MDMA

This week molecule will give you ecstasy! It is, indeed, 3,4-methylenedioxy-metamphetamine, which you will probably know as MDMA or ecstasy.

ecUnknown

The structure of this molecule is very simple and it acts as presynaptic releasing agent of different neurotransmitters and as a monoamine transporter substrate. If you want to know more about MDMA, its mechanism of action and the relation between its structure and its pharmacological activity, click here!

ANTIPSYCOTICH DRUGS AND THEIR MECHANISM OF ACTION

Schizophrenia is a mental disease that appears with different symptoms: hallucinations, delusions, changes in behaviour, muddled thoughts based on hallucinations or delusions.

untitled

This disease, which is very serious and equally affects men and women, is frequently treated with antipsycotich drugs and they can be classified in different groups depending on their mechanism of action. This is related to their chemical structure and the consequent interaction with correspondent receptors.

Find out more about the drugs used to treat schizophrenia and how they act, by reading this interesting review: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811864/

Read also more about schizophrenia here: http://www.nhs.uk/conditions/Schizophrenia/Pages/Introduction.aspx

“I’M DEAD TIRED! THE IMPORTANCE OF SLEEP”

Evelina Petitto

Everybody sleep2will agree that sleep is an important aspect of our life, important for our physical and mental health and also a great pleasure! It is so important that during our life we spend almost a third of our time sleeping. However, we still don’t really know why we do it… despite years of research about it, the true function of sleep is still uncertain. One of the main theories on sleep states that the brain needs it. The question then is how is sleeping useful to our brain? It is now proved that sleep helps in memory consolidation and, therefore, learning. A study published some years ago by Giulio Tononi (Wisconsin University) showed that during sleep the brain eliminates redundant and useless connections. Furthermore, a recent experiment by Robert Stickgold (Harvard University) showed that if students have the possibility of sleeping between two tests, they will perform better on the second one. While sleeping, the brain appears to repeat a pattern of neuronal activation that occurred when the person was last awake, as if it is trying to reinforce the traces of the information recently learnt. According to these findings, the purpose of sleep would be helping us to remember what is important whilst letting us forget what’s not. Sleep has physiological effects too; indeed, prolonged sleep deprivation can lead to death, as proven in experiments conducted by Rechtschaffen (University of Chicago). In these experiments, rats were sleep deprived by placing them on a disk suspended over a tank of water. If the rats fell asleep, they would fall in the water and wake up again. After two weeks, every rat was dead. However, necropsies on the animals didn’t find anything significantly wrong with them. All the organs and vital markers were not altered, and the only reason of death was exhaustion, that is lack of sleep.

PHYSIOLOGY OF SLEEP

The sleep-wake cycle is controlled by two internal influences: sleep homeostasis and circadian rhythms. Sleep, like other body conditions such as blood pressure and temperature, is under homeostatic control; in other words, the body maintains these parameters in a steady state. From the time we wake up, the homeostatic drive for sleep accumulates until late evening, when we will eventually fall asleep again. One neurotransmitter, adenosine, seems to be the sleep-inducing chemical. In fact, the level of adenosine rises consistently when someone is awake, resulting in an increasing need for sleep. Conversely, the level of adenosine decreases during the night, satisfying the need for sleep. Some drugs (like caffeine!) act on the adenosine receptor, disrupting this process to some extent. Circadian rhythms are cyclical changes occurring in a 24-hour period driven by the brain’s “biological clock”. This consists in a group of neurons in the hypothalamus, called the suprachiasmatic nucleus (SCN). The physiology and behaviour regulated in these cycles are synchronised to the external physical environment and social schedules. The strongest synchronising factors are light and darkness, the external stimuli that set the “biological clock” and determine when we need to fall asleep and wake up. Although we think of sleep as a period where we shut down, sleep is actually an active physiological process. There are two types of sleep: rapid eye movements (REM) and non REM (NREM) sleep, characterised by distinct brain activities. NREM sleep, characterised by a reduction in physiological activity, consists of 4 stages:

  • Stage 1: the transition from being awake to falling asleep – this is characterised by slow brain waves and diminished muscular activity.
  • Stage 2: period of light sleep where eye movements stop, brain waves become slower and spontaneous periods of muscle tone are mixed with periods of muscle relaxation.
  • Stages 3-4: these are characterised by slow brain waves known as delta-waves interspersed with small faster waves. Sleep is deep, with no eye movements and decreased muscle activity, although movement is possible.

REM sleep is a paradoxical change in brain activity: the brain is extremely active, its waves are fast and desynchronised, similar to those characteristic of the waking state. Breath becomes irregular, eyes moves rapidly and limb muscles become temporarily paralysed. This is the stage where most dreams occur. The role of each phase in overall health is still uncertain; however, striking a good balance between the phases appears to be crucial in achieving beneficial sleep. A complete sleep cycle lasts about 90-110 minutes, and is repeated from 4 to 6 times every night. The composition of each cycle is not constant during the night (REM sleep increases after each cycle), and also changes during the life of an individual, with children having significantly longer periods of REM sleep compared to adults.

