Heat Stopping

‘Heart Stopping ‘

Issue 2940 October 28^th

‘Would you have an operation to fix a hole in your heart even though no one is sure if the benefits outweigh the risks ?’

The facts

1 in 4 of us is walking around with septal defects (a type of congenital heart disease) it can lead to strokes, migraines, decompression sickness in divers and perhaps other issues.

Strokes occur as blood leaks through the hole in the heart bypasses the lungs, where small blood clots would normally be filtered out. This means the clots may end up reaching the brain (or other parts of the body) potentially triggering a stroke.

It is relatively easy to fix the hole surgically so why do we not fix more people’s hearts?

That is what doctors cannot agree on, some argue that the operation does more harm than good; the condition has potentially devastating consequences. So why is such a heart problem with such potential devastating conditions so common?

The septal defects are a result of our time in the womb during which the blood flows by the completely different route. An unborn baby doesn’t use its lungs to breathe it instead gets all its oxygen through the placentae. As a result a fetal heart has an opening between the right and left upper chambers (atrial) known as the foramen ovale to bypass the lungs? When the baby is born and takes its first breaths, a flap closes over the hole- at least in most people. For about one in four of us however the hole stays open, either all the time or more commonly it gapes open when the pressure rises in the chest, such as during a coughing fit, or straining to defecate (hahaha) or when lifting something heavy. This is known as a patent (open) foramen ovale or PFO and is shown the the picture bellow. Remember that these septal defects caused by the foramen ovale as specific to holes in the atrial (atrial septal defects).

While having little initial effect upon the day to day life of a sufferer doctors worry that this hole allows things to sneak through which would normally be filtered out be the lungs, things such as blood clots. Normally small blood clots get stuck in the lungs and dissolve harmlessly however, should the clot pass by the lungs, it might lodge in a blood vessel elsewhere in the body, maybe the brain causing a stroke after all the leading cause of strokes is blockage of blood flow.

Strokes are an especial public health problem. One in five of us will suffer a stroke in our life time and they are the current cause of disability in the western world (with depression coming a close second).

The evidence or the linking of congenital heart disease and strokes first mounted in the 1990s when various studies suggested that arterial septal defects are present in 40% to 60% of people who had unexplained strokes. It is also important to remember that only 25% of the population is thought to have PFO which has led to many leading stroke experts to believe that PFO must somehow play a role.

The detection of a PFO is easy once you suspect that it is there. A vein in the subjects arm is injected with tiny bubbles, too small to do any harm. The microbubbles travel to the heart where the can be imaged using ultrasound. Patients are asked to hold their breath and bear down forcing the flap open. If the bubbles can be imaged passing to the lungs then the Foramen ovale has naturally shut and all is well. However should the bubble be detected traveling to the left side of the heart then it suggest that the PFO is still open (it could also be the result of a ventricular septal defect however this is diagnosed most often by a heart murmur).

The first reaction of many when a hole in such a vital organ is found is often to plug it. This used to mean open heart surgery, but medicine has moved on and devices have been devolved that can close the heart without the need for the opening of the chest. One such device is shaped like a tiny umbrella which is pushed into the groin, threaded up into the heart by a wire, then opened up and left in place while the wire is withdrawn. Eventually, tissue grows over it, thus sealing the flap.

As the confidence in the safety of this operation in PFO closure grew it became increasingly offered to people who had, had unexplained strokes, in hope of reducing their chance of having another stroke. Note that this would be as well as or instead of the standard treatment of blood-thinning medicines or other drug treatments. Yet unlike the drugs, no trials have been done to demonstrate the operation would achieve the intended goal, and doctor’s opinions differed about how often the procedure should be carried out. The most enthusiastic tend to be the cardiologists who carry out the procedure perhaps influenced by their close relationship with the manufactures of the device.

Soon the closure became an operation for divers too, after research revealed that people who are prone to decompression sickness are more likely to have large or permanently open flaps.. Divers get the bends when bubbles of nitrogen form in the blood as they ascend, leading to symptoms ranging from itching and joint pain to strokes and paralysis. Normally the nitrogen is gradually breathed out through the lungs, as long as the divers ascend slowly enough. In people with PFO’s the bubbles might bypass the lungs, making the bends more likely as the diver struggles up a ladder with wet heavy kit on.

