An article titled "The Prisons of the Arab Mind" on the website of the so-called Reform Party of Syria, by a man called Tarek Haggy, bears a striking resemblance to an angry exchange I had with a man called Elie Hajj on the Creative Syria website. Mr Haggy calls himself an 'Egyptian liberal intellectual'. At the time, my comments pointing out the fallacious, if not downright mallicious, intent behind Mr Hajj's comments were subjected to scathing criticism. Good. If people thought Mr Hajj's comments, or Mr "Haggy's" for that matter, are a good idea, they deserve every irreverant remark and insult under the sun. For those not interested, my response to Mr. Tarek Haggy's article. To date I have not received a response from him.
I write to you with regards to your article "The Prisons of the Arab Mind" which was published on the website of the "Syrian Reform Party". Whilst I respect that your professional experience as chairman for a large multinational oil company as well as your life experience would qualify you for many things, I believe after reading your articles that politics and in particular what you refer to as "the Arab mindset" is not one of them. I have neither the time, nor the inclination, to detract from the major part of your article, which a reasonably studious undergraduate student of the Middle East would quickly pick apart. However, as I do have a particular interest in Islamic philosophy and history, I will focus instead on pointing out the fallacies upon which you build your narrative.
Firstly with regards to Kant, the concept of transcendental idealism is one which humanity itself may never have grasped. This is because the human mind is imprinted from birth with the "grid reference" of time and space, as such, it would be impossible for us to grasp a reality which lies beyond such reference points. This, Kant calls the noumenal world. Please note that you criticise Ghazali for this very position when you say that he did not believe "the human mind capable of grasping the Truth as ordained by God". This is exactly what Kant was referring to. Now I find it hard to believe, based on your flimsy use of this term, that you have understood (on the assumption that you have even read) Kant's writings on this term. But it might be a thought to actually know what a philosopher is talking about before using his nomenclature in future articles that you pen. In addition, it is tragic that you are ignorant of the nuances in thought between men such as Ibn Hanbal and Abdul Wahab, and between what they believed and what the Prophet Muhammad taught. That subtlety has been butchered in order for the subject matter to fit nicely into your categorisation. Especially when you tie this all in with Saudi Arabia, ironically a key ally of your sponsor, the United States of America. My main problem in your article lies with the great injury that you have done to the Iberian peripatetics, tying them with the Mutazilites. Ibn Rushd, if you had bothered to read his thought, was trying to revive a pure Aristotelianism, rather than the neoplatonist interpretation that had become prevalent in the Byzantine and later Islamic worlds. Neoplatonism is a 1000 year effort to reconcile the philosophy of Plato with Aristotle on one scale, and the contrary positions of Aristotle with himself on another, the result, coming from Plotinus in Alexandria, was neoplatonism, which was taken as "the" way to interpret Aristotle. Had you bothered to read the Decisive Treatise, you would have seen that Averroes was in fact *against* the spread of philosophy to those who were incapable of grasping the truths it brought. Effectively his position would be something we'd recognise as "a little knowledge is a dangerous thing", an adage which is painfully poignant the more I read your article. Anybody who was to break this rule should, as Averroes put it, be executed. Hardly the shining beacon of liberal rational thought that you put him out to be - not that I am condemning him, but I understand his context and his philosophical contributions, something which, sadly, you do not. The Mutazila, apart from the disastrous Mihna that they imposed on the Islamic world, were kalam theologians, not philosophers. Their use of kalam put an emphasis on reason but in a nuance that again you have either not bothered acquainting yourself with or just willfully ignored. It is the Mutazila who are the origin of the Asharites, who had broken off with the Mutazila due to differences and inconsistencies in Mutazila thought and in fact al Ghazali is an Ashaarite himself. So your category is firstly incorrect to lump the Mutazila with the falasifa on one side and al Ghazali on the other. Secondly, it is not the Mutazila, but mainly Avicenna, the most important figure in Islamic philosophy, who Ghazali criticised, and in specific on three areas. The eternity of the world, the reincarnation on the day of judgement and with regards to God knowing particulars. All other philosophy and science was not a problem. Also, Avicenna had in fact fused the thought of the falasifa and the kalam people (this includes Mutazila don't forget) and made what he thought a solution to the divide. So Ghazali did not just criticise Avicenna, but also the kalam theologians for what he saw were errors in their positions. What Ghazali did was in fact demonstrate that Avicenna's theory was not airtight and that there are problems. Again, you appear to have neither read Avicenna's work on the necessary existent, nor have you read Ghazali's tahafut, maqasid or miyar al ilm, any one of which would have given you a more coherent understanding of the history of Islamic philosophy. You will also be amazed to know that the inheritors of Avicennan logic and philosophy, as well as kalam (who included the Mutazila), are the Sunni and Shia theologians who use arguments which were criticised, and also built upon by Ghazali. Ghazali's Asharism changed during his life, and whilst he devoted himself to being a Sufi, the new theological interpretation he fused with philosophy would form the bedrock and incubator for Avicennan thought. If you want an example of this, read something about Imam Khomeini, Mullah Sadra or Suhrawardi...Ghazali was called Hujat al Islam by both the Sunnah and the Shia because of the strength of his writings and the acceptance of his criticisms as valid. It is unfortunate that I must say this, but you are a living embodiment of the adage, "grey hair does not a wise man make". Your article is factually incorrect, racist, and wilfully misrepresentative of the facts.
1- chain weighing the Arab mindset down and preventing it from joining the march of human progress is the regressive, medieval, Bedouin understanding of religion: well I would certainly say he has a point here, especially in recent years and especially in countries like Egypt where people are excessively religious in as much as they carry out the rituals with great zeal and yet they have little understanding of the basics/ general ethics of Islam. islam is essentially a religion which promotes excellent manners and morals and compassion for one's fellow man...on an average day one would be exauhsted to count the number of times that a supposedly pious person goes against all these. Moreover, many 'religious' observances are purely tradition rather than based on real religious edicts- I do admit this seems to be more the case in Egypt than in the Levant but I guess Mr Haggy is speaking from his own experience.
2- Haggy refers to a "cultural climate which has encouraged the spread of tribal values, including such negative values as individualism (instead of tolerance) and insularity (instead of open-mindedness)"....would you not say he has a point here...again from my own experience I believe that this is most true in Egypt than any other Arab country. In your response to his article you do not refer to this "second chain" so I am supposing you are (to some extent) in agreement?
So just to recap...Haggy's argument is essentially flawed if we are to evaluate it in terms of his background knowledge which confuses many historical issues together but he does bring up several excellent points.


text:
Die Stierkopfhaie (Heterodontus), Hornhaie oder Doggenhaie sind die einzige rezente Gattung der monotypischen Familie der Heterodontidae, die wiederum allein die Ordnung der Stierkopfhaiartigen (Heterodontiformes) bildet. Ihr Verbreitungsgebiet sind die warm-gemäßigten und tropischen Meere vom westlichen Indischen Ozean bis zum östlichen Pazifik. Im Atlantik sind Stierkopfhaie nicht vertreten.

Merkmale
Ihren deutschen Namen verdanken sie ihrem für Haie untypischen Kopf mit deutlichen Augenwülsten und der abgerundeten Schnauze. Sie haben keine Nasenbarteln. Ihre Augen haben keine Nickhaut und liegen seitlich an der Kopfoberseite (dorsolateral).

Das Maul ist mittelgroß, vorn mit kleinen mehrspitzigen, hinten mit abgeflachten Mahlzähnen besetzt. Der griechische Gattungsname (Heterodontus – "verschiedenartige Zähne") nimmt darauf Bezug. Die äußeren Nasenlöcher sind klein und durch eine tiefe Falte mit dem Maul verbunden. Außerdem besitzen sie fünf Kiemenspalten, von denen die erste vergrößert ist und am weitesten unten liegt. Zwei oder drei Kiemenspalten liegen hinter der Basis der Brustflossen.

Allen Stierkopfhaien ist das Vorhandensein von Analflossen und zwei Rückenflossen (Finnen), denen jeweils ein Dorn vorangeht, gemeinsam. Im Vorhandensein der Rückenflossendorne unterscheiden sie sich von allen anderen galeomorphen Haien. Eine Afterflosse ist vorhanden. Ihr Rumpf ist zylindrisch oder seitlich leicht abgeflacht. Stierkopfhaie haben 98 bis 123 Wirbel.

Stierkopfhaie sind kleiner als andere Haiarten. Die größte Art, der Port-Jackson-Stierkopfhai (Heterodontus portusjacksoni) oder Hornhai, wird lediglich 165 Zentimeter lang. Von dieser zuerst beschriebenen Haiart leitet sich eine der englischen Bezeichnungen für die Familie der Heterodontidae Port Jackson sharks ab.

Stierkopfhaie sind eierlegend. Die Eikapseln sind schraubenförmig.

Lebensweise
Stierkopfhaie sind träge Grundfische, die sich hauptsächlich von Muscheln, Seeigeln und anderen hartschaligen Tieren ernähren. Sie können auf ihren paarigen Flossen über den Grund laufen und schwimmen nur gelegentlich. Ihr Lebensraum liegt auf den Kontinentalsockeln und zu Inseln gehörenden Schelfgebieten in Tiefen bis 275, meist weniger als 100 Metern. Von Tauchern belästigt beißen sie zu.

Arten

Es sind neun rezente Arten beschrieben.
 Hornhai (Heterodontus francisci (, 1855))
 Kamm-Stierkopfhai (Heterodontus galeatus (, 1870))
 Japanischer Stierkopfhai (Heterodontus japonicus  & , 1884)
 Mexikanischer Stierkopfhai (Heterodontus mexicanus  & , 1972)
 Heterodontus omanensis , 2005
 Port-Jackson-Stierkopfhai (Heterodontus portusjacksoni (, 1793))
 Galapagos-Stierkopfhai (Heterodontus quoyi (, 1840))
 Weißgepunkteter Stierkopfhai (Heterodontus ramalheira (, 1949))
 Zebra-Stierkopfhai (Heterodontus zebra (, 1831))

Stammesgeschichte

Die Gattung Heterodontus ist fossil schon aus dem Oberjura bekannt.
Neben Heterodontus wird auch die oberjurassische Gattung Paracestracion der Familie Heterodontidae zugerechnet.

Einzelnachweise

Literatur
 Joseph S. Nelson: Fishes of the World: John Wiley & Sons, 2006, ISBN 0-471-25031-7.
 Kurt Fiedler: Lehrbuch der Speziellen Zoologie. Band 2, Teil 2: Fische. Gustav Fischer Verlag, Jena 1991, ISBN 3-334-00339-6.