SLEEP DEPRIVATION sleep3

Sleep deprivation, chronic or acute, is the condition of not having enough sleep. The short-term consequences of this condition are well-documented, including diminished cognitive performance, impaired memory and low levels of alertness. Prolonged periods of inadequate sleep have cumulative side effects. In one of the most extensive studies on human sleep deprivation, subjects were restricted to 6 hours of sleep per night for two weeks. Subsequently, in cognitive and motor tasks, they performed as poorly as subjects who were entirely deprived of sleep for two consecutive nights. In the long term, poor sleep habits negatively impact the functions of several organs (such as heart, lung and kidneys), on metabolism and weight control, immune responses, sensitivity to pain, as well as mood and cognitive functions. Sleep deprivation is also a risk factor for depression and substance abuse, and it has been linked to increased risk of diabetes, heart disease, obesity, and certain forms of cancer. Obviously, the consequences on humans of total sleep deprivations are not well documented, and our knowledge about this comes from only a few studies, world-record attempts and distressing stories like the one told by the psychotherapist John Schlapobersky, who was tormented with sleep deprivation: “I was kept without sleep for a week in all. I can remember the details of the experience, although it took place 35 years ago. After two nights without sleep, the hallucinations start, and after three nights, people are having dreams while fairly awake, which is a form of psychosis. By the week’s end, people lose their orientation in place and time — the people you’re speaking to become people from your past; a window might become a view of the sea seen in your younger days. To deprive someone of sleep is to tamper with their equilibrium and their sanity”. People who are left without sleep for long periods of time usually recover after a few days. So far, no human death has been attributed to forced or intentional wakefulness. However, some rare instances where humans are literally unable to sleep have ended in death. This is known as fatal familial insomnia (FFI), which is an extremely rare prion brain disease, which results in total inability to sleep, dementia and ultimately death, within a time frame of 7-36 months. The disease progresses from insomnia, hallucinations, temperature fluctuations, to complete loss of sleep, weight loss, dementia, irresponsiveness, and eventually to sudden death. These symptoms suggest that prolonged periods without sleep would end in death by disrupting critical functions such as those related to metabolism. The person becomes hypometabolic, and cannot appropriately manage energy intake and expenditure, so that the energy is wasted.

CONCLUSIONS

sleep4Sleep is a fundamental physiological function that serves vital roles to the organisms. All animals sleep, from birds to fish, and some of them can do it with one hemisphere at a time to maintain a certain level of alertness. Many sleep disorders can lead to mild sleep deprivation that will have negative repercussions on cognition and physical health. In the most severe cases, sleep deprivation can eventually cause dementia and death. It is therefore important that we take care of our sleep, keeping in mind that is not only the quantity that matters, but most importantly the quality of the sleep and in what sleep phase we are in when we wake up. That is the case of when we are forced to wake up and we end up feeling sleepy all day, opposed to when we naturally wake up, maybe at the same time of day, but feel great and full of energy. We can roughly calculate how much time we should sleep if we want to wake up in a better state by considering the length of the sleep phases. However, no matter what, I find myself agreeing with Wilson Mizner, who wisely said: “The right amount of sleep required by the average person is 5 minutes more”. Do you want to find out if you suffer from a sleep disorder? Take this simple test: http://www.edinburghsleepcentre.com/sleep_disorders/online_questionnaire.htm

References:

http://ngm.nationalgeographic.com/2010/05/sleep/max-text http://sleepfoundation.org/sites/default/files/SleepWakeCycle.pdf https://en.wikipedia.org/wiki/Sleep_deprivation http://io9.com/can-you-die-from-sleep-deprivation-1684235719    

NOBEL PRIZES AND CHOCOLATE CONSUMPTION

Would you like to win a Nobel prize one day? Start to eat chocolate!

images

A study, in fact, showed the correlation between chocolate consumption per Country and number of Nobel Laureates.

Read the full article to find out if you have more chances than others to win a Nobel prize in the future: http://blogs.scientificamerican.com/the-curious-wavefunction/chocolate-consumption-and-nobel-prizes-a-bizarre-juxtaposition-if-there-ever-was-one/

“The Milwaukee Protocol and beyond: Is rabies really a death sentence?”

Stuart Mather

Within the discipline of virology, rabies is pretty unanimously regarded as the world’s deadliest human virus. Most commonly transmitted from the bite of an infected dog, the virus begins to spread to the central nervous system (CNS), originally causing pain, fever, headache and a tingling sensation (known as paraesthesia), before leading in some ases to paralysis and coma, whilst in others developing the characteristic rage, hyperactivity and hydrophobia associated with the disease. In either instance, the result is almost certainly death – statistically, the case-fatality rate of symptomatic rabies infection is 100%.

