Cerebrospinal Fluid Study Reveals Potential New Gene Associated With Alzheimer’s Disease

A genomic study of cerebrospinal fluid (CSF) has added a new gene to the list of potential genetic contributors to Alzheimer’s disease, a national research team led by Indiana University School of Medicine scientists has reported.

The research team conducted a genome-wide analysis of potential CSF biomarkers that could be used for early detection of Alzheimer’s disease, using samples from 374 participants in the national Alzheimer’s Disease Neuroimaging Initiative (ADNI).

“This study was one of the first genome-wide analyses of biomarkers in cerebrospinal fluid, which has direct access to the brain and allows you to look at biochemical features that might be more directly tied to the disease,” said Andrew J. Saykin, Psy.D., Raymond C. Beeler Professor of Radiology and Imaging Sciences and director of the IU Center for Neuroimaging. The study was reported in the online edition of Neurology, the journal of the American Academy of Neurology.

In the genome-wide association study, researchers looked for genetic variations that could be related to CSF levels of three proteins – beta amyloid, tau and phosphorylated tau – that are linked to damage seen in brains of Alzheimer’s patients.

The primary novel finding was that a gene known as enhancer of polycomb homolog 2 (EPC2) was associated with total levels of the tau protein in the cerebrospinal fluid. This gene, which has not previously surfaced in other studies looking for Alzheimer-related markers, has been associated with a gene deletion syndrome that includes mental retardation, short stature and epilepsy.

EPC2 is also involved in the formation of a DNA structure, heterochromatin, that plays a role in the activation and control of gene activity. That process, called epigenetics, refers to the alteration of gene expression by factors beyond the instructions in the DNA itself, including environmental factors.

“The association of CSF tau and the EPC2 gene suggests a possible epigenetic mechanism that warrants follow-up in other samples. These epigenetic processes, in which genome function can be modified through interacting with the internal or external environment, are suspected of playing a role in neurodegenerative diseases such as Alzheimer’s,” said Dr. Saykin, who leads the Alzheimer’s Disease Neuroimaging Initiative genetics component.

The co-first authors of the study were Sungeun Kim, Ph.D., assistant research professor of radiology and imaging sciences, and Shanker Swaminathan, Ph.D. candidate in medical and molecular genetics, at IU School of Medicine, which is located on the campus of Indiana University-Purdue University, Indianapolis. Other investigators from IU include Li Shen, Ph.D., assistant professor of radiology and imaging sciences, Shannon L. Risacher, Ph.D. candidate in medical neuroscience, Kwangsik Nho, Ph.D., post doctoral fellow and Tatiana Foroud, Ph.D., P. Michael Conneally Professor of Medical and Molecular Genetics and director of the Hereditary Genomics Division.

The research team also included collaborating scientists from the University of Pennsylvania School of Medicine; University of California, Irvine; The Translational Genomics Research Institute in Phoenix; Pfizer Inc.; University of California, San Diego; and the Mayo Clinic College of Medicine. Michael W. Weiner, MD, of the University of California, San Francisco and the Department of Veterans Affairs Medical Center, San Francisco, is the principal investigator of the ADNI.

The Alzheimer’s Disease Neuroimaging Initiative is funded by the National Institute on Aging (NIA), a component of the National Institutes of Health (NIH), with additional support from pharmaceutical and related industries and not-for-profit organizations including the Alzheimer’s Association. The initiative combines clinical, brain imaging (MRI and PET scans) and genetic data with other measurements including CSF and plasma to search for biomarkers that could be used for early diagnosis of Alzheimer’s disease and design of more efficient clinical trials.

Source:

IU School of Medicine

No-smoking Rules Not Common Enough For Asthmatic Children

Urban children with persistent asthma living in homes with smokers are 10 times less likely to be protected by a smoking ban in the home and car than asthmatic children living with no smokers, according to a new study (embargoed until 6 a.m. March 16) by researchers at the University of Rochester Medical Center.

The study, published in the March-April issue of Ambulatory Pediatrics, shows that the message has not reached every parent that any secondhand smoke exposure for children ??” especially those suffering from asthma ??” is detrimental to their health. Parents and caregivers may be trying to limit smoke exposure by smoking in a different room or by opening a window in the car, but these strategies aren’t very effective.

“Of course, the best case scenario is if the parents or guardians can quit smoking,” said lead author Jill Halterman, M.D., M.P.H., assistant professor at Golisano Children’s Hospital at Strong. “But that’s not always immediately possible. Another option is for parents to institute a “no-smoking” rule in the home and the car, and allow no exceptions to this rule. It is best if smokers always go outside to smoke, and this strategy may also help the parents to eventually quit.”

