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In either case it's nice to see Java's back on the right path.
Did kdawson even read the article before writing the summary? I don't see anything in the article about Java becoming more like Haskell!
In either case it's nice to see Java's back on the right path.
Did kdawson even read the article before writing the summary?
You must be new here.
Garbage collection is an amazingly boring field of computer science. It's all about tracking references and trying to keep memory from filling up while also trying to keep the overall impact on the running system down. But as boring as it may be, it's also absolutely critical in today's interpreted languages.
Where Java really fails is in the inability to trust the finalize method. At least in C++, the destructor of an object is guaranteed to be called as soon as the object is deleted. Java has no such guarantee, so expecting an object to clean itself up once it goes out of scope is a fool's errand. It will get finalized eventually, but the lack of deterministic behavior in this critical part of the object lifecycle means that there is a very big chance that unacceptable delays may occur in practice.
Give me deterministic behavior over faster GC any day.
Deterministic behaviour => use reference counting. E.g. Python has it.
But the situation with C++ is not as rosy as you paint it.
E.g. there are no guarantee that destructors on static object will be called.
Nor are destructors called on longjmp.
Nor are destructors called on longjmp.
That's one reason why setjmp was deprecated in favor of try/catch and longjmp in favor of throw.
Nor are destructors called on longjmp.
For the love of God, man, use exceptions! That's what they're for!
there are no guarantee that destructors on static object will be called.
Actually, Section 3.6.3p1 of the C++ standard [open-std.org] guarantees it. (Wonder why people who can't validate technical language claims feel qualified to mod posts that make them).
Where Java really fails is in the inability to trust the finalize method. At least in C++, the destructor of an object is guaranteed to be called as soon as the object is deleted.
Destructor!? Finalize!? Deleted!? You talking like a crazy man, have you never heard of a system REBOOT?
Give me deterministic behavior over faster GC any day.
The thing is, there really is no middle ground. You need to use a mark-and-sweep algorithm to avoid leaking cyclic references, which means you have no way of determining if an object should or should not be destroyed if it leaves scope. The good news is that a modern generational garbage collector is optimized toward collecting younger objects, so it's fairly likely that your resource objects will be collected fairly soon after you're done using them.
C++ doesn't have heap compaction
There are ways around this, such as the buddy heap [wikipedia.org] and the Windows XP low-fragmentation heap [microsoft.com], which round sizes up to a power of 2 and keep similarly-sized allocations together.
With C++ there is always a way to get (around) a feature. The trick is to let these tricks play nice with the rest of your pogram including the used libraries and different runtime environments.
The trick is to let these tricks play nice with the rest of your [program] including the used libraries and different runtime environments.
That's an issue with any std::malloc replacement, but this page [stackoverflow.com] claims that Firefox manages to work around it.
The reason why you are confused is because you're used to a compiled environment, where every call is an immediate action. A C/C++ program must be coded to (i.e. explicitly) deletes memory references. If you explicitly delete, you can also tie in other explicit behavior; therefore, it's common "duh this is how you do it" practice to tie "finalize" behavior to the object's deletion. But remember, it is your program's logic that has decided when to get rid of it. In a GC environment, deletion is no longer an explicit event--it is autonomous, automatic; therefore, it is illogical to tie anything to the deletion of the memory reference to anything other than deletion of the memory reference. There is no connection between when the object was dereferenced and when the GC chooses to clean up the reference. Generally, the only events that are tied to the finalize method are sanity checks to make sure non-Java code knows the reference is going away. Put differently: in Java, memory deallocation is not a part of the running logic of your program and so the program must create an explicit method of releasing resources in your program's logic. In other words, do what you were doing before, just don't call it finalize. That's a gripe of mine about Java: It confuses C++ users who are used to using the function finalize because Java gives finalize a specific purpose that cannot act the same way.
But in C++, many programs don't really deal with resource deallocation directly: That's what reference counting pointers are for. The resources get wiped the moment nothing references them anymore, and we can release both memory and connections at the exact moment they are not used anymore. In Java, just as you said, we end up doing it explicitly, doing a lot more work by hand, and risking destroying a resource that someone still has a reference to.
Sure, the code can still work, but it's a lot harder to get
If you're coding in lots of explicit memory reference deletes, what you're writing is not C++ but C. A C++ codebase would use RRID and automatic memory management to obviate the need for any explicit memory management. My last C++ project at work contained zero (yes, zero) calls to delete/free() out of around 20000 lines of code and a year of development/testing.
You're making the same mistake you're accusing C++ developers of making - you're viewing C++ through Java lenses.
This means that a resource, other than memory, can't be tied completely to an object. Anything using the object has to handle the resource manually, like basic C++ memory management, breaking the abstraction.
For example, I might want to tie, say, a database to an object. I create the object which opens/creates a database. I then use the object normally, and it makes transactions with the database as needed, but since finalize() is not reliable I have to explicitly call a close() method before I let the obje
Yeah, I remember reading up on finalization before I even knew Java's syntax. I decided to create a method in every class - "deleteMe", which nulls everything out when called.
I'm sure the garbage collector cleans it up soon after. Good enough. Has worked fine ever since.
Amazingly boring? Jeez, there is a lot of ways of doing garbage collection. You can mix GC types, have multiple levels of GC, heap sizes to tweak for these levels etc. Java has got an upper limit to the amount of memory the process uses, but I can think of other schemes that dont. Then you can do a lot of multithreading stuff, but you cannot break code anytime, because in that case the whole VM can die unexpectedly. Then you have to choose when and how long to garbage collect, if you only do so if CPU utili
Garbage collection is an amazingly boring field of computer science.
And so is , unless it isn't. Any time some one says, "X is boring," or, "X is interesting," that really means, "X is boring TO ME," or, "X is interesting TO ME." "Boring" or "interesting" is opinion. Personally, I find GC rather interesting, in particular the latest advances in real-time GC. I did compiler/programming languages work for my M.S., and I believe that most people would think that it is boring as well, but it is not to me.
It's all about tracking references
There is a lot more than that.
"Where Java really fails..."
I add to my 'what-evar!' list, consider the rant it in my app design and continue programming my [insert ANY app here] in Netbeans (likelt the app that pays my mortgage).
Thanks for the [usual academic] opinion.
On the flip side, Java says, separate implementation representation (i.e. low-level, on the metal, specific to vendor, dependencies, etc...) from logical representation (move robot arm 10 degrees). That forc
I think you're looking at deterministic in a different way than I. I know that when there are no longer any references to an Object, that object is completely out of scope from my application. I don't care how the system I'm on cleans it up, the same way that 99% of the time, you don't care about what a free/delete/close really does behind the scenes. What does matter is that:
1. The process of cleaning up this memory doesn't negatively impact the application's runtime performance
At least in C++, the destructor of an object is guaranteed to be called as soon as the object is deleted. Java has no such guarantee, so expecting an object to clean itself up once it goes out of scope is a fool's errand.
So? I switched from C/C++ to Java over 10 years ago, and have not once needed to even consider implementing finalize. The only thing this "lack of deterministic behavior" really means in practice is that you have to explicitly close input/output streams, rather than let objects go out
Of course you don't implement finalize in Java. Since it may or may not get called, it's almost completely useless. The reason the non-deterministic behavior is not an issue is that it is assiduously avoided. What is an issue is the lack of a useful analog to finalize.
In other words, instead of calling delete, you call close.
I don't call delete in C++ programs, in general. I let smart pointers take care of all of it. This means that all my resources, including memory, are automatically man
Smart pointers, as something you can just use, were introduced in Boost several years ago, and are in the standard now via Technical Report 1. In the mid-90s, they were possible (given template support, which was not universally good at the time), but not widespread.
Nor do I roll my own. I write the destructors, of course, and then I just use smart_ptr instead of * (okay, a bit more syntax difference than that). By now, it's not custom code.
So, in about 2000 the Java approach was generally better.
Smart pointers are an essentially reference counting solution, with all its pitfalls. I don't doubt it works in 90% of scenarios, but when things get really complicated, things can get hairy.
I don't find it boring, but then I am geeky.
Wow, I've done a lot of Java development and have never had a need for a finalizer. So while you may have a niche need in your C++/Java work, you certainly don't represent a majority of use-cases, and thus I can disregard your claim of Java's failure. There are many many other programming paradigms for resource cleanups. try-catch-finally (or better yet, pass a runnable to try-catch-finally processor to guarantee consistent resource-management). One particularly elegant form is Thread-Local Transactions
Contracts for garbage collection eh? I knew Sun was in cahoots with the mafia. Just ask these guys [reuters.com] if they don't wish they had stuck with the old Java...
Next thing you know, they'll be asking for memory protection money.
Sun didn't "quietly edit" the release notes; they announced it [sun.com] publicly and appologized for having been unclear (which seems like a bit dishonest, but not quiet).
What you said here. People were so buy foaming at the mouth that they never bothered to read the actual article or the thousands of posts that spelled out pretty clearly how and why the slashdot story got it wrong.
Never seen that before. No, not ever.
It's funny when you can cut+paste your comment and drop it into multiple discussions without having to modify it. It is truly one-size-fits-all.
"Stop. Look. Listen, learn, read, think
People were so buy foaming at the mouth that they never bothered to read the actual article
But but but! Oracle is eviiiiiiiiiiiil! Who cares what the truth was? Did you know that Oracle was eviiiiiiiiiiiiiiiiiiiiiiiil!
Sun didn't "quietly edit" the release notes; they announced it [sun.com] publicly and appologized for having been unclear (which seems like a bit dishonest, but not quiet).
It was established in the prior slashdot post ranting about it that it was just headline mongering. Nobody commenting had trouble understanding the true meaning.
But as usual, anything Java is SLOW, EVIL, BAD and out to steal your monies!
This is not a change, it was clear in the previous thread that the article was completely misinterpreted. The Slashdot summary made no sense at all once it was pointed out that G1 was GPL+Classpath.
I would guess a developer said something vauge like "don't use this in production without a support contract" and it got misunderstood by the person writing the release notes. If they really wanted to forbid it I'd expect them to be competant enough to do that in the license.
I tend to agree. If they really wanted a pay-to-use-this garbage collector, then they would have made the garbage collector a upgrade or add-on to the existing JVM and not distributed it in it's fully functional form for free.
Fully functional software tends to get used, and Oracle is not such a newbie to think that a piece of paper (or an electronic equivalent of that) will block use of a revenue generating item all by itself. Nor are they interested in auditing and suing everyone who might have a product
A kdawson article that totally blew something out of proportion? What a shock!
Argh, so I'm turning into the kind of person who comments without reading *either* article in question but
Last time this came up, plenty of people pointed out that the G1 garbage collector was available to anyone, Open Source but that it was in development and you weren't recommended to use it in production without a support contract. A number of people even pointed out the settings that anybody could change to enable the experimental G1 garbage collector on their own system.
