"It is very possible that PATERNAL AGE is the major predictor of(non-familial) autism." Harry Fisch, M.D., author "The Male Biological Clock". Sperm DNA mutates and autism, schizophrenia bipolar etc. results. What is the connection with autoimmune disorders? Having Type 1 diabetes, SLE,etc. in the family, also if mother had older father. NW Cryobank will not accept a sperm donor past 35th BD to minimize genetic abnormalities.VACCINATIONS also cause autism.

Wednesday, July 30, 2008

Vaccination Induced (Mitochondrial?) Autism -

July 30, 2008
Heckenlively on the Omnibus Autism Proceeding 7/21-23
Going for the Knock-Out Punch! – The Omnibus Autism Proceeding – Second Set of Hearings (Thimerosal & Autism) – Days Fifteen through Eighteen – July 21-23, 2008

By Kent Heckenlively, Esq.

It’s the kind of knock-out punch every attorney dreams of delivering in an important case. Turning the opposing side’s expert witnesses to your side.

While I’m sure some may quibble with whether that actually happened with the withdrawal of the expert testimony of thimerosal experts Drs. Magos and Clarkson, it is certainly what attorneys for the families argued. Even more damning was that fact that Dr. Clarkson was one of the co-authors on the Burbacher monkey study which showed thimerosal-containing vaccines delivered high levels of mercury to the brain which in turn caused neuro-inflammation.

Many of the arguments and counter-arguments in the third of this group of hearings, and sixth in the entire proceeding, have been made before, but the withdrawal of the expert reports of Drs. Magos and Clarkson makes it very difficult (in my opinion) for the government to prevail. And it was a point which family attorney Timothy Powers made sure stuck out like a sore thumb.

In his opening remarks Powers briefly reviewed the history of Colin Dwyer and that Dr. Mumper would show the legal sequence of cause and effect leading to Colin’s autism.

In her opening remarks, government attorney Lynn Ricciardella remarked that this case was only about specific causation, and that the issue if general causation was now closed. The case had to rest on good, credible science, and had to comport with the standard established in the Daubert case.

Direct Examination of Maria Dwyer (Mother of Colin Dwyer) by Mr. Powers – Attorney for the Families

Mrs. Dwyer, who had worked in media for NBC radio and MTV reviewed the history of her son, Colin. He developed normally until approximately 20 months when he had a vaccination. Colin lost language, would scream and cry, and became difficult to pick up. In addition, he later developed self-injurious behaviors.

The Dwyers tried numerous, costly interventions, before beginning work with Dr. Kenneth Bock, a DAN (Defeat Autism Now) doctor. Colin was put on a gluten/casein free diet and there were immediate improvements in his bowels and physical appearance. Chelation therapy showed his mercury levels were off the charts.

There have been no suggestions that Colin is mentally retarded, as he seems to learn quickly and uses his PECS (picture exchange system) with good proficiency. On a daily basis he still seems to have rigid and compulsive behavior and may hit himself if he becomes frustrated.

While Colin is not recovered, in comparing Colin with three other similarly affected children who were roughly similar many years ago, Colin is the most high-functioning of the group.

Cross-Examination of Mrs. Dwyer by Ms. Lynn Ricciardella (Attorney for the Government)

Mrs. Dwyer believes Colin’s autism was caused by his thimerosal-containing vaccines because his regression started right after receiving his vaccines in July 2000.

Questions from Special Master Denise Vowell

Colin received 4 hepatitis B vaccines rather than the usual 3 vaccines. Although Colin started the gluten/casein free diet, the Dwyers noticed later that it seemed he could handle the gluten without any negative effects.

Direct Examination of Timothy Dwyer (Father of Colin Dwyer) by Mr. Timothy Powers – Attorney for the Families

Mr. Dwyer worked for the New York fire department for 16 years and the police department for 4 years. He was in the second wave of fire-fighters during the 9/11 attacks in New York, arriving just as the towers were coming down.

In Colin’s first year of life there were no problems for him with sirens and he did not appear to have any sound sensitivities. He recalled his wife saying at 13 months that Colin was “into everything.” He also recalls how during the 17-18 month period he spent a lot of time with Colin, going out into the neighborhood, or the beach, and that Colin was fine. After 20 months however, that all changed.

In early 2001 Colin started hand-flapping and displaying other sensory issues. While Colin is better today than he used to be, Mr. Dwyer is worried about Colin’s future. He doesn’t like the idea of Colin living in a group home or being lonely......


Tuesday, July 29, 2008

Jonathan Sebat Is Sporadic Autism Not Related to Increasing Paternal Age???

Summary for 2007 [at-glance overview of Jonathan Sebat work for the selected year as suggested by data mining algorithms]
This is an Authoratory overview of author Jonathan Sebat. According to available data, in 2007 Jonathan Sebat published at least 4 articles. This work was completed in collaboration with several authors including Geschwind, Daniel H and Ye, Kenny. Many other authors have collaborated with Jonathan Sebat as well. At least 2 different grants are awarded to Jonathan Sebat to support this work. All time total of the grant awards on file exceeds $1,703,066.

Jonathan Sebat has rank 235 when compared to all other authors using the keyword Genome, Human. Analysis of the article abstracts and the titles suggests that Jonathan Sebat professional interests are focused around "de novo copy", "novo copy number" and "theory sporadic inherited". These might also be referred to as "de novo", "major changes" or "copy number". Statistical analysis shows that Jonathan Sebat's writing is likely to contains terms "autism", "genetic", "novo", "de", "risk" and "families".

The majority of Jonathan Sebat articles are affiliated with Cold Spring Harbor Laboratory, One 1 Bungtown Road, Cold Spring Harbor, New York NY 11724, USA. Luckily, one email address is on file.


This fact should be taught in Middle School, High School, College, All Doctors Should Know this and Advise Their Patients

"Men's reproductive health is most robust in their twenties, and after that it's downhill. Each year after puberty, a man's spermmaking cells divide about 23 times. By age 40, these vital human building blocks have gone through about 610 rounds of replication, each with a chance for genetic error."

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Saturday, July 26, 2008

There Is Contempt for the Public Not to Warn About Paternal Age and Autism and to Push Vaccines on Children

There is no doubt that there will be less problems for offspring of men fathered babies in their 20s to very early 30s and stopped. There is no doubt that we do NOT know what is in these vaccinations and that giving them in such numbers to infants is detrimental to some.

We have to become informed. No forced vaccinations and spread the word that paternal age and genetic disorders that are new, sporadic, worse is a problem.
Dr. Wilhelm Weinberg noticed and reported in the 19th century that offspring of older fathers had more genetic defects.

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Friday, July 25, 2008

Conflicts of Interests in the Vaccine and Pediatric Industries

Adventures in Autism: CBS News on AAP, Every Child by Two and Paul Offit's Conflicts of Interest in Vaccine Promotion

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Thursday, July 24, 2008

A mysterious connection: autism and Minneapolis’ Somali children

A mysterious connection: autism and Minneapolis’ Somali children
Short yellow school buses deliver children with special education needs to Minneapolis public schools every weekday morning. As students arrive at the elementary school where I work part time, I can’t help but notice something about the autistic kids as they climb down the buses’ steep steps: Almost all are Somali children.


Tuesday, July 22, 2008

65% Autistic Children Found To Have Mitochondrial Disorder According to this article

Home » Blogs » drdavidlipman's blog
65% Autistic Children Found To Have Mitochondrial Disorder
Posted July 22nd, 2008 by drdavidlipman

Mitochondrial Dysfunction is a very common problem amongst children on the spectrum. NEWS12 - LI Naturally host Mary Mucci spent hours with my colleague, Dr. Michael Gruttadauria and two moms of patients in his practice last week for an upcoming story on Autism and Mitochondrial Dysfunction.

See the story here:

"There are two boys with Autism in my practice whose moms have given them baby brothers recently. We wanted to see if siblings of children on the spectrum indeed had metabolic issues and/or Mitochondrial Dysfunction. Metametrix donated their Organic Acids Profile for both families so we could test these two babies for clinical signs of metabolic imbalance/Mitochondrial Dysfunction."

"Because both babies are developing typically, both mom's were shocked to find out that their boys indeed had metabolic changes, including markers for Mitochondrial Dysfunction, come back in the test results."

"You can read more about Mitochondrial Dysfunction in the article below, and sign up for a FREE teleconference on Autism that I am hosting on August 14th at 7 pm EST by clicking this link which will take you to a registration page."

