Unique pattern of gene expression can indicate acetaminophen overdose

Contact: Robin Mackar
rmackar@niehs.nih.gov
919-541-0073
NIH/National Institute of Environmental Health Sciences

May lead to new tool for physicians

In a new study, researchers found they could detect toxic levels of acetaminophen in laboratory animals by analyzing gene expression in the blood. This study by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health, could be a first step in developing accurate new tools to detect acetaminophen overdose in humans. Overdose of acetaminophen, the active ingredient in many over-the-counter pain relievers, is a leading cause of liver failure in the United States and is often difficult to diagnose. An estimated 50,000 people seek emergency room treatment for acetaminophen overdose each year.

The research published online this week in the Proceedings of the National Academy of Sciences shows that gene expression data from blood cells can provide valuable information about acetaminophen levels well before liver damage can be detected by other methods, including serum markers and liver biopsies.

“In time, this approach could give physicians a powerful new genomics tool to help patients who cannot estimate how much acetaminophen they consumed. Early detection of acetaminophen overdoes can be helpful in preventing or treating resulting liver damage,” said Richard S. Paules, Ph.D., principal investigator and director, Microarray Core Facility at NIEHS and senior author on the new paper.

The researchers would like to build on this body of research to develop a simple procedure that clinicians could use in the emergency room to estimate the level of acetaminophen exposure and the potential damage to the liver. This would be especially beneficial for patients such as the elderly, suicidal, semi-comatose who are unable to provide an accurate estimate.

To carry out their study, the researchers developed and then analyzed gene expression signatures — patterns of gene activity —in rats exposed to various doses of acetaminophen. Using microarrays, or tools that allow scientists to see how differences in gene expression are linked to specific diseases, the researchers were able to determine which genes were turned on or turned off in response to the different levels of acetaminophen. Once they selected the gene sets, they tested them for accuracy, and found the signature gene lists were able to predict exposure to toxic versus nontoxic doses with very high accuracy (88.9-95.8 percent), while the more traditional predictors, of clinical chemistry, hematology and pathology were approximately 65 to 80 percent accurate.

“Although it was not the main focus of our study, we wanted to see how applicable this gene expression profiling of blood cells was to humans,” said Raymond W. Tennant, Ph.D., in the NIEHS Laboratory of Molecular Toxicology, and a co-author on the study.

The NIEHS researchers compared the animal data with data from RNA from blood drawn from individuals who had been admitted to the University of North Carolina emergency room for acetaminophen overdose intoxication. When they compared the toxic blood samples to the samples from normal healthy volunteers they saw a striking difference.

“Although there are already some good tools available to emergency room physicians to detect liver injury, additional information concerning the level of exposures and/or the degree of liver injury could significantly help us in treating acetaminophen overdose patients,” said Paul Watkins, M.D., Director, General Clinical Research Center at the University of North Carolina, Chapel Hill and co-author on the paper.

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The National Institute of Environmental Health Sciences (NIEHS), a component of the National Institutes of Health, supports research to understand the effects of the environment on human health. For more information on environmental health topics, please visit our website at http://www.niehs.nih.gov/.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Reference: Bushel PR, Heinloth AN, Li J, Huang L, Chou JW, Boorman GA, Malarkey DE, Houle CD, Ward SW, Wilson RE, Fannin RD, Russo MW, Watkins PB, Tennant RW, and Paules RS. Blood gene expression signatures predict exposure levels. Proceedings of the National Academy of Science DOI 10.1073 PNAS.0706987104 (2007).

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Prevalence of Interpersonal Abuse in Primary Care Patients Prescribed Opioids for Chronic Pain.

Balousek S, Plane MB, Fleming M.

Department of Family Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

BACKGROUND: Interpersonal abuse is associated with clinical problems including chronic pain disorders. OBJECTIVES: The objective of this study is to describe 30-day and lifetime prevalence of emotional, physical, and sexual abuse found in men and women prescribed opioids for chronic pain.

DESIGN: Cross-sectional interview is the design of this study.

