Feeding the Schwanns: New technique could bring cell therapy for nerve damage a step closer

ScienceDaily (Oct. 11, 2012) — A new way to grow cells vital for nerve repair, developed by researchers from the University of Sheffield, could be a vital step for use in patients with severe nerve damage, including spinal injury (1).
Schwann cells are known to boost and amplify nerve growth in animal models, but their clinical use has been held back because they are difficult, time-consuming and costly to culture.
The Sheffield team, led by Professor John Haycock, has developed a new technique with adult rat tissue which overcomes all these problems, producing Schwann cells in less than half the time and at much lower cost.
"The ability of Schwann cells to boost nerve growth was proved many years ago in animals, but if you want to use this technique with patients, the problem is: where do you get enough cells from?" says Professor Haycock, from the University's Department of Materials Science and Engineering.
"To reduce immune rejection, the cells have to be grown from the patient's own tissue. Of course, you want to take the smallest amount of tissue necessary, so the technique must be efficient. It must also be fast, so treatment can begin as soon as possible after injury. For clinical use, it must also provide pure Schwann cells. And finally, to make it viable, it has to be at a reasonable cost."
Existing methods for growing Schwann cells from adult tissue promote the growth of another type of cell, called fibroblasts, which swamp the Schwann cells, reducing the speed they grow and their numbers. This means that large amounts of tissue are needed at the outset, to grow sufficient cells for therapeutic use. It also requires extra purification stages added to the process, making it slow and costly -- taking up to 3 months to complete.
Professor Haycock and his team have come up with a very simple solution: feed the Schwann cells but starve the fibroblasts. The research, published October 11 in Nature Protocols
, uses an amino acid that only the Schwann cells can break down and feed off, and are able to produce a 97 per cent pure population of Schwann cells in a much shorter space of time -- just 19 days -- from a small sample of adult tissue.
Professor Haycock is confident the technique can be replicated in humans. His team are trialling same method using human nerve tissue, with results expected within the next 6 months.
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The above story is reprinted from materials provided by University of Sheffield, via EurekAlert!, a service of AAAS.
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Journal Reference:
Rossukon Kaewkhaw, Andy M Scutt, John W Haycock. Integrated culture and purification of rat Schwann cells from freshly isolated adult tissue. Nature Protocols, 2012; 7 (11): 1996 DOI: 10.1038/nprot.2012.118
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Preemies from low-income families at high risk for dangerous brain bleeds

ScienceDaily (Oct. 11, 2012) — Babies born prematurely to low-income parents have a disproportionately high risk for developing dangerous brain bleeds that require multiple surgeries and extensive follow-up, according to a small Johns Hopkins Children's Center study.
The findings -- published online Sept. 28 in the journal Pediatric Neurosurgery
and based on an analysis of 38 patients referred to Johns Hopkins for treatment of brain hemorrhages related to premature birth -- offer a sobering reminder of the role socio-economic factors can play in health outcomes, the researchers say.
The link between poverty and premature birth has been well-documented, the investigators say, but the new findings go a step further and focus on the consequences of one particularly dire and fairly common complication of prematurity -- brain hemorrhages.
"Our study shows just how detrimental and far-reaching the effects of prematurity can be, medically and otherwise, highlighting the critical need to better identify high-risk pregnancies and reduce the number of premature births," says Edward Ahn, M.D., pediatric neurosurgeon and senior author on the research.
"Brain hemorrhages can have a lifelong impact on a child's neurological and cognitive development, but also create a financial burden on the families, many of whom in our study were already economically challenged," Ahn adds.
The premature brain's blood vessels are highly vulnerable to rapid changes in blood and brain pressure that occur around birth. While some brain bleeds are small and contained within the blood vessel, others can spread further and significantly damage the brain, particularly if not diagnosed and treated promptly. Serious hemorrhages require surgery, intensive follow-up and, often, long-term care to deal with the neurological and developmental after-effects of the condition.
The study tracked 38 babies treated at Hopkins Children's between 2007 and 2010 for complications of brain hemorrhages they had suffered during preterm birth. Most infants in the study (65 percent) were from low-income families and received public health insurance(63 percent). Household income is not part of a standard medical record, but the researchers used zip code and Medicaid status as proxies for income. Medicaid is the public health insurance program for low-income children.
In addition to the higher risk for brain bleeds, the study showed babies from lower-income homes and those with public health insurance had fewer scheduled follow-up appointments and more emergency room visits, compared with babies with private health insurance and with those from higher income homes. The researchers note the differences were clear, even though they didn't reach statistical significance due to the small number of patients in the study.
"If a family foregoes a scheduled follow-up and instead ends up in the ER with a serious, yet likely preventable complication, the medical and financial consequences can be far worse not only for the family but for the health care system as a whole because ER care is more expensive than routine check-ups," Ahn says.
The investigators said their findings need to be replicated on a wider scale in order to further tease out the reasons behind the disproportionate risk.
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Airborne superbugs elude hospital cleaning regimes

ScienceDaily (Oct. 11, 2012) — Hospital superbugs can float on air currents and contaminate surfaces far from infected patients' beds, according to University of Leeds researchers.
The results of the study, which was funded by the Engineering and Physical Sciences Research Council (EPSRC), may explain why, despite strict cleaning regimes and hygiene controls, some hospitals still struggle to prevent bacteria moving from patient to patient.
It is already recognised that hospital superbugs, such as MRSA and C-difficile, can be spread through contact. Patients, visitors or even hospital staff can inadvertently touch surfaces contaminated with bacteria and then pass the infection on to others, resulting in a great stress in hospitals on keeping hands and surfaces clean.
But the University of Leeds research showed that coughing, sneezing or simply shaking the bedclothes can send superbugs into flight, allowing them to contaminate recently-cleaned surfaces.
PhD student Marco-Felipe King used a biological aerosol chamber, one of a handful in the world, to replicate conditions in one- and two-bedded hospital rooms. He released tiny aerosol droplets containing Staphyloccus aureus, a bacteria related to MRSA, from a heated mannequin simulating the heat emitted by a human body. He placed open Petri dishes where other patients' beds, bedside tables, chairs and washbasins might be and then checked where the bacteria landed and grew.
The results confirmed that contamination can spread to surfaces across a ward. "The level of contamination immediately around the patient's bed was high but you would expect that. Hospitals keep beds clean and disinfect the tables and surfaces next to beds," said Dr Cath Noakes, from the University's School of Civil Engineering, who supervised the work. "However, we also captured significant quantities of bacteria right across the room, up to 3.5 metres away and especially along the route of the airflows in the room."
"We now need to find out whether this airborne dispersion is an important route of spreading infection," added co-supervisor Dr Andy Sleigh.
The researchers are hoping that computer modelling will help them determine the risk. The findings have been compared to airflow simulations of the mock-up hospital rooms and the research team have shown that they are able to accurately predict how airborne particles can be deposited on surfaces.
"Using our understanding of airflow dynamics, we can now use these models to investigate how different ward layouts and different positions of windows, doors and air vents could help prevent microorganisms being deposited on accessible surfaces," said Mr King.
The international design and engineering firm Arup, which designs hospitals, part sponsored the study.
Phil Nedin, director and global healthcare business leader at Arup, said: "We are looking at healthcare facilities of the future and it is important that we look at key issues such as infection control. Being involved in microbiological studies that inform airflow modelling in potentially infectious environments allows us to get a clear understanding of the risks in these particular environments."
The paper "Bioaerosol Deposition in Single and Two-Bed Hospital Rooms: A Numerical and Experimental Study" is published in the journal Building and Environment
.
This research is funded by an EPSRC Challenging Engineering grant held by Dr Cath Noakes. Marco-Felipe King's PhD was also partially sponsored by Arup.
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Journal Reference:
M.F. King, C.J. Noakes, P.A. Sleigh, M.A. Camargo-Valero. Bioaerosol Deposition in Single and Two-Bed Hospital Rooms: A Numerical and Experimental Study. Building and Environment, 2012; DOI: 10.1016/j.buildenv.2012.09.011
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England World Cup wins and losses linked to 30 percent rise in domestic violence, study finds