Weblinks

redpajama_set_name: RedPajamaWikipedia


Get down & get funky!
Today is the 34th anniversary of Studio 54 – the iconic disco that represented all that was evil, fun and famous in society in 1977. A friend reminded me of this event (we were both in NYC last week and he did a pilgrimage to the site. I did a pilgrimage to Murray's Cheese Shop!). So, if you're about the "Mirror Image age" (over 50), and didn't live under a rock — you did your share of disco dancing!
Do the hustle! (Click on the link, go to iTunes or YouTube right now and put some funky music on! Staying Alive is fine. Fly, Robin, Fly. I Will Survive…) What great music we had! Ok, it wasn't that great, but it was really good to dance to. The Bus Stop, the Get Down and all the other silly line dances were easy enough for most to follow along. And you didn't have to worry about someone asking you to dance. Great exercise, too. And you worked up a thirst and could keep going all night.
My favorite memory was on a ski trip to Powderhorn in Michigan. We went out to the only bar/lodge/disco walkable (and there were 2 busloads of us, so we could only walk). This was the cafeteria during the day where families of skiers clomped through in wet ski boots and gloves and hats and sat down at long picnic tables with bad chili – that was magically transformed when they moved out the tables and turned on the disco ball in the evening.
My ski club group often took over the bar, making friends with skiers from other areas, and leading the dj in requests for disco songs and setting up the evening's "dance routine." We looked great – flared pants, flower print flowy tops, probably platform shoes or at least cool shoes to dance in. After MANY cocktails, we were out on the floor in a spirited Bus Stop (do a bunch of arm movements and easy steps, turn to the right, repeat….) I was at the end of the line as a leader and putting all my enthusiasm into the dance. Turn right, turn right, turn right, turn right… when I realized I was the only person on the dance floor. My friends had quietly conspired to get the entire bar – probably 70 people – to vacate the floor when I turned to face the wall, On the next "turn right" I realized there was no one in front of me, and then no one next to or behind me. And I kept on dancing. Like there was nothing odd. Though I guess I had quite a surprised look on my face. Plus I always thought I was a better dancer than I really was. So the Powderhorn Lodge had an impromptu show that night. At least I hadn't lost my clothes or anything.
Disco was fun. We were in our twenties and social life was so important. We worked hard during the day and let off a bundle of steam at night. Disco was our exercise routine, our friends, our "sense of place", our fashion guide (no John Travolta white suits, fortunately) our family.
So today, crank up the CD or iTunes and dance to celebrate all the fun times of the 70s. Bet the Hustle comes right back to you!
What was your favorite disco song? And memory? Please share!
This entry was posted on Tuesday, April 26th, 2011 at 10:36 am	and is filed under blog items. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.


