Autism: Birth hormone controls the expression of the syndrome in animals

Researchers found that a drug affecting chloride levels improves autistic-like behaviour in offspring of mouse models of autism. 

The drug restores the so-called GABA switch in the neurons of fetal mice when given to the mother one day before delivery. 

Credit: D.C. Ferrari

The scientific community agrees that autism has its origins in early life—foetal and/or postnatal.

The team led by Yehezkel Ben-Ari, Inserm Emeritus Research Director at the Mediterranean Institute of Neurobiology (INMED), has made a breakthrough in the understanding of the disorder.

In an article published in Science, the researchers demonstrate that chloride levels are elevated in the neurons of mice used in an animal model of autism, and remain at abnormal levels from birth.

These results corroborate the success obtained with the diuretic treatment tested on autistic children by the researchers and clinicians in 2012, and suggest that administration of diuretics to mice before birth corrects the deficits in the offspring.

They also show that oxytocin, the birth hormone, brings about a decrease in chloride level during birth, which controls the expression of the autistic syndrome.

This work is due to appear in the 7 February 2014 issue of Science.

Neurons contain high levels of chloride throughout the entire embryonic phase. As a result, GABA, the main chemical messenger of the brain, excites the neurons during this phase instead of inhibiting them, in order to facilitate construction of the brain.

Subsequently, a natural reduction in chloride levels allows GABA to exercise its inhibitory role and regulate the activity of the adolescent/adult brain.

In many brain disorders (childhood epilepsy, cranial trauma, etc.), studies have shown abnormally high chloride levels.

Having made various observations, Dr Lemonnier's team (Brest), and Yehezkel Ben-Ari's team at Inserm carried out a clinical trial in 2012, based on the hypothesis of high chloride levels in the neurons of patients with autism.

The researchers showed that administration of a diuretic to children with autism (which reduces neuronal chloride levels) has beneficial effects.

The results of the trial supported this hypothesis, but because high neuronal chloride levels could not be demonstrated in children with autism, it was not possible to prove the mechanism proposed or justify the treatment.

In the present study, the researchers therefore used two animal models of autism, a genetic model, Fragile X syndrome, which is the genetic mutation most frequently associated with autism, and another, generated by injecting the pregnant mice with sodium valproate, a product known to generate abnormalities in children, including autistic spectrum disorder.

A high level of chloride in the brain
For the first time, the researchers recorded the activity of neurons at the embryonic stage and immediately after birth to observe modifications in chloride levels.

These observations showed that neuronal chloride levels are abnormally high in both young and adult animals used in the autism model.

GABA strongly excites neurons, and the researchers recorded aberrant electrical activities in the brain, which persist in adult animals.

The fall in chloride level, a particularly impressive phenomenon seen at birth in control animals, is absent in both of these animal models, and the neurons have the same chloride level before and after birth.

These high levels are due to reduced activity of a chloride transporter, thus preventing transport of chloride out of the neuron. As a result, a major feature of neurons during birth is abolished in animal models of autism.

Clinical trials of the drug bumetanide administered in young children with autistic symptoms are showing progress. 

Credit: D.C. Ferrari

"Chloride levels during delivery are determinants of the occurrence of autism spectrum disorder," explains Yehezkel Ben-Ari, an Emeritus Research Director at Inserm.

Beneficial effects of the diuretic on brain activity.
The researchers administered a diuretic treatment to the mother (in both animal models) for 24 hours shortly before delivery to see if this would restore brain inhibition in the offspring.

They showed that the drop in chloride level was re-established in the neurons several weeks after a single treatment during birth.

According to the research team, antenatal treatment restored brain activity to approximately normal levels, and corrected the "autistic" behaviour in the animals once they became adults.

"These results thus validate the working hypothesis that led us to the treatment we developed in 2012," states the principal author of the study.

Oxytocin, the birth hormone, naturally reduces chloride levels
The role of oxytocin in reducing neuronal chloride was also studied. The researchers had previously shown in 2006 that this hormone, which triggers labour, also has many beneficial actions on the brains of newborns, including protective effects in the event of complications during delivery, and even analgesic properties.

Oxytocin acts like the diuretic, reducing the intracellular chloride levels.

By administering the drug bumetanide to pregnant mice with models of autism, the researchers were able to reduce chloride levels in the brains of their offspring to their appropriate levels -- and in turn, to restore the GABA switch mechanism required for healthy brain development. 

Credit: D.C. Ferrari

In the present study, the team tested the long-term effects of blocking the actions of the hormone before birth.

A drug that blocks the signals generated by oxytocin was injected into pregnant mice.