ScienceDaily (Oct. 11, 2012) — Domestic violence rates rose by an average of 30 percent each time England won or lost their games during the 2010 World Cup, but draws had little impact on the statistics.
Those are the key findings of research carried out by statistician Professor Allan Brimicombe and BBC News journalist Rebecca Cafe and published in the October issue of Significance
, the magazine of The Royal Statistical Society and the American Statistical Association.
As a consequence of this and previous research, Professor Brimicombe believes there is a strong case for schools to educate pupils of the dangers of domestic violence, event organisers should promote initiatives that tackle domestic violence and that police forces should prepare themselves for peaks in domestic violence around major sporting events.
"Domestic violence is widespread, accounting for 15 percent of all violent crimes and 35 percent of murders in the UK," explains Professor Brimicombe, from the Centre for Geo-Information Studies at the University of East London.
"It is a crime that is estimated to affect some 30 percent of women and 17 percent of men at some point in their lives."
The researchers based their findings on statistics provided by 33 of the 39 police forces in England, which between them cover 77 percent of the country's population.
The data, for the period covering the 2010 World Cup and the same period in 2009, was obtained under the Freedom of Information Act 2000, which enables members of the public to request official information from public bodies.
The figures showed that when England drew 1-1 against the USA, domestic violence fell by 1.9 percent and when England drew 0-0 against Algeria it rose by 0.1 percent.
However when England won its game against Slovenia 1-0, domestic violence rose by 27.7 percent. And England's exit from the World Cup, after losing 4-1 to Germany, was accompanied by a 31.5 percent rise in domestic violence.
The research aimed to test the validity of an analysis carried out by the Home Office that showed that domestic violence had risen during the 2006 World Cup. "Major sporting events do not cause domestic violence, as perpetrators are responsible for their actions," said the analysis, "but the levels of alcohol consumption linked to the highly charged emotional nature of those events seems to increase the prevalence of such incidents."
Professor Brimicombe concludes that the Home Office findings were right in some respects but fell short in their analysis in other respects.
Professor Brimicombe explains: "Our research shows that increased levels of domestic violence are associated with national football matches, but only if there is a definite win or lose result. The failing of the earlier Home Office analysis was that it ignored the outcome of the match, which as we have seen is crucial.
"The percentage differences that we found are so great that we believe we have established a strong case for linking wins and losses, but not draws, to increased domestic violence.
"I hope that the findings will encourage improved education around the links between major sporting events and peaks in domestic violence and greater awareness of the risk.
"And I would applaud initiatives like the recent beer mat campaign highlighting the dangers of domestic violence, run by the London Borough of Newham and Metropolitan Police during the 2012 Olympics."
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Journal Reference:
Allan Brimicombe, Rebecca Cafe. Beware, win or lose: Domestic violence and the World Cup. Significance, 2012; 9 (5): 32 DOI: 10.1111/j.1740-9713.2012.00606.x
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Nurture trumps nature in study of oral bacteria in human twins, study finds

ScienceDaily (Oct. 11, 2012) — A new long-term study of human twins by University of Colorado Boulder researchers indicates the makeup of the population of bacteria bathing in their saliva is driven more by environmental factors than heritability.
The study compares saliva samples from identical and fraternal twins to see how much "bacterial communities" in saliva vary from mouth to mouth at different points in time, said study leader and CU-Boulder Professor Kenneth Krauter. The twin studies show that the environment, rather than a person's genetic background, is more important in determining the types of microbes that live in the mouth.
For the new study, doctoral student Simone Stahringer sequenced the microbial DNA present in the saliva samples of twins. She and the research team then determined the microbes' identities through comparison with a microbe sequence database. Saliva samples were gathered from twins over the course of a decade beginning in adolescence to see how salivary microbes change with time.
After determining the oral "microbiomes" of identical twins, who share the same environment and genes, and the microbiomes of fraternal twins who share only half their genes, the researchers found the salivary microbes of the identical twins were not significantly more similar to each other than to those of fraternal twins. "We concluded the human genome does not significantly affect which bacteria are living in a person's mouth," said Krauter of CU-Boulder's molecular, cellular and developmental biology department. "It appears to be more of an environmental effect."
Krauter said while the twin data from the oral microbiome study indicates that genetics plays a more minor role, it's possible the genes still affect the oral microbiome in more subtle ways -- an effect he plans to further explore.
A paper on the subject was published online Oct. 12 in the journal Genome Research
. Other co-authors included doctoral student William Walters of MCD Biology, Jose Clemente and Rob Knight of the chemistry and biochemistry department, Robin Corley and John Hewitt of the Institute for Behavioral Genetics and Dan Knights, a former doctoral student in the computer science department.
The researchers also found that the salivary microbiome changed the most during early adolescence, between the ages of 12 and 17. This discovery suggests that hormones or lifestyle changes at this age might be important, according to the team.
Stahringer said that when several pairs of identical twins moved out of their homes and, for example, went off to college, the oral microbes they carried changed, which is consistent with the idea that the environment contributes to the types of microbes in the saliva. "We were intrigued to see that the microbiota of twin pairs became less similar once they moved apart from each other," Stahringer said.
Krauter said there appears to be a core community of oral bacteria that is present in nearly all humans studied. "Though there are definitely differences among different people, there is a relatively high degree of sharing similar microbial species in all human mouths," he said.
The authors say the new study has established a framework for future studies of the factors that influence oral microbial communities. "With broad knowledge of the organisms we expect to find in mouths, we can now better understand how oral hygiene and environmental exposure to substances like alcohol, methamphetamines and even foods we eat affect the balance of microbes," said Krauter.
The saliva samples used in the new study came from the university's Longitudinal Twin Study and Colorado Adoption Project, which have involved hundreds of identical and fraternal twin pairs. Researchers also are analyzing additional frozen saliva samples collected during their studies for another project assessing possible relationships of oral bacteria to drug addiction, he said.
CU has a strong research focus on the human microbiome. In a 2011 study led by the Washington University School of Medicine and involving CU-Boulder, researchers found the diversity and abundance of gut microbes in animals varied depending on whether they were carnivores, omnivores or vegetarians. Knight is a member of a national research team funded by the Bill & Melinda Gates Foundation to look at the gut microbes of normal and malnourished infants and children around the world in search of novel microbial therapeutics.
In 2012, some 200 researchers from the NIH-funded Human Microbiome Project, including eight CU-Boulder researchers, mapped the microbial makeup of healthy humans for the first time. The study involved nearly 250 healthy U.S. volunteers and targeted 15 to 18 individual sites on the body harboring microbial communities.
Other recent studies involving CU researchers included one that found the delivery methods of babies have a big effect on their individual microbiomes, and second that showed women have a greater diversity of hand bacteria than men. Another showed personal bacterial communities living on the fingers and palms of individual computer users can be matched up with bacterial signatures on the computers and computer mice they recently used, a potential new tool for forensic scientists in the future.
According to scientists, about 100 trillion microorganisms inhabit surfaces and cavities of our bodies, which amounts to roughly 10 microbes per human cell.
Genome Research is an international, peer-reviewed journal that focuses on research that provides new insights into the genome biology of all organisms, including advances in genome medicine.
Funding for the study was provided by National Institutes of Health grants HD-010333 and DA-011015.
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Journal Reference:
Stahringer SS, Clemente JC, Corley RP, Hewitt J, Knights D, Walters WA, Knight R, Krauter KS. Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood. Genome Research, 2012; DOI: 10.1101/gr.140608.112
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Single gene variant in donors may affect survival of transplanted kidneys

ScienceDaily (Oct. 11, 2012) — A single genetic variant in kidney donors' cells may help determine whether their transplanted organs will survive long term, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). The findings provide new information that might be used to improve transplant longevity by revealing that the genetic make-up of kidney transplant donors affects the survival of transplanted organs.
A transplant recipient must take lifelong immunosuppressive drugs to prevent rejection of the new organ, but these drugs can have serious side effects, including kidney damage. So, ironically, the very drugs needed to prevent kidney rejection can also be toxic to the kidneys. Research suggests that how well certain proteins pump these drugs out of kidney cells may influence the drugs' kidney toxicity.
Richard Borrows, MB (Queen Elizabeth Hospital Birmingham, in the UK) and his colleagues looked to see if variants in the genes that encode such pumps might influence the health of transplanted kidneys. They investigated the links between donor and recipient gene variants with kidney outcome among 811 immunosuppressant-treated kidney transplant recipients.
Among the major findings:
One particular variant within the multidrug resistance 1 (MDR-1) gene in donors was linked to a 69% increased risk for long-term failure of transplanted organs.The researchers validated the link in another 3,660 donors, making this the largest study of its kind.This variant affects the expression of the protein that the MDR-1 gene encodes, the drug transporter P-glycoprotein.No other genetic variants in donors or recipients were linked with organ survival or failure.
"The study of donor, as opposed to recipient, gene variation is relatively uncommon in the field of transplantation, and it certainly warrants more attention," said Dr. Borrows. He added that a single genetic variant probably has limited effect on its own, but when combined, multiple genetic variants may play an important role in transplant longevity.
Study co-authors include Jason Moore, MBBS, Amy Jayne McKnight, PhD, Bernd Döhler, PhD, Matthew Simmonds, PhD, Aisling Courtney, PhD, Oliver Brand, PhD, David Briggs, PhD, Simon Ball, PhD, Paul Cockwell, PhD, Christopher Patterson, PhD, Alexander Maxwell, PhD, Stephen Gough, PhD, and Gerhard Opelz, PhD.
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Journal Reference:
Richard Borrows et al. Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure. Journal of the American Society of Nephrology, 2012; DOI: 10.1681/ASN.2012030260
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All healthcare professionals need training to deal with the sexual needs of patients, study finds