65% Autistic Children Found To Have Mitochondrial Disorder
At an American Academy of Neurology meeting last Sunday it was revealed in a recent research paper, see below, that 65% of children with Austistic Spectrum Disorders assessed were found to have mitochondrial disorder (MtD) and so were always at risk of autism caused by one or more vaccines.
Oxidative Phosphorylation (OXPHOS) Defects in Children with Autistic Spectrum Disorders [IN1-1.004]
John Shoffner, Lauren C. Hyams, Genevieve N. Langley, Atlanta, GA
OBJECTIVE: To retrospectively survey patients with autistic spectrum disorders that were evaluated clinically for mitochondrial disease and to assess the clinical and laboratory features of this group of patients.
BACKGROUND: Autism is a developmental disorder characterized by disturbance in language, perception and socialization. A variety of biochemical, anatomical and neuroradiographical studies imply a disturbance of brain energy metabolism in autistic patients. Recent studies confirmed the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. (J Autism Dev Disord, 2006. 36:1137) Although rare, Mecp2 mutations can produce autistic features and the mouse model has significant mitochondrial defects. (Mol Cell Biol, 2006. 26: 5033) Additional genetic defects associated with mitochondrial dysfunction include inverted 15q11-13 duplication (Complex III defect) (Ann Neurol, 2003,53,801), A3243G mutation (mitochondrial transfer RNALeucine(UUR) gene, mtDNA depletion(J Pediatr, 2004,144,81), G8363A mutation (mitochondrial transfer RNALysine gene. (J Child Neurol, 2000,15,357).
DESIGN/METHODS: Retrospective analysis of 37 children with autistic spectrum disorders. Clinical, biochemical, metabolic, and genetic data is assessed.
RESULTS: Twenty four children (65%) had skeletal muscle OXPHOS defects: Complex I (16), Complex I and Complex III (5), Complex III (1), Complex I and Complex IV (2). Thirteen (35%) had normal skeletal muscle OXPHOS enzyme activities for Complexes I-IV. Clinical, metabolic, protein chemistry, and sequencing of coding regions of the mitochondrial DNA will be reported.
CONCLUSIONS/RELEVANCE: Most children with autistic spectrum disorders do not have recognizable abnormalities on a broad range of imaging, metabolic and genetic studies. However, a subset of patients do harbor significant defects in oxidative phosphorylation function. Complex I abnormalities are the most frequently encountered defect. Recognition of these children is important for understanding how genes that produce autistic spectrum disorders impact mitochondrial function. Supported by: Horizon Molecular Medicine.

Category - Neurogenetics and Gene Therapy SubCategory – Other Sunday, April 13, 2008 2:45 PM
Platform Session: Integrated Neuroscience: Autism (2:00 PM-3:15 PM) Annual Meeting American Academy of Neurology"


From Brasscheck TV

The White House won't protect them,
the Congress won't protect them, your
doctor won't protect them.

If you have small children in your
life, you must protect them.

Start with this video:


Saturday, July 19, 2008

Dr. David Ayoub | Springfield, Ill Autism-vaccine link should not be dismissed

Autism-vaccine link should not be dismissed


Bob Wilmott's column regarding the vaccine link to autism reads more like a press release from the vaccine manufacturers than a balanced journalistic piece looking critically at both sides of the debate ("Doctor dismisses link of autism to vaccines," July 14). As a physician who has researched this topic extensively, I fully believe there is an autism link to vaccines.

Studies that are alleged to dismiss this link are designed poorly, are biased and, in some instances, are fraudulent, often funded by the drug industry, authored by individuals who have strong financial ties to vaccine makers.
Pediatricians trust and rely on information published by the American Academy of Pediatrics, which receives tens of millions of dollars each year from pharmaceutical companies. Some studies published in Pediatrics, its trade journal, have been criticized or proven wrong, such as a large epidemiological study last year by autism "expert" Eric Fombonne.

Dr. Wilmott's plea to be wary of Internet resources is akin to the directive to "ignore the man behind the curtain." With the recent concession by government health officials that childhood vaccines worsened a rare, underlying disorder that ultimately led to autism-like symptoms in a Georgia girl, and that she should be paid from a federal vaccine-injury fund, the facade of lies is beginning to crumble. I urge parents and pediatricians to do their own research with a thorough review of available literature and stop trusting reassuring claims from the very agencies that are responsible for this horrible debacle.

Dr. David Ayoub | Springfield, Ill

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Tuesday, July 15, 2008

Very Important Must See Video

male biological clock

Universities Are Funded to Hide and Obfuscate the Truth

Scientific Misconduct Blog: Crooked academics and the Universities that shield them - more on Brown and Keller

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Monday, July 14, 2008

the damage to the sperm becomes part of the embryo's genetic make-up," she said.

Sheena Lewis, Ph.D.
Tuesday, July 15, 2008Timing is key to fathering children
In this section »
Doctors say women's age remains the major factorCan regular sex preserve potency?THERESA JUDGENew research suggests men's biological clocks are also ticking

FERTILITY EXPERTS have warned there is a growing body of evidence showing that the man's age is a significant factor affecting the chances of a couple conceiving and of having a healthy child.

A new study presented last week at the annual meeting of the European Society of Human Reproduction and Embryology in Barcelona found that miscarriage rates increased significantly when the man was older than 35, and that pregnancy rates dropped when the man was older than 40. The study was based on more than 12,000 couples attending a fertility clinic in Paris.

Professor of reproductive medicine at Queen's University Belfast, Sheena Lewis, who also presented a paper at the conference, said the Paris study "provided more data to add to an emerging picture" relating to the significance of the age of the father.

She said people needed to realise that they are taking a risk by waiting until they were 35 years or older to have children - as an increasing number of women and men are. "You cannot assume that it will happen, that it will not be a problem," she said.

Prof Lewis, who is a scientist at the Regional Fertility Centre at the Royal Victoria Hospital in Belfast, said there was a growing trend of people leaving it later to have children when their careers were established, and of people trying to start second families later in life. She said the clinic was seeing an increasing number of men in their 40s and 50s who wanted to have children, often in a second relationship.

People often mistakenly assume they will be able to have children later in life, she said. "What happens is that we are inclined to take anecdotal evidence and assume that it applies to the whole population - so people hear about Cherie Blair and Madonna having babies and assume that older mothers can have easy pregnancies.

"And they hear about Picasso fathering a child when he was 81, and they believe that every man can do it, and it becomes the accepted wisdom, but unfortunately it is not the case. We are perpetuating a myth and people often believe it until it is too late," Prof Lewis said.

She said there were now quite a number of studies showing that as a man ages, the likelihood of his sperm being damaged increases. "A sperm is a very specialised little cell - it is just DNA with a tail and it has one single function, to get the DNA to the egg to fertilise it. In order to do that, the cell gets rid of everything but DNA, so it gets rid of repair mechanisms that you find in other cells. So if it gets damaged it can't repair itself."

She said that after fertilisation, the DNA damage of the sperm becomes part of the genetic make-up of the embryo. "If a poor sperm fertilises an egg, and even if you get a pregnancy, there is quite often a miscarriage," Prof Lewis said. While one study had suggested that an egg could repair a damaged sperm, she said there was not a great deal of evidence to support this, and further research would be needed to test it. She said other studies had shown that when a man is older it takes longer for a couple to conceive.

Dr Stephanie Belloc, who led the study at the Eylau Centre for Assisted Reproduction in Paris, told the Barcelona conference: "Until now gynaecologists only focused on maternal age and the message was to get pregnant before the age of 35 or 38, because afterwards it would be difficult. But now gynaecologists must also focus on paternal age and give this information to the couple."

The study examined 12,236 couples who had decided to try intra-uterine insemination (IUI) after having difficulty conceiving. This procedure involves spinning sperm in a centrifuge to separate it from seminal fluid and then inserting it directly into the womb.

Pregnancy, miscarriage and delivery rates were recorded as were the quality, activity and shape of the men's sperm. The analysis separated out male and female factors.

As expected, women over the age of 35 were less likely to get pregnant but the man's age was also found to be a significant factor both in miscarriage rates and pregnancy rates.

For men aged 34, the miscarriage rate was 16.7 per cent, but for men aged between 35 and 39 it rose to 19.5 per cent, and by age 44 it had reached 32.4 per cent.

Pregnancy rates only began to change significantly when the men reached the age of 40. As the men's age rose from 39 to 44 the proportion of treatment cycles producing a pregnancy fell from 13.4 per cent to 10.9 per cent.

Dr Belloc said the study "proves for the first time that there is a strong paternal age-related effect on IUI outcomes" and she said the findings were relevant to all couples wishing to have children.

Prof Lewis and her colleagues in Belfast are currently conducting research into "lifestyle hazards" that affect male fertility. These include smoking, alcohol, sexually transmitted diseases, recreational drugs and substances that mimic oestrogens which are found in some products ranging from certain foods, aerosols and body creams, and plastic food coverings. Much of the research in this area was prompted by a Danish finding in 1992 that men's sperm count had declined by 50 per cent in 50 years.

Prof Lewis said a recent study in Denmark had also found that 40 per cent of young men had a low sperm count. "It appears to be a particular problem in northern Europe," she said.

The paper she presented at last week's Barcelona conference concerned the impact of cannabis use on male fertility. The study found that cannabis use decreased sperm motility - the pace at which sperm can swim. Other studies have also shown that cannabis use reduces sperm production.

She said that men who wanted to become fathers should be aware that it takes about 70 days for a sperm to be produced, so the "lifestyle hazards" such as smoking and recreational drugs should be avoided for at least three months if they want their sperm to be healthy.