Perhaps this is case of adjusting their wording to make it easier for Slashdot to not report incorrectly
So does this mean it was all one huge typo? Or was Oracle/Sun tentatively testing the waters to see the community's reaction? In either case it's nice to see Java's back on the right path."
No, it means that the original article was a misleading pile of FUD since the G1 garbage collector was released GPL + Classpath exception from the beginning. It's amusing that after being pointed out that the original submission was misleading and wrong that instead of this being a retraction that this article still tries to implicitly claim that Sun or Oracle did something wrong.
1) Java is slow
2) Java is not yet open source (or only parts of it are or isn't "really" open source)
3) Java is not available in any Linux distro's package manager
4) Java does not meet the needs of the enterprise
5) Nobody uses Java anymore
6) "Java is a heavyweight ball and chain"
7) Sun is charging people to use the new G1 garbage collector.
Java has some weaknesses and disadvantages, but the above are not among them.
1) Java is slow.
I'm generally a Java advocate, but you have to take into accounts when Java *is* slow. This is mostly where Java has to get down to the nitty gritty of the bare metal. Examples are cryptography (lots and lots of low level operations on bytes, 32 and 64 bit words) and processor based instructions. In those cases it makes sense to use a well defined C library (avoiding C++ if possible) and interface with that. These are also the places where it makes sense to really optimize the hell out of an application or library.
But for general business logic this arguement is indeed long gone. I do believe that my Java applications are normally faster than their C++ counterparts for the simple reason that I've got more time to design my classes well. Even if it's slower then it's offset by the much lower maintainance cost. And it's way faster than most specialized languages. Then again, specialized languages can make sense if they are delivering lower maintainance cost. Lets just say that not choosing Java because is it slower *per se* is absolutely wrong.
I'm generally a Java advocate, but you have to take into accounts when Java *is* slow. This is mostly where Java has to get down to the nitty gritty of the bare metal. Examples are cryptography (lots and lots of low level operations on bytes, 32 and 64 bit words) and processor based instructions.
It's surprising. Why would operations on bytes (or machine words) in Java be any slower than in C? After all, the JIT will compile them to the same stuff as a C compiler would do, and Java HotSpot is widely recognized as the most sophisticated JIT in production out there.
So far as I know, most of Java slowness doesn't actually come from bit twiddling being slow. It's because of things like all calls being virtual by default, and all objects being allocated on heap and not stack by default (yes, I know Java
Things like Cryptography and Compression which are process intensive are already implemented in native hooks in the base JVM. For instance, if you're using a GZIPOutputStream to GnuZip compress your data, the actually compression is done in a native block. Just because -a part- of your code requires high thoughtput, it doesn't mean that the entire piece of code needs to be developed in said language. Think of it like the distinction between C and ASM. You'd never write your entire code in assembly anymore,
1) Java is slow
Semi-true, java is what you get when you take a language that is slow by design and optimise the hell out of it. Overall perforamnce is reasonable but not brilliant (shootout.alioth.debian.org places it at arround 1.5 to 2 times slower than C). Predictability of performance can be a problem though because instanciating a new class can mess with the inheritance tree and hence the performance of seemingly unrelated code.
2) Java is not yet open source (or only parts of it are or isn't "really" o
I would hardly call Java slow by design. TCL or Bourne shell would be slow by design. It seems like C programmers, and C-like language programmers think everything except C and its ilk to be "slow by design".
Well, the keys are right next to each other...
By the way, the research paper describing G1 is here [sun.com].
Until the deal closes Oracle has nothing to do with Sun's Day to Day operations. Once Oracle takes over take bets on what happens to MySql and Glassfish. Until then, they don't have squat to do with it.
Uh. Sure. This will be a problem when Microsoft makes
I have no idea what you mean by SQL Server being ahead of Oracle, but SQL Server also only runs on Microsoft OSes and is thus only useful for people who run Microsoft OSes.
basically letting Microsoft get ahead with SQL Server in many respects
True. This [xkcd.com] only works in SQL Server, not Oracle.
Or was Oracle/Sun tentatively testing the waters to see the community's reaction?
It'd be great if my fellow slashdotters stop giving in the PROFIT conspiration theory, just one time.
Or was Oracle/Sun tentatively testing the waters to see the community's reaction?
It's a little early to talk about Sun as a part of Oracle. It's probable that the acquisition will clear regulatory approval, but until it does, Oracle can't play anything resembling a decision-making role in something like this.
I work at Sun, and right now our contacts with Oracle are actually more circumscribed than they'd normally be.
It's a little early to talk about Sun as a part of Oracle. It's probable that the acquisition will clear regulatory approval, but until it does, Oracle can't play anything resembling a decision-making role in something like this.
That's a laugh. At the operational level, Oracle will not interfere much until the acquisition is approved.
But at the strategic level? You can bet your bottom dollar that Sun isn't blowing its nose without checking with Oracle to see if it's OK first.
And you know this to be true because...
I think the intent was simple.
Until the code is stable, if you use the new, beta quality garbage collector in production, don't go crying to Sun for help unless you're willing to pay for a support contract.
How is that any different from most open source companies such as Red Hat?
"No, no, I don't mind being called the smartest man in the world. I just wish it wasn't this one." -- Adrian Veidt/Ozymandias, WATCHMEN


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I was playing around in YouTube today and discovered Tommy Emmanuel. I cannot believe that this guy has been around for over 30 years and I have never heard of him. If you want, check him out at
He has a lot more arrangement if you like this one. There is another that is a tribute to Chet Atkins that is probably better than this one. If you enjoy exceptional finger picking Tommy will probably float your boat.

subset: commoncrawl


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FAIRFIELD, Conn. – The Sacred Heart men's lacrosse team rallied from a three-goal third quarter deficit Saturday to force overtime against Vermont Saturday afternoon, but lost in the extra period to the Catamounts 8-7.
Senior midfielders Matt King (Brewster, N.Y.) and Shane Foley (South Brunswick, N.H.) each scored two goals and had two assists in the game. Junior attack Matt Gannon (Huntington, N.Y.) led all players with three assists. Stephen Kontos (Danvers, Mass.) won 15 of 19 faceoffs, including all nine in the second half and overtime. He also had a game-high 11 ground balls. Jon Flood (Bay Shore, N.Y.) made nine saves in goal.
Vermont (3-5) opened the scoring six minutes into the game as A.J. Masson scored his fifth goal of the season. Sacred Heart (0-8) tied the game 1-1 with 7:20 remaining in the first quarter when Foley assisted Cody Marquis' (Londonderry, N.H.) lone goal of the game. The Catamounts took a 2-1 lead with 5:48 left in the first, but the Pioneers tied the game 2-2 less than a minute later when Alex Miller (Ridgewood, N.J.) scored his second goal of the season.
Vermont took back the lead with 7:15 to play in the second quarter when Drew Philie scored a man-up goal to make the score 3-2. The Pioneers responded with goals from Foley and Mike Mawdsley (Innisfil, Ontario) to take their first lead of the game, 4-3, with 5:05 to play in the first half. However, Vermont tied the game 4-4 with 20 seconds left in the half on a Graham Horvath extra-man goal that sent both teams to the locker room on level terms.
The Catamounts controlled the third quarter, outshooting Sacred Heart 12-5 and outscoring the Pioneers 3-0 to take a 7-4 lead heading into the fourth quarter. Sacred Heart got back in the game with 12:14 to play in the fourth when King scored off a Foley assist to make the score 7-5. Forty-five seconds later, the duo teamed up again for a goal. This time it was King that assisted on Foley's tally, making the score 7-6. King tied the game 7-7 with 6:08 remaining in regulation. The Pioneers had a chance to take the lead with 3:04 remaining but Marquis' chance was stopped by Vermont goalie Justin Rosenberg. Flood did his part to keep the game tied, stopping a Horvath shot with 2:05 remaining as the game headed for overtime.
Kontos won the opening draw of overtime to give Sacred Heart possession. King had two shots go wide before Vermont caused a turnover that gave the Catamounts possession. Vermont quickly moved the ball upfield, but lost control of the ball in the offensive zone. Horvath found the ball right in front of the goal, scooped it up, and scored to give Vermont the 8-7 win.
Sacred Heart outshot Vermont 34-30 for the game and held a 34-24 advantage in ground balls. However, the Pioneers committed 19 turnovers to the Catamounts' 14. Vermont was 3-5 with the extra-man, shutting out the Pioneers on three different occasions man-up. Horvath led the Catamounts with three goals and added an assist. Rosenberg made 12 saves in goal.
The Pioneers open Northeast Conference play on the road next Saturday at Mount St. Mary's. The opening faceoff is at 1 p.m.


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Retro Part 1: A Suite of New Therapies (or, My Funny Valentine)
10th Conference on Retroviruses and Opportunistic Infections, February 10-14, 2003, Boston
April 2003
Some 20 years ago Françoise Barré-Sinoussi spotted RNA in the biopsied lymph node of a 33-year-old man with an apparently acquired immune deficiency. Ten years after that U.S. clinicians and researchers organized "The First National Conference on Human Retroviruses and Related Infections." And 10 years on most of those same clinicians -- lacking too many of their 1993 patients and gaining too many more -- gathered again for the tenth refrain of what has become the Conference on Retroviruses and Opportunistic Infections (CROI). This year's CROI (rhymes with Troy) had some novel features:
This tender lovers' fete -- celebrated in defiance of dark winter's remorseless slog -- might seem a cruelly ironic capstone for a meeting about a lethal virus spread in bed. But, in truth, there has always been something a little sad and sinister about Valentine's Day.
After all, on the liturgical calendar February 14 commemorates one of two people (as with many things liturgical, there is some confusion), both named Valentinus and both slain by the Romans in the unhappy third century (by beheading or "languishing in a dungeon," depending on the source). But no apparent link has yet emerged between these Valentines and the ones traded by schoolchildren.1 Then there was the fabled St. Valentine's Day Massacre, a Chicago gangland slaughter visited upon hirelings of George ("Bugs") Moran by triggermen allied to Al Capone. Even the most touching of Valentine ballads, "My Funny Valentine," makes its mark mainly through Lorenz Hart's rueful lyrics:
Your looks are laughable,
Indeed, when you look at antiretroviral art through Hart's self-mocking lens, Valentine's Day isn't a bad match. Some tries at thwarting the virus could be called pathetic (if not exactly laughable), and some of this therapy's failures ought to be unphotographable (though cruel science demands otherwise). But antiretrovirals -- commonly abbreviated ARTs -- have proved "favorite works of art" to countless individuals and vast populations.
