(NaturalNews) A new study published in the journal Environmental Health Perspectives has revealed that children are dangerously vulnerable to the effects of environmental pesticides, and for far longer than originally suspected.
Scientists at the University of California, Berkeley have discovered that children lack sufficient levels of the enzyme most responsible for detoxifying pesticides up to the age of seven and possibly for longer. Known as paraxonase or PON1, the enzyme is the most important defense the body has against organophosphate chemicals, a major ingredient of the most commonly used agricultural pesticides.
458 children from rural communities were tested for levels of the enzyme, with results showing it to be consistently around a third lower than that of the mother of each child. To compound the concern, more than 40% of the children tested positive for a genetic type that made them particularly susceptible due to the inactivity of the enzyme, whilst nearly one in ten had a genetic profile that made them 'extremely vulnerable'.
Additionally, older children are thought to be around five times more susceptible to organophosphates than adults.
"What's important about this study is that it shows that young children are potentially susceptible to certain organophosphates for a longer period of time than previously thought," said Brenda Eskenazi, UC Berkeley professor of epidemiology and director of CHAMACOS and the Center for Children's Environmental Health Research in a University of Berkeley press release.
Of particular concern to the researchers were chlorpyrifos and diazinon, pesticide chemicals still used ubiquitously in US agriculture. Pesticides have been cited as a possible cause of developmental difficulties and childhood cancers. Both the study authors and environmental health campaigners have urged a complete re-examination of the way in which home chemical products are tested for safety and of the consensus on acceptable exposure levels.
"Current EPA standards of exposure for some pesticides assume children are three to five times more susceptible than adults, and for other pesticides the standards assume no difference", wrote lead author Nina Holland.
"Our results suggest that the EPA standards need to be re-examined to determine if they are adequately protecting the most vulnerable members of the population".[1]
Activists point to several ways in which young children are at an increased risk of physical exposure, including more rapid breathing rates, the vulnerability of having smaller bodies relative to adults and habits such as crawling on the floor and playing on the ground.
The Pesticide Action Network of North America (PANNA) has described the findings as "extremely concerning".
"Even before these results were known, EPA scientists argued that organophosphate pesticides -- posing serious threats to children's neurological development -- were too toxic to be used; we need to ban them, starting with chlorpyrifos", said PAN senior scientist Margaret Reeves, in response to the study. [2]
Green campaigners have suggested eating organically as an important way of reducing pesticide exposure. A University of Washington study found that children fed mostly organic produce and juice had only one-sixth of the level of organophosphate pesticide byproducts in their urine compared to children who ate conventionally grown foods. [3]
[1] Huen at al. Developmental Changes in PON1 Enzyme Activity in Young Children and Effects of PON1 Polymorphisms. Environmental Health Perspectives. 2009 June. doi: 10.1289/ehp.0900870 (available at http://dx.doi.org/)
[2] www.panna.org/resources/panups/panu...
[3] Curl et al. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets. Environmental Health Perspectives.. 2003 March. 111(3): 377-382.
Vaccine struggle embodies U.S. health reform battle
By Maggie Fox, Health and Science Editor
WASHINGTON (Reuters) - The confusion surrounding adult vaccination help illustrates some of the big problems looming for Congress as it struggles with healthcare reform legislation, doctors and health officials said on Wednesday.
They released two surveys showing how few adults realize they can get vaccines against deadly diseases such as meningitis, whooping cough, tetanus and pneumonia or painful conditions such as shingles.
But awareness and demand are only part of the problem, the experts said. The system itself is a barrier to vaccination, said Dr. William Schaffner of Vanderbilt University in Tennessee and the National Foundation for Infectious Diseases.
Some insurance companies pay for the vaccines, others do not, doctors get paid very little to administer them and no one is responsible for ensuring the vaccines are available.
"It is cumbersome almost to the point of not being able to get the vaccine," Schaffner told a news conference.
Schaffner and other vaccine experts said they hope Congress addresses the issue in any healthcare reform legislation. Better vaccination would save billions of dollars, they said.
"More than $10 billion a year is spent in direct medical costs and indirect costs" of vaccine-preventable diseases such as pneumonia, meningitis and influenza, Schaffner said.
Dr. Anne Schuchat of the U.S. Centers for Disease Control and Prevention released a survey of 22,000 U.S. adults that showed most are not getting the vaccinations they need.
"About half of adults had received a tetanus shot within the past 10 years," Schuchat told the news conference. Tetanus shots should be given every 10 years.
WARTS AND CHICKENPOX
Just 11 percent of 19- to 26-year-old women had received the human papillomavirus, or HPV vaccine, which protects against genital warts and cervical cancer, the survey found. Only 6.7 percent of all people over age 60 had been vaccinated against shingles -- an extremely painful recurrence of chickenpox.
While people are often not even aware that they can get these vaccines, the system -- or lack of a system -- means doctors often forget to recommend them.
Dr. Cora Christian of the AARP, which represents people over age 50, said doctors get just $18 to administer a flu shot under Medicare, the federal health insurance plan for the elderly. "This should be 100 percent covered by insurance," Christian said.
Dr. Susan Rehm of the Cleveland Clinic in Ohio said the shingles vaccine is expensive, tricky to store and administer, and ends up costing $200 to $400 a dose.
Some private insurers cover adult vaccines and some do not. "You can imagine there is an extraordinary variety of schemes out there," Schaffner said.
"Speaking as an individual, I am totally confused," Rehm said.
She said alternative settings -- such as retail clinics or box stores -- offer an opportunity to vaccinate adults. Some seasonal flu and pneumococcal vaccines are offered at such clinics.
Healthcare reform experts have said such alternatives to the doctor's office may offer a less expensive and easier way for people to get a range of medical services, from cholesterol tests to simple walk-in emergency care.
Companies that make adult vaccines include Wyeth, which is testing a vaccine against Streptococcus pneumoniae for adults, Merck, which makes the Gardasil HPV vaccine and a shingles vaccine, and GlaxoSmithKline, which makes the Cervarix HPV shots, hepatitis shots, flu vaccines and others.
(Editing by Xavier Briand)
WASHINGTON (Reuters) - The confusion surrounding adult vaccination help illustrates some of the big problems looming for Congress as it struggles with healthcare reform legislation, doctors and health officials said on Wednesday.
They released two surveys showing how few adults realize they can get vaccines against deadly diseases such as meningitis, whooping cough, tetanus and pneumonia or painful conditions such as shingles.
But awareness and demand are only part of the problem, the experts said. The system itself is a barrier to vaccination, said Dr. William Schaffner of Vanderbilt University in Tennessee and the National Foundation for Infectious Diseases.
Some insurance companies pay for the vaccines, others do not, doctors get paid very little to administer them and no one is responsible for ensuring the vaccines are available.
"It is cumbersome almost to the point of not being able to get the vaccine," Schaffner told a news conference.
Schaffner and other vaccine experts said they hope Congress addresses the issue in any healthcare reform legislation. Better vaccination would save billions of dollars, they said.
"More than $10 billion a year is spent in direct medical costs and indirect costs" of vaccine-preventable diseases such as pneumonia, meningitis and influenza, Schaffner said.
Dr. Anne Schuchat of the U.S. Centers for Disease Control and Prevention released a survey of 22,000 U.S. adults that showed most are not getting the vaccinations they need.
"About half of adults had received a tetanus shot within the past 10 years," Schuchat told the news conference. Tetanus shots should be given every 10 years.
WARTS AND CHICKENPOX
Just 11 percent of 19- to 26-year-old women had received the human papillomavirus, or HPV vaccine, which protects against genital warts and cervical cancer, the survey found. Only 6.7 percent of all people over age 60 had been vaccinated against shingles -- an extremely painful recurrence of chickenpox.
While people are often not even aware that they can get these vaccines, the system -- or lack of a system -- means doctors often forget to recommend them.
Dr. Cora Christian of the AARP, which represents people over age 50, said doctors get just $18 to administer a flu shot under Medicare, the federal health insurance plan for the elderly. "This should be 100 percent covered by insurance," Christian said.
Dr. Susan Rehm of the Cleveland Clinic in Ohio said the shingles vaccine is expensive, tricky to store and administer, and ends up costing $200 to $400 a dose.
Some private insurers cover adult vaccines and some do not. "You can imagine there is an extraordinary variety of schemes out there," Schaffner said.
"Speaking as an individual, I am totally confused," Rehm said.
She said alternative settings -- such as retail clinics or box stores -- offer an opportunity to vaccinate adults. Some seasonal flu and pneumococcal vaccines are offered at such clinics.
Healthcare reform experts have said such alternatives to the doctor's office may offer a less expensive and easier way for people to get a range of medical services, from cholesterol tests to simple walk-in emergency care.
Companies that make adult vaccines include Wyeth, which is testing a vaccine against Streptococcus pneumoniae for adults, Merck, which makes the Gardasil HPV vaccine and a shingles vaccine, and GlaxoSmithKline, which makes the Cervarix HPV shots, hepatitis shots, flu vaccines and others.
(Editing by Xavier Briand)
Minister Misled Parliament Over MMR Autism Link
Dawn Primarolo as UK Government Health Minister misled Parliament in a written answer to Conservative MP Mark Pritchard that Bailey Banks’ successful damages claim in the US Federal Court for an autistic condition caused by the MMR vaccine was “non autistic”, stating Bailey had a “non-autistic development delay”.
Now, health minister Mike O’Brien has agreed in a letter to an MP that the ruling referred to a diagnosis of an Autistic Spectrum Disorder. “Pervasive Developmental Disorder, Not Otherwise Specified” is a category of Autistic Spectrum Disorders which does not fall into any other autism category”. There is no misunderstanding amongst experts of what it means. The paediatrician advising the court, Dr Lopez, decided against a diagnosis of autism not because Bailey Banks did not have autistic symptoms but because his condition was vaccine induced.
The designation “Pervasive Developmental Disorder” is the US diagnostic term for “Autistic Spectrum Disorder” used in the rest of the world. “Pervasive Developmental Disorder” is also the term used by The Royal Free Hospital researchers in their 1998 Lancet study which first suggested a possible link between the MMR vaccine and autistic conditions. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children Lancet 1998; 351: 637-41
Primarolo told Parliament in April when a health minister:
In 2007 the United States Court of Federal Claims made a ruling in favour of compensation to the father of Bailey Banks for his non-autistic developmental delay as a result of Acute Disseminated Encephalomyelitis (ADEM) following receipt of measles, mumps and rubella (MMR) vaccine. ADEM is an extremely rare condition that has been reported after rabies, diphtheria-tetanus-pertussis, smallpox, MMR, Japanese B encephalitis, pertussis, influenza and hepatitis B vaccines. The Bailey Banks case has no implications for MMR vaccine policy. http://www.publications.parliament.uk/pa/cm200809/cmhansrd/cm090318/text/90318w0021.htm#090318108002328
Special Master Abell’s judgement in the Bailey Banks case states unequivocally (p.27):
Furthermore, Bailey’s ADEM was severe enough to cause lasting, residual damage, and retarded his developmental progress, which fits under the generalized heading of Pervasive Developmental Delay, or PDD. The Court found that Bailey would not have suffered this delay but for the administration of the MMR vaccine, and that this chain of causation was not too remote, but was rather a proximate sequence of cause and effect leading inexorably from vaccination to Pervasive Developmental Delay. .
Master Abell explained (p.7):
Moving on to the alternative hypothesis/diagnosis of autism, Dr. Lopez distinguishes autism as a more generalized condition without a known etiology, and contrasted it to Bailey’s condition, which he says is clearly attributable to demyelination based on neuroimaging evidence. Tr. at 41-42. Dr. Lopez also differentiated Bailey’s condition from autism, because Bailey has been affected in more than one developmental skill area; he clarified by stating that Bailey has “induced pervasive developmental delay…due to ADEM.” Tr. at 32. He noted that the conflation of designations resulted from a medical convention created for the sake of explanation to laymen, but that the two are not properly interchangeable, but actually quite distinct. Id. Speaking more directly, Dr. Lopez stated that “Bailey does not have autism because he has a reason for his deficits.” Tr. at 42. http://big.assets.huffingtonpost.com/BANKS_CASE.pdf
Now in a letter to an MP, health minister Mike O’Brien agrees that the term ‘PDD’ or ‘PDD-NOS’ (Pervasive Development Delay-Not Otherwise Specified) was that used by the court:
I understand that Mr X… believes that the answer should have referred to pervasive development disorder rather than non-autistic development delay. Relevant information is given on page 2 of the Bailey Banks ruling available at www.uscfc.uscourts.gov by searching for ‘Bailey Banks’. This specifies the ruling refers to ‘Pervasive Development Disorder, Not Otherwise Specified’ in which full features of autism are not identified’.
O’Brien has, therefore, conceded that there were features of autism, which undermines Dawn Primarolo’s claim that Bailey Banks had a ‘non-autistic development delay’: Bailey would undoubtedly be classified as having an Autistic Spectrum Disorder in the UK, even if he did not have “the full features of autism”, or was “atypical” as in many cases, and/or had additional learning difficulties (not usually grounds for withholding an autism diagnosis). Governments, heath officials and vaccine manufacturers are evading responsibility by exploiting confused terminology for a range of developmental problems, nearly all of which are non-specific diagnoses.
When the Banks decision came to light earlier this year Robert F Kennedy Jr, writing in Huffington Post commented that vaccine court cases were more likely to be awarded if the word “autism” did not appear as consequential on brain-damage from encephalopathy:
Medical records associated with these proceedings clearly tell the tale. In perhaps hundreds of these cases, the children have all the classic symptoms of regressive autism; following vaccination a perfectly healthy child experiences high fever, seizures, and other illnesses, then gradually, over about three months, loses language, the ability to make eye contact, becomes “over-focused” and engages in stereotypical head banging and screaming and then suffers developmental delays characteristic of autism. Many of these children had received the autism diagnosis. Yet the radioactive word “autism” appears nowhere in the decision. http://www.huffingtonpost.com/robert-f-kennedy-jr-and-david-kirby/vaccine-court-autism-deba_b_169673.html
The problems are compounded in the UK by the policy of not monitoring, recording or investigating adverse reactions to vaccines, and then citing absence of data as evidence of safety. National Health Service advice is to ignore reactions to MMR vaccine, and to come back for repeat doses (against the fundamental medical ethics and even manufacturers’ instructions).
From an NHS website:
Q:My son had a sever [sic] reaction to the first MMR jab. Does this mean that he is well protected from these diseases, or is a second dose still necessary?
A: If a child has responded to all the components of the vaccine the first time, he will not have a problem being exposed to the viruses again. It’s like any one of us who is already immune meeting someone with the disease – the infection can’t get established. If he hasn’t made protection to all three diseases after the first time, then he would still be susceptible to those natural infections, and still needs the 2nd dose. Reactions after the 2nd dose are essentially the same as after the 1st dose, but if they do occur they are even rarer. There are no new side effects after the 2nd dose that do not occur after the 1st dose. The advice is therefore that it is safe for your child to have the 2nd dose in order that he is properly protected. http://tiny.cc/7vA7g
The casual dismissal of even “severe reactions” shows that Primarolo’s claim that cases of ADEM (Acute Disseminated Encephalomyelitis) which led to Bailey Banks’ pervasive development delay are “extremely rare” has no foundation. The most that the UK Department of Health could truthfully state about the incidence of ADEM is that they do not know how often it occurs, and that the failure to collect data is a matter of policy. Meanwhile, scientists and officials continue to ignore over-whelming statistical evidence from Japan of the correlation between the vaccine programme and incidence of autism, collated and presented by ChildHealthSafety and Age of Autism: http://childhealthsafety.wordpress.com/2009/06/03/japvaxautism/
http://www.ageofautism.com/2009/06/japanese-data-shows-vaccines-cause-autism.html
The failure of candour over these issues by government politicians and officials continues to obstruct public scrutiny of what is going on over MMR, other vaccines and autism. UK citizens should contact their members of parliament http://tinyurl.com/ljxtgv to complain about continuing government dissimulation over these matters.
WHAT YOU CAN DO
If you are concerned write to your political representative. Don’t complain when politicians do nothing if you do not write and keep on writing. It is their job to represent you. All our kids deserve proper science to protect their safety.
Contacting Your UK or US Political Representative
USA
Contact the Senate
Find Your Representative
Write Your Representative
UK Residents – Write To Your Politicians – Do It Now!
To email your MP, all you need to know is your MP’s name. MP’s email addresses are in the form:-
surname.initial@parliament.uk.
To find out who your MP is click on this link:-
http://www.writetothem.com/
Now, health minister Mike O’Brien has agreed in a letter to an MP that the ruling referred to a diagnosis of an Autistic Spectrum Disorder. “Pervasive Developmental Disorder, Not Otherwise Specified” is a category of Autistic Spectrum Disorders which does not fall into any other autism category”. There is no misunderstanding amongst experts of what it means. The paediatrician advising the court, Dr Lopez, decided against a diagnosis of autism not because Bailey Banks did not have autistic symptoms but because his condition was vaccine induced.
The designation “Pervasive Developmental Disorder” is the US diagnostic term for “Autistic Spectrum Disorder” used in the rest of the world. “Pervasive Developmental Disorder” is also the term used by The Royal Free Hospital researchers in their 1998 Lancet study which first suggested a possible link between the MMR vaccine and autistic conditions. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children Lancet 1998; 351: 637-41
Primarolo told Parliament in April when a health minister:
In 2007 the United States Court of Federal Claims made a ruling in favour of compensation to the father of Bailey Banks for his non-autistic developmental delay as a result of Acute Disseminated Encephalomyelitis (ADEM) following receipt of measles, mumps and rubella (MMR) vaccine. ADEM is an extremely rare condition that has been reported after rabies, diphtheria-tetanus-pertussis, smallpox, MMR, Japanese B encephalitis, pertussis, influenza and hepatitis B vaccines. The Bailey Banks case has no implications for MMR vaccine policy. http://www.publications.parliament.uk/pa/cm200809/cmhansrd/cm090318/text/90318w0021.htm#090318108002328
Special Master Abell’s judgement in the Bailey Banks case states unequivocally (p.27):
Furthermore, Bailey’s ADEM was severe enough to cause lasting, residual damage, and retarded his developmental progress, which fits under the generalized heading of Pervasive Developmental Delay, or PDD. The Court found that Bailey would not have suffered this delay but for the administration of the MMR vaccine, and that this chain of causation was not too remote, but was rather a proximate sequence of cause and effect leading inexorably from vaccination to Pervasive Developmental Delay. .
Master Abell explained (p.7):
Moving on to the alternative hypothesis/diagnosis of autism, Dr. Lopez distinguishes autism as a more generalized condition without a known etiology, and contrasted it to Bailey’s condition, which he says is clearly attributable to demyelination based on neuroimaging evidence. Tr. at 41-42. Dr. Lopez also differentiated Bailey’s condition from autism, because Bailey has been affected in more than one developmental skill area; he clarified by stating that Bailey has “induced pervasive developmental delay…due to ADEM.” Tr. at 32. He noted that the conflation of designations resulted from a medical convention created for the sake of explanation to laymen, but that the two are not properly interchangeable, but actually quite distinct. Id. Speaking more directly, Dr. Lopez stated that “Bailey does not have autism because he has a reason for his deficits.” Tr. at 42. http://big.assets.huffingtonpost.com/BANKS_CASE.pdf
Now in a letter to an MP, health minister Mike O’Brien agrees that the term ‘PDD’ or ‘PDD-NOS’ (Pervasive Development Delay-Not Otherwise Specified) was that used by the court:
I understand that Mr X… believes that the answer should have referred to pervasive development disorder rather than non-autistic development delay. Relevant information is given on page 2 of the Bailey Banks ruling available at www.uscfc.uscourts.gov by searching for ‘Bailey Banks’. This specifies the ruling refers to ‘Pervasive Development Disorder, Not Otherwise Specified’ in which full features of autism are not identified’.