Patent foramen ovales were also suspect of causing migraines, specifically the kind accompanied by strange visual disturbances known as aura. People who get migraines with aura are twice as likely to have PFO as the rest of the population and about six times as likely to have a large opening. Although the cause of migraines is unknown is unknown the current theory is that a PFO allows whatever causes migraines is allowed to bypass the lungs and reach the brain. Doctors found that migraines with aura tended to disappear in people-le who had their PFO closed for other reasons.

So a trial was set up. Funded by Starflex a company that was the producer of a new closure device (that’s was a good idea I’m sure they didn’t have any personal interest on the results of the trail). It was the first large trial to test PFO closure against people having shame operations. In this trial patients who had, had the trail were compared with those who experienced a placebo- they were put under a general antithetic and an incision made. This in fact was the first large scale study of its kind which had involved a placebo group, where both the patients and the doctors who assessed the outcomes were kept in the dark about whether patients had, had the real operation or not. The results did not show the outcome wanted. Not only did the data show that the device failed to stop people having migraines, but it also caused a higher rate of heart problems than you would expect with this procedure; in two cases the device came loose in the heart, which could have been fatal.

The trial was also the centre of a libel case against one of the principle investigators, Peter Wilmshurst. At a cardiology conference, Wilmshurst said to a reporter that in some patients, the device may not have completely close their PFO’s and that there were flaws in the way that the trial was conducted. See link http://www.theguardian.com/science/2010/dec/01/company-suing-peter-wilmshurst-libel

Starflex’s manufacture NMT Medical sued, in case Wilmshurst’s comments helped spur the on-going campaign to reform UK libel law. Fortunately for Wilmshurst, the company went bankrupt before the case could reach court. Wilmshurst said on the matter ‘‘ We need to take into account both the benefit of the closure and the risk’’ ‘’ Often there is little or no benefit and a significant risk ‘’ . After all no surgical procedure is completely safe, during PFO closure there is an estimated 1 in 100 chance of complications. That maybe not seem like much but if you did 1000 operations then it is likely that you would have 100 people for that group how experienced complications which could range from bruising or damage of the blood vessels to the device falling out. There is even the risk that the operation could trigger another stroke, if a blood clot or air bubble travels through the PFO as the device is pushed through.

The migraine trial also highlights problems with the industry in a wider context. Medical device manufactures, unlike drug companies do not have to prove that their products work all they have to pass is a safety test. In the US medical devices are subject to the same trials that drug companies have to comply to but as seen in the article ‘rethinking depression’ the companies still don’t have to publish the results of negative trials. However in the US there is much more ‘’off label’’ use where devices are used despite not having gone through the official approval process for that particular kind of operation. Doctors in the US tend to be more gung ho about medical inovations than there UK counter parts which could help explain why the US carries out some 8000 patent foramen ovale closures a year, which is more than 10 times the UK numbers  despite having 5 times the population.

It is believed that the best way to resolve uncertainties over the procedures risks and benefits are further randomised trials. In January of 2013 only one trial had been published involving Starflex , this trial found no significant difference between the rate of subsequent strokes after surgical or drug treatment. There were criticisms however that the studies design meant that it could have underestimated the benefits of the intervention. Since then only two further trials have been published and even the most favourable could be taken as evidence to both support of criticises the procedure depending on which ways the data was crunched.

‘If the patent Forman ovale closure device were a drug we would just walk away ‘says neurologist Clay Johnston of the University of California SF. At the moment all doctors can do is to perform the surgery on those who most need it, which is determined by questioning patients closely to see if they have another risk factors that could have caused there stroke.

In the UK, official guidelines now say that the operation should only take place at a few specialist centres that keep good records, so that the resulting data can be pooled. While this is not a randomised trial it still provides much needed data on the individuals who have the procedure and the outcomes that the procedure has on their health.

This case has brought to our attention that some of the products for which we use in potentially lifesaving operations we need definitive evidence from bigger and better trials about the effects and the outcomes that they have in a much wider and transparent environment. 