The researchers evaluated the effects of this blockage on the offspring, and showed that it reproduced the entire autism-like syndrome in them, both with respect to the electrical and behavioural aspects (identical to the two animal models of autism).

As a result, the hormone's natural actions, just like those of the diuretic, are crucial to this delicate phase, and may control the pathogenesis of autism via the cellular chloride levels.

"These data validate our treatment strategy, and suggest that oxytocin, by acting on the chloride levels during delivery modulates/controls the expression of autism spectrum disorder," states Yehezkel Ben-Ari.

Taken together, these observations suggest that earliest possible treatment is essential for maximum possible prevention of the disorder.

This work raises the importance of carrying out early epidemiological studies in order to better understand the pathogenesis of the disorder, especially through analysing data on deliveries where a drop in chloride has occurred.

Indeed, complicated deliveries with episodes of prolonged lack of oxygen, for example, or complications during pregnancy, such as viral infections, are often suggested as risk factors.

Finally, given the role of oxytocin in triggering labour, "although it is true that epidemiological data suggesting that scheduled caesarean deliveries may have increased the incidence of autism are controversial, it nonetheless remains that these studies should be followed up and extended to confirm or refute this relationship, which is still possible," insists Yehezkel Ben-Ari, who concludes,

"To treat this type of disorder, it is necessary to understand how the brain develops and how genetic mutations and environmental insults modulate brain activity in utero."

More information: : "Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring," by R. Tyzio et al. Science, 2014. DOI: 10.1126/science.1247190

Tip-of-the-Tongue Syndrome (TotTS) and Transactive Memory - An aside

Tip-of-the-tongue syndrome is an experience so common that cultures worldwide have a phrase for it.

Cheyenne Indians call it navonotootse’a, which means “I have lost it on my tongue”; in Korean it’s hyeu kkedu-te mam-dol-da, which has an even more gorgeous translation: “sparkling at the end of my tongue.”

The phenomenon generally lasts only a minute or so; your brain eventually makes the connection.

But … when faced with a tip-of-the-tongue moment, many of us have begun to rely instead on the Internet to locate information on the fly.

If life-logging … stores “episodic,” or personal, memories, Internet search engines do the same for a different sort of memory: “semantic” memory, or factual knowledge about the world.

When you visit Paris and have a wonderful time drinking champagne at a café, your personal experience is an episodic memory.

Your ability to remember that Paris is a city and that champagne is an alcoholic beverage – that’s semantic memory. …

What’s the line between our own, in-brain knowledge and the sea of information around us? Does it make us smarter when we can dip in so instantly? Or dumber with every search?

Thompson, the author of the book 'Smarter than you Think,' reminds us of the anecdote, by now itself familiar “to the point of banality,” about Socrates and his admonition that the “technology” of writing would devastate the Greek tradition of debate and dialectic, and would render people incapable of committing anything to memory because “knowledge stored was not really knowledge at all.”

He cites Socrates’s parable of the Egyptian god Theuth and how he invented writing, offering it as a gift to the king of Egypt, Thamus, who met the present with defiant indignation:

"This discovery of yours will create forgetfulness in the learners’ souls, because they will not use their memories; they will trust to the external written characters and not remember of themselves. 

 

The specific which you have discovered is an aid not to memory, but to reminiscence, and you give your disciples not truth, but only the semblance of truth; they will be hearers of many things and will have learned nothing; they will appear to be omniscient and will generally know nothing; they will be tiresome company, having the show of wisdom without the reality".

Read more of this article by Mary Popova

Newly approved drug Surfaxin® for infant Respiratory Distress Syndrome (RDS)

Scientific advances at The Scripps Research Institute have led to a new drug Surfaxin® (lucinactant), approved March 7 by the U.S. Food and Drug Administration (FDA) to treat infant respiratory distress syndrome.

The FDA statement announcing the approval. 

"I am excited that our scientific findings will help save lives," said Charles Cochrane, MD, professor emeritus at Scripps Research.

"Many years of work in our basic research laboratory at The Scripps Research Institute made this landmark development possible."

The Study
In the study, the infants were treated with lucinactant (Surfaxin), colfosceril palmitate (Exosurf), or beractant (Survanta) within 30 minutes of birth. Those treated with lucinactant had significant improvement in respiratory distress syndrome at 24 hours after birth

RDS
Respiratory distress syndrome (also known as neonatal respiratory distress syndrome) is a life-threatening condition affecting pre-term infants.

The more premature an infant is, the more likely he or she is to suffer from it and die.

The condition occurs when infants are born prior to the time when natural surfactant is made in their lungs.