O’Brien has, therefore, conceded that there were features of autism, which undermines Dawn Primarolo’s claim that Bailey Banks had a ‘non-autistic development delay’: Bailey would undoubtedly be classified as having an Autistic Spectrum Disorder in the UK, even if he did not have “the full features of autism”, or was “atypical” as in many cases, and/or had additional learning difficulties (not usually grounds for withholding an autism diagnosis). Governments, heath officials and vaccine manufacturers are evading responsibility by exploiting confused terminology for a range of developmental problems, nearly all of which are non-specific diagnoses.
When the Banks decision came to light earlier this year Robert F Kennedy Jr, writing in Huffington Post commented that vaccine court cases were more likely to be awarded if the word “autism” did not appear as consequential on brain-damage from encephalopathy:
Medical records associated with these proceedings clearly tell the tale. In perhaps hundreds of these cases, the children have all the classic symptoms of regressive autism; following vaccination a perfectly healthy child experiences high fever, seizures, and other illnesses, then gradually, over about three months, loses language, the ability to make eye contact, becomes “over-focused” and engages in stereotypical head banging and screaming and then suffers developmental delays characteristic of autism. Many of these children had received the autism diagnosis. Yet the radioactive word “autism” appears nowhere in the decision. http://www.huffingtonpost.com/robert-f-kennedy-jr-and-david-kirby/vaccine-court-autism-deba_b_169673.html
The problems are compounded in the UK by the policy of not monitoring, recording or investigating adverse reactions to vaccines, and then citing absence of data as evidence of safety. National Health Service advice is to ignore reactions to MMR vaccine, and to come back for repeat doses (against the fundamental medical ethics and even manufacturers’ instructions).
From an NHS website:
Q:My son had a sever [sic] reaction to the first MMR jab. Does this mean that he is well protected from these diseases, or is a second dose still necessary?
A: If a child has responded to all the components of the vaccine the first time, he will not have a problem being exposed to the viruses again. It’s like any one of us who is already immune meeting someone with the disease – the infection can’t get established. If he hasn’t made protection to all three diseases after the first time, then he would still be susceptible to those natural infections, and still needs the 2nd dose. Reactions after the 2nd dose are essentially the same as after the 1st dose, but if they do occur they are even rarer. There are no new side effects after the 2nd dose that do not occur after the 1st dose. The advice is therefore that it is safe for your child to have the 2nd dose in order that he is properly protected. http://tiny.cc/7vA7g
The casual dismissal of even “severe reactions” shows that Primarolo’s claim that cases of ADEM (Acute Disseminated Encephalomyelitis) which led to Bailey Banks’ pervasive development delay are “extremely rare” has no foundation. The most that the UK Department of Health could truthfully state about the incidence of ADEM is that they do not know how often it occurs, and that the failure to collect data is a matter of policy. Meanwhile, scientists and officials continue to ignore over-whelming statistical evidence from Japan of the correlation between the vaccine programme and incidence of autism, collated and presented by ChildHealthSafety and Age of Autism: http://childhealthsafety.wordpress.com/2009/06/03/japvaxautism/
http://www.ageofautism.com/2009/06/japanese-data-shows-vaccines-cause-autism.html
The failure of candour over these issues by government politicians and officials continues to obstruct public scrutiny of what is going on over MMR, other vaccines and autism. UK citizens should contact their members of parliament http://tinyurl.com/ljxtgv to complain about continuing government dissimulation over these matters.
WHAT YOU CAN DO
If you are concerned write to your political representative. Don’t complain when politicians do nothing if you do not write and keep on writing. It is their job to represent you. All our kids deserve proper science to protect their safety.
Contacting Your UK or US Political Representative
USA
Contact the Senate
Find Your Representative
Write Your Representative
UK Residents – Write To Your Politicians – Do It Now!
To email your MP, all you need to know is your MP’s name. MP’s email addresses are in the form:-
surname.initial@parliament.uk.
To find out who your MP is click on this link:-
http://www.writetothem.com/
Sunday Times Defies Press Complaints Commission
Paper Notifies Media Oversight Agency that it Will Not Remove from its Website False Stories about MMR and Dr. Andrew Wakefield
(Austin, Texas) – The Sunday Times of London, a Rupert Murdoch News Corporation paper, has defied direction from the UK’s Press Complaints Commission (PCC) to remove from its web site controversial stories it has failed to substantiate, which allege Dr. Andrew Wakefield “fixed” data relating to the MMR vaccine. The reports by correspondent Brian Deer are the subject of an extensive complaint filed with the PCC by Wakefield.
The PCC last week issued an unpublished directive that the stories be removed (see below). They were taken down immediately, unannounced, but the Sunday Times has now defied the PCC by putting the stories back online after complaining Dr. Wakefield publicly announced the PCC’s directive.
Stephen Abell, Deputy Director of the PCC, wrote in his unpublished directive,
Given the ongoing nature of the dispute, the articles should be removed from the newspaper’s website until this matter has been concluded.”
The Sunday Times has an obligation to “cooperate swiftly” with the PCC in the resolution of complaints under the UK’s PCC Code, which states it is “the cornerstone of the system of self-regulation to which the UK [press] industry has made a binding commitment.” The PCC is a non-statutory self-regulatory body run by the press.
(Austin, Texas) – The Sunday Times of London, a Rupert Murdoch News Corporation paper, has defied direction from the UK’s Press Complaints Commission (PCC) to remove from its web site controversial stories it has failed to substantiate, which allege Dr. Andrew Wakefield “fixed” data relating to the MMR vaccine. The reports by correspondent Brian Deer are the subject of an extensive complaint filed with the PCC by Wakefield.
The PCC last week issued an unpublished directive that the stories be removed (see below). They were taken down immediately, unannounced, but the Sunday Times has now defied the PCC by putting the stories back online after complaining Dr. Wakefield publicly announced the PCC’s directive.
Stephen Abell, Deputy Director of the PCC, wrote in his unpublished directive,
Given the ongoing nature of the dispute, the articles should be removed from the newspaper’s website until this matter has been concluded.”
The Sunday Times has an obligation to “cooperate swiftly” with the PCC in the resolution of complaints under the UK’s PCC Code, which states it is “the cornerstone of the system of self-regulation to which the UK [press] industry has made a binding commitment.” The PCC is a non-statutory self-regulatory body run by the press.
Swine torque teno virus detection in pig commercial vaccines, enzymes for laboratory use and human drugs containing components of porcine origin.
Kekarainen T, Martínez-Guinó L, Segalés J.
Centre de Recerca en Sanitat Animal (CReSA), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Tuija.Kekarainen@cresa.uab.es
Torque teno viruses (TTVs) are vertebrate infecting, single-stranded circular DNA viruses. Two genetically distinct TTV genogroups (TTV1 and TTV2) infect swine worldwide with high prevalence. Currently, swine TTVs are considered non-pathogenic, although TTV2 has been linked to post-weaning multisystemic wasting syndrome, a porcine circovirus disease. On the other hand, pig materials are an important source of components used in porcine vaccine manufacturing, human drugs and commercial enzyme products. However, there is little information about the possible existence of extraneous viruses in products containing porcine-derived components. In the present study, 26 commercial swine vaccines, seven human drugs and three enzyme products from porcine origin were tested for the presence of TTV1 and TTV2 genomes by PCR. Four vaccines against Mycoplasma hyopneumoniae were positive for TTV2 by PCR. Three M. hyopneumoniae, one porcine parvovirus and one porcine reproductive and respiratory syndrome virus vaccines were PCR positive for TTV1. One human drug contained TTV1 DNA as well as a trypsin enzyme; a porcine-derived elastase product was positive for both TTV genogroups. These results show that swine TTVs are contaminants not only of swine vaccines but also of human drugs containing porcine components and enzymes for laboratory use.
PMID: 19218210 [PubMed - indexed for MEDLINE]
Centre de Recerca en Sanitat Animal (CReSA), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Tuija.Kekarainen@cresa.uab.es
Torque teno viruses (TTVs) are vertebrate infecting, single-stranded circular DNA viruses. Two genetically distinct TTV genogroups (TTV1 and TTV2) infect swine worldwide with high prevalence. Currently, swine TTVs are considered non-pathogenic, although TTV2 has been linked to post-weaning multisystemic wasting syndrome, a porcine circovirus disease. On the other hand, pig materials are an important source of components used in porcine vaccine manufacturing, human drugs and commercial enzyme products. However, there is little information about the possible existence of extraneous viruses in products containing porcine-derived components. In the present study, 26 commercial swine vaccines, seven human drugs and three enzyme products from porcine origin were tested for the presence of TTV1 and TTV2 genomes by PCR. Four vaccines against Mycoplasma hyopneumoniae were positive for TTV2 by PCR. Three M. hyopneumoniae, one porcine parvovirus and one porcine reproductive and respiratory syndrome virus vaccines were PCR positive for TTV1. One human drug contained TTV1 DNA as well as a trypsin enzyme; a porcine-derived elastase product was positive for both TTV genogroups. These results show that swine TTVs are contaminants not only of swine vaccines but also of human drugs containing porcine components and enzymes for laboratory use.
PMID: 19218210 [PubMed - indexed for MEDLINE]
The antibiotic and DNA-transfecting peptide LAH4 selectively associates with, and disorders, anionic lipids in mixed membranes
A. James Mason*,,1, Amélie Martinez, Clemens Glaubitz, Olivier Danos, Antoine Kichler and Burkhard Bechinger*
* Faculté de chimie, University Louis Pasteur/CNRS UMR717-LC3, Institut le Bel, Strasbourg, France;
Généthon-CNRS UMR8115, Evry, France; and
Centre for Biomolecular Magnetic Resonance and Institut für Biophysikalische Chemie, J. W. Goethe Universität, Frankfurt, Germany
1 Correspondence: Institut Isis, 8 rue Gaspard Monge, Strasbourg 67000, France. E-mail: jmason@chimie.u-strasbg.fr
SPECIFIC AIMS
The efficient delivery of nucleic acids to eukaryotic cells by nonviral means has potential applications from basic research to gene therapeutic approaches for congenital disorders, cancer and viral infection. It has been proposed previously that cationic DNA containing complexes enter the cell through disruption of the endosomal membrane during endocytosis. It has also been observed that transformed cell lines are more easily transfected than primary cell lines by the cationic amphipathic DNA vector peptide LAH4. We therefore sought to determine whether anionic lipids, found in eukaryotic cells and presented on the surface of tumorigenic cells, perform a role in LAH4 mediated DNA delivery.
PRINCIPAL FINDINGS
1. Solid-state NMR methods show that LAH4 interacts preferentially with anionic lipids in mixed model membranes
LAH4 is a 26 residue peptide which adopts an amphipathic -helical conformation when associated with lipid bilayers. It adopts a transmembrane orientation at pH 7.5 where lysine residues at each terminus act as hydrophilic anchors. At acidic pH it switches into an in-plane orientation concomitant with the protonation of its four histidine residues. LAH4 is capable of complexing DNA, associating with the cell surface membrane and then, when enveloped within an endosome, disrupts the endosomal membrane as the pH drops.
The first step in our study was to determine whether cationic LAH4, as expected, would interact preferentially with anionic lipids in model membranes. The 31P NMR isotropic chemical shift of phospholipids incorporated into lipid vesicles has been shown previously to be a sensitive reporter of surface charge with upfield shifts accompanying an increase in positive charges and vice versa. We followed the isotropic resonances of the bilayer phospholipids by 31P magic angle sample spinning (MAS) NMR of vesicles containing anionic [phosphatidylserine (PS) and phosphatidylglycerol (PG)] as well as zwitterionic [phosphatidylcholine (PC)] lipids. On the addition of the cationic peptide LAH4, the isotropic chemical shifts of the anionic lipids were observed to shift upfield by a greater magnitude than those of PC while the line widths, as determined by measuring the full peak width at half height, also showed far greater increase for anionic lipids. The changes in line width and chemical shift as well as the differences between anionic lipids and PC were more marked at acidic pH than at pH 7.5.
A second solid-state NMR method revealed that addition of LAH4, to lipid vesicles containing chain-deuterated PC as a reporter of structure and motions within the lipid acyl chain, caused only a very weak reduction of order within the chain region. The effect was attenuated when unlabeled PS was included in the vesicles in place of unlabeled PC. Taken together, these results show that LAH4 preferentially interacts with anionic lipids in model membranes and this interaction is stronger at acidic pH, which the peptide would experience in the endosome during transfection of the cationic DNA/peptide complex.
2. 2H NMR of chain-deuterated phosphatidylserine shows that LAH4 effectively disrupts the lipid acyl chains at acidic pH
Following our observation that LAH4 interacts preferentially with anionic lipids, we sought to characterize this interaction further by using wide line 2H NMR to monitor the acyl chain order of vesicles containing chain-deuterated PS as a reporter. Incorporation of LAH4 did not significantly affect 2H NMR spectra of mixed lipid vesicles containing PC/PS/cholesterol at pH 7.5. However, when the samples were resuspended and buffered at pH 5 a sharp reduction in lipid acyl chain order is observed. This data shows that not only does LAH4 associate preferentially with anionic lipids but it is also capable of disrupting their lipid chains with a much greater efficiency than those of zwitterionic PC.
3. The disruption of the lipid acyl chains can be manipulated by altering the angles subtended by the positively charged histidine residues and this activity is mirrored by the in vitro transfection efficiency of the peptides against eukaryotic cells
We investigated how the angle subtended by the histidine residues, positively charged at acidic pH, influences the interaction of LAH4 derivatives with anionic PS. The membrane disordering due to the presence of the peptide was assessed again using 2H NMR of mixed PC/PS/cholesterol vesicles with chain-deuterated PS as reporter. LAH4 peptide isomers (Fig. 1 ) with angles of 80° and 100° were shown to disrupt lipid chain order with the highest efficiency while those with angles of 60° and 180° were noticeably weaker (Fig. 2 A). The same peptides were then tested in vitro for their transfection efficiency against four eukaryotic cell lines. It was found that the transfection efficiency for the LAH4 isomers in all cell lines tested mirrored the chain disruption efficiency as shown by solid-state NMR (Fig. 2B ), hence demonstrating a close relationship (Fig. 2C ) between the peptide activity in model membranes and in live cells. The same dependency of transfection efficiency against charged angle was found for all cell lines, including MRC-5 cells which are primary lung fibroblasts. These healthy cells are unlikely to have anionic lipids presented in the external leaflet of the cell membrane and hence our study is in agreement with a model whereby anionic lipids are recruited from the internal leaflet by lipid flip-flop, peptide induced or otherwise, to combine and destabilize the cationic DNA/peptide complex.
Figure 1. Helical wheel diagrams for LAH4 (A) and isomers LAH4-L0 (B), LAH-L1 (C), LAH4-L2 (D), and LAH4-AL6 (E). The angles subtended by the positively charged helix face, at pH 5, for the peptides are 60° (L0), 80° (L1), 100° (L2 and LAH4), and 180° (AL6). The pdb files were generated using Insight II and the figures rendered using Raswin.
Figure 2. 2H order parameter profiles for peptide/POPS-d31 containing vesicles, calculated relative to POPS-d31 in peptide free vesicles (A) and a comparison of the relative transfection efficiency of the LAH4 vectors on four eukaryote cell lines (B). In the transfection experiments, increasing amounts of peptide were tested and only the formulation giving the highest luciferase activity is shown. Error bars represent the SEM. *P < 0.05 compared with LAH4 for each cell type. The relationship between the transfection data and order parameter is shown (C) by comparing normalized transfection efficiencies and normalized disruption efficiencies calculated for the lowest five segments of the acyl chain.
CONCLUSIONS AND SIGNIFICANCE
The mechanism by which nonviral cationic DNA vectors deliver their cargo to eukaryotic cells is not well understood. What is known for LAH4 is that the peptide has the ability to complex with DNA in solution, when associated with a biological membrane the peptide can exist in surface oriented or transmembrane topologies, where the in-plane alignment results in a more powerful membrane disrupting ability, and that endosomal acidification plays an important part in the transfection process. It has also been suggested previously that anionic lipids may perform a role in destabilizing cationic complexes leading to release of DNA to the interior of the cell. Anionic lipids are normally sequestered to the internal leaflet of eukaryotic cell membranes and hence the outer leaflet of endosomal membranes and so lipid flip-flop is thought to be a prerequisite for this process in healthy cells. This is not an unreasonable hypothesis as other membrane active peptides have been shown to induce lipid flop. Certain cells that are tumorigenic or, for example, infected with HIV, have been shown to present anionic PS at the external membrane leaflet, which may cause enhanced adsorption of cationic complexes and, according to the hypothesis above, also enhances transfection efficiency since more anionic lipids would be present in the internal leaflet of the endosomal membrane.
Our data shows that LAH4 does indeed interact with anionic lipids and is capable of disrupting these lipids in model membranes. Furthermore, a close relationship was demonstrated between these effects, studied in model membranes, and the process of LAH4 mediated transfection in live cells. This supports an important role for anionic lipids during the endosomal acidification phase in transfection mediated by cationic compounds such as LAH4.
The dependence on the positively charged angle was the same for all cell lines including the primary cell line MRC-5 as discussed above. It is notable, however, MRC-5 V2 cells, which are the same lung fibroblasts transformed with sv40 virus, showed the same angle dependence but were overall much more susceptible to transfection by all the peptides tested in this work.
Our study may explain therefore why the transfection by cationic amphipathic peptides such as LAH4 is more effective for cells that display anionic lipids such as PS at the external membrane surface. This information and the knowledge that the relative transfection efficiency of different cell lines can be manipulated in the manner shown will help in the design of new, more efficient and specific transfectants.
* Faculté de chimie, University Louis Pasteur/CNRS UMR717-LC3, Institut le Bel, Strasbourg, France;
Généthon-CNRS UMR8115, Evry, France; and
Centre for Biomolecular Magnetic Resonance and Institut für Biophysikalische Chemie, J. W. Goethe Universität, Frankfurt, Germany
1 Correspondence: Institut Isis, 8 rue Gaspard Monge, Strasbourg 67000, France. E-mail: jmason@chimie.u-strasbg.fr
SPECIFIC AIMS
The efficient delivery of nucleic acids to eukaryotic cells by nonviral means has potential applications from basic research to gene therapeutic approaches for congenital disorders, cancer and viral infection. It has been proposed previously that cationic DNA containing complexes enter the cell through disruption of the endosomal membrane during endocytosis. It has also been observed that transformed cell lines are more easily transfected than primary cell lines by the cationic amphipathic DNA vector peptide LAH4. We therefore sought to determine whether anionic lipids, found in eukaryotic cells and presented on the surface of tumorigenic cells, perform a role in LAH4 mediated DNA delivery.
PRINCIPAL FINDINGS
1. Solid-state NMR methods show that LAH4 interacts preferentially with anionic lipids in mixed model membranes
LAH4 is a 26 residue peptide which adopts an amphipathic -helical conformation when associated with lipid bilayers. It adopts a transmembrane orientation at pH 7.5 where lysine residues at each terminus act as hydrophilic anchors. At acidic pH it switches into an in-plane orientation concomitant with the protonation of its four histidine residues. LAH4 is capable of complexing DNA, associating with the cell surface membrane and then, when enveloped within an endosome, disrupts the endosomal membrane as the pH drops.