The study surveyed 231 parents of children with persistent and severe asthma at three Rochester pediatric practices. Almost half of the children lived with a smoker. Among all the families surveyed, only 64 percent had complete “no-smoking rules” for the home and car with no exceptions, and among the homes with smokers only 40 percent had such a rule. Children with severe asthma symptoms were no more likely to be protected by a no smoking rule than those with less severe symptoms.

Most caregivers surveyed said their health care providers asked them about smoke exposure in the home, but only 40 percent said they had been asked about exposure in the car ??” where concentration is higher than in the home ??” and few said they were offered resources to help them quit smoking.

“We, as health care providers, can do more to help parents understand better how to limit their children’s exposure to secondhand smoke. If parents are having trouble quitting, we can find them help. If caregivers want to limit their child’s exposure, we can talk about strategies to reducing exposure in the home and the car,” Halterman said.

Research for the study was funded by grants from Halcyon Hill Foundation and the Robert Wood Johnson Foundation’s Generalist Physician Faculty Scholars Program.

Contact: Heather Hare
heather_hareurmc.rochester
University of Rochester Medical Center

No-smoking Rules Not Common Enough For Asthmatic Children

Urban children with persistent asthma living in homes with smokers are 10 times less likely to be protected by a smoking ban in the home and car than asthmatic children living with no smokers, according to a new study (embargoed until 6 a.m. March 16) by researchers at the University of Rochester Medical Center.

The study, published in the March-April issue of Ambulatory Pediatrics, shows that the message has not reached every parent that any secondhand smoke exposure for children ??” especially those suffering from asthma ??” is detrimental to their health. Parents and caregivers may be trying to limit smoke exposure by smoking in a different room or by opening a window in the car, but these strategies aren’t very effective.

“Of course, the best case scenario is if the parents or guardians can quit smoking,” said lead author Jill Halterman, M.D., M.P.H., assistant professor at Golisano Children’s Hospital at Strong. “But that’s not always immediately possible. Another option is for parents to institute a “no-smoking” rule in the home and the car, and allow no exceptions to this rule. It is best if smokers always go outside to smoke, and this strategy may also help the parents to eventually quit.”

The study surveyed 231 parents of children with persistent and severe asthma at three Rochester pediatric practices. Almost half of the children lived with a smoker. Among all the families surveyed, only 64 percent had complete “no-smoking rules” for the home and car with no exceptions, and among the homes with smokers only 40 percent had such a rule. Children with severe asthma symptoms were no more likely to be protected by a no smoking rule than those with less severe symptoms.

Most caregivers surveyed said their health care providers asked them about smoke exposure in the home, but only 40 percent said they had been asked about exposure in the car ??” where concentration is higher than in the home ??” and few said they were offered resources to help them quit smoking.

“We, as health care providers, can do more to help parents understand better how to limit their children’s exposure to secondhand smoke. If parents are having trouble quitting, we can find them help. If caregivers want to limit their child’s exposure, we can talk about strategies to reducing exposure in the home and the car,” Halterman said.

Research for the study was funded by grants from Halcyon Hill Foundation and the Robert Wood Johnson Foundation’s Generalist Physician Faculty Scholars Program.

Contact: Heather Hare
heather_hareurmc.rochester
University of Rochester Medical Center

New Study Compares Avian Flu With A Notorious Killer From The Past

In the waning months of the First World War, a lethal virus known as the Spanish flu (influenza A, subtype H1N1), swept the United States, Europe and Asia in three convulsive waves. The year was 1918. The ensuing pandemic claimed up to 100 million victims, most of whom succumbed to severe respiratory complications associated with rapidly progressing pneumonia. Many died within days of the first symptoms.

In a new study, Carole Baskin, formerly assistant research professor at Arizona’s Biodesign Institute, currently with Science Foundation Arizona, and an interdisciplinary team of collaborators, compared the recent avian strain known in the scientific community as H5N1, with genetic ressortants of the 1918 virus – source of the most severe influenza pandemic in recorded history. The results, which appear in the latest issue of the Proceedings of the National Academy of Science, are sobering. H5N1 was found to replicate profusely within the first 24 hours, causing severe damage to respiratory tissues while sending the host’s innate immune response into a lethal overdrive, reminiscent of the trajectory of the original 1918 virus.

The threat of an avian flu pandemic hasn’t gone away and emergency preparedness efforts may be inadequate to deal with the scope of such a pandemic, were one to occur. “In order to come up with vaccines and therapies, you have to understand the disease,” Baskin stresses. “That’s why I think this type of pathogenesis study is so important.”

