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When and how does CP strike?

When looking at the risk factors present during pregnancy and around birth in children with CP, there are no clear factors that can be singled out, and often there are different combinations of risk factors.(22.03.2013) There is still great uncertainty surrounding the causes of cerebral palsy (CP), but new research suggests that the brain injury which leads to CP in infants with low birth weight occurs before they are born.

When and how does CP strike?

When looking at the risk factors present during pregnancy and around birth in children with CP, there are no clear factors that can be singled out, and often there are different combinations of risk factors.(22.03.2013) There is still great uncertainty surrounding the causes of cerebral palsy (CP), but new research suggests that the brain injury which leads to CP in infants with low birth weight occurs before they are born.

In premature children the causes are often a combination of several risk factors; whereas in infants born at full term, it could be the child's inherent abilities to withstand unfortunate events at birth that cause some children to develop CP and others not.

In addition there seems to be a correlation between high prevalence of CP and low neonatal death rates in some Norwegian counties.

"There could be several explanations for this," says PhD candidate Magne Stoknes at the Department of Laboratory Medicine, Children's and Women's Health (LBK), NTNU. One explanation could be that more children that already have a brain injury before birth are saved that otherwise would not have survived.

"Survival rates were higher in smaller counties, but these counties also had a higher prevalence of CP, which could suggest that the distance to hospital may be of some relevance. But we cannot say for certain whether the correlation is due to differences in quality or external factors."

Individual factors.

  • CP affects around 120 children in Norway every year. About 8000 people in Norway have CP.
  • CP is caused by damage to the brain's motion control centre and can occur during pregnancy, birth and up to an age of two to three years.
  • Known risk factors include: Premature birth, infections during pregnancy, illness in the mother, fertility treatment, multiple births, disease in the placenta, low birth weight (small for gestational age – SGA), abnormal positioning of the foetus, preterm rupture of membranes, induced labour and lack of oxygen (hypoxia) in the newborn.

When looking at the risk factors present during pregnancy and around birth in children with CP, there are no clear factors that can be singled out, and often there are different combinations of risk factors. It is also not clear when in the pregnancy CP occurs:

"The background for a child developing brain injury leading to cerebral palsy is complex. There are probably several risk factors that independently or combined contribute to a process that leads to brain injury, and these risk factors operate together in a certain order of events (so-called causal pathways).

"In addition some children seem to be more vulnerable to the various combinations of risk factors, so that there are different combinations of risk factors leading to CP in individual children," Stoknes explains.

Still a puzzle

The research nevertheless offers a new piece to a larger puzzle, but there are still many pieces left to be found before we with certainty can say something about why some children develop CP and how this could be prevented.

Stoknes says the research team now wishes to continue with larger studies that look even closer at how different risk factors come together to contribute to brain injury which again causes CP.

The studies

Stoknes' research is based on three studies. The first study which looked at low birth weight at full term included 400,488 Norwegian children born in the period 1996-2003, where 36,604 had low birth weight. Of these 104 did not live and 69 developed CP.

The second study, which looked at how risk factors were combined, included 176,979 children born in the period 1996-98, where 241 developed CP.

In the last study where the share of neonatal deaths was compared with the prevalence of CP in surviving children, the researchers used data from 468,443 children born in the period 1996-2003, where 1020 were diagnosed with CP.

Viva

Magne Stoknes will defend his thesis "Novel Approaches to the Study of Risk Factors for Cerebral Palsy" on 8. April 2013 at 12.15 in ØHA11 at NTNU.

The trial lecture will take place at 10.15.

Publications


Do teenagers adopt chronic pain from their parents?

There is an association between chronic pain experienced by parents and chronic, unspecific pain experienced by teenagers. (iStock photo)(22.11.2012) There is an association between chronic pain experienced by parents and chronic, unspecific pain experienced by teenagers, according to recent research from the Department of Laboratory Medicine, Children's and Women's Health (LBK) at NTNU.

Do teenagers adopt chronic pain from their parents?

There is an association between chronic pain experienced by parents and chronic, unspecific pain experienced by teenagers. (iStock photo)(22.11.2012) There is an association between chronic pain experienced by parents and chronic, unspecific pain experienced by teenagers, according to recent research from the Department of Laboratory Medicine, Children's and Women's Health (LBK) at NTNU.

"This is an interesting find, and it is probably caused by a mix of environment and genetics," says PhD candidate Gry Børmark Hoftun.

"When we looked at teenagers with divorced parents, we saw a stronger association between pain experienced by teenagers and pain in the parent with whom they lived. For example: In teenagers living with their mother, there was a strong association between pain experienced by the mother and pain experienced by the teenager, but there was no clear association with father's pain."

