Researchers report initial success in promising approach to prevent tooth decay



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Scientists find major susceptibility gene for Crohn's disease

Discovery offers hope of better-targeted therapy for millions of people with inflammatory bowel diseases

Oct. 26 -- A consortium of American and Canadian researchers report in Science Express, a rapid online publication by the journal Science, the discovery of a new genetic link to Crohn's disease. Mutations of a gene, which codes for a receptor in a major inflammatory pathway, are strongly associated with Crohn's disease, the researchers found. Surprisingly, one type of mutation appears to confer significant protection, prioritizing a crucial target for drugs that might better manage Crohn's disease and ulcerative colitis.

More than 1 million Americans have Crohn's or colitis, known collectively as inflammatory bowel disease (IBD).

The study's authors represent the IBD Genetics Consortium, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH). The Consortium's member institutions include Cedars-Sinai Medical Center in Los Angeles, the University of Chicago, Johns Hopkins University, Université de Montréal, the University of Pittsburgh, Mount Sinai Hospital in Toronto and the University of Toronto, and Yale University.

According to senior author Judy H.Cho, M.D., associate professor in the departments of medicine and genetics at Yale School of Medicine, the findings highlight a major inflammatory pathway and change in thinking about disease-associated genetic variation. "This pathway is particularly intriguing because we appear to have identified a gene variant that protects against development of IBD, a finding that may lead us to think about the genetics of health as much as about the genetics of disease," said Dr. Cho, who also is director of the Inflammatory Bowel Disease Center at Yale.

Because IBD tends to run in families and is more frequent in certain ethnic populations, especially Ashkenazi Jews, scientists have long suspected a significant genetic component. Although previous genetic studies found a link between Crohn's disease and mutations in a gene known as CARD15, those mutations alone are not considered to account for all of the genetic components of the disease.

To identify additional genes that are associated with IBD, the international team of researchers scanned the genome--all 22,000 or so genes--by testing more than 300,000 single nucleotide polymorphisms, or SNPs, in people with Crohn's disease. They looked for the presence of these SNPs in a similar number of people without IBD for comparison.

Out of the hundreds of thousands of SNPs, the genome-wide scan found three that were most strongly associated with Crohn's disease. Of those, two were in the CARD15 gene. However, the third SNP was in a different gene on a different chromosome.

When the researchers looked at the specific gene where the third SNP resided, they found that it coded for a protein that is part of the immune cell receptor for interleukin-23 (IL-23), an important mediator of inflammation in the body. However, when they began looking for all of the polymorphisms in the IL-23 receptor gene of affected individuals to determine which ones were the most detrimental, they made an unexpected discovery.

Although several polymorphisms were associated with a significantly increased risk of developing IBD, one appeared to confer a very strong protection against IBD.

"Of all the SNPs we studied in people with and without IBD, this protective SNP was the most statistically significant finding in our study. So, it took us a bit by surprise," said first author, Richard H. Duerr, M.D., associate professor of medicine and human genetics at the University of Pittsburgh. "What it means in terms of improving treatments for IBD patients, we are not sure yet. But, we speculate that it may be possible to mimic the conditions within the IL-23 inflammatory pathway that result from the chain of events initiated by this particular genetic variant."

Members of the consortium are attempting to tease out the specific downstream effects of this protective polymorphism. Yet, because IL-23 plays an important role in activating inflammation, including in the organs of the digestive tract, it could be an extremely important target for improving the management of Crohn's disease and other IBDs.

"We identified multiple genetic signals in the IL-23 receptor gene that were strongly associated with Crohn's disease. In fact, the statistical significance for some IL-23 receptor SNPs was two orders of magnitude greater than that of other SNPs in other genes. So, we believe that blocking the activity of IL-23 or manipulating its pathway will be an effective way to manage IBD," said Dr. Duerr, who also is head of the Inflammatory Bowel Disease Genetics Program at the University of Pittsburgh School of Medicine and co-director of the Inflammatory Bowel Disease Center at the University of Pittsburgh Medical Center.