Although H5N1 is not readily communicable between humans, it has nevertheless killed over 400 people to date as a result of human-avian interactions, primarily in Vietnam, Thailand, China, Egypt and Indonesia, according to the World Health Organization. The mortality rate for those stricken with highly pathogenic avian influenza (HPAI) H5N1 is 63 percent. Should a series of modifications allow the virus to pass from person to person, the consequences for humankind could be catastrophic.

In the new study, Baskin and colleagues examine the host-pathogen responses to a common influenza virus and two ressortant strains of the 1918 H1N1 virus, each containing HA and NA – key surface antigens closely linked to the 1918 strain’s potent virulence. The effects of these strains on host tissues and gene expression was compared with those of a 2004 Vietnam isolate of the Highly Pathogenic Avian Influenza (HPAI) H5N1. In a non-human primate model of the disease, the avian virus was found to significantly outpace not only run-of-the-mill influenza but even the highly virulent 1918 ressortants, in terms of its relentless pathogenicity.

Ressortant viruses occur when different influenza subtypes or strains simultaneously infect the same host. A shuffling and exchange of genetic material between two or more such viruses can occur under these conditions, giving rise to new viral forms which share genetic characteristics with each parent strain but may also possess novel attributes, including heightened virulence. (Researchers borrow this ressortant technique from nature in order to create deactivated viral strains for use in yearly influenza vaccines.)

The perfect storm

Unlike typical seasonal flu which poses the greatest threat to juveniles, elderly and those with compromised immunity; the 1918 flu reserved the worst of its wrath for healthy young adults with robust immune systems. In the case of the avian H5N1 virus, statistics of human fatalities reveal a similar trend. In both cases, the highly pathogenic strains replicate rapidly and induce a massive transcription of genes associated with the innate immune response, the body’s first line of defense for combating viral challenges.

The group sought to compare the 1918 flu strain with H5N1 through a systems biology approach, pioneered by Dr. Baskin’s mentor, Michael G. Katze, Ph.D. at the University of Washington. Using this strategy, respiratory tissue was analyzed with high-throughput technologies of functional genomics, proteomics and transcriptomics to measure gene expression and regulation in fine-grained detail. Such techniques have opened a new window onto the genetic underpinnings of infectious disease.

A large number of these genes code for cytokines and chemokines – immunomodulating agents which include interleukins, interferons and other factors involved with the host’s innate inflammatory response to infection. The result of this overwhelming transcription induction, shown graphically in figure 1, is a “cytokine storm” often leading to acute respiratory distress syndrome in the viral host, while proving entirely ineffective in blunting prodigious replication of the H5N1 virus.

Respiratory tissues sampled on days 1, 2 4 and 7 post-infection were subjected to pathological, viral and microarray analysis. Although the 1918 ressortant strains were found to be highly virulent, they were outmatched by H5N1′s rapid onset, overwhelming transcription induction of cytokine and chemokine genes and headlong, sustained viral replication with wider distribution in the lungs. As Baskin notes, referring to the group’s measurements of Tissue Culture Infectious Dose or TCID over the course of H5N1′s infection, “the take home message is that for H5N1 there is hardly any viable tissue left to infect by day 7, yet there is still very strong viral replication.” Further, despite the broad and sustained upregulation of inflammatory genes, they were of no use in limiting the H5N1 infection.

While the new study found that the 1918 ressortant strains and H5N1 each attacked specialized respiratory cells called pneumocytes, the 1918 chimaraes showed preference for so-called type I pneumocytes, responsible for air exchange in the lungs. In contrast, H5N1 characteristically infects the more numerous type II pneumocytes, a critical distinction, as Dr. Baskin explains: “Basically, when you injure type II pneumocytes as opposed to type I, you impair the ability of lung tissue to repair itself. In addition, when type II are infected, they produce chemokines and cytokines, which contribute directly to the overall inflammatory response.” In this way, H5N1 delivers a devastating one-two punch to the host’s ability to recover from the infectious siege. The researchers observed that within 24 hours, H5N1 had caused severe bronchiolar and alveolar lesions in lung tissue.

H5N1′s penchant for infecting type II rather than type I pneumocytes is due to the receptor preference found in avian viruses as opposed to human viruses, (including the 1918 ressortants used in the study), which primarily attack type I cells in the lung.

H5N1′s attack on type II pneumocytes was sustained, from the point of initial infection through the 7 days of the study, as seen in figure 2. Examination of lung tissue showed widespread, prolonged replication of viruses and associated tissue destruction. “The fact that the infection of type II pneumocytes was so protracted directly contributed to the damage we saw,” notes Baskin.