PARTICIPANTS: Patients, 1,009, currently prescribed opioids for chronic noncancer pain. They were recruited from the practices of 235 Family Physicians and Internists in Wisconsin. The most common pain diagnoses were arthritis, low back pain, headache, and fibromyalgia/myofascial pain.

MEASUREMENT: Data for this secondary analysis on rates of interpersonal abuse were based on 3 questions from the Addiction Severity Index (ASI) regarding 30-day and lifetime emotional, physical, and sexual abuse.

RESULTS: Forty-seven percent of women and 22% of men reported a history of lifetime physical abuse. Thirty -five percent of women and 10% of men reported lifetime sexual abuse. Binary logistic regression identified the following variables associated with lifetime physical abuse: female gender (RR 2.81, CI 2.01-3.94), age 31-50 (RR1.77, CI 1.30-2.41), Caucasian (RR1.67, CI 1.19-2.35), increased psychiatric symptoms as measured by the ASI (RR 2.14, CI 1.56-2.94), and lifetime suicide attempts (RR 3.98, CI 2.76-5.74).
CONCLUSIONS: This study reports prevalence of abuse in both men and women prescribed opioids for chronic pain in primary care settings. Subjects who report experiencing interpersonal abuse also report significantly higher rates of suicide attempts and score higher on the ASI psychiatric scale. Screening patients taking opioids for chronic pain for interpersonal abuse may lead to a better understanding of contributors to their physical and mental health.

PMID: 17641933 [PubMed - as supplied by publisher]

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SOUNDING OFF ABOUT FIBROMYALGIA AWARENESS WEEK

By Jeanne Hambleton© UK Fibromite

I know I am always going on about raising awareness and fibromyalgia and this is especially important as far as the UK Government is concerned. Although we have E Petitions allegedly for the eyes of the Prime Minister, asking for support for various aspects of fibromyalgia, I have my doubts as to whether these will actually achieved any funding for research or recognition for FM – oh me of little faith.

Two of the 4 E Petitions about fibromyalgia on the No.10 Downing Street website will end this month (August) and as a supporter I am hoping to receive comments from the No.10 Downing Street web team (almost certainly not the Prime Minister). I feel sure the Prime Minister does not have time to read all the E Petitions – too busy with his politics. I almost have the impression the E Petitions were designed to save the postman delivering hundred and hundreds of letters which someone has to open and read, although rumour has it the idea of E Petitions was thought to be a bad idea.

As a matter of interest my new E Petition is to help replace those that are about to expire and can be found at the following website. It only takes a minute to do and you will feel go you have supported us. PLEASE would you please sign? I need 1000 signatures before it will be considered – 2000 would be nice. Tell your friends and family PLEASE. I am not on commission!

http://petitions.pm.gov.uk/FIBROFUNDING/

But my reason for writing is other ways to raising awareness during Fibromyalgia Awareness Week.

For us here in the UK and possibly the world over, the 8th to 15th September is Fibromyalgia Awareness Week. We do still of course have another annual event on 12th May – World Fibromyalgia Awareness Day. If you did nothing on that day to further the cause, now is your big chance.

Yes you have guessed it. I am going to talk about doing your bit for this FM Week. Raising funds would be a plus but raising awareness is far more important. Not sure about you, but I am pig sick of people looking at me and saying, “Fibro what?” If you listen carefully you can hear them thinking, “Poor girl – I wonder how long she has to live?”

If you are going to dismiss that thought be sure to tell them, we may not die from FM but as sure as eggs are eggs we will live with the pain for the rest of our lives or until someone finds a cure. (That is why you are signing the E Petition!)

What can you do? I have made several suggestions below with varying amounts of effort, so no excuses please.

NOT TOO HARD WITH FAMILY HELP
Find everything you have in your home that refers to fibromyalgia and invite your friends and neighbours to a need-to-know coffee morning, or afternoon tea and cake (if you don’t do mornings!) You can talk about each item connected with FM, or ask how the last 10 years has been for each of your visitors. When it is your turn you can recall what you used to do and how disabled you are now. Remind them it is an invisible disability and although you look so well you feel so awful.
Keep it bright and light with a few funny fibro stories. This event could even provide you with a few fit helpers for the future if you stage a fund raising event for FM to help your local Support Group.