Tracking rates of AIDS and death in nearly 10,000 EuroSIDA cohort members, Amanda Mocroft (Royal Free and University College Medical School, London) traced a continued dwindling of both endpoints through the most recent year of follow-up, 2002 [abstract 180*, see "Of Cohorts and Copies" below]. Reckoning "excess death rates" in Swiss people with HIV infection relative to the whole population, Bernard Hirschel (University Hospital, Geneva) learned that those with HIV (but without hepatitis C) have a lower excess death rate than successfully treated cancer patients, "a group who is able to obtain life insurance" [abstract 917a, see "Of Cohorts and Copies" below].
* Abstracts from the 10th CROI -- and some posters -- are available online at www.retroconference.org.
Hearts, Flowers, HAART
There's another way this year's CROI at first seemed to resemble Valentine's Day -- in carefree excess. One does not buy one's honey just one rose, but a dozen roses. For one's sweetie, a few well-picked bon-bons are a non-non; one needs a double-decker box of caloric bomblets. Just so, the stacks of tempting new antiretrovirals on review at CROI recalled juvenile fantasies of entrapment in a candy factory.
At the meeting's opening press conference, John Mellors (University of Pittsburgh) alerted scribes that the "pipeline of new antiretrovirals is fuller than it's been for a long time." And the riches didn't stop there. Alluring cellular (CEM15) and genetic (siRNA) strategies outlined by Mario Stevenson (University of Massachusetts, Worcester) bespoke an ever-sharpening focus on novel shortcuts to arrest the retrovirus (see the next section).
Impressed by this honest enthusiasm, and caught up in the 10th CROI anniversary spirit, this reporter thought it would be clever to compare 2003's deluxe bouquet of fresh therapies with the meager, seedy offerings of 1993. Further, a calculation of how many "new drugs" of yesteryear later won regulatory sanction seemed instructive. Entry criteria for the list were simple: at least one meeting abstract for an agent -- or cellular or genetic manipulation -- that constrained viral replication or boosted CD4 cells in people, other animals, or cell cultures.
As anticipated, the list for this year's conference impresses (Table 1). One could count six new protease inhibitors (PIs), four nucleosides (NRTIs), two nonnucleosides (NNRTIs), four integrase inhibitors (still not called IIs), 13 binding, fusion, or entry inhibitors -- even a viral budding inhibitor -- plus a suite of immune-based therapies and the aforementioned genetic étoile du jour, small interfering RNA (siRNA). The total of vernal viral nemeses reached a lavish 45.
Then there was 1993. The list of hopefuls included some future stalwarts -- lamivudine (3TC), nevirapine, and indinavir. But who, besides the presenters, remembers cyclopiazonic acid (another Merck PI), RO24-7429 (Roche's tat inhibitor), or the organosilicon compound from the University of Bordeaux? Toting up this 10-year-old list, one counts -- 45 vernal viral nemeses!
Of course one could argue that the 1993 roster includes some off-the-wall offerings (even back then lots of docs looked askance at infusing people with plasma rich in anti-p24 antibody) and some dandy shockers (hypericin, the prime mover in St. John's wort, studied in ACTG protocol 150). But the list also includes a few agents still hotly debated, and used, today, viz hydroxyurea (in a Franco Lori poster) and interleukin-2 (with Cliff Lane as the senior author). IL-2 isn't the only therapy to appear on both lists -- the others are FTC, now called emtricitabine, the embattled immune stimulant Remune, and interferon alfa2B. And who's to say the failures of yore -- for example, antisense -- made less sense then than today's genetic pole sitter, siRNA? To be sure, many a gene therapy and antisense savant from 1993 resurfaced in 2003 espousing siRNA.
So here we are 10 years later, without the benefit of hindsight that smarty pants of 2013 will enjoy, and the job of everyone with a stake in stopping HIV remains the same: Without passion (ardent Valentines begone), fathom the cold data coolly gathered by the world's top HIV researchers and decide which will blossom in one year or two, which will flourish as the decade matures, and which will wither neath the insensate harrow of scientific scrutiny.
Starting Anew (Again)
Every HIV meeting worth sitting through starts with the same question: What's new? CROI's organizers give reporters a head start by stapling together a sheaf of abstracts with trenchant analyses by scientific committee members. Some of those Solons show up at a first-day press conference to construe their best-of-show picks and to twine the strands of discrete studies into signals of important change. Hence, John Mellors, as just mentioned, nudged the new-therapies bandwagon to the starting line, inviting willing reporters to push. Eyeing vaccine research and some budding benchwork, David Ho (Aaron Diamond Center, New York) and Mario Stevenson also espied possibly pivotal developments. There were three, and a fourth caught the fancy of the mainstream press:
HIV vaccine research began -- and has continued for many a year -- with attempts to summon antibodies that will neutralize a newly transmitted retrovirus. Early on, this worked well in the lab, but not on the street or in the field -- breeding grounds for unimpressed "field isolates." So vaccine research reversed course, prodding troops of viral proteins to excite cell-mediated responses that would stymie HIV after infection but not prevent infection itself.
Bad news on that front, said David Ho. Daniel Barouch, working in Norman Letvin's Beth Israel Deaconess lab in Boston, reported that three of four monkeys given a vaccine that dragoons cytotoxic T lymphocytes (CTLs) against the virus had fallen sick after only three years of follow-up [abstract 76]. The infecting simian immunodeficiency virus, or SIV, had wriggled free from strong-arm CTLs through "a stereotypic pattern of viral escape." This doleful outcome does not spell the end of so-called prime-boost CTL strategies because the animals got only the priming shots and newer prime-boost medleys may prove more potent.
But this study and others, Ho commented, make it clear that "protection against disease progression may be lost with time" if one riles only cell-mediated immunity. So, it's back to antibodies, in Ho's opinion. He cited "significant progress" in finally tracking down spots on HIV's envelope that may prove vulnerable to antibody attack. "The new information," he told the press corps, "is already generating novel ideas for creating 'immunogens' that could be tested in animals for the ability to induce HIV neutralizing antibodies."
The tenth CROI had no word on one antibody vaccine -- in fact, the only vaccine -- to confront HIV in big efficacy trials, VaxGen's AIDSVAX. But that news came a few weeks later, confirming majority opinion that the gp120 vaccine would not work and rousing controversy about whether the small numbers of African Americans and Asians enrolled supported a claim that AIDSVAX may protect them.
Tufts University's John Coffin, in the first talk at the Boston gathering [abstract 1], displayed two stark and still inescapable statistics:
Number cured of HIV: <1
And, Coffin added, these null results "will probably not change for a considerable time." VaxGen later claimed that Coffin's second dictum no longer holds -- in African Americans and Asians -- but many demurred pending closer scrutiny of the AIDSVAX results and their statistical analysis.
If it has nothing else going for it, small interfering RNA has a sleek, digital-age moniker: siRNA. But, then, antisense and even gene therapy exuded linguistic cachet in their prime.
Here's an amazing tale. "Because of proteins like APOBEC," according to Mario Stevenson, "humans are innately resistant to infection by viruses like HIV." So what goes wrong? Most human cells carry an APOBEC protein called CEM15, which slams the door on HIV replication. But HIV, never at a loss, has a gene whose sole function seems to be knocking out CEM15. The gene is vif, the appropriately named viral infectivity factor.
Michael Malim (King's College, London) amplified on this classic tug of war in a plenary talk [abstract 5]. The vif gene and its protein product Vif, he explained, show up in most lentiviruses and in all mammalian lentiviruses, such as HIV-1, HIV-2, SIV, and FIV. Vif makes budding virions infectious. Without Vif, virions still bud from infected cells, but they can't infect fresh cells. Malim offered some details:
To get a better handle on how APOBEC/CEM15 stymies HIV, Roberto Mariani and colleagues at the Salk Institute in La Jolla tracked the action of this protein's mouse equivalent [abstract 72]. They found it in lymphoid tissues including spleen, thymus, and lymph nodes, and in heart and lung. Mouse APOBEC shut down HIV replication even better than human APOBEC. As little as 1 ng, the Salk team learned, "effectively blocked HIV-1 infectivity." And HIV-1 Vif failed to reverse this action unless APOBEC levels were low.
Can science exploit CEM15's innate antiviral moxie in humans? It should be "considered," Malim opined, but it won't be easy. Eviscerating vif may be preferable to boosting CEM15, because this protein's panoply of activities remains poorly understood. In animal models, Malim noted, meddling with CEM15 makes tumors grow.
Can you fight a virus with a virus? If one is GBV-C and the other HIV-1, the answer may be yes. GBV-C, once labeled hepatitis G virus, turned out not to cause hepatitis or any other known disease. But when GBV-C actively replicates in people infected with HIV, it seems to blunt HIV's virulence. If a GBV-C-infected person clears that virus, however, HIV runs amok.
Studying 230 people with HIV infection, Per Björkman (Malmö University Hospital, Sweden) found that harboring active GBV-C at HIV diagnosis does not affect progression to AIDS or death [abstract 157]. But the viruses seem to interact. Whereas two of 31 people (6 percent) who had AIDS when diagnosed with HIV also had GBV-C in their blood, 54 of 175 (31 percent) diagnosed with asymptomatic HIV disease carried GBV-C (P=0.008).
During a median 4.33 years of follow-up, 11 of 44 people originally infected with GBV-C cleared that virus without evidence of GBV-C antibody seroconversion. Compared with others in the study, those people had:
Scrutinizing stored plasma samples from gay men enrolled in the Multicenter AIDS Cohort Study (MACS), Carolyn Williams (National Institute of Allergy and Infectious Diseases, Bethesda) and MACS colleagues confirmed two of Björkman's findings: Early GBV-C status does not affect survival (after five to six years in this study). And clearing GBV-C has nasty consequences [abstract 159lb].
Williams found that GBV-C status at the five- to six-year follow-up visit had a dramatic impact on mortality. Compared with men who had circulating GBV-C at both visits:
Men with GBV-C viremia at both visits lost an average 26 CD4 cells/mm3 yearly; men negative for GBV-C at both visits lost 37 cells/mm3 yearly; and men who cleared GBV-C between visits lost 107 cells/mm3 yearly. These three groups did not differ in median duration of follow-up, date of seroconversion, antiretroviral use, median HIV load, or prevalence of the protective CCR5 delta32 mutation.
What's the link between GBV-C and HIV? Coreceptors and chemokines, according to a cell study by Jack Stapleton (University of Iowa, Iowa City) [abstract 156]. He found curtailed expression of the HIV coreceptors CCR5 and CXCR4 on peripheral blood mononuclear cells (PBMCs) exposed to GBV-C isolates or infectious clones. Inhibition of HIV replication in these cells required ongoing GBV-C replication. Compared with mock-infected PBMCs, cells spiked with GBV-C produced more of the cytokines IL-2 and IL-8 and more of the chemokines MIP-1 alpha, MIP-1 beta, SDF-1, and RANTES.