1Fortunately, rabies is as preventable as it is fatal. Through human and canine vaccination, the number of cases of the virus has significantly decreased in many countries. Furthermore, the administration of post-exposure prophylaxis – or PEP – following suspected occurrences of infection is estimated to avoid hundreds of thousands of rabies-attributed deaths every year.

Nevertheless, rabies still circulates on every continent other than Antarctica, is endemic in 150 countries worldwide, with roughly 60,000 individuals succumbing to the disease annually. Why is this? One o2f the main obstacles to further reducing the public health burden of rabies is poor accessibility to the most resource-deprived areas of the world, typically in Africa and Asia. It is not straightforward to roll out mass vaccination schemes in these regions, and many potential rabies transmission events, such as dog or wild animal bites, are not promptly reported to local medical services. And once the virus fully manifests itself within a host and reaches the CNS, there are no licensed medical treatments available to prescribe.

So, is there any way to combat rabies when it’s in the full swing of infection? This blog post explores some of the evidence to suggest that being diagnosed with rabies is not necessarily always a death sentence.

First of all, it is important to acknowledge that rabies is probably one of the oldest infectious diseases known to man. Reports of the virus date back to as far as 2300 BC, where Babylonian dog owners in the ancient city of Eshnunna were severely fined for deaths caused by bites from their dogs. Rabies was then consistently documented in Ancient Greece by the philosophers Democritus and Aristotle, as well as being alluded to in Homer’s The Iliad. They even dedicated two Gods to the prevention and healing of rabies – Arisaeus and Artemis, respectively. Mesopotamian and Roman physicians detailed4 the symptoms of rabid dogs and developed a cleaning regimen for management of bite wounds. In the following 1500 years, the infection steadily spread throughout Arabia and Europe, causing notable outbreaks in Germany (13th century) and Spain (15th century) before wreaking havoc in Paris and finally reaching the shores of England by the 1730s. At a similar time, undoubtedly due to the emergence of the global empires, the growing merchant shipping industry and the slave trade, rabies emerged in the West Indies, Barbados and Mexico, before spreading in both directions throughout North and South America, on its way to becoming the globally ubiquitous virus we see today.

Although the literature throughout history clearly focuses on the death and devastation caused by rabies, it is highly likely that, on rare occasions, some individuals may survive the infection, whether that be because of a very strong and rapid immune response in the patient or exposure to a particularly weak strain of the virus. Certainly nowadays, researchers are well aware that some wild animals conquer rabies alone, without vaccination or medical intervention. After all, viruses must hijack host cellular machinery to replicate themselves and flourish, so a virus that decimates every single host it infects is not necessarily a successful virus, with respect to its own self-preservation and evolution. And rabies can definitely be described as ‘successful’!

Speculation aside, the5 first reported instance of a human surviving the full force of rabies (perhaps contrary to popular belief) is that of Matthew Winkler, a 6-year-old boy from Ohio, USA, during the Autumn of 1970. One night, a bat managed to get into Matthew’s bedroom through a hole in the attic and firmly bit his thumb. The father managed to catch the bat after hearing his son screaming and upon sampling it a few days later, public health officials declared the animal rabid, prompting paediatrician Dr John Stechschulte to initiate a course of rabies vaccine for the boy over a fortnight. However, in the following weeks, Matthew developed a fever, stiffness of the neck and left side, and slipped into a semi-comatose state. The vaccine had failed and rabies had taken hold. Rather than resign themselves to the fact that the patient would soon die, they opted to fight the disease based on the assumption that death may be brought about as a result of the ailment’s symptoms, as opposed to the presence of the virus itself. So if, for instance, the physicians could perform a tracheotomy when Matthew’s throat contracted, or prescribe anti-convulsants to prevent hyperactive twitching and spasming, then they may be able to stave off death long enough to give his immune system time to mount a response against the rabies virus, altering the outcome for the boy. Three months after being admitted, Matthew had recovered enough to be released from hospital on his 7th birthday, and has since gone on to live a life relatively unhindered by neurological complications.

Definitely the most famous and well-documented case of rabies survival is that of Jeanna Giese, the first person to have overcome rabies with no vaccination or PEP whatsoever prior to symptom development. Jeanna was 15 years old when she attended a regular church Mass in September 2004. During the service, a bat was circling overhead, getting increasingly near to the attendants before finally being knocked to the ground by a church usher. Out of compassion and a love of animals, Jeanna decided to pick the bat up and take it outside, sustaining a small bite to her index finger in the process. After cleaning and dressing the wound, her family thought nothing more of the incident. A few weeks later, Jeanna started complaining of double vision and tingling in her limbs; suffering from fatigue, nausea and fever. When her arms started to stiffen and jerk involuntarily and her speech slurred, she was hospitalised and tested for a number of neurological diseases. Every result came back negative. In desperation, Jeanna’s mother mentioned the recent bat bite, which was an important step in achieving a rabies diagnosis, and soon after Jeanna was transferred to the Children’s Hospital of Wisconsin, where she was referred to Dr Rodney Willoughby, an infectious diseases consultant.