Rethinking Depression Update - Depression lifted without the trip

New Scientist Issue 2939
Mirages Of The Mind
Date 19th of October 2013

Ketamine has been one of the significant developments in the treatment of treatment resistant depression. Thought to help the production of the neurotransmitter glutamate which is a key component in helping link neurons together. Ketamine originally showed promises by having almost imitate effects in reveling depression in people (around 60% of the relativity small sample size of 72 people ) of which no other treatment had worked however ketamine has adverse side affects. Ketamine was originlay developed as a horse tranquilizer but has also found popularity as a party drug and so it comes as little surprise that one of the side effects are hallucinations and other psychotic symptoms thus making it unsuitable for general use.
A team lead by Gerard Sanacora of Yale University and Mike Quirk of pharmaceutical firm AstraZeneca looked for an alternative compound, they decided to test lanicemine a drug originaly developed to treat epilepsy and targets the same receptors as ketamine.
The team gave 152 people with moderate with severe depression and a history of poor response to anti depressants either lanicemine or a placebo three times a week for three weeks (they were allowed to continue taking medication they were already on for ethical reasons ).
Before and after the paitents levels of depression were rated on a 60 point scale. After 3 weeks those taking lanicemine were less depressed on average by 13.5 points 5.5 points higher than those on the placebo. The results were still at there hightened levels two weeks after the final dosage had been given. The only common side effect of the drug being dizziness.
'what this tells us is some of the concerns around ketamine might not be such a big problem as originally thought' says Quirk 'There are ways around them with the right molecule'
The only downside determined from the experiment was that lanicemine didn't have as an immediate effect as ketamine. The effects of Lanicemine took up to 3 weeks for effects to be seen as opposed to ketamines almost instantaneous effects, however a smaller scale study with 32 people not taking other depression related medication showed the effects to be more quickly present and so it is though that delayed effects could be down to the taking of other medications.The effects of lanicemine were also more pronounced in the study with patients on just that drug.
Even though these are small steps there are no the less essential. By 2020 the world health organisation estimates that depression will be the leading cause of disability in the world. This makes these studies especially important as around a third of people do not respond to current medication. The hope is that ketamine-like drugs will offer a real alternative as they work via a different chemical (glutamate) in the brain which is thought to stimulate regrowth of the brain cells that may have atrophied  (of body tissue or an organ)waste away, especially as a result of the degeneration of cells, or become vestigial during evolution.)
'This could be revolutionary the first new drug treatment for depression in years says former Uk government adviser David Nutt 

Rethinking Depression

From: The New Scientist
Issue :2927
Date  :27th of July 2013

'Depression that resists every treatment is on the rise, but luckily the key to a cure may already be in our hands, says Samantha Murphy.

Over the past decades it has been found that the effectiveness of anti-depressant drugs is overstated, so much so that some pharmaceutical companies have stopped researching the drugs altogether. The stubborn nature of these cases of depression has, however spurred research into new and sometime unorthodox treatments. Surprising and impressive results suggest that we have fundamentally understood the disorder.

In fact the new research has has opened the doors to thinking about depression not as a single condition nut a continuum of illnesses, all with different underlying neurological mechanisms which if understood could come to help us produce effective treatments. This new idea has sparked a recent interest in drug development which has not been since the 1950's.

Depression is a illness that it is estimated to effect 1/6 of the population at some point of our lives. The symptoms include insomnia, hopelessness, loss of interest in life, chronic exhaustion and is thought (although not proven ) to increase chances of ailments such as heart disease.
It is often thought that the social stigma surrounding depression prevents around half of suffers from reviving treatment and the world health organisation has stated depression as the leading cause if disability in the world. 