Stapleton believes results of his experiments and the two cohort studies mean GBV-C infection may have "a direct inhibitory effect" on HIV replication. The Swedes aren't so sure. They suggest that "GBV-C status in HIV-1 infection is probably a secondary phenomenon during disease progression rather than an independent prognostic factor." But Stapleton thinks researchers should even consider injecting GBV-C into people already burdened by HIV.3 Yet the notion of exposing people to a virus discovered only nine years ago -- even though it seems innocuous now -- sounds scary to some, because the immune system could not be allowed to clear GBV-C. All three studies suggest that, once infected with GBV-C, getting rid of that virus would be worse than never having it at all.
No Lack of New Drugs
Only a few years ago, drug industry merger mania occasioned concern over the future of antiretroviral development. How many HIV drugs could one reasonably expect from one company where once there had been two, three, or even four? Indeed, one heard nothing at the 10th CROI about the second-generation NNRTIs once being developed by DuPont but now the property of Bristol-Myers Squibb. And if GlaxoSmithKline buys Bristol-Myers Squibb, what then? Yet the bleakest versions of this doomsday scenario remain dark imaginings. Instead, old hands long absent from the fray (Pfizer, Schering-Plough) and fresh faces with new wares (Tanox, Panacos) peopled the new antiretroviral slide session and poster boards.
But wait. Before auditioning CROI's cavalcade of new candidates, consider two mainstays of the antiretroviral repertoire -- nevirapine and efavirenz -- on stage together for the first time. Well, at least for the first time in a big, multicontinental, randomized trial: 2NN.
Who Won 2NN? You
Before there was 2NN, the 1,216-person head-to-head showdown between nevirapine and efavirenz, there was SENC, the Spanish Efavirenz-Nevirapine Comparison trial, which also randomized treatment-naive people to begin one or the other NNRTI plus two nucleosides.4 This little-noted trial differed from 2NN in two important ways: it enrolled only 67 people, and it excluded people with viral loads above 100,000 copies/mL. After 48 weeks SENC's intent-to-treat analysis determined that 64 percent assigned to nevirapine and 74 percent to efavirenz had a viral load under 50 copies/mL. But that difference lacked statistical significance. The authors appropriately noted that such a difference may have emerged in a bigger trial.
2NN was 18 times bigger than SENC, and nevirapine still kept statistical pace with efavirenz through 48 weeks, even among people who began treatment with a viral load above 100,000 copies/mL. Joep Lange, who heads the IATEC trials group at the University of Amsterdam, and IATEC's Frank van Leth spelled out the details in a slide talk [abstract 176] and poster [abstract 752].
Lange and colleagues on six continents randomized untreated adults to take stavudine (d4T) and 3TC plus 400 mg of nevirapine once daily, 200 mg of nevirapine twice daily, standard once-daily efavirenz, or nevirapine plus efavirenz at 400/800 mg once daily. About 400 people got assigned to arms two and three to ensure statistical power to discriminate between those standard doses, while about 200 got assigned to the unconventional dosage arms, one and four. Baseline traits matched well from arm to arm, with (for all groups) 63 percent men, a median age of 34 years, a median CD4 count of 190 cells/mm3 (range 70 to 330 cells/mm3), and a median viral load of 4.7 logs (range 4.4 to 5.5 logs). Equivalent proportions had hepatitis B virus (HBV) coinfection (5.3 percent overall) or hepatitis C virus (HCV) coinfection (9.5 percent overall).
The researchers defined failure by four criteria:
A week 48 missing-data-equal-failure analysis found a significant response difference only between the efavirenz arm and the nevirapine/efavirenz arm (Table 2). Nor did the single-nevirapine arms differ from the single-efavirenz arm in intent-to-treat or on-treatment analyses of proportions with viral loads below 50 copies/mL at 48 weeks. For people starting therapy with a viral load above 100,000 copies/mL, those taking efavirenz met the trial's success criteria slightly more often (61.3 percent) than those taking nevirapine/efavirenz (57.1 percent), twice-daily nevirapine (57.3 percent), or once-daily nevirapine (51.5 percent), but between-arm differences fell shy of statistical significance. CD4 gains proved equivalent across arms.
The 2NN team did tease out some differences in side effect rates. Grade 3 or 4 hepatobiliary side effects trended higher in the twice-daily (2.6 percent) and once-daily (1.8 percent) nevirapine groups than in the double-NNRTI arm (1.0 percent) or the efavirenz arm (0.5 percent) (P=0.082 across arms). Clinical hepatitis also cropped up more in the nevirapine groups (2.1 and 1.4 percent) than with nevirapine/efavirenz (1.0 percent) or efavirenz (0.3 percent), but these differences lacked statistical significance. (One woman without evidence of HBV or HCV coinfection died of hepatitis while taking nevirapine.) The once-daily nevirapine group had a significantly higher rate of grade 3 or 4 hepatobiliary lab toxicities (13.2 percent) than did the efavirenz arm (4.5 percent,PGrade 3 or 4 rash proved more common with once-daily (4.1 percent) and twice-daily (3.1 percent) nevirapine than with efavirenz (1.8 percent), though again these differences lacked statistical significance. (A man taking nevirapine died of septicemia while recovering in the hospital from Stevens-Johnson syndrome.) Grade 3 or 4 central nervous system or psychiatric side effects troubled more people in the efavirenz arms (5.7 percent with nevirapine/efavirenz and 5.5 percent with efavirenz) than in the nevirapine arms (3.6 percent twice daily and 1.4 percent once daily) (P=0.001 across arms).
The bottom line in the toxicity match-ups is a distinct disadvantage for nevirapine/efavirenz, with 29.7 percent in that group stopping therapy temporarily or permanently for any side effect, compared with 24.1 percent for once-daily nevirapine, 21.2 percent for twice-daily nevirapine, and 15.5 percent for efavirenz (P<0.001 across arms). Are those differences between the single-nevirapine arms and the single-efavirenz arm statistically significant? By the strictest interpretation, Frank van Leth told IAPAC Monthly, the answer is no. Blunt pairwise comparisons between the once-daily and twice-daily nevirapine arms and the efavirenz arm did suggest significantly more dropouts with nevirapine (P=0.009 once-daily versus efavirenz and P= 0.039 twice-daily versus efavirenz). But after statisticians scrupulously adjusted those figures to account for multiple testing in four preplanned comparison arms, the only significant difference remained between efavirenz and nevirapine/efavirenz.
This is probably more than most readers want to know -- or need to know -- about side effect statistics. As so often proves true when statistical hair-splitting requires electron microscopy to discern differences, the proper question becomes not "Are these differences statistically significant?" but "Are these differences clinically meaningful?" Most seasoned HIV clinicians will be content to walk away from 2NN with the primary endpoint message -- equivalent failure rates in the three single-NNRTI arms and more failures with the more toxic double-NNRTI tactic. From there, picking between these two drugs for first-line regimens will not be a roll of the dice, but an already set appreciation of corollary risks and benefits.
Among nevirapine's possible benefits, earlier work suggested, may be its effect on lipids. 2NN confirmed findings of an Atlantic trial substudy that saw an apparently antiatherogenic profile with nevirapine but not with indinavir.5 Considering only people who stayed with their assigned 2NN regimen for 48 weeks and lumping the two nevirapine arms to compare them with the single efavirenz group, van Leth charted three significant benefits for nevirapine [abstract 752]:
Whereas the total-to-HDL-C ratio stayed fairly flat among people taking efavirenz (5.9 at baseline and 6.3 at week 48), it narrowed with nevirapine (5.3 at baseline and 4.5 at week 48).
Again, the savvy clinician will ask whether these statistically significant lipid differences translate into clinical benefit. The context is complicated -- a chronic disease that will require treatment for two, three, or more decades with drugs that will be as different 10 years from now as today's best antiretrovirals are from 1993's crop. Add to that the still-muzzy datastream from cohort studies metering antiretroviral fallout on cardiovascular quiddities.
For now, 2NN confirms what many prescribers have long sensed: In the peerless treatment-naive person with world-class liver function, no propensity to rash, zero cardiovascular risk factors, exemplary psyche scores, and a fondness for vivid dreams, nevirapine and efavirenz are both swell picks. If you see imperfect patients, more thought will be needed. On average, nevirapine looks more inclined to cause rashes and is more hepatotoxic. Careful liver function monitoring guidelines are on the books for people starting this drug.6 Efavirenz can play mean tricks on the central nervous system, and it's a bad choice for women who may become pregnant. And, oh yes, nevirapine costs less.
Atazanavir at 108 Weeks, and After Nelfinavir
Researchers are still puzzling through the poor results of the atazanavir-versus-efavirenz trial presented last year.7 A 48-week intent-to-treat analysis of that multinational study counted only 32 percent of treatment-naive people randomized to atazanavir with a viral load under 50 copies/mL, and only 37 percent assigned to efavirenz reached that mark. The trial's official conclusion underlined atazanavir's "equivalence" with efavirenz. But at the Retrovirus meeting Martin Hirsch (Massachusetts General Hospital, Boston) [abstract 187] called that analysis "difficult to reconcile" with results of an atazanavir-versus-nelfinavir trial in treatment-naive people, which also showed 48-week virologic equivalence.8 Yet nelfinavir did not keep pace with efavirenz in a study Hirsch planned, ACTG 384,9 and no one would consider nelfinavir today's standard of comparison for the phase III trial of a new drug.
The 2NN results (preceding section) contradict the poor showing of efavirenz in the atazanavir-efavirenz trial and confirm earlier studies, like ACTG 384, attesting to this NNRTI's antiviral vigor. Even though 2NN, like the atazanavir-efavirenz study, counted consecutive viral loads above 50 copies/mL as a virologic failure, the 48-week intent-to-treat rate of sub-50-copy responses measured 70 percent with efavirenz (as well as with once-daily nevirapine). But atazanavir scored some virologic points at CROI in a long-term analysis of the atazanavir-nelfinavir trial.
After 48 weeks of random assignment to atazanavir or nelfinavir (plus d4T/3TC), study participants could continue one of the two atazanavir doses (400 or 600 mg once daily) or switch from nelfinavir to 400 mg of atazanavir [abstract 555]. Robert Murphy (Northwestern University, Chicago) reported that 63 people made the switch, while 283 continued atazanavir. At the switch point 70 percent in the nelfinavir-to-atazanavir arm had a viral load below 400 copies/mL, and 48 percent had fewer than 50 copies/mL. After 24 weeks on atazanavir those rates improved to 86 percent under 400 copies/mL and 59 percent under 50 copies/mL. No one in the switch arm stopped atazanavir because of treatment failure. At 108 weeks after randomization in the initial study, an intent-to-treat analysis counted 51 percent in the 600-mg atazanavir arm, 47 percent in the continuous 400-mg arm, and 49 percent in the nelfinavir-to-atazanavir arm with a viral load under 50 copies/mL.