This last finding indicates that environment is of great importance. That is, parents can act as role models for their children – pain is something the teenagers learn.

"These findings are useful when examining or treating children with chronic, unspecified pain. It is important to make the parents aware of this association and that children learn behaviour patterns from their parents. In other words, it is important not to focus too much on their own or their children's pain. One should rather promote the use of distraction techniques," Hoftun says.

Nearly half experience chronic pain

Nearly half (44%) of the 7373 teenagers who responded to the pain related questions in the health study Ung-HUNT 3 said they experience chronic, unspecific pain – that is, chronic pain with no obvious medical cause.

Most of these said they had pain in more than one location, and 80% said the pain affected leisure activities and every-day life.

This is important knowledge, not least to reassure parents worrying that children with chronic pain suffer from serious disease. Most often this is not the case – it is in fact quite common that children and teenagers experience pain, and it is usually due to factors other than serious illness.

Girls more affected than boys

There are also many more girls than boys suffering from chronic pain. As many as 54% of the girls say they suffer from pain, as opposed to only a third of the boys. But is it really the case that girls experience more pain than boys?

"The girls do report more pain for unknown reasons, but it could have something to do with gender roles – whereas boys are supposed to be ‘tough' and handle pain, girls talk more about it and share more with their friends. Sex hormones may also have an impact, as several studies have shown that the difference between boys and girls arises when they hit the teens – and it has been shown that sex hormones affect pain paths differently," Hoftun explains.

"At the same time both anxiety and depression are more common among girls, and these are also associated with chronic pain."

Possible causes?

The researchers also looked into other factors associated with chronic pain.
"What show the greatest association with pain among teenagers are symptoms of anxiety and depression," Hoftun says.

She warns, however, that this specific study cannot say whether anxiety and depression cause chronic pain, or whether pain over longer periods leads to anxiety and depression. There is some support for the first hypothesis though in other studies.

"We also saw that being overweight, smoking and alcohol are strongly associated with pain," she says.

This is knowledge which could prove useful when meeting teenagers who are referred to hospital for chronic, unspecified pain. At the same time as asking the teenagers about smoking and alcohol, one can make them aware of the connection. This could then be a starting point for treatment and to promote a healthy lifestyle.

In addition, one needs to focus on mental health and offer help if there is suspicion of anxiety or depression, or other mental problems.

Does it pass?

It would be interesting to follow-up the teenagers from HUNT 3 to see how many of these still suffer from chronic pain as adults, and to see what characterised these during their teens, Hoftun concludes.

Viva

Gry Børmark Hoftun will defend her thesis Chronic Non-Specific Pain in Adolescence Prevalence, Disability, and Associated Factors – Young-JHUNT and HUNT 3, 2006-2008, at 12.15 on Friday 30. November in the Auditorium at MTFS.

She will hold a trial lecture at 10.15 in the same place.

Related publications

CP – risks and treatment

One of the complications that can occur in children with more severe CP is dislocation of the hip.(11.09.2012) Every year 120 children are diagnosed with cerebral palsy (CP) in Norway. The causes are many and complex, and there are also different methods for treating its complications. Researchers are now working on an overview of risk factors and treatment methods to improve prevention and treatment.

CP – risks and treatment

One of the complications that can occur in children with more severe CP is dislocation of the hip.(11.09.2012) Every year 120 children are diagnosed with cerebral palsy (CP) in Norway. The causes are many and complex, and there are also different methods for treating its complications. Researchers are now working on an overview of risk factors and treatment methods to improve prevention and treatment.

PhD-candidate Areej Ibrahim Elkamil at the Department of Laboratory Medicine, Children and Women's Health (LBK), NTNU, has looked at risk factors for CP, and how best to treat the complications connected to it.

Complex risk factors

Cerebral palsy (CP)

  • CP affects 120 children in Norway annually. There are around 8000 people living with CP in Norway.
  • CP is caused by damage in the brain's movement centre and can occur during pregnancy, birth, and up to the age of two-three years.
  • The severity of CP is divided into five levels, where level five is the most severe.
  • Common complications with CP are spasticity (muscle stiffness), spasms and problems with the joints.

"There are many risk factors around birth which could harm the child: If the mother is ill; the child is conceived through assisted fertilization; there is more than one child (e.g. twins); there are problems with the placenta; bleeding during pregnancy; etc.," Elkamil says.

"We are pretty sure that if you combine two or more of these factors, the risk of CP increases."

One of the results that stands out is that induced labour seems to increase the risk for CP. Elkamil therefore wants to ask medical staff and parents to think twice before inducing labour without medical cause.