So what causes people to become depressed ?
The dominant theory is that depression results from chemical imbalance in the brain, with the neurotransmitter serotonin thought to be the key chemical. Many think that depression is linked to low levels of serotonin something that was thought to disrupt the brains ability to pass messages across synapses (tiny gaps between neurons)
The theory was that a boost in serotonin should return neural signalling and mood to normal levels. (Interestingly the primary compound in ecstasy- MDMA is also a know serotonin  booster.)
The first drug developed on the serotonin hypothesis was launched  in the 1980's and nearly all anti depressants developed since have worked on the same principles i.e. keep levels of serotonin high and prevent the brain from reabsorbing and recycling it.
Though such drugs remain the go-to tools for fighting depression they however seem to be getting less and less effective. Clinical trial sin the 80's and 90's indicated that the drug should help up to 90 per cent of depressed people go into remissions. More recent studies however paint a different picture in the 2000's studies showed that standard antidepressants worked only 60 to 70 percent for suffers.
Is it possible that the drugs were not as effective as first thought ?
To approve a given antidepressant the  US Food and Drug Administration only requries two large scale studies to verify that the drug is superior to a placebo.However the companies are under no legal obligation to supply the FDA with every study that they have conducted. When David Mischoulon, director of psychiatry research at the Massachusetts General Hospital in Boston and shifted through data of  from pharmaceutical trials he found that there were in fact many more negative results. A high percentage of the studies showed that the drugs were only slightly better than the placebo.
''now we think its more in the neighborhood of 50% of people who may respond to a given antidepressant.'' says Mischoulon.

Indeed a 2007 study showed that the serotonin levels in the brains of depressed people not receiving treatment were double those in volunteers who were not depressed. It was in wake of this that several pharmaceutical companies have stopped their work on mood disorders altogether. GlaxoSmithKline- the company that makes the well known antidepressant Paxil and Wellbutrin announced in 2010 that it would be halting research into depression
With a reduction of new more effective treatment clinicians began to look for new therapies that could treat patients that did not respond to traditional serotonin deficit reducing drugs.
After drug treatment and behavioral therapy failed one treatment that patients responded to is know as repetitive transcranial magnetic stimulation (rTMS). Patients would put a big cap on there head and sit under a large machine for about 20 minutes while a brief electric current passed through a small coil positioned a few inches above the left temple, creating a fleeting high-intensity magnetic pulse. After treatments a previously drug resistant patients stopped self harming and found it easier to get out of bed in the mornings.
Since the start of 2013 10 people have been successfully treated using rTMS. The treatment is by no means producing paradigm shifting results in a study only 12 out of 28 people responded to rTMS however considering that these people had failed to respond to all other treatment it presents a step in the right definition.
The treatment is by no means cheap treatment is not available on the NHS due to insignificant evidence and so treatment will cost an individual up to £6000
A possible cheaper alternative came from the US which shows similar promises. Cranial electrical stimulation. It is also more simply it involves delivering a tiny current with two electrodes strapped to the head using a sweatband. Unlike rTMS equipment, which is very bulky this device is roughly the size of a deck of cards and is available with a prescription.
Stephen Xenakis is a doctor, former general and former adviser to the US department of defense. He asks patients to use the device for 20 minutes twice a day. He says ''sometimes this can help in ways that the medication does not'' '' The thing that I've seen it help the most with is insomnia and anxiety'' conditions which fuel and is both fueled by depression (and therefore treatment related depression )

In terms of the most convenient alternative treatments however the most promising appears to be in the drug ketermine. Ketamine was initially developed and still is used as a house tranquilizer and has found popularity over the last decade as a recreational club narcotic .  A study in 2000 with 8 people showed that when given intravenously it had almost instant effects on lifting previously untreatable depression. Several larger scale studies have replicated results. A clinical study involving 72 people with previously untreated depression experienced relief from suicidal thoughts for up to 40 minutes.  Some doctors are suggesting that it could work for up to 60% of people, while initially this may not seem like a large percentage these are people for which no standard form of treatment had been successful. Some patients go into remission within a day and some can remain free from depression for up to 10 days .

So why have this group of patients responded to Ketermine as a treatment when all conventional methods have failed ? Researchers have investigated the mechanisms by which they think ket works and have come up with the link of Glutamate. Glutamate is the most dominant stimulatory neurotransmitter in the brain, playing key roles in learning, motivation, memory and plasticity. Some researchers think that that levels of glutamate like serotonin are too low in the brains of depression suffers.
Glutamate differs from serotonin as instead of simply aiding in the transport between neurons, it is thought that glutamate may be a factor in helping the brains neurons repair themselves. This is line with a recent theory that depression causes some dendrites (message relaying fingers at the end of neurons ) to shrivel . The synapes effectively become like broken bridges with messages unable to cross the effective neurons.
Ketamine trials were the first indicators of glutamates possible significance. Ketamine sets off a complexed set off complex chain reactions. First it blocks the specific receptors that glutamate binds to, thus relesaing a tide of the chemicals into the synapes. This leads to an increase in the production of a protein called 'brain-derived neurotrophic factor' which has been shown in animal studies to help dendrites to sprout new spines which help them receive messages from nearby neurons.
A experiment where rats were injected with ketermine at Yale university showed that there was a boost of glutamate in the prefrontal cortex along with a fast increase in the formation of synapses. Similar studies with rTMS have shown similar results. Suggested ideas inculde that in some cases depression may be better explained as a disorder of neuron structure rather than being due to a chemical inbalance. This still doesn't mean that serotonin is out of the picture.

