Today’s post is a recap of Day 3 – the final day – at the World Parkinson’s Congress meeting in Kyoto, Japan.
I will highlight some of the presentations I was able to catch and try to reflect on what was an amazing meeting.
The final day of the WPC meeting for me started with Parkinson’s advocate Heather Kennedy‘s presentation on “Your radical new life: Creative ways to overcome our challenges”. In her talk, she spoke of the mindset that is required for tackling Parkinson’s and provided some advice on what-to-do and what-not-to-do.
And Heather was speaking from personal experience. Having been diagnosed in 2012, she has become an active advocate, supporter of Davis Phinney and Michael J Fox Foundations, and an administrator on several online sites. And she regularly speaks about different methods for overcoming the challenges of Parkinson’s:
“It is not ‘why is this happening to me?’, it is ‘what is this teaching me?”
Here is a presenation she gave at the recent Parkinson’s Eve meeting in the UK earlier this year:
Key among her pieces of advice is the need to make connections:
Every three years the Parkinson’s community – patients, families, researchers, and clinicians – comes together to learn from each other, discuss where we are, and explore where we should be going.
The World Parkinson’s Congress (or WPC) is a very special event – rather unique in the world of conferences and scientific meetings.
The WPC meeting which is being held in Kyoto is the first one I have attended, and in today’s post, I will share what I observed on Day 0, and my impressions/thoughts of those observations.
The SoPD is at the 2019 World Parkinson’s Congress being held in Kyoto this year.
For the sake of those who are unable to be here, I will endeavour (famous last words coming up) to provide some of my impressions and observations of what is happening at the meeting on each day. We have previously discussed what the World Parkinson’s Congress is (Click here to read that post), so this post is literally just what happened each day.
And this is my first time attending the WPC, so any comments here will be coming from a novice. And I have been told by many individuals that WPC is not like other conferences.
Apparently, WPC is very special.
I have a request to make of readers.
I have been invited – with Parkinson’s advocate AC Woolnough – to conduct a round table at the upcoming 2019 World Parkinson’s Congress meeting in Kyoto. The round table is a discussion involving 10-20 people sitting around a table. Our topic will be how can we better align the efforts of researchers and patients.
And this is where we would like your help. Or at least, we would like your input.
Specifically, we are seeking topics for discussion at the table regarding how we can better join the goals/focus of the community on the research side of things.
In today’s post, we look at what the World Parkinson’s congress is, how the round table topic came about, and what we are currently thinking regarding the structure of our roundtable session.
Yasaka Pagoda and Sannen Zaka Street. Source: JT
It was the capital of Japan for more than one thousand years (from 794 to 1869).
It sits 315 miles southwest of Tokyo and 25 miles east of Osaka.
It was the setting of the world’s first novel in the world (Shikibu Murasaki’s The Tale of Genji).
It has over 1000 Buddhist temples (including the hugely impressive Fushimi-Inari-Taisha), and more than 2,000 temples and shrines collectively.
Fushimi-Inari-Taisha. Source: Medium
It has the oldest restaurant in Kyoto, Japan (called Honke Owariya, which was founded in 1465).
It had its own civil war – referred to as “Onin no Ran” (Onin War) – in the 15th century. The war lasted 11 years (1467-1477) and focused on two families of samurai warriors seeking power in Kyoto.
It is the home of the video game company Nintendo and Nightingale Floors:
It has 1.5 million residents (and 50 million tourists per year).
It consumes more bread and spends more money on coffee than any other city in Japan (I wonder why?).
It has the longest train platform in Japan (at JR Kyoto Station – 564 meters long!).
It is Kyoto.
Kinkaku-ji. Source: AWOL
And in June of this year, the World Parkinson’s congress will be held in this beautiful city.
What is the World Parkinson’s congress?
Parkinson’s is a neurodegenerative condition. This means that cells in the brain are being lost over time. Any ‘cure’ for Parkinson’s is going to require some form of cell replacement therapy – introducing new cells that can replace those that were lost.
Cell transplantation represents one approach to cell replacement therapy, and this week we learned that the Japanese regulatory authorities have given the green light for a new cell transplantation clinical trial to take place in Kyoto.
This new trial will involve cells derived from induced pluripotent stem cells (or IPS cells).