Another aspect of lung function debilitated by H5N1 involves the loss of surfactants, produced by type II pneumocytes and responsible for pliability of lung tissue. Without such surfactants, breathing becomes impossible.

The final act

A further critical finding of the study is that H5N1, having swamped the innate immune response, turns its attention next to the body’s adaptive response, specifically, dendritic cells whose job it is to phagocytize protein components from the virus and present these to T cells, either locally or at the lymph nodes that drain the lungs. Normally, through this process, specific antibodies are then produced to combat the viral infection. Tissue sampling for the H5N1 found a notable absence of these dendritic cells, suggesting they were destroyed during the infection process, which would point to H5N1′s ability not only to disable the present infection but to block the body’s ability to build immunity against later infection by the same type of virus.

Baskin points out that the new research presented to PNAS has been several years in the making, supported in part by her career award from the National Institute of Infectious Disease and by a large program project grant from the same. “The study was done at Battelle Biomedical Research Center, which had the required containment level, ABSL-3ag. These facilities are very rare and in great demand.” Referring to the challenges of such complicated, long distance collaborations, she insists “you have to have just the right people to make something like this happen.”

Continuing studies of host-pathogen responses at the tissue, cellular and molecular level may provide the understanding needed to stave off a viral pandemic, whether from H5N1 or some other emergent strain. Time is critical. Currently, the anti-viral known as Tamiflu, taken before or immediately after infection, offers the only known protection against highly pathogenic avian influenza and the first Tamiflu-resistant strains have already emerged.

In terms of how many modifications would be required for H5N1 to become a highly contagious human virus, Baskin expresses concern: “There have been some estimations and it’s not a lot,” she notes. “That’s the short and simple answer.”

Carole Baskin, formerly an assistant research professor at Arizona’s Biodesign Institute, now a Program Director at Science Foundation Arizona, worked with a multidisciplinary team from Washington University, the CDC in Atlanta, Colorado State University, Battelle Biomedical Research Center in West Jefferson, Ohio, and Mount Sinai School of Medicine in New York. The research was supported by Battelle Internal Research and Development funds, and by several grants from the National Institute of Health.

Richard Harth
Science Writer
The Biodesign Institute at
Arizona State University

About the Biodesign Institute at ASU

The Biodesign Institute at Arizona State University pursues research to create personalized medical diagnostics and treatments, outpace infectious disease, clean the environment, develop alternative energy sources, and secure a safer world. Using a team approach that fuses the biosciences with nanoscale engineering and advanced computing, the Biodesign Institute collaborates with academic, industrial and governmental organizations globally to accelerate these discoveries to market. For more information, go to: biodesign.asu

Source: Joe Caspermeyer

Arizona State University

View drug information on Tamiflu capsule.

Dangers Of Global Food Security

The global food security crisis endangers the lives of millions of people, particularly the world’s poorest who live in countries already suffering from acute and chronic malnutrition.

Multiple factors are behind the crisis, including:

– rapidly increasing energy prices
– lack of agricultural sector investment
– rapidly rising demand for food arising from economic growth and higher incomes
– trade distorting subsidies
– recurrent bad weather and environmental degradation
– subsidized production of bio-fuels that substitute food production
– imposition of export restrictions leading to hoarding and panic buying

The health implications are immense, particularly in the 21 countries that WHO says suffer from acute or chronic malnutrition.

To respond to the health threats, WHO provides guidance to the UN Secretary-General’s High Level Task-Force on the Global Food Security Crisis. The Task-Force was formed in April 2008 to create and coordinate the implementation of a prioritized action plan.

WHO’s fundamental considerations are to:

– Underscore the human dimension of the crisis.
– Monitor its impact on nutrition, health and poverty, plus its effect on the Millennium Development Goals.
– Provide sound information and analyses to target the most vulnerable groups.
The consequences of inaction will be enormous for public health, and include:

– Increased malnutrition, child and maternal mortality and morbidity, and communicable diseases.
– An inability for the poorest to afford healthy food, forcing them to buy low-quality products, negatively changing dietary patterns, and increasing the burden of noncommunicable diseases.
– Less money to spend on health services because of higher food bills. This will affect greatly people living with HIV/AIDS and tuberculosis in particular.
– Likely impaired mental development, diminished learning ability, reduced work productivity, and increased prevalence of chronic disease.
– Likely increase in wasting (low weight for height) among young children, plus anaemia and other micronutrient deficiency conditions, especially among women and children.
– A delay in attaining health and nutrition-related Millennium Development Goals (1, 4, 5 and 6).