People who continued atazanavir in the extension study had little change from initial baseline levels of total cholesterol, ominous low-density lipoprotein cholesterol (LDL-C), or triglycerides. HDL-C rose from 40 mg/dL at baseline to 46 mg/dL at week 48 of the first study and stayed there for another 24 weeks of atazanavir. People who traded nelfinavir for atazanavir enjoyed four significant lipid benefits 12 weeks after the switch:
For total cholesterol, LDL-C, and triglycerides, the significant improvements held through another 12 weeks. About 10 percent in each study arm had clinician-reported lipodystrophy, while 26 percent taking continuous 400- mg atazanavir, 44 percent taking continuous 600- mg atazanavir, and 13 percent switching from nelfinavir to atazanavir had grade 3 or 4 bilirubin elevations. Respective jaundice rates were 3 percent, 3 percent, and 6 percent.
Fosamprenavir: First Line or Later?
As with atazanavir, U.S. Food and Drug Administration (FDA) analysts are even now threshing through trial data on another PI, GlaxoSmithKline's GW433908, the amprenavir prodrug (fosamprenavir) also called 908. CROI attendees scanned an ample load of those data in two slide talks, one involving a comparison with nelfinavir in treatment-naive people and one pitting ritonavir-boosted 908 against lopinavir in people with PI experience. The GlaxoSmithKline PI shares at least one trait with rival atazanavir: It can be taken once daily (but only when boosted by ritonavir). Unlike atazanavir, 908 outdistanced twice-daily nelfinavir in treatment-naive people. But it may lag lopinavir as a second- or third-line PI.
The naive trial randomized 251 people in a 2-to-1 ratio to 1,400 mg of 908 or 1,250 mg of nelfinavir twice daily [abstract 177]. Everyone also took abacavir and 3TC. Though most study participants lived in the U.S. (n=153), sizable proportions signed up in Panama (n=52), Puerto Rico (n=25), and South Africa (n=21). About one third were women. The median baseline viral load measured a little over 4.8 logs (about 63,000 copies/mL) in both treatment groups, and more than 40 percent in both groups had a viral load above 100,000 copies/mL. The median CD4 count stood at 214 cells/mm3 in the 908 arm and 212 cells/mm3 in the nelfinavir arm, and close to half had fewer than 200 cells/mm3.
After 48 weeks 66 percent taking 908 and 51 percent taking nelfinavir reached the primary endpoint, a viral load below 400 copies/mL in an analysis that defined failure as never going below 400 copies/mL, rebounding from below 400 copies/mL, or stopping treatment. Jeffrey Nadler (University of South Florida College of Medicine, Tampa) did not report whether this (or any) difference reached statistical significance. By the same type of analysis, 55 percent taking 908 and 41 percent taking nelfinavir had a 48-week viral load below 50 copies/mL. In the 908 arm nearly equal proportions starting treatment above or below the 100,000-copy mark reached a sub-50 viral load. Not so in the nelfinavir group, where 54 percent starting below 100,000 copies/mL ended up under 50 copies/mL compared with 24 percent starting above 100,000 copies/mL. The median CD4-cell gain measured 201 cells/mm3 with 908 and 216 cells/mm3 with nelfinavir.
Side effect rates proved similar in the two groups, except that 18 percent taking nelfinavir versus 5 percent taking 908 endured diarrhea (P=0.002). While 9 percent taking 908 had a hypersensitivity reaction or rash, 5 percent taking nelfinavir did, a nonsignificant difference. Mean fasting triglycerides and total-to-HDL-C ratio were below U.S. National Cholesterol Education Program cutoffs (200 mg/dL and 6.5) in both treatment groups.
The second 908 study randomized 320 people who had taken one or two PIs (a handful had taken more) to genotype-selected NRTIs (usually including tenofovir) plus 908/ritonavir (1,400/200 mg once daily or 700/100 mg twice daily) or standard-dose lopinavir [abstract 178]. No one could take a nonnucleoside. Median baseline viral loads stood over 4.1 logs (about 12,500 copies/mL), and the median starting CD4 count was 263 cells/mm3.
The study's primary endpoint is time-averaged change in viral load from baseline (AAUCMB) at 48 weeks. The trial lacks the power to show statistically significant between-group differences in rates of sub-50 or sub-400 viral loads. Edwin DeJesus (Infectious Disease Clinic, Altamonte Springs, Florida) reported 24-week findings, which did not include a reckoning of statistical significance for AAUCMB. At 24 weeks the numbers showed "noninferiority" of either 908 arm to lopinavir, although virologic trends all ran in lopinavir's favor (Table 3).
Some attendees wondered whether AAUCMB is the best endpoint for a study population like this. Such an area-under-the-curve calculation makes sense for study groups with highly drug-resistant virus and faint chance of reaching a viral load under 50 copies/mL, explained session cochair Julio Montaner (University of British Columbia). But because respectable proportions in this trial did notch sub-50 loads (Table 3), AAUCMB may not be the most telling yardstick. Another way to size up 908 in PI-experienced people would be to chart virologic responses against baseline resistance mutations and viral susceptibility. DeJesus said that analysis will come with the 48-week results. Fewer people taking once-daily 908 (19 percent) than twice-daily 908 (35 percent) or lopinavir (34 percent) had a grade 2 to 4 side effect.
Whether this amprenavir prodrug can find a following as an unboosted or a boosted first-line agent, or a boosted rescue PI, cannot be surmised from findings so far. What can be said is that boosted 908 given to treatment-naive people spawned no protease mutations, while unboosted 908 did [abstract 598]. This analysis, presented by GlaxoSmithkline's Sarah Macmanus, involved people with consecutive viral loads above 1,000 copies/mL in two 908 studies -- the nelfinavir comparison outlined by Jeffrey Nadler (above) and a contest between once-daily 908/ritonavir (1,400/200 mg) and twice-daily nelfinavir, both with abacavir and 3TC. Comparing baseline genotypes with on-therapy genotypes during viral rebounds, Macmanus consistently mapped more protease and nucleoside mutations in Nadler's unboosted 908 group:
The GlaxoSmithKline team suggested the results support using boosted 908 as "first-line [therapy] or early in the treatment continuum."
Tipranavir: Hare-Raising Comparison
The much-heralded PI tipranavir had a head start over atazanavir and 908 in the race to regulatory sanction. But it became the laggard hare in this marathon, only recently reaching the phase III leg because of difficulties defining the best dose and delays due to a shift in developers. A phase II trial detailed by Joseph Gathe (Therapeutic Concepts, Houston) confirmed tipranavir's activity against virus laden with some infamous protease mutations [abstracts 179 and 596].
Because the study aimed to pick the phase III dose of tipranavir in a cohort with treatment experience, the primary endpoints were viral load drop at two weeks (before other drugs in the regimen could be changed) and side effects at four weeks. Study entry thresholds included treatment with all three antiretroviral classes and one or more mutations at protease sites 30, 46, 48, 50, 82, 84, and 90. Researchers randomized 216 people to one of three twice-daily tipranavir/ritonavir doses: 500/100 mg, 500/200 mg, or 750/200 mg. The median starting CD4 count stood at 153 cell/mm3 and the median viral load at 4.53 logs (about 33,900 copies/mL).
Whereas half the people assigned to 500/100 mg failed to hit a target trough concentration above 20 µM, more than three quarters in the other two arms did. By a last-observation-carried-forward analysis, week-two viral load drops measured 0.87 log with 500/100 mg, 0.97 log with 500/200 mg, and 1.18 logs with 750/200 mg; differences between arms lacked statistical significance. Boehringer Ingelheim, tipranavir's developer, chose the 500/200-mg dose for phase III studies because it yielded better troughs than 500/100 mg, with less interpatient variability than 750/200 mg. Fewer people taking 500/200 mg than 750/200 mg had to suspend treatment because of side effects. Gathe reported that 12.5 percent taking 500/200 mg and 16.9 percent taking 750/200 mg had one or more severe side effects. Overall, about 15 percent suffered grade 2 diarrhea and 12 percent vomiting.
Genotypic analysis focused on four changes that Boehringer Ingelheim calls universal PI-associated mutations or UPAMs -- L33I/V/F, V82A/F/L/T, I84V, and L90M. Virus with one or two UPAMs at baseline hardly tarnished susceptibility to tipranavir but proved resistant to other PIs. Two UPAMs, for example, yielded a median 1.3-fold change in tipranavir IC50 (50 percent inhibitory concentration) relative to wild-type virus, compared with a 9.6-fold change for saquinavir, 13.1-fold for amprenavir, 21.1-fold for indinavir, 32.8-fold for nelfinavir, 79.6-fold for lopinavir, and 97.9-fold for ritonavir. Only people with three UPAMs, and as many as 16 to 20 mutations in all, had more than a 2-fold change in susceptibility to tipranavir.
A 2-fold change in IC50 may mark the cutoff for virologic response to tipranavir, the researchers propose. Across the three study arms, the median viral load fell over 1 log in people with a 1- to 2-fold change in viral susceptibility to tipranavir. But responses nose-dived to a median 0.2 log or less when virus had a 2- to 4-fold change in susceptibility. Yet even in this PI-experienced population (93 percent had more than 10 protease mutations at baseline), 69 percent began the study with less than a 2-fold change in IC50 to tipranavir.
FTC: Once-Daily Mate for Tenofovir?
Although the once-a-day nucleoside emtricitabine (FTC) did not earn a slide slot at the 10th CROI, four posters sated the inquisitive. Interest in this long-studied drug leapt a quantum or two when Gilead bought its developer, Triangle. This union raised the winsome possibility of a once-daily double nuke in a single pill -- FTC and tenofovir -- heady competition for twice-daily Combivir (ZDV/3TC).
The longest FTC study presented, by Triangle's Charles Wakeford, involved 215 people originally randomized to take FTC (200 mg once daily) in a 48-week comparison with continued 3TC [abstract 550]. All 215 had a viral load under 400 copies/mL at week 48 and agreed to continue FTC in an extension study, along with 74 other people. A Kaplan-Meier estimate of time to virologic failure (consecutive viral loads above 400 copies/mL) stood at 10 percent 250 days after people started FTC. At 1,450 days that estimate had inched to 11 percent. The Kaplan-Meier probably of tolerability failure (permanent discontinuation because of death or toxicity) measured 13 percent after four years of FTC.