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text:
Interview with Virologist Christian Drosten "We Managed to Stop a Pandemic Wave with Relatively Mild Measures"
Titelmotiv (Digital) DER SPIEGEL 23/2020, Christian Drosten
Germany's most famous virologist Christian Drosten has been the target of hatred and adoration. In an interview, he tells DER SPIEGEL how he is dealing with his newfound fame and what comes next in the fight against COVID-19.
Interview Conducted by Rafaela von Bredow und Veronika Hackenbroch
DER SPIEGEL: Professor Drosten, millions of people listen to your podcast and you have more than 300,000 followers on Twitter. Each of your tweets is shared hundreds of times and receives thousands of likes. How are you enjoying your newfound fame?
Drosten: I don't really notice it all that much. I'm not really a social media guy, and prior to the pandemic, I hadn't sent out a tweet in two years. I am also now reading very little about myself. And my podcast feels more like a dialogue with the science journalist who interviews me. As if it were just the two of us.
DER SPIEGEL: Are you sometimes approached by people on the street?
Drosten: If I have recently been on a talk show, then yes, people will recognize me for a few days afterwards. I'll notice that people look at me differently. Sometimes, I can hear people whispering, but they are always friendly, and nobody says: "You idiot!" like they do in the hate mail that I have recently begun receiving more often.
DER SPIEGEL: At the beginning of the corona crisis, you stepped out onto the public stage of your own free will. Why?
Drosten: I didn't want to expose myself to later accusations that I had failed to issue timely warnings that people here could die too. And who else should inform people about the pandemic and explain it to them? As somebody who works with coronaviruses, I simply felt it was my duty. That's why I made the decision in mid-January to invest the majority of my time in informing the public and to shift my working group's focus to the introduction of a test.
DER SPIEGEL: And to neglect your research projects?
Drosten: Our decision in January to devote ourselves to the development of a diagnostic test and to send it around half the world was not particularly spectacular from a scientific point of view. It took an incredible amount of time, but it was more of a public service than a research breakthrough.
DER SPIEGEL: Without you, would Germany have been worse prepared for the pandemic?
Drosten: Yes, of course. By mid-February, we had got university clinics to the point that they could perform diagnostic tests, and they frequently shared their knowledge and material with other labs. In mid-February, we in Germany were able to perform routine tests for SARS-CoV-2 at a time when hardly any other country could do so. Around the time of Carnival, we had our first positive test from someone who had not been travelling prior to infection. That was in the state of Baden-Württemberg. Nobody knew where he had become infected. At that point it was clear: The virus was already spreading unnoticed in Germany.
DER SPIEGEL: Wouldn't that have become obvious at some point anyway?
Drosten: Yes, but only a month later when the dead started piling up as they did in Italy, Spain and Britain. That's how long it takes from infection to death in the intensive care unit. And we – and by that, I mean, my laboratory – managed to use that month to give Germany a head start. That is why we find ourselves in such a good position today. If we hadn't been able to perform tests so early, if we scientists had not informed the politicians, then I think that we in Germany would have seen 50,000 to 100,000 more fatalities.
DER SPIEGEL: You financed your medical studies by working as a nurse in an intensive care unit. Did that help you understand how dangerous COVID-19 could be?
Drosten: Of course. When I first saw the images from the intensive care units in Italy, where the patients were lined up on their stomachs being artificially ventilated, I immediately knew: This is really bad. Patients who undergo such treatment don't recover after just a few days, it takes several weeks. And that means that intensive care units are jammed for a long time, and the chances of survival are poor.
DER SPIEGEL: Why did you become a virologist and not an intensive care doctor?
Drosten: I realized at the time that when patients could no longer be saved and when their families had to bid farewell, I was taking the trauma home with me. At around that time, I met the man who would later become my Ph.D. adviser and my interest in molecular biology and virology began to grow.
DER SPIEGEL: Now, you find yourself in a conflict with Germany's best-selling tabloid Bild. The paper has gone on the attack against you and accused you of erroneous research.
Drosten: Should I be afraid? I don't think so. The last time I read a copy of Bild was at the time when Boris Becker was on the cover after he won Wimbledon. Bild is not part of my daily life and nobody in my circle of acquaintances reads Bild. So, I really don't know much about it.
DER SPIEGEL: The paper's headline this week, "Drosten Study about Contagious Children Badly Wrong," was intended to discredit you as a scientist.
Drosten: It could be that people who only read Bild believe that Drosten is a bad scientist, that I am clueless and that I have steered this country's fate in the wrong direction – and all the other fables that have been produced. But to discredit me as a scientist, other scientists would have to believe what Bild writes. In reality, I have been receiving only support recently, a couple of isolated exceptions notwithstanding.
DER SPIEGEL: Your study focuses on whether children who have become infected with the novel coronavirus are just as contagious as adults. The answer to that question is crucial to the decision as to whether schools and daycare centers can be allowed to reopen.
Drosten: On these vital questions, there is unfortunately still a lack of serviceable studies. And as long as the schools remain closed, such studies can't be carried out. That's why we decided to take a look at the viral load in the throats of infected children. That is an indication of how contagious they are.
DER SPIEGEL: Just as your study was released, it was criticized – in statements, in expert articles, on twitter and in emails.
Drosten: Yes, most of the criticism came from experts in statistics. Some of it was rather bizarre. Astrophysicists recommended we use statistical methods that can be used to analyze the signal coming from a quasar. Extremely high-precision methods, but perhaps a bit much when it comes to the viral load in the throats of children. For the rather rough data at our disposal, we chose a less precise statistical tool.
DER SPIEGEL: The question is whether the results of your study correct. Can children be just as contagious as adults?
Drosten: Our data shows – at first glance, really – that some children who exhibit no symptoms can have a viral load that is just as high as that of adult COVID-19 patients. Many of the suggestions we received from statistics experts were nevertheless extremely valuable for us. We have now revised the study and intend to submit it for publication shortly. We even managed to bring one of the critics on board as a co-author. But the result of the study did not change as a result of the revisions.
DER SPIEGEL: The Bild reporter Filipp Piatov saw things differently and wrote you an email on Monday …
Drosten: … in which he demanded that I provide comment within one hour.
DER SPIEGEL: You then posted the email from the Bild reporter on Twitter and wrote: "I have better things to do."
Drosten: The statistical models in question are so complex that they cannot be explained in a brief comment, even if you devote far more than an hour to it. And I didn't have the impression that Bild was really interested in understanding the scientific issue at hand. It was clear that they were planning a tendentious article. After it was published, it became clear that they didn't even speak with the four critical statistics experts, and instead just took quotes out of context that they found online. The experts in question had no idea what was happening and distanced themselves from the Bild article via Twitter.
DER SPIEGEL: Bild Editor-in-Chief Julian Reichelt countered that you could have asked for the deadline for responding to the paper to be pushed back.
Drosten: I didn't feel that the query was sufficiently rooted in a desire to understand the subject matter at hand. And I have only known since Monday who Mr. Reichelt is.
DER SPIEGEL: Many people hate you for your role in the pandemic, and many more people idolize you. There are hashtags like #TeamDrosten and there are people that want to be tattooed with an image of your face. Some see you as a kind of super-scientist. Are you enjoying the adoration?
Drosten: I think that only really happens in the media and it isn't relevant for me and my colleagues in scientific research. There are certainly better scientists than me working in virology in Germany. I don't think any of them see me as the best. I'm just in the center of attention at the moment because my work is currently focusing on the virus.
DER SPIEGEL: On the other hand, you have also been confronted by hatred. As you wrote on Twitter, you received a vile piece of mail on Tuesday. What was it?
Drosten: The state criminal office is analyzing it. It looked like a human blood serum (laughs), but it could also have come from a goat. There was a message along with it: "drink this – then you'll be immune." Such hate mail has become normal, often they are completely crackpot texts full of spelling mistakes. Some of those who write are just pitiable, while others are extremely narcissistic, malicious and manipulative.
DER SPIEGEL: There was also that poster showing you together with the concentration camp doctor Josef Mengele.
Drosten: I believe that was a criminal offense and it resulted in an immediate criminal complaint. I hope they find who did it. And I hope to see them in court.
DER SPIEGEL: Thus far, Germany has managed well in the pandemic, yet there are still angry protests from corona rebels, anti-vaxxers and right-wingers, both on the streets and in the internet. But there are also more moderate critics who believe that researchers like you overshot the mark and are responsible for Germany's economic collapse. Have you or the politicians been guilty of poor communication?
Drosten: I don't believe that we have done anything wrong. We managed to stop a pandemic wave with relatively mild measures, and we did so quite efficiently and without a huge number of fatalities. I think we should tell the corona-deniers: Take a look abroad. We have managed to do something in Germany that no other comparable country in the world has been able to do.
DER SPIEGEL: Many people have the feeling that nothing actually happened.
Drosten: Yes, prevention is a bit of a paradox: Nothing happened because we managed to prevent it from happening. That was the point of the measures we adopted. And now, when we recommend the careful lifting of measures, some say: Aha, the experts are flip-flopping. Drosten is reversing course. Now, he is suddenly recommending something completely different. I mean, did anyone really think that once we shut things down, we never planned to open them up again?
DER SPIEGEL: Is the hate directed at you also informed by a general skepticism of science, fueled by anti-vaxxers in their filter bubbles on social media?
Drosten: I think something is being projected on my person. It's not general skepticism of science, it is more that people have suffered under the shutdown measures, as mild as they may have been. Many people simply have the feeling that drastic limitations on their daily lives are being implemented over their heads.
DER SPIEGEL: Limitations that you were involved in, since you advised Chancellor Angela Merkel and the leaders of Germany's federal states to implement them.
Drosten: My role as a political adviser has been radically exaggerated. It is largely a fable.
DER SPIEGEL: Then Interior Minister Horst Seehofer was incorrect when he said in a talk show that you were initially opposed to shutting down the schools, only to voice support for the idea the very next day in a conference call with Germany's state governors?
Drosten: Let me tell you what happened. For one thing, a number of scientists took part in that conference. And our message was simple: We simply can't know how dangerous schools are as a potential source of infection.
DER SPIEGEL: And where did your change of opinion come from?
Drosten: I really did think that we could leave the schools open and start by banning large gatherings. But on the evening before the conference, a scientist from the U.S. wrote me and she said: Be careful Drosten, you are wrong, the schools play a special role and here are the arguments. She explained it to me and attached a study, and it was exactly this scientific knowledge that I shared in the conference of state leaders. There wasn't anything more to it.
DER SPIEGEL: Do you mean to say that you had no influence on political decisions?
Drosten: I do believe that my podcast is closely monitored in ministerial departments. I mean, how can I, as a researcher, make my message any more transparent than I do in the podcast?
DER SPIEGEL: You even used your study on viral loads to provide recommendations to political leaders. It explicitly states that you warned against reopening schools and daycare centers.
Drosten: If you read the entire study, then you will find a detailed list of the uncertainties. In that context, there is a sentence that was formulated extremely carefully saying that, according to the data we currently have at our disposal, as uncertain as it may be, we cannot with a clear conscience recommend that schools be reopened without restrictions.
DER SPIEGEL: The media psychologist Frank Schwab compared you in DER SPIEGEL with Gandalf from "Lord of the Rings" or Obi Wan Kenobi in "Star Wars:" You aren't fighting on the front lines, but you are standing alongside the heroes, sharing your experience and wisdom. Is that an accurate comparison?
Drosten: Who is that? I don't know those characters.
DER SPIEGEL: Seriously?
Drosten: I've never read "Lord of the Rings" and I've never seen "Star Wars." And regarding my role as a political adviser, I'm neither the captain nor the coxswain. At most, perhaps, a navigator. I read the maps.
DER SPIEGEL: How will things continue from here?
Drosten: We are really in a good situation at the moment. The shutdown has largely been lifted and more and more things are opening – and there hasn't been an immediate flourishing of the pandemic. It could very well be that the virus largely leaves us alone for a time.
DER SPIEGEL: For how long?
Drosten: Not forever. But perhaps we can avoid a second shutdown. In the beginning, we definitely needed the entire palette of measures because we didn't know for sure what would help. Now, we have a better understanding of the virus and we know more about how it spreads.
DER SPIEGEL: What about schools and daycare centers? Would you like to see them open now as well?
Drosten: It's clear that we have to open them, and they can't really be opened halfway. Even if we still don't know for sure how contagious children are. And then we have to see what tools can be used to prevent a big outbreak there in its early phase – an outbreak that is otherwise certain to come.
DER SPIEGEL: No singing in church. No cruises. No big parties. Is that our lives for the next several months?
Drosten: Parties could be a possibility if they are held outside and not too many people are involved. One could certainly imagine such a thing this summer.