- WHO and the Global Food Crisis: The Health and Nutrition Dimensions

World Health Organization (WHO)
who.int

Smoking Ban In Enclosed Public Places In England From July 1

If you want to have a cigarette in England after July 1, make sure it is not in an enclosed public place – otherwise you will be breaking the law. As of July 1, it will be illegal to smoke in enclosed public places – offices, pubs, bars, factories and public buildings. You can still smoke outdoors and in your home.

This new law is aimed at protecting the health of the non-smoker, who allegedly risks his/her health by breathing secondhand smoke (passive smoking). Some government ministers have said they hope this new legislation will encourage many smokers to quit.

In England, just over 100,000 people die prematurely as a result of smoking. Cancer charities say countries which have imposed similar legislation have witnessed a significant drop in the number of smokers.

Not everyone is happy about this new law. Some argue that people’s civil liberties are being undermined. Others quote health figures, for example, childhood asthma – there are many more children with asthma today than there were 30 years ago, however, 30 years ago there were nearly twice as many smokers in England.

Although the smoking ban is generally popular throughout the country, some pubgoers are horrified at the prospect of not being able to light up at their ‘local’. Many say that it is more a case of victimization than common sense; why not insist on first-class ventilation systems in pubs, or allow publicans to decide for themselves whether smoking should be allowed. There are scores of non-smoking pubs throughout the country anyway, people say.

As the date looms, thousands of pubs throughout England are scrambling to have their garden smoking shack ready by Sunday (where smokers may retire to for a quick puff).

Whether or not this spells the beginning of the end of the English pub remains to be seen.

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BLF Supports Fresh Calls To Tackle Air Pollution

The British Lung Foundation (BLF) welcomes the Environmental Audit Committee report, out today, which raises awareness of the importance of tackling air pollution in the UK.

The report says that more could be done to prevent the early deaths of up to 50,000 people each year hastened by air pollution. Furthermore, it states that failure to reduce pollution had put an “enormous” cost on the NHS and could cost millions in EU fines.

In the recent Manifesto, the British Lung Foundation calls for action to be taken to reduce the harmful emissions and improve the UK’s air quality. The report is now a step forward in highlighting the dangers of air pollution for people with lung conditions such as asthma or chronic obstructive pulmonary disease (COPD), an umbrella term for emphysema and chronic bronchitis.

Research suggests that air pollution contributes to the development of COPD and it may also play a significant role in causing other lung problems. It is estimated that 38% of the population are at risk from suffering adverse health effects from exposure to air pollution.[1]

The Environmental Audit Committee report says that the most likely victims of air pollution are those who already have a respiratory illness such as asthma or COPD. It adds ‘poor air quality reduces the life expectancy of everyone by an average of 7-8 months and up to 50,000 people a year may die prematurely; however, in pollution hotspots the life expectancy falls by 8-9 years’.

Dame Helena Shovelton, Chief Executive of the British Lung Foundation says: “We welcome this report which raises the awareness of the dangerous impact air pollution has. Air pollution has been a longstanding problem for the 1 in 7 people living with a lung condition, exacerbating and possibly even causing COPD (chronic obstructive pulmonary disease), lung cancer and other lung conditions. The British Lung Foundation is calling for more action to improve air quality and to implement initiatives that will lower harmful emissions and improve air quality.”

Notes

1.The British Lung Foundation is the only UK charity working for everyone affected by lung disease. The charity focuses its resources on providing support for people affected by lung disease today; and works in a variety of ways (including funding world-class research) to bring about positive change, to improve treatment, care and support for people affected by lung disease in the future.

2.It provides information via the website lunguk.

3.One person in every seven in the UK is affected by lung disease – this equates to approximately 8 million people

4.Respiratory disease is the second biggest killer in the UK (117,456 deaths in 2004) after all non-respiratory cancers combined which only account for slightly more deaths (122,500 deaths in UK in 2004)

5.Respiratory disease now kills one in five people in the UK

6.The UK’s death rate from respiratory disease is almost double the European average and the 6th highest in Europe

7.Respiratory disease is the most commonly reported long term illness in children and the third most commonly reported in adults. One in 7 boys and 1 in 8 girls aged 2 – 15 report having long term respiratory illness in England

Source
British Lung Foundation

Warning To Hospitals That Harmful Bacteria And Yeast Transmitted By Wet Breathing System Filters

Doctors have highlighted potential problems with the breathing system filters used in anaesthesia, including intensive care units, after demonstrating that they don’t provide protection from harmful bacteria and yeast when they become wet.

Research in the July issue of Anaesthesia has shown that when they were wet, six commonly available filters allowed substantial passage of Candida albicans (a yeast infection linked to a range of chronic illnesses) and coagulase-negative staphylococci (a common hospital-acquired bacterial infection).