In today’s post we will discuss what induced pluripotent stem cells are, what previous research has been conducted on these cells, and what we know about the new trial.
Source: Glastone Institute
The man in the image above is Prof Shinya Yamanaka.
He’s a rockstar in the biomedical research community.
Prof Yamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application (CiRA); and a professor at the Institute for Frontier Medical Sciences at Kyoto University.
But more importantly, in 2006 he published a research report that would quite literally ‘change everything’.
In that report, he demonstrated a method by which someone could take a simple skin cell (called a fibroblast), grow it in cell culture for a while, and then re-program it so that it would transform into a stem cell – a cell that is capable of becoming any kind of cell in the body.
The transformed cells were called induced pluripotent stem (IPS) cell – ‘pluripotent’ meaning capable of any fate.
It was an amazing feat that made the hypothetical idea of ‘personalised medicine’ suddenly very possible – take skin cells from anyone with a particular medical condition, turn them into whatever cell type you like, and then either test drugs on those cells or transplant them back into their body (replacing the cells that have been lost due to the medical condition).
Personalised medicine with IPS cells. Source: Bodyhacks
IPS cells are now being used all over the world, for all kinds of biomedical research. And many research groups are rushing to bring IPS cell-based therapies to the clinic in the hope of providing the long sort-after dream of personalised medicine.
This week the Parkinson’s community received word that the Pharmaceuticals and Medical Devices Agency (PMDA) – the Japanese regulatory agency that oversees clinical trials – have agreed for researchers at Kyoto University to conduct a cell transplantation trial for Parkinson’s, using dopamine neurons derived from IPS cells. And the researchers are planning to begin their study in the next month.
In today’s post we are going to discuss this exciting development, but we should probably start at the beginning with the obvious question:
What exactly is an IPS cell?
In large datasets, strange anomalies can appear that may tell us something new about a condition, such as the curious association between melanoma and Parkinson’s disease.
These anomalies can also appear in small datasets, such as the idea that spring babies are more at risk of developing Parkinson’s disease. But the smaller dataset results may be a bit misleading.
In today’s post, we will look at what evidence there is supporting the idea that people born in the spring are more vulnerable to Parkinson’s disease.
Spring lambs. Source: Wenatcheemumblog
When is your birthday?
More specifically, which month were you born in? Please feel free to leave your answer in the comments section below this post.
Why do I ask?
In 1987, an interesting research report was published in a scientific research book:
Title: Season of birth in parkinsonism.
Authors: Miura, T., Shimura, M., and Kimura, T.
Book: Miura T. (ed) Seasonality of birth:Progress in biometeorology, 1987.p157-162. Hague, Netherlands.
In the report, the researchers outlined a study that they had conducted on the inhabitants of an asylum for the aged in Tokyo (Japan). They had found not only a very high rate of Parkinsonism (6.5% of the inhabitants), but also that the majority of those individuals affected by the Parkinsonism were born in the first half of the year (regardless of which year they were actually born).
Sounds crazy right? (excuse the pun)
And that was probably what everyone who read the report thought….
…except that one year later this independent group in the UK published a very similar result:
In 2000, a research paper investigating the incidence of Parkinson’s disease in Bulgaria was published in the journal Neuroepidemiology.
The results were rather startling.
In their study, the researchers included a subpopulation of over 6,000 gypsies. In a population of that size they had expected to find 10-30 cases of Parkinson’s disease (based on the incidence in other populations of people).
What they actually found didn’t make any sense.
In this post we will look at the incidence of Parkinson’s disease around the world and why the Bulgarian gypsies are unique in the data.
Bulgarian gypsies. Source: Youtube
Trying to determine how frequently a particular phenomenon occurs within a given population sounds like a pretty straightforward task, right?
In practise, however, it proves to be very difficult. In some cases, almost impossible. In the western/developed world – where the medical records databases exist – the task of determining certain medical characteristics within a population of interest is slightly easier, but most experts will agree that most measures of incidence still include a pinch of error and a smidgen of guesstimating.
Beyond the developed world, determining incidence in a population is a ‘door-knocking’ job. Researchers literally have to go from house to house and asking for a survey to be filled in, or conduct doorstep evaluations of the inhabitants. A much harder task and cultural characteristics begin to play a role in the outcomes (such as lower incidence of a particular disease in communities that don’t like to ‘lose face’).