"We know that induced labour saves lives if the mother is ill – it can save both mother and child. But we want doctors to have in the back of their mind that induced labour can also be associated with a risk for CP," she explains.

We know, however, that around a quarter of children with CP do not have any known risk factors. Elkamil believes there could be genetic reasons why these children cannot cope with the impacts of birth as well as other children, and researchers have already started looking into this.

Treatment not corresponding to severity

Elkamil and the researchers at LBK also looked at the treatment options for children with CP. One of the studies looked at the use of the muscle paralysing substance botulinum neurotoxin – also known as ‘botox'.

Two thirds of children with CP are treated with botox to reduce muscle spasticity (muscle stiffness), which is a common complication in CP. Not surprisingly, the researchers found that the proportion of children receiving botox treatment correlates with the severity of CP – but only to a point.

When looking at children classified at level five, the highest severity grade, the proportion of children receiving botox treatment is lower than on level four. This is despite the fact that these children have more muscle stiffness, spasms and corresponding pain.

"Some think that if we were to treat children at level five, we would have to administer botulinum toxin everywhere. This would result in very high doses, which could lead to serious complications. We think that perhaps we should set specific goals for botulinum toxin use, and administer it in places that would ease care or reduce pain," Elkamil says.

"Children at level five often have to be strapped to their wheelchair, and cannot move. They have problems with spams and pains which can make daily care difficult. It is worth keeping in mind that something as simple as dressing the child can be a challenge due to spasticity."

Early screening against hip problems

One of the complications that can occur in children with more severe CP is dislocation of the hip. It can be difficult to discover this in children with high levels of muscle stiffness and spasms. The worst is that a dislocated hip can become very painful without the children being able to communicate this to their parents or carers.

Elkamil has compared the follow-up programme to prevent hip dislocation in Sweden with Norwegian practice in the years 1998-2003. In Norway there has been a tradition not to intervene early, but rather wait until it becomes unavoidable. The reasoning has been that the children are still growing and developing, and that it therefore is better to wait as long as possible to avoid further operations later.

In Sweden, on the other hand, the practice has been to screen the children from an early age and operate early to avoid complete hip dislocation.

Elkamil found that the total number of operations did not increase with early intervention. When looking at the type of operation, it turned out that Sweden had less serious operations and no operations resulting in the removal of the femur head from the thigh bone (femur).

"The hip is a ball-and-socket joint, and when the hip is dislocated over a period of time, the cartilage protecting the hip socket is damaged, something which becomes very painful. With early intervention we can keep it in place, avoiding pain and larger operations. So it pays off to begin early," Elkamil says.

Importantly, the Norwegian practice has changed since 2003 and we now follow the same model as in Sweden.

CP registers worth their weight in gold

In her research, Elkamil has made use of data from the Norwegian CP register, one of Norway's 19 national medical quality registers. The CP register has made it possible to identify risk factors, and it can provide an overview of treatment practice.

As more countries establish CP registers, it will also become possible to conduct larger studies giving even better data, which ultimately could lead to better prevention and treatment.

Thesis defence

Areej Ibrahim Elkamil will defend her thesis on 27. September 2012 at 12.15. There will be a lecture at 10.15.

Related publications

Closer to an understanding of prostate cancer

A new method for gathering tissue samples from patients having undergone prostate cancer surgery is giving researchers better tools for understanding the mechanisms behind the disease, which affects more than 4000 Norwegian men annually. With time, it could lead to better diagnosis and more targeted treatment.(30.08.2012) A new method for gathering tissue samples from patients having undergone prostate cancer surgery is giving researchers better tools for understanding the mechanisms behind the disease, which affects more than 4000 Norwegian men annually. With time, it could lead to better diagnosis and more targeted treatment.

Closer to an understanding of prostate cancer

A new method for gathering tissue samples from patients having undergone prostate cancer surgery is giving researchers better tools for understanding the mechanisms behind the disease, which affects more than 4000 Norwegian men annually. With time, it could lead to better diagnosis and more targeted treatment.(30.08.2012) A new method for gathering tissue samples from patients having undergone prostate cancer surgery is giving researchers better tools for understanding the mechanisms behind the disease, which affects more than 4000 Norwegian men annually. With time, it could lead to better diagnosis and more targeted treatment.

"Today there is no common consensus on how best to gather fresh tissue samples to understand the disease progression in individual prostate cancer patients," says urologist Helena Bertilsson at the Department of Laboratory Medicine Children's and Women's Health (LBK), NTNU, and the Department of Urology at St. Olavs Hospital.