She also pointed out that studies suggest that a father smoking, and the resulting damage to the sperm DNA, can lead to an increase in certain childhood illnesses, in particular some forms of cancer and more recently an association has been found with autism.

"When a mother smokes and damages the egg, the egg has the capacity to repair the damage, but the damage to the sperm becomes part of the embryo's genetic make-up," she said.

© 2008 The Irish Times

This article appears in the print edition of the Irish Times

Professor Sheena E.M. Lewis, BSc PhD
School of MedicineObstetrics and GynaecologyQueen’s University BelfastInstitute of Clinical ScienceGrosvenor RoadBelfast BT12 6BJN Ireland
t: +44-28-9063-3987
f: +44-28-9032-8247
I am Professor and Director of the Reproductive Medicine research group here in Queen's having previously been Reader in Obstetrics and Gynaecology at Queen's University since October 2000. I was also appointed as an Honorary Consultant in the Royal Group of Hospitals in Belfast in 2003.Services to the scientific communityNationally, I am a regular reviewer for 10 specialist journals and for research charities including The Wellcome Trust, Wellbeing, and BBSRC.I am a member of the Practice and Policy committee of the British Fertility Society and on the Research and Development Fellowship Committee and Northern Ireland Forum for Health and Social Care Research for Northern Ireland.RESEARCH PUBLICATIONS62 peer reviewed publications, 9 review articles, 6 invited chaptersincluding 23 since 2000 (First or final author on 20)RESEARCH GRANTS AWARDED£1,000,000 including three from The Wellcome Trust.PROFESSIONAL SOCIETIES• British Fertility Society• British Andrology Society• Society for the Study of Fertility• International Society of Andrology• Institute of Learning and Teaching in Higher Education• Research and Development Fellowship Committee, N.I• Ulster Obstetrical and Gynaecological Society• Vice Chairperson of the Ladies Committee, Royal Maternity Hospital• Association of University TeachersINVITED GUEST SPEAKER AT RECENT SCIENTIFIC CONFERENCES• First Mediterranean Congress of Reproductive Medicine, Taormina, Sicily• Opening Doors-scientific workshop organised by British and Spanish Councils, Spain,• GSRMC (Good Samaritan Regional Medical Centre Phoenix, Arizona, USA)• UKEMS (The United Kingdom Environmental Mutagen Society)• British Fertility Society• British Andrology Society• Biology of Spermatozoa Annual Meeting• Senior Staff Conference, Royal College of Obstetrics and Gynaecologists• Association of Clinical Biochemists in IrelandINVITED SPEAKER BY MEDIA• BBC Radios 1, 2, 4 and 5• BBC News• Sky news• Ulster Television; UTV LIFE – CHAPS UK Study• Radio Eireann – Donor Sperm• Radio Ulster – Comment on Health Minister’s proposal and comment on BFS in Belfast.• British Satellite News - for CNN news, Tokyo News, Mid Eastern broadcasting and others• Ulster Television The Family Show- Infertility and LifestyleCENTRAL UNIVERSITY ACTIVITIES• Member of Academic Council of Queens University, Belfast• Mentor and mentee in Gender Initiative in Queen’s University, BelfastRESEARCH INTERESTSOur research interest is in Andrology; the study of male reproductive function. Our twin aims are:i) to understand the endocrine, cellular and molecular reproductive dysfunctions in infertile men compared with a fertile baseline. Within this framework, we have focused on specific lifestyle, environmental and disease factors that may exacerbate infertilityii) to establish novel prognostic tests to enhance assisted conceptionOngoing projects:Lifestyle hazards: recreational drugsi) to determine the in vivo and in vitro effects of tetrahydrocannabinoid; THC the primary psychoactive cannabinoid in marijuana on human sperm functionii)the effects of Viagra on sperm function and early embryo development using human and animal modelsEnvironmental hazardsthe effects of dietary phytoestrogens on male reproductive healthDiseases exacerbating male infertilityEndocrine, cellular and molecular effects of diabetes and impotence treatments (first generation Viagra and second generation Tadalafil) on male fertilityDevelopment of novel male fertility tests with prognostic value in assisted conception• assessment of sperm nuclear and mitochondrial DNA iv)investigation of the failure of post-vasectomy testicular sperm to achieve pregnancies by ICSI• the regulation of spermatogenesis by apoptosis in fertile men and males with obstructive azoospermia- clinical implications• Ubiquitin tagging ( internal and surface) on sperm and its implications for male fertility (in collaboration with Dr Peter Sutovsky, Columbia-Missouri )Future Studies• Genetic and epigenetic alterations associated with spontaneous abortion achieved by assisted conception (in collaboration with Dr Ken McIlreavey, Pasteur Institute, Paris and Dr Colum Walsh, University of Ulster )


Video on Vaccination

Sunday, July 13, 2008


The same biological process that causes more miscarriages in the mates of older men, cause de novo autism, schizophrenia, cancers, autoimmune disorders and single gene defects etc.

Genetic clock ticks for menArticle from: Font size: Decrease Increase Les Sheffield

June 12, 2008 12:00am
MOST men would have been surprised to read that overseas researchers had found the death rate of young adults was higher if they had been born to older fathers.

This is no surprise to me. It has been scientifically established that genetic changes occur more often in the sperm of older fathers than younger fathers.

As men age there is a higher chance of changes in the genes in the sperm.

These changes can cause genetic conditions in their offspring, such as birth defects, autism and schizophrenia.

Their partners can also have an increased risk of miscarriages.

The presumed reason for the increase occurrence of all of these conditions is that they are all due to a new genetic change in the sperm of the older father.

Genetic changes are occurring all the time. Sometimes they have a beneficial effect, such as making the individual stronger, taller or smarter.

This is part of the concept of "survival of the fittest".

Sometimes, when the gene change is in a non-coding part of the genome, they have no effect. At other times, they can be harmful.

The problem is that these harmful effects are extremely varied because they can affect any one of the 20,000 or so human genes.

For example, they often change the structure of the body. One example is dwarfism, where the arms and legs are short due to a genetic change. The commonest type of dwarfism is achondroplasia.

An individual with this condition will have a 50 per cent risk of having an affected child themselves.

Indeed, about 20 per cent of the parents of achondroplastic babies have one of the parents with this condition, but the remaining 80 per cent do not.

If you look at the parents of babies with achondroplasia, who do not have the condition themselves, you find their average age is older than other people having babies in the population.

Significantly, statistics show it is the father's age which is important and not the mother's.

Achondroplasia is rare and it is only one of the many genes that can go wrong. Collectively, any of the 20,000 genes can change and this causes an increase in risk from about the age of 40.

The risk in men for any single gene change is one in 200 at age of 40, 20 at age 50 and rises steeply after that.

This increase in risk with paternal age is no surprise to me, but it is a surprise to practically everyone else.

The increase risk for older mothers for Down syndrome is well-known.

As part of my work as a clinical geneticist, I see couples every week who come to ask about the risk of having babies because of the age of the mother.

We talk about this and often, as the male partner is also older, we talk about the risk of his age. Most of the partners are quite surprised and even taken aback with this news.

In today's society, delaying pregnancy until later is often done for career and other purposes but usually only the age of the mother is taken into account in planning when to start a family. Why is the increased risk in relation to a father's age not widely known?

There are many possible reasons. Some of the information - such as increased death rates of adults - is new.

But information about single gene changes, such as achondroplasia, has been around for many years.

I think the real reason for the lack of knowledge is the conditions that can be caused are varied and can't really be prevented by a screening program like the one offered for Down syndrome.

In fact, most of the conditions, such as achondroplasia, can't even be picked up by the normal ultrasound scan for abnormalities done at 18-20 weeks of a pregnancy.

So, if you're a male, the only way not to be exposed to this increased risk of genetic defects in your offspring is to plan your children early and regard the increasing risks of the woman in her late 30s and early 40s as also applying to you.

In other words, stop your child bearing at the same sort of age that women stop child bearing. This may not be what older men want to hear, but they need to seek information about what the risks actually are before making child-bearing decisions.

We hear about the positive sides of parenthood in some older celebrity fathers but the story last week about the increase in death rates of the offspring brings out the hidden risks associated with fathering children at an older age.

Associate Professor Les Sheffield is a clinical geneticist with the Victorian Clinical Genetics Services


Expert calls for vigilance on IVF problems
Friday, 13 June 2008 Anna Salleh

As men age the DNA of their sperm gets damaged and this can cause disease in their children later in life (Source: iStockphoto)

Related Stories
Infertility, ABC Health and Wellbeing
Male biological clock probed
IVF: who's pushing who?
Map: Newcastle 2300

As humans become more dependent on reproductive technologies, an Australian reproductive biologist say we must remain vigilant to avoid the spread of genetic or epigenetic defects.

The warning comes in an editorial by Professor John Aitken, of the University of Newcastle, in the current issue of Expert Review of Obstetrics and Gynecology.

"People shouldn't be too confident that just because the baby looks normal there is no damage there that won't appear later in life," he says.

"People underestimate how much genetic damage they're passing onto the embryos."