In the diagnostic and statistical manual of mental disorders, the bible of psychiatry in the US already subdivides depression into different categories such as post-natal or dipolar with the the same underlying neurophysiologial mechanisms however new research could change that with depression being potentially a wide continuum of illnesses lumped together under the general term with either serotonin and glutamate as a key factor.

New Beginnings
The next question to ask is how do we determine what kind of treatment a person will best respond to. Studies have shown that if you don't get a day one response to ketamine then you are unlikely to ever get one. Work to produce diagnostic tests are already under way with scientists trying to identify certian factors in the blood that could be ascribed to certain types of depression. Brain scans are another possibility of which are already used to find if somebody is responding to talk-theray or medication.
It is important to note that these ideas are in their infancy but luckly recently at least 5 companies have started work on ketamine, drugs such as GLYX-13 which has shown promise in preclinical trails. Large scale companies such as AstraZenca, Roche and Jassen among others are also developing pills and intervenous drugs the first of which are still a few years away from shelves. Some companies are focusing on use of glutamates drugs as a first line of treatment as opposed to last.

We are left with one tantalising possibility, if glutamate affects neuroplasicity could both treatment and depression lead to lasting changes in the structure of the brain ? George Aghajanian from Yale whose seminal work inspied the ketamine trials says that for people predisposed to to recurring depression depression, ketamine may help neurons permanently maintain new and thicker connections. In his recent work on rats he found that the drug combine with other compounds leads to long term structual repairs in the brain but whether the same is true in humans remains to be seen.
Whatever the future holds, glutamate and the new possibilities it has raised has at least enabled us to start thinking about depression in a different way which is a rare event in the troubled waters of psychiatry.

Congenital Heart Disease

From Biological Science (review) September 2013 volume 26 number 1

There are three main types of heat disease
1) Septation defects- Where the different areas of the heart do not separate properly from each other when the heart is formed

2) Unilateral Blocks- Defects of the heart valves

3) Routing Abnormalities - defects caused by failure to connect the main vessels that supply the heart with blood to the correct chambers of the heart.

It is estimated that between 1 and 5 % of the population suffers from structural or functional problems with the heart (known as congenital heart disease). This is caused by errors that happen when the baby's heart is forming in the womb, congenital heart problems are the most common birth defect and the leading cause of child death.
Many defects go unnoticed and some do not require treatment as a result it is very possible that the actual numbers of people with congenital heart problems is greater than the statistics suggest. The actual impact of the various problems vary, some can be diagnosed before birth with imaging technology some can be corrected with surgery while others are so server that the baby dies soon after being born.

The Mammalian Heart

In order to understand how congenital heart disease arises we must first understand how the heart develops.
During development the heart is transformed from a single tube to a four-chambered, muscular organ.

AS Recap

The heart has four chambers two atria and two ventricles
Blood leaves the heart to the body via the Aorta (oxygenated )
Blood reenters the heart via the Vena cava of which there is a superior and inferior vessel.(deoxygenated )
Blood returns to the heart form the longs via the pulmonary vien (oxygenated )
Blood leaves the heart to the lungs via the pulmonary artery (deoxygenated )

The walls of the left ventricle are stronger than that if the right this is because the left ventricle when it contracts has to pump blood all the way around the body whereas the right pumps blood only to the lungs.
The coronary blood vessels are the vessels that supply the heart mussels with the nutrients that they need such as oxygen and glucose for aerobic respiration.

The heart mussel is Myogenic- self stimulating.
Special structures such as the Sinoatrial node (SAN)  and the Atrioventricular node (AVN) regulate and control the rhythm that the heart beats.