“Breathing systems filters are commonly used to reduce the passage of drug-resistant respiratory infections, but current international standards only require them to prevent bacterial transfer when dry” explains Dr David H T Scott, Consultant Cardiothoracic Anaesthetist and Intensive Care Specialist at the Royal Infirmary of Edinburgh, UK.

“The current ISO standard does not replicate the circumstances in clinical practice, where filters get wet with condensed water and airway secretions. We believe that our study shows that commonly available breathing filters cannot be relied upon to prevent bacterial transfer.”

The researchers used six breathing system filters available in hospitals in Edinburgh:
three hydrophobic pleated filters designed for use as heat and moisture exchanging filters (PhobA, PhobB and PhobC)
one hydrophilic unpleated heat and moisture exchanging filter (PhilD)
two simple filters (FilE and FilF).

These were tested using suspensions of two microbes:
Candida albicans, because of its large cell unit size (12 micrometres)
coagulase staphylococcus, because it is a common organism and its cell unit size (one micrometre) is representative of a large range of potential pathogens.

“All the filters tested permitted substantial passage of bacteria and yeast” says Dr Scott. “Even in a one microlitre loop of filtered solution, the number of colony-forming units transmitted through the filters was too large to quantify.

“In most cases the bacterial cultures from filters could not be distinguished from the samples created using unfiltered bacteria.”

The authors conclude that their study shows that viable organisms pass across all types of breathing systems filters tested under conditions that may occur in clinical practice.

“In particular, simple filters required very little pressure to permit passage of microorganisms” says Dr Scott. “Although our experiment involved saturating the filters with test fluid, it provides important proof of the principle: organisms may traverse some filters very easily and even large yeasts like Candida albicans survive the passage.”

The authors are keen to point out that, although they tested six commonly available filters, the structure of gas filters suggest that products made by other manufacturers are just as likely to show the problem.

“It is important that clinicians are aware of the potential for microorganisms to pass through wet filters” says Dr Scott.

“Further studies are also required to investigate the potential for cross-contamination between patients if filters are used as the sole method of infection control in breathing systems for anaesthesia and intensive care.

“It should be pointed out that a microbe would have to make a long journey to infect a new patient by this route. Although a search of previous studies has revealed no evidence of cross-contamination relating to filter use, it could be theoretically possible in certain conditions.”

Notes:


Passage of pathogenic microorganisms through breathing system filters used in anaesthesia and intensive care. Scott et al. Anaesthesia. 65, pp 670-673. (July 2010). DOI: 10.1111/j.1365-2044.2010.06327.x

Source:
Annette Whibley

Wiley-Blackwell

Humira(reg) (Adalimumab) Improved Symptoms Of Psoriatic Arthritis And Ankylosing Spondylitis

Preliminary data from two studies showing encouraging results in treating psoriatic arthritis and ankylosing spondylitis with HUMIRA(reg) (adalimumab) 40 mg every other week were presented today at the European League Against Rheumatism (EULAR) annual congress in Berlin. Patients with psoriatic arthritis responded to HUMIRA treatment as early as two weeks after the initial dose showing significant improvement in both the signs and symptoms of the joint disease and skin manifestations with continued improvements at 12 weeks.

Analysis of a separate 12-week study shows that HUMIRA significantly improves spinal symptoms in patients with active ankylosing spondylitis after only one dose.

“The findings of these two studies are significant because they validate our research to assess HUMIRA’s potential to treat other autoimmune diseases in addition to rheumatoid arthritis,” said James B. Lefkowith, M.D., divisional vice president, development, Abbott Immunology.

HUMIRA PROVIDED JOINT AND SKIN IMPROVEMENT IN PSORIATIC ARTHRITIS

Fifteen patients with active psoriatic arthritis were treated with HUMIRA 40 mg every other week, in this open-label trial, and observed over a 12-week period to evaluate the potential therapeutic effects of the treatment. After two weeks, significant improvements were seen in the signs and symptoms of the joint disease and skin manifestations associated with disease. Further improvements in the skin and joint disease were evident at 12 weeks.

Forty-two percent of patients treated with HUMIRA experienced an ACR 20 response after only one dose. ACR (American College of Rheumatology) 20, 50 and 70 criteria represent percent improvement in tender and swollen joint counts and other relevant clinical measures. Also after two weeks, 77 percent of patients experienced at least 25 percent improvement in health-related quality of life as measured by the Health Assessment Questionnaire (HAQ) disability index, which is designed to capture patients’ assessment of activities of daily living such as grooming, dressing and walking. Health-related quality of life questionnaires are used to measure the impact of chronic illness on a patient’s life.