ARMCHAIR EFFORT
If life is a struggle and a coffee morning is all too much, you could start your own letter writing campaign. Here in the UK you could write to your MP or in the States try your Senator? The MP’s address will be in your local telephone book. If you cannot find it ring the local paper. If you are feeling inspired you could write to the Prime Minister himself – Gordon Brown PM, 10, Downing Street, London, SW1A2AA, or email his assistant james.bowler@hm-treasury.gsi.gov.uk. David Cameron can be reached at camerond@parliament.uk. I am guessing here but I would think that Sir Menzies Campbell could be reached using campbellm@parliament.uk

The mail address of most MPs is their surname followed by the initial and the address – for example the Health Minister Alan Johnson MP – his address is johnsona@parliament.uk.

If you are using snail mail send your letter to your MP at House of Commons, London, SW1A 0AA

For information about websites, biographies and email addresses search for your MP in alphabetical order at http://www.parliament.uk/directories/directories.cfm

If you do not know who your MP is try http://www.theyworkforyou.com/ and type on your postcode. This will produce a message box, so have our message ready to cut and pate into the box.

If you think you have written a good letter to the PM, the Health Minister and your MP about your FM appealing for Government support for research to find a cure, and speed up diagnosis, including details of your life as a person with an invisible disability – the symptoms – pain 24/7, chronic fatigue, sleeplessness, cognitive problems, IBS, RLS and all the other nasties – send a copy to the Editor of your local paper. Ask him to print it with the readers’ letters, adding your own comments about what you hope the PM will agree. It is a good idea to use bullet points for the symptoms (easier to read).

Now you are on roll! Why not send a copy to your local radio station and the regional TV station? You never know they just might wonder – like everyone else – exactly what fibromyalgia means.

GOING OUT TO THE PUBLIC
If you access to lots of fibromyalgia literature you could ask your local superstore manager if you can stand near the entrance one busy afternoon and hand out literature. If you have friends you could have a table and chairs with fibromites who can talk about the syndrome and maybe encourage anyone interested to join the Group.

EDUCATING STUDENT DOCTORS
By now you should be full of confidence and really ready to go anywhere to tell your story. Contact you local PCT – Primary Care Trust (details in your local telephone book) – who are responsible for the hospitals and doctors in your area. Ask if you could talk to a class of student doctors about fibromyalgia from a patient’s perspective? You could answer their questions and help them become more knowledgeable about diagnosing FM for future patients. You would indeed be raising awareness by doing this, as so many GPs believe it is all in our head. The Fibromyalgia Association of the UK, http://www.fibromyalgia-associationuk.org, has prepared literature for the medical profession. I believe the American NFA – http://www.fmaware.org – also had medical literature for doctors.

Yes we now believe it is all in our head – but not as the GP suggests. Does your GP think it is in your imagination and that you are a mad malingerer? If so tell him it is now said that FM is due to a chemical imbalance in the brain.

My final thought would be to festoon your house or garden with balloons with a sign in the window saying “Happy Anniversary Fibromyalgia”. Someone is bound to ask you who is Fibromyalgia. Take a photograph and send it to the local paper with a caption saying you are celebration Fibromyalgia Awareness Week. I feel sure you will find this an uplifting experience and enjoy the fun. At the end of all this raising awareness you will feel you have achieved something by spreading the word – which as we know is FIBROMYALGIA.

Do write and tell me about your achievements – we can then have another go at more publicity for FM.

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Genetics of chronic pain states.

Buskila D.

Department of Medicine H, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, P.O.B 151, Israel 84101.

Chronic pain states are common in the general population. Genetic factors can explain a significant amount of the variability in the perception of pain. Fibromyalgia syndrome (FMS) and related conditions are syndromes characterized by generalized pain sensitivity as well as a constellation of other symptoms. Family studies show a strong familial aggregation of FMS and related conditions, suggesting the importance of genetic factors in the development of these conditions. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the pathogenesis of FMS and related conditions. Environmental factors may trigger the development of these disorders in genetically predisposed individuals. Future large well-designed studies are needed to further clarify the role of genetic factors in FMS and related conditions. The knowledge of these gene polymorphisms may help with better subgrouping of FMS patients and in designing a more specific pharmacologic treatment approach.