DER SPIEGEL: And then a vaccine will solve the problem next spring?
Drosten: I am confident that by then there won't just be a single vaccine. The process is kind of in the background in Germany, but we are on an extremely good path toward a vaccine.
DER SPIEGEL: But before it arrives, we will have winter – and the virus will return?
Drosten: Yes, it is relatively clear that temperature has a certain effect. The question is: Where does that effect come from? It is probably from people gathering in closed rooms in the winter. But perhaps we have the opportunity over the summer to prepare by developing guidelines, planning a new testing regime and thinking about how to trace developing outbreaks. And we can already begin preparing for the fact that there won't be any congresses and conferences this fall and winter either.
DER SPIEGEL: Otherwise there could be a second wave?
Drosten: There is theoretically a possibility that we can forego a second wave. Because of the way the illness spreads: We have just a few people who infect many others …
DER SPIEGEL: … so-called super-spreaders.
Drosten: Exactly. And such an infection event is easier to control than a similar outbreak that is spreading under the radar, like we had in the beginning. When it becomes clear where such an outbreak is underway, we immediately have to take strict measures.
DER SPIEGEL: How? By testing everybody who has a bit of a cough?
Drosten: No, it is more a matter of understanding where and in what situations outbreaks are essentially a foregone conclusion. And how we can keep an eye on them. Confronting outbreaks has also become easier. There are new calculations that very clearly show that when an outbreak is identified, it doesn't really help to start testing all the possible contact people. No matter what, we'll always be too late. Inevitably. Instead, all contact persons should simply be quarantined, and not for 14 days anymore, but for just a bit longer than a week. The incubation and contagious periods – it's all quite a bit shorter than we thought in the beginning.
DER SPIEGEL: What are the most significant questions that still haven't been answered about this pandemic?
Drosten: The most obvious one is why children don't show any symptoms. It doesn't seem to be because they have a lower viral load in their throats. I also don't believe it's a plausible explanation that they have fewer of the receptors that are attacked by the virus in their nasal mucous membranes. And then, of course: What vaccine is the best?
DER SPIEGEL: What exactly do you mean?
Drosten: A vaccine should work in small doses and it should be easy to produce. And then, which vaccine should be used once the pandemic has passed? Do we have to vaccinate in perpetuity?
DER SPIEGEL: Is there anything about this virus that concerns you?
Drosten: The biggest question is: Will it become more virulent or will it weaken? It can certainly be optimized through evolution, that does worry me a bit. And what that might look like, whether it could become more deadly, we don't know. I don't want to be a pessimist, but there is an assumption that something similar happened in 1918 with the Spanish Flu, that the virus mutated as winter arrived.
DER SPIEGEL: What have you learned on your path from the laboratory to the national stage?
Drosten: I think I have become more thick-skinned. It's quite good for me, because I'm actually not the kind of person who can protect himself from personal hostilities, even if others have said differently. It is possible to, well, mature a little bit from the experience.
DER SPIEGEL: According to media reports, Bild Editor-in-Chief Reichelt has challenged you to a duel. Are you planning on accepting, or do you have better things to do?
Drosten: What does that even mean, "challenging me to a duel?" It sounds like the 19th century. I have no idea what the point is.
DER SPIEGEL: Professor Drosten, thank you for this interview.
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Importance of AMPA Receptors for Hippocampal Synaptic Plasticity But Not for Spatial Learning
Daniel Zamanillo1,*,
Rolf Sprengel1,†,
Øivind Hvalby2,
Vidar Jensen2,
Nail Burnashev1,
Andrei Rozov1,
Katharina M. M. Kaiser1,
Helmut J. Köster1,
Thilo Borchardt1,
Paul Worley3,
Joachim Lübke4,
Michael Frotscher4,
Peter H. Kelly5,
Bernd Sommer5,
Per Andersen2,
Peter H. Seeburg1,
Bert Sakmann1
1 Departments of Molecular Neuroscience and Cell Physiology, Max-Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.
2 Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway.
3 Departments of Neuroscience and Neurology, Johns Hopkins University, School of Medicine, Baltimore MD 21205, USA.
4 Department of Anatomy, University of Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany.
5 NS Research Novartis Pharma AG, Basel, Switzerland.
Science 11 Jun 1999:
Daniel Zamanillo
Rolf Sprengel
Øivind Hvalby
Vidar Jensen
Nail Burnashev
Andrei Rozov
Katharina M. M. Kaiser
Helmut J. Köster
Thilo Borchardt
Paul Worley
Joachim Lübke
Michael Frotscher
Peter H. Kelly
Bernd Sommer
Peter H. Seeburg
Bert Sakmann
Gene-targeted mice lacking thel-α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A−/− mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A−/− mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.
Brief high-frequency activation of many glutamatergic pathways causes a long-lasting increase in the efficacy of synaptic transmission, termed LTP (1), and is postulated to be a model for cellular mechanisms underlying learning and memory acquisition (2). In synapses between the glutamatergic Schaffer collateral-commissural fibers of hippocampal CA3 and CA1 pyramidal cells (SC-CA1), LTP induction requires activation of the N-methyl-d-aspartate (NMDA) receptor, Ca2+ influx into the postsynaptic dendritic spine, and gene activation resulting in de novo protein synthesis in the postsynaptic cell.
The hippocampus is thought to be important for spatial learning (3, 4). This has also been indicated by behavioral analysis of pharmacologically treated rats (4) and genetically manipulated mice (5). However, the link between hippocampal LTP and spatial learning is controversial (6), and the pre- or postsynaptic locus of LTP expression has not been resolved (7). Yet, there is consensus that the increased synaptic efficacy characteristic of LTP is expressed as an increased AMPA receptor-mediated response to test stimuli.
AMPA receptors mediate fast excitatory postsynaptic currents (EPSCs) and for the most part are composed of two different subunits (8). In hippocampal CA1 pyramidal cells, which express mainly GluR-A and GluR-B of the four receptor subunits (9), AMPA receptors display low permeability to Ca2+ due to the presence of the edited form of GluR-B in heteromeric channels (10). As a postsynaptic mechanism of LTP expression in CA1 pyramidal cells, AMPA receptors may undergo phosphorylation, perhaps at the GluR-A subunit (11). However, LTP expression may also involve insertion into the postsynaptic membrane of additional AMPA receptors (12) and may stimulate their biosynthesis (13).
GluR-A−/− Mice and AMPA Receptor Immunocytochemistry
To study the molecular basis for LTP expression, and to probe the link between hippocampal LTP and spatial learning, we generated mice lacking GluR-A (14) (Fig. 1, A and B). GluR-A−/− mice were smaller than their littermates during the first postnatal weeks, but after weaning their size was normal.
GluR-A alleles and GluR-A expression in wild-type and GluR-A−/− mice. (A) Schematic representation of the GluR-A subunit, the GluR-A+allele, the targeted GluR-Aneo allele, and the GluR-A− allele after Cre-mediated recombination (14). Black boxes represent membrane segments M1 to M4, open boxes are exonic sequences and the neo gene. LoxP sites are indicated by black triangles. Solid circles in GluR-Aneo indicate 5′ and 3′ ends of the targeting construct. Positions of Bam HI (B) and Hind III (H) restriction sites are given. The Sac I fragment (260 bp) used as probe for the genomic blot is indicated by a black bar; P1 to P3 represent primers for screening GluR-A alleles. (B) Southern blot analysis of Bam HI–digested ES cell DNA visualized parts of the GluR-A+, GluR-Aneo, and GluR-A− alleles as 7.2-, 9.2-, and 5.7-kb fragments, respectively. Size markers (kbp) are indicated on the left. (Cand D) Distribution of the GluR-A subunit visualized by immunostaining in coronal forebrain sections of wild-type (C) and GluR-A−/− (D) mice (16). Cx, cortex; H, hippocampus; CP, caudate-putamen; T, thalamus; Bl, basolateral amygdaloid nucleus.
GluR-A gene inactivation was demonstrated by immunocytochemistry (15, 16). As shown in coronal sections (Fig. 1, C and D), the absence of GluR-A in the forebrain mostly affected AMPA receptors of the hippocampus and amygdala, where GluR-A expression is high, and had smaller effects in areas such as the neocortex, where it is normally low (17).
Immunocytochemistry (16) in the hippocampus of GluR-A−/− mice relative to wild type revealed a redistribution of the GluR-B subunit in pyramidal and dentate granule cells with increased staining over the somata (stratum pyramidale) and decreased staining in the basal (stratum oriens) and apical (stratum radiatum) dendrites (18) (Fig. 2, A and B). The altered GluR-B localization upon lack of GluR-A may indicate that the edited GluR-B subunit requires a partner for assembly or dendritic targeting of GluR-B-containing AMPA receptors. A substantial amount of GluR-B remained in the stratum lacunosum-moleculare, possibly in the form of GluR-B/C heteromeric channels, in synapses at the distalmost part of the apical dendrites of CA1 and CA3 pyramidal neurons.
Hippocampal expression of glutamate receptor subunits. (A and B) Distribution of GluR-B in somata of pyramidal cells of wild-type (A) and GluR-A−/− (B) mice in immunostainings (15) of coronal forebrain sections. Or, stratum oriens; Ra, stratum radiatum; LM, stratum lacunosum-moleculare; Mo, molecular layer; Py; stratum pyramidale; Gr, granule cell layer. (C) Expression of the GluR-A, -B, and -C and the NR1 subunits, monitored by immunoblots of membrane proteins from hippocampi (52) of wild-type (WT) and GluR-A−/− mice.
Other glutamate receptor subunits (GluR-B, -C, and -D; NR1 and NR2A to C) were not up-regulated in the hippocampus of GluR-A−/−mice (shown for GluR-B, -C, and NR1 subunits in Fig. 2C).
Distribution of Functional AMPA Receptors and Excitatory Transmission
Glutamate-activated currents in nucleated soma-patches. The amount of functional AMPA and NMDA receptors located in the somatic membrane of CA1 pyramidal cells was determined in nucleated soma-patches from acute brain slices (15,19). The size of these membrane patches, which form around the nucleus, remains constant within cells of a given population, and the current amplitude elicited by glutamate application is proportional to the number of receptor channels in the patch. In wild-type mice, the mean size of currents was 2.6 ± 1.1 nA (mean ± SD;n = 5) through nucleated CA1 soma-patches mediated by AMPA receptors at a membrane potential of −60 mV and 0.46 ± 0.15 nA (n = 5) for NMDA receptors in Mg2+-free extracellular solution. In GluR-A−/− mice the AMPA receptor current was strongly reduced to 0.12 ± 0.13 nA (n = 8) (Fig. 3A), whereas the NMDA receptor current showed no significant difference with 0.44 ± 0.14 nA (n = 8; P = 0.76;t test) (15). These results are consistent with the assumption that high GluR-A expression is a determinant of the large AMPA receptor-mediated currents in wild-type CA1 pyramidal cells.
Glutamate-activated somatic and synaptic currents in CA1 pyramidal cells of wild-type (WT) and GluR-A−/− mice. (A) Currents in nucleated soma-patches activated by brief pulses (2 ms) of glutamate (1 mM), indicated by upward deflection in the trace above the current records, applied to nucleated soma-patches of CA1 pyramidal neurons at membrane potentials ranging in 20-mV steps from −80 to 60 mV in extracellular physiological solution with 1 mM MgCl2 (19). (B) fEPSP recorded in stratum radiatum of the CA1 region of brain slices after extracellular SC stimulation before and after addition of CNQX (10 μM) (19). Stimulus intensities were 40 μA (wild type) and 25 μA (GluR-A−/−). The stimulus artifact has been truncated. (C) mEPSCs recorded from individual CA1 pyramidal cells in slices at −70 mV holding potential and 23°C (19). (D) Peak amplitude distribution of mEPSCs from experiments as shown in (C). Distribution was similar for both genotypes and typically showed a tail of larger amplitudes. Mean peak amplitude was 12.4 ± 5.0 pA (n = 290) in wild-type and 14.4 ± 7.1 pA (n = 495) in GluR-A−/− mice. Observations and mEPSCs were recorded from one cell.
Evoked field excitatory postsynaptic potentials (fEPSPs). Unlike the large difference in glutamate-activated AMPA currents in the soma, no differences were observed in synaptically evoked currents, as determined by fEPSP in CA1 pyramidal cell layers (19). The extracellularly recorded fEPSP had the same wave shape, and the stimulation intensity necessary to elicit equally large fEPSPs in the CA1 region was not significantly different (Fig. 3B). The mean (±SEM) value of the 50-μs-long stimulation current used in slices from wild type was 57 ± 6 μA (n = 17) versus 58 ± 9 μA (n = 13) from GluR-A−/− mice (P = 0.93). The corresponding fEPSP amplitudes were also similar (wild type, 1.62 ± 0.14 mV; GluR-A−/−, 1.58 ± 0.17 mV;P = 0.86).
In SC-CA1 pyramidal cell synapses, the fEPSP was blocked in the presence of the AMPA kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 μM) (20), in slices from wild-type (n = 6) as well as GluR-A−/− mice (n = 10) (Fig. 3B), which demonstrates AMPA receptor-mediated neurotransmission in the absence of GluR-A.
Miniature EPSCs (mEPSCs). To determine directly the currents evoked by a single quantum of glutamate in individual dendritic spines of CA1 pyramidal cells, we analyzed size, time course, and peak amplitude distribution of mEPSCs (19) (Fig. 3, C and D). The average (±SD) peak amplitudes of mEPSCs recorded from wild-type and GluR-A−/− slices were similar [12.3 ± 1.4 pA (n = 7) and 11.9 ± 3.2 pA (n = 7); P = 0.75]. The decay time constant of mEPSCs in wild-type mice was monoexponential, with average time constants ranging from 4.7 to 6.1 ms in seven neurons (mean ± SD, 5.2 ± 0.6 ms). In GluR-A−/− mice the monoexponential mEPSC decays were comparable (4.7 ± 1.6 ms;n = 7). In two cells, however, a small percentage (10 to 20%) of the mEPSCs had double-exponential decays with a short decay time constant of 1.5 ms and a longer one of about 12 ms. The slowly decaying component was also observed in the presence of an NMDA receptor antagonist (19). Both the short and long decay components were reversibly blocked by an AMPA receptor antagonist (19).
In summary, in spite of a strong reduction in AMPA receptor currents in the somata of CA1 pyramidal cells of GluR-A−/− mice, AMPA receptor-mediated synaptic transmission in SC-CA1 synapses appeared to be largely unaffected.
Long- and Short-Term Changes in Hippocampal Synaptic Transmission
LTP. We examined LTP in CA1 in slices from adult mice. In wild-type mice, tetanic stimulation of the afferent fibers, in either stratum radiatum or stratum oriens, produced a persistent homosynaptic potentiation of the synaptic responses, characteristic of LTP (3, 21). The average fEPSP slope 40 to 45 min after tetanization was 135% ± 9% (mean ± SEM; n = 17; four mice) of the pretetanic control value and synaptic transmission in the control pathway was unchanged (100% ± 2%). In GluR-A−/− mice, however, the tetanized pathway was not significantly different from the control pathway (109% ± 6% versus 104% ± 5%; n = 13; five mice; P = 0.27) (Fig. 4A). Lack of LTP was not due to inefficient tetanization because the first fEPSP and the summed voltage integral of the high-frequency trains used to elicit LTP were not significantly different in wild-type and GluR-A−/−mice (P = 0.45 and P = 0.09), which is consistent with the normal excitatory transmission in the mutant animals.