Additional problems with measuring incidence
Other problems with measuring incidence within a population include:
- Unimpeded access to the population (eg. some people live in isolated locations/communities)
- Accurate measures/criteria of the disease (eg. remember we don’t have an accurate diagnostic test for Parkinson’s disease)
- No response bias (posted surveys receive a limited response, and many affected individuals within a community will live with a condition without alerting their doctor)
- The size of the effect (if only one or two people are affected by a characteristic, the task of determining incidence becomes much harder – consider the very low incidence of juvenile onset Parkinson’s disease – Click here for more on this)
With all of that said, many efforts have been made in trying to determine the incidence of Parkinson’s disease. Some consensus has become apparent, but there are some interesting differences.
The incidence of Parkinson’s disease
The incidence of Parkinson’s disease varies around the world and there are some interesting differences.
Most studies agree, however, that the incidence of Parkinson’s disease is approximately 0.3% of the general population in industrialized countries. That is, 1 person in every 2-300. As we are all aware, Parkinson’s disease is more common in the elderly, and as such the incidence rises to about 1% (or 1 in 100) in those over 60 years of age. The incidence rate continues to rise with age to 4% of the population over 80 years of age (almost 1 in every 20 people over 80 year of age).
In 2009, Parkinson’s UK published their report on the incidence of Parkinson’s disease within the UK and their numbers are very similar to those summarised above (Click here for a PDF file of that report).
Disease burden – another way of measuring a disease
Many epidemiologists (the people who measure all of this incidence stuff) now incorporate a different kind of population-disease measurement into their analysis: ‘Disease burden’.
Below is a map of ‘hotspot’ countries (in red) around the world that have the disease burden due to Parkinson’s disease according to the World Health Organisation (WHO) (click here for their raw data – Microsoft Excel file).
A world map of Parkinson’s disease burden (red = high incidence). Source: Wikipedia
The map illustrates the disability-adjusted life year (DALY) rates from Parkinson disease by country (per 100,000 inhabitants).
Yeah I know. It sound complicated, but it isn’t really.
The DALY is simply a measure of the overall disease burden that a population experiences, and it is expressed as the number of years lost due to ill-health, disability or early death. Put another way, the DALY for any given country is calculated by taking the total number of the years of life lost due to dying early and adding it to the number of years lost due to disability. So for the map above, the Maldives (dark red dot in the Indian Ocean) exhibits the highest burden with the country loses 557 years per 100,000 inhabitants.
And importantly these measures are ‘age adjusted’, so that countries with a higher proportion of elderly people (such as Japan) do not appear to have a higher burden due to Parkinson’s disease than a country with a younger population. The WHO numbers are provided by the government health services in each country.
The highest incidence of Parkinson’s disease
Ok, so if we leave the global/macro world of Parkinson’s disease incidence and focus on particular nations/communities of people, what does the research literature tell us about the incidence of Parkinson’s disease?
Well, one of the highest incidence occurs in the Amish community of the US midwest.
The Amish communities of the American midwest. Source: DartMed
The Amish community started in Switzerland in the 17th century. In the 18th and 19th centuries, many adherents
immigrated to the USA in an attempt to flee religious persecution. They now live in communities rather culturally isolated from society – maintaining a traditional way of life, ignoring the modern conveniences, and
marrying strictly within their religion (maintaining strict endogamy). They are not completely isolated, however, as they are work/conduct business with mainstream society. From a scientific standpoint, the Amish are a wonderful cases study. They have diligently kept meticulous family records dating far back in history. In addition, they forbid consumption of alcohol or use of tobacco.
Many years ago, researchers began to notice a high incidence of Parkinson’s features within the community. Several population studies have been conducted on the Amish, including this one:
Title: A population-based study of parkinsonism in an Amish community.
Authors: Racette BA, Good LM, Kissel AM, Criswell SR, Perlmutter JS.
Journal: Neuroepidemiology. 2009;33(3):225-30.
PMID: 19641327 (This article is OPEN ACCESS if you would like to read it)
The researcher in this study tried to recruit all of the individuals over the age of 60 (total 262 people) in an Old-Order Amish community of 4,369 people. Of the 213 subjects who agreed to participate, 15 had Parkinson’s disease while a further 73 individuals had a UPDRS (Unified Parkinson’s Disease Rating Scale) motor score of >9 (indicating early stages of Parkinson’s). The researchers calculated the prevalence of Parkinson’s disease in this population of people at 5,703/100,000 or 5% of the population over 60 years of age. This was far higher than the 1% of the 60+ years population in the rest of the world.