ScienceDaily (Oct. 11, 2012) — Providing healthcare staff with a one-day training course on dealing with the sexual needs of people with an acquired physical disability gave them greater understanding of the issues patients faced and enabled them to address intimate questions more comfortably and proactively.
The findings were so encouraging that the authors of the study, published in the November issue of the Journal of Advanced Nursing
, are calling for all healthcare practitioners to receive sexuality training, regardless of their role or the area of healthcare they work in.
Researchers surveyed 29 nurses, allied health professionals and care staff, before and after the course, on their ability and confidence to address sexual issues with patients. They also held in-depth interviews with 12 of them. All age ranges were represented (20 to 55 plus), the majority were female (79 per cent) and most had been working at their current hospital for one to five years (41 per cent).
"Changes associated with an acquired physical disability can diminish a person's self-esteem, sense of attractiveness, relationships and sexual functioning" explains lead author Agnes Higgins, Professor of Mental Health at the School of Nursing and Midwifery, Trinity College Dublin, Ireland.
"Previous research suggests that people with physical disability are dissatisfied with the quality of information and support around sexuality during their rehabilitation."
Subjects addressed during the course included the impact of disability on sexual expression, how to deal with patients' sexual behaviour in the hospital setting and responding to questions such as whether they will be able to have sex in the future.
Key findings included:
Participants rated their knowledge of 13 key areas related to patients' sexuality, including rights, aging, communication and help with specific medical conditions. The mean score was 1.9 out of four before the course and 2.5 after the course -- the equivalent of a 31.5 per cent increase in knowledge.The biggest rises in knowledge were in sexual rights and disability and brain injury and sexuality (both up 0.8 out of four). Other top increases included the impact of a stroke on sexuality and managing 'inappropriate' sexual behaviour (both up 0.7).Participants also rated their ability to deal with 15 situations, ranging from seeing a patient engaging in sexual behaviour to seeking advice on their future sexual ability. The mean score was 2.1 out of four before the course and 2.6 after the course -- the equivalent of a 23.5 per cent increase in ability.The biggest rises in ability were how to deal with walking in on a patient who was masturbating or engaged in sexual foreplay with their partner (both up 0.8). Other top increases included how to respond to a patient who asked if it was OK for them to have sex and advising young and old patients who wonder if they will ever have an erection or orgasm again (all up 0.7).
Staff reported finding the course very helpful.
One participant said it made them more able to respond to difficult issues in a sensitive manner. "I'm less uncomfortable and if they [patients] raise an issue, even in a joking manner, I'm kind of happy to say 'Well is that an issue for you… would you like to talk about that a little bit more?' rather than just kind of laughing and then moving onto the next subject, which is easy to do."
Another said it made them think of more than a patient's medical needs, citing the example of a woman who was incontinent and keen to return home and to work. Normally they would have suggested a urinary catheter, without further exploring the impact of this on the person's life, but the staff member said: "Because I'd done the sexuality course it made me think well actually one of the person's goals is she's got a fiancé, and relationships are important, and that [catheter] would be a huge barrier."
This was reinforced by other staff members. "I like to think I see the patient as a person, but you don't always, you honestly don't" said one. "That [course] made me very, very aware that there is a person here."
It also made it easier for them to deal with sexual comments from patients as one participant illustrated with a pre-course experience. "We are in a room and a young nurse is passing by and she is good looking but he [patient] expresses that in a way that is not exactly inappropriate. He's a young guy… I feel a little bit embarrassed and do not know how to react."
"Patient sexuality is an area that many healthcare practitioners may be reluctant to address or discuss because of embarrassment, particularly when patients have a disability" says Professor Higgins.
"Our study suggests that systematic education and training in sexuality leads to statistically significant changes in health care practitioners' knowledge, skills and comfort. Participants also reported numerous incidents where they were more willing to raise issues for discussion and create a supportive listening space for patients.
"This course provided an effective learning experience for the healthcare practitioners and could easily be replicated elsewhere. We believe that practitioners require education in patient sexuality, regardless of their discipline."
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Journal Reference:
Agnes Higgins, Danika Sharek, Maeve Nolan, Barbara Sheerin, Paul Flanagan, Sniguole Slaicuinaite, Sinead Mc Donnell, Heather Walsh. Mixed methods evaluation of an interdisciplinary sexuality education programme for staff working with people who have an acquired physical disability. Journal of Advanced Nursing, 2012; 68 (11): 2559 DOI: 10.1111/j.1365-2648.2012.05959.x
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Clues to cancer metastasis: Discovery points to potential therapies for bone metastasis

ScienceDaily (Oct. 11, 2012) — In recent years investigators have discovered that breast tumors are influenced by more than just the cancer cells within them. A variety of noncancerous cells, which in many cases constitute the majority of the tumor mass, form what is known as the "tumor microenvironment." This sea of noncancerous cells and the products they deposit appear to play key roles in tumor pathogenesis.
Among the key accomplices in the tumor microenvironment are mesenchymal stem cells (MSCs), a group of adult progenitor cells which have been shown to help breast cancers maneuver and spread to other parts of the body.
Now, new research sheds further light on how this is happening. Led by investigators at Beth Israel Deaconess Medical Center (BIDMC), the findings demonstrate that the lysyl oxidase (LOX) gene is spurred to production in cancer cells as a result of their contact with MSCs, and once produced, can help ensure the spread of otherwise weakly metastatic cancer cells from primary tumors to the lung and bones. Described on-line in the Proceedings of the National Academy of Sciences
(PNAS), this discovery not only provides key insights into the basic biology of tumor formation, but also offers a potential new direction in the pursuit of therapies for the treatment of bone metastasis.
"We don't have a lot of therapies that can target breast cancer once it has metastasized, particularly once cancer cells have lodged in the bone," says senior author Antoine Karnoub, PhD, an investigator in the Department of Pathology at BIDMC and Assistant Professor of Pathology at Harvard Medical School. "When breast cancer cells reach the skeleton, one way in which they cause damage is by breaking down bone tissue, which results in the bone's rich matrix releasing numerous factors. These factors, in turn, feed the cancer cells, setting in motion a vicious cycle that leaves patients susceptible to fractures, pain, and further metastasis."
MSCs are non-hematopoietic progenitor cells predominantly produced in the bone marrow that generate bone, cartilage, fat, and fibrous connective tissue. They additionally support immune cell development and are recruited to inflammatory sites throughout the body to help shut down immune responses and regenerate damaged tissues, as might occur during wound healing. Several years ago, as a postdoctoral researcher at the Whitehead Institute of the Massachusetts Institute of Technology, Karnoub began exploring the idea that MSCs were migrating to tumors after mistaking the cancer sites for inflammatory lesions in need of healing.
"We discovered that once MSCs had reached the tumor sites, they were actually helping in cancer metastasis, causing primary cancer cells to spread to other sites in the body," he explains. In this new paper, Karnoub wanted to find out, in greater molecular detail, how breast cancer cells respond to the influences of MSCs in order to better understand how cancer cells cross-talk with recruited cells in the microenvironment.
His scientific team first embarked on a straightforward experiment. "We took two dishes of cells, cancer cells and MSCs, and mixed them together," explains Karnoub. After three days, they removed the cancer cells and studied them to see how they had changed.
"We found that the lysyl oxidase [LOX] gene was highly upregulated in the cancer cells," he says. "It turns out that when a cancer cell comes in contact with an MSC, it flips on this LOX gene, turning it up by a factor of about 100. So our next question was, 'What happens to the cancer cells when they encounter this boost of LOX that they themselves have produced?'"
The answer, as revealed in subsequent experiments, was that LOX was setting in motion a cell program called epithelial-to-mesenchymal transition (EMT). During EMT, cancer cells that usually clump together undergo a transformation into cells that exhibit decreased adhesion to their neighbors and go their own way. As a result, these cancerous cells are able to migrate, significantly enhancing their ability to metastasize.
"When we put these cells back into mice, they not only formed tumors that metastasized to the lung, but also to the bone," says Karnoub. "This makes you wonder whether the cancer cells in primary tumors have become so acclimated to interacting with bone-derived MSCs that they can now grow more easily in the bone once they leave the tumor."
The investigators also wanted to find out if, by going through the EMT process, cancer cells were also acquiring the phenotypes of another highly aggressive feature of malignant cancer cells, those of cancer stem cells within the cores of most tumors.
"Cancer stem cells are believed to be responsible for the resurgence of tumors following chemotherapy treatment, and an increasing body of science is focused on understanding how CSCs function and how they originate," says Karnoub. "The processes of EMT and CSC formation have been described as being closely coupled and we asked whether LOX might be regulating CSC phenotypes, just as it was regulating EMT. To our surprise, this was not the case. This tells us that pathways that were once thought to be intimately intertwined and commonly tweaked may, in fact, be separate, and now we can start to tease out the respective circuitries with a bit more clarity."
Lastly, the investigators identified the mechanism that was enabling LOX to be turned on from outside the cell, a set of molecules called hyaluronic acid (HA) and CD44. "It turns out that the MSCs provide the HA while the cancer cells provide the CD44 and they work in tandem like a lock and key to upregulate LOX expression," explains Karnoub, adding that antagonists to HA and CD44, already in extensive investigations and clinical exploration, might be of increased use from a clinical standpoint, perhaps in managing bone metastasis.
"This work reveals yet another important component of the complexity of malignant progression," says Robert Weinberg, PhD, Professor of Biology and Director of the MIT Ludwig Center for Molecular Oncology at the Massachusetts Institute of Technology. "The bidirectional communication between breast cancer cells and the nearby MSCs results in the acquisition of malignant traits by cancer cells, including their spread to distant sites in the body where they seed potentially lethal metastases."
Says Karnoub, "Now that the functions of tumor promoters and tumor suppressors are being appreciated with increased clarity, it would aid greatly if we can understand how these major cancer regulators are themselves regulated by what's outside the cancer cell. In concert with designing therapies that can enter inside the cell to directly inhibit such active players, one could perhaps design a therapy that inhibits the interaction of the cancer cell with its microenvironment, thereby shutting off the desired pathways altogether."
Study coauthors include BIDMC investigators Christelle P. El-Haibi (first author), Antoine Campagne, Anthony Y. Collmann, and Eva Csizmadia; George W. Bell of the Whitehead Institute for Biomedical Research; Jiangwen Zhang of the Faculty of Arts and Sciences, Harvard University; David Wood and Sangeeta N. Bhatia of the Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cally M. Scherber, Mehmet Toner and Daniel Irimia of Massachusetts General Hospital; and Odette Mariani and Anne Vincent-Salomon of the Institut Curie, Paris, France.
This work was supported by grants from the National Institutes of Health (R21CA135601) and startup funds from BIDMC and the Sidney Kimmel Cancer Research Foundation. Antoine Karnoub is a 2010 Kimmel Scholar and a recipient of a 2012 Career Catalyst Research Award from Susan G. Komen for the Cure.
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Journal Reference:
C. P. El-Haibi, G. W. Bell, J. Zhang, A. Y. Collmann, D. Wood, C. M. Scherber, E. Csizmadia, O. Mariani, C. Zhu, A. Campagne, M. Toner, S. N. Bhatia, D. Irimia, A. Vincent-Salomon, A. E. Karnoub. Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1206653109
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One CVD death in China every 10 seconds