The first step in our study was to determine whether cationic LAH4, as expected, would interact preferentially with anionic lipids in model membranes. The 31P NMR isotropic chemical shift of phospholipids incorporated into lipid vesicles has been shown previously to be a sensitive reporter of surface charge with upfield shifts accompanying an increase in positive charges and vice versa. We followed the isotropic resonances of the bilayer phospholipids by 31P magic angle sample spinning (MAS) NMR of vesicles containing anionic [phosphatidylserine (PS) and phosphatidylglycerol (PG)] as well as zwitterionic [phosphatidylcholine (PC)] lipids. On the addition of the cationic peptide LAH4, the isotropic chemical shifts of the anionic lipids were observed to shift upfield by a greater magnitude than those of PC while the line widths, as determined by measuring the full peak width at half height, also showed far greater increase for anionic lipids. The changes in line width and chemical shift as well as the differences between anionic lipids and PC were more marked at acidic pH than at pH 7.5.
A second solid-state NMR method revealed that addition of LAH4, to lipid vesicles containing chain-deuterated PC as a reporter of structure and motions within the lipid acyl chain, caused only a very weak reduction of order within the chain region. The effect was attenuated when unlabeled PS was included in the vesicles in place of unlabeled PC. Taken together, these results show that LAH4 preferentially interacts with anionic lipids in model membranes and this interaction is stronger at acidic pH, which the peptide would experience in the endosome during transfection of the cationic DNA/peptide complex.
2. 2H NMR of chain-deuterated phosphatidylserine shows that LAH4 effectively disrupts the lipid acyl chains at acidic pH
Following our observation that LAH4 interacts preferentially with anionic lipids, we sought to characterize this interaction further by using wide line 2H NMR to monitor the acyl chain order of vesicles containing chain-deuterated PS as a reporter. Incorporation of LAH4 did not significantly affect 2H NMR spectra of mixed lipid vesicles containing PC/PS/cholesterol at pH 7.5. However, when the samples were resuspended and buffered at pH 5 a sharp reduction in lipid acyl chain order is observed. This data shows that not only does LAH4 associate preferentially with anionic lipids but it is also capable of disrupting their lipid chains with a much greater efficiency than those of zwitterionic PC.
3. The disruption of the lipid acyl chains can be manipulated by altering the angles subtended by the positively charged histidine residues and this activity is mirrored by the in vitro transfection efficiency of the peptides against eukaryotic cells
We investigated how the angle subtended by the histidine residues, positively charged at acidic pH, influences the interaction of LAH4 derivatives with anionic PS. The membrane disordering due to the presence of the peptide was assessed again using 2H NMR of mixed PC/PS/cholesterol vesicles with chain-deuterated PS as reporter. LAH4 peptide isomers (Fig. 1 ) with angles of 80° and 100° were shown to disrupt lipid chain order with the highest efficiency while those with angles of 60° and 180° were noticeably weaker (Fig. 2 A). The same peptides were then tested in vitro for their transfection efficiency against four eukaryotic cell lines. It was found that the transfection efficiency for the LAH4 isomers in all cell lines tested mirrored the chain disruption efficiency as shown by solid-state NMR (Fig. 2B ), hence demonstrating a close relationship (Fig. 2C ) between the peptide activity in model membranes and in live cells. The same dependency of transfection efficiency against charged angle was found for all cell lines, including MRC-5 cells which are primary lung fibroblasts. These healthy cells are unlikely to have anionic lipids presented in the external leaflet of the cell membrane and hence our study is in agreement with a model whereby anionic lipids are recruited from the internal leaflet by lipid flip-flop, peptide induced or otherwise, to combine and destabilize the cationic DNA/peptide complex.
Figure 1. Helical wheel diagrams for LAH4 (A) and isomers LAH4-L0 (B), LAH-L1 (C), LAH4-L2 (D), and LAH4-AL6 (E). The angles subtended by the positively charged helix face, at pH 5, for the peptides are 60° (L0), 80° (L1), 100° (L2 and LAH4), and 180° (AL6). The pdb files were generated using Insight II and the figures rendered using Raswin.
Figure 2. 2H order parameter profiles for peptide/POPS-d31 containing vesicles, calculated relative to POPS-d31 in peptide free vesicles (A) and a comparison of the relative transfection efficiency of the LAH4 vectors on four eukaryote cell lines (B). In the transfection experiments, increasing amounts of peptide were tested and only the formulation giving the highest luciferase activity is shown. Error bars represent the SEM. *P < 0.05 compared with LAH4 for each cell type. The relationship between the transfection data and order parameter is shown (C) by comparing normalized transfection efficiencies and normalized disruption efficiencies calculated for the lowest five segments of the acyl chain.
CONCLUSIONS AND SIGNIFICANCE
The mechanism by which nonviral cationic DNA vectors deliver their cargo to eukaryotic cells is not well understood. What is known for LAH4 is that the peptide has the ability to complex with DNA in solution, when associated with a biological membrane the peptide can exist in surface oriented or transmembrane topologies, where the in-plane alignment results in a more powerful membrane disrupting ability, and that endosomal acidification plays an important part in the transfection process. It has also been suggested previously that anionic lipids may perform a role in destabilizing cationic complexes leading to release of DNA to the interior of the cell. Anionic lipids are normally sequestered to the internal leaflet of eukaryotic cell membranes and hence the outer leaflet of endosomal membranes and so lipid flip-flop is thought to be a prerequisite for this process in healthy cells. This is not an unreasonable hypothesis as other membrane active peptides have been shown to induce lipid flop. Certain cells that are tumorigenic or, for example, infected with HIV, have been shown to present anionic PS at the external membrane leaflet, which may cause enhanced adsorption of cationic complexes and, according to the hypothesis above, also enhances transfection efficiency since more anionic lipids would be present in the internal leaflet of the endosomal membrane.
Our data shows that LAH4 does indeed interact with anionic lipids and is capable of disrupting these lipids in model membranes. Furthermore, a close relationship was demonstrated between these effects, studied in model membranes, and the process of LAH4 mediated transfection in live cells. This supports an important role for anionic lipids during the endosomal acidification phase in transfection mediated by cationic compounds such as LAH4.
The dependence on the positively charged angle was the same for all cell lines including the primary cell line MRC-5 as discussed above. It is notable, however, MRC-5 V2 cells, which are the same lung fibroblasts transformed with sv40 virus, showed the same angle dependence but were overall much more susceptible to transfection by all the peptides tested in this work.
Our study may explain therefore why the transfection by cationic amphipathic peptides such as LAH4 is more effective for cells that display anionic lipids such as PS at the external membrane surface. This information and the knowledge that the relative transfection efficiency of different cell lines can be manipulated in the manner shown will help in the design of new, more efficient and specific transfectants.
Is Aborted Fetal DNA in Vaccines Linked to Autism?
July 21, 2009 (LifeSiteNews.com) - Just when the pharmaceutical industry thought the vaccine-autism controversy had been resolved, the National Vaccine Advisory Committee has recommended further study of vaccine safety. A perceived fear of the safety of the U.S. vaccination schedule has led increasing numbers of parents to opt out of full compliance. The numbers of children who are not fully vaccinated has now reached a point where "herd" immunity may be compromised, compelling the Centers for Disease Control to hold town-hall meetings and convene a Vaccine Safety Working Subgroup. Despite research ruling out mercury (Thimerosal) or the measles portion of one specific vaccine, autism continues to rise to a level of one in every 64 children in the UK.
The NVAC draft report recommends further study of the potential for vaccines to contribute to autism in children who have underlying mitochondrial disease, a worthwhile study given the clinical history of such children developing autism after vaccinations (see Poling case). What the NVAC has overlooked, however, in their recommendations, is that epidemic regressive autism is associated with the switch from using animal cells to produce vaccines to the use of aborted human fetal cells for vaccine production. Now when we vaccinate our children, some vaccines also deliver contaminating aborted human fetal DNA. The safety of this has never been tested.
Autism and autism spectrum disorder are polygenic diseases, meaning that multiple genes have been shown to be associated with these diseases. Studies have also clearly shown that there is an environmental component, a trigger, that is required. Vaccines are an obvious potential environmental trigger for autism because of the almost universal childhood exposure to vaccines in first world countries. The vaccine-autism connection was first hypothesized following the introduction of a new measles, mumps and rubella (MMR) vaccine to the U.S. in 1979, with complete U.S. market share by 1983, and to the UK in 1988. Autism rates began to rise in the U.S. after 1979 and rose dramatically after 1983, and likewise rose in the UK after 1988, leading physicians to suspect a link. Initially, the measles component of this vaccine, MMR II, was suspected to be the culprit. Subsequent studies have also focused on the presence of mercury in vaccines, which incidentally, the MMR II vaccine did not contain.
Those studies have largely ruled out the new measles portion of the MMR II or mercury as the environmental trigger for autism. However, the compelling temporal association between this new MMR vaccine and autism cannot be ignored or explained away. What has been ignored is the fact that this new MMR vaccine introduced the use of aborted fetal cells for vaccine production. At one point, as much as 94 percent of children in the U.S. and 98 percent of children in the UK were given this vaccine.
Today, more than 23 vaccines are contaminated by the use of aborted fetal cells. There is no law that requires that consumers be informed that some vaccines are made using aborted fetal cells and contain residual aborted fetal DNA. While newer vaccines produced using aborted fetal cells do inform consumers, in their package inserts, that the vaccines contain contaminating DNA from the cell used to produce the vaccine, they do not identify the cells as being derived from electively aborted human fetuses.
In other words, they tell you what is in the vaccine, but they don't fully inform you where it came from. The earliest aborted fetal cell-produced vaccines such as Meruvax (rubella) and MMR II do not even inform consumers that the vaccines contain contaminating DNA from the cell used to produce them. Furthermore, it is unconscionable that the public-health risk of injecting our children with residual contaminating human aborted fetal DNA has been ignored.
How could the contaminating aborted fetal DNA create problems? It creates the potential for autoimmune responses and/or inappropriate insertion into our own genomes through a process called recombination. There are groups researching the potential link between this DNA and autoimmune diseases such as juvenile (type I) diabetes, multiple sclerosis and lupus. Our organization, Sound Choice Pharmaceutical Institute (SCPI), is focused on studying the quantity, characteristics and genomic recombination of the aborted fetal DNA found in many of our vaccines.
Preliminary bioinformatics research conducted at SCPI indicates that "hot spots" for DNA recombination are found in nine autism-associated genes present on the X chromosome. These nine genes are involved in nerve-cell synapse formation, central nervous system development and mitochondrial function.
Could genomic insertion of the aborted fetal DNA, found in some of our childhood vaccines since 1979, be an environmental trigger for autism? Could the fact that genes critical for nerve synapse formation and nervous system development are found on the X chromosome provide some explanation of why autism is predominantly a disease found in boys? Could the "hot spots" identified in these autism-associated genes be sites for insertion of contaminating aborted fetal DNA?
These questions must be answered, and quickly. Recent literature suggests that autism spectrum disorder may now impact one out of every 100 children. The pharmaceutical industry is also currently moving to replace more animal-produced vaccines with aborted-fetal-cell production and also to produce biologic drugs using aborted fetal cells.
The practice of using aborted fetal cells for vaccine and drug production creates wrenching moral dilemmas for parents and consumers, ignores informed consent rights, and exposes our children and ourselves to contaminants lacking safety evaluations. We cannot ignore this issue in good conscience, and we cannot afford to wait.
The NVAC draft report recommends further study of the potential for vaccines to contribute to autism in children who have underlying mitochondrial disease, a worthwhile study given the clinical history of such children developing autism after vaccinations (see Poling case). What the NVAC has overlooked, however, in their recommendations, is that epidemic regressive autism is associated with the switch from using animal cells to produce vaccines to the use of aborted human fetal cells for vaccine production. Now when we vaccinate our children, some vaccines also deliver contaminating aborted human fetal DNA. The safety of this has never been tested.
Autism and autism spectrum disorder are polygenic diseases, meaning that multiple genes have been shown to be associated with these diseases. Studies have also clearly shown that there is an environmental component, a trigger, that is required. Vaccines are an obvious potential environmental trigger for autism because of the almost universal childhood exposure to vaccines in first world countries. The vaccine-autism connection was first hypothesized following the introduction of a new measles, mumps and rubella (MMR) vaccine to the U.S. in 1979, with complete U.S. market share by 1983, and to the UK in 1988. Autism rates began to rise in the U.S. after 1979 and rose dramatically after 1983, and likewise rose in the UK after 1988, leading physicians to suspect a link. Initially, the measles component of this vaccine, MMR II, was suspected to be the culprit. Subsequent studies have also focused on the presence of mercury in vaccines, which incidentally, the MMR II vaccine did not contain.
Those studies have largely ruled out the new measles portion of the MMR II or mercury as the environmental trigger for autism. However, the compelling temporal association between this new MMR vaccine and autism cannot be ignored or explained away. What has been ignored is the fact that this new MMR vaccine introduced the use of aborted fetal cells for vaccine production. At one point, as much as 94 percent of children in the U.S. and 98 percent of children in the UK were given this vaccine.
Today, more than 23 vaccines are contaminated by the use of aborted fetal cells. There is no law that requires that consumers be informed that some vaccines are made using aborted fetal cells and contain residual aborted fetal DNA. While newer vaccines produced using aborted fetal cells do inform consumers, in their package inserts, that the vaccines contain contaminating DNA from the cell used to produce the vaccine, they do not identify the cells as being derived from electively aborted human fetuses.
In other words, they tell you what is in the vaccine, but they don't fully inform you where it came from. The earliest aborted fetal cell-produced vaccines such as Meruvax (rubella) and MMR II do not even inform consumers that the vaccines contain contaminating DNA from the cell used to produce them. Furthermore, it is unconscionable that the public-health risk of injecting our children with residual contaminating human aborted fetal DNA has been ignored.
How could the contaminating aborted fetal DNA create problems? It creates the potential for autoimmune responses and/or inappropriate insertion into our own genomes through a process called recombination. There are groups researching the potential link between this DNA and autoimmune diseases such as juvenile (type I) diabetes, multiple sclerosis and lupus. Our organization, Sound Choice Pharmaceutical Institute (SCPI), is focused on studying the quantity, characteristics and genomic recombination of the aborted fetal DNA found in many of our vaccines.
Preliminary bioinformatics research conducted at SCPI indicates that "hot spots" for DNA recombination are found in nine autism-associated genes present on the X chromosome. These nine genes are involved in nerve-cell synapse formation, central nervous system development and mitochondrial function.
Could genomic insertion of the aborted fetal DNA, found in some of our childhood vaccines since 1979, be an environmental trigger for autism? Could the fact that genes critical for nerve synapse formation and nervous system development are found on the X chromosome provide some explanation of why autism is predominantly a disease found in boys? Could the "hot spots" identified in these autism-associated genes be sites for insertion of contaminating aborted fetal DNA?
These questions must be answered, and quickly. Recent literature suggests that autism spectrum disorder may now impact one out of every 100 children. The pharmaceutical industry is also currently moving to replace more animal-produced vaccines with aborted-fetal-cell production and also to produce biologic drugs using aborted fetal cells.
The practice of using aborted fetal cells for vaccine and drug production creates wrenching moral dilemmas for parents and consumers, ignores informed consent rights, and exposes our children and ourselves to contaminants lacking safety evaluations. We cannot ignore this issue in good conscience, and we cannot afford to wait.
Alzheimer's-causing Amyloid and Bacteria Trigger Same Immune Response in the Brain
*Can anyone say gut/brain link?* ~Cher
Amyloid plaques, bacteria biofilm both cause inflammation that destroys neurons
(HealthNewsDigest.com) - SACRAMENTO, Calif. — In a new study published today in the July issue of the journal Cell Host & Microbe, UC Davis researchers report that both amyloid plaques found in the brains of Alzheimer’s patients and structures made by some gut bacteria likely elicit the same response by human immune cells.
“Alzheimer’s disease may be a case of mistaken identity,” said Andreas Bäumler, a professor of microbiology and medical immunology. Bäumler and his colleagues showed that the immune systems of mice injected with E. coli and salmonella are triggered by curli fibrils, fiber-like structures consisting of curli proteins that allow bacteria to stick to host tissue and to each other and form colonies.
Curli fibrils are morphologically identical to amyloid fibrils found in Alzheimer’s plaques. When they presented human cells with the two kinds of fibrils, they saw the same immune response — even though the two have nothing in common in their amino acid sequences.
“Our results suggest that it’s the structure of these protein aggregates that matter and that, to the innate immune system, Alzheimer’s plaques may look like colonies of bacteria. This would result in the chronic inflammation we see in Alzheimer’s disease that damages neurons,” Bäumler explained.
Amyloid plaques are the sticky buildup of proteins that accumulate outside nerve cells. They are characteristic of several illnesses, including Alzheimer’s disease, Huntington’s disease, type 2 diabetes, secondary amyloidosis and prion diseases, like Creutzfeldt-Jakob (the human form of mad cow disease). These diseases all involve marked inflammation at the sites of amyloid deposition, resulting in tissue injury.
The protein forming plaques in Alzheimer’s patients is normally soluble. When the protein folds improperly, it forms amyloid deposits that are associated with brain inflammation. Until now, scientists have not been able to identify what causes this destructive, chronic inflammation.
Bäumler and his colleagues did not expect to be studying Alzheimer’s disease. They were studying inflammation of the gut caused by bacteria when they discovered that the innate immune system was being triggered by a structural feature of bacterial amyloids and not by the amino acids that make up the proteins in the biofilms.
“When we destroyed the ability of the proteins to aggregate, we no longer saw the same immune response,” Bäumler said.
When the researchers figured out the amyloid structure was responsible for triggering the immune system, they decided to see whether the same immune response was being triggered by structurally identical amyloids associated with human disease. They chose to study the synthetic form of the proteins that make up Alzheimer’s plaques because the disease has been widely studied and a lot is known about the biochemistry of these plaques.
In the current study, Bäumler and his team found that, in mice, the immune response to curli fibrils is controlled by a protein called TLR-2 (Toll-like receptor 2). TLR-2 is expressed on the surface of certain cells that recognize foreign substances and passes on appropriate signals to the cells of the immune system.
Next, the team used cultures of human immune system cells to see if synthetic versions of the major curli fibril protein (CsgA) and the major protein found in amyloid plaques, (beta-amyloid) would trigger the TLR-2 response. They used cultures of macrophage cells, immune cells that engulf and digest cellular debris and pathogens. They also used microglia, which are essentially macrophages of the brain.
The team found that the mechanism involving TLR-2 was triggered by both CsgA and beta-amyloid but only when these proteins were allowed to aggregate into amyloids.
“The CsgA peptide and beta-amyloid don’t have anything genetically in common. The similarity is only in the structure of the amyloids they form. Our study indicates that there is some structural feature of amyloids that triggers the innate immune system,” Bäumler said.
The current findings are only the first step in what may ultimately be a drug treatment for amyloid diseases. If researchers can find a drug that inhibits the TLR-2-dependent immune response, Bäumler said, they could potentially slow down the progression of amyloid diseases, including Alzheimer’s.
“You have to know what causes the diseases in order to find the right drug target. Now we know what’s causing the chronic inflammation associated with amyloids. It’s a start, though we’re still a long from finding a treatment,” he said.