Synaptic plasticity in the hippocampal CA1 region. (A) (Left) Diagram of electrode arrangement. Stimulation electrodes placed in stratum radiatum (rad) and stratum oriens (or). Synaptic field responses were monitored by two extracellular recording electrodes placed in the corresponding synaptic layers. (Right) Extracellular recording of fEPSPs in slices before and after tetanization. The two pairs of traces show superimposed averages of 10 consecutive field responses from the tetanized pathway before (ctrl) and 45 min after LTP induction (45') in a wild-type (WT) and a GluR-A−/− slice. (B) Summary graphs of extracellular fEPSP slopes evoked in the tetanized (filled circles) and untetanized (open circles) pathways from slices of wild-type (WT; n = 17; five mice) and GluR-A−/− (n = 20; six mice). Data were obtained in bicuculline methochloride (10 μM) and 4 mM Ca2+ and Mg2+. Arrow, time of tetanic stimulation. (C) Mean paired-pulse ratios for wild-type (open circles) and GluR-A−/− (filled circles) mice at three interstimulus intervals (50, 100, and 200 ms). Vertical bars indicate SEM.
Induction of LTP is facilitated by γ-aminobutyric acid type A (GABAA) receptor blockade, whereas the magnitude of LTP is unchanged (22). Thus, we added bicuculline (10 μM) to ensure that the lack of LTP in GluR-A−/− mice was not due to an induction failure. To reduce the resulting hyperexcitability, we cut between the CA3 and CA1 areas and raised both Ca2+ and Mg2+ to 4 mM, which yielded a similar amount of LTP (134% ± 4%; n = 9; four mice; P = 0.90). In the presence of bicuculline, LTP in slices from wild-type mice measured 140% ± 6% (control pathway, 100% ± 2%) (n = 17; five mice), whereas LTP was absent in GluR-A−/− mice (tetanized versus control pathway: 100% ± 5% versus 99 ± 3%;n = 20; six mice; P = 0.93) (Fig. 4B). To ensure that the tetanization paradigm gave robust and long-lasting LTP, we sometimes followed responses in wild-type slices for 4 or 8 hours. The measured fEPSP slope relative to the pretetanic value was 168% ± 23% (n = 6) after 4 hours and 160% ± 8% (n = 2) after 8 hours.
Paired-pulse facilitation. CA1 excitatory synapses show paired-pulse facilitation (23), a form of short-term presynaptic plasticity (24) that decays within a few hundred milliseconds. The facilitation in slices from wild-type and GluR-A−/− mice, tested at three interstimulus intervals (Fig. 4C), was not significantly different (25). Hence, the failure to generate LTP in SC-CA1 connections suggests that there is a postsynaptic deficiency in GluR-A−/− animals.
Hippocampal CA1 Pyramidal Cell Dendrites and Spines
Structure of excitatory synapses. The vast majority of synapses in stratum radiatum of CA1 are formed by collaterals of ipsilateral and contralateral CA3 pyramidal cell axons. These glutamatergic terminals form asymmetric contacts on dendritic spines (Fig. 5, A and B) and shafts (Fig. 5, C and D) of CA1 pyramidal neurons. Electron microscopic analysis (26) of more than 100 spine and shaft synapses in both wild-type and GluR-A−/− mice did not reveal differences between the two groups. At the light microscopic level, we evaluated the total number of dendritic spines, spine density, and spine distribution on main apical dendrites of identified, Golgi-impregnated CA1 pyramidal cells. We found no significant differences in spine density between wild-type (1.71 ± 0.14 spines per micrometer) and GluR-A−/− (1.73 ± 0.14;P = 0.34) mice.
Synaptic contacts on pyramidal cell dendrites in CA1 stratum radiatum. Representative, supposedly glutamatergic, asymmetric axospinous synaptic contacts (arrows) formed on dendritic spines (s) arising from dendritic shafts (d). Morphologically, synaptic contacts in wild-type (A) and GluR-A−/−(B) mice were indistinguishable. (C andD) Axodendritic synaptic contacts in wild-type (C) and GluR-A−/− (D) mice were indistinguishable. Bar = 0.25 μm.
Dendritic calcium transients. We next measured dendritic Ca2+ transients (27) as an indicator of stimulus-evoked postsynaptic membrane depolarization (Fig. 6, A and B). Dendritic resting Ca2+ concentrations were 167 ± 83 nM (mean ± SD; n = 4) for wild-type and 149 ± 93 nM (n = 7) for GluR-A−/− mice. During tetanic stimulation, the dendritic Ca2+ transients evoked by a single stimulus accumulated to reach a steady-state plateau, which was similar (P = 0.73) in wild-type (690 ± 193 nM; n = 4) and GluR-A−/− (624 ± 343 nM; n = 7) mice. This, together with the comparable stimulus intensities, indicated that dendritic AMPA receptor-mediated membrane depolarization during tetanic stimulation and postsynaptic Ca2+ entry were unaffected in GluR-A−/− mice.
Dendritic (A and B) and spinous (C and D) Ca2+ transients in CA1 pyramidal cells during synaptic stimulation. (A and B) (Upper traces) Somatically recorded action potentials evoked by tetanic stimulation of SC in CA1 pyramidal neuron in a slice of wild-type (WT) (A) and GluR-A−/− (B) mouse. (Lower traces) Corresponding dendritic Ca2+ signal measured simultaneously in the same neuron. (C and D) Images of an apical oblique dendritic branch and spines of a CA1 pyramidal cell in a slice from wild-type (C) and GluR-A−/− (D) mouse. Lines indicate positions of line scans for fluorescence recording of individual spines (arrows). (Upper traces) Somatic recording of a single EPSP evoked by focal extracellular stimulation of SC nerve terminals synapsing on a CA1 pyramidal cell. (Middle traces) EPSP-evoked Ca2+ fluorescence transient recorded in a single active dendritic spine shown in the image above. (Lower traces) Fluorescence record after addition of 50 μM AP-5.
Spinous calcium transients. We analyzed spinous Ca2+ transients (27) mediated by NMDA receptors in hippocampal spines to determine whether induction of the signal cascade for LTP is functional (Fig. 6, C and D). In wild-type slices the EPSP-evoked Ca2+ transients in single spines generated a fluorescence amplitude, ΔF/Fmax, of 0.40 ± 0.13 (mean ± SD; n = 8), similar to that in GluR-A−/− mice (0.44 ± 0.16; n = 8;P = 0.49). The fluorescence change in the parent dendritic shaft during an evoked EPSP was <30% of the amplitude recorded in the spine (n = 5) in both genotypes.d(−)-2-Amino-5-phosphonopentanoic acid (AP-5) (50 μM) in the extracellular solution reduced Ca2+ transients to 12% in wild-type and 14% in GluR-A−/− mice (n = 2 each), which suggests that the NMDA receptor-mediated Ca2+ entry into CA1 pyramidal cells is not altered in the mutant.
Immediate-early gene (IEG) expression. We compared wild-type and GluR-A−/− mice for IEG expression, acutely up-regulated after a maximal electroconvulsive shock (MECS) (28,29). The induction, which largely depends on NMDA receptors, of c-fos, c-jun, zif268, andRGS2, and the cellular expression patterns did not differ in the two genotypes, as determined by in situ hybridization in brain sections (28). We conclude that the link between physiological synaptic activity and activity-dependent gene expression is preserved in GluR-A−/− mice.
Spatial Learning
Given the strong effect of GluR-A deficiency on hippocampal CA1 LTP, one might expect deficits in the water maze test (2,6). However, spatial learning of GluR-A−/−mice was not significantly different from that of wild-type mice (30). In both groups, the latency between start of swimming and finding the hidden platform decreased from about 60 to 20 s after about 5 days of training (Fig. 7A). There were no differences between groups in latency or distance swum before they found the platform (analysis of variance, P= 0.26 and 0.52, respectively) and no group–trial block interactions (P = 0.15 and 0.07, respectively), but trial block effects were highly significant (P < 0.001 for both). The slightly increased latency in GluR-A−/− mice during the first training trials can be explained by the reduced swimming performance of GluR-A−/− mice compared with wild type (Fig. 7B). Spatial memory acquisition was further compared by a transfer test, with the platform removed from the pool after 10 blocks of trials. Both wild-type and GluR-A−/− mice spent most of 60 s in the SE quadrant, which previously contained the platform (Fig. 7C), with no significant difference between genotypes (P = 0.19). The groups also did not differ in the number of times they crossed the annulus representing the platform position (mean ± SEM: wild-type, 5.4 ± 0.7; GluR-A−/−, 5.5 ± 0.9; P = 0.98).
Spatial learning. (A) In a Morris water maze the mean latency (±SEM) to escape from the pool to the submerged platform (eight trials per day in blocks of four) is presented as a function of trial block for male wild-type (n = 19) (filled squares) and GluR-A−/−(n = 21) (open squares) mice. (B) Swim test gives the mean distance covered by the two genotypes in 50 s in the pool without a platform before training. (C) In a transfer test after trial block 10, the platform was removed and wild-type and GluR-A−/− mice were allowed to search for 60 s. Both groups searched selectively in the target quadrant (SE). Ordinate, percent time spent in each quadrant. (D) Quadrant preference was not observed when distal visual cues were invisible in the transfer test.
When we performed the transfer test without visual cues, there was no quadrant preference (Fig. 7D). In neither group did the time spent in the target quadrant differ from chance (P > 0.25) and the groups did not differ (P = 0.65) in this measure.
There are three main observations: (i) in spite of the severe loss of AMPA receptors in soma-patches of CA1 cells, excitatory synaptic transmission appeared normal in GluR-A−/− mice; (ii) although synaptic transmission was normal, NMDA receptor-mediated LTP was lacking in CA1 pyramidal neurons; (iii) despite the lack of SC-CA1 LTP, spatial learning was normal.
Normal excitatory synaptic transmission. GluR-A deficiency underlies the selective loss of extrasynaptic AMPA receptors in CA1 pyramidal cells. This is demonstrated by the strong reduction of AMPA receptor-mediated currents in soma-patches versus the normal responses at CA1 dendritic synapses, as shown by mEPSCs with regular amplitude range and rise times and fEPSP in response to radiatum fiber activation. It might suggest that, in wild-type mice, GluR-A-containing receptors do not contribute to synaptic transmission and that synaptic transmission is carried by GluR-B/C and GluR-B/D AMPA receptor subtypes, which are not affected in GluR-A−/− mice. This is unlikely because high-resolution immunocytochemistry indicates that GluR-A-containing receptors are located in synapses (31). Moreover, the additional slow component occasionally observed in mEPSC decay in the mutant might indicate a change in synaptic AMPA receptor subtypes. Therefore, we think that, after a strong reduction in the total number of AMPA receptors in GluR-A−/− CA1 cells, the remaining GluR-B/C and GluR-B/D receptors are preferentially transported and targeted to synapses and substitute for the missing GluR-A/B subtype. There are not enough AMPA receptors left for extrasynaptic sites.
This preference of dendritic over somatic membrane insertion, revealed by GluR-A−/− mice, also may explain why, in certain neuronal cell populations such as cerebellar granule cells, synaptic AMPA receptor currents are prominent even though the soma-patch currents are very low (32). In such neuronal populations AMPA receptor expression is lower than in CA1 pyramidal cells and thus, as in CA1 cells of GluR-A−/− mice, the number of available receptors might not suffice to occupy extrasynaptic sites.
An intriguing consequence of GluR-A deficiency is the intracellular redistribution of the GluR-B subunit, which, in the mutant, becomes largely restricted to the soma of hippocampal pyramidal and dentate granule cells, where it may reside in the endoplasmic reticulum or Golgi apparatus. Explanations for this redistribution could be that GluR-B homomeric channels do not form efficiently or that GluR-B homomers do not reach synapses. Hence, we postulate that, in GluR-A−/− CA1 neurons, a major fraction of GluR-B has no partner subunit for heteromeric AMPA receptor assembly.
Lack of hippocampal SC-CA1 LTP. The observation that the dendritic and spinous Ca2+ transients are not different between wild-type and GluR-A−/− mice shows that the initial steps of the induction mechanism of LTP, which depend on NMDA receptor and voltage-dependent calcium-channel activation, are unaltered. In GluR-A−/− mice, Ca2+-dependent cellular signaling cascades can be activated, and IEG responses in MECS-treated GluR-A−/− mice are the same as in wild type. Thus, the expression of LTP is likely to be blocked in the mutant.
LTP expression is manifested by an increased fEPSP amplitude and probably reflects a modification of the molecular structure of the postsynapse. The enhanced AMPA receptor-mediated response to presynaptically released glutamate could depend on the number or the subunit composition of functional AMPA receptors in the subsynaptic membrane. In GluR-A−/− mice LTP expression could be compromised in several ways.
CA1 neurons of wild-type mice may contain excess GluR-A–containing AMPA receptors, which are essential for rapid incorporation of additional AMPA receptors into the postsynaptic membrane after tetanization. Because of the lack of GluR-A, and hence of spare AMPA receptors (33), this postulated step in LTP expression would be deficient in GluR-A−/− mice. Alternatively, LTP expression may require AMPA receptor subunit modification. One hypothesis is that the signaling cascade initiated by Ca2+ influx during tetanization might be linked to phosphorylation of AMPA receptors, preferentially via the GluR-A subunit (11). In the absence of this subunit, AMPA receptor phosphorylation would be expected to be strongly reduced. This study cannot distinguish between these alternatives, although the residual LTP in the dentate gyrus of GluR-A−/− mice (34) argues against a general requirement for GluR-A in LTP expression.
Normal spatial learning in the absence of SC-CA1 LTP. This finding adds to a growing number of examples of a dichotomy between LTP and learning (6, 35). One explanation could be that mice may use extrahippocampal structures to solve the Morris water maze. It is possible that LTP, although not critical for the type of reference memory test used here, could be important in spatial tasks that involve only episodic or working memory (36). Alternatively, learning is associated with LTP at a degree of synaptic involvement that is too small to be detected with conventional electrophysiological field recordings. Furthermore, the spatial task might not require LTP in SC-CA1 synapses.
Notably, a genetically engineered CA1 NMDA receptor deficiency had also generated LTP deficiency, but learning in the water maze was impaired (5). One explanation for the difference in learning might be that the induction phase of LTP is impaired in the NMDA receptor but not in the AMPA receptor mutant. During this phase the spinous Ca2+ transients affect numerous signaling pathways, which might be essential for memory acquisition. In this context, it might be asked how the fEPSP LTP phenomenon is related to normal physiology in the hippocampus. The highly synchronous ensemble activity of CA3 pyramidal neurons required to induce standard fEPSP-LTP may not normally occur.