ScienceDaily (Oct. 11, 2012) — Urgent actions including smoking bans in public places, salt restrictions and improved blood pressure control are needed to fight rising cardiovascular disease in China. Half of male physicians in China smoke and they can lead the way to healthy lifestyles by kicking the habit.
Cardiovascular disease is the top cause of death in China and causes more than 40% of all deaths.
"Every year three million Chinese people die from cardiovascular disease and every 10 seconds there is one death from CVD in China," said Professor Dayi Hu, chief of the Heart Centre at the People's Hospital, Peking University and president of the Chinese Society of Cardiology (CSC) (1). He adds: "Prevention has not been a priority in China because for the last 20 to 30 years the medical system has mainly been treating the late stages of heart disease. The number of patients treated with stents has increased dramatically."
Professor Hu was speaking ahead of the 23rd Great Wall International Congress of Cardiology and Asia Pacific Heart Congress, which take place 11-14 October 2012 in Beijing, China. The European Society of Cardiology (ESC) will present a full day of scientific sessions at the event, on October 13, as part of its Global Scientific Activities (GSA) programme.
ESC President Panos Vardas will head the European delegation (2). He said: "The ESC is delighted to return to China, where I anticipate fruitful discussions between Chinese and European experts on how the latest ESC Clinical Practice Guidelines on Prevention can be applied. I also look forward to comparing the results of Chinese and European registries, since we know that registries are an important tool for monitoring lifestyle behaviours and implementation of guidelines."
China has experienced fast industrialization. In just over 30 years GDP per capita increased by nearly 80-fold, from 381 Yuan in 1978 to 29,748 Yuan in 2010. The country has also had fast urbanization. In 1978 just 18% of the population lived in cities. This had risen to 50% by 2010 and is predicted to reach 55% by 2015. These social transformations have led to dramatic changes in the lifestyle of the entire population.
Smoking is a massive problem in Chinese men -- 54% of men smoke. "Half of male physicians are smokers and one-third of Chinese male cardiologists are smokers, so it's a real problem," said Professor Hu.
There are a total of 350 million smokers in China and this is expected to rise to 430 million by 2032. The average age to have the first cigarette is decreasing. In men this dropped from 22 years of age in 1984 to 19 years in 1996 and 18 years in 2002. In women the age fell from 25 years in 1984 to 22 years in 1996 and 20 years in 2002.
There is an increasing epidemic of hypertension in China. Some 200 million Chinese people have hypertension and the rate of hypertension is rising in all age groups. But awareness, treatment and control of hypertension are low. Just 30% of patients with hypertension in China are aware they have it, compared to 80% awareness in the US. Only 24% of Chinese patients with hypertension receive treatment (vs 73% in the US) and only 6% of patients have their blood pressure under control (vs 50% in the US).
"We need to work together with the big hospitals to improve the control of hypertension," said Professor Hu. "It will also be important to measure blood pressure levels of people living in rural areas so that we can identify people with hypertension."
There are 92 million with type 2 diabetes in China. In the urban population, levels of diabetes increased by more than 50% over a 5-year period, from 6% in 2002 to nearly 10% in 2007. Hospital admission rates for acute complications of diabetes are extremely high, and were reported at 160 per 100,000 in 2008. This is more than 16 times the rate in the Netherlands of less than 10 per 100,000 in 2005. Professor Hu said: "The numbers are big and the control is low."
CVD accounted for nearly half of the burden of disease in China in 2010, as measured by disability adjusted life years (DALYs) which indicates the number of years lost due to ill health, disability or early death. It is predicted that by 2030, CVD will be top cause of future total DALY lost in China. But tobacco control could avert around 10 million DALYs at just a few cents (US) or less than 0.04 Yuan per capita annually.
Tobacco control measures include: Banning smoking in public places, increasing taxes on tobacco, enforcing bans on tobacco advertising, promotion and sponsorship and helping smokers to quit and warning about the dangers of smoking.
China does not have national laws to ban smoking in public areas and there is no central government policy. There are some smoke free hospitals and some cities and provinces have instigated smoking bans in public areas but Professor Hu said these efforts are not sufficient.
He said: "The government needs to make strict laws to prohibit smoking in public places. The Chinese Society of Cardiology plans to work with the government to control tobacco. Given the high level of smoking in male physicians and cardiologists, efforts to quit should start with them."
Salt intakes are also high. More than 80% of Chinese adults living in urban areas consume more than five grams of salt each day. Reducing daily salt intake from 10 grams to 5g could reduce stroke rates by 23% and CVD rates by 17% at a cost of less than US$1 per person per year if combined with a tobacco control strategy.
Strategies for reducing salt intake include: Developing nutrition guidelines that are easily understood by the general population, making healthy good more available and affordable through voluntary or legislated pricing and food labelling, encouraging food manufacturers to reduce levels of salt, educating the public and monitoring dietary intake of the population.
"In China we should educate the public through television to eat less salt," said Professor Hu. "We also need to promote healthy cafeteria food with a lower salt content because many children eat in the school cafeteria and many working people eat lunch and dinner in the company cafeteria rather than at home."
Obesity has increased in China, with unhealthy lifestyles starting at a young age. Professor Hu said: "We should do more health promotion and health education at a population level, starting with children, to encourage people to do more exercise and to eat healthy food."
"I think a healthy China has to be started from the healthy physician," said Professor Hu. "Physicians and cardiologists need to quit smoking, eat healthily, exercise and control their body weight so that they can be a good example for patients and the public, and effectively promote CVD prevention measures with the government, pharmaceutical companies and food manufacturers. I believe that if there is no healthy physician there will be no healthy China."
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Kidney grafts function longer in Europe than in the United States