Aitken says 1 in every 35 babies born in Australia are a result of IVF.

"In some countries it's more like 1 in 20 and there are models that predict it will be 1 in 10 before too long," he says.

Aitken says because IVF allows infertile men to reproduce, the more we use it the more it will be needed in the future.

"So we better make sure it's safe because a large proportion of the population will be generated in this way," he says.

Ageing sperm
Aitken says a number of factors are known or suspected to cause genetic damage to sperm, that don't necessarily cause defects obvious at birth.

For example, Aitken says the sperm of ageing males is thought to contribute to conditions such as autism, schizophrenia and epilepsy.

He says there is strong evidence linking sperm DNA damage to smoking, which can lead to the development of childhood cancers.

Epigenetic changes to sperm DNA that can affect fertility through several generations have also been reported.

For example, several recent papers have shown that infertile men have a dramatically altered DNA methylation profile.

Screening and monitoring
Aitken says genetic problems mean it is important that reproductive clinics do a good job at screening sperm samples for genetic damage.

He is presenting the latest evidence on one screening technique he is developing with biotech company NuSep at the Australian Research Council's Graeme Clark Research Outcomes Forum in Canberra next week.

But Aitken says long-term monitoring of children born through IVF and other reproductive technologies is also essential because such techniques can not pick up epigenetic damage.

"There are all kinds of things that can and could still go wrong," he says.

While he says IVF children are being monitored, he is concerned about complacency among clinics who celebrate their ability to produce normal looking babies from sperm with high levels of DNA damage.

IVF defended
Professor Michael Chapman of the Fertility Society of Australia, who also works for IVF Australia, says genetic damage is considered by IVF clinics.

"They're concerns that are shared within the IVF profession," he says.

Chapman says one rare epigenetic disease has shown up in IVF children - at a rate of 1 in 1500 versus 1 in 5000 in the general population.

But he says Aitken's "provocative" article overstates the problem since in the 20 years that IVF has been around, few long-term problems have arisen despite thousands of children being monitored.

"I'm sure that if something starts to turn up, it will jump out at us," he says.

Sandra Hill, CEO of ACCESS Australia, a group led by patients seeking IVF treatment, is confident that IVF is well-monitored, and she agrees this should continue.

But she says many of the concerns raised by Aitken also apply to natural conception and she thinks the use of IVF should not be singled out.

She says it could be useful to educate men in general about the concerns raised by Aitken - especially the need for men to have children before they get too old.

Aitken says this may be so, but IVF still presents a unique challenge.

"With IVF you are facilitating the fertilisation of eggs with sperm that would otherwise be unsuccessful," he says.

Aitken also says the rate of birth defects in IVF children are up to twice that of normally-conceived children, although he expects that to improve as techniques improve.

Tags: fertility-and-infertility, pregnancy-and-childbirth, reproductive-technology, biotechnology, inventions


June 26, 2008 in Biology | 5 comments | Post a comment

Fact or Fiction: Men Have a Biological Clock
Does male fertility have an expiration date?
By Anne Casselman

TICKING CLOCK: Male fertility declines just like female fertility.
The female biological clock—its tick-tock marking the decline of fertility that grows louder as a woman reaches middle age—is deeply ingrained in popular consciousness. Take this scene from the film Bridget Jones's Diary: Bridget's Uncle Geoffrey reminds her that as a career girl she "can't put it off forever," alluding to her declining fertility. His wife Una chimes in: "tick-tock, tick-tock," her finger wagging like a metronome.

The biological clock, although just a metaphor, refers to a real phenomenon: Women over 35 years of age are only half as likely to become pregnant in the most fertile part of their menstrual cycle than women younger than 26.

So do men suffer from the same thing?

"For women, a biological clock is a decline in fertility and an increased chance of having genetically abnormal babies as they age," says Harry Fisch, director of New York City's Male Reproductive Center and author of The Male Biological Clock: The Startling News About Aging, Sexuality, and Fertility in Men. "And that's exactly what's happening with men."

So how did Indian farmer Nanu Ram Jogi sire a healthy child at the age of 90 last year? Such a feat would be impossible for a woman, even in an age when Carmela Bousada, 67, gave birth to twins in January 2007 after lying about her age to the doctors who gave her in vitro fertilization. Whereas fertility declines along with testosterone levels as men age, it doesn't drop to zero.

Still, Jogi is definitely the exception rather than the rule. One study found that the odds of fatherhood for those under the age of 30 was 32.1 percent compared with 20 percent over the age of 50, signifying a 38 percent drop in male fertility across that age gap.

One study examined 97 men between the ages of 22 and 80 and found that as they aged their semen volume decreased by 0.001 ounce (0.03 milliliter) per year from an average total of 0.09 ounce (2.7 milliliters) and their "total progressively motile sperm count"—a rough index for the fertility potential of one's sperm based on its movement—decreased about five percent with each year they aged.

Fisch and his colleagues have also found that the children of women over 35 whose babies' fathers were also of that age were more likely to have Down's syndrome than offspring whose fathers were younger.

In other studies, older men were more likely to father children with mental illness or other deficits. Roughly 11 children out of a thousand conceived by men over age 50 developed schizophrenia compared with under three children out of a thousand for fathers under 20 in one study from the Archives of General Psychiatry. And the children of men 40 years or older were nearly six times more likely to have autism spectrum disorders than kids begot by men under 30.

So do men's sperm get staler over time? To maintain sperm levels, cells known as germ cells must continue dividing. After all, men find ways to dispose of sperm—ahem—and once ejaculated they only survive for several days. By the age of 50, these germ cells will have divided 840 times. Each one of those divisions is an opportunity for something to go wrong. "There's more of a chance to have genetic abnormalities the more the cells divide," Fisch says. In sperm these mutations dot the genes with changes in the basic structure of the DNA—and can lead to problems in the resulting offspring.

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Saturday, July 12, 2008

Schizophrenia Risk and the Paternal Germ Line (Autism Too

Schizophrenia Risk and the Paternal Germ Line
By Dolores Malaspina

Paternal age at conception is a robust risk factor for schizophrenia. Possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The predisposing genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.

Seminal findings
We initially examined the relationship between paternal age and the risk for schizophrenia because it is well established that paternal age is the major source of de novo mutations in the human population, and most schizophrenia cases have no family history of psychosis. In 2001, we demonstrated a monotonic increase in the risk of schizophrenia as paternal age advanced in the rich database of the Jerusalem Perinatal Cohort. Compared with the offspring of fathers aged 20-24 years, in well-controlled analyses, each decade of paternal age multiplied the risk for schizophrenia by 1.4 (95 percent confidence interval: 1.2-1.7), so that the relative risk (RR) for offspring of fathers aged 45+ was 3.0 (1.6-5.5), with 1/46 of these offspring developing schizophrenia. There were no comparable maternal age effects (Malaspina et al., 2001).

Epidemiological evidence
This finding has now been replicated in numerous cohorts from diverse populations (Sipos et al., 2004; El-Saadi et al., 2004; Zammit et al., 2003; Byrne et al., 2003; Dalman and Allenbeck, 2002; Brown et al., 2002; Tsuchiya et al., 2005). By and large, each study shows a tripling of the risk for schizophrenia for the offspring of the oldest group of fathers, in comparison to the risk in a reference group of younger fathers. There is also a "dosage effect" of increasing paternal age; risk is roughly doubled for the offspring of men in their forties and is tripled for paternal age >50 years. These studies are methodologically sound, and most of them have employed prospective exposure data and validated psychiatric diagnoses. Together they demonstrate that the paternal age effect is not explained by other factors, including family history, maternal age, parental education and social ability, family social integration, social class, birth order, birth weight, and birth complications. Furthermore, the paternal age effect is specific for schizophrenia versus other adult onset psychiatric disorders. This is not the case for any other known schizophrenia risk factor, including many of the putative susceptibility genes (Craddock et al., 2006).

There have been no failures to replicate the paternal age effect, nor its approximate magnitude, in any adequately powered study. The data support the hypothesis that paternal age increases schizophrenia risk through a de novo genetic mechanism. The remarkable uniformity of the results across different cultures lends further coherence to the conclusion that this robust relationship is likely to reflect an innate human biological phenomenon that progresses over aging in the male germ line, which is independent of regional environmental, infectious, or other routes.

Indeed, the consistency of these data is unparalleled in schizophrenia research, with the exception of the increase in risk to the relatives of schizophrenia probands (i.e., 10 percent for a sibling). Yet, while having an affected first-degree relative confers a relatively higher risk for illness than having a father >50 years (~10 percent versus ~2 percent), paternal age explains a far greater portion of the population attributable risk for schizophrenia. This is because a family history is infrequent among schizophrenia cases, whereas paternal age explained 26.6 percent of the schizophrenia cases in our Jerusalem cohort. If we had only considered the risk in the cases with paternal age >30 years, our risk would be equivalent to that reported by Sipos et al. (2004) in the Swedish study (15.5 percent). When paternal ages >25 years are considered, the calculated risk is much higher. Although the increment in risk for fathers age 26 through 30 years is small (~14 percent), this group is very large, which accounts for the magnitude of their contribution to the overall risk. The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent.