In summary, adult hippocampal LTP depends on the number and subunit composition of AMPA receptors. Therefore, in adult animals, LTP appears to be essentially a postsynaptic mechanism. However, this particular form of synapse modifiability in CA1 is not required for a reference memory test.
↵* Present address: Laboratorios Doctor Esteve, Avenida Mare de Deu de Montserrat 221, 08041 Barcelona, Spain.
↵† To whom correspondence should be addressed. E-mail: sprengel{at}mpimf-heidelberg.mpg.de
T. V. Bliss,
T. Lømo
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D. M. Bannerman
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K. J. Jeffery
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S. A. Siegelbaum
R. J. Wenthold
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K. Keinänen
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N. Burnashev
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The targeting vector pFC II contained 10.7 kb of the murine GluR-A gene (GRIA1) with parts of introns 10 and 11 and exon 11, numbered according to the GluR-B gene (37). The neo selection marker (ploxpneo3) (38) was inserted into an Eco NI site, 700 base pairs (bp) into intron 11. In addition, 225 nucleotides upstream of exon 10, a 28-bp Pfl MI fragment was substituted by a 34-bp loxP site. Embryonic stem (ES) cells (R1) (39) were electroporated with the targeting vector and linearized at the unique Hind III site in the polylinker, and five positive clones were identified by polymerase chain reaction (PCR) with primers P1 (5′ TCTCATTGTGATGGACCCATCC 3′) and P2 (5′ CTGCCCATGAATAATAACTTCG 3′) and confirmed by Southern blotting (Fig. 1B) with a 162-bp Sac I fragment of intron 10 as 5′ outside probe. ES cell clone 12.5 was transfected with an expression vector for Cre recombinase (pMC-Cre) (40), and clones with one remaining loxP site were identified by PCR with primers P1 and P3 (5′ CTGCCTGGGTAAAGTGACTTGG 3′) (Fig. 1A). Subclone 36.5 was injected into C57BL6 blastocysts, chimeric animals were backcrossed to C57BL6, and intercrosses produced 25% GluR-A−/− mice.
For all analyses we used littermates of F2 and F3 backcrosses to C57BL6. Electrophysiological analyses were restricted to animals between P42 and P45. For the anatomical and behavioral analyses mice were 2 to 3 months old. LTP measurements were performed on mice at 3 months of age. To preclude bias, the experimenters of the LTP, anatomical, and behavioral measurements were blind with respect to the genotype of the mice analyzed. All data were statistically evaluated by two-tailed t tests.
Vibratome-cut sections (50 μm) were incubated for 15 min in phosphate-buffered saline (PBS) containing 50% methanol and 30% H2O2, washed with PBST (PBS containing 0.2% Triton X-100), blocked for 30 min with PBST containing 5% normal goat serum (NGS), and preincubated for 30 min at room temperature (RT) in 4% NGS containing 0.4% Triton X-100. Sections were kept overnight at 4°C in 2% NGS containing 0.4% Triton X-100 with glutamate receptor 1 polyclonal antibody at 1 to 3 μg/ml (Chemicon, Temecula, CA) and glutamate receptor 2 polyclonal antibody at 5 μg/ml (Pharmingen, San Diego, CA). Sections were rinsed repeatedly with PBST and incubated for 30 min in PBST containing a 1:200 dilution of biotinylated secondary antibody (Vector Laboratories). Sections were washed with PBST, incubated for 30 min in PBST containing horseradish peroxidase–avidin-biotin complex (1:50) (Vectastain ABC Elite Kit, Vector Laboratories), washed with PBST, washed with PBS, and developed for peroxidase activity in 0.05% 3,3-diaminobenzidine hydrochloride (Sigma) containing 0.01% peroxide. After a brief rinse in PBS, sections were mounted to glass slides, dried overnight at RT, dipped into xylol, and coverslipped in Vitro-Clud (R. Langenbrinck, Emmerdingen).
E. Molnár et al., Neuroscience 53, 307 (1993).
R. S. Petralia
, J. Comp. Neurol. 385, 456 (1997).
Brain slices were prepared (41) and recordings from nucleated patches (42) isolated from the soma of CA1 pyramidal neurons were done with pipettes of 5 to 7 MΩ access resistance. On average, one to three cells per mouse were analyzed. The NMDA and AMPA receptor-mediated currents were measured in nominally Mg2+-free extracellular solution in the presence of 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (5 μM) and AP-5 (50 μM), respectively. Membrane potentials were clamped to values changing stepwise from −80 to 60 mV. Soma-patch currents were evoked by brief (2 ms) application of glutamate (1 mM). mEPSCs were recorded from slices (one slice per mouse) at −70 mV in the presence of the GABAA receptor blocker bicuculline (20 μM) and tetrodotoxin (1 μM) and analyzed as described (43). To enhance the rate of mEPSCs, we increased the extracellular K+ concentration in some experiments from 2.5 to 5 mM (2 to 10 min). Only mEPSCs with a 20 to 80% peak amplitude rise time of ≤1 ms were selected for measurements of peak amplitude and decay time course. A single or the sum of two exponential functions was fitted to the mEPSC decay by SIMPLEX minimization. fEPSPs were recorded in CA1 of hippocampal slices prepared from mice sacrificed with halothane. Brain slices were maintained in an interface chamber (44). Orthodromic synaptic stimulation (50 μs, <119 μA, 0.2 Hz) in CA1 was delivered alternately through two tungsten electrodes to activate synapses in the apical (stratum radiatum) and basal (stratum oriens) dendrites. Extracellular potentials were monitored by similarly placed glass electrodes filled with extracellular solution. After stable synaptic responses in both pathways for at least 15 min, one pathway was tetanized (100 Hz, 1 s), and the other served as a control. To standardize the tetanization strength, we set the tetanic stimulation strength in response to a single shock at an intensity just above the threshold for generation of a population spike. We assessed synaptic efficacy by measuring the slope of the fEPSP in the middle third of its rising phase. Six consecutive responses (1 min) were averaged and normalized to the mean value recorded 4 to 7 min before tetanic stimulation.
J. F. Blake,
M. W. Brown,
, Neurosci. Lett. 89, 182 (1988).
H. Wigström,
B. Gustafsson
, ibid. 301, 603 (1983);
, Acta Physiol. Scand. 125, 159 (1985).
, Acta Physiol. Scand. 48, 178 (1960).
B. Katz and R. Miledi, J. Physiol.(London) 195, 481 (1968).
At pulse intervals of 50, 100, and 200 ms, the facilitation ratios (mean ± SEM) were 1.42 ± 0.05 (n = 16), 1.30 ± 0.07 (n = 10), and 1.22 ± 0.06 (n = 10) in wild-type and 1.34 ± 0.04 (n = 18), 1.29 ± 0.05 (n = 12), and 1.13 ± 0.03 (n = 12) in GluR-A−/− mice. Ratios were calculated from experiments in which the second facilitated response was just below threshold for eliciting a population spike. The ratios in the two groups were not significantly different (P = 0.17, 0.90, and 0.12, respectively).
Animals were anesthetized with sodium pentobarbital (50 mg/kg) and perfused transcardially with 0.9% NaCl followed by a fixative containing 1% paraformaldehyde, 2.5% glutaraldehyde, and 0.1% picric acid in 0.1 M phosphate buffer (pH 7.4). After postfixation of the brain overnight (4°C), we processed vibratome sections (100 μm) for electron microscopy (45). Ultrathin sections were cut on a Reichert Ultracut microtome, stained with uranyl acetate and lead citrate, and examined in a Philips CM 100 electron microscope. In addition to regular electron microscopy of spine and shaft synapses in stratum radiatum of the CA1 region, the total number and density of spines on apical dendrites of identified CA1 pyramidal cells were quantified in two wild-type and two GluR-A−/− mice. Golgi impregnation of vibratome sections (150 μm) was carried out by the sandwich technique (46). We stained randomly selected CA1 pyramidal neurons and counted the total number of spines along the main apical dendrite from the soma to the terminal bifurcation in camera lucida drawings of individual dendrites (n = 10). We calculated spine density (spines per micrometer) for the main apical dendrite and for proximal, intermediate, and distal segments of equal length.
Fluorescence measurements of Ca2+ transients in apical dendrites were made after CA1 pyramidal cells were loaded via the recording pipette with fura-2 (250 μM) (47). Cells were stimulated via SC inputs at 50 Hz for 1 s with an extracellular tungsten electrode. The stimulation strength was first set to evoke a subthreshold EPSP and then increased to evoke a single action potential. Stimulation parameters (typically 180 μA, 70 μs) were similar in wild-type and GluR-A−/− mice. Dendritic Ca2+ transients were recorded during tetanic SC stimulation with a back-illuminated frame transfer charge-coupled device camera with a 10-ms time resolution. Dendritic regions of interest for fluorescence measurements were located on the main apical dendrite 26 ± 15 μm (mean ± SD; n = 11) distal to the soma. We used the standard ratioing equation to convert fluorescence transients to Ca2+ concentrations (48). Spinous Ca2+ transients evoked by single subthreshold EPSPs were recorded with multiphoton microscopy (49) using the Ca2+ indicator Oregon Green 488 BAPTA-1 (200 μM). Fluorescence was recorded in line scan mode. We evoked EPSPs by focal stimulation of SC afferents with an extracellular pipette with its tip placed close (<10 μm) to the dendrite. Spines were selected on secondary or tertiary dendritic branches 100 to 300 μm from the soma. Fluorescence transient amplitudes are given by the maximal fluorescence increase F max relative to basal fluorescence F 0, as in (ΔF/F) max = (F max − F 0)/(F 0 − background).
MECS was induced with a constant current signal generator (ECT Unit, UGO Basile) connected by nontraumatic ear clips. The signal parameters were as follows: pulse duration, 1 s; frequency, 100 Hz; pulse width, 0.3 ms; current, 17 mA. MECS produced an immediate tonic seizure with hindlimb extension that lasted for 10 to 20 s. Mice regained consciousness after 1 to 2 min. Mice were sacrificed by cervical dislocation 75 to 90 min after MECS, and brains were promptly dissected. Brains from unstimulated and from MECS-stimulated wild-type and GluR-A−/− mice were frozen together in Tissue-Tek (Sakura Finetek) and were blocked and sectioned together for better comparison. Horizontal sections (20 μm), which included cingulate, sensory, motor, and pyriform cortical regions; amygdala; dentate gyrus; CA1-4; and subiculum were prepared on a cryostat (Microm) and processed for in situ hybridization with 35S-labeled RNA probes (50).
P. F. Worley et al., Cold Spring Harbor Symp. Quant. Biol. 55, 213 (1990).
Morris water maze: The pool was 133 cm in diameter with white interiors and 60-cm-high walls and it rested on a 40-cm pedestal. The platform was 8 × 8 cm, with the top surface painted white and covered with wire mesh (8 mm between wires), and 42 cm high. The water level was 1.6 cm above the level of the platform, which was placed in the middle of one quadrant (SE) of the pool, midway between wall and pool center. The water (21° ± 2°C) was made opaque by the addition of 7.2 kg of powdered low-fat milk. Tracking of mice was as described (51). A month before the actual experiment, the mice swam daily for 13 days (platform NW) in a smaller pool (60 cm), which accustomed them to mounting the platform. Spatial navigation trials: Mice (19 wild type, 21 GluR-A−/−) were gently placed into the water at the edge of the pool at one of four start positions arbitrarily named N, S, E, and W. In a block of four trials all start positions were used in a semirandom order that differed every day. Finding the platform was defined as climbing onto it and staying for at least 5 s. Once on the platform, the mouse was allowed to stay for 30 s. For any mouse that failed to find the platform within 90 s, a latency of 90 s was recorded, and the mouse was placed on the platform. To ensure that the mouse did not use cues inside the pool, we rotated the pool daily and removed floating debris and feces before every trial. Transfer trials: On transfer trials the mice were placed onto the edge of the pool and allowed to swim with no platform present. The video system recorded the percentage of time spent in the various quadrants. The experimenter recorded from a video monitor the number of times the mouse crossed the previous position of the platform; crosses were defined by the head fully entering the square representing the platform position. Transfer trial in the absence of visual cues: To hide distal visual cues, we hung white curtains from the ceiling in a circle (2 m diameter around the pool).
A. Baude
, Neuroscience 69, 1031 (1995);
M. E. Rubio,
R. A. Silver et al., J. Physiol. (London) 493, 167 (1996).
We studied LTP in the lateral and medial perforant path synapses of dentate granule cells. In adult GluR-A−/− mice, the magnitude of LTP was about half that of wild type. In wild-type mice (n = 4) the values (±SEM) were 128% ± 11% (n = 10) and 132% ± 7% (n = 8) of the pretetanic amplitudes for the lateral and medial perforant path synapses, whereas GluR-A−/− mice (n = 5) showed 113% ± 4% (n = 10) and 118% ± 5% (n = 11) for the same two inputs. The data are not explained by a smaller proportion of mutant slices showing potentiation.
N. Meiri
, Proc. Natl. Acad. Sci. U.S.A. 95, 15037 (1998);
S. Schurmans
, ibid. 94, 10415 (1997);
; M. Nosten-Bertrand et al., Nature 379, 826 (1996);
Y. Y. Huang
, Cell 83, 1211 (1995);
S. Okabe
R. G. M. Morris and U. Frey, Philos. Trans. R. Soc. London Ser. B 352, 1489 (1998).
M. Köhler,
H.-C. Kornau,
P. H. Seeburg
, J. Biol. Chem. 269, 17367 (1994).
D. Feldmeyer
, Nature Neurosci. 2, 57 (1999).
A. Nagy,
J. Rossant,
R. Nagy,
W. Abramow-Newerly,
J. C. Roder
, Proc. Natl. Acad. Sci. U.S.A. 90, 8424 (1993).
H. Gu,
Y.-R. Zou,
K. Rajewsky
H. Markram et al., J. Physiol. (London) 500, 409 (1997).
W. Sather,
S. Dieudonne,
J. F. MacDonald,
P. Ascher
, ibid. 450, 643 (1992).
P. Jonas, G. Major, B. Sakmann, ibid. 472, 615 (1993).
R. Sprengel
, Cell 92, 279 (1998).
K. D. Phend,
R. J. Weinberg,
A. Rustioni
, J. Histochem. Cytochem. 40, 1011 (1992).
M. Frotscher
, Microsc. Res. Tech. 23, 306 (1992).
F. Helmchen,
K. Imoto,
B. Sakmann
, Biophys. J. 70, 1069 (1996).
G. Grynkiewicz, M. Poenie, R. Y. Tsien, J. Biol. Chem. 260, 3440 (1985).
W. Denk,
J. H. Strickler,
W. W. Webb
, Science 248, 73 (1990);
; H. J. Koester and B.Sakmann, Proc. Natl. Acad. Sci. U.S.A. 95, 9596 (1998).
D. W. Saffen et al., Proc. Natl. Acad. Sci. U.S.A. 85, 7795 (1998).
P. H. Kelly,
J. Malanowski
, Can. J. Physiol. Pharmacol. 71, 352 (1993).
K. Kask et al., Proc. Natl. Acad. Sci. U.S.A. 95, 13777 (1998). Membrane proteins of hippocampi were processed for immunoblot analysis with glutamate receptor 1 polyclonal antibody (Chemicon, Temecula, CA) at 0.5 to 1 μg/ml. After visualization by enhanced chemiluminescence (ECL, Amersham Corp.) blots were stripped and reprobed with glutamate receptor 2 polyclonal antibody at 1 μg/ml (T62-3B) (18) and with an NR1 monoclonal antibody (54.1) at 3 μg/ml.
Supported in part by the Volkswagen-Stiftung (R.S., P.H.S., B.S.), the Deutsche Forschungsgemeinschaft (P.H.S.), and Bristol-Myers Squibb (P.H.S.). We thank H. Gu for the plasmid pMC-Cre, A. Nagy for the R1 ES cell line, R. Morrison and J. R. Wenthold for providing antibodies, and M. Lang, A. Herold, S. Nestel, and B. Joch for technical assistance. D.Z. was the recipient of a postdoctoral fellowship from the Human Frontier Science Program.
You are going to email the following Importance of AMPA Receptors for Hippocampal Synaptic Plasticity But Not for Spatial Learning
By Daniel Zamanillo, Rolf Sprengel, Øivind Hvalby, Vidar Jensen, Nail Burnashev, Andrei Rozov, Katharina M. M. Kaiser, Helmut J. Köster, Thilo Borchardt, Paul Worley, Joachim Lübke, Michael Frotscher, Peter H. Kelly, Bernd Sommer, Per Andersen, Peter H. Seeburg, Bert Sakmann
Science 11 Jun 1999 : 1805-1811