In a previous study by other investigators, an early stage clinical trial showed that IBD patients exhibit improvement when given a monoclonal antibody that blocks IL-23 and a related inflammatory mediator. Furthermore, recent studies in mice in which the gene for IL-23 is deleted demonstrated that IL-23 is essential for the development and maintenance of chronic intestinal inflammation. Such evidence, combined with the current discovery, suggests therapies that target the IL-23 pathway may lead to more individualized, better-directed therapies for IBDs, the authors say.

"This important discovery not only offers new hope for better therapies for patients with Crohn's disease, it also highlights the promise of the human genome project and subsequent investments by the NIH in large scale, collaborative research projects to unravel the causes of, and hopefully better treatments for complex, enigmatic diseases," said Stephen P. James, M.D., director of the Division of Digestive Diseases and Nutrition at the National Institutes of Health's NIDDK.

Dr. Cho offers a cautionary note, however. "The IL-23 pathway may serve a very useful purpose in protecting us from other diseases, so when seeking to block or manipulate its activity with drugs or other means, we need to take this balancing act into consideration," she said.


Healthcare staff under report child physical abuse and 1 in 5 worry about getting it wrong

Sixty per cent of healthcare professionals have seen a child they suspect was being physically abused, but only 48 per cent reported it to the authorities, according to research published in the latest Journal of Advanced Nursing.

Just under three-quarters of doctors, dentists and community nurses said they were aware of some of the mechanisms of reporting child physical abuse, but 79 per cent felt they needed further information.

Over a fifth (21 per cent) said they were worried about getting it wrong. Confronting families, inexperience and fear of litigation were also common barriers to reporting.

"The ability to recognise physical abuse and willingness to report it varied between the groups" says lead researcher Dr Anne Lazenbatt, from the School of Nursing and Midwifery at Queen's University Belfast, Northern Ireland.

"Our survey of 419 healthcare professionals showed that community nurses were most likely to recognise and report physical abuse.

"It also revealed that fears, anxieties and lack of knowledge stop primary healthcare professionals from reporting abuse and that they need more education, training and support in this area."

74 per cent were aware of the mechanisms for reporting – with community nurses showing the highest levels of awareness, followed by doctors and dentists. 99 per cent said recognising and reporting child physical abuse should be part of undergraduate and postgraduate training and 79 per cent wanted further in-service training.

Research published by the United Nations in 2002 suggests that 3,500 children under the age of 15 die from child physical abuse every year in the industrialised world.

And seven per cent of children in the UK have been reported as suffering from physical abuse from a parent or carer, according to the National Society for the Prevention of Cruelty to Children.

Lazenbatt's research, carried out with Professor Ruth Freeman from the University's School of Dentistry, drew questionnaire responses from 139 Community Nurses, 147 General Medical Practitioners and 133 General Dental Practitioners in Northern Ireland – a response rate of 43 per cent.

The majority were in the 30-49 age group (71 per cent) and 43 per cent were male. They had been in practice for an average of 15 to 16 years.

Four key issues arose during the research:

* Healthcare professional were worried about misidentifying physical abuse and unwilling to confront the family. They wanted to remain anonymous and feared hostility, damage to their relationships with families and repercussions for the child and the family. They were also concerned about possible legal action.

"The barriers for me are an uncertainty about what I am looking for and not wanting to start a problem for the family" said one of the Dentists who took part.

"I would be hesitant to get involved in child protection work for fear that this would trigger a formal complaint, a disciplinary hearing or even litigation" added one of the Doctors.

* Respondents cited lack of clear guidelines and protocols as a barrier to reporting abuse. They were also concerned about their inexperience and poor interview techniques, especially when they were faced with parents who were keen to avoid detection.

"Recognising child abuse is always going to be a difficult and emotive area" said one Community Nurse. "Often parents, as carers, can give a plausible explanation for any injuries, bruising etc. Frequently this is the explanation people want to believe, as it will be less difficult to deal with by everyone concerned. What makes management of suspected cases of child abuse easier is having clear protocols and guidelines."

"Identifying and reporting is always more difficult when a child is seen infrequently" pointed out one Dentist.

* Other barriers to reporting included workload pressures, red tape and hierarchy, reporting procedures and lack of sensitivity and support from social services and colleagues. Some Dentists felt that child abuse was not relevant to their profession and another burden in an already stressful occupation.