Additional authors of the study include UC Davis’ Cagla Tükel, R. Paul Wilson, Jessalyn Nishimori and Milad Pezeshki; and Brett Chromy of Lawrence Livermore National Laboratory.
The study was funded by Public Health Service grants to Bäumler and a Scientist Development Grant from the American Heart Association to Çagla Tükel.
UC Davis School of Medicine is among the nation's leading medical schools, recognized for its specialty-and primary-care programs.The school offers combined medical and master's degree programs in public health, business administration, and rural health, as well as a combined medical and doctoral degree for physician scientists interested in addressing specific scientific, social, ethical and political challenges of health care. Along with being a leader in health-care research, the school is known for its commitment to people from underserved communities and a passion for clinical care. For more information, visit www.ucdmc.ucdavis.edu/medschool.
Amyloid plaques, bacteria biofilm both cause inflammation that destroys neurons
(HealthNewsDigest.com) - SACRAMENTO, Calif. — In a new study published today in the July issue of the journal Cell Host & Microbe, UC Davis researchers report that both amyloid plaques found in the brains of Alzheimer’s patients and structures made by some gut bacteria likely elicit the same response by human immune cells.
“Alzheimer’s disease may be a case of mistaken identity,” said Andreas Bäumler, a professor of microbiology and medical immunology. Bäumler and his colleagues showed that the immune systems of mice injected with E. coli and salmonella are triggered by curli fibrils, fiber-like structures consisting of curli proteins that allow bacteria to stick to host tissue and to each other and form colonies.
Curli fibrils are morphologically identical to amyloid fibrils found in Alzheimer’s plaques. When they presented human cells with the two kinds of fibrils, they saw the same immune response — even though the two have nothing in common in their amino acid sequences.
“Our results suggest that it’s the structure of these protein aggregates that matter and that, to the innate immune system, Alzheimer’s plaques may look like colonies of bacteria. This would result in the chronic inflammation we see in Alzheimer’s disease that damages neurons,” Bäumler explained.
Amyloid plaques are the sticky buildup of proteins that accumulate outside nerve cells. They are characteristic of several illnesses, including Alzheimer’s disease, Huntington’s disease, type 2 diabetes, secondary amyloidosis and prion diseases, like Creutzfeldt-Jakob (the human form of mad cow disease). These diseases all involve marked inflammation at the sites of amyloid deposition, resulting in tissue injury.
The protein forming plaques in Alzheimer’s patients is normally soluble. When the protein folds improperly, it forms amyloid deposits that are associated with brain inflammation. Until now, scientists have not been able to identify what causes this destructive, chronic inflammation.
Bäumler and his colleagues did not expect to be studying Alzheimer’s disease. They were studying inflammation of the gut caused by bacteria when they discovered that the innate immune system was being triggered by a structural feature of bacterial amyloids and not by the amino acids that make up the proteins in the biofilms.
“When we destroyed the ability of the proteins to aggregate, we no longer saw the same immune response,” Bäumler said.
When the researchers figured out the amyloid structure was responsible for triggering the immune system, they decided to see whether the same immune response was being triggered by structurally identical amyloids associated with human disease. They chose to study the synthetic form of the proteins that make up Alzheimer’s plaques because the disease has been widely studied and a lot is known about the biochemistry of these plaques.
In the current study, Bäumler and his team found that, in mice, the immune response to curli fibrils is controlled by a protein called TLR-2 (Toll-like receptor 2). TLR-2 is expressed on the surface of certain cells that recognize foreign substances and passes on appropriate signals to the cells of the immune system.
Next, the team used cultures of human immune system cells to see if synthetic versions of the major curli fibril protein (CsgA) and the major protein found in amyloid plaques, (beta-amyloid) would trigger the TLR-2 response. They used cultures of macrophage cells, immune cells that engulf and digest cellular debris and pathogens. They also used microglia, which are essentially macrophages of the brain.
The team found that the mechanism involving TLR-2 was triggered by both CsgA and beta-amyloid but only when these proteins were allowed to aggregate into amyloids.
“The CsgA peptide and beta-amyloid don’t have anything genetically in common. The similarity is only in the structure of the amyloids they form. Our study indicates that there is some structural feature of amyloids that triggers the innate immune system,” Bäumler said.
The current findings are only the first step in what may ultimately be a drug treatment for amyloid diseases. If researchers can find a drug that inhibits the TLR-2-dependent immune response, Bäumler said, they could potentially slow down the progression of amyloid diseases, including Alzheimer’s.
“You have to know what causes the diseases in order to find the right drug target. Now we know what’s causing the chronic inflammation associated with amyloids. It’s a start, though we’re still a long from finding a treatment,” he said.
Additional authors of the study include UC Davis’ Cagla Tükel, R. Paul Wilson, Jessalyn Nishimori and Milad Pezeshki; and Brett Chromy of Lawrence Livermore National Laboratory.
The study was funded by Public Health Service grants to Bäumler and a Scientist Development Grant from the American Heart Association to Çagla Tükel.
UC Davis School of Medicine is among the nation's leading medical schools, recognized for its specialty-and primary-care programs.The school offers combined medical and master's degree programs in public health, business administration, and rural health, as well as a combined medical and doctoral degree for physician scientists interested in addressing specific scientific, social, ethical and political challenges of health care. Along with being a leader in health-care research, the school is known for its commitment to people from underserved communities and a passion for clinical care. For more information, visit www.ucdmc.ucdavis.edu/medschool.
Autism and Vaccines: Is the Case Closed?
July 22, 2009 03:22 PM ET | Deborah Kotz | Permanent Link | Print
I'll be the first to confess that I wasn't a fully informed parent when it came to getting my kids their early immunizations. They got every shot on time without my weighing the risks and benefits. I barely glanced at the consent form except to note when to dispense Tylenol for crankiness or fever. Thankfully, they all sailed through with no more than a few tears. Then it was time for my 12-year-old daughter to get Gardasil, the vaccine against the cervical-cancer-causing human papillomavirus (HPV). I was a little worried because it was a new vaccine and, after talking with some experts, decided to delay getting her vaccinated until she was older.
My primary concern was that since this vaccine was so new, no one knew exactly how long its protective effects would last. The vaccine could wear off, some experts told me, before my daughter was even exposed to the sexually transmitted HPV. I was also told that, although the vaccine was very safe, no one knew whether it caused rare side effects since not enough young girls have received the vaccine to detect them.
This spurred me to do extensive reporting on the immunization system in this country—how new vaccines get approved, how their safety is monitored, how adverse events are dealt with by the medical community. I explored these issues in this piece on new scrutiny for vaccines. After reading my article and this one on the need for more research by my colleague Bernadine Healy, M.D., leaders at the American Academy of Pediatrics wrote to U.S. News expressing their concerns that the articles would drive parents away from having their children vaccinated.
We invited the AAP president, David Tayloe, and president-elect, Judith Palfrey, to participate in a videotaped roundtable discussion on various issues concerning vaccines. Below is the first video excerpt: Is there still a need for more research into whether vaccines are associated with autism? Other videos will be posted soon on the following topics: the pros and cons of taking a flexible approach to the vaccine schedule; Gardasil concerns; how to communicate risks and benefits to parents; and the swine flu vaccine and other new immunizations.
Video: Vaccines and Autism—What the Pediatricians Think
I'll be the first to confess that I wasn't a fully informed parent when it came to getting my kids their early immunizations. They got every shot on time without my weighing the risks and benefits. I barely glanced at the consent form except to note when to dispense Tylenol for crankiness or fever. Thankfully, they all sailed through with no more than a few tears. Then it was time for my 12-year-old daughter to get Gardasil, the vaccine against the cervical-cancer-causing human papillomavirus (HPV). I was a little worried because it was a new vaccine and, after talking with some experts, decided to delay getting her vaccinated until she was older.
My primary concern was that since this vaccine was so new, no one knew exactly how long its protective effects would last. The vaccine could wear off, some experts told me, before my daughter was even exposed to the sexually transmitted HPV. I was also told that, although the vaccine was very safe, no one knew whether it caused rare side effects since not enough young girls have received the vaccine to detect them.
This spurred me to do extensive reporting on the immunization system in this country—how new vaccines get approved, how their safety is monitored, how adverse events are dealt with by the medical community. I explored these issues in this piece on new scrutiny for vaccines. After reading my article and this one on the need for more research by my colleague Bernadine Healy, M.D., leaders at the American Academy of Pediatrics wrote to U.S. News expressing their concerns that the articles would drive parents away from having their children vaccinated.
We invited the AAP president, David Tayloe, and president-elect, Judith Palfrey, to participate in a videotaped roundtable discussion on various issues concerning vaccines. Below is the first video excerpt: Is there still a need for more research into whether vaccines are associated with autism? Other videos will be posted soon on the following topics: the pros and cons of taking a flexible approach to the vaccine schedule; Gardasil concerns; how to communicate risks and benefits to parents; and the swine flu vaccine and other new immunizations.
Video: Vaccines and Autism—What the Pediatricians Think
Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells.
Olivieri G, Brack C, Müller-Spahn F, Stähelin HB, Herrmann M, Renard P, Brockhaus M, Hock C.
Neurobiology Laboratory, Psychiatric University Hospital, Basel, Switzerland. Olivieri@ubaclu.unibas.ch
Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer's disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl2) on oxidative stress, cell cytotoxicity, beta-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 microg/L (180 nM) HgCl2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n = 13, p<0.001). Preincubation of cells for 30 min with 1 microM melatonin or premixing melatonin and HgCl2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that 50 microg/L HgCl2 for 24 h produced a 50% inhibition of MTT reduction (n = 9, p<0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MTT reduction equaling control levels. The release of beta-amyloid peptide (Abeta) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl2 was shown to be different: Abeta 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas Abeta 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n = 9, p<0.001). Preincubation of cells with melatonin resulted in an attenuation of Abeta 1-40 and Abeta 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n = 9, p<0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD.
PMID: 10617124 [PubMed - indexed for MEDLINE
Neurobiology Laboratory, Psychiatric University Hospital, Basel, Switzerland. Olivieri@ubaclu.unibas.ch
Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer's disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl2) on oxidative stress, cell cytotoxicity, beta-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 microg/L (180 nM) HgCl2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n = 13, p<0.001). Preincubation of cells for 30 min with 1 microM melatonin or premixing melatonin and HgCl2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that 50 microg/L HgCl2 for 24 h produced a 50% inhibition of MTT reduction (n = 9, p<0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MTT reduction equaling control levels. The release of beta-amyloid peptide (Abeta) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl2 was shown to be different: Abeta 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas Abeta 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n = 9, p<0.001). Preincubation of cells with melatonin resulted in an attenuation of Abeta 1-40 and Abeta 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n = 9, p<0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD.
PMID: 10617124 [PubMed - indexed for MEDLINE
Biomarkers May Predict Alzheimer's
By Steven Reinberg
HealthDay Reporter – Tue Jul 21, 7:04 pm ET
TUESDAY, July 21 (HealthDay News) -- Certain proteins found in cerebrospinal fluid may accurately identify the people with mild cognitive impairment who are most likely to develop Alzheimer's disease, a new study finds.
Changes in the chemistry of cerebrospinal fluid have been identified as early signs of Alzheimer's disease. If and when treatments are available for Alzheimer's, diagnosing the disease early may help prevent it from developing, experts say.
"We confirmed, in a large multi-center study, that proteins in cerebrospinal fluid identify early-stage Alzheimer's disease, as suggested by previous smaller studies," said lead researcher Dr. Niklas Mattsson, from the Institute of Neuroscience and Physiology, Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital in Molndal, Sweden.
"These proteins may be used in research, in particular in drug trials, and also as a complement to clinical diagnostics, in particular when disease-modifying drugs become available," he said.
The report is published in the July 22/29 issue of the Journal of the American Medical Association.
For the study, Mattsson's team studied the accuracy of using three biomarkers found in spinal fluid in predicting Alzheimer's diseases. The biomarkers are beta-amyloid1-42 (Aβ42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau).
The researchers tested for these biomarkers in 750 people with mild cognitive impairment, 529 people with Alzheimer's disease and 304 healthy people. After two years, 271 of those with mild cognitive impairment progressed to Alzheimer's disease and 59 developed other dementias.
The researchers found that people who developed Alzheimer's had lower levels of Aβ42 and higher levels of P-tau and T-tau compared with patients with mild cognitive impairment who did not develop Alzheimer's.
Mattsson's group found these biomarkers were highly accurate in predicting which patients would develop Alzheimer's disease. "The cerebrospinal fluid proteins Aβ42, T-tau, and P-tau are useful in diagnosis of early-stage Alzheimer's disease," Mattsson noted.
Dr. Sam Gandy, the Mount Sinai Professor in Alzheimer's Disease Research at Mount Sinai School of Medicine in New York City, said this study really quantifies the accuracy of these tests in predicting Alzheimer's.
"There have been a number of smaller reports that Aβ falls and P-tau rises as the clinical course progresses from aging to mild cognitive impairment to Alzheimer's," Gandy said. "The sensitivities and specificities of these smaller studies have varied widely."
This larger study is definitive in establishing sensitivity and specificity that are somewhat lower than those reported by the smaller studies, Gandy said. "The larger study also points up the importance of harmonizing assays across multiple study sites in order to optimize the sensitivity and specificity."
Maria Carrillo, director of medical and scientific relations at the Alzheimer's Association, hopes that one day Alzheimer's can be screened for as routinely as cholesterol levels are checked today.
"We are very excited that cerebrospinal fluid biomarkers are holding up in terms of their specificity and sensitivity in diagnosing the disease early," Carrillo said. "The next step is to make sure these tests are standardized so that the test will mean the same thing, no matter where it is taken."
If these tests are standardized, it could be a biomarker that identifies the disease, Carrillo said. "If over the next two or three years we also have a therapy, then we need to examine how that therapy works in an incipient form of Alzheimer's, not once those memories have already started fading," she said.
HealthDay Reporter – Tue Jul 21, 7:04 pm ET
TUESDAY, July 21 (HealthDay News) -- Certain proteins found in cerebrospinal fluid may accurately identify the people with mild cognitive impairment who are most likely to develop Alzheimer's disease, a new study finds.
Changes in the chemistry of cerebrospinal fluid have been identified as early signs of Alzheimer's disease. If and when treatments are available for Alzheimer's, diagnosing the disease early may help prevent it from developing, experts say.
"We confirmed, in a large multi-center study, that proteins in cerebrospinal fluid identify early-stage Alzheimer's disease, as suggested by previous smaller studies," said lead researcher Dr. Niklas Mattsson, from the Institute of Neuroscience and Physiology, Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital in Molndal, Sweden.
"These proteins may be used in research, in particular in drug trials, and also as a complement to clinical diagnostics, in particular when disease-modifying drugs become available," he said.
The report is published in the July 22/29 issue of the Journal of the American Medical Association.
For the study, Mattsson's team studied the accuracy of using three biomarkers found in spinal fluid in predicting Alzheimer's diseases. The biomarkers are beta-amyloid1-42 (Aβ42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau).
The researchers tested for these biomarkers in 750 people with mild cognitive impairment, 529 people with Alzheimer's disease and 304 healthy people. After two years, 271 of those with mild cognitive impairment progressed to Alzheimer's disease and 59 developed other dementias.
The researchers found that people who developed Alzheimer's had lower levels of Aβ42 and higher levels of P-tau and T-tau compared with patients with mild cognitive impairment who did not develop Alzheimer's.
Mattsson's group found these biomarkers were highly accurate in predicting which patients would develop Alzheimer's disease. "The cerebrospinal fluid proteins Aβ42, T-tau, and P-tau are useful in diagnosis of early-stage Alzheimer's disease," Mattsson noted.
Dr. Sam Gandy, the Mount Sinai Professor in Alzheimer's Disease Research at Mount Sinai School of Medicine in New York City, said this study really quantifies the accuracy of these tests in predicting Alzheimer's.
"There have been a number of smaller reports that Aβ falls and P-tau rises as the clinical course progresses from aging to mild cognitive impairment to Alzheimer's," Gandy said. "The sensitivities and specificities of these smaller studies have varied widely."
This larger study is definitive in establishing sensitivity and specificity that are somewhat lower than those reported by the smaller studies, Gandy said. "The larger study also points up the importance of harmonizing assays across multiple study sites in order to optimize the sensitivity and specificity."
Maria Carrillo, director of medical and scientific relations at the Alzheimer's Association, hopes that one day Alzheimer's can be screened for as routinely as cholesterol levels are checked today.
"We are very excited that cerebrospinal fluid biomarkers are holding up in terms of their specificity and sensitivity in diagnosing the disease early," Carrillo said. "The next step is to make sure these tests are standardized so that the test will mean the same thing, no matter where it is taken."
If these tests are standardized, it could be a biomarker that identifies the disease, Carrillo said. "If over the next two or three years we also have a therapy, then we need to examine how that therapy works in an incipient form of Alzheimer's, not once those memories have already started fading," she said.
Research targets chemical in plastics
By Blythe Bernhard
ST. LOUIS POST-DISPATCH
07/16/2009
A chemical commonly used in plastics causes damage to reproductive systems in mice, according to new research from the University of Illinois at Urbana-Champaign.
Bisphenol A, found in some baby bottles, compact discs, plastic utensils and food containers, has already been proved to cause reproductive issues in the babies of mice that were exposed to the chemical in pregnancy. Now researchers have shown the chemical reduces the production of hormones in adult mice.
The study, led by veterinary biosciences professor Jodi Flaws, is believed to be the first to show that Bisphenol A (BPA) exposure can harm adult reproductive cells. Researchers are scheduled to present their findings next week in Pittsburgh at the Society for the Study of Reproduction's annual meeting.
More studies are needed to determine if the same negative effects would be seen in humans, researchers said.
Some plastics manufacturers have already started removing the chemical following earlier research that raised concerns about BPA levels found in human urine, blood and breast milk.
In one sample from 2004, the federal Centers for Disease Control and Prevention found BPA in the urine of 93 percent of the 2,517 Americans who were tested. Women generally had higher BPA levels than men, the testing showed.
The structure of BPA is similar to the steroid hormone called estradiol. The BPA, like estradiol, can attach to estrogen receptors on cells. The BPA may then block or stimulate the effects of estrogen.
In the study on mice, researchers found that the chemical harms the cells, follicles and hormones necessary for ovulation.
"These are the only follicles that are capable of ovulating and so if they don't grow properly, they're not going to ovulate and there could be fertility issues," Flaws said in a statement.
The hormones are not only required for reproduction, but also contribute to bone and heart health.
Researchers found that BPA affected follicle growth in the mice in two days following an exposure. About a week after a heavy exposure, the levels of the hormones progesterone, testosterone and estradiol were lowered by nearly 100 percent.
Federal health officials have said humans are not exposed to the high levels of BPA that have been shown to be harmful in animals. But the 2008 report from the U.S. Department of Health and Human Services also said the previous research does cause concern for exposure to fetuses, infants and children.
The Illinois scientists said their research suggests possible problems for adults, including infertility issues.
ST. LOUIS POST-DISPATCH
07/16/2009
A chemical commonly used in plastics causes damage to reproductive systems in mice, according to new research from the University of Illinois at Urbana-Champaign.
Bisphenol A, found in some baby bottles, compact discs, plastic utensils and food containers, has already been proved to cause reproductive issues in the babies of mice that were exposed to the chemical in pregnancy. Now researchers have shown the chemical reduces the production of hormones in adult mice.