Further improvement was seen at 12 weeks in both the arthritic symptoms and in health-related quality of life. Sixty-six percent of patients achieved an ACR 20 response and approximately 30 percent attained ACR 50. The HAQ disability index also showed further improvement at week 12 compared to week two.

Substantial improvements also were evident in the skin disease of these patients. Target lesion scores, an evaluation of the severity of a single psoriasis lesion, improved by nearly 30 percent after one dose. After 12 weeks, the target lesion score improved by more than 70 percent.

“The initial results and analysis of this study show that HUMIRA provided significant benefit to many patients with psoriatic arthritis shortly after the first dose,” said Christopher T. Ritchlin, M.D., associate professor and lead investigator, University of Rochester, Rochester, New York. “While more research is necessary, these early findings are promising and support HUMIRA’s potential as a treatment for psoriatic arthritis.”

ABOUT PSORIATIC ARTHRITIS

Psoriatic arthritis is an inflammatory arthritis that is associated with the skin condition psoriasis. It causes inflammation and stiffness in and around the joints, including the knees, wrists, ankles, lower back and neck. Psoriatic arthritis may stem from an autoimmune disorder in which a human protein, tumor necrosis factor-alpha (TNF-???), accumulates in the joints and initiates an inflammatory response that causes swelling and pain.

If left untreated, psoriatic arthritis can be a progressively disabling disease. Epidemiological studies indicate that psoriatic arthritis affects as many as 30 percent of people who have psoriasis, a non-contagious, chronic skin disease characterized by red plaques covered with white scales. Common symptoms of psoriatic arthritis include varying degrees of psoriasis activity along with stiffness, pain, swelling and tenderness of the joints that can lead to a reduced range of motion and potential severe joint destruction.

HUMIRA IMPROVED SYMPTOMS OF ACTIVE ANKYLOSING SPONDYLITIS

To examine the potential therapeutic effects of HUMIRA in patients with non-steroidal anti-inflammatory drug (NSAID)-refractory ankylosing spondylitis (i.e. patients not readily responding to NSAID therapy), researchers studied 10 patients over a 12-week period that received HUMIRA 40 mg every other week. In this open label study, all 10 patients suffered from spinal pain.

HUMIRA treatment induced a positive response in patients after the first dose, with further improvement at the end of the initial 12-week therapy, as measured by Assessment of Ankylosing Spondylitis (ASAS) criteria. ASAS evaluates four primary categories: function, pain, patient’s global assessment and inflammation. Scores of ASAS20, ASAS40 and ASAS70 indicate corresponding symptom improvement percentages in at least three of the evaluation categories with no worsening in the remaining category.

The majority of patients in the trial experienced improvement in their symptoms with 70 percent achieving a score of ASAS20, 50 percent reached ASAS40 and 20 percent attained ASAS70.

Also at week 12, 50 percent of the patients experienced 50 percent or greater improvement in scores according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a patient-assessed composite index of disease activity measuring pain, stiffness and fatigue.

HUMIRA was well tolerated by patients in the study and no serious infections occurred during the study.

ABOUT ANKYLOSING SPONDYLITIS

Ankylosing spondylitis (AS), or arthritis of the spine, is thought to be an autoimmune disorder in which a human protein has been suggested to play a role in the disease development. As one of the many forms of inflammatory arthritis known as spondyloarthropathies, AS is a chronic disease that primarily affects the spine but can also affect other joints and ligaments, resulting in severe joint and back stiffness and deformity over time.

It is estimated that between 350,000 and one million people in the United States are affected by AS or a related disease and nearly three million in the European community.

Spondyloarthropathies are arthritic in nature, but unlike many other rheumatic conditions, they affect young adults and commonly begin before the age of 35.

ABOUT HUMIRA

HUMIRA is the first human monoclonal antibody available in Europe for RA, and the first tumor necrosis factor alpha (TNF-B) antagonist approved in Europe with an indication for use with methotrexate or as monotherapy. HUMIRA resembles antibodies normally found in the body. It works by blocking TNF-B, a protein that plays a central role in the inflammatory responses of autoimmune diseases such as RA.

Available in many countries, HUMIRA is indicated for the treatment of moderate to severe, active RA in adult patients when the response to disease modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate.

To ensure maximum efficacy, HUMIRA is given in combination with methotrexate. In Europe, HUMIRA can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. The European Medicines Evaluation Agency (EMEA) issued a positive opinion in April to authorize a label extension for HUMIRA for use in the treatment of adult RA patients for reducing the rate of progression of joint damage and to improve physical function. Such authorizations generally occur approximately 90 days after the issuance of the EMEA opinion.

Abbott received a positive opinion from the EMEA in May 2003 for the treatment of adult RA and was granted European Union approval to market HUMIRA in September 2003. HUMIRA received approval from the U.S. Food and Drug Administration on December 31, 2002. To date, HUMIRA has been approved in 41 countries and launched in 26.

The recommended dose of HUMIRA is 40 mg every other week by subcutaneous injection (a shot beneath the skin). Abbott offers HUMIRA in specially designed pre-filled syringes so patients do not have to mix and measure the medicine or leave their homes for treatment. The pre-filled syringe features handles and a plunger head designed for use by patients whose hands have been affected by their RA.

At the present time, HUMIRA has not received regulatory approval for the treatment of psoriatic arthritis or AS. Clinical trials are currently underway in autoimmune diseases.

IMPORTANT SAFETY INFORMATION

Common adverse events (>1/100 and 1/10 patients.

Patients must be monitored closely for infections, including tuberculosis (TB), before, during and after treatment with HUMIRA. Treatment should not be initiated in patients with active infections until infections are controlled. Patients who develop new infections while using HUMIRA should be monitored closely. HUMIRA should not be used by patients with active TB or other severe infections such as sepsis and opportunistic infections. HUMIRA should be discontinued if a patient develops a new serious infection until infections are controlled. Physicians should exercise caution when considering use of HUMIRA in patients with a history of recurring infection or with underlying conditions that may predispose patients to infections.

TNF-antagonists, including HUMIRA, have been associated in rare cases with exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Prescribers should exercise caution in considering the use of HUMIRA in patients with pre-existing or recent-onset central nervous system demyelinating disorders.

HUMIRA should be used with caution in patients with mild heart failure, and is contraindicated in patients with moderate or severe heart failure. HUMIRA must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.

About Abbott

Abbott Laboratories is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs more than 55,000 people and markets its products in more than 130 countries.

More information about Abbott Immunology is available at abbottimmunology/.

View drug information on Humira.

Journal Of Clinical Investigation Online Early Table Of Contents: Sept. 11, 2008

PULMONARY: Resolving acute lung injury with an agonist

Individuals with a number of clinical conditions, including pneumonia, and those treated by mechanical ventilation for a prolonged period of time are at risk of acute lung injury, a life-threatening disorder for which there is no treatment. It is hoped that understanding the natural processes by which acute lung injury spontaneously resolves in some individuals might provide new therapeutic targets. Thus, Holger Eltzschig and colleagues, at the University of Colorado Health Sciences Center, Denver, suggest that their observation in mice with ventilator-induced lung injury (VILI) implicate the protein A2BAR as a potential therapeutic target for acute lung injury.

In the study, mice lacking A2BAR were found to have reduced survival time and more severe VILI, when compared with normal mice. Consistent with this, normal mice treated with an A2BAR antagonist exhibited more severe lung damage than untreated mice, whereas an A2BAR agonist attenuated the severity of VILI. Further analysis revealed that one way in which the A2BAR agonists helped was by enhancing the clearance of fluid in the lungs (i.e., they helped dry out the lungs). These data indicate that agonists of A2BAR are likely to be part of the natural mechanism by which acute lung injury spontaneously resolves and might make good therapeutics.

TITLE: A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice

AUTHOR CONTACT:
Holger K. Eltzschig,
University of Colorado Health Sciences Center, Denver, Colorado, USA.

View the PDF of this article at: https://the-jci/article.php?id=34203

IMMUNOLOGY: New way for immune cells to enhance clearance of bacteria

Oliver S?¶hnlein and colleagues, at the Karolinska Institutet, Sweden, have identified a new function for a number of proteins secreted by human immune cells known as neutrophils or PMNs: they enhance the uptake of bacteria by other immune cells (known as macrophages) that are capable of destroying the microbes.

In the study, proteins secreted by human PMNs, specifically HBP and HNP1-3, were found to enhance the in vitro ability of human and mouse macrophages to take up bacteria coated in the immune molecule IgG. Mechanistically, HBP and HNP1-3 activated the macrophages to secrete soluble factors that, in turn, induced the macrophages to express proteins to which IgG can bind (CD32 and CD64). The authors therefore suggest that HBP and HNP1-3 secreted by PMNs have a role in clearing bacterial infections.

TITLE: Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages

AUTHOR CONTACT:
Oliver S?¶hnlein
Karolinska Institutet, Stockholm, Sweden.

View the PDF of this article at: https://the-jci/article.php?id=35740

Source: Karen Honey

Journal of Clinical Investigation