 Heart Formation 

The heart is the first organ formed in the embryo and can start beating for as early as 22 days of gestation.
(Gestation is the carrying of an embryo or fetus inside female viviparous animals, including mammals, as well as some non-mammalian species. Mammals during pregnancy can have one or more gestations at the same time). 
The heart starts of as a crescent-shaped structure at about 2 weeks of gestation. This structure then transforms into a Y-shaped tube during which it will first start beating. 
The next stage of development - cardiac looping - which brings the different areas of the heart to their correct positions relative to one another. During cardiac looping the the heart tubes bend in a precise manner, this process is key and it is vital that each area of the heart is brought into the correct positions at the correct times.
Problems with this process can cause malfunctions in the heart which can disrupt or prevent later stages of development. Abnormalities at this stage can also prevent the correct attachment of blood vessels to the different chambers of the heart, leading to the previously mentioned Routing Abnormalities (meaning that the blood cannot flow through the heart properly).

After looping, chamber formation occurs. this process involves separating the atria and the ventricles from each other and connecting the growing heart  to the coronary blood vessels. This usually happens during weeks 6-8 of the pregnancy. It is during this period that the heart valves also develop if not developed properly then Unilateral blocks can come about. Other Malformations at this stage come usually in the form of 'holes in the heart' one such condition is a 'primary atrial septal defect' in other words a hole in the septum that divides the left and right atrial. Doctors can detect heart mummers by listening to the heart with a stethoscope where they should hear the irregular or unusual flow of blood through the heart. It is important to note that this is the most common type of heart disease and many people who have it do not even realize that they said defects. It is only when the individual reaches adult hood that it can become a problem when risk of pulmonary hypertension and stroke become greater. Larger holes can result in poor growth and lung problems in children.


The developing fetal heart also contains several specialised structures that are not present in the adult heart. One of these is the foramen ovale which is a small gap through which blood passes from the right atrium into the left atrium. This structure  is present in the fetus as it does not yet receive oxygen from its lungs but instead receives oxygenated blood from the placenta. The foramen ovale normally closes naturally after birth when the baby's hearts starts to pump blood around it whole body but in some cases it doesn't close possibly being asymptomatic (showing no symptoms) or otherwise needing corrective surgery. 

Genetic Investigation 

In order to understand why congenital heart disease occurs we must look at the genetics that control how the heart develops. Research scientists are currently looking at the effects of mutant DNA has on the development of the heart in order to discover which mutations cause specific heart defects.DNA can be thought as the instruction manual that controls how we are built, a fault in the final developmental of the heart can usually be tasted back to a fault in the DNA .

Forward And Reverse Genetics 

One method scientists are using to work out how the heart formation is regulated is called mutant screening. There are different ways that mutant screen investigations can be conducted.

1) Forward Genetics 

Involves studying individuals with certain characteristics of interest. The genetic sequences of individuals with selected characteristics (i.e. heart defects) are analysed to establish which gene or genes can cause the particular characteristic (for example a hole between the left and right atrial.

2) Reverse Genetics  

Reverse genetics involves examining the effect of a know gene on a specific characteristic. This leads o either the removing or mutating of a gene in mice to establish the impact that it has on heart development. 

Removing mutations has been used to establish the functions of several genes in heart development, for example knocking out a gene called Nkx2.5 in mice has been shown to disrupt the formation of the heart. Genetic study's in humans have shown that mutations in the Nkx2.5 gene is linked to atrial septal defects in some families.

Reverse genetics has allowed the identification of a gene responsible for several types of congenital heart disease in humans. The gene responsible is found on the 22nd chromosome and is the code for a protein called TBX1. Studies in mice have shown that this protein has significance in the early development of the heart.

Developments like this allow us to screen embryos for this mutation, making detection and treatment of congenital heart disease easier. It is hoped that one day it may be possible to intervene during the development of the fetus overriding or correcting the damaging  mutation, thus enabling the heart to developed normally.  

 

  

What this is

This is just a blog for me to keep track of all the relevant publications that I come across during my application for medicine. It is meant to help me keep track of what I have read and enables me to better remember or talk about medical shit should I get an interview anywhere.
Should any other med applicant find this then good luck and I hope someone somewhere may also find this usual.
(also to note i have pretty shit understanding of how gamma works and the spelling of stuff )
Edward