In a placebo-controlled comparison of FTC with d4T (plus didanosine [ddI] and efavirenz) involving 571 treatment-naive people, FTC outperformed d4T by every measure [abstract 606]. Resistance patterns in people who suffered virologic failure also painted an interesting picture. After 48 weeks of treatment, Pedro Cahn (Fundacion Huesped, Buenos Aires) reported, FTC won the primary endpoint battle -- proportion with a viral load under 50 copies/mL -- and several other contests (Table 4).
Among people who had a virologic failure, 71.4 percent taking FTC and 97.1 percent taking d4T had at least one resistance mutation (P=0.019). In this virologic failure group, 42.9 percent taking FTC and none taking d4T had the M184V mutation (P<0.001), 7.1 percent taking FTC and 20.0 percent taking d4T had a thymidine analog mutation (at positions 41, 67, 70, 210, 215, or 219) (not significant), none taking FTC and 11.4 percent taking d4T had the ddI-associated L74V mutation (not significant), 71.4 percent taking FTC and 88.6 percent taking d4T had an NNRTI mutation (not significant), and 28.6 percent taking FTC versus 2.9 percent taking d4T had wild-type virus (P=0.019).
An open-label study randomized people with a viral load below 400 copies/mL while taking one or two PIs to continue the PIs or switch to a once-daily medley of FTC, ddI, and efavirenz [abstract 551]. Defining virologic failure as consecutive rebounds above 400 copies/mL, Jean-Michel Molina (Saint-Louis Hospital, Paris) found equivalent 48-week failure rates in the two groups by a missing-data-equal failure analysis: 22 of 177 (12 percent) for continued PI therapy and 18 of 178 (10 percent) for the once-daily FTC regimen. In an on-treatment analysis 95 percent taking once-daily therapy and 87 percent continuing PIs had a 48-week viral load below 50 copies/mL (P=0.01). Kaplan-Meier estimates of serious side effects or treatment discontinuations disclosed no significant differences between groups.
Clinicians from Panama, South Africa, Mexico, and the United States studied FTC in 51 treatment-naive children and 31 experienced children, evenly divided between girls and boys and 72 percent of them black [abstract 872]. Ages ranged from three months to 17 years, and all took FTC at a dose of 6 mg/kg once daily to a maximum of 200 mg daily (the adult dose). Treatment-experienced children had viral loads below 400 copies/mL while taking a regimen including 3TC, which they replaced with FTC. Clinicians could also switch other drugs in the regimen.
In a week-24 noncompleter-equals-failure analysis, 63 percent in the naive group and 71 percent in the experienced group had a viral load under 50 copies/mL. Respective proportions below 400 copies/mL were 92 percent and 84 percent. Median follow-up extended to 31 weeks in the naive group and 48 weeks in the experienced group. Xavier Sáez-Llorens (Panama City) and colleagues attributed five severe toxic episodes to study drugs, including pancreatitis, vomiting, leukopenia, anemia, and pleural effusion. One treatment-naive child (2 percent) and four treatment-experienced children (13 percent) had a grade 3 or 4 lab abnormality. The researchers determined that the 6 mg/kg FTC dose yielded exposure similar to 200 mg once daily in adults.
And More, and More ...
Atazanavir, GW433908, and tipranavir weren't the only new antiretrovirals -- or even the only new protease inhibitors -- to get PowerPoint treatment at the 10th CROI. Table 5 outlines 10 others, including two more PIs, a trio of nonnukes, a bevy of entry inhibitors, and a budding inhibitor. A few claims made for these hopefuls seem especially intriguing -- or at least worthy of note:
Do people with HIV infection really need all these new antiretrovirals? That is probably not the apposite question, since only a handful of these candidates will survive the treacherous gauntlet that ends in the regulator's den. Some fast math shows that 18 percent of the antiretroviral philters in focus at the 1993 Retro gathering found spots on the pharmacy shelf, and one of those (delavirdine) pretty much stayed there. If a similar proportion of the 2003 meeting candidates wins a license, clinicians would have eight more antiretrovirals to add to today's 16.
With luck the next batch of anti-HIV meds will not merely inflate the current total, but will include agents of unique value. And -- if the genie grants a second wish and a third -- these drugs will be easy to take and will not require a home equity loan to pay for a year's dosing. Looking at the list of 45 debutantes on parade at the 10th CROI, and imagining the best of Panglossian worlds, one could envision:
The amazing thing is that one can propose that list with a straight face.
Of Cohorts and Copies
Even as the promise of new, stronger, simpler, kinder antiretrovirals tantalizes, evidence suggests that the drugs at hand have flattened the epidemic -- at least in Western Europe, North America, Brazil, and Australia. But whether lean hints of replication at sub-50 loads portend a load of trouble, or mere spillage, remains controversial.
"Excess Deaths" Now Less Excessive
The strongest sign that today's antiretrovirals can make HIV infection a chronic disease came from a EuroSIDA analysis of 3,793 people in the pre-HAART epoch (1994-1995), 3,425 in the early HAART era (1996-1997), and 2,585 in the late HAART age (1998-2002) [abstract 180]. The early HAART-propelled drop in new AIDS diagnoses and deaths has not bottomed out, Amanda Mocroft reported.
This incessant decrescendo reflects overall trends in CD4 counts of this cohort, which is now about three quarters male. Whereas people with 50 or fewer cells/mm3 made up about 30 percent of the cohort in late 1994 and early 1995, they now account for fewer than 5 percent. The proportion with 51 to 200 cells/mm3 ebbed from about 30 percent in 1994-1995 to about 15 percent today. Meanwhile, the group with more than 200 cells/mm3 grew from 40 percent before HAART to over 80 percent today.
The risk of AIDS or death -- adjusted for age, prior HAART, AIDS status, and CD4 count at cohort entry -- fell from near 10 percent in 1994 and 1995, to 1 percent in late 1998 and early 1999, to less than 1 percent after September 2001. After September 1998, Mocroft figured the risk of AIDS or death slipped by 10 percent per six-month period (P<0.0001). The incidence of death alone fell significantly during that period only among people whose latest CD4 count languished below 50 cells/mm3. But the incidence of AIDS proved 50 percent lower in the late HAART era than in pre-HAART days regardless of CD4 count (P<0.0001). In a multivariate model considering baseline differences, the risk of AIDS (P=0.0004) or death (P=0.0013) dropped by about one third from the early HAART era to the late HAART era.
Bernard Hirschel and Swiss HIV Cohort Study colleagues took a different tack in tracking the ongoing effect of HAART [abstract 917a]. They charted the "excess death rate" among HIV-infected people versus the population at large. Swiss HIV Cohort members still die at a faster rate than the whole population, but not faster than successfully treated cancer patients, "a group who is able to obtain life insurance."
The study involved more than 2,000 HIV-infected people (29 percent of them women) treated after January 1, 1997 and followed through the last day of 2001. People with HIV but without HCV had a substantially lower excess death rate than did those coinfected with HCV. Among people who reached a CD4 count above 250 cells/mm3 with treatment, nadir CD4 count seemed not to affect mortality. Excess death rates range from 5 to 20 per 1,000 people per year among successfully treated cancer patients. Hirschel reported these excess death rates per 1,000 per year for HIV-infected people with or without HCV:
The Swiss team noted that keeping the viral load below 400 copies/mL appears to confer an extra survival benefit among people whose CD4 tally climbs above 250 cells/mm3 with HAART.
Yet these macroviews of mortality may not reflect the microreality of individual clinics, reported W. Christopher Mathews from the Owen Clinic at the University of California, San Diego [abstract 911]. As elsewhere in Western Europe and North America, death rates began to plunge at that clinic in 1995, when better therapies for HIV and opportunists arrived. That trend continued downward until 1998 -- then turned back up. Analyzing data from nearly 5,000 people who entered the clinic from 1991 on, Mathews traced the post-1998 upswing to two groups -- those who first sought care with a CD4 count below 200 cells/mm3, and those with no CD4 data on file within 90 days of their first visit.
Looking more closely at 2,278 people who came to the clinic after 1997, Mathews noted nine factors that changed the risk of death stratified by year of entry:
Gender did not affect the risk of death in the post-1997 cohort. An entry CD4 count between 200 and 349 (versus more than 350) cells/mm3 raised the risk 1.7 times, but that difference fell shy of statistical significance (P=0.089).
Low-Level Viremia: Smoke or Fire?
Despite bringing the Western epidemic to a virtual standstill, today's antiretrovirals still suffer the steely-eyed scrutiny of scientists who can show that these drugs do not stamp out every ember of replication. So the question becomes whether those smolderings yield only smoke, or also fire.
Jan van Lunzen (University Hospital Eppendorf, Hamburg) saw some ominous flickerings in lymphoid tissue of people taking apparently suppressive HAART [abstract 187]. All 32 study participants had viral loads below 25 copies/mL for more than nine months and had taken the same regimen for more than 12 months. Fourteen used a PI combination (only one with ritonavir boosting), 11 used a nonnucleoside, and seven used two or three nucleosides (including one taking two nucleosides and hard-gel saquinavir).
Axillary lymph node biopsies turned up productively infected cells in everyone, but the people taking only nucleosides had a much higher rate of viral trapping on follicular dendritic cells. Three of six in the nucleoside group, including one taking Combivir/abacavir and one taking two nukes plus hard-formula saquinavir, had HIV ensnared in dendritic tendrils. Only one of 14 taking a PI and none of eight taking an NNRTI had similar evidence. The M184V mutation arose during viremic blips in lymph nodes of the person taking Combivir/abacavir, but that mutation did not appear in peripheral blood mononuclear cells. Yet the nucleoside group didn't do much worse than the other groups when rated for HIV-infected germinal centers (16 of 26 samples overall) or HIV in extrafollicular tissue (21 of 26 overall).
Using a high-octane viral load assay with a dynamic range of 1 to 1,000,000 RNA copies/mL, Frank Maldarelli (National Cancer Institute [NCI], Frederick, Maryland) turned up viral traces in 14 of 15 people in whom a standard assay clocked viral loads below 50 copies/mL for at least 131 days [abstract 466]. In the 14 with these midgey loads, RNA numbers ranged from 1 to 40 copies/mL and averaged 9.3 copies/mL. Five people with serial measures had stubby but utterly stable loads for seven to 12 months. While higher pretreatment viral load correlated with higher low-level viremia, baseline CD4 count, treatment-induced CD4 change, and treatment duration did not.
Maldarelli also found that people taking four or more antiretrovirals had lower levels of Lilliputian viremia than did people taking only three drugs. "The apparent relation between regimen potency and level of viremia," the NCI team proposed, suggests sub-50-copy viremia "may be sustained by ongoing HIV-1 replication."