There are over 200,000 Amish in North America, and they have played a prominent historical role in Parkinson’s disease research – the first Parkinson’s-related genetic mutations were identified in genetically isolated Amish populations (Click here for more on this). The genetics of Parkinson’s disease in the Amish is not clear, however, as a recent large population analysis demonstrated:
Title: Parkinson disease loci in the mid-western Amish.
Authors: Davis MF, Cummings AC, D’Aoust LN, Jiang L, Velez Edwards DR, Laux R, Reinhart-Mercer L, Fuzzell D, Scott WK, Pericak-Vance MA, Lee SL, Haines JL.
Journal: Hum Genet. 2013 Nov;132(11):1213-21.
PMID: 23793441 (This article is OPEN ACCESS if you would like to read it)
The scientists behind this study collected DNA samples from 798 individuals (31 with diagnosed Parkinson’s disease) who are part of a 4,998 individuals living in the Amish communities of Indiana and Ohio. Although there were a couple of areas of DNA that may confer susceptibility towards Parkinson’s disease, the researchers did not find any major/significant regions (or loci) suggesting that even within the Amish the genetics of Parkinson’s disease may be more extensive than previously appreciated.
Is there a gender bias in the incidence of Parkinson’s disease?
Yes there is.
On average women have a later onset of Parkinson’s disease than men. In addition, around the world, men are more likely to be affected by Parkinson’s disease than women by a ratio of approximately 2:1.
Curiously, there is one country that bucks this trend: Japan
There are now several studies that find the incidence of Parkinson’s disease in Japan is higher in females than males (Click here for more on this), and we have previously looked at this curious difference in a previous post (Click here to read that post)
Is there any evidence that the incidence of Parkinson’s disease is increasing?
Interesting question, and yes there is:
Title: Time Trends in the Incidence of Parkinson Disease
Authors: Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA.
Journal: JAMA Neurol. 2016 Aug 1;73(8):981-9.
This very recent study analysed the incidence of Parkinson’s disease by using medical records from the Rochester Epidemiology Project to identify incidence cases of Parkinson’s disease and other types of parkinsonism in Olmsted County (Minnesota) between 1976 to 2005. And the researchers made an interesting discovery: between 1976 and 2005, the incidence of Parkinson’s disease has increased, particularly in men 70 years and older. The researchers speculate as to whether this increase is associated with a dramatic decrease in the rates of smoking or other environmental/life styles changes.
We should add that there is some research that refutes this finding and we are waiting to see what follow up analysis shows us – we will report that when it is available.
So what about the Bulgarian gypsies?
Oh yeah, almost forgot.
Title: Prevalence of Parkinson’s disease in Bulgarian Gypsies.
Authors: Milanov I, Kmetski TS, Lyons KE, Koller WC.
Journal: Neuroepidemiology. 2000 Jul-Aug;19(4):206-9.
So between January and November of 1997, the Bulgarian scientists sent out their questionnaire, and they conducted door-to-door visits, eventually collecting a pool of over 6,000 people of gypsy descent. They were trying to determine the incidence of Parkinson’s disease within this community, but what they discovered was not what they expected:
Just one case of Parkinson’s disease.
A 61 year old man.
Given the incidence in most other communities, in a population of 6,000 people one might expect to see maybe 20 cases. Not just one!
The researchers concluded that the prevalence of Parkinson’s disease in the Gypsies was found to be 16/100,000 (based on that 1 case out of 6163 people), compared to 137/100,000 for Caucasians (based on 119 cases from 87,025 people). This means that Bulgarian gypsies have the lowest incidence of Parkinson’s disease in the world.
Our answer: ????
We really do not know. No one does.
The authors of the research paper suggest that gypsies are believed to originate from North India, and given that the inhabitants of Asia have a lower rate of Parkinson’s disease than their western counterparts, this may partly explain the low frequency in the Bulgarian gypsies. This is only applicable, however, if similar low rates of Parkinson’s disease are found in other gypsy populations. To our knowledge, these studies have not been done (please feel free to correct us on this matter).