Biological plausibility
We used several approaches to examine the biological plausibility of paternal age as a risk factor for schizophrenia. First, we established a translational animal model using inbred mice. Previously it had been reported that the offspring of aged male rodents had less spontaneous activity and worse learning capacity than those of mature rodents, despite having no noticeable physical anomalies (Auroux et al., 1983). Our model carefully compared behavioral performance between the progeny of 18-24-month-old sires with that of 4-month-old sires. We replicated Auroux's findings, demonstrating significantly decreased learning in an active avoidance test, less exploration in the open field, and a number of other behavioral decrements in the offspring of older sires (Bradley-Moore et al., 2002).

Next, we examined if parental age was related to intelligence in healthy adolescents. We reasoned that if de novo genetic changes can cause schizophrenia, there might be effects of later paternal age on cognitive function, since cognitive problems are intertwined with core aspects of schizophrenia. For this study, we cross-linked data from the Jerusalem birth cohort with the neuropsychological data from the Israeli draft board (Malaspina et al., 2005a). We found that maternal and paternal age had independent effects on IQ scores, each accounting for ~2 percent of the total variance. Older paternal age was exclusively associated with a decrement in nonverbal (performance) intelligence IQ, without effects on verbal ability, suggestive of a specific effect on cognitive processing. In controlled analyses, maternal age showed an inverted U-shaped association with both verbal and performance IQ, suggestive of a generalized effect.

Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age.

A variant of schizophrenia
A persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980).

It is possible that the genetic events that occur in the paternal germ line


12 Babies from Poor Families Die in Glaxo Vaccine Trials



Prevent Non Familial Schizophrenia and Autism Complete Your Fathering of Babies Before 34

Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4.Related Articles, Links
Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.

Wohl M, Gorwood P.

INSERM U675, 16 rue Henri Huchard 75018 Paris, France.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.

Publication Types:

PMID: 17142012 [PubMed - indexed for MEDLINE]



Time to Repeat an Older Post, Maybe The Genetic Male Biological Clock Will Be Understood

Dad's Hidden Influence A father's legacy to a child's health may start before conception and last generations

Dad's Hidden Influence
A father's legacy to a child's health may start before conception and last generations
Tina Hesman Saey

Pregnant women know the drill. Don't drink. Don't smoke. Don't eat too much fish. Take vitamins. Mothers have long shouldered the responsibility, and the blame, for their children's health. Fathers don't usually face the same scrutiny.

How a man lives, where he works, or how old he is when his children are conceived doesn't affect their long-term health, scientists used to think. But growing evidence suggests that a father's age and his exposure to chemicals can leave a medical legacy that lasts generations.

Animal studies demonstrate that drugs, alcohol, radiation, pesticides, solvents, and other chemicals can lead to effects that are handed from father to son. Human studies are less clear, but some show that fathers play a role in fetal development and the health of their children.

Teenage dads face increased risk that their babies will be born prematurely, have low birth weight, or die at birth or shortly afterward, a new study in Human Reproduction shows.

Babies of firefighters, painters, woodworkers, janitors, and men exposed to solvents and other chemicals in the workplace are more likely to be miscarried, stillborn, or to develop cancer later in life, according to a review in the February Basic & Clinical Pharmacology & Toxicology.

Fathers who smoke or are exposed at work to chemicals called polycyclic aromatic hydrocarbons put their children at risk of developing brain tumors.

And, older fathers are more likely to have children with autism, schizophrenia, and Down syndrome and to have daughters who go on to develop breast cancer.

Though some of these observations are decades old, attitudes lag even further behind, says Cynthia Daniels, a political scientist at Rutgers University–New Brunswick in New Jersey. Dads aren't held accountable if something goes wrong during fetal development.

Matter of math
Since men make new sperm every 74 days, people used to reason, the genetic slate is wiped clean every couple of months. And even if a man makes defective sperm, the "all-or-nothing" view of reproduction holds that damaged sperm don't fertilize eggs. No harm. No foul.

So no one bothers to remind men to protect themselves against environmental toxins. There are no images of "crack dads" and "crack babies" in the media like those of women who harm developing fetuses with drug and alcohol use, Daniels said in February at a meeting of the American Association for the Advancement of Science held in Boston.

When someone does study fathers-to-be, the focus is usually on fertility, not on the consequences for children's health, she says.

Yet even fertility messages meet resistance from many men.

Harry Fisch, director of the Male Reproductive Center and a urologist at Columbia University Medical Center, found that out when he suggested that men, like women, have ticking biological clocks.

Men can produce sperm throughout life, but that doesn't mean their cells are forever young.

"Every cell in the body ages," says Fisch. "Every cell. The older you get, the more chance of an abnormality. The same thing goes for sperm."

Men younger than 20 and older than 30 make more abnormal sperm than men in their 20s. These damaged sperm could create an unhealthy embryo or pass on damage that could lead to birth defects or illness in offspring.

It is not a popular message.

"Men do not want to hear this," Fisch says. "When my book came out, I got e-mails. I got faxes saying, 'How dare you say this? How can you say this? We know that there are men in their 70s having healthy children.'"

Despite these anecdotal accounts of elderly dads, studies demonstrate that older men are at increased risk of passing on genetic abnormalities. It's a matter of math.

Women are born with all the eggs they will produce in their lifetime. The cells that give rise to eggs divide 24 times, all before birth. But the cells that produce sperm continue to divide throughout a man's lifetime. Each year after puberty, a man's sperm-producing cells replicate about 23 times. Every time the cells divide is another chance for error.

As a result, the sperm produced by a 40-year-old man have gone through about 610 rounds of replication. That's 610 chances of introducing a mutation in the DNA, or improperly divvying up genetic material.

Parents over age 40 are six times more likely to have children with Down syndrome than 25-year-old parents, Fisch and colleagues showed in a 2003 study in the Journal of Urology. An extra copy of chromosome 21 causes Down syndrome. This extra chromosome is just as likely to come from dad as mom in the older couples.

Older dads also have a higher risk of fathering children with rare mutations that cause dwarfism or a premature aging disease called Hutchinson-Gilford progeria syndrome.

But sometimes aging fathers pass along traits that can't be traced to only a single mutation. Fathers 40 and older have an increased chance that their children will develop complex disorders such as autism or schizophrenia. There is growing evidence that those disorders are caused by defects in many genes and the way genes are turned off and on.

Scientists don't yet understand the changes that age induces in sperm-making germ cells, and environmental exposure presents an even bigger mystery. People come in contact with a plethora of chemicals every day. But it is no easy task to sort out exactly which ones, or which combinations, cause heritable problems. The effects chemicals and radiation may have on offspring don't always follow predictable patterns either.

And when researchers do find a clear link between a father's lifestyle and his children's health, it's not always clear what the data mean.

"What we can say is that we identified a group of fathers with adverse outcomes for their fetuses, but we don't have an idea of the mechanism," says Shi Wu Wen of the University of Ottawa in Canada and one of the lead authors of the study showing that babies of teenage fathers have a greater risk of birth problems.

Wen and his colleagues examined birth records for more than 2.6 million babies born between 1995 and 2000 to married, first-time, 20-something mothers in the United States. Looking at the husbands' ages, the team found that babies of teenage fathers, but not middle-age men, had an elevated risk of still birth, low birth weight, and other birth problems. The study was published online Feb. 6 in Human Reproduction.

'Preposterous' inheritance
Some animal studies showing paternal effects emerged years ago but were roundly dismissed, says Gladys Friedler, professor emeritus at Boston University.

OLDER AGE, HIGHER RISK. As men age, they stand a greater chance of fathering children who will develop schizophrenia by age 34. Paternal age is only one of many factors linked to schizophrenia.
E. Roell, (Source: D. Malaspina, et al., Arch. of Gen. Psychiatry, 2001)

Four decades ago, Friedler was studying tolerance to narcotics, one of the first steps of addiction. To find out if a mother rat could pass tolerance on to her offspring along with antibodies and other immune factors, as some scientists theorized, Friedler exposed female rats to morphine before pregnancy. Babies of exposed mothers were born much smaller than average. And those babies also went on to give birth to tiny babies, even though the offspring had never encountered the drug.

Friedler also gave male rats morphine before they bred. "To my total disbelief and bewilderment, paternal exposure also affected progeny," Friedler said at the AAAS meeting.

Her adviser dismissed the result. Morphine doesn't cause mutations, so the idea that males could hand down a trait without passing along a mutation seemed preposterous. The whole thing smacked of Lamarckism, the long-rejected idea that environmental influences can change an animal or plant's structure and offspring can inherit that change.

But in recent decades, scientists have discovered that chemical modifications to DNA and proteins can change the way genes are packaged and regulated without changing the genes themselves. Such modifications are known as epigenetic changes.

"What was Lamarckian is now epigenetic," Friedler says.

Epigenetic modifications act as a molecular scrapbook, preserving memories of events in parents' lives and handing them down to the next generation and beyond.