Despite his expertise in the discipline, Dr Willoughby had never encountered a patient with rabies before, and as neither licensed treatments nor promising but unpublished approaches were available, the plan of action for combatting the infection was completely unclear. So with Jeanna’s condition rapidly declining, Rodney went back to basics and pored over old case files and publications, trying to find clues about how the disease’s progression could be halted. One point, highlighted several times in the literature, caught the doctor’s eye –rabies pathology does not primarily function by physically destroying neuronal cells or causing lesions in the brain an6d CNS, but rather by disrupting the controlled release of neurotransmitters, such as acetylcholine and serotonin. Dr Willoughby and his colleagues therefore decided to place Jeanna into an induced coma, which could suppress her neuronal activity and delay the progression of rabies symptoms, effectively buying time for her adaptive immune system to produce enough antibodies directed against the virus o overcome, or neutralise, the infection. While comatose, Jeanna was also prescribed ketamine and midazolam to further dampen brain function, as well as the antivirals ribavirin and amantadine. After six days, Jeanna displayed protective antibody levels against rabies and was brought out of the coma to begin her gradual recovery. She had to re-learn how to stand and walk, then regain fine motor skills and so on. A decade on, Jeanna has undergone a pretty complete recovery, now only unable to run and speak at full speed. She graduated from college in 2011 with a degree in Biology and got married in 2014.

Dr Willoughby’s innovative treatment approach was subsequently dubbed the ‘Milwaukee Protocol’. Despite this initial success story, the protocol is a controversial and divisive subject for medical professionals and scientists in the field. Since 2004, the treatment has been attempted approximately 35 times, with only 5 resulting in patient survival. It is also unsure whether these successes can be attributed to the protocol itself, or rather exposure to a low-pathogenic variant of the rabies virus coupled with a robust immune response from the patient. Furthermore, the location of the bite wound may play an influential role in the propensity for the patient to overcome the infection. Both Matthew Winkler and Jeanna Giese were bitten on a finger or thumb, meaning that the rabies virus would have to travel further along nerve cell axons before reaching the CNS (at a rate of 1-2cm per day), allowing a longer timespan for patient immune responses to develop.

More recently, in 2012, one study published in the American Journal of Tropical Medicine and Hygiene detailed new evidence suggesting that rabies infections in humans may not be as lethal as first thought, potentially revolutionising the way the virus is regarded clinically. Dr Amy T Gilbert of the Centers for Disease Control and Prevention led a serosurveillance study in two communities at risk of vampire bat bites in the Peruvian Amazon – this involved taking blood samples from a number of community members and assessing levels of rabies virus neutralising antibodies in their serum. Over half claimed to have previously been bitten by bats and remarkably, 11% of those tested carried rabies antibodies at levels sufficient to protect them from subsequent infection. Out of these seven seropositive individuals, only one had received the rabies vaccine, indicating that the remaining six people had been naturally exposed to the virus, with a non-fatal outcome. Potential alternative explanations for these findings could be that these people were infected with a virus highly related to rabies, which can induce the production of cross-reactive antibodies but which is not fatal to humans; or that they were exposed to a large enough dose of rabies to virus to elicit an immune response, but that viral replication did not occur. In any instance, if these individuals possess some inherent genetic resistance to rabies, being able to understand why may lead to novel treatment strategies.

Other interesting approaches to rabies therapy have also been studied. It seems logical to try and identify antiviral drugs for the treatment of rabies, and the two agents known to have activity against the virus are ribavirin and interferon-α. These have both shown promise as treatments in in vitro and animal model studies, but have failed to display beneficial effects when administered to human patients in early stages of clinical rabies. A major limitation to the use of these antivirals is that they often have to penetrate the blood-brain barrier to reach the primary sites of infection, meaning they can’t reach many of the rabies virions.

Another approach that seems more experimental is deliberate hypothermia. Body cooling has previously proven effective in trials involving cardiac arrest patients, and works by reducing metabolism, oxidative stress and inflammation in the brain. These effects could also be beneficial in the treatment of rabies, but have not undergone clinical trials at any phase as of yet.

The cases discussed in this blog prove that rabies can be survived, albeit very rarely, and offer hope that more successful treatment strategies may be developed in the future. For now, it retains its place on top of the list of deadliest human viruses, so the best plan of action to survive rabies is… don’t get rabies!

Check out these great resources for more information:

Images: