bone morphogenetic protein 2 (BMP2) and Bardet-Biedl syndrome 9 protein (BBS9). Both proteins are known to play a role in skeletal development.
Richtsmeier studies the processes of growth and development that translate genetic information into tissues of specific shapes and sizes, using computed tomography scans of patients with craniofacial diseases and animal models for those same conditions. Heuzé analysed the computed tomography data of cases in this genetic analysis, both qualitatively to establish the degree of suture closure and quantitatively to estimate the magnitude of dysmorphology, to guarantee that the individuals whose genes were analysed in the study showed physical traits of the disease and were not mixing the sample with outlier cases.
The findings were replicated in another population of 172 cases of children with the condition and 548 unrelated controls. The extensive international collaboration came about because of the desire to include as many cases as possible worldwide to strengthen the findings.
‘Our results provide strong evidence that non-syndromic sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate,’ said Simeon Boyadjiev, a researcher affiliated with the University of California Davis MIND Institute. ‘The genetic changes we discovered could provide important clues for explaining how craniosynostosis occurs. This will be a critical first step in determining how it might be prevented.’
He added that the genetic differences do not fully explain the development of the condition and that other genes and environmental factors are also likely important. Further research is planned. Penn State