"There's a chromosomal memory," says Anne Ferguson-Smith, a developmental geneticist at Cambridge University in England. "The chromosomes remember whether they came from the mother or the father."

That memory is established in the form of a chemical mark called methylation. Methylation usually turns a gene off. At least 100 genes in humans are turned off only on the chromosome contributed by the mother or only on the chromosome that came from the father. Such genes are called imprinted genes because of the indelible impression parents leave on their offspring's DNA.

Several imprinted genes help build the placenta or encode growth factors that need to be tightly controlled so an embryo will develop correctly. "There's a contribution from both parents that is essential," Ferguson-Smith says. "One can't do without the other. They must work together to have a healthy offspring."

Imprints and other methylation marks are not encoded in the DNA. Instead the epigenetic modifications decorate chromosomes like ornaments on a Christmas tree. But these ornaments are heirlooms of a different type. It's as if a seedling grows straight from the ground already gussied up with tinsel and lights in the same places its parents were decorated. If a chemical or aging alters the epigenetic pattern on a man's chromosomes, his heirs could bequeath mismarked DNA to their children, too. Some mistakes may be as benign as exchanging a red bulb for a blue one. Other alterations, akin to placing the star on the lowest branch instead of the treetop, are likely to have more profound consequences.

Male mice exposed to cocaine, for example, pass memory problems on to their pups, a 2006 study in Neurotoxicology and Teratology shows. The male mice inhaled cocaine in long daily sessions akin to crack binges. When they mated with females never given coke, they had pups that had trouble learning and remembering where to find food in simple mazes. The problem was especially severe for female offspring. The researchers couldn't find any obvious DNA damage in coke-smoking males' sperm, but did find altered levels of two enzymes involved in the methylation of DNA in sperm-producing tissue in the father mice. The result suggests that epigenetic changes may be responsible for the offspring's behavior problems.

Fungicide legacy
Matthew Anway doesn't know whether the rats in his lab at the University of Idaho in Moscow have methylation problems. Some studies suggest they do, but Anway doesn't yet have definitive proof.

He can prove that male rats exposed to a fungicide in the womb can pass tumors and diseases of the prostate and kidney down for at least three generations. The rats could provide the first model for how prostate disease is inherited, he says.

Male babies born to mothers that had been injected with fungicide had prostate problems that mimic those seen during human aging. The second-generation rats also had more tumors, kidney defects, and higher rates of abscesses, cysts, and other infections than unexposed control rats. Germ cells in the testes of exposed rats also died more quickly than those in the control rats.

Subsequent generations of male rats also had the prostate and testes defects, and both male and female offspring developed kidney problems and tumors.

But only male rats could pass along the defects. The exposed rats bequeathed their fungicide legacy to their sons, grandsons, and great-grandsons even though none of the later generations were exposed to the chemical.

Exposed animals decrease production of enzymes that methylate DNA, Anway says. But he hasn't yet found consistent changes in the methylation patterns in exposed rats.

It's not clear whether Anway's results have any implication for human health. The rats were exposed to extremely high doses of fungicide through the completely unnatural route of injection.

What's important is that the male shares experiences with descendants for years to come. Further research could give new insights, Anway says, into how alterations in early development could lead to adult disease in humans.



Risk of Miscarriage and Older Fathers Old News Worn out Pasta Machine Analogy

Thursday, April 24, 2008

The biological clock may no longer be ticking on just the woman's side of the bed.

If current research is correct, a man's baby-making alarm may start to ring not too long after a woman's chimes its final warning toll -- around age 40.

"I don't want there to be a panic, but I think it's safe to say that the father's age should be one of many factors couples should put into the equation when planning a family," says Karine Kleinhaus, MD, PhD, a researcher at Columbia University who recently spearheaded a study on paternal age and miscarriage.

Over the past decade -- and particularly during the last five years -- studies have been mounting indicating that the age of the father may affect the health of the offspring in more ways than one.

Risk of Birth Defects
Associations have been made between paternal age and the risk of birth defects and developmental disorders such as autism and Apert's syndrome, as well as mental illnesses like schizophrenia. Moreover, studies conducted by Kleinhaus and colleagues at Columbia University looked at some 90,000 births and concluded the older a man is when he conceives a child, the more likely his partner is to miscarry -- even when she is young, healthy, and has no other risk factors.

Many believe this is just the beginning of what there is to learn.

"What we know now may be just the tip of the iceberg, particularly regarding birth issues we don't fully understand. We are just beginning to look at the role of a father's age. And as time goes by it's likely we are going to learn a lot more," says Jeremy Silverman, PhD, a professor of psychiatry at Mt. Sinai Medical Center in New York City, and the researcher of a study that associated paternal age with risks of autism.

Aging Dads: What Goes Wrong
Like every system in the body, experts say the male reproductive organs have not been spared the ravages of time.

"First there seems to be some clear changes that happen on a purely chemical level as a man ages. He has lower testosterone levels, lower DHEA, lower estrogen, plus higher levels of FSH and LH, which signal pretty much the same thing in men as in women -- reproductive failure," says Hackensack University embryologist Dave McCulloh, PhD, director of laboratory services at University Reproductive Associates in Hasbrouck Heights, N.J.

In a French study of nearly 2,000 men published in 2005 in the journal Fertility and Sterility, doctors concluded that even in couples undergoing IVF an aging father could figure into the pattern of pregnancy failure, more than previously thought.

But it's not just the idea of making fewer babies that is of concern. The new research is also tampering with conventional fertility wisdom, which has long asserted that because new sperm is made daily, male fertility remains untouchable.

And while the notion of unending sperm production hasn't changed, some researchers now believe that as a man ages, the task of churning out that daily supply is a little like trying to make a fresh batch of macaroni in a worn-out pasta machine

In short, while the ingredients may be fresh, the mechanism that puts it all together gets slower and works less efficiently with age. And that means far fewer perfect macaroni -- and sperm -- to show for it.


Public release date: 3-Aug-2006
[ | E-mail Article ]

Contact: Stephanie Berger
Columbia University's Mailman School of Public Health

Miscarriage significantly associated with increasing paternal age
In a study conducted at Columbia University's Mailman School of Public Health and the New York Psychiatric Institute researchers found that increasing paternal age is significantly associated with increased rates of spontaneous abortion, a pregnancy loss occurring before twenty weeks of gestation. Results indicate that as the male partner ages there is a steady increase in rate of miscarriage. Women with partners aged 35 or older had nearly three times as many miscarriages as compared with women conceiving with men younger than 25 years of age. This finding is independent of the woman's age and not explained by other factors such as diabetes, smoking, or previous spontaneous abortions, and adds to the growing realization of the importance of paternal characteristics for successful reproductive outcome.

"There has been a tremendous amount of research on women, and how their characteristics affect pregnancy outcomes. Of course, women's importance and centrality to pregnancy cannot be overstated. However, scientists seem to have forgotten that men are equal partners in reproduction, and their influence should be studied to the same degree. Our group has focused on men's influence on the health of their offspring, and we have made some fascinating discoveries," said Karine Kleinhaus, MD, MPH currently in Columbia's Department of Psychiatry and first author of the study. "This study shows how a man's age affects the likelihood of miscarriage."

Earlier research by the Columbia scientists showed that older men's wives suffer from preeclampsia, while the offspring of older men are more likely to get schizophrenia. "This is not as surprising as it may sound at first, as it was already shown by other researchers that older men have more abnormalities in their sperm, and that their children are more susceptible to certain birth defects," observes Dr. Klienhaus. In fact, the American Society for Reproductive Medicine has set an upper age limit of 40 years old for semen donors because of the increased risk of genetic abnormalities in the offspring of older fathers.

The international team of scientists involved in the study used a large historical data set containing information on many characteristics of mothers and fathers that might contribute to spontaneous abortion. The researchers analyzed data from the ante-natal or post-partum interviews of 13,865 women. This data was recorded in the Jerusalem Perinatal Study, a population-based cohort derived from 92,408 births in Jerusalem in 1964-1976.

Accordingly, the study, which focused exclusively on spontaneous abortion as the outcome, has as one of its strengths its large sample size and its extensive data, which permit consideration of important potential confounders not included together in other analyses. These include variables such as maternal diabetes, parity, history of prior spontaneous and induced abortions, and history of maternal smoking, and socioeconomic status.

The cohort used for this study is unique, with immigrants from many origins, including Iran, Iraq, Afghanistan and countries of North Africa, as well as Central and Eastern Europe. "This broad mix of backgrounds makes our study findings more generalizable," observed Susan Harlap, MD, professor of clinical epidemiology in the Mailman School of Public Health's Department of Epidemiology, and the leader of this research team. "While several previous studies suggested that father's age might contribute to miscarriage, they failed to clarify whether there is a cut-off age or a progressive trend over the whole range of ages."