Does this runty replication portend full-fledged rebounds? Not according to results of a study of 12 children with viral loads below 50 copies/mL for one to six years [abstract 619]. Using an assay that spots 5 RNA copies/mL, Deborah Persaud and colleagues in Robert Siliciano's Johns Hopkins laboratory logged viral loads every three months in children who had kept an undetectable load since starting therapy or since switching to a PI regimen after taking suboptimal combinations. Persaud also managed to amplify and genotype viral samples from these children.
In 18 of 21 samples analyzed, the viral load always remained under 50 copies/mL. In three samples from three children, Persaud recorded blips to 69, 124, and 140 copies/mL. Sequencing 199 viral clones, she found that HIV spilling into plasma during suppressive HAART almost always proved wild-type or housed mutants that arose during earlier suboptimal therapy and hung on in the absence of drug pressure. There were two exceptions: The V82I protease mutation sullied two of six clones derived during a blip in a child taking nelfinavir. Another protease change, N88S, popped up in one of six clones from a nelfinavir-treated child with fewer than 20 copies/mL of circulating virus. Both children maintained viral suppression.
The Hopkins team concluded that "ongoing [low-level] viremia ... during effective HAART in children represents release of largely archival drug-sensitive or drug-resistant HIV-1 rather than recently generated, drug-resistant mutations." Viremia below the 50-copy mark or blips below 200 copies/mL, they added, "does not necessarily represent impending therapeutic failure or the evolution of resistance and it therefore may not require a change in therapy." Earlier, Siliciano and colleagues failed to detect genotypic evidence of viral evolution in 11 adults with sub-50 viremia.10
If compelled to posit a single conclusion from the last six studies -- the cohort analyses by Mocroft, Hirschel, and Mathews, and the sub-50 fathomings of van Lunzen, Maldarelli, and Persaud -- one might say this:
In people without a dire treatment history or untreated but dangerously advanced disease, improved regimens of recent years do a credible job of crippling HIV.
So why, as the 10th CROI amply demonstrated, do drugmeisters maintain their frenzied pace of discovery and development? This is an easy question to answer:
Those are the topics for Part 2 of this review, due next month.
Mark Mascolini writes about HIV infection (firstname.lastname@example.com).
References and Notes
This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly.


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Thor's Powers
Thor possesses physical powers superior to those of normal Asgardian gods. He has an extended lifespan augmented (although not immortal) by the Golden Apples of Idunn, immunity to conventional diseases, enhanced endurance (Thor's Asgardian metabolism is far greater than a human), superhuman strength ([lifting 100 tons]), which increases further when he succumbs to "warrior's madness," a berserker rage, the mindless battle passion that increases a warriors strength tenfold. By chanting and performing an ancient ritual, Thor can also invoke the berserker rage to increase his strength. His skin and bones are several times denser than those of mortals, granting him extreme resistance to injury.
Thor shares a unique bond [1] and affinity with Mjolnir, which has been increased further after Dr. Stephen Strange bound Thor's lifeforce to Mjolnir to repair the hammer [2]. Via this bond, Thor has a strong affinity with the forces of weather and acting as a conduct can channel Mjolnir's powers through himself allowing him to summon lighting from his hands. Thor's affinity with Mjolnir is so strong that even when damaged, as long as there is a significant piece remaining intact, Thor can use Mjolnir's powers. However due to the increased bond via Thor's lifeforce, if Mjolnirwere to be damaged, Thor himself would perish. Thor can channel his godly energies/lifeforce through Mjolnir into blasts called "Godforce" so powerful that they can slay even immortals, although it leaves him in a weakened state afterwards.
Thor wears a full body hauberk composed of Asgardian steel. It belt has the Norse symbol of physical health as a belt buckle along with the Norse symbol of Gemini most likely to symbolize his bond with Dr. Donald Blake. [3]
While empowered with the Odinforce, or more accurately called Thorforce since the Asgardian lifeforce resided within Thor, Thor was able to tap into a near-infinite resource of cosmic and mystical power, enhancing all of his powers. With the Odinforce's vast power, Thor was even able to dent Captain America's Vibranium/steel alloy shield. At regular intervals (usually occurring once per year) or when using the Thorpower too greatly, Thor would be required to enter the "Thorsleep." Learning from his father's mistakes, Thor had Falki, Odin's metalsmith, create a casket that contains enchantments that create a coma-like state to replenish and retain mastery over the Thorpower in order to heal more quickly. Once closed, it can only be opened from within. When Thor entered this casket of Thorsleep and into the Thorsleep, Donald Blake emerged from the Void until Thor awoke once again. Thor briefly had mastery of the Norse runes and could use them to break any Asgardian enchantment.
Thor occasionally dons a Belt of Strength, which doubles his strength but weakens him after its use. He also possesses a pair of iron gauntlets to protect him when unleashing Mjolnir's most potent powers. For extended periods of travel, Thor rides a chariot drawn by the Asgardian goats Toothgnasher and Toothgrinder.
During the period when he was cursed by Hela with brittle bones that would not heal, Thor wore a full body suit of armor composed of Asgardian steel for protection. This armor possessed ancient rune symbols of power emblazoned by lightning upon the armor along with an exoskeleton complete with circuits connected to a series of feedback microcomputers programed to respond to minute changes in electrical conductivity of the nerves to prevent the broken bones from shifting, while allowing Thor to use his arm.
source: marvel.com
Mjolnir is a virtually unbreakable hammer enchanted by Odin with various enchantments by augmenting its physical qualities via the Odinforce, the life essence of the Asgardian gods, and forged from mystically uru metal, whose chief properties are durability, the ability to maintain enchantment, and absorb energies. Thor shares a unique bond and affinity with Mjolnir, which has been increased further after Dr. Stephen Strange bound Thor's lifeforce to Mjolnir to repair the hammer. Via this bond, Thor has a strong affinity with the forces of weather and acting as a conduct can channel Mjolnir's powers through himself allowing him to summon lighting from his hands. Thor's affinity with Mjolnir is so strong that even when damaged, as long as there is a significant piece remaining intact, Thor can use Mjolnir's powers. However due to the increased bond via lifeforce, if Mjolnir were to be damaged again, Thor himself would perish. Thor can channel his godly energies/lifeforce through Mjolnir into blasts called "Godforce" so powerful that they can slay even immortals, although it leaves him in a weakened state afterward.
Mjolnir is specially enchanted to prevent it from being wielded by anyone save those who have been found worthy and possess superhuman strength. Thus far, this includes Thor, Odin, Tiwaz, Red Norvell, and Beta Ray Bill. Those who are worthy enough are empowered with Thor's essence held within Mjolnir to gain the powers of Thor. However, in times of need, Thor can will others to lift Mjolnir and overcome this enchantment, allowing them to lift the hammer. Thus far, this includes Steve Rogers, Eric Masterson, and a red and blue costumed adventurer from another universe. While holding Mjolnir together, Thor can empower others with his essence to gain the powers of Thor. Thus far, Eric Masterson has been the only one to receive this enchantment. To anyone else, Mjolnir cannot be lifted from the ground nor wrested from Thor's grip. This enchantment does not affect non-sentient beings (such as robot drones), but even non-sentient forces must possess some level of superhuman strength to lift Mjolnir. However, without the presence of gravity, anyone can overcome this enchantment and lift, or more accurately "push," and hold Mjolnir, but can not access or use the enchantments within the hammer.
Wielding Mjolnir, Thor can summon and control the powers of the storm, causing rain, wind, thunder and lightning. Thor can channel the storm's fury into devastating energy blasts that can destroy even secondary Adamantium. Mjolnir can also generate energy blasts called "Anti-Force." Due to its uru metal composite, Mjolnir can absorb other energies into itself, which Thor can then release.
Mjolnir can also transform Thor into his civilian guise as Donald Blake by striking the hammer against the ground once. When Thor becomes Blake, and vise-versa, Thor is sent into the limbo-like dimension known as the Void. Mjolnir assumes the appearance of an old wooden cane and in this form Mjolnir can be lifted by anyone. Mjolnir's enchantments usually restore Thor to Blake's form if he is separated from the hammer for more than 60 seconds.
By throwing Mjolnir while grasping its leather thong, Thor can simulate flight at speeds up to Mach 32 (over 24,000 mph). Thor can steer Mjolnir's path via his mental control over Mjolnir while traveling and can "hover" in place by spinning Mjolnir in his hand. While throwing Mjolnir when "hovering," Thor can use winds to keep himself afloat allowing him to appear to be in flight. Mjolnir obeys Thor's mental commands, via his bond with the hammer, as though it was alive and, if Thor's will is strong enough, the hammer can pass through nearly any barrier to reach his hand should he so desire. Once thrown, Mjolnir returns to Thor's grasp when he mystically calls upon it to return to him.
Thor often uses Mjolnir defensively to deflect attacks by spinning it around his body at terrific speeds. By spinning Mjolnir in a circle, Thor can open interdimensional portals, allowing him to travel to other dimensions. Mjolnir has occasionally served as a power source for the Avengers' Quinjets, enabling them to attain faster-than-light travel. Mjolnir enables Thor to sense the use of magic, particularly Asgardian enchantments. Thor has also used Mjolnir to break spells such as the one that allows the Wrecker to share his power with the Wrecking Crew. Formerly, it could also allow him to travel through time, but Immortus removed this power.
source credit: marvel.com


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- The Dickson Baseball Dictionary
- by Paul Dickson
Baseball slang is an avalanche of skewed logic. The commonest words take on very precise meanings. "Stuff" refers quite specifically to the totality of a pitcher's arsenal: his array of pitches and the velocity and movement with which he throws them. A pitcher can easily have good stuff but not succeed if his "command"--the ability to locate pitches accurately--is erratic. Terms associated with dirt and filth are highly complimentary. A hitter respectfully calls an excellent pitcher "filthy," a term that evolved out of common adjectives from a decade ago: "nasty" and "dirty." "Dirtbags" and "dirt dogs" are consummate hustlers, guys with perpetually soiled uniforms and caps and batting helmets stained with sweat, tobacco juice and pine tar. Naturally, dirtbags and dirt dogs play "dirtball." A player who is "pretty" is the opposite of a dirtbag, as is a "muffin." Food references are as prevalent as the television announcers who longingly mention the hallowed postgame buffet in the players' clubhouse. The ball itself can be an egg, apricot, apple or stitched potato. "Jelly beans" are rookies and inexperienced kids, the type a veteran might relentlessly call bush for a year before acknowledging him properly. Reaching base for your team's big hitters is "setting the table." "Fat" pitches are hittable ones, almost exclusively delectable treats, my favorite being "ham-and-cheese." And then there's the colorful (although unfortunately out of fashion) term for pep or spirit: "jinegar." Forms of kinship lurk suggestively, with positive connotations only for the hitter. Batters aspire to find their "cousin," the pitcher they manage to hit inexplicably well. In the early 2000s the Yankees' weak-hitting utility infielder Enrique Wilson found an unlikely cousin in the Red Sox's masterful Pedro Martínez, and Pedro's tough luck against the Yankees culminated in his admitting in an infamous interview that the Yanks were his "daddy." It was a rare moment of hearing baseball slang invented in real time.