"I understand the child's welfare is paramount, but living in small communities it is difficult for social services to be seen to be sensitive or impartial" said one Community Nurse.

And a Doctor expressed frustration with colleagues. "In one case of suspected neglect/abuse it was reported several times and nothing was done. I eventually reported it to an on-duty social worker who dealt with it, but there was a time lapse of 12-18 months."

* The majority of participants wanted multidisciplinary workshops, in-service education and accessible training tools. They also highlighted perceived deficiencies in the education they had already received.

"There is no more time for complacency" said one Doctor. "To do this we need knowledge and input from a wide range of professionals and agencies, all of whom should be communicating, working in partnership and educated at all levels with a multi-professional / agency framework. This should be mandatory and frequent."

"The findings suggest that recognising child physical abuse is both a complex and difficult task for primary healthcare professionals and illustrates a substantial gap between their ability to recognise maltreatment and knowledge of the pathways for reporting it" concludes Dr Lazenbatt.

"Although the consequences of failing to identify child physical abuse can be catastrophic, it is also essential that professionals are educated to recognise conditions that might inadvertently be mistaken as abuse so that unnecessary distress can be avoided.

"Child abuse is an important global problem and primary healthcare professionals can play an essential role in recognising and reporting abuse, but only if they receive the education and support they need to make informed decisions.

"Developing clear policies and co-ordinated local responses that involve all those concerned with the welfare and protection of children is also essential."

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Notes to editors

* Recognizing and reporting child abuse: a survey of primary healthcare professionals. Lazenbatt A and Freeman R, Queen's University Belfast, UK. Journal of Advanced Nursing. Volume 56.3, pages 227-236.

* Journal of Advanced Nursing, which is celebrating its 30th anniversary in 2006, is read by experienced nurses, midwives, health visitors and advanced nursing students in over 80 countries. It informs, educates, explores, debates and challenges the foundations of nursing health care knowledge and practice worldwide. Edited by Professor Alison Tierney, it is published 24 times a year by Blackwell Publishing Ltd, part of the international Blackwell Publishing group.
New genetic analysis forces re-draw of insect family tree

The family tree covering almost half the animal species on the planet has been re-drawn following a genetic analysis which has revealed new relationships between four major groups of insects.

Scientists have found that flies and moths are most closely related to beetles and more distantly related to bees and wasps, contrary to previous theory.

The findings are published in the special Honey Bee Genome issue of the journal Genome Research which coincides with Nature's publication of the honey bee genome sequence (also Thursday 26 October 2006).

The results are based on an analysis of the same 185 genes found in the genomes of eight different insect families, which together represent 45 per cent of all known animal species.

This enabled the international group of scientists to work out the evolutionary relationships between the insects based on changes and mutations within those genes.

Previously scientists had assumed that flies and moths were most closely related to bees and wasps, with beetles more distantly related to these groups.

This new family arrangement also brings the different species of social insects, such as termites and bees, closer together - suggesting that the ability of insects to cooperate in social groupings may have evolved just once, rather than independently in several different species.

“About half of all animal species belong to just four groups of insects but, surprisingly, we never knew for sure how they are related to each other,” said Dr Martin Lercher from the University of Bath, who lead the research.

“While there was never unequivocal evidence for it, scientists believed for a long time that, based on morphology, flies and moths were most closely related to bees, with beetles more distantly related to these three groups.

“By comparing genetic information from 185 genes that were sequenced in species from all of these groups, we found that in fact flies and moths are most closely related to beetles, and more distantly related to bees.

“This sheds new light on a large number of evolutionary questions, as a correct understanding of the evolutionary relationships is fundamental to any interpretation of similarities or differences among species.



“For example, social colonies are common among bees and wasps and their relatives, ants, as well as among more distantly related insects, such as termites and aphids.

“That beetles don't show this tendency, known as eusociality, has been interpreted as a sign that eusociality has evolved several times independently.

“Now that we know that bees, wasps and ants are in fact the closest relatives to the more distantly related (or ‘basal’) species, it appears more likely that the genetic basis for eusociality may have evolved only once, and was lost in the common ancestor of beetles, moths, and flies.”