The study, led by veterinary biosciences professor Jodi Flaws, is believed to be the first to show that Bisphenol A (BPA) exposure can harm adult reproductive cells. Researchers are scheduled to present their findings next week in Pittsburgh at the Society for the Study of Reproduction's annual meeting.
More studies are needed to determine if the same negative effects would be seen in humans, researchers said.
Some plastics manufacturers have already started removing the chemical following earlier research that raised concerns about BPA levels found in human urine, blood and breast milk.
In one sample from 2004, the federal Centers for Disease Control and Prevention found BPA in the urine of 93 percent of the 2,517 Americans who were tested. Women generally had higher BPA levels than men, the testing showed.
The structure of BPA is similar to the steroid hormone called estradiol. The BPA, like estradiol, can attach to estrogen receptors on cells. The BPA may then block or stimulate the effects of estrogen.
In the study on mice, researchers found that the chemical harms the cells, follicles and hormones necessary for ovulation.
"These are the only follicles that are capable of ovulating and so if they don't grow properly, they're not going to ovulate and there could be fertility issues," Flaws said in a statement.
The hormones are not only required for reproduction, but also contribute to bone and heart health.
Researchers found that BPA affected follicle growth in the mice in two days following an exposure. About a week after a heavy exposure, the levels of the hormones progesterone, testosterone and estradiol were lowered by nearly 100 percent.
Federal health officials have said humans are not exposed to the high levels of BPA that have been shown to be harmful in animals. But the 2008 report from the U.S. Department of Health and Human Services also said the previous research does cause concern for exposure to fetuses, infants and children.
The Illinois scientists said their research suggests possible problems for adults, including infertility issues.
Sensitive to an array of pollutants, Kathy Hemenway uprooted herself to find a clean environment. Should the rest of us worry? By Karen Ravn >>> July
Study of a potentially fatal food-triggered disease has uncovered a process that may contribute to many autoimmune disorders
By Alessio Fasano
Foods containing wheat, rye or barley trigger an autoimmune reaction (against the body's own tissues) in people afflicted with celiac disease. The response harms the intestinal lining and impairs the body's absorption of nutrients. Chronic exposure to those foods can also lead to cancer and other ill effects in such individuals.
Key Concepts
Celiac disease (CD) is an autoimmune disorder triggered by ingestion of gluten, a major protein in wheat, or of related proteins in other grains.
Research into the root causes indicates that the disorder develops when a person exposed to gluten also has a genetic susceptibility to CD and an unusually permeable intestinal wall.
Surprisingly, essentially the same trio—an environmental trigger, a genetic susceptibility and a “leaky gut”—seems to underlie other autoimmune disorders as well. This finding raises the possibility that new treatments for CD may also ameliorate other conditions.
My vote for the most important scientific revolution of all time would trace back 10,000 years ago to the Middle East, when people first noticed that new plants arise from seeds falling to the ground from other plants—a realization that led to the birth of agriculture. Before that observation, the human race had based its diet on fruits, nuts, tubers and occasional meats. People had to move to where their food happened to be, putting them at the mercy of events and making long-term settlements impossible.
Once humans uncovered the secret of seeds, they quickly learned to domesticate crops, ultimately crossbreeding different grass plants to create such staple grains as wheat, rye and barley, which were nutritious, versatile, storable, and valuable for trade. For the first time, people were able to abandon the nomadic life and build cities. It is no coincidence that the first agricultural areas also became "cradles of civilization."
This advancement, however, came at a dear price: the emergence of an illness now known as celiac disease (CD), which is triggered by ingesting a protein in wheat called gluten or eating similar proteins in rye and barley. Gluten and its relatives had previously been absent from the human diet. But once grains began fueling the growth of stable communities, the proteins undoubtedly began killing people (often children) whose bodies reacted abnormally to them. Eating such proteins repeatedly would have eventually rendered sensitive individuals unable to properly absorb nutrients from food. Victims would also have come to suffer from recurrent abdominal pain and diarrhea and to display the emaciated bodies and swollen bellies of starving people. Impaired nutrition and a spectrum of other complications would have made their lives relatively short and miserable.
If these deaths were noticed at the time, the cause would have been a mystery. Over the past 20 years, however, scientists have pieced together a detailed understanding of CD. They now know that it is an autoimmune disorder, in which the immune system attacks the body’s own tissues. And they know that the disease arises not only from exposure to gluten and its ilk but from a combination of factors, including predisposing genes and abnormalities in the structure of the small intestine.
What is more, CD provides an illuminating example of the way such a triad—an environmental trigger, susceptibility genes and a gut abnormality—may play a role in many autoimmune disorders. Research into CD has thus suggested new types of treatment not only for the disease itself but also for various other autoimmune conditions, such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis.
Early Insights
After the advent of agriculture, thousands of years passed before instances of seemingly well-fed but undernourished children were documented. CD acquired a name in the first century A.D., when Aretaeus of Cappadocia, a Greek physician, reported the first scientific description, calling it koiliakos, after the Greek word for “abdomen,” koelia. British physician Samuel Gee is credited as the modern father of CD. In a 1887 lecture he described it as “a kind of chronic indigestion which is met with in persons of all ages, yet is especially apt to affect children between one and five years old.” He even correctly surmised that “errors in diet may perhaps be a cause.” As clever as Gee obviously was, the true nature of the disease escaped even him, as was clear from his dietary prescription: he suggested feeding these children thinly sliced bread, toasted on both sides.
Identification of gluten as the trigger occurred after World War II, when Dutch pediatrician Willem-Karel Dicke noticed that a war-related shortage of bread in the Netherlands led to a significant drop in the death rate among children affected by CD—from greater than 35 percent to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels. Following up on Dicke’s observation, other scientists looked at the different components of wheat, discovering that the major protein in that grain, gluten, was the culprit.
By Alessio Fasano
Foods containing wheat, rye or barley trigger an autoimmune reaction (against the body's own tissues) in people afflicted with celiac disease. The response harms the intestinal lining and impairs the body's absorption of nutrients. Chronic exposure to those foods can also lead to cancer and other ill effects in such individuals.
Key Concepts
Celiac disease (CD) is an autoimmune disorder triggered by ingestion of gluten, a major protein in wheat, or of related proteins in other grains.
Research into the root causes indicates that the disorder develops when a person exposed to gluten also has a genetic susceptibility to CD and an unusually permeable intestinal wall.
Surprisingly, essentially the same trio—an environmental trigger, a genetic susceptibility and a “leaky gut”—seems to underlie other autoimmune disorders as well. This finding raises the possibility that new treatments for CD may also ameliorate other conditions.
My vote for the most important scientific revolution of all time would trace back 10,000 years ago to the Middle East, when people first noticed that new plants arise from seeds falling to the ground from other plants—a realization that led to the birth of agriculture. Before that observation, the human race had based its diet on fruits, nuts, tubers and occasional meats. People had to move to where their food happened to be, putting them at the mercy of events and making long-term settlements impossible.
Once humans uncovered the secret of seeds, they quickly learned to domesticate crops, ultimately crossbreeding different grass plants to create such staple grains as wheat, rye and barley, which were nutritious, versatile, storable, and valuable for trade. For the first time, people were able to abandon the nomadic life and build cities. It is no coincidence that the first agricultural areas also became "cradles of civilization."
This advancement, however, came at a dear price: the emergence of an illness now known as celiac disease (CD), which is triggered by ingesting a protein in wheat called gluten or eating similar proteins in rye and barley. Gluten and its relatives had previously been absent from the human diet. But once grains began fueling the growth of stable communities, the proteins undoubtedly began killing people (often children) whose bodies reacted abnormally to them. Eating such proteins repeatedly would have eventually rendered sensitive individuals unable to properly absorb nutrients from food. Victims would also have come to suffer from recurrent abdominal pain and diarrhea and to display the emaciated bodies and swollen bellies of starving people. Impaired nutrition and a spectrum of other complications would have made their lives relatively short and miserable.
If these deaths were noticed at the time, the cause would have been a mystery. Over the past 20 years, however, scientists have pieced together a detailed understanding of CD. They now know that it is an autoimmune disorder, in which the immune system attacks the body’s own tissues. And they know that the disease arises not only from exposure to gluten and its ilk but from a combination of factors, including predisposing genes and abnormalities in the structure of the small intestine.
What is more, CD provides an illuminating example of the way such a triad—an environmental trigger, susceptibility genes and a gut abnormality—may play a role in many autoimmune disorders. Research into CD has thus suggested new types of treatment not only for the disease itself but also for various other autoimmune conditions, such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis.
Early Insights
After the advent of agriculture, thousands of years passed before instances of seemingly well-fed but undernourished children were documented. CD acquired a name in the first century A.D., when Aretaeus of Cappadocia, a Greek physician, reported the first scientific description, calling it koiliakos, after the Greek word for “abdomen,” koelia. British physician Samuel Gee is credited as the modern father of CD. In a 1887 lecture he described it as “a kind of chronic indigestion which is met with in persons of all ages, yet is especially apt to affect children between one and five years old.” He even correctly surmised that “errors in diet may perhaps be a cause.” As clever as Gee obviously was, the true nature of the disease escaped even him, as was clear from his dietary prescription: he suggested feeding these children thinly sliced bread, toasted on both sides.
Identification of gluten as the trigger occurred after World War II, when Dutch pediatrician Willem-Karel Dicke noticed that a war-related shortage of bread in the Netherlands led to a significant drop in the death rate among children affected by CD—from greater than 35 percent to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels. Following up on Dicke’s observation, other scientists looked at the different components of wheat, discovering that the major protein in that grain, gluten, was the culprit.
In search of a nontoxic home
Sensitive to an array of pollutants, Kathy Hemenway uprooted herself to find a clean environment. Should the rest of us worry?
By Karen Ravn
July 27, 2009
No paint on the walls. No carpets on the floors. No TV in the living room. Or the bedroom. Or the kitchen. No TV anywhere in the house.
Kathy Hemenway's home in Snowflake, Ariz., is a refuge from the gases, chemicals and electromagnetic fields that are nearly ubiquitous in our 21st century world.
Her chemical sensitivities began when she was just a kid. "I couldn't figure out why people liked perfume," she says. "It gave me a headache. And fabric stores gave me a sore throat."
Those problems grew more severe in adulthood, so she started making small changes -- using natural, fragrance-free shampoos and soaps; avoiding air fresheners, fresh paint, pesticides and lawn-care chemicals; and becoming super-diligent about housekeeping, but only with natural cleaners such as baking soda and vinegar.
Then she started moving -- from homes with carpet to homes with hardwood floors, then from Menlo Park, Calif., where she was a successful software engineer, to Santa Cruz and a home with all the other safe stuff plus fresh ocean air.
But after an accidental exposure there to nearby lawn chemicals, Hemenway began to have trouble breathing and even more trouble sleeping. She grew agitated, jittery and depressed, and felt as if she were in a fog, she says. She also became sensitive to many more substances than usual and had to use an oxygen tank to recover from even mild exposures, such as breathing exhaust fumes on the freeway. She wound up at the Environmental Health Center in Dallas for treatment, which included oxygen therapy and sauna sessions (for detoxification), a special diet (rotated every four days) and nutritional supplements she took orally and intravenously. After that, she says, "I was desperate for a safe home, and that's when I decided to go to the safest place I could find."
She found Snowflake.
"It's hard, frequently devastating, to accept that you're never going to get better unless you move to a whole other environment," Hemenway says of her leap 10 years ago. But, she decided, the quality of her life depended on it.
The house she built in this remote high desert town is not only a no-paint, no-carpet zone, but also a no-plywood, no-particleboard, no-tar paper zone. And no pesticides were used on the foundation or on the land before the foundation was laid.
The exterior of the house is made of masonry blocks, and most of the interior framing is made of steel. So is the roof. The floors are glazed ceramic tile throughout the house, and in the bedroom the walls and ceiling are too.
The house has radiant in-floor heating instead of forced-air heating. "It doesn't blow the dust around," Hemenway says, "and you don't have the combustion byproducts of a forced-air furnace."
And not to worry -- she can watch TV. But to avoid its electromagnetic field, she keeps the set in a barn about 200 feet from the house and records programs there, then brings the DVDs inside and plays them on a projection system.
Hemenway is one of millions of Americans who believe that sprays meant to freshen the air actually pollute it, that chemicals meant to beautify our yards in fact poison them, and that many of the products and materials that make modern life fast and convenient also make people sick. They cite studies connecting a host of suspect substances to a host of human illnesses, from headaches and sniffles to immune disorders and cancer.
Most people can't move to Snowflake and build "safe houses," of course (and if too many of us did, we'd mess up the air quality anyway). Fortunately, most are not as sensitive to environmental pollutants as Hemenway, whose condition is recognized by many -- but not all -- medical professionals as "environmental illness."
Still, a connection between health and the environment is widely recognized in the medical and scientific communities. More than 30 years ago, for example, the Air Pollution Health Effects Laboratory was established at UC Irvine especially to study the connections between air quality and health. Raising awareness of these connections empowers people, says Robert Phalen, the laboratory's founder and current director and also a professor of medicine.
"Within the last year or two, there's been a tremendous awareness about green buildings -- and healthy buildings too," says Peter Sierck, the principal of Environmental Testing & Technology in San Diego, which specializes in testing for mold, moisture, electromagnetic fields and general indoor air quality.
But some researchers worry that consumers' fears are getting ahead of the scientific evidence. Some have ripped out carpets to avoid chemical releases or renounced miracle fabrics in favor of natural fibers.
Many people have concerns about perfumes, shampoos, soaps and other products that produce odors, says Dr. Ware Kuschner, an associate professor of pulmonary and critical care medicine at the Stanford University School of Medicine who practices at the U.S. Department of Veterans Affairs. He does research on the health effects of indoor and outdoor air pollution. "But the link between exposure to these products and serious adverse health effects is often quite tenuous."
That's because the harm a substance can do generally depends on how much of it you're exposed to and how long you're exposed to it -- as well as how sensitive you are.
Knowing whether to be concerned, or how much to be concerned, isn't easy. Scientists at regulatory agencies spend years making official risk assessments.
Still, it's possible to set some priorities, and you probably shouldn't spend too much time worrying about things that are very unlikely to happen, says Dr. Philip Harber, a professor of occupational and environmental medicine at UCLA. "Many more people die of drowning in a swimming pool than die of exposure to mold. . . . It's really important not to overlook the obvious."
By Karen Ravn
July 27, 2009
No paint on the walls. No carpets on the floors. No TV in the living room. Or the bedroom. Or the kitchen. No TV anywhere in the house.
Kathy Hemenway's home in Snowflake, Ariz., is a refuge from the gases, chemicals and electromagnetic fields that are nearly ubiquitous in our 21st century world.
Her chemical sensitivities began when she was just a kid. "I couldn't figure out why people liked perfume," she says. "It gave me a headache. And fabric stores gave me a sore throat."
Those problems grew more severe in adulthood, so she started making small changes -- using natural, fragrance-free shampoos and soaps; avoiding air fresheners, fresh paint, pesticides and lawn-care chemicals; and becoming super-diligent about housekeeping, but only with natural cleaners such as baking soda and vinegar.
Then she started moving -- from homes with carpet to homes with hardwood floors, then from Menlo Park, Calif., where she was a successful software engineer, to Santa Cruz and a home with all the other safe stuff plus fresh ocean air.
But after an accidental exposure there to nearby lawn chemicals, Hemenway began to have trouble breathing and even more trouble sleeping. She grew agitated, jittery and depressed, and felt as if she were in a fog, she says. She also became sensitive to many more substances than usual and had to use an oxygen tank to recover from even mild exposures, such as breathing exhaust fumes on the freeway. She wound up at the Environmental Health Center in Dallas for treatment, which included oxygen therapy and sauna sessions (for detoxification), a special diet (rotated every four days) and nutritional supplements she took orally and intravenously. After that, she says, "I was desperate for a safe home, and that's when I decided to go to the safest place I could find."
She found Snowflake.
"It's hard, frequently devastating, to accept that you're never going to get better unless you move to a whole other environment," Hemenway says of her leap 10 years ago. But, she decided, the quality of her life depended on it.
The house she built in this remote high desert town is not only a no-paint, no-carpet zone, but also a no-plywood, no-particleboard, no-tar paper zone. And no pesticides were used on the foundation or on the land before the foundation was laid.
The exterior of the house is made of masonry blocks, and most of the interior framing is made of steel. So is the roof. The floors are glazed ceramic tile throughout the house, and in the bedroom the walls and ceiling are too.
The house has radiant in-floor heating instead of forced-air heating. "It doesn't blow the dust around," Hemenway says, "and you don't have the combustion byproducts of a forced-air furnace."
And not to worry -- she can watch TV. But to avoid its electromagnetic field, she keeps the set in a barn about 200 feet from the house and records programs there, then brings the DVDs inside and plays them on a projection system.
Hemenway is one of millions of Americans who believe that sprays meant to freshen the air actually pollute it, that chemicals meant to beautify our yards in fact poison them, and that many of the products and materials that make modern life fast and convenient also make people sick. They cite studies connecting a host of suspect substances to a host of human illnesses, from headaches and sniffles to immune disorders and cancer.
Most people can't move to Snowflake and build "safe houses," of course (and if too many of us did, we'd mess up the air quality anyway). Fortunately, most are not as sensitive to environmental pollutants as Hemenway, whose condition is recognized by many -- but not all -- medical professionals as "environmental illness."
Still, a connection between health and the environment is widely recognized in the medical and scientific communities. More than 30 years ago, for example, the Air Pollution Health Effects Laboratory was established at UC Irvine especially to study the connections between air quality and health. Raising awareness of these connections empowers people, says Robert Phalen, the laboratory's founder and current director and also a professor of medicine.
"Within the last year or two, there's been a tremendous awareness about green buildings -- and healthy buildings too," says Peter Sierck, the principal of Environmental Testing & Technology in San Diego, which specializes in testing for mold, moisture, electromagnetic fields and general indoor air quality.
But some researchers worry that consumers' fears are getting ahead of the scientific evidence. Some have ripped out carpets to avoid chemical releases or renounced miracle fabrics in favor of natural fibers.
Many people have concerns about perfumes, shampoos, soaps and other products that produce odors, says Dr. Ware Kuschner, an associate professor of pulmonary and critical care medicine at the Stanford University School of Medicine who practices at the U.S. Department of Veterans Affairs. He does research on the health effects of indoor and outdoor air pollution. "But the link between exposure to these products and serious adverse health effects is often quite tenuous."
That's because the harm a substance can do generally depends on how much of it you're exposed to and how long you're exposed to it -- as well as how sensitive you are.
Knowing whether to be concerned, or how much to be concerned, isn't easy. Scientists at regulatory agencies spend years making official risk assessments.
Still, it's possible to set some priorities, and you probably shouldn't spend too much time worrying about things that are very unlikely to happen, says Dr. Philip Harber, a professor of occupational and environmental medicine at UCLA. "Many more people die of drowning in a swimming pool than die of exposure to mold. . . . It's really important not to overlook the obvious."
Children more vulnerable to pesticides until age 7 due to lower enzyme level
Huen K, K Harley, J Brooks, A Hubbard, A Bradman, B Eskenazi and N Holland. 2009. Developmental changes in PON1 enzyme activity in young children and effects of PON1 polymorphisms. Environmental Health Perspectives doi:10.1289/ehp.0900870.
Synopsis by Kim Harley, Ph.D.
Children are more susceptible to the toxic effects of certain pesticides than adults, and this vulnerability lasts longer than previously believed.
A new study finds that young children have significantly lower levels of a key enzyme that protects against the toxic effects of certain pesticides. The youngsters' enzyme levels do not catch up to an adult's until after age seven – far longer than previously thought.