I write this from my sickbed, listening to heavy Preston rain coming horizontally at my window.
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Here's to lack of blogging commitment!


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text:
2hrs Morning Digest: Four Nirbhaya case convicts to be hanged on Feb 1, parents' birth place question in NPR form can be skipped, and more
Woman injured in bomb blast in Yemen operated upon in Hyderabad
HYDERABAD , January 11, 2020 23:18 IST
Updated: January 11, 2020 23:18 IST
Doctors at a corporate hospital here performed 'Modified Capanna's technique' on a 24-year-old woman who had suffered fracture of the left femur (thigh bone) in a bomb blast in Yemen five years ago. As per the technique, which was said to be the first in the Telugu states, an allograft (femur bone) and free vascularised fibula are placed. She lost 15% bone in the blast.
Earlier in 2015, an implant was placed but it failed and she was not able to walk. The patient, Suaad Ahmed Hamed, was brought to Sunshine Hospitals, Gachibowli, in October 2019 when she started undergoing medical procedures.
"Usually, such bone losses are seen only in major road accidents and bomb blasts," said Dr AV Gurava Reddy, Managing Director, Sunshine Group of Hospitals.
An orthopaedic surgeon at the hospital, Dr Vasudeva Juvvadi said that although other methods such as distraction osteogenesis (bone formation) could be used, treatment was prolonged and needed multi stage procedures.
The doctors decided to perform 'Modified Capanna's technique' — a single stage reconstruction, using a combination of free vascularised fibular graft with allograft.
"Allograft was brought from bone bank in Bangalore and vascularised fibula was taken from the patient with the support of plastic surgeons Ravichander Rao and Venkatesh. Fibula was pegged into the allograft and was placed in the gap of bone loss and fixed with plate. Vascular anastomoses (surgical connection between adjacent blood vessels or other channels of body) was done," said Dr Vasudeva.
The 10-hour surgery was performed on November 26. The patient began to walk with the help of crutches, without putting weight on the operated leg.
Depending on X-Ray reports, progressive weight bearing and full weight bearing would be initiated. "The average time for bone union will be six months" he said.
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Printable version | Jan 18, 2020 10:00:28 AM | https://www.thehindu.com/news/cities/Hyderabad/woman-injured-in-bomb-blast-in-yemen-operated-upon-in-city/article30545865.ece
2019: an eventful year for Telangana State
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text:
package gov.nih.nci.caadapter.ui.mapping.sdtm.actions;