The researchers used the genomes of six different insects from the holometabolous group of insects (insects which undergo complete metamorphosis): fruit fly (Drosophila melanogaster), mosquito (Anopheles gambiae), silk moth (Bombyx mori), flour beetle (Tribolium castaneum), honey bee (Apis mellifera) and sibling parasitic wasp species (Nasonia vitripennis and Nasonia giraulti).

These insects represent the four major orders of holometabolous insects, beetles (Coleoptera), moths (Lepidoptera), flies (Diptera) and bees and wasps (Hymenoptera), which together represent 45 per cent of the animal species on earth.

They also included one orthopteran (the grasshopper Locusta migratoria) and one hemipteran (the pea aphid Acyrthosiphon pisum), both of which are uncontested out-groups to the holometabolous insects.

The researchers are from the University of Cologne (Germany), Baylor College of Medicine (USA), University of Rochester (USA), the Institute for Genomic Research (USA), the University of Bath (UK) and the European Molecular Biology Laboratory (Germany).

The research was funded by the Human Frontier Science Program Organization, the Deutsche Forschungsgemeinschaft (DFG), the Royal Society and the 21st Century Research & Technology Fund.

The University of Bath is one of the UK's leading universities, with an international reputation for quality research and teaching. In 16 subject areas the University of Bath is rated in the top ten in the country. View a full list of the University's press releases: http://www.bath.ac.uk/news/releases
Three-in-one virus killer prevents common, often fatal infections

A novel combination therapy drastically reduces the infection rate of three viruses – and risk of death – in transplant patients with compromised immune systems. The findings, to be reported in the Nov. 1 print edition of Nature Medicine, originate from a study conducted at Baylor College of Medicine, The Methodist Hospital, and Texas Children's Hospital.

The journal has posted the findings online.

The phase 1 trial, funded by the National Heart, Lung, and Blood Institute, one of the National Institutes of Health, tested the first multivirus killer of its kind, called Trivirus-specific cytotoxic T lymphocytes (CTLs), which control infections caused by three commonplace viruses – cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus. Although benign in people with normal immune systems, the viruses can cause life-threatening illnesses in transplant patients and others with compromised immune systems.

The CTLs proved effective and safe in all 11 bone marrow transplant patients, who recovered completely within two to four weeks of being treated without any side effects or toxicity. Preexisting therapies for adenovirus have had little success – there is an 80 percent chance of death following the development of adenovirus.

"Not only were patients prevented from getting these infections after transplant, but those patients who had infections responded to the T-cell therapy and did not require any other treatment," said senior author Dr. Catherine Bollard, assistant professor of pediatrics, immunology, and medicine at BCM and a researcher at the Center for Cell and Gene Therapy at BCM, Methodist and Texas Children's. "To make dramatic recoveries like these was really quite something."

The research team drew cells from bone marrow donors and "trained" T-cells to target the three viruses before injecting them into transplant recipients.

"Drugs only control the virus. They don't cure the underlying problem," said Bollard. "Whereas by introducing these specialized T-cells, we are fixing the underlying problem. Using your own immune system is preferable to chemical agents, which can have toxic side effects."

Although the CTLs must undergo further testing, the early results suggest the combination therapy to be more, cost-effective, and safe than traditional therapies and more practical than cell-based therapies that target EBV and CMV separately, both of which are carried in roughly 80 percent of all people. Adenoviruses are common viruses carried in all populations.

"There is no safe and effective therapy for patients with adenovirus infections at the moment, so if you get an infection after a transplant it becomes very problematic," said first author Dr. Ann Leen, BCM instructor of pediatrics at the Center for Cell and Gene Therapy. "So we trained certain T-cells to target this virus."

Bollard envisions one day extending the application of CTLs to other people with compromised immune systems, such as cancer patients undergoing chemotherapy. The therapy could also potentially be used in babies, who are more susceptible to adenovirus infections than other age groups.