In addition, a person's genes dictate how effective the enzyme is at breaking down the pesticides. This is one reason why some people are more susceptible to the effects of pesticides than others.
Regulations governing organophosphate pesticide use should recognize that some individuals are more susceptible to the toxic effects of pesticides, say the researchers from the University of California, Berkeley who authored the study. Children are also more susceptible and this increased vulnerability appears to continue into school age.
The enzyme, called paraoxonase, plays a key role in helping the body neutralize and eliminate organophosphate pesticides. Organophosphates are a class of acutely toxic insecticides that have been largely banned for home use, but continue to be widely used in agriculture. Organophosphate pesticides target the nervous systems of insects, but have similar effects on humans. Some studies have shown reduced IQs among young children whose mothers were exposed to these pesticides during pregnancy.
Although it has been known that newborns have low levels of the paraoxonase enzyme, it was previously believed that paraoxonase concentrations reached adult levels by 2 years of age.
This assumption was based on one earlier study of 9 children. Now a new study of 458 children followed from birth to age 7 shows that paraoxonase levels continue to increase steadily until age 7. At age 7, the average paraoxonase level in children was similar to, but still lower than, adult levels.
Researchers measured paraoxonase levels in children’s blood at birth and at 1, 2, 5 and 7 years of age. They compared these levels with those of their mothers.
In addition to the gains with age, paraoxonase also varied by a child's genetics. Both the quantity and the quality (i.e. how fast it detoxifies the pesticide) of the enzyme are dependent of variations in the paraoxonase gene. Children with certain variations of the gene had significantly lower enzyme levels and activity.
Synopsis by Kim Harley, Ph.D.
Children are more susceptible to the toxic effects of certain pesticides than adults, and this vulnerability lasts longer than previously believed.
A new study finds that young children have significantly lower levels of a key enzyme that protects against the toxic effects of certain pesticides. The youngsters' enzyme levels do not catch up to an adult's until after age seven – far longer than previously thought.
In addition, a person's genes dictate how effective the enzyme is at breaking down the pesticides. This is one reason why some people are more susceptible to the effects of pesticides than others.
Regulations governing organophosphate pesticide use should recognize that some individuals are more susceptible to the toxic effects of pesticides, say the researchers from the University of California, Berkeley who authored the study. Children are also more susceptible and this increased vulnerability appears to continue into school age.
The enzyme, called paraoxonase, plays a key role in helping the body neutralize and eliminate organophosphate pesticides. Organophosphates are a class of acutely toxic insecticides that have been largely banned for home use, but continue to be widely used in agriculture. Organophosphate pesticides target the nervous systems of insects, but have similar effects on humans. Some studies have shown reduced IQs among young children whose mothers were exposed to these pesticides during pregnancy.
Although it has been known that newborns have low levels of the paraoxonase enzyme, it was previously believed that paraoxonase concentrations reached adult levels by 2 years of age.
This assumption was based on one earlier study of 9 children. Now a new study of 458 children followed from birth to age 7 shows that paraoxonase levels continue to increase steadily until age 7. At age 7, the average paraoxonase level in children was similar to, but still lower than, adult levels.
Researchers measured paraoxonase levels in children’s blood at birth and at 1, 2, 5 and 7 years of age. They compared these levels with those of their mothers.
In addition to the gains with age, paraoxonase also varied by a child's genetics. Both the quantity and the quality (i.e. how fast it detoxifies the pesticide) of the enzyme are dependent of variations in the paraoxonase gene. Children with certain variations of the gene had significantly lower enzyme levels and activity.
Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscl
Click title to read full study.
Macrophagic myofasciitis (MMF) is an emerging condition of unknown
cause, detected in patients with diffuse arthromyalgias and fatigue, and
characterized by muscle infiltration by granular periodic acid-Schiff's
reagent-positive macrophages and lymphocytes. Intracytoplasmic
inclusions have been observed in macrophages of some patients. To assess
their significance, electron microscopy was performed in 40 consecutive
cases and chemical analysis was done by microanalysis and atomic
absorption spectrometry. Inclusions were constantly detected and
corresponded to aluminium hydroxide, an immunostimulatory compound
frequently used as a vaccine adjuvant. A lymphocytic component was
constantly observed in MMF lesions. Serological tests were compatible
with exposure to aluminium hydroxide-containing vaccines. History
analysis revealed that 50 out of 50 patients had received vaccines
against hepatitis B virus (86%), hepatitis A virus (19%) or tetanus
toxoid (58%), 3-96 months (median 36 months) before biopsy. Diffuse
myalgias were more frequent in patients with than without an MMF lesion
at deltoid muscle biopsy (P < 0.0001). Myalgia onset was subsequent to
the vaccination (median 11 months) in 94% of patients. MMF lesion was
experimentally reproduced in rats. We conclude that the MMF lesion is
secondary to intramuscular injection of aluminium hydroxide-containing
vaccines, shows both long-term persistence of aluminium hydroxide and an
ongoing local immune reaction, and is detected in patients with systemic
symptoms which appeared subsequently to vaccination.
Macrophagic myofasciitis (MMF) is an emerging condition of unknown
cause, detected in patients with diffuse arthromyalgias and fatigue, and
characterized by muscle infiltration by granular periodic acid-Schiff's
reagent-positive macrophages and lymphocytes. Intracytoplasmic
inclusions have been observed in macrophages of some patients. To assess
their significance, electron microscopy was performed in 40 consecutive
cases and chemical analysis was done by microanalysis and atomic
absorption spectrometry. Inclusions were constantly detected and
corresponded to aluminium hydroxide, an immunostimulatory compound
frequently used as a vaccine adjuvant. A lymphocytic component was
constantly observed in MMF lesions. Serological tests were compatible
with exposure to aluminium hydroxide-containing vaccines. History
analysis revealed that 50 out of 50 patients had received vaccines
against hepatitis B virus (86%), hepatitis A virus (19%) or tetanus
toxoid (58%), 3-96 months (median 36 months) before biopsy. Diffuse
myalgias were more frequent in patients with than without an MMF lesion
at deltoid muscle biopsy (P < 0.0001). Myalgia onset was subsequent to
the vaccination (median 11 months) in 94% of patients. MMF lesion was
experimentally reproduced in rats. We conclude that the MMF lesion is
secondary to intramuscular injection of aluminium hydroxide-containing
vaccines, shows both long-term persistence of aluminium hydroxide and an
ongoing local immune reaction, and is detected in patients with systemic
symptoms which appeared subsequently to vaccination.
Etiologic Classification of Attention-Deficit/Hyperactivity Disorder
J. Gordon Millichap, MD, FRCP
Division of Neurology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois
ABSTRACT
Attention-deficit/hyperactivity disorder is a neurobiological syndrome with an estimated prevalence among children and adolescents of 5%. It is a highly heritable disorder, but acquired factors in etiology are sometimes uncovered that may be amenable to preventive measures or specific therapy. Early reports have described symptoms similar to attention-deficit/hyperactivity disorder that followed brain trauma or viral encephalitis, and recent MRI studies have demonstrated brain volumetric changes that may be involved in the pathophysiology of the syndrome. The American Psychiatric Association's Diagnostic Statistical Manual, introduced in 1968, emphasizes symptomatic criteria in diagnosis. Here, an overview of environmental factors in the etiology of attention-deficit/hyperactivity disorder is presented to encourage more emphasis and research on organic causal factors, preventive intervention, and specific therapies. An organic theory and the genetic and biochemical basis of attention-deficit/hyperactivity disorder are briefly reviewed, and an etiologic classification is suggested. Environmental factors are prenatal, perinatal, and postnatal in origin. Pregnancy- and birth-related risk factors include maternal smoking and alcohol ingestion, prematurity, hypoxic-ischemic encephalopathy, and thyroid deficiency. Childhood illnesses associated with attention-deficit/hyperactivity disorder include virus infections, meningitis, encephalitis, head injury, epilepsy, toxins, and drugs. More controversial factors discussed are diet-related sensitivities and iron deficiency. Early prenatal recognition, prevention, and treatment of environmental etiologies of attention-deficit/hyperactivity disorder may reduce physician reliance on symptomatic modification with medication, a frequent reason for parental concern.
Key Words: attention deficit • hyperactivity • etiology • environmental • viral • nicotine • thyroid
Abbreviations: ADHD—attention-deficit/hyperactivity disorder • GRTH—generalized resistance to thyroid hormone
Attention-deficit/hyperactivity disorder (ADHD), a neurobiological syndrome that affects an estimated 5% or more of school-aged children, has been recognized under different names for more than a century. In the earliest reports, behavioral abnormalities similar to ADHD were described after head injury1 and as a complication of encephalitis after the influenza epidemic of 1918.2,3 "Organic drivenness" was a term used to describe the behavior after epidemic encephalitis, and damage to the brainstem was suggested as the cause.4 This description of behavioral symptoms caused by encephalitis or brain damage was followed by a variety of reports linked to brain dysfunction and described by various terms including "minimal brain dysfunction" in 19665 and "hyperkinetic reaction of childhood or adolescence" in 1968. The American Psychiatric Association's Diagnostic Statistical Manual and its subsequent revisions6 omit reference to frequently associated motor perceptual and subtle neurologic signs, favoring symptomatic diagnostic criteria. Similarly, a clinician's approach to the management of ADHD is concerned primarily with symptomatic treatment. The purpose of this critical assessment of our approach to ADHD is to present an overview of organic and genetic causes and reports of environmental factors in the etiology of ADHD. A greater emphasis on etiology might encourage a preventive or specific approach to treatment, with less reliance on symptom modification with medications.
ORGANIC THEORY OF ADHD
Numerous experimental studies of cortical ablation and subcortical lesions in animals and clinical studies of brain-damaged children and adults have correlated the sites of cerebral lesions with the symptoms of hyperkinesia, distractibility, and inattention.7,8 A cortical-striatal circuit has been proposed to explain the heterogeneous nature of the ADHD syndrome.9 A decrease in volume of the right anterior frontal region and loss of normal right-to-left asymmetries in striatal nuclei have been shown on MRI studies. These findings support the involvement of the frontal lobes and striatal connections in the pathophysiology of ADHD.10 A temporal lobe arachnoid cyst–ADHD syndrome has also been described in patients with coincidental learning and language disabilities.11 In 1 case report of a patient with this syndrome who presented with headaches after a head injury, surgical intervention with shunt procedure resulted in improved cognitive function and behavior.12
Prefrontal and cingulate brain regions are involved in inhibitory control, a function typically deficient in children with ADHD. A functional MRI study of 17 subjects with ADHD and 15 healthy controls showed that, in relation to control subjects, children with ADHD failed to activate the anterior cingulate cortex and the left ventrolateral prefrontal cortex after unsuccessful inhibition. The patients were treatment-naive, and the findings were unrelated to long-term treatment or abrupt withdrawal of stimulant medications before imaging.13
GENETIC AND BIOCHEMICAL BASIS OF ADHD
Genetic factors account for 80% of the etiology of ADHD.14 Family, twin, and adoption studies support the theory that ADHD is a highly heritable disorder, with the majority of patients having a first- or second-degree relative with a history of ADHD or learning disorder. Learning disability is frequently associated with ADHD as an interrelated, overlapping problem15 and is reported in 70% of patients and among their relatives. In a study of 145 children with ADHD, boys outnumbered girls by 3 to 1, and 30% had siblings with learning disabilities compared with only 7% among control children without ADHD. A familial-genetic factor in this group of patients was expressed by the preponderance of boys and the increased frequency of learning disabilities in siblings.16
Gender differences in the prevalence of ADHD have been attributed to the sample examined and the increased disruptive behavior of boys. Little is known about the causes of ADHD in girls, because the incidence is relatively infrequent. A study of the familial transmission of ADHD ascertained through girls revealed that proband gender was not an influencing factor, which suggests that the genetic contributions to ADHD are similar in boys and girls.17 Familial risk factors cannot account for gender differences in prevalence or the clinical variability of Diagnostic Statistical Manual, 4th Edition, subtypes. First-degree relatives (parents, siblings, and children) of patients with ADHD have a higher risk of being affected, with a frequency that is five- to sixfold greater than that in the general population.18,19 Twin studies of children with ADHD have shown 79% concordance in monozygotic twins compared with 32% in same-gender dizygotic twins.19 A review of 283 adult adoptees divided into 2 groups, with or without behaviorally disturbed biological parents, revealed that those with childhood histories of hyperactivity had both a biological parent affected and a placement in a poor socioeconomic adoptive home.20 Adoption studies support the role of both genetic and environmental factors in the etiology of ADHD.
Genetic syndromes associated with ADHD include fragile X, Klinefelter, velocardiofacial (22q.11.2 deletion), Williams, Turner, Prader-Willi, and neurofibromatosis type 1, but these disorders are rare among ADHD-clinic patients. The prevalence of cytogenetic abnormalities was assessed in 100 children (64 boys) with combined-type ADHD and normal intelligence. One girl with ADHD had a sex chromosome aneuploidy (47,XXX) and 1 boy had a permutation-sized allele for fragile X, but none of the subjects showed the full mutation. Results of testing for 22q11.2 microdeletion were negative for all children with ADHD screened. In the absence of clinical signs or family history, routine chromosome analysis in children with ADHD is not generally recommended.21
Molecular genetic studies support the involvement of the dopamine receptor and dopamine transporter genes. Many ADHD gene studies, most of which have been focused on catecholaminergic candidates, emphasize the role of dopaminergic genes in clinical phenotypes and drug effects.22 Deficits in dopamine-modulated frontal-striatal circuits are correlated with subtypes of ADHD, and the relation of dopamine deficits to fetal and perinatal stresses may explain the mechanism of environmental etiologies of ADHD.23 Preterm birth complicated by susceptibility to cerebral ischemia may contribute to increased dopamine receptor availability, deficient dopaminergic neurotransmission, and subsequent development of ADHD.24 Evidence of environmental mediators in ADHD has been demonstrated in twin studies, with affected twins having greater exposure to risk factors such as maternal smoking, lower birth weights, and delayed growth and development compared with unaffected co-twins.25 Gene-environment interaction is increasingly recognized as an important mechanism in the etiology and development of ADHD, with some genes (eg, DAT1) affecting the individual sensitivity to environmental etiologic factors.26
ENVIRONMENTAL FACTORS IN ETIOLOGY
Environmental factors may be classified as prenatal, perinatal, and postnatal in origin, as shown in Table 1. Pregnancy- and birth-related risk factors include maternal smoking, exanthema, maternal anemia, breech delivery, prematurity, low birth weight, hypoxic-ischemic encephalopathy, small head circumference, cocaine and alcohol exposure, and iodine and thyroid deficiency. Childhood illnesses associated with occurrence of ADHD include viral infections, meningitis, encephalitis, otitis media, anemia, cardiac disease, thyroid disease, epilepsy, and autoimmune and metabolic disorders. Other causative factors include head injury involving the frontal lobes, toxins and drugs, and nutritional disorders, the involvement of many being controversial (eg, food additives, food allergies, sucrose, gluten sensitivity, and fatty acid and iron deficiencies). Of all the factors implicated during pregnancy, maternal smoking has attracted the greatest attention in the recent literature.
Maternal Smoking
In a population-based sample of twin pairs, genetic influences accounted for most of the variance in offspring with ADHD, but maternal smoking during pregnancy showed a significant environmentally mediated association.27 A systematic search of the literature found 24 studies on maternal tobacco smoking published between 1973 and 2002, all of which indicated an increased risk of ADHD in the offspring.28 One study that used data from the National Health and Nutrition Examination Survey of 1999–2002 found that of 4704 children 4 to 15 years of age, 4.2% were reported to have ADHD and be taking stimulant medication treatment, equivalent to 1.8 million affected children in the United States. Prenatal tobacco exposure was significantly associated with ADHD and accounted for 270000 excess cases of ADHD.29
Prenatal Exposure to Alcohol
In contrast to the risk of ADHD with prenatal nicotine exposure, the results of studies that have linked alcohol with ADHD are less uniform, and the findings reported from 9 alcohol studies have been contradictory.28 Studies with a positive association include 26 children whose mothers abused alcohol during pregnancy. When examined at 11 and 14 years of age for neuropsychiatric problems, of 24 alcohol-exposed children seen at follow-up, 10 had ADHD, 2 had Asperger syndrome, and 1 had mild mental retardation. The severity of the disorder was correlated with the degree of alcohol exposure in utero. Children whose mothers discontinued alcohol consumption by the 12th week of gestation developed normally and had no learning problems in school.30
A retrospective, case-control study of the effects of in utero exposure to alcohol and nicotine found that among 280 patients with ADHD and 242 controls without ADHD, patients with ADHD were 2.5 times more likely to have been exposed to alcohol in utero (P = .03) and 2.1 times more likely to have been exposed to cigarettes (P = .02) than the controls. Alcohol is considered a risk factor for ADHD that is independent of prenatal exposure to nicotine and other familial risk factors.31 Analysis of a large Australian twin cohort showed that offspring of twins with a history of maternal alcohol-use disorder were significantly more likely to exhibit ADHD than offspring of nonalcoholic controls. Maternal smoking probably contributes to the association of alcohol and ADHD, but with adjustment for the nicotine risk factor, a significant genetic correlation exists. Genes that influence the risk of alcohol use also influence vulnerability to ADHD.32
Prenatal Exposure to Lead
Data obtained from the 1999–2002 National Health and Nutrition Examination Survey found higher blood lead concentrations in mothers of children with ADHD, with lead exposure accounting for 290000 excess cases of ADHD in US children, equal to the number of cases related to prenatal tobacco exposure.29 A study that reviewed blood lead screening in 102 children with ADHD revealed a mean level of 2.29 µg/dL, with only 1 child having a mildly elevated lead level.33 In contrast, 2 studies that evaluated the relationship between hair lead levels and attention-deficit disorders in the classroom revealed positive correlations. Scalp hair specimens obtained from 277 first-grade pupils had lead concentrations that ranged from 1.0 to 11.3 ppm (µg/g). A dose-response relationship between lead levels and negative teacher ratings remained significant after controlling for age, ethnicity, gender, and socioeconomic status. The relationship was even stronger between physician-diagnosed ADHD and hair lead levels. No "safe" threshold for lead concentration was apparent as a risk factor for ADHD.34 In 43 boys aged 8 to 12 years attending schools for learning disorders in the Netherlands, those with relatively high concentrations of lead in their hair reacted slower in reaction-time tasks and were less flexible in changing focus of attention than those with relatively low lead levels.35 Although the results of these studies have been variable, lead, and particularly prenatal exposure to lead, seems to be a risk factor for ADHD.