ScienceDaily (Oct. 12, 2012) — Kidney transplants performed in Europe are considerably more successful in the long run than those performed in the United States. While the one-year survival rate is 90% in both Europe and the United States, after five years, 77% of the donor kidneys in Europe still function, while in the United States, this rate among white Americans is only 71%. After ten years, graft survival for the two groups is 56% versus 46%, respectively. The lower survival rates compared to Europe also apply to Hispanic Americans, in whom 48% of the transplanted kidneys still function after ten years, and particularly to African Americans, whose graft survival is a mere 33%.
Researchers from Heidelberg have described the large discrepancy for the first time, after systematically comparing data from the world's most comprehensive study on transplant results, the Collaborative Transplant Study (CTS) in Heidelberg, with transplant data from the United States. Their research findings have now been published online in the journal Transplantation
.
The results of the study show particularly large differences in graft survival among children and young adults between Europe and the US. One reason for the poorer results in the United States may be the fact that costs of anti-rejection drugs are usually reimbursed by Medicare for only three years, while in Europe, the statutory health insurance guarantees lifelong reimbursement of costs. In the United States, patients who have undergone kidney transplants often have to pay for these drugs themselves. Costs amount to around US $20,000 per year.
Heidelberg CTS Study evaluates international data on transplantation
The CTS Study conducted for the past 30 years at Heidelberg University Hospital's Transplantation Immunology department, headed by Prof. Gerhard Opelz, has collected data on transplants performed worldwide and evaluates them. These days, kidney transplants are generally very successful. A major reason for this is the anti-rejection drugs, or immunosuppressants, which must be taken by kidney-transplant recipients on a lifelong basis.
"For the comparison of the long term graft survival in the United States and Europe, we had access to data from the US United Network for Organ Sharing (UNOS),"explained Dr. Adam Gondos, who works as an epidemiologist at the Division of Clinical Epidemiology and Aging Research of the German Cancer Research Center (DKFZ). In the United States, all data on transplants are systematically collected and available to the public, in contrast to German and most European countries, where generally no comparable national registry exists. Participation in the CTS Study is voluntary. "However, since a high percentage of the European centers participate, the data for Europe are representative," said Prof. Opelz. Around 23,500 kidney transplants in Europe were used for the current evaluation, along with data on 32,000 kidney transplants performed in the United States.
"We cannot conclusively identify the reasons for the discrepancy between the United States and Europe based on the statistical analyses performed here," said Dr. Gondos. However, the fact that the results in the first year are equally good and that they become successively worse in the United States may indicate that posttransplant care in general, and the supply of immunosuppressants or lack thereof in particular, may play an certain role here, he added.
Dialysis more expensive than immunosuppressants
In February 2012, Canadian nephrologists already sharply criticized the current US practice in the New England Journal of Medicine
(NEJM 366;7). If patients have to return to dialysis, their life expectancy is shortened, even if a new kidney is available. According to the experts, this rationing is neither ethically responsible nor does it make sense in economic terms, since dialysis costs around US$ 75,000 per year, more than triple the costs of immunosuppressive treatment. So far, however, all of the political efforts in the United States have failed that call for immunosuppressive treatment to be continued for more than three years after kidney transplant.Share this story on Facebook, Twitter, and Google:
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Prospective Alzheimer's drug builds new brain cell connections, improves cognitive function of rats

ScienceDaily (Oct. 11, 2012) — Washington State University researchers have developed a new drug candidate that dramatically improves the cognitive function of rats with Alzheimer's-like mental impairment.
Their compound, which is intended to repair brain damage that has already occurred, is a significant departure from current Alzheimer's treatments, which either slow the process of cell death or inhibit cholinesterase, an enzyme believed to break down a key neurotransmitter involved in learning and memory development. Such drugs, says Joe Harding, a professor in WSU's College of Veterinary Medicine, are not designed to restore lost brain function, which can be done by rebuilding connections between nerve cells.
"This is about recovering function," he says. "That's what makes these things totally unique. They're not designed necessarily to stop anything. They're designed to fix what's broken. As far as we can see, they work."
Harding, College of Arts and Sciences Professor Jay Wright and other WSU colleagues report their findings in the online "Fast Forward" section of the Journal of Pharmacology and Experimental Therapeutics
.
Their drug comes as the pharmacological industry is struggling to find an effective Alzheimer's treatment. Last month, the Pharmaceutical Research and Manufacturers of America, or PhRMA, reported that only three of 104 possible treatments have been approved in the past 13 years.
"This 34-to-one ratio of setbacks to successes underlines the difficulty of developing new medicines for Alzheimer's," the trade group said in a news release. Development of the WSU drug is only starting. Harding and Wright must first satisfy the Food and Drug Administration that it is safe. Only then would clinical trials begin to see if a drug that works in a rat will work in a human.
Safety testing alone could cost more than $1 million, says Harding, who is looking to fund the drug's development through his and Wright's company, M3 Biotechnology Inc., the WSU Research Foundation, and ultimately large pharmaceutical company partners.
Harding, a medicinal chemist, and Wright, a neuroscientist, have been working on their compound since 1992, when they started looking at the impact of the peptide angiotensin IV on the hippocampus, a brain region involved in spatial learning and short-term memory. Typically, angiotensins have been linked to blood pressure regulation, but Harding and Wright noticed that angiotensin IV, or early drug candidates based on it, were capable of reversing learning deficits seen in many models of dementia.
The practical utility of these early drug candidates, however, was severely limited because they were very quickly broken down by the body and couldn't get across the blood-brain barrier, a cellular barrier that prevents drugs and other molecules from entering the brain. The only way the drug could be delivered was by direct brain application.
Says Harding: "We said, 'That's useless. I mean, who wants to drill holes in people's heads? It's not going to work. It's certainly not going to work for the big population.'"
Five years ago, Harding designed a smaller version of the molecule that he and Wright called Dihexa. Not only is it stable but it can cross the blood-brain barrier. An added bonus is it can move from the gut into the blood, so it can be taken in pill form.
The researchers tested the drug on several dozen rats treated with scopolamine, a chemical that interferes with a neurotransmitter critical to learning and memory. Typically, a rat treated with scopolamine will never learn the location of a submerged platform in a water tank, orienting with cues outside the tank. After receiving the WSU drug, however, all of the rats did, whether they received the drug directly in the brain, orally, or through an injection.
"Same result, every time," says Harding.
Harding and Wright also reported similar but less dramatic results in a smaller group of old rats. In this study the old rats, which often have difficulty with the task, performed like young rats. While the results were statistically valid, additional studies with larger test groups will be necessary to fully confirm the finding. Currently, the "gold standard" compound for creating neuronal connections is brain-derived neurotrophic factor, or BDNF, a growth-promoting protein associated with normal brain development and learning. Autopsies of Alzheimer's patients have found lower levels of BDNF in the brain.
In bench assays using living nerve cells to monitor new neuronal connections, Harding, Wright, and their colleagues found Dihexa to be seven orders of magnitude more powerful than BDNF, which has yet to be effectively developed for therapeutic use. In other words, it would take 10 million times as much BDNF to get as much new synapse formation as Dihexa.
"We quickly found out that this molecule was absolutely, insanely active," says Harding. These results further suggest that Dihexa or molecules like it may have applications in other neurodegenerative disease or brain traumas where neuronal connections are lost.
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The above story is reprinted from materials provided by Washington State University. The original article was written by Eric Sorensen, WSU science writer.
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Journal Reference:
A. T. McCoy, C. C. Benoist, J. W. Wright, L. H. Kawas, J. Bule-Ghogare, M. Zhu, S. M. Appleyard, G. A. Wayman, J. W. Harding. Evaluation of metabolically stabilized angiotensin IV analogs as pro-cognitive/anti-dementia agents. Journal of Pharmacology and Experimental Therapeutics, 2012; DOI: 10.1124/jpet.112.199497
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How food marketers can help consumers eat better while improving their bottom line

ScienceDaily (Oct. 11, 2012) — Food marketers are masters at getting people to crave and consume the foods that they promote. In this study authors Dr. Brian Wansink, co-director of the Cornell University Center for Behavioral Economics in Child Nutrition and Professor of Marketing and Dr. Pierre Chandon, professor of Marketing at the leading French graduate school of business, INSEAD challenge popular assumptions that link food marketing and obesity.
Their findings presented last weekend at the Association for Consumer Research Conference in Vancouver, Canada point to ways in which smart food marketers can use the techniques that peak consumer appetite for calorie-dense fast foods to help people eat better -- and improve their bottom line as well.
"People generally want food that tastes good while being affordable, varied, convenient and healthy -- roughly in that order. Our research suggests that consumption of healthy and unhealthy food respond to the same marketing tactics, particularly price reduction. In this study we present food marketers with a 'win-win' situation in which they can turn the tables, compel consumers to eat healthier foods, and maintain profitability. For example, marketers can steer consumers away from high-calorie sugary drinks by offering meal discounts if a person buys a diet drink -- or by offering a healthy habit loyalty card when consumers opt for milk, juice or water instead of sugary drinks. "When all sides win, no one resists," Wansink said.
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Journal Reference:
Pierre Chandon, Brian Wansink. Does food marketing need to make us fat? A review and solutions. Nutrition Reviews, 2012; 70 (10): 571 DOI: 10.1111/j.1753-4887.2012.00518.x
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New gene test flags risk of serious complications in sarcoidosis