Surfactant is a liquid that coats the inside of the lungs, helping to keep the air sacs open and making normal breathing possible. Without enough surfactant, the lungs collapse and the body can be starved of oxygen.

In addition to mechanical ventilation, current treatments for pre-term infants involve using surfactants derived from chopped cow or pig lungs.

Current Disadvantages
However, animal-derived surfactants are expensive, contain material that can be injurious to the lungs, and cannot be produced in quantities sufficient to treat pre-term infants worldwide.

In addition, animal-derived surfactants can only be used once since they cause an immune reaction; in contrast, the new synthetic surfactant is not immunogenic.

The Cochrane lab first created a synthetic version of surfactant in the 1990s, mimicking a natural peptide known as Surfactant Protein B; the inventors of the technology are Cochrane and Susan Revak.

After this formative work at Scripps Research, the therapy was developed by Discovery Labs of Warrington, PA, which oversaw the three phases of clinical trials required by the FDA.

These clinic trials provided data on the drug's success.

Beckwith-Wiedemann Syndrome - BWS Support Network UK and Europe

Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome.

An overgrowth syndrome can cause part or all of the body to grow larger than expected.

In BWS, overgrowth is associated with body overgrowth (increased birth weight, height, and head circumference), macroglossia (large tongue), hemihypertrophy (one side of the body -in part or in whole - growing larger than the other side), Omphalocele (Abdominal wall defect) and certain types of tumours as well as other physical characteristics.

The syndrome was first described by Dr Beckwith in 1963 and Dr Wiedemann in 1964.

BWS occurs in approximately 1:14,500 births.

There are roughly thirty characteristics that can be associated with BWS. Those which are used to make a diagnosis (the 5 major characteristics) are listed below.

It is very rare for a child with BWS to have all the characteristics; most cases have only a few of them. Some of the distinctive features of BWS may need to be corrected.

Some of the main characterisics to look for in Beckwith-Wiedemann Syndrome (BWS)Large birth weight and length (over 90-95th %)
Hypoglycemia (low blood sugar) in the first four months of life
Macroglossia (large tongue)

Omphalocele: Abdominal wall defect (including even a mild navel hernia)
Ear grooves (creases) or pits

we can also be found at: www.facebook.com/groups/B.W.S.supportnetwork

www.twitter.com/BwsNetwork

BWS Support Network UK and Europe

Read more on BWS in the USA

Shaken-Baby Cases Rising During the Recession

Shaken-Baby Cases Rising During the Recession - TIME

The stressful effects of a faltering economy, skyrocketing unemployment and precarious personal finances can be dire. People take up smoking or use alcohol to cope, they become depressed or suicidal, and they develop stress-related illnesses like heart disease.

Now researchers report that the harm may be spreading to children too, when parents' stress leads them to injure their children, inadvertently.

Presenting May 1 at the Paediatric Academic Societies annual meeting in Vancouver, a team of researchers led by child-abuse expert Dr. Rachel Berger at Children's Hospital of Pittsburgh reported a significant increase in cases of shaken-baby syndrome, in which youngsters are shaken violently by an adult, since the start of the current recession.

Researchers analysed data on 512 cases of head trauma in the children's centers of four hospitals (in Pittsburgh, Pa.; Cincinnati, Ohio; Columbus, Ohio; and Seattle) and found that the number of cases had increased to 9.3 per month as of Dec. 1, 2007, compared with 6 per month prior to that date — a rate that had held steady since 2004.

Read more: http://www.time.com/time/health/

Dystonia: A brief descriotion

Dystonia is a syndrome of sustained muscle contractions that produce twisting and repetitive movements or abnormal postures. The extent and severity of muscle involvement are remarkably variable, ranging from intermittent contraction limited to a single body region to a more generalised dystonia, involving the limbs and axial muscles.

• According to the body regions affected, dystonia is described as focal if a single area is involved, such as (1) the face, (2) oromandibular area, (3) arm, or (4) neck.
• It is described as segmental if 2 or more contiguous areas are affected, such as (1) cranial and cervical areas or (2) the face, jaw, and tongue.
• It is multifocal if 2 or more noncontiguous body regions are involved, such as (1) an arm and a leg with cranial muscle involvement or (2) blepharospasm and leg dystonia. Finally, it is generalised if both legs and 1 other body region are involved.

Many dystonic movements are action-specific. Some individuals develop involuntary movements only during writing (eg, writer's cramp), while others may have dystonic movements in the arm and trunk when walking but not when dancing.

Controlling
Many patients with dystonia can partially control their arms using small tactile maneuvres, such as touching the chin in the case of cervical dystonia or touching the brow in the case of blepharospasm (geste antagonistique). These tactile maneuvres may mislead physicians to the erroneous diagnosis of malingering or hysteria.