The banner for today’s post was sourced from BalkanMusicNight
At the bottom of our previous post, we mentioned that Japan is the only country where women have a higher incidence of Parkinson’s disease than men.
We also suggested that we have no idea why this difference exists. Well, a study presented at the Cardiovascular, Renal and Metabolic Diseases conference in Annapolis City (Maryland) last week may now be able to explain why this is.
The prevalence of Alzheimer’s disease is significantly higher in women compared to men. One recent estimate suggested that almost two-thirds of individuals diagnosed with Alzheimer’s disease are women (More information here). One possible reason for this is that Alzheimer’s disease is a condition of the elderly and women live longer.
So why is it then is the exact opposite true in Parkinson’s disease???
Source: The Telegraph Newspaper
Men are approximately twice as likely to develop Parkinson’s disease as females (More information here)
In addition, women are on average diagnosed 2 years later than men (More information here)
This gender difference has long puzzled the Parkinson’s research community. But now a group from the University of North Texas Health Science Center think that they may have the answer.
The researchers – lead by Shaletha Holmes from Dr Rebecca Cunningham’s lab – observed that when they stressed dopamine neurons, adding the male hormone testosterone made the damage worse. Interestingly, they found that testosterone was doing this by acting on a protein called cyclooxygenase 2 (or COX2). When they blocked the actions of COX2 while stressing dopamine neurons, they found that they also blocked the damaging effect of testosterone. The researchers concluded that testosterone may exacerbate the damage (and death) in dopamine neurons that occurs in Parkinson’s disease, thus possibly explaining the sex differences described above.
Now, there are several interesting aspects to this finding:
Firstly, the use of Ibuprofen, the nonsteroidal anti-inflammatory drug used for relieving pain, has long been associated with reducing the risk of Parkinson’s disease (More information here).
Ibuprofen is a COX2 inhibitor.
But more importantly, several years ago it was shown that Japanese men have lower levels of testosterone than their Western equivalents. Here is the study:
Title: Evidence for geographical and racial variation in serum sex steroid levels in older men.
Authors: Orwoll ES, Nielson CM, Labrie F, Barrett-Connor E, Cauley JA, Cummings SR, Ensrud K, Karlsson M, Lau E, Leung PC, Lunggren O, Mellström D, Patrick AL, Stefanick ML, Nakamura K, Yoshimura N, Zmuda J, Vandenput L, Ohlsson C; Osteoporotic Fractures in Men (MrOS) Research Group.
Journal: Journal of Clinical Endocrinol. Metab. 2010 Oct;95(10):E151-60.
The study suggested that total testosterone levels (while similar in men from Sweden, Tobago and the US) were 16 per cent higher in men from Hong Kong and Japan. BUT – and here’s the catch – Japanese men also had higher levels of a testosterone-binding hormone (Sex hormone-binding globulin or SHBG), so there is less of the testosterone floating around free to act. As a result, Japanese men had the lowest levels of active testosterone in the study.
Intriguingly, the researchers found that Japanese men who emigrated to the US had similar testosterone levels to men of European descent, suggesting that environmental influences may be having an effect of testosterone levels. Diet perhaps?
If testosterone is found to play a role in the gender difference found in Parkinson’s disease, the lower levels of free testosterone observed in Japanese men may explain why women in Japan have a higher risk of Parkinson’s disease than men.
EDITOR’S NOTE: WHILE WE HAVE NO DOUBTS REGARDING THE RESEARCH OF DR CUNNINGHAM AND HER GROUP, WE ARE TAKING A LEAP IN THIS POST BY APPLYING THE TESTOSTERONE RESULTS TO THE GENDER DIFFERENCE IN JAPAN. THIS IS PURE SPECULATION ON OUR PART. WE HAVE SIMPLY SAT DOWN AND TRIED TO NUT OUT POSSIBLE REASONS AS TO WHY THERE IS A REVERSED GENDER DIFFERENCE FOR PARKINSON’S DISEASE IN JAPAN. OUR THEORY IS YET TO BE TESTED, AND MAY BE COMPLETELY BONKERS. WE PRESENT IT HERE PURELY FOR DISCUSSION SAKE AND WELCOME YOUR THOUGHTS.