ScienceDaily (Oct. 11, 2012) — Researchers at the University of Illinois Hospital & Health Sciences System have identified a genetic signature that distinguishes patients with complicated sarcoidosis, an inflammatory lung disease that can be fatal, from patients with a more benign form of the disease. The gene signature could become the basis for a simple blood test.
Their findings are reported online in the journal PLOS ONE
.
In sarcoidosis, tiny clumps of abnormal tissue form in organs of the body. These clusters of immune cells, called granulomas, cause inflammation. Sarcoidosis can occur in the lymph nodes, liver, eyes, skin or other tissues, but almost always also in the lungs. The cause of the disease is unknown. African Americans are at higher risk for the disease and for more severe cases.
"One of the perplexing aspects of this disease is that two thirds of the people who get sarcoidosis get better with only minimal therapy," says Dr. Joe G.N. "Skip" Garcia, vice president for health affairs at the University of Illinois and principle investigator on the study.
But one third of patients go on to develop complicated sarcoidosis -- neurologic sarcoidosis, cardiac sarcoidosis and progressive lung disease, Garcia said. Complicated sarcoidosis can leave patients with lung damage, and in a small percentage of cases the disease can be fatal.
The challenge, Garcia says, is that there is no difference in the clinical presentation between patients with simple sarcoidosis and those who will go on to develop more serious disease.
The researchers took blood from patients with simple and complicated sarcoidosis as well as patients without the disease to look for a pattern of gene expression unique to complicated sarcoidosis.
They were able to identify a distinct 20-gene pattern of gene expression that could reliably identify those most likely to progress to complicated sarcoidosis.
A 31-gene expression signature had been identified previously, but a smaller panel of genes makes the new test less expensive and more useful clinically, said Garcia.
"We are dedicated to looking for new insights as well as new therapies for sarcoidosis and hope to someday be able to identify people at risk for it ahead of time," Garcia said.
UI Health has partnered with the Bernie Mac Foundation to form the Bernie Mac Star Clinic for Sarcoidosis, where the researchers hope to further validate use of the genetic signature.
They hope the genetic signature could someday be the basis for a biochip that could identify patients most likely to progress to life-threatening disease.
The study was supported by NIH grants NHLBI HL58094, RO1HL112051, HL68019, HL83870, UO1HL105371-01, RC2 HL101740-01 and NHLBI K23HL098454; and by the Johns Hopkins Sarcoidosis gene bank/database and the Hospital for the Consumptives of Maryland.
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Journal Reference:
Tong Zhou, Wei Zhang, Nadera J. Sweiss, Edward S. Chen, David R. Moller, Kenneth S. Knox, Shwu-Fan Ma, Michael S. Wade, Imre Noth, Roberto F. Machado, Joe G. N. Garcia. Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis. PLoS ONE, 2012; 7 (9): e44818 DOI: 10.1371/journal.pone.0044818
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Nurses help cut admissions of homeless people to hospital

ScienceDaily (Oct. 11, 2012) — A nurse outreach programme to treat people using a homeless shelter in London led to a fall of 77 per cent in hospital admissions from the shelter and a cut of 52 per cent in emergency department attendances.
Statistics show that people who are homeless in England attend emergency departments (EDs) five times more often than people who have a home and they are admitted to hospital three times as often.
As a result, a one-year pilot programme -- the Homeless Intermediate Care Pilot Project -- was set up at St Mungo's hostel in Clapham, south London.
It was staffed during the week by a clinical nurse specialist and a health support worker while a general practitioner worked at the hostel once a week for four and a half hours. A district nursing team took over at weekends.
Clinical interventions included comprehensive health assessments, daily monitoring of acute and chronic disease, vaccination, medication adherence checks and venepuncture. The health support worker also undertook non-clinical interventions such as escorting clients to appointments, and helping them find voluntary work and claim benefits.
During the trial, 34 clients were admitted onto the caseload with presenting conditions such as acute bacterial endocarditis, acute syphilis, end-stage liver failure, renal failure and pulmonary tuberculosis.
Writing in the journal Emergency Nurse, Kendra Schneller, clinical nurse specialist at Guy's and St Thomas's Foundation trust in London, compares data from St Mungo's with other hostels in the area, which did not show similar falls in hospital or ED admissions.
'Clients problems are identified early so their conditions can be managed by the project team in the community. Overall, the team demonstrates that homeless clients' health outcomes can be improved, while ambulance calls, ED attendance and re-admission rates can be reduced.'
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Journal Reference:
Kendra Schneller. Intermediate care for homeless people: results of a pilot project. Emergency Nurse, 2012; 20 (6) [link]
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Enzyme triggers cell death in heart attack

ScienceDaily (Oct. 11, 2012) — University of Iowa researchers have previously shown that an enzyme called CaM kinase II plays a pivotal role in the death of heart cells following a heart attack or other conditions that damage or stress heart muscle. Loss of beating heart cells is generally permanent and leads to heart failure, a serious, debilitating condition that affects 5.8 million people in the United States.
Now the UI team, led by Mark Anderson, M.D., Ph.D., professor and head of internal medicine at the UI Carver College of Medicine, has honed in on how CaM kinase II triggers heart cell death following heart damage, showing that the action takes place in the cells' energy-producing mitochondria. In animal tests, the team reports that blocking the enzyme can prevent heart cells from dying, and protects the animals from heart failure.
Mitochondrial are the cells' batteries, generating the energy cells need to work. In heart cells, energy produced by these small cellular components fuels each heartbeat. However, when the heart is stressed, for example during a heart attack, the mitochondria become leaky and non-functional, which triggers cell death and heart failure.
"We found that activity of the CaM kinase II enzyme in mitochondria promotes cell death when the heart is stressed," says Mei-ling Joiner, Ph.D., UI assistant professor of internal medicine and lead author of the study, which was published online Oct. 10 in the journal Nature
. "The findings might help us advance treatment of heart diseases and reduce mortality after a heart attack."
The new study shows that activated CaM kinase II promotes leakiness of mitochondria and increases heart muscle damage by allowing too much calcium to enter mitochondria. Specifically, the UI team found that CaM kinase II regulates calcium entry into mitochondria by modifying a special mitochondrial calcium channel. Too much enzyme activity increased the amount of calcium flowing into mitochondria, and this calcium overload triggers cell death.
Using genetically modified mice, the team also showed that inhibiting CaM kinase II activity in mitochondria prevented the calcium overloading, reduced mitochondrial disruption, and protected the mice from heart cell death during heart attack.
These findings provide insight into molecular mechanisms for mitochondrial function and suggest that inhibiting the CaM kinase II enzyme in mitochondria could lead to new and more effective therapies for common forms of heart disease.
"Because mitochondria also play important roles in other diseases in brain and skeletal muscle, for example, our findings could also have broad implications for understanding and treating non-cardiac diseases," says Anderson, who also is director of the UI Cardiovascular Research Center.
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Journal Reference:
Mei-ling A. Joiner, Olha M. Koval, Jingdong Li, B. Julie He, Chantal Allamargot, Zhan Gao, Elizabeth D. Luczak, Duane D. Hall, Brian D. Fink, Biyi Chen, Jinying Yang, Steven A. Moore, Thomas D. Scholz, Stefan Strack, Peter J. Mohler, William I. Sivitz, Long-Sheng Song, Mark E. Anderson. CaMKII determines mitochondrial stress responses in heart. Nature, 2012; DOI: 10.1038/nature11444
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Pulmonary Carcinoid Tumors and Asbestos Exposure

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Bénédicte Clin1,2,*, Pascal Andujar1,3,4, Issam Abd Al Samad5, Chantal Azpitarte6, FranÇoise Le Pimpec-Barthes7, Marie-Annick Billon-Galland8, Claire Danel9, FranÇoise Galateau-Salle10, Bruno Housset1,3,4, Karinne Legrand-Cattan11, Mireille Matrat1,3,4, Isabelle Monnet4, Marc Riquet7 and Jean-Claude Pairon1,3,4