The study findings generate strong support for the association of increasing paternal age with increasing rates of spontaneous abortion, and are corroborated by other published studies. "Advanced paternal age may result in only a slight increase in the chance of spontaneous abortion for a specific couple. Nevertheless, as child bearing is increasingly delayed in Western societies, this study provides important information for people who are planning their families," said Dr. Kleinhaus. "The study also adds to a growing understanding of how men's age, health, and occupations can affect their partner's pregnancies and the offspring's future development."

In addition to the Mailman School of Public Health and the New York Psychiatric Institute, the international team of scientists included researchers from Braun School of Public Health and Community Medicine and the Department of Hematology, Hebrew University-Hadassah, Jerusalem, Israel.

The Jerusalem Perinatal Cohort, is among those being followed by the life course studies program within the Mailman School's Department of Epidemiology. Department Chair Ezra Susser, MD, DrPH, has been building a program of life course research -- called the Imprints Center -- in which epidemiologists seek to uncover the causes of a broad range of disease and health outcomes, following individuals from an early point in life and examining their risks for disease. Life course studies are particularly well positioned to examine the interplay of genetic and environmental risk factors - the key to understanding many complex diseases.

The study findings are published in the August 1, 2006 issue of Obstetrics & Gynecology 2006;108:369-377 ?2006 by The American College of Obstetricians and Gynecologists.

About the Mailman School of Public Health
The only accredited school of public health in New York City, and among the first in the nation, Columbia University's Mailman School of Public Health provides instruction and research opportunities to more than 950 graduate students in pursuit of masters and doctoral degrees. Its students and more than 270 multi-disciplinary faculty engage in research and service in the city, nation, and around the world, concentrating on biostatistics, environmental health sciences, epidemiology, health policy and management, population and family health, and sociomedical sciences.

Founded in 1896, the New York State Psychiatric Institute (PI) continues to contribute importantly to knowledge about understanding and treating psychiatric disorder and is ranked among the best psychiatric research facilities in the world today. Noted for its research on depression and suicide, schizophrenia, anxiety and child psychiatric disorders, PI is also at the forefront of research dedicated to unraveling the brain's mysteries. Its scientists constitute the core of the Department of Psychiatry at Columbia University. In 2000, Dr. Eric Kandel was awarded the Nobel Prize in Physiology or Medicine for research in his labs at PI on the cellular basis of memory.



Thursday, July 10, 2008

Warning Older Paternal Age Causes Some Non-Familial Autism and other more Subtle Genetic Neurodevelopmental Disorders

Saturday, April 05, 2008
Should Older Men Stop Fathering Babies And Adopt to Add To or Begin New Families?

Minding Your Mind

New Key to Autism

September 25, 2006

By Michael Craig Miller, M.D.
Harvard Medical School

Convincing Evidence

What Causes These Genetic Errors?

Should Older Men Stop Fathering Babies?

A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older.

What Is Autism?
Autism is a profoundly disabling disorder that starts in early childhood. The key features are:

Abnormal social development – little or no eye contact, prefers to be alone
Difficulty communicating – impaired language ability, uses gestures or pointing rather than words
Unusual behavior – spins objects, doesn't like being cuddled
Evidence of strong abilities sometimes in non-verbal areas, such as math or music
Older people with autism may have some ability to interact with people, but about two-thirds are mentally retarded and most cannot live on their own
Unfortunately, the incidence of this illness appears to be on the rise. Some experts think autism is diagnosed more often simply because more people are aware of it. But that's probably not the whole explanation.

Genetic factors almost certainly play a big role. So autism researchers are eager to discover anything that might increase a person's genetic vulnerability, such as delaying parenthood until age 40 or beyond.

The risk was smallest for children of fathers younger than 20 and greatest for children of fathers older than 50. A man in his 40s, for example, was almost 6 times as likely to have an autistic child as a man age 20. This relationship held even after researchers adjusted the results for the year of the person's birth, their socioeconomic status, or the mother’s age.

This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.

Convincing Evidence

The Archives study took advantage of the extraordinarily complete health records of over 300,000 Israeli men and women who underwent a complete health assessment when they were 17-year olds — draft age. This gave researchers a good way to determine the incidence of autism in the population. The researchers had access to intellectual, medical and psychiatric evaluations of almost all Israeli boys and three-quarters of girls. (Their identities were kept secret, however.) For most individuals, the father’s age at birth was known.

Although boys were more likely to develop autism than girls, the risk for girls also increased as fathers got older. When fathers were young, about 1 in 6 children with autism were girls. After fathers passed the 40 year-old mark, the proportion of girls with autism rose to about 1 in 3. This suggests that the genetic factors in play for offspring of older fathers are different from those for offspring of younger fathers.

What Causes These Genetic Errors?

All children inherit genetic material in equal amounts from both parents. In the case of autism, scientists think that the genetic material in the sperm of these older fathers has somehow become altered in harmful ways. These flaws make the child more vulnerable to developing the disease.

According to one theory, mutations (changes) are more likely to develop as men get older. Germ cells give rise to sperm throughout a man's life. These cells make copies of themselves and after several decades, the germ cells are copies of copies of copies. A second theory suggests that the offending genes passed down by older men are not properly marked or "imprinted." Accurate marking — which establishes whether a gene is from the father or the mother — determines if it will be active or not. If there is an error, the gene may function abnormally.

Should Older Men Stop Fathering Babies?

It's true that medical technology and general improvements in health have made life much more enjoyable for people in middle to late life. Maybe 50 is the new 30 when it comes to some aspects of aging. But a healthy and active lifestyle does not make 50-year-old sperm the new 30-year-old sperm.

The increased risk of passing on any genetic vulnerability to a child is significant when you are older. When it comes to autism, however, the numbers are sobering. A man younger than 30 has no more than a 1 in 1,000 chance of fathering a child with autism. But the risk bumps up to approximately 3 in 1,000 for a man in his 40s and 5 in 1,000 above age 50. If a father in his fifties has a son, the risk of autism may approach 1 in 100.

The researchers did not have access to information about the child's birth environment or development.
Until recently, health care professionals have focused almost exclusively on the mother's age as a risk factor for health problems in the child. But we now know that the father's age also adds to the risk of potentially devastating diseases. And there is no practical way to detect these illnesses during pregnancy. For those weighing the risks, the decision can be wrenching. Adoption and in some instances a sperm donation may be acceptable alternatives to older fathers wanting to build a healthy family.

Michael Craig Miller, M.D. is Editor in Chief of the Harvard Mental Health Letter. He is also associate physician at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School. He has been practicing psychiatry for more than 25 years and teaches in the Harvard Longwood Psychiatry Residency Program
Labels: Michael Craig Miller speaks out on older fathers autism and schizophrenia


Wednesday, July 09, 2008

This article will examine the composition of the society of experts who will use scientific technique to dominate the masses as discussed

The Rule of the Scientific Expert

Scientific Outlook Part 2

Brent Jessop
Knowledge Driven
Tuesday, July 8, 2008

“Equality, like liberty, is difficult to reconcile with scientific technique, since this involves a great apparatus of experts and officials inspiring and controlling vast organizations. Democratic forms may be preserved in politics, but they will not have as much reality as in a community of small peasant proprietors. Officials unavoidably have power. And where many vital questions are so technical that the ordinary man cannot hope to understand them, experts must inevitably acquire a considerable measure of control.” - Bertrand Russell, 1931 (p224)

This article will examine the composition of the society of experts who will use scientific technique to dominate the masses as discussed in Bertrand Russell’s 1931 book The Scientific Outlook [1]. At the forefront of this society of experts is the expert “manipulator”, whom Lenin is the archetype. This society will also aim to conceal its power and influence behind political veils like democracy.

Bertrand Arthur William Russell, 3rd Earl Russell (1872-1970) was a renowned British philosopher and mathematician who was an adamant internationalist and worked extensively on the education of young children. This included running an experimental school in the 1920’s with his second wife Dora Black. He was the founder of the Pugwash movement which used the spectre of Cold War nuclear annihilation to push for world government. Among many other prizes, Russell was awarded the Nobel Prize in Literature in 1950 and UNESCO’s (United Nations Educational, Scientific, and Cultural Organization) Kalinga prize for the popularization of science in 1957.

(Article continues below)

Part 1 of this series examined science as power-thought and the use of scientific technique to increase the power of an elite scientific minority over the unscientific masses.

[Italicised text is original emphasis and bolded text is added by author.]

The Expert Manipulator

“When I speak of scientific government I ought, perhaps, to explain what I mean by the term. I do not mean simply a government composed of men of science. [...] I should define a government as in a greater or less degree scientific in proportion as it can produce intended results: the greater the number of results that it can both intend and produce, the more scientific it is. [...]

Owing to the increase of knowledge, it is possible for governments nowadays to achieve many more intended results than were possible in former times, and it is likely that before very long results which even now are impossible will become possible. [...] Eugenics, except in the form of sterilization of the feeble-minded, is not yet practical politics, but may become so within the next fifty years. As we have already seen, it may be superseded, when embryology is more advanced, by direct methods of operating upon the foetus.