In 1950, Dr Tavia Gordon noticed that while the overall mortality rates for men in the USA and Japan were very similar, the incidence of heart disease was significantly lower in Japan. This observation resulted in three longitudinal studies – one of which became known as the Honolulu Heart Study.
Dr Travis Gordon. Source: JSTOR
The original purpose of the study was to determine whether there was a difference in heart disease incidence between Japanese people living in Japan and individuals of Japanese ancestry living in Hawaii.
The subjects recruited for the study were “non-institutionalized men of Japanese ancestry, born 1900-1919, resident on the island of Oahu.” In all, 12,417 men were identified as meeting the criteria. Of those contacted, 1,269 questionnaires were ‘return to sender’, 2,962 men declined to participate in the study, and 180 died before the study commenced. That left 8,006 participants who would be studied and followed for the rest of their lives.
From October 1965 onwards, the participants were interviewed and given physical examinations every few years. The interview processed asked for:
- Family and personal history of illness
- Sociological history
- Smoking status
- Physical activity level
The physical examination was very thorough, looking at:
- ECG (Electrocardiography – electrical activity of the heart)
- Urine analysis
- Measurements of weight, height, skinfold thickness, etc.
- Blood pressure and serum cholesterol
As a result, the study built up a HUGE amount of epidemiological information regarding these 8,006 individuals.
So, what does this have to do with Parkinson’s disease????
Given the enormous number of individuals involved in the study and the length of time that they were followed, it was inevitable that a certain percentage of them would develop Parkinson’s disease as the study progressed. As a result, the Honolulu Heart Study represents one of the largest epidemiological study of Parkinson’s to date. In 1994, a group of research involved in the study, published some very interesting findings relating to Parkinson’s disease. That published article was:
Title: Epidemiologic observations on Parkinson’s disease: incidence and mortality in a prospective study of middle-aged men.
Authors: Morens DM, Davis JW, Grandinetti A, Ross GW, Popper JS, White LR.
Journal: Neurology, 1996 Apr;46(4):1044-50.
In total, 92 of the 8006 individuals enrolled in the study developed Parkinson’s disease. The incidence of Parkinson’s cases was registered between 1965 and November 30th 1994. The majority of the cases were diagnosed between 55 and 79 years of age (n=80). Diagnosis after the age of 80 was very rare. It is interesting to note that when the researchers divided the group into those ‘born before 1910’ and those ‘born after 1910’, the older group (born before 1910) had a lower risk of Parkinson’s disease.
In another study, the same group of investigators noted
Title: Prospective study of cigarette smoking and the risk of developing idiopathic Parkinson’s disease.
Authors: Grandinetti A, Morens DM, Reed D, MacEachern D.
Journal: American Journal of Epidemiology 1994 Jun 15;139(12):1129-38.
In this study the authors found that men who had smoked cigarettes at any time prior to their enrollment in the study in 1965, had a reduced risk of developing idiopathic Parkinson’s disease (relative risk = 0.39). That is to say, smoking reduced the chance of developing Parkinson’s disease. And a few years later the authors published a follow up paper which rejected the possibility that smoking was killing people before they could develop Parkinson’s disease (selective mortality representing a false positive). That follow up report can be found here.
EDITOR’S NOTE: THIS DOES NOT MEAN THAT EVERYONE SHOULD RUSH OUT AND START SMOKING. THERE DOES, HOWEVER, APPEAR TO BE SOME INGREDIENT IN CIGARETTES THAT REDUCES THE INCIDENCE OF PARKINSON’S DISEASE. A LOT OF RESEARCH IS CURRENTLY TRYING TO IDENTIFY THAT INGREDIENT.
This finding was made alongside other interesting correlations (Note: coffee and alcohol reduce the risk of Parkinson’s disease):
From Grandinetti et al (1994).
It should be noted that many of these associations (smoking in particular) had been reported before, but the Honolulu Heart Study was the first epidemiological study providing definitive proof. And it should be noted that subsequent epidemiological studies have found similar results.
INTERESTING FACTS ABOUT THE JAPANESE:
- The Japanese as a population have a lower incidence of Parkinson’s disease (much like most of the Asian nations) than their western equivalents, despite living longer.
- Japan is the only country in the world where females have a higher incidence of Parkinson’s disease than men (and we have no idea why!). Look here for more on this.