INFECTIONS AND ADHD
Reports of a seasonal pattern of birth for subtypes of ADHD suggest an association with seasonally mediated viral infections. In a study of 140 boys with ADHD and 120 normal controls, September births were significantly correlated with ADHD and learning disability (odds ratio: 5.4). A trend toward an increase in winter births was also evident. Exposure to viral infections during winter months in the first trimester of fetal life or at the time of birth may be a predisposing factor in 10% of subjects with ADHD with comorbid learning disabilities.36 Viral infections during pregnancy, at birth, and in early childhood have been linked to an increased risk of developing ADHD. In a case-control study in Italy, children born to women who had a viral exanthematous rash during pregnancy had an increased risk of ADHD. Measles, varicella, or rubella was reported by 4 of 71 mothers of children with ADHD and none of the 118 control mothers (P < .01). The difference was significant after adjusting for other potential risk factors.37 Other viral infections associated with an increased prevalence of ADHD and learning disorders included HIV, enterovirus 71, and varicella zoster encephalitis. Herpes simplex virus antibodies showed no significant correlation with ADHD or other neuropsychiatric disorders.38 Febrile seizures, frequently associated with human herpesvirus 6 in the United States and with influenza A in Asia are a risk factor for subsequent development of hyperactive behavior and ADHD.39–41
Influenza Virus
Since the initial report of an influenza-associated postencephalitic behavior disorder,3 influenza viral infection as a potential cause of ADHD has received little attention.42 A literature search uncovered only 1 influenza-related ADHD epidemiologic study that showed frequency of health care utilization for influenza and ADHD.43 Data from the National Ambulatory Medical Care Survey (1996–2001) showed that rural children 5 to 9 years old were seen more frequently than nonrural children for treatment of ADHD (P = .001) and influenza (P = .037).
HIV Infection
Among 274 previously treated HIV-infected children aged 2 to 17 years, the most common behavioral problems, as measured by the Conners' Parent Rating Scale, were learning (25%), hyperactivity (20%), impulsive-hyperactive (19%), conduct (16%), and anxiety (8%) problems. Mean Wechsler Intelligence Scale for Children-III scores were less than average norms, and hyperactivity was more frequent in children with a performance IQ of <90.44
Enterovirus 71 Infection
Enterovirus 71 infection with central nervous system involvement may be associated with neurologic sequelae, delayed neurodevelopment, and reduced cognitive functioning. Of 47 patients who were recovering from enterovirus 71 aseptic meningitis or encephalitis and attending school, 6 (13%) had ADHD and required medication, and 3 were in special education.45
Varicella Zoster Encephalitis
A patient with encephalitis caused by primary varicella zoster infection developed ADHD and a tic disorder. MRI studies localized the encephalitis to the basal ganglia.46
Borrelia burgdorferi Infection
B burgdorferi is the spirochete that causes Lyme disease; it has numerous psychiatric and neurologic presentations, including ADHD.47
Streptococcal Infections
Pediatric autoimmune neuropsychiatric disorders associated with group A β-hemolytic streptococcal infections, in addition to obsessive-compulsive disorder and tic disorders, include hyperactive behavior, cognitive deficits, and oppositional behaviors. Symptom onset and exacerbations of ADHD seem to be triggered by streptococcal infection according to some reports.48,49 In contrast, a more recent study that examined the temporal relationship between newly acquired streptococcal infections and acute exacerbations of tic and obsessive-compulsive disorders revealed no clear correlation.50 A possible relation between ADHD and streptococcal infection requires confirmation.
Otitis Media
In preschool-aged children, otitis media was linked to hyperactive behavior and/or inattention, independent of learning disability, in 21 of 138 children evaluated in a child development clinic. Children with ADHD had significantly more complaints of earaches during the preceding 3 months and year of observation.51 My analysis of a total of 7 articles obtained through PubMed and published between 1978 and 1999 revealed a positive association between a history of recurrent otitis media and subsequent development of typical ADHD in only 1 study; hyperactive behavior was reported in 4, combined with language and/or learning disorders in 2, and speech, language, and learning deficits in 2 patient groups. The studies were retrospective in design, and each involved between 18 and 507 children. Although typical ADHD seems to have a weak association with otitis media, some researchers consider a history of significant middle-ear disease in early childhood to be a risk factor for hyperactivity and especially speech and language disorders in children who present with learning problems in school.52
PERINATAL AND EARLY-LIFE RISK FACTORS
The roles of prematurity and perinatal hypoxic-ischemic encephalopathy in the pathophysiology of ADHD have been reviewed by researchers at the John F. Kennedy Institute in Glostrup, Denmark.53 Up to one third of premature infants with birth weights of <1500 g have ADHD when examined at 5 to 7 years. The striatum and cingulate-cortical loop are vulnerable to the ischemia-induced release of glutamate, which results in hyperactive behavior, impulsivity, and inattention. The magnitude of this cause of ADHD increases with the advances in NICU nursing care and improved survival rates among premature infants.
A case-control study of 305 children with ADHD at the Mayo Clinic revealed that pregnancy and labor characteristics, low birth weight, and twin birth were not associated with ADHD. Positive risk factors included male gender and low parental education levels.54 In contrast to the findings in this US study, a retrospective analysis of parental questionnaires regarding birth history of 196 children with ADHD followed in Iceland showed a statistically significant increased risk associated with low birth weight, young age of mother, and cesarean delivery.55
POSTNATAL RISK FACTORS
Cerebral trauma, meningitis, encephalitis, metabolic and endocrine disorders, toxins and drugs, and nutritional deficiencies, additives, and sensitivities are some of the factors known to be associated with ADHD. In a high proportion of these cases, a genetic factor is a likely basic cause, and the environmental factor in etiology is probably secondary, acting as a trigger. The relative importance of acquired etiologies of ADHD requires additional study. The following are some of the potentially preventable ADHD etiologic factors, although studies have provided variable results, and their significance is controversial.
Iron Deficiency and ADHD
Iron deficiency has been invoked as a risk factor in a number of neurologic disorders. The report of low ferritin levels in children with cognitive and learning disorders56 prompted our own investigation of serum ferritin levels in patients with ADHD.57 The mean serum ferritin level of 39.9 ± 40.6 ng/mL was not different than that of control children without ADHD, but 18% had levels below 20 ng/mL, which was considered abnormal. None had evidence of iron-deficiency anemia. A comparison of the clinical characteristics of 12 patients with the lowest serum ferritin levels (<20 ng/mL) and 12 with the highest serum ferritin levels (>60 ng/mL) disclosed no significant difference in severity or frequency of ADHD and comorbid symptoms or response to medications. In our patient cohort, a causative role for low serum ferritin levels in ADHD was not confirmed.57 A controlled trial of ferrous sulfate supplementation may be justified for patients with ADHD and abnormally low serum ferritin levels. Supplemental iron therapy does not provide a substitute for medication in the management of ADHD, but given the positive findings in the following report, additional studies are indicated to define a possible adjuvant role.
In a French study, 84% of the patients with ADHD had serum ferritin levels of <30 ng/mL (vs 18% of controls), and 32% had levels of <15 ng/mL (compared with 3% of controls). The iron-storage levels in children in France were generally lower than those in children in Chicago, Illinois, and the results of the studies are not comparable. The authors found supplemental iron to be beneficial, but they agreed that a controlled trial is required.58
Role of Zinc in ADHD
In a study at Teheran University (Teheran, Iran), zinc sulfate supplements (55 mg/day), as adjunctive therapy with methylphenidate (1 mg/kg per day) in a double-blind, placebo-controlled trial in 40 children with ADHD, provided significantly greater improvement than methylphenidate/placebo treatment.59 Several controlled studies have demonstrated a deficiency of zinc in patients with ADHD and a beneficial response to zinc sulfate supplements.60 The majority of these reports were from Turkey and Iran, countries with suspected endemic zinc deficiency. In a single study of zinc and ADHD in the United States, the median serum zinc level in 48 children with ADHD was at the lowest 30% of the laboratory reference range. Low serum zinc levels were correlated with parent/teacher-rated inattention but not with hyperactivity/impulsivity.61 Additional trials are recommended.
Omega-3 Fatty Acids and ADHD
The effects of dietary supplementation with fish oil and evening primrose oil were assessed in a randomized, controlled trial in 117 children with developmental coordination disorder, 32 of whom also had ADHD. Significant improvements in reading, spelling, and behavior occurred over a 3-month treatment period, but motor skills were not benefited. Comparing the Conners' Teacher Rating Scale-L/ADHD scores, a reduction and improvement of >0.5 SD were reported for children in the treatment group, whereas no change was seen in those in the placebo group (P < .0001). Children who continued treatment during the 3- to 6-month follow-up phase showed improvements in mean reading age of 13.5 months, a mean spelling gain of 3.5 months, and a decrease in the mean Conners' scores from a baseline of 74.7 to 52.6. The gain in reading was 3 times that expected, and spelling advanced twice the normal rate. Fatty acid daily dosages were omega-3 (558 mg of eicosapentaenoic acid and 174 mg of docosahexaenoic acid), omega-6 linoleic acid (60 mg), and vitamin E (9.6 mg of -tocopherol, natural form). Placebo capsules contained olive oil.62 These findings confirmed previous reports of abnormally low levels of serum essential fatty acids in hyperactive children with learning disabilities and improvements in reading ability in dyslexic patients treated with omega-3 fatty acid supplements.
Dietary modifications or supplements in the treatment of learning and behavior disorders of children have frequently fallen short of initial expectations after close and more prolonged study. Some etiologic factors invoked in ADHD have been described as myths.63 They may include the additive-salicylate-free, hypoallergenic, sugar-restricted, megavitamin, and mineral and trace-element diets.64 Despite the excellent experimental design of the above-mentioned study, additional controlled trials are indicated before advocating fish, with its attendant mercury exposure, or fatty acids as a general substitute for medication. The introduction of a relatively safe and well-tolerated dietary treatment could, if proven successful, serve as a complementary or substitute treatment and offset the increase in concern regarding adverse effects of drug therapies. Initial trials of adjunctive therapy with fatty acids in our attention-deficit disorder clinic have been disappointing.
Iodine Deficiency and ADHD
A prospective study of the neuropsychological development of offspring of 16 women from an iodine-deficient area in Italy found ADHD in 11 (68.7%) of 16 children and no cases from an iodine-sufficient area. The mothers of affected children were hypothyroxinemic at early gestation. Maternal hypothyroxinemia caused by iodine deficiency results in a critical reduction of intracellular triiodothyronine available to the developing fetal brain.65 Iodine deficiency and hypothyroidism are both prenatal and postnatal risk factors for ADHD in some environments.
THYROID FUNCTION AND ADHD
ADHD has been reported in association with generalized resistance to thyroid hormone (GRTH), a disease caused by mutations in the thyroid receptor β gene and characterized by reduced responsiveness of peripheral and pituitary tissues to thyroid hormone. An evaluation of 18 families with a history of GRTH at the National Institutes of Health in Bethesda, Maryland, found that 19 (70%) of 27 affected children and 5 (20%) of 25 unaffected by GRTH had met the criteria for a diagnosis of ADHD (P < .001). ADHD was strongly associated with GRTH.66 A prospective screening study for thyroid abnormalities in 277 children with ADHD at the University of Chicago found 14 children with thyroid abnormalities, but GRTH could not be demonstrated in a detailed study of 4 of 9 in whom it was suspected. The prevalence of thyroid abnormalities is higher (5.4%) in children with ADHD than in the normal population (<1%). The prevalence of ADHD in subjects with GRTH is reported to be 46%.67 Despite reports of a lack of association between thyroid function and ADHD,68 the number of studies that have shown positive associations support the proponents of routine screening for thyroid function, especially for patients with a family history of thyroid dysfunction.
Case reports of thyrotoxicosis and ADHD are rare and sometimes lead to a missed diagnosis when symptoms are subtle and routine testing is not performed. In a center in which thyroid-function tests were a part of the routine evaluation of children with developmental learning disabilities and ADHD, 3 patients were diagnosed with hyperthyroidism, with no systemic signs. Treatment lead to control of hyperactive behavior, increased attention span, and improved language function.69 Suresh et al recommend thyroid screening in children with ADHD.
In our neurology ADHD clinic at Children's Memorial Hospital, thyroid screening is routine. In the past year we have uncovered 4 cases of hyperthyroidism, 2 with goiter, in patients who presented with ADHD and learning disorders. The relation of thyroid dysfunction to ADHD and learning disorders requires additional study. In pediatric practice, thyroid tests are probably justified in subjects with ADHD and a positive history of thyroid dysfunction. In a specialty clinic, on the basis of personal experience, I consider routine testing for thyroxine and thyrotropin levels justified for a child who presents with ADHD, even with absent family history, goiter, or other physical signs, but with the admission of other dissenting opinions.
CONCLUSIONS
The etiology of ADHD is multifactorial. A genetic cause linked to dopamine deficit is frequent and primary, but various environmental factors, including viral infection, maternal smoking during pregnancy, prematurity, cerebral hypoxic ischemia, alcohol exposure, and nutritional and endocrine disorders may contribute as secondary causes. The etiology is probably a combination of genetic and acquired factors in most cases. The early prenatal recognition, prevention, and treatment of environmental causes may provide more effective management and reduce the reliance on symptom modification with medication. Advice regarding hazards of nicotine and alcohol exposure and monitoring of blood count and thyroid function during pregnancy are particularly important for patients with a family history of ADHD.
ACKNOWLEDGMENTS
I am indebted to Michelle Yee, CPNP, for her assistance with the management of patients attending our attention-deficit disorder clinic and to Dr Leon G. Epstein, Head of the Division of Neurology, for his interest and support.
FOOTNOTES
Accepted Jul 5, 2007.
Address correspondence to J. Gordon Millichap, MD, FRCP, Division of Neurology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL 60614. E-mail: gmillichap@childrensmemorial.org
The author has indicated he has no financial relationships relevant to this article to disclose.
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Division of Neurology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois
ABSTRACT
Attention-deficit/hyperactivity disorder is a neurobiological syndrome with an estimated prevalence among children and adolescents of 5%. It is a highly heritable disorder, but acquired factors in etiology are sometimes uncovered that may be amenable to preventive measures or specific therapy. Early reports have described symptoms similar to attention-deficit/hyperactivity disorder that followed brain trauma or viral encephalitis, and recent MRI studies have demonstrated brain volumetric changes that may be involved in the pathophysiology of the syndrome. The American Psychiatric Association's Diagnostic Statistical Manual, introduced in 1968, emphasizes symptomatic criteria in diagnosis. Here, an overview of environmental factors in the etiology of attention-deficit/hyperactivity disorder is presented to encourage more emphasis and research on organic causal factors, preventive intervention, and specific therapies. An organic theory and the genetic and biochemical basis of attention-deficit/hyperactivity disorder are briefly reviewed, and an etiologic classification is suggested. Environmental factors are prenatal, perinatal, and postnatal in origin. Pregnancy- and birth-related risk factors include maternal smoking and alcohol ingestion, prematurity, hypoxic-ischemic encephalopathy, and thyroid deficiency. Childhood illnesses associated with attention-deficit/hyperactivity disorder include virus infections, meningitis, encephalitis, head injury, epilepsy, toxins, and drugs. More controversial factors discussed are diet-related sensitivities and iron deficiency. Early prenatal recognition, prevention, and treatment of environmental etiologies of attention-deficit/hyperactivity disorder may reduce physician reliance on symptomatic modification with medication, a frequent reason for parental concern.
Key Words: attention deficit • hyperactivity • etiology • environmental • viral • nicotine • thyroid
Abbreviations: ADHD—attention-deficit/hyperactivity disorder • GRTH—generalized resistance to thyroid hormone
Attention-deficit/hyperactivity disorder (ADHD), a neurobiological syndrome that affects an estimated 5% or more of school-aged children, has been recognized under different names for more than a century. In the earliest reports, behavioral abnormalities similar to ADHD were described after head injury1 and as a complication of encephalitis after the influenza epidemic of 1918.2,3 "Organic drivenness" was a term used to describe the behavior after epidemic encephalitis, and damage to the brainstem was suggested as the cause.4 This description of behavioral symptoms caused by encephalitis or brain damage was followed by a variety of reports linked to brain dysfunction and described by various terms including "minimal brain dysfunction" in 19665 and "hyperkinetic reaction of childhood or adolescence" in 1968. The American Psychiatric Association's Diagnostic Statistical Manual and its subsequent revisions6 omit reference to frequently associated motor perceptual and subtle neurologic signs, favoring symptomatic diagnostic criteria. Similarly, a clinician's approach to the management of ADHD is concerned primarily with symptomatic treatment. The purpose of this critical assessment of our approach to ADHD is to present an overview of organic and genetic causes and reports of environmental factors in the etiology of ADHD. A greater emphasis on etiology might encourage a preventive or specific approach to treatment, with less reliance on symptom modification with medications.
ORGANIC THEORY OF ADHD
Numerous experimental studies of cortical ablation and subcortical lesions in animals and clinical studies of brain-damaged children and adults have correlated the sites of cerebral lesions with the symptoms of hyperkinesia, distractibility, and inattention.7,8 A cortical-striatal circuit has been proposed to explain the heterogeneous nature of the ADHD syndrome.9 A decrease in volume of the right anterior frontal region and loss of normal right-to-left asymmetries in striatal nuclei have been shown on MRI studies. These findings support the involvement of the frontal lobes and striatal connections in the pathophysiology of ADHD.10 A temporal lobe arachnoid cyst–ADHD syndrome has also been described in patients with coincidental learning and language disabilities.11 In 1 case report of a patient with this syndrome who presented with headaches after a head injury, surgical intervention with shunt procedure resulted in improved cognitive function and behavior.12
Prefrontal and cingulate brain regions are involved in inhibitory control, a function typically deficient in children with ADHD. A functional MRI study of 17 subjects with ADHD and 15 healthy controls showed that, in relation to control subjects, children with ADHD failed to activate the anterior cingulate cortex and the left ventrolateral prefrontal cortex after unsuccessful inhibition. The patients were treatment-naive, and the findings were unrelated to long-term treatment or abrupt withdrawal of stimulant medications before imaging.13
GENETIC AND BIOCHEMICAL BASIS OF ADHD
Genetic factors account for 80% of the etiology of ADHD.14 Family, twin, and adoption studies support the theory that ADHD is a highly heritable disorder, with the majority of patients having a first- or second-degree relative with a history of ADHD or learning disorder. Learning disability is frequently associated with ADHD as an interrelated, overlapping problem15 and is reported in 70% of patients and among their relatives. In a study of 145 children with ADHD, boys outnumbered girls by 3 to 1, and 30% had siblings with learning disabilities compared with only 7% among control children without ADHD. A familial-genetic factor in this group of patients was expressed by the preponderance of boys and the increased frequency of learning disabilities in siblings.16
Gender differences in the prevalence of ADHD have been attributed to the sample examined and the increased disruptive behavior of boys. Little is known about the causes of ADHD in girls, because the incidence is relatively infrequent. A study of the familial transmission of ADHD ascertained through girls revealed that proband gender was not an influencing factor, which suggests that the genetic contributions to ADHD are similar in boys and girls.17 Familial risk factors cannot account for gender differences in prevalence or the clinical variability of Diagnostic Statistical Manual, 4th Edition, subtypes. First-degree relatives (parents, siblings, and children) of patients with ADHD have a higher risk of being affected, with a frequency that is five- to sixfold greater than that in the general population.18,19 Twin studies of children with ADHD have shown 79% concordance in monozygotic twins compared with 32% in same-gender dizygotic twins.19 A review of 283 adult adoptees divided into 2 groups, with or without behaviorally disturbed biological parents, revealed that those with childhood histories of hyperactivity had both a biological parent affected and a placement in a poor socioeconomic adoptive home.20 Adoption studies support the role of both genetic and environmental factors in the etiology of ADHD.
Genetic syndromes associated with ADHD include fragile X, Klinefelter, velocardiofacial (22q.11.2 deletion), Williams, Turner, Prader-Willi, and neurofibromatosis type 1, but these disorders are rare among ADHD-clinic patients. The prevalence of cytogenetic abnormalities was assessed in 100 children (64 boys) with combined-type ADHD and normal intelligence. One girl with ADHD had a sex chromosome aneuploidy (47,XXX) and 1 boy had a permutation-sized allele for fragile X, but none of the subjects showed the full mutation. Results of testing for 22q11.2 microdeletion were negative for all children with ADHD screened. In the absence of clinical signs or family history, routine chromosome analysis in children with ADHD is not generally recommended.21
Molecular genetic studies support the involvement of the dopamine receptor and dopamine transporter genes. Many ADHD gene studies, most of which have been focused on catecholaminergic candidates, emphasize the role of dopaminergic genes in clinical phenotypes and drug effects.22 Deficits in dopamine-modulated frontal-striatal circuits are correlated with subtypes of ADHD, and the relation of dopamine deficits to fetal and perinatal stresses may explain the mechanism of environmental etiologies of ADHD.23 Preterm birth complicated by susceptibility to cerebral ischemia may contribute to increased dopamine receptor availability, deficient dopaminergic neurotransmission, and subsequent development of ADHD.24 Evidence of environmental mediators in ADHD has been demonstrated in twin studies, with affected twins having greater exposure to risk factors such as maternal smoking, lower birth weights, and delayed growth and development compared with unaffected co-twins.25 Gene-environment interaction is increasingly recognized as an important mechanism in the etiology and development of ADHD, with some genes (eg, DAT1) affecting the individual sensitivity to environmental etiologic factors.26
ENVIRONMENTAL FACTORS IN ETIOLOGY
Environmental factors may be classified as prenatal, perinatal, and postnatal in origin, as shown in Table 1. Pregnancy- and birth-related risk factors include maternal smoking, exanthema, maternal anemia, breech delivery, prematurity, low birth weight, hypoxic-ischemic encephalopathy, small head circumference, cocaine and alcohol exposure, and iodine and thyroid deficiency. Childhood illnesses associated with occurrence of ADHD include viral infections, meningitis, encephalitis, otitis media, anemia, cardiac disease, thyroid disease, epilepsy, and autoimmune and metabolic disorders. Other causative factors include head injury involving the frontal lobes, toxins and drugs, and nutritional disorders, the involvement of many being controversial (eg, food additives, food allergies, sucrose, gluten sensitivity, and fatty acid and iron deficiencies). Of all the factors implicated during pregnancy, maternal smoking has attracted the greatest attention in the recent literature.
Maternal Smoking
In a population-based sample of twin pairs, genetic influences accounted for most of the variance in offspring with ADHD, but maternal smoking during pregnancy showed a significant environmentally mediated association.27 A systematic search of the literature found 24 studies on maternal tobacco smoking published between 1973 and 2002, all of which indicated an increased risk of ADHD in the offspring.28 One study that used data from the National Health and Nutrition Examination Survey of 1999–2002 found that of 4704 children 4 to 15 years of age, 4.2% were reported to have ADHD and be taking stimulant medication treatment, equivalent to 1.8 million affected children in the United States. Prenatal tobacco exposure was significantly associated with ADHD and accounted for 270000 excess cases of ADHD.29
Prenatal Exposure to Alcohol
In contrast to the risk of ADHD with prenatal nicotine exposure, the results of studies that have linked alcohol with ADHD are less uniform, and the findings reported from 9 alcohol studies have been contradictory.28 Studies with a positive association include 26 children whose mothers abused alcohol during pregnancy. When examined at 11 and 14 years of age for neuropsychiatric problems, of 24 alcohol-exposed children seen at follow-up, 10 had ADHD, 2 had Asperger syndrome, and 1 had mild mental retardation. The severity of the disorder was correlated with the degree of alcohol exposure in utero. Children whose mothers discontinued alcohol consumption by the 12th week of gestation developed normally and had no learning problems in school.30
A retrospective, case-control study of the effects of in utero exposure to alcohol and nicotine found that among 280 patients with ADHD and 242 controls without ADHD, patients with ADHD were 2.5 times more likely to have been exposed to alcohol in utero (P = .03) and 2.1 times more likely to have been exposed to cigarettes (P = .02) than the controls. Alcohol is considered a risk factor for ADHD that is independent of prenatal exposure to nicotine and other familial risk factors.31 Analysis of a large Australian twin cohort showed that offspring of twins with a history of maternal alcohol-use disorder were significantly more likely to exhibit ADHD than offspring of nonalcoholic controls. Maternal smoking probably contributes to the association of alcohol and ADHD, but with adjustment for the nicotine risk factor, a significant genetic correlation exists. Genes that influence the risk of alcohol use also influence vulnerability to ADHD.32
Prenatal Exposure to Lead
Data obtained from the 1999–2002 National Health and Nutrition Examination Survey found higher blood lead concentrations in mothers of children with ADHD, with lead exposure accounting for 290000 excess cases of ADHD in US children, equal to the number of cases related to prenatal tobacco exposure.29 A study that reviewed blood lead screening in 102 children with ADHD revealed a mean level of 2.29 µg/dL, with only 1 child having a mildly elevated lead level.33 In contrast, 2 studies that evaluated the relationship between hair lead levels and attention-deficit disorders in the classroom revealed positive correlations. Scalp hair specimens obtained from 277 first-grade pupils had lead concentrations that ranged from 1.0 to 11.3 ppm (µg/g). A dose-response relationship between lead levels and negative teacher ratings remained significant after controlling for age, ethnicity, gender, and socioeconomic status. The relationship was even stronger between physician-diagnosed ADHD and hair lead levels. No "safe" threshold for lead concentration was apparent as a risk factor for ADHD.34 In 43 boys aged 8 to 12 years attending schools for learning disorders in the Netherlands, those with relatively high concentrations of lead in their hair reacted slower in reaction-time tasks and were less flexible in changing focus of attention than those with relatively low lead levels.35 Although the results of these studies have been variable, lead, and particularly prenatal exposure to lead, seems to be a risk factor for ADHD.
INFECTIONS AND ADHD
Reports of a seasonal pattern of birth for subtypes of ADHD suggest an association with seasonally mediated viral infections. In a study of 140 boys with ADHD and 120 normal controls, September births were significantly correlated with ADHD and learning disability (odds ratio: 5.4). A trend toward an increase in winter births was also evident. Exposure to viral infections during winter months in the first trimester of fetal life or at the time of birth may be a predisposing factor in 10% of subjects with ADHD with comorbid learning disabilities.36 Viral infections during pregnancy, at birth, and in early childhood have been linked to an increased risk of developing ADHD. In a case-control study in Italy, children born to women who had a viral exanthematous rash during pregnancy had an increased risk of ADHD. Measles, varicella, or rubella was reported by 4 of 71 mothers of children with ADHD and none of the 118 control mothers (P < .01). The difference was significant after adjusting for other potential risk factors.37 Other viral infections associated with an increased prevalence of ADHD and learning disorders included HIV, enterovirus 71, and varicella zoster encephalitis. Herpes simplex virus antibodies showed no significant correlation with ADHD or other neuropsychiatric disorders.38 Febrile seizures, frequently associated with human herpesvirus 6 in the United States and with influenza A in Asia are a risk factor for subsequent development of hyperactive behavior and ADHD.39–41
Influenza Virus
Since the initial report of an influenza-associated postencephalitic behavior disorder,3 influenza viral infection as a potential cause of ADHD has received little attention.42 A literature search uncovered only 1 influenza-related ADHD epidemiologic study that showed frequency of health care utilization for influenza and ADHD.43 Data from the National Ambulatory Medical Care Survey (1996–2001) showed that rural children 5 to 9 years old were seen more frequently than nonrural children for treatment of ADHD (P = .001) and influenza (P = .037).
HIV Infection
Among 274 previously treated HIV-infected children aged 2 to 17 years, the most common behavioral problems, as measured by the Conners' Parent Rating Scale, were learning (25%), hyperactivity (20%), impulsive-hyperactive (19%), conduct (16%), and anxiety (8%) problems. Mean Wechsler Intelligence Scale for Children-III scores were less than average norms, and hyperactivity was more frequent in children with a performance IQ of <90.44
Enterovirus 71 Infection
Enterovirus 71 infection with central nervous system involvement may be associated with neurologic sequelae, delayed neurodevelopment, and reduced cognitive functioning. Of 47 patients who were recovering from enterovirus 71 aseptic meningitis or encephalitis and attending school, 6 (13%) had ADHD and required medication, and 3 were in special education.45
Varicella Zoster Encephalitis
A patient with encephalitis caused by primary varicella zoster infection developed ADHD and a tic disorder. MRI studies localized the encephalitis to the basal ganglia.46
Borrelia burgdorferi Infection
B burgdorferi is the spirochete that causes Lyme disease; it has numerous psychiatric and neurologic presentations, including ADHD.47
Streptococcal Infections
Pediatric autoimmune neuropsychiatric disorders associated with group A β-hemolytic streptococcal infections, in addition to obsessive-compulsive disorder and tic disorders, include hyperactive behavior, cognitive deficits, and oppositional behaviors. Symptom onset and exacerbations of ADHD seem to be triggered by streptococcal infection according to some reports.48,49 In contrast, a more recent study that examined the temporal relationship between newly acquired streptococcal infections and acute exacerbations of tic and obsessive-compulsive disorders revealed no clear correlation.50 A possible relation between ADHD and streptococcal infection requires confirmation.
Otitis Media
In preschool-aged children, otitis media was linked to hyperactive behavior and/or inattention, independent of learning disability, in 21 of 138 children evaluated in a child development clinic. Children with ADHD had significantly more complaints of earaches during the preceding 3 months and year of observation.51 My analysis of a total of 7 articles obtained through PubMed and published between 1978 and 1999 revealed a positive association between a history of recurrent otitis media and subsequent development of typical ADHD in only 1 study; hyperactive behavior was reported in 4, combined with language and/or learning disorders in 2, and speech, language, and learning deficits in 2 patient groups. The studies were retrospective in design, and each involved between 18 and 507 children. Although typical ADHD seems to have a weak association with otitis media, some researchers consider a history of significant middle-ear disease in early childhood to be a risk factor for hyperactivity and especially speech and language disorders in children who present with learning problems in school.52
PERINATAL AND EARLY-LIFE RISK FACTORS
The roles of prematurity and perinatal hypoxic-ischemic encephalopathy in the pathophysiology of ADHD have been reviewed by researchers at the John F. Kennedy Institute in Glostrup, Denmark.53 Up to one third of premature infants with birth weights of <1500 g have ADHD when examined at 5 to 7 years. The striatum and cingulate-cortical loop are vulnerable to the ischemia-induced release of glutamate, which results in hyperactive behavior, impulsivity, and inattention. The magnitude of this cause of ADHD increases with the advances in NICU nursing care and improved survival rates among premature infants.
A case-control study of 305 children with ADHD at the Mayo Clinic revealed that pregnancy and labor characteristics, low birth weight, and twin birth were not associated with ADHD. Positive risk factors included male gender and low parental education levels.54 In contrast to the findings in this US study, a retrospective analysis of parental questionnaires regarding birth history of 196 children with ADHD followed in Iceland showed a statistically significant increased risk associated with low birth weight, young age of mother, and cesarean delivery.55
POSTNATAL RISK FACTORS
Cerebral trauma, meningitis, encephalitis, metabolic and endocrine disorders, toxins and drugs, and nutritional deficiencies, additives, and sensitivities are some of the factors known to be associated with ADHD. In a high proportion of these cases, a genetic factor is a likely basic cause, and the environmental factor in etiology is probably secondary, acting as a trigger. The relative importance of acquired etiologies of ADHD requires additional study. The following are some of the potentially preventable ADHD etiologic factors, although studies have provided variable results, and their significance is controversial.
Iron Deficiency and ADHD
Iron deficiency has been invoked as a risk factor in a number of neurologic disorders. The report of low ferritin levels in children with cognitive and learning disorders56 prompted our own investigation of serum ferritin levels in patients with ADHD.57 The mean serum ferritin level of 39.9 ± 40.6 ng/mL was not different than that of control children without ADHD, but 18% had levels below 20 ng/mL, which was considered abnormal. None had evidence of iron-deficiency anemia. A comparison of the clinical characteristics of 12 patients with the lowest serum ferritin levels (<20 ng/mL) and 12 with the highest serum ferritin levels (>60 ng/mL) disclosed no significant difference in severity or frequency of ADHD and comorbid symptoms or response to medications. In our patient cohort, a causative role for low serum ferritin levels in ADHD was not confirmed.57 A controlled trial of ferrous sulfate supplementation may be justified for patients with ADHD and abnormally low serum ferritin levels. Supplemental iron therapy does not provide a substitute for medication in the management of ADHD, but given the positive findings in the following report, additional studies are indicated to define a possible adjuvant role.
In a French study, 84% of the patients with ADHD had serum ferritin levels of <30 ng/mL (vs 18% of controls), and 32% had levels of <15 ng/mL (compared with 3% of controls). The iron-storage levels in children in France were generally lower than those in children in Chicago, Illinois, and the results of the studies are not comparable. The authors found supplemental iron to be beneficial, but they agreed that a controlled trial is required.58
Role of Zinc in ADHD
In a study at Teheran University (Teheran, Iran), zinc sulfate supplements (55 mg/day), as adjunctive therapy with methylphenidate (1 mg/kg per day) in a double-blind, placebo-controlled trial in 40 children with ADHD, provided significantly greater improvement than methylphenidate/placebo treatment.59 Several controlled studies have demonstrated a deficiency of zinc in patients with ADHD and a beneficial response to zinc sulfate supplements.60 The majority of these reports were from Turkey and Iran, countries with suspected endemic zinc deficiency. In a single study of zinc and ADHD in the United States, the median serum zinc level in 48 children with ADHD was at the lowest 30% of the laboratory reference range. Low serum zinc levels were correlated with parent/teacher-rated inattention but not with hyperactivity/impulsivity.61 Additional trials are recommended.
Omega-3 Fatty Acids and ADHD
The effects of dietary supplementation with fish oil and evening primrose oil were assessed in a randomized, controlled trial in 117 children with developmental coordination disorder, 32 of whom also had ADHD. Significant improvements in reading, spelling, and behavior occurred over a 3-month treatment period, but motor skills were not benefited. Comparing the Conners' Teacher Rating Scale-L/ADHD scores, a reduction and improvement of >0.5 SD were reported for children in the treatment group, whereas no change was seen in those in the placebo group (P < .0001). Children who continued treatment during the 3- to 6-month follow-up phase showed improvements in mean reading age of 13.5 months, a mean spelling gain of 3.5 months, and a decrease in the mean Conners' scores from a baseline of 74.7 to 52.6. The gain in reading was 3 times that expected, and spelling advanced twice the normal rate. Fatty acid daily dosages were omega-3 (558 mg of eicosapentaenoic acid and 174 mg of docosahexaenoic acid), omega-6 linoleic acid (60 mg), and vitamin E (9.6 mg of -tocopherol, natural form). Placebo capsules contained olive oil.62 These findings confirmed previous reports of abnormally low levels of serum essential fatty acids in hyperactive children with learning disabilities and improvements in reading ability in dyslexic patients treated with omega-3 fatty acid supplements.
Dietary modifications or supplements in the treatment of learning and behavior disorders of children have frequently fallen short of initial expectations after close and more prolonged study. Some etiologic factors invoked in ADHD have been described as myths.63 They may include the additive-salicylate-free, hypoallergenic, sugar-restricted, megavitamin, and mineral and trace-element diets.64 Despite the excellent experimental design of the above-mentioned study, additional controlled trials are indicated before advocating fish, with its attendant mercury exposure, or fatty acids as a general substitute for medication. The introduction of a relatively safe and well-tolerated dietary treatment could, if proven successful, serve as a complementary or substitute treatment and offset the increase in concern regarding adverse effects of drug therapies. Initial trials of adjunctive therapy with fatty acids in our attention-deficit disorder clinic have been disappointing.
Iodine Deficiency and ADHD
A prospective study of the neuropsychological development of offspring of 16 women from an iodine-deficient area in Italy found ADHD in 11 (68.7%) of 16 children and no cases from an iodine-sufficient area. The mothers of affected children were hypothyroxinemic at early gestation. Maternal hypothyroxinemia caused by iodine deficiency results in a critical reduction of intracellular triiodothyronine available to the developing fetal brain.65 Iodine deficiency and hypothyroidism are both prenatal and postnatal risk factors for ADHD in some environments.
THYROID FUNCTION AND ADHD
ADHD has been reported in association with generalized resistance to thyroid hormone (GRTH), a disease caused by mutations in the thyroid receptor β gene and characterized by reduced responsiveness of peripheral and pituitary tissues to thyroid hormone. An evaluation of 18 families with a history of GRTH at the National Institutes of Health in Bethesda, Maryland, found that 19 (70%) of 27 affected children and 5 (20%) of 25 unaffected by GRTH had met the criteria for a diagnosis of ADHD (P < .001). ADHD was strongly associated with GRTH.66 A prospective screening study for thyroid abnormalities in 277 children with ADHD at the University of Chicago found 14 children with thyroid abnormalities, but GRTH could not be demonstrated in a detailed study of 4 of 9 in whom it was suspected. The prevalence of thyroid abnormalities is higher (5.4%) in children with ADHD than in the normal population (<1%). The prevalence of ADHD in subjects with GRTH is reported to be 46%.67 Despite reports of a lack of association between thyroid function and ADHD,68 the number of studies that have shown positive associations support the proponents of routine screening for thyroid function, especially for patients with a family history of thyroid dysfunction.
Case reports of thyrotoxicosis and ADHD are rare and sometimes lead to a missed diagnosis when symptoms are subtle and routine testing is not performed. In a center in which thyroid-function tests were a part of the routine evaluation of children with developmental learning disabilities and ADHD, 3 patients were diagnosed with hyperthyroidism, with no systemic signs. Treatment lead to control of hyperactive behavior, increased attention span, and improved language function.69 Suresh et al recommend thyroid screening in children with ADHD.
In our neurology ADHD clinic at Children's Memorial Hospital, thyroid screening is routine. In the past year we have uncovered 4 cases of hyperthyroidism, 2 with goiter, in patients who presented with ADHD and learning disorders. The relation of thyroid dysfunction to ADHD and learning disorders requires additional study. In pediatric practice, thyroid tests are probably justified in subjects with ADHD and a positive history of thyroid dysfunction. In a specialty clinic, on the basis of personal experience, I consider routine testing for thyroxine and thyrotropin levels justified for a child who presents with ADHD, even with absent family history, goiter, or other physical signs, but with the admission of other dissenting opinions.
CONCLUSIONS
The etiology of ADHD is multifactorial. A genetic cause linked to dopamine deficit is frequent and primary, but various environmental factors, including viral infection, maternal smoking during pregnancy, prematurity, cerebral hypoxic ischemia, alcohol exposure, and nutritional and endocrine disorders may contribute as secondary causes. The etiology is probably a combination of genetic and acquired factors in most cases. The early prenatal recognition, prevention, and treatment of environmental causes may provide more effective management and reduce the reliance on symptom modification with medication. Advice regarding hazards of nicotine and alcohol exposure and monitoring of blood count and thyroid function during pregnancy are particularly important for patients with a family history of ADHD.
ACKNOWLEDGMENTS
I am indebted to Michelle Yee, CPNP, for her assistance with the management of patients attending our attention-deficit disorder clinic and to Dr Leon G. Epstein, Head of the Division of Neurology, for his interest and support.
FOOTNOTES
Accepted Jul 5, 2007.
Address correspondence to J. Gordon Millichap, MD, FRCP, Division of Neurology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL 60614. E-mail: gmillichap@childrensmemorial.org
The author has indicated he has no financial relationships relevant to this article to disclose.
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