PMID: 17602998 [PubMed - in process]

1: Best Pract Res Clin Rheumatol. 2007 Jun;21(3):535-47.

Genetics of chronic pain states.
Best Practice & Research Clinical Rheumatology, Volume 21, Issue 3, Pages 535-547
D. Buskila

Reference

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Increased Levels of Neurotrophins Are Not Specific for Chronic Migraine: Evidence from Primary Fibromyalgia Syndrome.

Sarchielli P, Mancini ML, Floridi A, Coppola F, Rossi C, Nardi K, Acciarresi M, Alberto Pini L, Calabresi P.

Neurologic Clinic, Department of Medical and Surgical Specialties and Public Health, University of Perugia, Perugia, Italy.

All data obtained in experimental animal pain models support the role of nerve growth factor (NGF) as a putative candidate intervening in the pathogenesis of chronic pain, including chronic daily headache (CDH). Few studies have been carried out to establish its role in maintaining pain states in humans. The present study was aimed at investigating cerebrospinal fluid (CSF) levels of NGF and brain-derived neurotrophic factor (BDNF), both measured by sensitive immunoassay, in 20 chronic migraine (CM) patients and 20 patients affected by primary fibromyalgia syndrome (PFMS), compared with those of 20 age-matched control subjects. Significantly higher levels of both neurotrophins and glutamate were found. A significantly positive correlation emerged between CSF values of BDNF and those of NGF (See Note) in CM and PFMS patients, respectively. These findings suggest the possibility of a NGF-mediated up-regulation of BDNF involved in the pathophysiological events underlying long-term neuroplastic changes in persistent chronic painful conditions, such as CM and fibromyalgia. NGF might indirectly exert its effect through enhancing glutamatergic transmission via BDNF. The above mechanisms could account for sustained central sensitization in both chronic pain states. PERSPECTIVE: This article presents findings of higher NGF and BDNF levels correlated to increased glutamate levels in the CSF of both chronic migraine and fibromyalgia patients. This opens new insights into the pathogenic mechanisms of chronic pain and offers clinicians new therapeutic perspectives targeting the above mechanisms in both painful disorders.

PMID: 17611164 [PubMed - as supplied by publisher]

1: J Pain. 2007 Jul 3; [Epub ahead of print]

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Note: (r = .61, P

Cranial electrotherapy stimulation and fibromyalgia.

Gilula MF.

President and Director,
Life Energies Research Institute,
2510 Inagua Avenue, Miami,
FL 33133, USA.
mgilula@mindspring.com.

Cranial electrotherapy stimulation (CES) is a well-documented neuroelectrical modality that has been proven effective in some good studies of fibromyalgia (FM) patients. CES is no panacea but, for some FM patients, the modality can be valuable. This article discusses aspects of both CES and FM and how they relate to the individual with the condition. FM frequently has many comorbidities such as anxiety, depression, insomnia and a great variety of different rheumatologic and neurological symptoms that often resemble multiple sclerosis, dysautonomias, chronic fatigue syndrome and others. However, despite long-standing criteria from the American College of Rheumatology for FM, some physicians believe there is probably no single homogeneous condition that can be labeled as FM. Whether it is a disease, a syndrome or something else, sufferers feel like they are living one disaster after another. Active self-involvement in care usually enhances the therapeutic results of various treatments and also improves the patient’s sense of being in control of the condition. D-ribose supplementation may prove to significantly enhance energy, sleep, mental clarity, pain control and well-being in FM patients. A form of evoked potential biofeedback, the EPFX, is a powerful stress reduction technique which assesses the chief stressors and risk factors for illness that can impede the FM patient’s built-in healing abilities. Future healthcare will likely expand the diagnostic criteria of FM and/or illuminate a group of related conditions and the ways in which the conditions relate to each other. Future medicine for FM and related conditions may increasingly involve multimodality treatment that features CES as one significant part of the therapeutic regimen. Future medicine may also include CES as an invaluable, cost-effective add-on to many facets of clinical pharmacology and medical therapeutics.

PMID: 17605684 [PubMed - in process]

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How pain distracts the brain

Contact: Erin Doonan
edoonan@cell.com
617-397-2802
Cell Press

Anybody who’s tried to concentrate on work while suffering a headache knows that pain compellingly commands attention—which is how evolution helped ensure survival in a painful world. Now, researchers have pinpointed the brain region responsible for pain’s ability to affect cognitive processing. They have found that this pain-related brain region is distinct from the one involved in cognitive processing interference due to a distracting memory task.

Ulrike Bingel and colleagues at the University Medical Center Hamburg-Eppendorf published their discovery in the July 5, 2007 issue of the journal Neuron, published by Cell Press.

To search for the region responsible for pain’s ability to usurp attention, the researchers asked volunteers to perform a cognitive task involving distinguishing images, as well as a working memory task involving remembering images. The researchers asked the volunteers to perform the tasks as they experienced different levels of pain caused by the zapping of their hands by a harmless laser beam.

During these tests, the volunteers’ brains were scanned using functional magnetic resonance imaging (fMRI). In this widely used analytical technique, harmless magnetic fields and radio waves are used to scan the brain to determine blood flow across regions, which reflects brain activity.

The researchers’ experiments identified a brain region called the lateral occipital complex (LOC) as the cognitive-related area affected by both “working memory load” and pain. This finding was expected, since the LOC is known to be involved in processing images.

The researchers next sought to identify the brain region by which pain affects the functioning of the LOC. They theorized that the best candidate for this region was one called the rostral anterior cingulate cortex (rACC). This region is known to be involved in the brain’s processing of pain, and it is part of the anterior cingulate cortex, which plays an important role in “executive” functions such as attentional control. These structures are located deep in the brain in the region of connection between the two hemispheres.

Indeed, the researchers’ fMRI scans indicated that the rACC is, indeed, the brain center through which pain influences the LOC. By contrast, they found a working memory load affects the LOC through a different region, the inferior parietal cortex.

The researchers noted that the modulation of visual processing by pain that they observed in their fMRI studies is behaviorally relevant, because as their fMRI scans showed pain affecting the LOC, they also observed a parallel impairment of accuracy in subjects’ recognition of the images.

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The researchers include U. Bingel, M. Rose, J. Glascher, and C. Büchel of University Medical Center Hamburg-Eppendorf, Germany. This work was supported by grants from Volkswagenstiftung, DFG and BMBF, and the EFIC Grünenthal grant 2006.

Bingel et al.: “fMRI Reveals How Pain Modulates Visual Object Processing in the Ventral Visual Stream.” Publishing in Neuron 55, 157–167, July 5, 2007. DOI 10.1016/j.neuron.2007.05.032. http://www.neuron.org.

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Chronic widespread pain in the spectrum of rheumatological diseases.

Bliddal H, Danneskiold-Samsøe B.

The Parker Institute, Frederiksberg Hospital, Ndr Fasanvej 57, 2000 Frederiksberg, Denmark.

Chronic pain is very common in all European countries, with musculoskeletal problems predominating. About 1% of the adult population develops a syndrome of chronic muscle pain, fibromyalgia (FMS), characterized by multiple tender points, back or neck pain, and a number of associated problems from other organs, including a high frequency of fatigue. Evidence points to central sensitization as an important neurophysiological aberration in the development of FMS. Importantly, these neurological changes may result from inadequately treated chronic focal pain problems such as osteoarthritis or myofascial pain. It is important for health professionals to be aware of this syndrome and to diagnose the patients to avoid a steady increase in diagnostic tests. On the other hand, patients with chronic widespread pain have an increased risk of developing malignancies, and new or changed symptoms should be diagnosed even in FMS. In rheumatology practice it is especially important to be aware of the existence of FMS in association with immune inflammatory diseases, most commonly lupus and rheumatoid arthritis. Differential diagnoses are other causes of chronic pain, e.g. thyroid disease. The costs of this syndrome are substantial due to loss of working capability and direct expenses of medication and health-system usage. Fibromyalgia patients need recognition of their pain syndrome if they are to comply with treatment. Lack of empathy and understanding by healthcare professionals often leads to patient frustration and inappropriate illness behavior, often associated with some exaggeration of symptoms in an effort to gain some legitimacy for their problem. FMS is multifaceted, and treatment consists of both medical interventions, with emphasis on agents acting on the central nervous system, and physical exercises.

PMID: 17602990 [PubMed - in process]

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Pain acceptance moderates the relation between pain and negative affect in female osteoarthritis and fibromyalgia patients.

Kratz AL, Davis MC, Zautra AJ.
.

Background: Chronic pain is often intractable despite advanced medical and psychotherapeutic treatments. Pain acceptance is emerging as a promising complement to control-based pain management strategies and a likely approach to maintaining quality of life for chronic pain patients.

Purpose: This theoretically based analysis of an existing database examined the extent to which pain acceptance predicted weekly reports of positive affect (PA) and negative affect (NA), and the relations of pain severity to both PA and NA.

Methods: Participants were women, 36 with osteoarthritis and 86 with fibromylagia, who completed an initial assessment for demographics, pain catastrophizing, and pain acceptance, and 2 to 12 weekly assessments of pain severity, PA, and NA.

Results: Multilevel modeling analyses indicated that pain acceptance was related to higher levels of PA but was unrelated to NA. Furthermore, pain acceptance moderated the relation of NA and pain severity, such that expected increases in NA during pain exacerbations were buffered by higher levels of pain acceptance.

Conclusions: These findings suggest that pain patients with greater capacity to accept pain may be emotionally resilient in managing their condition.

PMID: 17600456 [PubMed - in process]

1: Ann Behav Med. 2007 Jun;33(3):291-301.

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Aquatic Training and Detraining on Fitness and Quality of Life in Fibromyalgia.

Tomas-Carus P, Häkkinen A, Gusi N, Leal A, Häkkinen K, Ortega-Alonso A.

1 Fitness and Lifequality Laboratory, Faculty of Sports Sciences, University of Extremadura, Cáceres, SPAIN; 2 Department of Sports Sciences, Physical Activity and Health, University of Evora, Evora, PORTUGAL; 3 Department of Physical Medicine and Rehabilitation, Jyväskylä Central Hospital, Jyväskylä, FINLAND; 4 Hospital of Cáceres, Cáceres, SPAIN; 5 Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, FINLAND; and 6 Department of Health Sciences, University of Jyväskylä, Jyväskylä, FINLAND.

PURPOSE:: To evaluate the effects of a 12-wk period of aquatic training and subsequent detraining on health-related quality of life (HRQOL) and physical fitness in females with fibromyalgia.

METHODS:: Thirty-four females with fibromyalgia were randomly assigned into two groups: an exercise group, who exercised for 60 min in warm water, three times a week (N = 17); and a control group, who continued their habitual leisure-time activities (N = 17). HRQOL was assessed using the Short Form 36 questionnaire and the Fibromyalgia Impact Questionnaire. Physical fitness was measured using the following tests: Canadian Aerobic Fitness, hand grip dynamometry, 10-m walking, 10-step stair climbing, and blind one-leg stance. Outcomes were measured at baseline, after treatment, and after 3 months of detraining.

RESULTS:: After 12 wk of aquatic exercise, significant positive effects of aquatic training were found in physical function, body pain, general health perception, vitality, social function, role emotional problems and mental health, balance, and stair climbing. After the detraining period, only the improvements in body pain and role emotional problems were maintained.

CONCLUSION:: The present water exercise protocol improved some components of HRQOL, balance, and stair climbing in females with fibromyalgia, but regular exercise and higher intensities may be required to preserve most of these gains.

PMID: 17596770 [PubMed - as supplied by publisher]

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