import gov.nih.nci.caadapter.dataviewer.MainDataViewerFrame;
import gov.nih.nci.caadapter.ui.common.AbstractMainFrame;
import gov.nih.nci.caadapter.ui.common.actions.AbstractContextAction;

import javax.swing.*;
import java.awt.*;
import java.awt.event.ActionEvent;
import java.awt.event.KeyEvent;

/**
 * @author OWNER: Harsha Jayanna
 * @author LAST UPDATE $Author: phadkes $
 * @version Since caAdapter v3.2 revision $Revision: 1.4 $
 * @date       $Date: 2008-09-29 21:22:50 $
 */
public class OpenQueryBuilderAction extends AbstractContextAction
{

    /**
     *
     */
    private static final long serialVersionUID = 1L;

    private static final String COMMAND_NAME = "SQL Query Builder";

    private static final Character COMMAND_MNEMONIC = new Character('Q');

    private static final KeyStroke ACCELERATOR_KEY_STROKE = KeyStroke.getKeyStroke(KeyEvent.VK_Q, Event.CTRL_MASK, false);

    private AbstractMainFrame mainFrame;

    /**
     * Defines an Action object with a default description
     * string and default icon.
     */
    public OpenQueryBuilderAction(AbstractMainFrame mainFrame)
    {
        this(COMMAND_NAME, mainFrame);
        // mainContextManager = cm;
    }

    /**
     * Defines an Action object with the specified
     * description string and a default icon.
     */
    public OpenQueryBuilderAction(String name, AbstractMainFrame mainFrame)
    {
        this(name, null, mainFrame);
    }

    /**
     * Defines an Action object with the specified
     * description string and a the specified icon.
     */
    public OpenQueryBuilderAction(String name, Icon icon, AbstractMainFrame mainFrame)
    {
        super(name, icon);
        this.mainFrame = mainFrame;
        setMnemonic(COMMAND_MNEMONIC);
        setAcceleratorKey(ACCELERATOR_KEY_STROKE);
        setActionCommandType(DESKTOP_ACTION_TYPE);
        // do not know how to set the icon location name, or just do not
        // matter.
    }

    /**
     * The abstract function that descendant classes must be overridden to
     * provide customsized handling.
     *
     * @param e
     * @return true if the action is finished successfully; otherwise,
     *         return false.
     */
    protected boolean doAction(ActionEvent e) throws Exception
    {
        // new NewSDTMWizard(mainFrame);
//        if (_qbFrame != null)
//        {
//            _qbFrame._jf.setVisible(true);
//            //_qbFrame._jf.setAlwaysOnTop(true);
//            return true;
//        }
        //MainDataViewerFrame _qbFrame;
        /*
          old start
         */
//        final Dialog d = new Dialog(mainFrame, "SQL Query", true);
//        (new Thread()
//        {
//            public void run()
//            {
//                MainDataViewerFrame _qbFrame = new MainDataViewerFrame(mainFrame, false, d);
//                d.dispose();
//            }
//        }).start();
//        //d = new Dialog(mainFrame, "SQL Query", true);
//        JPanel pane = new JPanel();
//        TitledBorder _title = BorderFactory.createTitledBorder("Visual SQL Builder");
//        pane.setBorder(_title);
//        pane.setLayout(new GridLayout(0, 1));
//        JLabel _jl = new JLabel("SQL Query Builder Loading , please wait.....");
//        pane.add(_jl);
//        d.add(pane, BorderLayout.CENTER);
//        d.setLocation(400, 400);
//        d.setSize(500, 130);
//        d.setVisible(true);
//        setSuccessfullyPerformed(true);
//        return isSuccessfullyPerformed();
        /*
           old end
         */

       // new MainDataViewerFrame(mainFrame, false, null);
        return true;
    }

    /**
     * Return the associated UI component.
     *
     * @return the associated UI component.
     */
    protected Component getAssociatedUIComponent()
    {
        return mainFrame;
    }
}
/**
 * HISTORY      : $Log: not supported by cvs2svn $
*/

redpajama_set_name: RedPajamaGithub


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During an interview with Sun Sentinel editorial board editor Rosemary O'Hara Parkland shooting survivors David Hogg and Sari Kaufman express opposition to the idea of arming teachers.
Most classroom teachers would be unable to carry firearms under the bill passed Monday by the Florida Senate in response to the Marjory Stoneman Douglas High School shooting.
But there would still be guns in schools.
With Gov. Rick Scott against arming teachers and the legislative black caucus having united against the idea, the Florida Senate amended its bill Monday to exclude classroom teachers from participating.
The overall bill passed 20-18, with Republicans and Democrats coming down on both sides. Republicans who voted no took issue with the bill's age limit of 21 for all firearms purchases, while many Democrats felt that the new limits on the plan to arm school staff weren't enough.
"Do I think this bill goes far enough? No, no I don't. But what I disagree with more is letting the great be the enemy of the good," said state Sen. Lauren Book, D-Plantation. "We have been elected to represent the will of the people and their will is clear — let's get something done."
But even other Broward Democrats disagreed with the incremental change supported by Book.
"The mentality that we take what we get and come back next year, for me? I'm sorry, I can't do that," said state Sen. Gary Farmer, D-Fort Lauderdale. "Next year, the buses won't be here, the pressure will be reduced, and the NRA will be omnipotent again."
Librarians, media specialists, advisers and other school personnel would still be able to carry firearms. Additionally, classroom teachers who don't teach exclusively — such as teachers who also coach sports — would be allowed to carry.
Current service members, current or former law enforcement and teachers in a Junior Reserve Officers' Training Corps program would also be allowed to carry.
The amendment sponsor, state Sen. Rene Garcia, R-Hialeah, was one of just two Republicans who has sided with Democrats in trying to get an assault-weapon ban and some other gun-control measures put into the bill. The other is state Sen. Anitere Flores, R-Miami.
The program would remain optional, with both county sheriffs and school district superintendents having to approve and school staff having the option of participating.
The 105-page bill does far more than potentially arm teachers, though. With $400 million in funding for mental health programs, school resource officers, school safety upgrades and more, many senators who were wary of arming teachers decided there was more good in the bill than bad.
The Senate version of the bill also renamed the program to arm teachers, previously known as the Florida Sheriff's Marshal Program, to the Coach Aaron Feis Guardian Program.
Feis was an assistant football coach at Stoneman Douglas who died during the shooting, reportedly while shielding students from gunfire. The sponsor of the renaming amendment, state Sen. Bill Galvano, R-Bradenton, said he had spoken with Feis' widow before offering it.
Of the $400 million in funding, $67 million goes toward the guardian program. Almost $100 million goes to school security upgrades such as reinforced doors and bulletproof glass, with a similar amount going to mental health programs and a similar amount going to school safety, including the potential hiring of more police in schools.
With the bill through the Senate, the House is set to amend its version on Tuesday, then pass it Wednesday. Significant differences remain between the two bills, and they must be identical to go to Gov. Rick Scott for signing.
The House makes sheriffs implementing the program a requirement, though its still optional for superintendents and school staff to participate.
The new, watered-down version of the guardian program is different as well.
The Senate version also offers law enforcement a way to legally take people's guns away if they pose a threat, language that is not in the House version.
All of that has to be agreed upon before Scott can sign the bill.
The bill also includes $25 million for tearing down the Stoneman Douglas building where the shooting took place and rebuilding a new facility, as well as $1 million more to build a memorial to the victims.
Here's how state senators voted on SB 7026, the Marjory Stoneman Douglas High School Public Safety Act.


Park at WRFC across the roundabout from Sixways where you can park for £5. There is also a bar open to all.
Remember that the law is on their side. It isn't particularly helpful to those wanting to attend matches but there is nothing the club or anyone else can do to prevent the council enforcing the law. From the Highway Code.
Tell everyone you know about the parking issues.
Edited 1 time(s). Last edit at 2019:02:12:09:57:23 by Powick Eastander.
The Park and Ride bus was little better!
Or you can pay a fiver to a good cause, (WRFC) walk through the tunnel and be on your way promptly.
Best be early though, it's getting very popular.
I do wish you'd shut up about WRFC Ted; it's getting fuller every week!
And I don't often use it! Mrs Ted is now well known for a quick in/out drop off though.
I do use the clubhouse pre ko though, so much better than the stadium for ale, food and chat.


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Total War: Arena's multiplayer brings a fresh look to the RTS experience
I imagine when the folks from Wargaming met with Creative Assembly it went something like this:
Wargaming: "I love strategy and war."
Creative Assembly: "I love strategy and war, too!"
Wargaming: "Did we just become best friends?!"
And thus the partnership that's led to Total War: Arena started. (Okay, not really.)
The Total War series isn't known really for its multiplayer options. It's single-player has always shined, of course, with players reliving the campaigns of history's greatest conflicts against the computer. On the multiplayer front, though, all you had were two human players standing at the heads of their respective armies in a one-on-one setting, or more recent iterations maxed out with a four-on-four offering.
Total War: Arena changes this by offering a full, 10-on-10, free-to-play showdown, with each player allowed to select their own legendary general from the annals of history, like Rome's Julius Caesar or the English barbarian queen Boudica. Players can then bring into battle three different unit squads appropriate to their general, like foot soldiers, cavalry, siege weapons, or even war dogs. Each general also features a bevy of passive buffs and abilities you can activate in order to better assist your army.
Those three units are all that is available to players, though. Your three units and general will need to coordinate with the units other players on your team is bringing into battle in order to hopefully rout your opponents, or capture their base and ensure victory. It can lead to glorious multi-front chaos only available in a large player setting like this, but still relies heavily on the classic tenants of real-time strategy games in terms of how your units move and attack. It even touts the classic Total War morale system, where if you break an opponent unit's spirit, they may just start a hasty retreat and give you the victory.
With any free-to-play offering, the question always comes up about how a game will monetize itself. There are some limited customization options you can pick up for each of your generals, but Total War: Arena leans more heavily on the highly successful World of Tanks model. This allows players to spend real world money to expedite levels, which in turn unlocks new and more powerful units for each of your respective generals.
Even though you're in control of a legendary general, you're really just one piece of a much larger army in each match you play, and in that regard Total War: Arena looks to capitalize on the greatest strategic endeavor there is: working as a team. If players can successfully come together, not only will you have a variety of legendary generals working together for a common goal, but also the strategic possibilities are endless. From blitzkriegs to pincer maneuvers, the 10-on-10 scenario feels like it is bringing true war to Total War, and is shaping up to be an excellent alternative for people looking for competitive multiplayer without the need for twitch reflexes.
Total War: Arena is currently in closed alpha on PC and is moving to closed beta later this year.
Tags: arena, Boudica, E3 2017, F2P, PC, rts, sega, total war, Wargaming
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