Bertilsson and her colleagues have found a new method for handling fresh tissue from prostate glands to study the genetics, proteins and metabolites. The goal is to understand the tumour's biology and what makes cancer aggressive or not.

Magnetic resonance spectroscopy (MRS) is a method for looking at the metabolism in cells, which gives information about the cells' biochemical reactions.

Metabolites are molecules that participate in, or are made as a result of the metabolism in the cell.

Prostate cancer is a malignant tumour in the prostate gland and is the most common form of cancer among Norwegian men.

"We have developed a quick and simple method which preserves the tissue through quick freezing, at the same time as the fresh tissue is kept in a form that enables researchers to answer many research questions of high current interest. One should be able to easily adopt it in the laboratory and know exactly what types of cells are present in the sample – and one should be able to analyze not only genes, but also proteins and metabolites."

Bertilsson adds that when analyzing tissue at a molecular level, it is important that the quality of the genetic materials is as high as possible to obtain reliable results – and the make-up of the tissue is an important factor in the quality of the genetic material.

Better understanding

The new method could also hold a key to a better understanding of prostate cancer. Through the use of magnetic resonance spectroscopy (MRS), the researchers have looked at the cancer cells' metabolism and compared this with the cells' DNA profile (gene expression).

We already know that the level of the metabolite citrate is lower in prostate cancer cells, whereas the level of choline is higher. What we do not know so much about is why. Bertilsson has therefore studied these variations together with genetic data to see if and how they correlate.

One of the findings is that although some genes may seem very important in isolation, it is not given that they are the genes that actually impact the cancer cells' ability to grow and spread. By comparing metabolic differences with genetic variation, different genes can emerge as important – genes that otherwise might have been dismissed as unimportant.

This is something Bertilsson wants to study further:

"This is what makes research fun – new ideas are formed all the time! It is something I would like to look more into in an animal model. What if we blocked this gene? The hypothesis is that the tumour would decrease and that we would see this as a reaction in the metabolite citrate.

"We will also look more at the genetic data, as we have only scratched the surface," Bertilsson says.

This is something that could lead to more targeted treatment in the future.

More forms of cancer

The method developed at LBK also applies to other forms of cancer, such as kidney cancer, testicle cancer and breast cancer. There is also an on-going pilot study for intestinal cancer.

Related publications

Thesis defence

Helena Bertilsson will defend her thesis: "Prostate Cancer - translational research optimizing tissue sampling suitable for histopathologic, transcriptomic and metabolic profiling" at the Auditorium, Medisinsk teknisk forskningssenter, NTNU, Friday 21. September at 12.15.

Playtime at the lab

Illustration photo: Ann-Kristin Gunnes Elvrum(30.07.2012) A test based on play is being developed at NTNU to measure and analyse spontaneous hand use among children with cerebral palsy (CP). The aim is to contribute to better treatment, making everyday life easier.

Playtime at the lab

Illustration photo: Ann-Kristin Gunnes Elvrum(30.07.2012) A test based on play is being developed at NTNU to measure and analyse spontaneous hand use among children with cerebral palsy (CP). The aim is to contribute to better treatment, making everyday life easier.

"We know little about the development of hand function among children with cerebral palsy affecting both sides of the body (bilateral CP), and there is little knowledge about which treatment works, and which doesn't," says occupational therapist and PhD candidate Ann-Kristin Gunnes Elvrum at the Department of Laboratory Medicine, Children's and Women's Health (LBK).

"The goal is to make their everyday life easier, making it easier to dress, play, participate in daily life and recreational activities. A large part of these children's childhood is spent practicing various tasks, and it is therefore important that we know whether all this practice actually works."

There are tests to measure the ability to for example grab hold of something on demand (capacity), but there are fewer methods to map the use of hands in everyday situations (spontaneous use).

CP and hand use

  • CP is the most common cause of physical disability amongst children and youngsters, with an occurrence of around 2/1000 live births;
  • 60-70% of all children with CP have difficulties using one or both hands;
  • The extent to which children manage to use their hands in everyday situations is also dependent on their ability to register and interpret sense impressions, as well as their ability to devise good strategies to solve different tasks (cognitive ability);
  • In clinical practice it is important to be aware of the difference between the child's capacity and its actual activity to target treatment and to measure its effect.

A test based on play has been developed in Sweden to measure spontaneous use of hands in children aged 18 months to 12 years with one-sided (unilateral) CP. Elvrum and her colleagues at LBK and Karolinska Institutet in Sweden are now further developing this for children with bilateral CP.

Child's play

During the test, children aged 18 months to 6 years are presented with certain toys demanding the use of both hands, and which they can play with at their own leisure. The older children (6-12 years) are given the same toys, but in a game-setting where they have to rescue a prisoner from a fortress by solving different tasks. The play session is filmed for later analysis.