Oppenheim
In 1911, Oppenheim introduced the term dystonia to describe the variable tone present in patients with abnormal muscle spasms. Persistent dystonia was introduced by the French to describe the late complications of chlorpromazine therapy.

Keegan and Rajput
In 1973, Keegan and Rajput introduced the term dystonia tarda to describe drug-induced sustained muscle spasm causing repetitive movements or abnormal postures in patients who were treated with levodopa.

Burke
In 1982, Burke coined the term tardive dystonia; tardive derives from the Latin word meaning late onset. They proposed the following 4 criteria for diagnosis:

1. The presence of chronic dystonia
2. A history of antipsychotic drug treatment preceding or concurrent with the onset of dystonia
3. The exclusion of known causes of secondary dystonia by appropriate clinical and laboratory evaluation
4. A negative family history of dystonia

A fifth criterion was also proposed but appeared to gain little acceptance from other researchers — "If other involuntary movements (such as dyskinesia, akathisia) are additionally present, the dystonia is the most prominent."

Tardive Dystonia
Traditionally, tardive dystonia is considered an extremely disabling subtype of a broader syndrome known as tardive dyskinesia. The original descriptions of tardive dyskinesia referred to stereotyped orolingual and masticatory movement of a choreic nature, taking the form of lip smacking and pursing, tongue protrusion, and licking and chewing movements.

This term should only be used for those movement disorders developing after long-term exposure to dopamine receptor–blocking agents, However, this traditional view has come under attack in recent years, as some argue these should be characterised as 2 separate disorders.

Further information on Dystonia and related topics available here ...........

Dyslexia Untied: The Importance of Good Eyesight

Unfortunately, 20% (1 in 5) of all school age children have undetected vision problems. Don't panic! Not all of these are acute or permanent and not all are detrimental to the child's development but there are a number of issues that need to be addressed, as soon as possible (ASAP).

If your child has an undetected, undiagnosed or undefined vision problem, they can appear to demonstrate symptoms or behaviours that can be mistaken for dyslexia, but only superficially. Consultation with a qualified expert in the field will dispel or confirm this concern. Rapid intervention is important.

The worst case, and possibly your worst fear, is that your child does have dyslexia and their vision problems are making it more difficult.

Regular Eye Checkups
It is important for all young children that their eyesight is checked regularly and corrected accordingly. It is more important than for adults and older children, because the younger child may be growing and developing at a much quicker rate.

Unfortunately, even if you get your child's eyesight checked as part of a normal screening process, there is a possibility that the average optician will miss the telltale signs of dyslexia, unless it is brought to their attention. It falls back on the parent to be more aware and to be more insistant or assertive, on behalf of their child(ren).

Symptoms to look for
Symptoms that are often associated with Dyslexia can be as obscure as the slight tilt of the head when trying to read or follow words in a text or book. More complex issues are;

• Amblyopia (lazy eye) - When one of your child's eyes doesn't work as well as the other. 3% 0f children under the age of 6 are reported to have Amblyopia. Treatment: eye exercises, eye patch, etc. Long Term: If it's not treated early it can lead to poor vision into adulthood.


• Strabismus (deviating eyes) - When your child's eyes appear dis-coordinated and don't look towards the same object, together. It may be a fixed or permanent defect or it may only be temporary and brought on by stress and tiredness. Either way you should seek qualified expert advice.

These conditions are not rare and neither is the situation whereby your child has the 'normal' 20/20 vision but is having difficulties in sustaining their gaze, co-ordinating their eyes, holding and varying their focus, when objects move closer and away from them.

Scotopic Sensitivity Syndrome - Some children with Dyslexia have difficulty tracking words and letters along a line or sentence. This is known as Scotopic Sensitivity Syndrome, a known issue that can be addresed separately. The Irlen Method of treatment concentrates on this specific issue.

If you have concerns, take this up with your doctor or with a qualified optometrist or opthamologist. The qualifications of the local high street franchise opticians can vary quite dramatically. Check their credentials.

Early detection and diagnosis is important in all childhood issues and none moreso than in vision and hearing, as these can very much affect the child(dren)'s development, education and behaviour.

Summary

Don't Panic! The majority of Dyslexia consultants and experts will agree that vision problems 'alone' do not cause or lead to the onset of Dyslexia but it does complicate the situation for the child(ren), the family and the teachers.

Therefore, the message here is; be aware of the impact that vision has on the development of the child and their well being and importantly, early detection, diagnosis and correction or treatment by qualified experts, is essential.