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The other study investigators are Drs. G. Doug Myers, Uluhan Sili, M. Helen Huls, Heidi Weiss, Kathryn S. Leung, George Carrum, Robert A. Krance, Adrian P. Gee, Malcolm K. Brenner, Helen Heslop, and Cliona Rooney, all of BCM, Methodist and Texas Children's.; Dr. Chung-Che Chang, of Cornell University and Methodist; and Dr. Jeffrey J. Molldrem, of The University of Texas M.D. Anderson Cancer Center.
Survivors of organized violence often left with traumatic memories

Victims of torture found to have permanent mental trauma

University Park, Pa. October 26, 2006 - A series of studies, conducted by a psychotraumatology research group headed by Thomas Elbert in collaboration with Penn State psychologist William Ray, has examined a group of people who have been exposed to different magnitudes of torture and found the appearance of dissociation (mental separation from the incident) long after the event. The research is published in the latest issue of Psychological Science.

Those who experienced multiple and extreme trauma stopped responding physiologically and began to feel numb. The researchers believe that, just as the body can turn off some of its stress response during feelings of great terror or helplessness, the mind has a way of turning off strong emotions in overwhelming situations.

The research group examined the functional architecture of the brain in relation to varying degrees of dissociation. They observed that dissociative experiences are reflected in slow, abnormal brainwaves in an area that contributes to verbalizing and the ability to plan and prepare for actions.

Observation of structural or functional brain lesions has led the authors to interpret their findings as a sign of the brain decoupling these regions from sensory experience and action. They believe this is the only response that seems possible during serious torture but note that, when maintained later in life, the long-term consequences are devastating. This brain reorganization is maintained even when the torture is over.

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This study is published in the current issue of Psychological Science. Media wishing to receive a PDF of this article please contact journalnews@bos.blackwellpublishing.net
For crying out loud - pick up your baby

Parents should listen to their instincts and pick up their newborn babies when they cry, Queensland University of Technology researcher Professor Karen Thorpe said.

A joint study with QUT and the Riverton Early Parenting Centre has found many parents of infants up to 12 weeks, were uncertain about how best to settle their crying baby and whether or not it was "right" to pick them up.

"A lot of parents are unsure if they should pick up their baby when their baby cries," Professor Thorpe from QUT's Faculty of Education said.

"The answer is: you should. Babies in the first 12 weeks of their life need highly responsive parents. They want and need a parent that is responsive to their cries."

Professor Thorpe said the study was initiated by concerns by clinical nurses from the Riverton centre that parents were choosing to ignore their crying newborn for fear it would "spoil" their baby to pick them up.

Riverton clinical nurse and co-researcher Claire Halle said parents felt picking up their crying baby would create "bad habits" which would impact negatively on their child's behaviour in the future.

"Parent's felt torn between what they thought and what they felt was the right thing to do, and this uncertainty seemed to heighten their stress levels," Ms Halle said.

The study found about 20 per cent of first time parents and 30 per cent of experienced parents admitted they were uncertain about picking up their crying baby. It also revealed that almost 25 per cent of first time parents and just over 10 per cent of experienced parents believed picking up a crying baby would spoil them.

"One parent said 'I feel guilty for not picking him up when he cries'," Ms Halle said. "Another said 'frequent and sudden changes in baby's behaviour make it hard to judge...too much attention may spoil them'."

But Professor Thorpe said in the first three month's of a baby's life, having responsive parents was very important to the child's emotional and neurological development.

She said the study highlighted there was a problem because parents were getting mixed messages about how best to settle their newborn baby.

"We need to ensure nurses, educators and health professionals are providing parents with consistent and appropriate guidelines for caring for their baby," Professor Thorpe said.

"It is also important for parents to have the confidence to trust their instincts when it comes to caring for their baby."

The study, funded by the Royal Children's Hospital Foundation, is a joint collaboration between Dr Toni Dowd from QUT's School of Nursing, Professor Karen Thorpe and the Settling Team at the Riverton Early Parenting Centre.

The study was a unique experience for clinical nurses to work as co-researchers and demonstrated the value of engaging clinical staff, academics and parents in research.

Media contacts - Sandra Hutchinson, media officer, 07 3864 2130 or s3.hutchinson@qut.edu.au

**Professor Karen Thorpe and Dr Toni Dowd are available for media interviews**



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