All these are things which, as soon as they become clearly feasible, will make a great appeal to energetic and practical idealists. Most idealists are a mixture of two types, which we may call respectively the dreamer and the manipulator. The pure dreamer is a lunatic, the pure manipulator is a man who cares only for personal power, but the idealist lives in an intermediate position between these two extremes. Sometimes the dreamer preponderates, sometimes the manipulator. William Morris found pleasure in dreaming of “News from Nowhere”; Lenin found no satisfaction until he could clothe his ideas in a garment of reality. Both types of idealist desire a world different from that in which they find themselves, but the manipulator feels strong enough to create it, while the dreamer, feeling baffled, takes refuge in phantasy. It is the manipulative type of idealist who will create the scientific society. Of such men, in our own day, Lenin is the archetype. The manipulator idealist differs from the man of merely personal ambition by the fact that he desires not only certain things for himself, but a certain kind of society. Cromwell would not have been content to have been Lord Lieutenant of Ireland in succession to Strafford, or Archbishop of Canterbury in succession to Laud. It was essential to his happiness that England should be a certain sort of country, not merely that he should be prominent in it. It is this element of impersonal desire which distinguishes the idealist from other men. For men of this type there has been in Russia since the Revolution more scope than in any other country at any other time, and the more scientific technique is perfected the more scope there will be for them everywhere. I fully expect, therefore, that men of this sort will have a predominant part to play in moulding the world during the next two hundred years.

The attitude of what may be called practical idealists among men of science at the present day towards problems of government is very clearly set forth in a leading article in Nature (September 6, 1930), from which the following are extracts:

“[...] In the modern world the dangers arising from mistakes caused by prejudice and neglect of impartial or scientific inquiry are infinitely more serious. In an age when nearly all the problems of [governmental and industrial] administration and development involve scientific factors, civilization cannot afford to leave administrative control in the hands of those who have no first-hand knowledge of science. …

Under modern conditions, therefore, more is required of scientific workers than the mere enlargement of the bounds of knowledge. They can no longer be content to allow others to take the results of their discoveries and use them unguided. Scientific workers must accept responsibility for the control of the forces which have been released by their work. Without their help, efficient administration and a high degree of statesmanship are virtually impossible.

The practical problem of establishing a right relationship between science and politics, between knowledge and power, or more precisely between the scientific worker and the control and administration of the life of the community, is one of the most difficult confronting democracy. The community is, however, entitled to expect from members of the British Association some consideration of such a problem and some guidance as to the means by which science can assume its place of leadership. …

It is significant that, in contrast to the relative impotence of scientific workers in national affairs, in the international sphere advisory committees of experts have since the War exerted a remarkable and effective influence even when devoid of all legislative authority. To committees of experts organized by the League of Nations, and exercising advisory functions only, is due the credit of the schemes which were successful in rescuing a European State from bankruptcy and chaos, and in handling an unemployment scheme which settled a million and a half refugees, following upon the greatest migration in history. These examples sufficiently demonstrate that, given the requisite stimulus and enthusiasm, the scientific expert can already exert an effective influence when normal administrative effort has failed, and when indeed, as in the case of Austria, the problem had been dismissed by statesmen as hopeless.

In truth, scientific workers occupy a privileged position in society as well as industry, and there are welcome signs that this is now recognized by scientific workers themselves. Thus, in his presidential address to the Chemical Society (at Leeds) last year, Professor Jocelyn Thorpe suggested that the age is at hand in which the changing majorities of governments will no longer be able to determine major policies, except in directions approved by organized industry, and, in advocating the closer organization of science and industry, stressed the political strength to be obtained thereby. [...] Whatever inspiration or encouragement the meetings of the British Association may give to scientific workers in the prosecution of their researches, there is no way in which the Association can more fittingly serve humanity than by calling scientific workers to accept those wide responsibilities of leadership in society as well as in industry which their own efforts have made their inevitable lot.”

It will be seen from the above that men of science are becoming conscious of the responsibility towards society conferred by their knowledge, and are feeling it a duty to take a larger part in the direction of public affairs than they have hitherto done.” - 227

The Society of Experts and the Oblivious Masses

“The society of experts which I am imagining will embrace all eminent men of science except a few wrong-headed and anarchical cranks. It will possess the sole up-to-date armaments, and will be the repository of all new secrets in the art of war. There will, therefore, be no more war, since resistance by the unscientific will be doomed to obvious failure. The society of experts will control propaganda and education. It will teach loyalty to the world government, and make nationalism high treason. The government, being an oligarchy, will instil submissiveness into the great bulk of the population, confining initiative and the habit of command to its own members. It is possible that it may invent ingenious ways of concealing its own power, leaving the forms of democracy intact, and allowing the plutocrats to imagine that they are cleverly controlling these forms. Gradually, however, as the plutocrats become stupid through laziness, they will lose their wealth; it will pass more and more into public ownership and be controlled by the government of experts. Thus, whatever the outward forms may be, all real power will come to be concentrated in the hands of those who understand the art of scientific manipulation.” -236

This idea of concealing the real power structure from the masses was later described by Bertrand Russell in his book The Impact of Science on Society[2] (1952):

“Although this science will be diligently studied, it will be rigidly confined to the governing class. The populace will not be allowed to know how its convictions were generated. When the technique has been perfected, every government that has been in charge of education for a generation will be able to control its subjects securely without the need of armies or policemen [...]” - 41


The application of scientific technique to education will be examined in part 3 with an emphasis on the distinction between the education for the “governing class” and the “working class”. Part 4 will look at the use of education, the Press, radio and Hollywood as propaganda. The use of behaviourism, psycho-analysis and physiological manipulation as applied to education will be examined in part 5. Part 6 will examine the application of scientific technique to the reproduction of human beings including the separate breeding techniques to be applied to the “governing class” compared with the “working class”. Changes to Freedom and equality in the scientific society will be examined in part 7. Part 8 will examine changes to free trade and labour in the scientific society. Finally, Part 9 will describe two examples of artificially designed societies, including the creation of a new religion specifically for that new planned society.

[1] Bertrand Russell, The Scientific Outlook (1931). First Edition.

[2] Bertrand Russell, The Impact of Science on Society (1952). ISBN0-415-10906-X.

Related Articles

The Scientific Outlook Part 1: Scientific Technique and Power

The Scientific Outlook Part 3: Scientific Technique and Education (July 14)

The Scientific Outlook Part 4: Propaganda: From the Class Room to Hollywood (July 21)

The Scientific Outlook Part 5: Behaviourism, Psycho-Analysis and Physiological Manipulation in Education (July 28)

The Scientific Outlook Part 6: Scientific Technique and Human Reproduction (August 4)

The Scientific Outlook Part 7: Freedom and Equality in a Scientific Society (August 11)

The Scientific Outlook Part 8: Free Trade and Labour in a Scientific Society (August 18)

The Scientific Outlook Part 9: Two Examples of Scientifically Created Artificial Societies: Japan and Soviet Russia (August 25)

Four Part Series on Bertrand Russell’s The Impact of Science on Society

As a more sensible, “user-friendly” vaccination schedule, Dr. Miller advises the following:

Is There a More Sensible Vaccination Schedule?

Dr. Donald Miller is a cardiac surgeon and Professor of Surgery at the University of Washington in Seattle and a member of Doctors for Disaster Preparedness. His more sensible vaccination schedule, which I published back in 2004, is worthy of being revisited at this time.

Many are both scared and confused as they try to make healthier choices for their children, and his guidelines may help you devise a more appropriate vaccination plan for your child - a schedule that takes the best interests of your child into consideration rather than what biased government planners cite as being best for society. His is a far better approach than the “one-size-fits-all” dogma foisted on Americans by the CDC panel.

And, as Dr. Blaylock describes so vividly in this article, there’s plenty of information and knowledge in neuroimmunology (the study of how the brain’s immune system works) that raises serious questions about the wisdom of injecting vaccines in children less than 2 years of age.

A Child’s Best Time Table

Your brain has its own specialized immune system, separate from that of the rest of your body. When you are vaccinated, specialized immune cells in your brain, the microglia, become activated. Multiple vaccinations spaced close together over-stimulate the microglia, causing them to release a variety of toxic elements — cytokines, chemokines, excitotoxins, proteases, complement, free radicals — that damage brain cells and their synaptic connections.

The damage caused by these toxic substances is what both Dr. Miller and Dr. Blaylock refer to as “bystander injury.”

In humans, the most rapid period of brain development begins in the third trimester and continues over the first two years. (By then, brain development is 80 percent complete.)

From a risk-benefit perspective, there is little doubt that the risk of neurological and autoimmune diseases from vaccinations at this stage far outweigh the benefits of avoiding the childhood infections that they (supposedly) prevent. (One exception is the hepatitis B vaccine, IF the mother tests positive for hepatitis B.)

As a more sensible, “user-friendly” vaccination schedule, Dr. Miller advises the following:

No vaccinations until your child is two years old.
No vaccines that contain thimerosal (mercury).
No live virus vaccines.
The following vaccines should be given one at a time (not as a combination vaccine), every six months, beginning at age 2:
Pertussis (acellular, not whole cell)
Polio (the Salk vaccine, cultured in human cells)

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