1Institut National de la Santé et de la Recherche Médicale, U955, Equipe 4, Créteil 94000, France

2Service de Santé au Travail et Pathologie Professionnelle, Centre Hospitalier Universitaire de Caen, Caen 14000, France

3Faculté de Médecine, Université Paris Est, Créteil 94000, France

4Service de Pneumologie et de Pathologie Professionnelle, Centre Hospitalier Intercommunal de Créteil, Créteil 94000, France

5Service d’Anatomie Pathologique, Centre Hospitalier Intercommunal de Créteil, Créteil 94000, France

6Service de Santé au Travail, Société Nationale des Chemins de Fer Français, Paris 75010, France

7Service de Chirurgie Thoracique, Assistance Publique -Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris 75015, France

8Laboratoire d’Etude des Particules Inhalées de la Ville de Paris, Laboratoire d'Etude des Particules Inhalées de la Ville de Paris, Paris 75013, France

9Assistance Publique -Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Paris 75018, France

10Service d’Anatomie Pathologique, Centre Hospitalier Universitaire de Caen, Caen 14000, France

11Service de Santé au Travail, Pôle Santé Travail, Lille 59000, France ?* Author to whom correspondence should be addressed. Tel: +33-2-31-06-54-65; Fax: +33-2-31-06-49-14; e-mail: clin-b{at}chu-caen.fr Received November 10, 2011. Accepted February 14, 2012. Objectives: The hypothesis that asbestos exposure may have more specific associations with particular histological types of lung cancer remains controversial. The aim of this study was to analyze the relationships between asbestos exposure and pulmonary carcinoid tumors.

Methods: A retrospective case–control study was conducted in 28 cases undergoing surgery for pulmonary carcinoid tumors and aged >40 years and in 56 controls with lung cancer of a different histological type, matched for gender and age, from 1994 to 1999, recruited in two hospitals in the region of Paris. Asbestos exposure was assessed via expertise of a standardized occupational questionnaire and mineralogical analysis of lung tissue, with quantification of asbestos bodies (AB). Results: Definite asbestos exposure was identified in 25% of cases and 14% of controls (ns). Cumulative asbestos exposure was significantly higher in cases than in controls (P < 0.05), and results of the quantification of AB tended to be higher in cases than in controls (24 and 9% had >1000 AB per gram dry lung tissue, respectively, P = 0.09). Mean cumulative smoking was lower in cases than in controls (P < 0.05). Conclusions: This study argues in favor of a relationship between asbestos exposure and certain pulmonary carcinoid tumors. © The Author 2012. Published by Oxford University Press on behalf of the British Occupational Hygiene SocietyThis ArticleAnn Occup Hyg (2012) 56 (7): 789-795. doi: 10.1093/annhyg/mes017 First published online: May 4, 2012 PubMed citationArticles by Clin, B.Articles by Andujar, P.Articles by Abd Al Samad, I.Articles by Azpitarte, C.Articles by Le Pimpec-Barthes, F.Articles by Billon-Galland, M. A.Articles by Danel, C.Articles by Galateau-Salle, F.Articles by Housset, B.Articles by Legrand-Cattan, K.Articles by Matrat, M.Articles by Monnet, I.Articles by Riquet, M.Articles by Pairon, J. C.Current Issue
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More on the Dynamics of Dust Generation: The Effects of Mixing and Sanding Chrysotile, Calcium Carbonate, and Other Components on the Characteristics of Joint-Compound Dusts

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D. Wayne Berman1,*, Gregory P. Brorby2, Patrick J. Sheehan3, Kenneth T. Bogen3 and Stewart E. Holm4

1Aeolus, Inc., 751 Taft Street, Albany, CA 94706, USA

2ToxStrategies, Inc., 265 Breezewalk Drive, Vallejo, CA 94591, USA

3Exponent, Inc., 475 14th Street, Suite 400, Oakland, CA 94607, USA

4Georgia-Pacific LLC, 133 Peachtree Street, NE, Atlanta, GA 30303, USA ?* Author to whom correspondence should be addressed. Tel: (510)-524-7855; fax: (510)-524-7854; e-mail: bermanw{at}comcast.net Received October 16, 2010. Accepted December 20, 2011. An ongoing research effort designed to reconstruct the character of historical exposures associated with use of chrysotile-containing joint compounds naturally raised questions concerning how the character (e.g. particle size distributions) of dusts generated from use of recreated materials compares to dusts from similar materials manufactured historically. This also provided an opportunity to further explore the relative degree that the characteristics of dusts generated from a bulk material are mediated by the properties of the bulk material versus the mechanical processes applied to the bulk material by which the dust is generated. In the current study, the characteristics of dusts generated from a recreated ready mix and recreated dry mix were compared to each other, to dusts from a historical dry mix, and to dusts from the commercial chrysotile fiber (JM 7RF3) used in the recreated materials. The effect of sanding on the character of dusts generated from these materials was also explored. Dusts from the dry materials studied were generated and captured for analysis in a dust generator-elutriator. The recreated and historical joint compounds were also prepared, applied to drywall, and sanded inside sealed bags so that the particles produced from sanding could be introduced into the elutriator and captured for analysis. Comparisons of fiber size distributions in dusts from these materials suggest that dust from commercial fiber is different from dusts generated from the joint compounds, which are mixtures, and the differences persist whether the materials are sanded or not. Differences were also observed between sanded recreated ready mix and either the recreated dry mix or a historical dry mix, again whether sanded or not. In all cases, however, such differences disappeared when variances obtained from surrogate data were used to better represent the ‘irreducible variation’ of these materials. Even using the smaller study-specific variances, no differences were observed between the recreated dry mix and the historical dry mix, indicating that chrysotile-containing joint compounds can be recreated using historical formulations such that the characteristics of the modern material reasonably mimic those of a corresponding historical material. Similarly, no significant differences were observed between dusts from sanded and unsanded versions of similar materials, suggesting (as in previous studies) that the characteristics of asbestos-containing dusts are mediated primarily by the properties of the bulk material from which they are derived.

© The Author 2012. Published by Oxford University Press on behalf of the British Occupational Hygiene SocietyThis ArticleAnn Occup Hyg (2012) 56 (7): 852-867. doi: 10.1093/annhyg/mes008 First published online: March 16, 2012 Current Issue
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Lethal Carbon Monoxide Poisoning in Wood Pellet Storerooms--Two Cases and a Review of the Literature

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Saskia Gauthier1,*, Hildegard Grass2, Martin Lory3, Thomas Krämer1, Michael Thali1 and Christine Bartsch1

1 Institute of Legal Medicine, University of Zurich 8057 Zurich, Switzerland;

2 Institute of Legal Medicine, University Hospitals 40225 Düsseldorf, Germany;

3 Forensic Institute 8004 Zurich, Switzerland ? * Author to whom correspondence should be addressed. Tel: +0416355611; fax: +41446356851 saskia.gauthier{at}irm.uzh.ch Received January 11, 2012. Revision received March 14, 2012. Accepted May 12, 2012. The installation of wood pellet heating as a cost-effective and climatically neutral source of energy for private households has increased steadily in recent years. We report two deaths that occurred within the space of about a year in wood pellet storerooms of private households in German-speaking countries and were investigated by forensic medical teams. This is the first report of fatalities in this special context as is shown in the literature review. Both victims died of carbon monoxide (CO) poisoning; one of the victims was a woman who was 4 months pregnant. Measurements at the scene detected life-threatening CO concentrations (7500 ppm, >500 ppm), which were not significantly reduced after ventilation of the storerooms as required by regulations. We carried out a series of experiments in order to confirm CO production by wood pellets. Thirty kilograms of freshly produced pellets from two different manufacturers were stored for 16 days in airtight containers at 26°C with different relative humidities. CO concentrations between 3100 and 4700 ppm were measured in all containers. There were no notable differences between the wood pellet products or storage at different humidities. Emission of CO from wood pellets has already been described, but fatal accidents have previously been reported only in association with pellet transport on cargo ships or storage in silos. It is therefore a new finding that fatal accidents may also occur in the wood pellet storerooms of private households. We show that significant CO concentrations can build up even when these rooms are ventilated in accordance with the regulations and that such levels may cause the death of healthy persons, as described in the following. As the safety recommendations from the wood pellet industry are inadequate, we consider that further fatal accidents are likely to occur and recommend urgent revision of the safety regulations.