"I have used the test on children with unilateral cerebral palsy, and most of them really enjoy it and think it's fun," Elvrum says.

To develop the test, Elvrum and hear team will film 120 children in Sweden and Norway with bilateral CP. 80 children have already been filmed in Sweden, and invitations will be sent this summer to 20-25 children in Sør-Trøndelag county, and 15-20 children at Rikshospitalet in Oslo and Vestfold County Hospital (Sykehuset i Vestfold).

The aim is to have filmed the children, analysed the results and developed the test for general use in 2013.

Related publications

Omega-3 slows growth in some cancer cells

Caroline Hild Pettersen(11.06.2012) The health benefits of omega-3 are well known, and now researchers have found that the omega-3 fatty acid docosahexaenoic acid (DHA) can reduce growth in some cancer cells.

Omega-3 slows growth in some cancer cells

Caroline Hild Pettersen(11.06.2012) The health benefits of omega-3 are well known, and now researchers have found that the omega-3 fatty acid docosahexaenoic acid (DHA) can reduce growth in some cancer cells.

Cand.scient. Caroline Hild Pettersen and colleagues at the Department of Laboratory Medicine, Children's and Women's Health (LBK), NTNU, have studied omega-3 fatty acids (DHA and EPA) to see how they affect the growth of cancer cells, and what mechanisms are involved.

She has found that omega-3 appears to reduce the growth of human colon cancer cells (SW620) and leukemia cells (HL-60). It also seems that DHA can have a positive effect on several target proteins for chemotherapy in colon cancer cells, but this however, requires further research.

At the same time as some cancer cells are affected by omega-3, research also shows that other cancer cells can remain unaffected – probably due to the different genetic make-up of various cancer cells.

Endoplasmic reticulum (ER) stress

ER is an organelle in the cell, which main task is to produce proteins, lipids and regulate the calcium levels in the cell. When these mechanisms are disturbed and the system becomes imbalanced, you get ER stress. While the cell tries to rebalance the system, cell growth is temporarily stopped – a cell cycle arrest occurs. If the rebalancing fails, ER stress can lead to cell death (apoptosis).

"We have shown that some cancer cells are sensitive – their growth is restricted when subjected to omega-3 fatty acids – whereas others are not sensitive to omega-3. Our goal is to find out which mechanisms are affected by omega-3 fatty acids; and we are the first to show that omega-3 fatty acids activate a signaling pathway that is involved in normal stress response (ER-stress) in cancer cells," Pettersen says.

‘Normal amounts' of omega-3 is not damaging to healthy cells, and the amounts of omega-3 used in the research correspond to an easily obtainable amount in the body through omega-3 dietary supplements.

Omega-3 and molecular mechanisms

Pettersen's PhD thesis consists of three articles based on gene expression analysis where the cancer cells were treated with omega-3 fatty acids, and where the researchers have studied genes which change their expression after treatment, to try and identify how biological pathways and mechanisms are affected.

In the first article Pettersen shows that DHA leads to changes in a molecular pathway called ER stress (see fact box) in the colon cancer cell SW620, which resulted in a slowing-down of cell growth. The researchers also found that the calcium- and cholesterol balance was changed after treatment with the omega-3 fatty acids – and such imbalances can also lead to ER stress.

By studying the effect of omega-3 fatty acids in cancer cells that are resistant to certain changes in calcium levels, the researchers have shown a correlation between changes in calcium levels in the cancer cells and the activation of ER-stress. It is therefore probable that the growth-inhibiting effect of omega-3 fatty acids is due to changes in the calcium levels in the cancer cells.

The study with colon cancer cells also showed that the same proteins that are target proteins for chemotherapy were affected by omega-3. This indicates that omega-3 in some cases can aid chemotherapy, but this requires further research, Pettersen warns.

Further research

The research is still ongoing, and the scientists continue to look for mechanisms that are affected by omega-3 fatty acids in different types of cancer to see if there are any common denominators for the sensitivity towards omega-3 fatty acids.
"In the future omega-3 fatty acids could become a supplement to cancer therapy, but it will take a long time to clarify this possibility," Pettersen says.

Viva

Pettersen will defend her thesis: "The effect of omega-3 polyunsaturated fatty acids on human cancer cells – molecular mechanisms involved" on Thursday 14. June, at 12.15 in the Auditorium, Medisinsk Teknisk Forskningssenter.

The trial lecture "Potential benefits of omega-3 against non-cancerous chronic diseases" will take place at 10.15 in the same room.

Foto: Geir Mogen

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