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The year 1962 was an interesting one. John Glenn became the first American to orbit the planet, Marilyn Monroe died at the age of 36, and those damn Yankees beat the San Francisco Giants in a close World Series, four games to three. This was also a great year for the Chevrolet marque, with the introduction of the venerable 327 small-block V-8, and models that fit every price range, from the Biscayne up to the Corvette. We happened upon a couple of '62 Chevys recently down in the warm climate of Florida, which is a perfect spawning ground for all types of automotive incarnations.
Big-Block SoundtrackLarry F. Thomas told us that his '62 Biscayne started as a project that "wouldn't have too much bling, but plenty of zing." This mantra is a welcome departure from the instincts of today's car owners, who often confuse simplicity with wild, "blingtastic" rims and flashy, "show queen" underhood adornments. The other factor Thomas included in the buildup was the necessity of a mammoth motor and a stick shift tranny.
Thomas purchased the car back in 2001, and towed it back to Florida to begin plans for the re-creation. The car originally came equipped with a six-cylinder lump, an automatic transmission, a bench seat interior, and without a radio-just the combination the new owner was looking for. Work began in 2004, with a complete disassembly of the car. The big-block power that resides under the hood comes via GM Performance Parts-specifically, a 502ci short-block mated to Brodix BB2 aluminum heads, with 9:1 compression and a Lunati hydraulic roller cam.
The fuel/air mixture is cooked up with an Edelbrock C-454 intake manifold with raised ports, and a Holley Dominator 750-cfm carburetor. Spent fuel travels to the rear of the car by way of Hooker Super Comp ceramic-coated headers and a Fabricated 3-inch exhaust. The motor is cooled with a BeCool aluminum radiator equipped with dual fans. Thomas also added March serpentine pulleys to help the motor run the Classic Auto Air system.
When all the pieces came together, the 502 made 550 hp at 5800 rpm to the rear wheels, and 580 lb-ft of torque at 5600 rpm. All that power makes it to the rear through a Tremec TKO600 five-speed box, equipped with a Sachs 11-inch clutch. The one-piece driveshaft is mated to a Currie 9-inch rearend, with 3.70 gears and a TruTrac LSD unit.
The suspension is mostly stock, with some modern additions. Up front, Thomas added McGaughys tubular A-arms, KYB shocks, and Eaton springs. Thomas also included a GM 11-inch disc brake setup. In the rear, the same KYB/Eaton combination is used, housed in a CurrieTrac four-link configuration. The 'Cane rolls on Billet Specialties Vintec Dish wheels-17x8 in the nose and 17x9.5 aft. The front of the car grabs the road with 225/45/ZR17 BFGoodrich G-Force TA/KD rubber, and massive 275/40/R17 Mickey Thompson ET Streets ensure proper burnouts, both at the dragstrip and on the boulevard.
When we received information on the interior from Larry, one section stood out from the others. Under the listing for radio, Thomas wrote a big "NO," and added that he has no need for one: "I listen to the engine. It's a true radio-delete car." That's music to our ears here at the magazine, as we thought we were some of the only humans left who love the low rumble of a V-8 going through the four-cycle process, the purr of the exhaust ... back to the details.
Cars Inc. was the source for the OEM-replacement vinyl and cloth '62 seats. Thomas also went with the same company for most of the interior, including the Fawn-colored door and side panels, and carpeting.
Outside, most of the car retains its original post-car theme, with the exception of the body-color bumpers from VFN Fiberglass, which Thomas believes gives the car a smoother look. Larry also kept the car very original looking with the color swatch, Roman Red, which was an offering on all Biscaynes in 1962.
The car was completed just months before the Super Chevy Show last January in Bradenton, Florida. Winning an Editor's Choice award at that event is the jewel in the crown for Larry Thomas ... so far. He plans to keep on driving it around to shows in the Southeast and to flog the hell out of it every chance he gets.
"It was awesome winning the Editor's Choice award," Thomas said, "since I just completed the car a few months previous. It was a tremendous satisfaction."
Boy In A BubbleThe more luxurious (at least in terms of original equipment offered) is Ronald Jekonski's bubbletop '62 Bel Air. This body shop manager from Palm Chevrolet (Ocala and Gainesville, Florida) spent a good amount of time searching out the perfect candidate for his project, and eventually found a '62 in Tennessee (after finding bondo-mobiles, and cars that resembled Swiss cheese in other locales).
Jekonski's bubbletop packs a Chevy 572 big-block crate motor, with virtually all GM parts. The engine is a modern-day work of art, with a massive Demon Tri-Power carburetor setup, and a Demon intake manifold. Headers come by way of Sanderson, mated to a Magnaflow 211/42-inch exhaust. The sum of the power parts equals about 620 hp, more than 1 hp per cubic inch, which is always an impressive number without other performance add-ons like a supercharger or nitrous system.
The car absorbs the road with an Air Ride Technologies suspension, and puts the power to the rear wheels via a Moser 9-inch rearend, with 31-spline axles, 4.10 gears, and Positraction. Perhaps one of the more interesting areas on Jekonski's car is the brake system. Ronald brought that over from an '05 Corvette Z06, so there's no doubt that the '62 bubbletop stops in a hurry.
Jekonski did all the bodywork himself on the classic lines of the '62, along with the spectacular '06 Viper Red color scheme. The car also comes equipped with power steering and windows, and air conditioning from Vintage Air.
Each of these '62s has interesting characteristics in their own right: Jelonski's wild approach to braking, and Thomas' radio-delete soundtrack that's music to our ears. To be sure, over the years fewer and fewer of these cars turn up to shows around the country. That's why we're so pleased that Larry Thomas and Ronald Jekonski have taken the time and effort to preserve and improve upon a couple survivors from 1962.


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For those unfamiliar with GripShift's amalgamation of gameplay genres, it's probably most similar to Nadeo's TrackMania series of PC games. A more appropriate parallel can be drawn between GripShift and Sega's Super Monkey Ball series, replacing the sphere-encased simians with floaty, nitrous-equipped cars. Each of the 120 main Challenge levels starts with a camera flyover, showing you the layout and letting you plan your route. Each stage also has multiple objectives, with the first requiring the player to simply reach the gate at the end of the course. Other objectives include collecting a certain number of stars or finding a hidden GripShift token.
You'll be required to drive in the wrong direction to complete objectives. For some levels, getting the fastest time will mean driving off the track at the very beginning, skipping the stage proper and quickly falling to the finish gate at the end of the course below. One level had a GripShift icon sitting on a floating platform on the interior of a loop-de-loop. To get it, you're required to come to a complete stop at the peak of loop--your car unrealistically grips the road until you actually lose all forward momentum--and fall to the floating platform below.
It wasn't the studio's choice to release the game on PSN before Xbox Live, as Sidhe managing director Mario Wynands said the developer actually wanted to bring the game to Microsoft's system before Sony's. "It was only really after we intended to produce a Live Arcade version that we became aware that the PSN was going to be available on PlayStation 3 because they only announced that at E3 last year," he told me.
"That's what we're labeling it--the definitive version," said Wynands. "It's really the culmination of taking those previous iterations' feedback, layering that back into tweaking the controls, the levels, adding the weapons, adding those leaderboards across all the modes, adding in the additional deathmatch mode. It really is trying to take the game as far as it can go in its current form."
The 149MB Live version of the game comes in right under Microsoft's 150MB limit, despite having all the content of the 332MB PSN version (save a few music tracks) and more--most notably the new deathmatch battle mode with 20 arenas. "The PSN version was developed in a very short timeframe, so there wasn't as much time or as much need to reduce the footprint because Sony doesn't really have a limit," Wynands said.
But entirely new in the Xbox Live version is the 20-arena, 13-weapon battle mode. These areas have even more loosely defined, open stages than the Challenge mode levels, giving players lots of freedom in ways they can zip around the level and blast opponents. I had a cross-hemisphere battle against some of Sidhe's employees in New Zealand and found it to be a frenzied, highly enjoyable experience--though I was destroyed pretty quickly by my skilled opponents. It actually felt more like a frantic first-person shooter's deathmatch than your typical vehicular combat game. One missile shot or hit from another car's flame shield will do you in, and Jump platforms and ramps abound, making insane aerial combat possible.
Wynand told me that a lot of the 120 Challenge mode tracks have actually been changed for the Xbox Live version, based on user feedback. Extra platforms were added in some stages to make even more crazy time-slashing stunts possible. And an extra hard difficulty level, Evil, has been added, increasing your car's speed and adding enhanced challenges to the levels--like car-frying electric barriers that must be avoided.
Even based on my short time with GripShift, I can tell it's going to be a more than worthy Xbox Live purchase. Hell, anyone who's played the PSP or PS3 version will tell you that. The addition of a battle mode, enhanced visuals, refined levels, and a ridiculous amount of content will make it arguably the best value on Xbox Live when it debuts on the platform.
GripShift (PS3, PSP, X360) is already available on PSP and PS3, and the Xbox Live version will arrive very, very soon.


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Wednesday, April 22, 2009
Sampson hurt, more of a man than A-Rod
Chris Sampson has a torn labrum in his hip. But unlike A-Rod and his alleged torn labrum (remember, I don't think A-Rod is hurt), Sampson will pitch through it. Where's Sampson's Details photo shoot where he kisses himself?
Labels: Chris Sampson, Injuries
2 comments:
- jphelps said...
Not in Details, it's in Field and Stream.
- April 22, 2009 at 6:44 PM
- The Constable. said...
- April 23, 2009 at 8:37 AM
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text: Untitled Document Type PKM and PM high-capacity find grinding systems allow the production of high-quality powders that are fine-tuned to market and customer requirements for bulk density, flowability, uniform particle size, and distribution. The youngest generation of this series is equipped with newly designed housings, individually exchangeable grinding elements, and a grinding gap that is easily settable from the outside and carries the Eco Advanced label. With the Plast-Agglomerator, type PFV thermoplastic waste and compounded materials are prepared and reintroduced into the production cycle. System advantages include relatively low acquisition costs and limited thermal stress to the material, which generally allows material to retain its original characteristics. The systems reduce installation time, increase the lifetime of the agglomerating elements, and reduce the cost of wear parts. Pallmann Pulverizers Company, Inc., Clifton, NJ 973-471-1450 www.pallmannpulverizers.com