Keywords: © The Author 2012. Published by Oxford University Press on behalf of the British Occupational Hygiene SocietyThis ArticleAnn Occup Hyg (2012) 56 (7): 755-763. doi: 10.1093/annhyg/mes047 Current Issue
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Thermal Burden of N95 Filtering Facepiece Respirators

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Raymond Roberge*, Stacey Benson and Jung-Hyun Kim

The National Personal Protective Technology Laboratory, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Pittsburgh, PA, USA ?* Author to whom correspondence should be addressed. e-mail: dtn0{at}CDC.GOV Received August 4, 2011. Accepted October 13, 2011. Increased thermal perceptions that affect comfort are a leading reason for intolerance to wearing respiratory protective equipment. Despite their popularity and use for decades, relatively little is known about the thermal burden imposed by the use of N95 filtering facepiece respirators (FFR) at normal work rates. Twenty healthy subjects exercised at a low-moderate work rate for 1 and 2 h while wearing four models of N95 FFR (two with an exhalation valve) as core and skin temperatures were monitored wirelessly. N95 FFR use resulted in non-significant minimal increases in core temperature and uncovered facial skin (cheek) temperatures. Facial skin temperature under the FFR was significantly increased over baseline values (P

< 0.001). Wearing N95 FFR for up to 2 h at a low-moderate work rate does not impose a significant thermal burden on core temperature and uncovered facial skin temperature but significantly increases the temperature of the facial skin that is covered by the FFR. Perceptions of increased body heat when wearing N95 FFR under the test conditions are likely not due to effects on core temperature but may relate more to warming of the facial skin covered by the respirator and warming of the inspired air. Published by Oxford University Press 2012.This ArticleAnn Occup Hyg (2012) 56 (7): 808-814. doi: 10.1093/annhyg/mes001 First published online: January 31, 2012 Current Issue
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Assessment of Swine Worker Exposures to Dust and Endotoxin during Hog Load-Out and Power Washing

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Patrick O’shaughnessy*, Thomas Peters, Kelley Donham, Craig Taylor, Ralph Altmaier and Kevin Kelly

Department of Occupational and Environmental Health, The University of Iowa College of Public Health, 105 River Street, Iowa City, IA 52242, USA ?* Author to whom correspondence should be addressed. Tel: 319-335-4202; fax: 319-335-4225; e-mail: patrick-oshaughnessy{at}uiowa.edu Received December 7, 2011. Accepted January 9, 2012. Field measurements of personal and area dust and endotoxin concentrations were obtained while agricultural workers performed two work tasks that have been previously unreported: hog load-out and swine building power washing. Hog load-out involves moving hogs from their pens in finishing buildings into a truck for transport to a meat processor. High pressure power washing is conducted for sanitation purposes after a building has been emptied of hogs to remove surface and floor debris. This debri consists of feed, feces, and hog dander as dust or an encrusted form. The hog load-out process necessarily increases pig activity which is known to increase airborne dust concentrations. An unintended consequence of power washing is that the material covering surfaces is forcibly ejected into the atmosphere, creating the potential for a highly concentrated aerosol exposure to workers. The load-out process resulted in a median personal inhalable mass concentration of 7.14 mg m- 3 and median endotoxin concentration of 12?150 endotoxin units (EU) m- 3. When converted to an 8-h time-weighted average for a ‘total’ sampler, one of the 19 samples exceeded a regulatory limit of 15 mg m- 3. An impinger was used to sample power washing endotoxin concentrations, which resulted in a median personal concentration of 40?350 EU m- 3. These concentrations were among the highest found in the literature for any occupation. With the lack of engineering controls present to reduce airborne contaminant concentrations in swine buildings, either respirator use or a reduction in exposure time is recommended while performing these tasks.

© The Author 2012. Published by Oxford University Press on behalf of the British Occupational Hygiene SocietyThis ArticleAnn Occup Hyg (2012) 56 (7): 843-851. doi: 10.1093/annhyg/mes013 First published online: March 16, 2012 Current Issue
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Monitoring and Analysis of Solvent Emissions from Metal Cleaning Processes for Practical Process Improvement

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Emi Kikuchi*, Yasunori Kikuchi and Masahiko Hirao

Department of Chemical System Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8656 Tokyo, Japan?* Author to whom correspondence should be addressed. Tel: +81-3-5841-7227; fax: +81-3-5841-6876; e-mail: e-kikuchi{at}pse.t.u-tokyo.ac.jp Received September 12, 2011. Accepted November 8, 2011. Objectives: Industrial cleaning processes are a major source of emissions of chlorinated organic solvents in Japan. Solvent emission mechanisms from metal cleaning processes were analysed to support process improvement aimed at emission reductions.

Methods: The amounts of solvents directly emitted from a washing machine and solvents taken out by metal parts to be cleaned were measured in laboratory experiments using an industrial washing machine. Direct emissions to a local ventilation system and to the workplace were analysed, while several process conditions were changed. The drying rate of solvents on surfaces was analysed for seven metal parts to clarify the effects of their materials and shape. Results: The results for direct solvent emissions show that solvents emitted because of the movement of metal parts inside a washing machine can be mainly exhausted through a local ventilation system, while the operation of an ultrasonic device can increase solvent diffusion to the workplace. Lowering the cooling water temperature can be effective in avoiding such solvent diffusion to the workplace. The results also show that the heat capacity and shape complexity of metal parts can affect the drying rate of solvents on their surfaces. Conclusions: Analysis of the results shows the effectiveness of using a local ventilation system and cooling pipes in controlling solvent emissions for several work tasks. The minimum time required to dry all solvents on the surface of metal parts was also estimated. Analyses of the emission mechanisms in this study clarified the major factors in solvent emissions and the effectiveness of process modifications for emission reductions. The findings are applicable to practical process improvement aimed at emission reductions in cleaning sites. © The Author 2012. Published by Oxford University Press on behalf of the British Occupational Hygiene SocietyThis ArticleAnn Occup Hyg (2012) 56 (7): 829-842. doi: 10.1093/annhyg/mer115 First published online: December 19, 2011 Current Issue
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Occupational Exposure to Aromatic Hydrocarbons and Polycyclic Aromatic Hydrocarbons at a Coke Plant

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Grazyna Bieniek* and Agnieszka Lusiak

Department of Instrumental Analysis, Faculty of Pharmacy, Medical University of Silesia in Katowice, Jagiellonska 4, 41-200 Sosnowiec, Poland ?* Author to whom correspondence should be addressed. e-mail: gbieniek{at}sum.edu.pl Received September 21, 2011. Accepted January 10, 2012. Objectives: The objective of this study was to assess the external exposure to aromatic hydrocarbons (AHs) and polycyclic aromatic hydrocarbons (PAHs) of coke-oven workers and by-product workers at a coke plant in Poland.

Methods: The content of benzene, toluene, xylene, and naphthalene in a gaseous phase and the content of dibenzo[a,h]anthracene, benz[a]anthracene, anthracene, benzo[a]pyrene, benzo[b]fluoranthene, benzo[k]fluoranthene, benz[ghi]perylene, chrysene, and indeno[1,2,3-c,d]pyrene in a particulate phase of coke plant workers were measured in the workers mentioned above. A toxic equivalency factor BaPeq was used to estimate human health risk associated with respiratory exposure to PAHs. Results: Time-weighted values of the exposure to AHs in the coke plant were as follows: benzene (range 0.01–2.71 mg m-3), toluene (0.01–1.73 mg m-3), xylene (0.01–0.78 mg m-3), naphthalene (6.0–6079 µg m-3), and the concentrations of hydrocarbons did not exceed the exposure limits. The results for particle-bound PAHs were equal to 1.96 µg m-3 for B(a)P, 0.73 µg m-3 for DBA, 3.23 µg m-3 for BaA, 4.35 µg m-3 for BbF, 3.02 µg m-3 for BkF, 4.54 µg m-3 for IND, 4.32 µg m-3 for CHR, and 0.73 µg m-3 for Ant. The results of personal air measurements (median values of the sum of nine carcinogenic PAHs) were 2.115 µg m-3 (coke-oven workers, n = 207), 0.326 µg m-3 (coke by-product workers, n = 33), and 0.653 µg m-3 (total area workers, n = 38). The benzo[a]pyrene equivalent concentrations (BaPeq) of 10 PAHs were 1.33, 0.183, and 0.284 µg m-3, respectively. Conclusions: We found out that coke plant workers are simultaneously exposed to a mixture of aromatic and polycyclic hydrocarbons present in the breathing zone air. Exposure levels are significantly influenced by job categories. Coke by-product workers are significantly more exposed to benzene, toluene, and xylene and less to PAHs. Coke-oven workers are mainly exposed to PAHs. Coke-oven workplaces (top side, coke side, and push side) are characterized by higher carcinogenic risk than other coke plant workplaces. © The Author 2012. Published by Oxford University Press on behalf of the British Occupational Hygiene SocietyThis ArticleAnn Occup Hyg (2012) 56 (7): 796-807. doi: 10.1093/annhyg/mes016 First published online: April 26, 2012 Current Issue
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